Frailty and objective hand grip strength (one of the components of the frailty phenotype) are both risk factors for worse health outcomes in SLE. Whether telomere length, an established cellular senescence marker, is a biologic correlate of the frailty phenotype and hand grip strength in patients with SLE is not clear. First, we aimed to evaluate differences in telomere length between frail and non-frail women with SLE and then assessed whether frailty or hand grip strength is differentially associated with telomere length after adjusting for relevant confounders.
Women ≥18 years of age with validated SLE enrolled at a single medical centre. Fried frailty status (which includes hand grip strength), clinical characteristics and telomere length were assessed cross-sectionally. Differences between frail and non-frail participants were evaluated using Fisher’s exact or Wilcoxon rank-sum tests. The associations between frailty and hand grip strength and telomere length were determined using linear regression.
Of the 150 enrolled participants, 131 had sufficient data for determination of frailty classification; 26% were frail with a median age of 45 years. There was a non-significant trend towards shorter telomere length in frail versus non-frail participants (p=0.07). Hand grip strength was significantly associated with telomere length (beta coefficient 0.02, 95% CI 0.004, 0.04), including after adjustment for age, SLE disease activity and organ damage, and comorbidity (beta coefficient 0.02, 95% CI 0.002, 0.04).
Decreased hand grip strength, but not frailty, was independently associated with shortened telomere length in a cohort of non-elderly women with SLE. Frailty in this middle-aged cohort may be multifactorial rather than strictly a manifestation of accelerated ageing.
It remains unclear how the presence of renal involvement will affect the cardiovascular (CV) risk factors and complications in patients with SLE.
We conducted a systematic review and meta-analysis using PubMed, EMBASE, MEDLINE and Scopus to identify studies published between 1947 and 2022 that evaluate the CV risk factors and complications in patients with SLE with or without lupus nephritis (LN).
58 studies were evaluated, with 22 two-arm studies (n=8675) included in two-arm meta-analysis and 45 studies (n=385 315) included in proportional meta-analysis. Patients with SLE with LN showed significantly higher risk of hypertension (HT) (OR=4.93, 95% CI=3.17 to 7.65, p<0.00001, I2=56%), hyperlipidaemia (OR=11.03, 95% CI=4.20 to 28.95, p<0.00001, I2=0%) and diabetes mellitus (DM) (OR=1.88, 95% CI=1.09 to 3.25, p=0.02, I2=32%) compared with those without LN. Patients with LN showed numerically higher prevalence of myocardial infarction (OR=1.35, 95% CI=0.53 to 3.45, p=0.52, I2=78%) and cerebrovascular accident (OR=1.64, 95% CI=0.79 to 3.39, p=0.27, I2=23%) than general patients with SLE. The incidence rates of CV mortality are also increased in patients with SLE with LN compared with those without LN (11.7/1000 patient-years vs 3.6/1000 patient-years).
Patients with SLE with LN show increased risk of CV risk factors including DM, HT and hyperlipidaemia. Early identification and optimal control of these CV risk factors may reduce the risk of CV disease and other non-CV complications.
CRD42022314682.
Celastrol is a bioactive constituent extracted from Tripterygium wilfordii (thunder god vine). It has been demonstrated to have a therapeutic effect on experimental disease models for chronic inflammatory and immune disorders. In the present study, we investigated whether and how celastrol exerts a regulatory effect on the autoimmune response in MRL/lpr mice.
We performed an in vivo study to determine the therapeutic effects of celastrol in MRL/lpr mice and then further investigated the underlying mechanism of celastrol in the regulation of the autoimmune response in MRL/lpr mice.
Celastrol showed a therapeutic effect in MRL/lpr mice by preventing the enlargement of the spleen and lymph nodes, alleviating renal injury, and reducing the levels of ANA and anti-double-stranded DNA antibodies. Furthermore, celastrol suppressed the in vivo inflammatory response in MRL/lpr mice by reducing the serum levels of multiple cytokines, including interleukin (IL)-6, tumour necrosis factor (TNF) and interferon (IFN)-, and the production of multiple antibody subsets, including total IgG, IgG1 and IgG2b. In vitro, celastrol reduced anti-CD3 antibody stimulation-induced T helper 1 and TNF-producing cells in CD4+ T cells of MRL/lpr mice. In addition, celastrol significantly affected B cell differentiation and prevented the generation of plasma cells from B cells in MRL/lpr mice by reducing the frequency of activated and germinal centre B cells. Celastrol treatment also affected T cell differentiation and significantly reduced central memory T cell frequencies in MRL/lpr mice. Importantly, celastrol treatment specifically promoted apoptosis of CD138+ but not CD138– T cells to suppress autoimmune T cell accumulation in MRL/lpr mice.
Celastrol exerted therapeutic effects on lupus by specifically promoting apoptosis of autoimmune T cells and preventing the progression of autoimmune response.
In SLE, deregulation of haematopoiesis is characterised by inflammatory priming and myeloid skewing of haematopoietic stem and progenitor cells (HSPCs). We sought to investigate the role of extramedullary haematopoiesis (EMH) as a key player for tissue injury in systemic autoimmune disorders.
Transcriptomic analysis of bone marrow (BM)-derived HSPCs from patients with SLE and NZBW/F1 lupus-prone mice was performed in combination with DNA methylation profile. Trained immunity (TI) was induced through β-glucan administration to the NZBW/F1 lupus-prone model. Disease activity was assessed through lupus nephritis (LN) histological grading. Colony-forming unit assay and adoptive cell transfer were used to assess HSPCs functionalities.
Transcriptomic analysis shows that splenic HSPCs carry a higher inflammatory potential compared with their BM counterparts. Further induction of TI, through β-glucan administration, exacerbates splenic EMH, accentuates myeloid skewing and worsens LN. Methylomic analysis of BM-derived HSPCs demonstrates myeloid skewing which is in part driven by epigenetic tinkering. Importantly, transcriptomic analysis of human SLE BM-derived HSPCs demonstrates similar findings to those observed in diseased mice.
These data support a key role of granulocytes derived from primed HSPCs both at medullary and extramedullary sites in the pathogenesis of LN. EMH and TI contribute to SLE by sustaining the systemic inflammatory response and increasing the risk for flare.
X chromosome has been considered as a risk factor for SLE, which is a prototype of autoimmune diseases with a significant sex difference (female:male ratio is around 9:1). Our study aimed at exploring the association of genetic variants in X chromosome and investigating the influence of trisomy X in the development of SLE.
X chromosome-wide association studies were conducted using data from both Thai (835 patients with SLE and 2995 controls) and Chinese populations (1604 patients with SLE and 3324 controls). Association analyses were performed separately in females and males, followed by a meta-analysis of the sex-specific results. In addition, the dosage of X chromosome in females with SLE were also examined.
Our analyses replicated the association of TMEM187-IRAK1-MECP2, TLR7, PRPS2 and GPR173 loci with SLE. We also identified two loci suggestively associated with SLE. In addition, making use of the difference in linkage disequilibrium between Thai and Chinese populations, a synonymous variant in TMEM187 was prioritised as a likely causal variant. This variant located in an active enhancer of immune-related cells, with the risk allele associated with decreased expression level of TMEM187. More importantly, we identified trisomy X (47,XXX) in 5 of 2231 (0.22%) females with SLE. The frequency is significantly higher than that found in the female controls (0.08%; two-sided exact binomial test P=0.002).
Our study confirmed previous SLE associations in X chromosome, and identified two loci suggestively associated with SLE. More importantly, our study indicated a higher risk of SLE for females with trisomy X.
To evaluate safety and mechanism of action of mezagitamab (TAK-079), an anti-CD38 monoclonal antibody, in patients with moderate to severe systemic lupus erythematosus (SLE).
A phase 1b double-blind, placebo-controlled, multicentre study was conducted in patients with SLE receiving standard background therapy. Eligible patients were adults who met the 2012 SLICC or ACR criteria for diagnosis, had a baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 and were positive for anti-double-stranded DNA antibodies and/or anti-extractable nuclear antigens antibodies. Patients received 45 mg, 90 mg or 135 mg of mezagitamab or placebo every 3 weeks over 12 weeks. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and pharmacodynamics. Exploratory assessments included disease activity scales, deep immune profiling and interferon pathway analysis.
22 patients received at least one dose of either mezagitamab or placebo. In patients exposed to mezagitamab (n=17), drug was well tolerated. Adverse event (AEs) were balanced across treatment groups, with no treatment emergent AEs exceeding grade 2. Responder analyses for Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and SLEDAI-2K did not reveal any observable differences across treatment groups. However, there was a trend for more profound skin responses among patients with higher CLASI scores (>10) at baseline. Pharmacodynamic analysis showed median CD38 receptor occupancy up to 88.4% on CD38+ natural killer cells with concurrent depletion of these cells up to 90% in the 135 mg group. Mean reductions in IgG and autoantibodies were less than 20% in all dose groups. Cytometry by time of flight and type 1 interferon gene analysis revealed unique fingerprints that are indicative of a broad immune landscape shift following CD38 targeting.
Mezagitamab had a favourable safety profile in patients with moderate to severe SLE and elicited a pharmacodynamic effect consistent with CD38+ cell depletion. These findings reveal novel insights into the drug’s mechanism of action and support the continued investigation of mezagitamab in autoimmune diseases.
Management of reproductive health-related issues is crucial for patients with SLE, given this is a disease that primarily affects women of childbearing age. Little is known as to how the 2020 American College of Rheumatology (ACR) Reproductive Health in Rheumatic Disease Guideline is experienced by an underserved, primarily Hispanic population and their physicians as it relates to pregnancy planning and contraception conversations. Given this population experiences high rates of unplanned pregnancies and worse SLE outcomes compared with the non-Hispanic white population, it is crucial to understand how reproductive health is discussed in this setting.
A survey based on the 2020 ACR Reproductive Health Guideline was created and distributed in English and Spanish in the outpatient setting to 151 patients with SLE to determine patients’ beliefs, experiences and limitations with reproductive health discussions. Associations between categorical variables were evaluated using Pearson’s 2 or Fisher’s exact test, as appropriate, and differences in continuous variables were assessed using Wilcoxon rank-sum test.
English language survey respondents were significantly more likely to report having conversations regarding contraception, pregnancy planning and peripartum medication use than the Spanish survey respondents. Two-thirds of all respondents relied on the rheumatologist as a top source of reproductive health information.
Disparities exist regarding reproductive health conversations on multiple topics between English-speaking and Spanish-speaking populations with SLE. Further understanding is needed to clarify why reproductive health conversations occur at lower frequencies in Spanish-speaking SLE populations.
Juvenile SLE (JSLE) is a complex autoimmune disorder that predominantly affects children and adolescents with several unique challenges, and microRNA-146a (miRNA-146a) might be an interesting anti-inflammatory molecule. Because exosomes in the blood might protect miRNAs, the association between circulating exosomal miRNA-146a and lupus proinflammatory genes, such as IRAK1 and TRAF6, was studied in peripheral blood mononuclear cells from people with JSLE.
Blood samples from 12 patients were collected every 3 months until 1 year with the recorded disease activity, and quantitative real-time PCR was used to determine the circulating exosomal miRNA-146a and the gene expression (IRAK1 and TRAF6).
The mean age was 12.60±0.43 years at diagnosis and all patients had a complete response at 12 months. According to the nanoparticle tracking analysis, the abundance of exosomes was significantly lower at 3, 6 and 12 months compared with 0 months, while the level of circulating exosomal miRNA-146a was significantly higher at 12 months than at diagnosis (p<0.001). There was a negative correlation between the level of circulating exosomal miRNA-146a expression and the level of TRAF6 mRNA (r=–0.30, p=0.049). Moreover, there were correlations between circulating exosomal miRNA-146a and disease severity such as SLE Disease Activity Index 2000 score, anti-double-stranded DNA antibody and proteinuria (urine protein–creatinine ratio), respectively. Therefore, increasing the level of circulating exosomal miRNA-146a, which might control TRAF6 mRNA expression, could have an effect on the production of inflammatory cytokines.
This suggests that miRNA-146a might serve as a non-invasive biomarker to evaluate the response to treatment in patients with juvenile lupus nephritis.
The efficacy of sirolimus in treating severe or refractory systemic lupus erythematosus (SLE) has been confirmed by small-scale clinical trials. However, few studies focused on mild or moderate SLE. Therefore, in this study we elucidated clinical efficacy of add-on sirolimus in patients with mild or moderate SLE.
Data of 17 consecutive patients with SLE were retrospectively collected. SLE Disease Activity Index-2000 (SLEDAI-2K), clinical manifestation, laboratory data and peripheral T lymphocyte subsets with cytokines were collected before and 6 months after sirolimus add-on treatment. T cell subsets were detected by flow cytometry and cytokines were determined by multiplex bead-based flow fluorescent immunoassay simultaneously. Twenty healthy controls matched with age and sex were also included in our study.
(1) The numbers of peripheral blood lymphocytes, T cells, T helper (Th) cells, regulatory T (Treg) cells, Th1 cells, Th2 cells and Treg/Th17 ratios in patients with SLE were significantly lower, while the numbers of Th17 cells were evidently higher than those of healthy control (p<0.05). (2) After 6 months of sirolimus add-on treatment, urinary protein, pancytopenia, immunological indicators and SLEDAI-2K in patients with SLE were distinctively improved compared with those before sirolimus treatment (p<0.05). (3) The numbers of peripheral blood lymphocytes, T cells, Th cells, Treg cells, Th2 cells and the ratios of Treg/Th17 in patients with SLE after treatment were clearly higher than those before (p<0.05). (4) The levels of plasma interleukin (IL)-5, IL-6 and IL-10 in patients with SLE decreased notably, conversely the IL-4 levels increased remarkably compared with pretreatment (p<0.05).
(1) Patients with SLE presented imbalanced T cell subsets, especially the decreased ratio of Treg/Th17. (2) Sirolimus add-on treatment ameliorated clinical involvement, serological abnormalities and disease activity without adverse reactions in patients with SLE. (3) The multi-target therapy facilitates the enhanced numbers of Treg cells, Treg/Th17 imbalance and anti-inflammatory cytokines, simultaneously, reducing inflammatory cytokines.
There is some evidence of a higher prevalence of coeliac disease (CD) among patients with SLE than in the general population. However, the prevalence estimates vary substantially.
To investigate the prevalence of CD among patients with SLE through systematic review and meta-analysis.
We performed searches in the databases of Medline, Embase, Cochrane and Web of Science Core Collection between 1 January 1990 and 9 July 2023. A total of 2053 publications were rendered in the searches, of which 68 were reviewed in full text and 14 included in the analyses. Primary analysis estimated the pooled prevalence of biopsy-verified CD in patients with SLE. In the secondary analysis, the prevalence of serological markers indicative of CD was investigated. The quality of studies was appraised using the Joanna Briggs Institute Critical Appraisal Tool. We conducted meta-regression analyses to investigate associations between the prevalence of CD in individuals with SLE and publication year, study population size, CD prevalence in the general population, proportion of females and quality assessment score.
A total of 14 studies met the inclusion criteria, of which 11 were included in the primary analysis of biopsy-verified CD. Among 1238 patients with SLE, 14 had CD. The weighted pooled prevalence of CD was 0.7% (95% CI 0.0 to 1.8). The weighted pooled prevalence of CD serological markers in 1063 patients with SLE was 3.7% (95% CI 1.4 to 6.7). In meta-regression analyses, no associations between CD prevalence and study characteristics, demographics and quality assessment scores were found.
In this meta-analysis, we found a weighted pooled prevalence of biopsy-verified CD in patients with SLE comparable with the prevalence in the general population. Our findings do not support routine screening for CD in patients with SLE. However, individual screening could be considered in cases of clinical suspicion and additional risk factors for CD.
CRD42022339594.
Circulating, extracellular RNA is the primary trigger of type I interferon in systemic lupus erythematosus (SLE), and interferon is known to play a central pathogenic role in the disease. RSLV-132 is a catalytically active human RNase molecule fused to human IgG1 Fc designed to digest RNA and thereby decrease the chronic inflammation associated with SLE. The drug was evaluated in a cohort of patients with SLE with moderate-severe cutaneous disease activity and the presence of RNA immune complexes. The primary objective of the study was the assessment of the impact of 13 doses of 10 mg/kg RSLV-132 over 6 months on the mean Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score.
Sixty-five patients meeting the entry criteria of a baseline CLASI score of 10 or greater and positivity of at least one of five autoantibodies to RNA-binding proteins (SM/RNP, SSA/Ro, SSB/La, Sm, RNP) were randomly assigned (2:1) to receive 13 doses of RSLV-132 10 mg/kg or placebo, respectively. Participants received study drug for 24 weeks on days 1, 8, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141 and 155 with an end-of-treatment visit on day 169 and a follow-up visit at the end of the study on day 215. The primary objective was assessed on days 85 and 169. Secondary objectives included assessment of systemic disease activity using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the British Isles Lupus Assessment Group 2004 Index and the Physician’s Global Assessment. Data from these instruments were used to calculate the SLE Responder Index 4 (SRI-4) and the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) scores.
The mean CLASI score change from baseline at day 169 was –5.7 (±7.0) in the placebo group and –6.2 (±8.5) in the RSLV-132 group. A subgroup of participants with moderate-severe systemic disease activity and high baseline SLEDAI scores (≥9) were analysed with respect to BICLA and SRI-4 responses. The RSLV-132 treated participants in the high SLEDAI subgroup had a greater percentage of BICLA responses (62% vs 44%) and SRI-4 responses (23% vs 11%) as compared with placebo. A second subgroup of participants with high baseline CLASI scores (≥21) were analysed with respect to BICLA and SRI-4 responses. The RSLV-132 treated participants in the high CLASI subgroup had a greater percentage of BICLA responses (28% vs 8%) and SRI-4 responses (39% vs 8%) as compared with placebo.
Six months of RSLV-132 therapy consisting of a weekly loading dose of RSLV-132 for 1 month, followed by 5 months of biweekly administrations did not significantly improve the mean CLASI score relative to placebo in this cohort of patients with SLE. The study entry criteria selected patients with moderate-severe cutaneous disease activity and no minimum SLEDAI score, which resulted in a wide range of systemic disease activity from inactive to severe as measured by SLEDAI. When the participants with higher SLEDAI and CLASI scores were analysed, a trend towards clinical improvement favouring RSLV-132 was observed. The results warrant further evaluation of RSLV-132 in SLE and suggest that patients with more active systemic disease are most likely to benefit from RNase therapy.
To illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar type I interferon response.
RNA sequencing of neutrophils from patients with SLE (n=15) and healthy controls (n=12) was analysed for differential gene expression and modulated pathways. The same analyses were performed on a similar neutrophil dataset from patients with SARS-CoV-2 infection (n=30) and healthy controls (n=8). Next, we carried out comparative analyses to identify common and unique transcriptional changes between the two disease contexts, emphasising genes regulated in opposite directions.
We identified 372 differentially expressed genes in SLE neutrophils compared with healthy donor neutrophils (≥2 fold, p<0.05), 181 of which were concordant with transcriptional changes in SARS-CoV-2-infected individuals compared with their respective healthy controls. In contrast, 118 genes demonstrated statistically significant alterations exclusive to SLE, including 28 genes that were differentially expressed in opposite directions in the two diseases.
The substantial overlap between neutrophil responses in SLE and COVID-19 suggests that the unknown cause of SLE is functionally similar to a viral infection and drives a similar immune activation and type I interferon response. Conversely, the genes regulated in the opposite direction represent responses unique to SLE. These include tyrosylprotein sulfotransferase-1 and nucleic acid deaminases of the APOBEC family, which can catalyse cytosine-to-uridine editing of both RNA and DNA, and other RNA-modifying enzymes.
Systemic autoimmune rheumatic diseases (SARDs) encompass a diverse group of complex conditions with overlapping clinical features, making accurate diagnosis challenging. This study aims to develop a multiclass machine learning (ML) model for early-stage SARDs classification using accessible laboratory indicators.
A total of 925 SARDs patients were included, categorised into SLE, Sjögren’s syndrome (SS) and inflammatory myositis (IM). Clinical characteristics and laboratory markers were collected and nine key indicators, including anti-dsDNA, anti-SS-A60, anti-Sm/nRNP, antichromatin, anti-dsDNA (indirect immunofluorescence assay), haemoglobin (Hb), platelet, neutrophil percentage and cytoplasmic patterns (AC-19, AC-20), were selected for model building. Various ML algorithms were used to construct a tripartite classification ML model.
Patients were divided into two cohorts, cohort 1 was used to construct a tripartite classification model. Among models assessed, the random forest (RF) model demonstrated superior performance in distinguishing SLE, IM and SS (with area under curve=0.953, 0.903 and 0.836; accuracy= 0.892, 0.869 and 0.857; sensitivity= 0.890, 0.868 and 0.795; specificity= 0.910, 0.836 and 0.748; positive predictive value=0.922, 0.727 and 0.663; and negative predictive value= 0.854, 0.915 and 0.879). The RF model excelled in classifying SLE (precision=0.930, recall=0.985, F1 score=0.957). For IM and SS, RF model outcomes were (precision=0.793, 0.950; recall=0.920, 0.679; F1 score=0.852, 0.792). Cohort 2 served as an external validation set, achieving an overall accuracy of 87.3%. Individual classification performances for SLE, SS and IM were excellent, with precision, recall and F1 scores specified. SHAP analysis highlighted significant contributions from antibody profiles.
This pioneering multiclass ML model, using basic laboratory indicators, enhances clinical feasibility and demonstrates promising potential for SARDs classification. The collaboration of clinical expertise and ML offers a nuanced approach to SARDs classification, with potential for enhanced patient care.
Patients with systemic lupus erythematosus (SLE) have increased risk of premature atherosclerosis but the exact mechanisms remains unclear. Flow-mediated dilatation (FMD) is an established non-invasive assessment of vascular endothelial function. Lipoprotein subfractions may be better predictors of FMD than conventional cholesterol measurements. We tested the hypothesis that lipoprotein subfractions are independently associated with FMD.
Forty-one consecutive adult patients with SLE without known cardiovascular risk factors or disease were recruited in this cross-sectional study. Endothelial function and early atherosclerosis were assessed by brachial FMD and common carotid artery (CCA) intima-media thickness (IMT). High-density lipoprotein (HDL)/low-density lipoprotein (LDL) subfractions were measured. Machine learning models were also constructed to predict FMD and CCA IMT.
Median FMD was 4.48% (IQR 5.00%) while median IMT was 0.54 mm (IQR 0.12 mm). Univariate analysis showed lower LDL1 (r=–0.313, p<0.05) and higher HDL2 subfractions (r=0.313, p<0.05) were significantly associated with higher log-transformed FMD. In a multiple linear regression model, HDL2 (β=0.024, SE=0.012, p<0.05) remained an independent predictor of higher FMD after adjusting for age, body mass index, LDL1 and systolic blood pressure. The machine learning model included parameters such as HDL2 (positive association), prednisolone dose, LDL cholesterol and LDL1 for prediction of FMD (r=0.433, p<0.01). Age, LDL cholesterol and systolic blood pressure were independently associated with higher CCA IMT after adjusting for body mass index and HDL2.
HDL 2, a large HDL particle, was independently associated with greater FMD and may be a biomarker of vascular health in SLE.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that can result in high morbidity if not treated. This retrospective study aimed to evaluate the outcomes of rituximab treatment in a paediatric SLE cohort in Taiwan.
The medical records of paediatric patients diagnosed with SLE at the National Taiwan University Hospital between January 1992 and August 2022 who received rituximab as maintenance therapy between January 2015 and August 2022 were retrospectively reviewed. To enhance our analysis, we included a contemporary comparison group, matching in case number and demographic characteristics. This study aimed to describe the indications, efficacy and safety of rituximab in the treatment of paediatric SLE and to analyse the factors associated with disease outcomes.
The study included 40 rituximab-treated patients with a median age of 14.3 years at the time of disease diagnosis. In the rituximab-treated cohort, the median score on the Systemic Lupus Erythematosus Disease Activity Index 2000 decreased from 8 before rituximab administration to 4 after 2 years. The levels of C3 and C4 increased and anti-double stranded DNA (anti-dsDNA) levels decreased significantly within 6 months. The equivalent oral prednisolone dose halved after 6 months. Finally, 8 (20%) patients achieved disease control and 35 (87.5%) patients had no flare-ups during the follow-up period (median, 2 years). Those patients who achieved disease control had a significantly shorter interval between diagnosis and rituximab administration. In terms of adverse effects, only one patient developed hypogammaglobulinaemia that required intravenous immunoglobulin (IVIG) replacement. Compared with the comparison group (n=53), the rituximab-treated cohort exhibited superior disease outcomes and a reduced incidence of flare-ups.
This study provides real-world data and illuminates rituximab’s role in maintaining disease stability among patients with paediatric-onset SLE who are serologically active without major clinical deterioration. Most importantly, no mortality or development of end-stage renal disease was observed in the rituximab-treated cohort.
Mycophenolic acid (MPA) is a primary immunosuppressive agent used in the treatment of lupus nephritis (LN). While therapeutic drug monitoring (TDM) of MPA is well established in organ transplantation, its role in LN treatment remains uncertain. Our objective was to review and summarise current knowledge on TDM of MPA in the LN treatment.
A systematic search was conducted in the online databases, specifically targeted patients diagnosed with LN receiving MPA treatment. The included studies had to report both MPA pharmacokinetic parameters and renal outcomes. A random-effects model meta-analysis was conducted to assess the relationship between clinical responses and MPA pharmacokinetics.
A total of 1507 studies were initially screened, resulting in the inclusion of 16 studies for meta-analysis, encompassing 433 patients. The response group exhibited significantly higher MPA area under the concentration-time curve (AUC) compared with the non-response group (51.44±21.73 mg·h/L vs 30.30±16.24 mg·h/L). The weighted mean difference (WMD) of MPA-AUC between responders and non-responders was 16.83 mg·h/L (95% CI 10.59 to 23.06; p<0.001). Similarly, trough concentration (C0) of MPA showed a strong association with renal response, evidenced by C0 values of 2.50±1.73 mg/L in the response group vs 1.51±1.33 mg/L in the non-response group (WMD 1.37 mg/L; 95% CI 0.77 to 1.97; p<0.001). There was no significant relationship identified between MPA-AUC and adverse events.
This meta-analysis emphasised the meaningful correlation between MPA AUC and C0 with renal response in LN treatment. Randomised controlled trials are necessary to validate this approach and determine its superiority over fixed dosing in the context of LN treatment.
With scarce data on the need and type of joint surgery in SLE, we investigated the long-term rates and underlying causes for arthroplasty, arthrodesis and synovectomy in patients with SLE.
Procedure dates for arthroplasty, arthrodesis or synovectomy were retrieved from the state-wide Hospital Morbidity Data Collection between 1985 and 2015 for patients with SLE (n=1855) and propensity-matched controls (n=12 840). Patients with SLE with ≥two additional diagnostic codes for rheumatoid arthritis were classified as rhupus. ORs and incidence rates (IRs) per 100 person-years for joint procedures (JPs) were compared among patients with rhupus, patients with other SLE and controls across three study decades by regression analysis.
More patients with SLE than controls underwent a JP (11.6% vs 1.3%; OR 10.8, CI 8.86 to 13.24) with a higher IR for JP in patients with SLE (1.9 vs 0.1, rate ratio 19.9, CI 16.83 to 23.55). Among patients with SLE, patients with rhupus (n=120, 60.5%) had the highest odds of arthroplasty (OR 4.49, CI 2.87 to 6.92), arthrodesis (OR 6.64, CI 3.28 to 12.97) and synovectomy (OR 9.02,CI 4.32 to 18.23). Over time, the IR for overall JP in patients with rhupus was unchanged (8.7 to 8.6, R2=0.004, p=0.98), although the IR for avascular necrosis underlying arthroplasty decreased for all patients with SLE (0.52 to 0.10, p=0.02). Patients with other SLE also had significantly higher OR and IR for all three JPs than controls with insignificant decreases in synovectomy and increases in arthroplasty over time in this group.
The overall burden of joint surgery in SLE is high and despite a reduction in avascular necrosis, arthroplasty and arthrodesis rates have not decreased over time. These data indicate a need for increased efforts to prevent joint damage in patients with lupus.
We aimed to evaluate the robustness of phase III randomised controlled trials (RCTs) for SLE and lupus nephritis (LN) using the fragility index (FI), the reverse FI (RFI) and the fragility quotient (FQ).
We searched for phase III RCTs that included patients with active SLE or LN. Data on primary endpoints, total participants and the number of events for each arm were obtained. We calculated the FI score for RCTs with statistically significant results (number of patients required to change from event to non-event to make the study lose statistical significance), the RFI for RCTs without statistically significant results (number of patients required to change from non-event to event to make study gain statistical significance) and the FQ score for both (FI or RFI score divided by the sample size).
We evaluated 20 RCTs (16 SLE, four LN). The mean FI/RFI score was 13.6 (SD 6.6). There were nine RCTs with statistically significant results (seven SLE, two LN), and the mean FI score was 10.2 (SD 6.2). The lowest FI was for the ILLUMINATE-2 trial (FI=2), and the highest FI was for the BLISS-52 trial (FI=17).
Twelve studies had non-statistically significant results (10 SLE, two LN) with a mean RFI score of 15.6 (SD 6.1). The lowest RFI was for the ILLUMINATE-1 trial (RFI=4), and the highest RFI was for the TULIP-1 trial (RFI=27). The lowest FQ scores were found in the ILLUMINATE trials and the highest in the Rituximab trials (EXPLORER and LUNAR), meaning that the last ones were the most robust results after accounting for sample size.
The evidence of therapies for patients with SLE and LN is derived mostly from fragile RCTs. Clinicians and trialists must be aware of the fragility of these RCTs for clinical decision-making and designing trials for novel therapeutics.
To determine if the serum levels of neutrophil extracellular trap (NET) remnants (Elastase-DNA and HMGB1-DNA complexes) at the time of a lupus nephritis (LN) flare predict renal outcomes in the following 24 months.
This was a retrospective study performed in prospectively followed cohorts. The study included two cohorts: an exploratory cohort to assess the association between NET remnant levels and the presence of active LN, and a separate LN cohort to determine the utility of NET remnants to predict renal outcomes over the subsequent 24 months.
Ninety-two individuals were included in the exploratory cohort (49 active systemic lupus erythematosus (SLE), 23 inactive SLE and 20 healthy controls (HC)). NET remnants were significantly higher in patients with SLE patients compared with HC (p<0.0001 for both complexes) and those with active LN (36%) had significantly higher levels of NET remnants compared with active SLE without LN (Elastase-DNA: p=0.03; HMGB1-DNA: p=0.02). The LN cohort included 109 active LN patients. Patients with proliferative LN had significantly higher levels of NET remnants than non-proliferative LN (Elastase-DNA: p<0.0001; HMGB1-DNA: p=0.0003). Patients with higher baseline levels of NET remnants had higher odds of not achieving complete remission (Elastase-DNA: OR 2.34, p=0.007; HMGB1-DNA: OR 2.61, p=0.009) and of progressing to severe renal impairment (Elastase-DNA: OR 2.84, p=0.006; HMGB1-DNA: OR 2.04, p=0.02) at 24 months after the flare.
Elastase-DNA and HMGB1-DNA complexes predict renal outcomes, suggesting they could be used to identify patients requiring more aggressive therapy at flare onset.
Despite widespread use of azathioprine (AZA) during pregnancy, no studies evaluated the impact of pregnancy on AZA metabolites 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine nucleotide (6-MMPN) disposition in rheumatic diseases. This study characterises changes in AZA metabolite concentrations throughout pregnancy in women with rheumatic disease and explores relationships between metabolite concentrations, maternal disease activity, and neonatal outcomes.
Patients with rheumatic disease from a single centre prescribed AZA prior to pregnancy and ≥1 blood sample during pregnancy (5/2016 to 4/2022) were included. Commercial laboratories quantified AZA metabolite concentrations. The upper safety limit for 6-MMPN was >5700 pmol/8x108 RBC. The therapeutic target for 6-TGN was ≥159 pmol/8x108 RBC. Repeated correlation measures were used to evaluate the relationship between metabolite concentrations and pregnancy duration, and the relationship between 6-TGN concentration and SLE Physician Global Assessment (PGA). The relationship between pregnancy average 6-TGN and neonatal gestational age at birth was analysed using linear regression.
Thirty-seven pregnancies in 35 women with 108 serum samples were included. There was no significant difference in dose-adjusted 6-TGN concentrations across pregnancy and peripartum, whereas 6-MMPN concentrations appeared higher during pregnancy. No elevated transaminases or cholestasis were observed concurrently with 6-MMPN above 5700 pmol/8x108 RBC. Metabolite concentrations were related to total AZA dosage, weight-based dosage and TPMT phenotype. In pregnant women with SLE achieving average 6-TGN in the therapeutic range, we observed a non-significant reduction in PGA and increase in neonatal gestational age at birth.
In this exploratory study, we did not observe systematic changes in 6-TGN concentrations throughout pregnancy and peripartum, whereas 6-MMPN concentrations were higher during pregnancy. Monitoring AZA metabolite concentrations in pregnancy is a potential tool to identify medication non-adherence as well as patients with high 6-MMPN in whom dosage adjustment or close laboratory monitoring may optimise safety.
There is limited evidence on long-term thrombosis risk in patients with obstetric antiphospholipid syndrome (OAPS). This study aimed to investigate the clinical features and risk factors associated with the first thrombosis in patients with isolated OAPS.
Data from patients with isolated OAPS were collected. All patients were followed up until the first thrombotic event during or after delivery or until the end of the study. Logistic regression analysis identified independent risk factors associated with the first thrombosis in patients with isolated OAPS.
The study enrolled 186 patients with OAPS. During a mean 5.4-year follow-up, 11 (5.9%) patients experienced thrombotic events. Multivariate binary logistic regression analysis revealed that triple-positive antiphospholipid antibodies (aPLs, OR=11.662, 95% CI=2.117 to 64.243, p=0.005) and hypocomplementemia (OR=9.047, 95% CI=1.530 to 53.495, p=0.015) were identified as independent risk factors for the first thrombosis in OAPS, after adjustment for low-dose aspirin and hydroxychloroquine.
Triple-positive aPLs and hypocomplementemia are risk factors for the first thrombosis in patients with OAPS.
The monoclonal anti-Blys antibody belimumab was approved for the treatment of systemic lupus erythematosus more than ten years ago, based on findings in two large, randomized trials demonstrating clinical efficacy and safety.1 2 A further analysis of these two trials clarified that patients with anti-DNA and low complement had the highest likelihood of benefitting from the treatment.3 In subsequent years, many additional studies have further defined the efficacy of belimumab: it was shown to be effective in a subcutaneous formulation as well as intravenously, to reduce flares, maintain responses for many years, allow glucocorticoid dose reductions, reduce the accrual of damage, and last but not least, as an add-on to conventional treatment, to improve the renal response in patients with lupus nephritis – leading to approval for this indication as well.4–6 Belimumab has an excellent safety profile, and is associated with slight increases in infections and an increase in certain psychiatric adverse events.
For the clinician, the main reasons to consider belimumab are:
Proven efficacy both for general lupus and for lupus nephritis Biomarkers for higher likelihood of response More than a decade of experience Safety Flexibility in administration: subcutaneous or intravenous
As with all treatments available today, response in the individual patient is impossible to predict. Therefore, a trial of belimumab may reasonably be considered for any patients who are not responding sufficiently to conventional therapy.
Furie R, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011 Dec;63(12):3918–30. doi: 10.1002/art.30613. van Vollenhoven RF, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012 Aug;71(8):1343–9. doi: 10.1136/annrheumdis-2011-200937. Bruce IN, et al. Long-term organ damage accrual and safety in patients with SLE treated with belimumab plus standard of care. Lupus. 2016 Jun;25(7):699–709. doi: 10.1177/0961203315625119. van Vollenhoven RF, et al. Cumulative corticosteroid dose over fifty-two weeks in patients with systemic lupus erythematosus: Pooled analyses from the phase III belimumab trials. Arthritis Rheumatol. 2016 Sep;68(9):2184–92. doi: 10.1002/art.39682. van Vollenhoven RF, et al. Clinical response beyond the Systemic Lupus Erythematosus Responder Index: post-hoc analysis of the BLISS-SC study. Lupus Sci Med. 2018 Nov 26;5(1):e000288. doi: 10.1136/lupus-2018-000288. van Vollenhoven RF, et al. Long-term safety and limited organ damage in patients with systemic lupus erythematosus treated with belimumab: a Phase III study extension. Rheumatology (Oxford). 2020 Feb 1;59(2):281–291. doi: 10.1093/rheumatology/kez279.
Describe the demonstrated efficacy and safety of belimumab in the treatment of SLE Explain the established biomarker combination anti-DNA and low complement for identifying patients at higher likelihood to benefit from belimumab Discuss the evidence base for use of belimumab in practice, both for general SLE and lupus nephritis Recognize the features of belimumab that may, in practice, help choose this therapeutic option for the patient
A 23-day-old newborn referred by his primary care pediatrician for skin lesions on the face, scalp, and upper trunk, in the form of erythematous annular plaques with hyperkeratosis, somewhat scaly. No other clinical manifestations were found. There was no history of fever and the baby was feeding well. No recent vaccination.
The mother had one spontaneous abortion in the past. The recent pregnancy was uneventful, and the baby was born from a spontaneous vaginal delivery at week 37. The birth weight was 2.6 kg and the Apgar score was normal.
The laboratory findings showed normal white blood cell count, no evidence of inflammation and hepatic and renal function. ANA 1/640; anti-Ro and anti-La antibodies were positive.
In relation to this clinical picture, indicate what your approach would be at this moment.
Describe the clinical features of neonatal lupus Describe the diagnostic and therapeutic approach of neonatal lupus Discuss the prenatal study of pregnant women with lupus
A 5-year-old boy presented with no significant medical history or known drug allergies. He was born at 39 weeks after an uncomplicated pregnancy to unrelated parents, birth weight 3.1 kg. There was no evidence of TORCH or other infections and he has been correctly vaccinated to date. His parents report that every winter, since he was 1 year old, he presents painful violaceous lesions on his hands and feet, but there are no lesions during summer. On examination, he presented chilblain lesions on his hands and feet.
Laboratory test findings were unremarkable, including liver and renal function and acute phase reactants. Rheumatic factor, ANA, anti-dsDNA antibodies, antiphospholipid serology were negative. Normal complement C3/C4. There was no evidence for hypergammaglobulinemia, cold agglutinins, viral or bacterial infection.
The father tells us that he suffers similar episodes and we see scars with tissue loss in his earlobes.
What additional examinations would you consider next?
Discus approach to the main causes of monogenic lupus Describe suggestions for genetic studies on suspicion of monogenic lupus
A 16-year-old female presents with asthenia, anorexia and low-grade fever in the last 2 weeks. She is otherwise asymptomatic with no other medical history of interest.
Laboratory test findings show lymphocytes 800/mm3; platelets 113.000/mm3, Hb 10.5 g/dl, creatinine 1.04 mg/dl, hypoalbuminemia 26 g/l, low C3 and C4 fractions (160 mg/l; < 29 mg/l); ESR 34 mm, CRP 4 mg/l. ANA 1/640, anti-dsDNA Ab >600 UI/ml. Urine: hematuria >100/hpf, pyuria 10/hpf, UPCR 4.74 mg/mg. Lupus anticoagulant negative, IgG/IgM β2-GPI negative, IgG/IgM anti-cardiolipin negative.
Kidney biopsy shows class IV glomerulonephritis -ISN classification-. She received pulsed methylprednisolone plus oral prednisone and mycophenolate mofetil 2 g/day.
One week later, she suddenly deteriorated with acute severe respiratory distress, severe hypoxemia, unstable shock, and hemoptysis. Chest X-ray showed bilateral lung infiltrate suggestive of diffuse alveolar hemorrhage. She was transferred to paediatric intensive care and mechanical ventilation, including high-frequency ventilation, was required. Flexible bronchoscopy confirmed diffuse alveolar hemorrhage. She was treated with pulses of methylprednisolone, intravenous cyclophosphamide, and plasmapheresis.
Explain pulmonary manifestations in lupus Discuss therapeutic approach to diffuse alveolar hemorrhage Describe prognosis of this life-threatening complication of SLE
A Caucasian female patient was diagnosed with systemic lupus erythematosus (SLE) at the age of 18 years due to malar rash, arthralgias, alopecia, oral ulcers and, positive anti-double-stranded DNA (anti-dsDNA). In 2008 she had a severe flare characterized by alopecia and hyperglobulinemia. She received plasma exchanges and later cycles of rituximab for 2 years. Follow-up was missed for several years. In 2015 she moved to Barcelona and visited our centre. In February 2015 she had a polyarticular flare that was treated with intermediate doses of steroids and methotrexate (MTX) up to 20 mg SC per week. In May 2016, she had a new polyarticular flare, and MTX was increased to 25 mg SC per week. In November 2016 she persisted with articular flares, therefore IV belimumab was started with good clinical response over 3 years. In March 2019, she presented a new flare. On physical examination, she had Cushingoid features, synovitis in both wrists with flexor tenosynovitis in the left wrist. She had severe limitations to flex extension in both wrists. X-rays of the wrists revealed loss of joint space and carpal bone erosions. Local infiltration in both wrists was made, but she persisted active. Treatment of erosive disease in SLE will be discussed in detail.
A 34-year-old Caucasian patient was diagnosed with SLE in 2020 after presenting with inflammatory arthritis, Raynaud’s phenomenon, chilblain lupus, and oral ulcers. She started treatment with hydroxychloroquine 200 mg/day plus prednisone 5 mg/day. Two months later she complained of joint pain, but no swollen joints were seen on physical examination. We performed a hand ultrasound assessment. Longitudinal examination at the level of the proximal interphalangeal joint indicates the presence of a discrete component of synovial effusion, irregularity, and prominence of the articular component of the distal epiphysis of the proximal phalanx. The Power Doppler evaluation showed a moderate increase in vascular uptake at the joint level of synovial capsular distention and periarticular soft tissues in the distal epiphysis of the proximal phalanx. Findings were suggestive of active synovitis with associated joint remodelling and active inflammatory and neovascular signs of the periarticular soft tissues. Treatment was changed. She started MTX treatment 15 mg/week initially oral and then SC. Eight weeks later she persisted with articular pain in MCP and proximal inter-phalangeal joints in both hands, but no evidence of synovitis was seen on clinical examination. She underwent magnetic resonance imaging of the hands and wrist - coronal STIR sequence. Mild synovitis was present in the second, third, and fourth metacarpophalangeal joints and the distal radioulnar joint, there was no structural or inflammatory bone damage.
Discuss the treatment approach for patients with SLE and erosive arthritis (rhupus) Discuss the role of imaging in SLE and treatment approaches in patients with articular involvement
Janus kinase (JAK) inhibitors have enriched our armamentarium to treat autoimmune rheumatic diseases, with their approval in inflammatory arthritides (rheumatoid arthritis, spondyloarthritides). The rationale supporting a role for inhibition of the JAK/STAT pathway in the management of systemic lupus erythematosus (SLE) was provided by two fundamental facts: first, interferons (IFN) type I (α/β) and II () are well-established and important players in SLE pathophysiology; second, the JAK/STAT signalling pathway has been identified as the cascade responsible for the signal transduction from the activated IFN receptor to the nucleus. Subsequently, evidence from in vitro studies and animal models supported a role for JAK inhibitors targeted against different JAKs in the treatment of cutaneous and systemic lupus erythematosus, including amelioration of lupus nephritis.1
Contrary to these encouraging preclinical data, clinical trials of JAK inhibitors in SLE were recently marked by the recent discontinuation of the development program of baricitinib (a selective JAK1/JAK2 inhibitor) for SLE, after the discordant results of the two identical SLE-BRAVE phase 3 trials, and following a very successful phase 2 trial.2 3 Post-hoc analyses of the two studies are eagerly awaited to clarify the reasons behind these results. Regarding other JAK inhibitors, only a phase 1 study of tofacitinib has been published with reassuring safety results, and more data are needed.4
Notwithstanding these setbacks, evidence from case series and case reports still support a role for JAK inhibitors in SLE, particularly in patients with skin and joint disease. This is further supported by the fact that baricitinib and upadacitinib are also indicated for autoimmune dermatologic diseases, like alopecia areata (baricitinib) and atopic dermatitis (baricitinib and upadacitinib).
Alunno A, et al. Pathogenic and therapeutic relevance of JAK/STAT signaling in systemic lupus erythematosus: integration of distinct inflammatory pathways and the prospect of their inhibition with an oral agent. Cells. 2019 Aug 15;8(8):898. doi: 10.3390/cells8080898. Morand EF, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I). Lancet. 2023 Mar 25;401(10381):1001–1010. doi: 10.1016/S0140-6736(22)02607-1. Petri M, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II). Lancet. 2023 Mar 25;401(10381):1011–1019. doi: 10.1016/S0140-6736(22)02546-6. Hasni SA, et al. Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus. Nat Commun. 2021 Jun 7;12(1):3391. doi: 10.1038/s41467-021-23361-z.
Explain the scientific rationale for testing JAK inhibitors in SLE Discuss preclinical data that provided proof-of-concept for clinical trials of JAK inhibitors in SLE Discuss the main results and conclusion from clinical trials of JAK inhibitors in SLE, with a focus on baricitinib Provide potential insight into the future of JAK-STAT inhibition of SLE following the failure of baricitinib and halting of its clinical programme in SLE
Clinical trials for lupus have a high failure rate with only two drugs approved for the treatment of general systemic lupus erythematosus (SLE) in the last 60 years, despite at least twenty late-stage clinical trial programmes being pursued. Reasons for the high failure rate, especially in phase 3 trials, potentially include issues with the product being tested, but also issues intrinsic to the disease area. One domain is biological heterogeneity, which will never be directly under our control, although it might one day be addressed in a personalised medicine approach. The other, while also complex, is directly under our control: how trials are designed.
Analysis of recent trial success rates suggests some common factors among successful trials, including the use of glucocorticoid tapering. However, other data point to issues relating to the outcome measures used;1 the SLE responder index (SRI) and BILAG-based composite lupus assessment (BICLA) endpoints are each based on 30-year-old disease activity measures that were never designed for use in clinical trials. A global academia-industry-patient collaboration has now commenced a project to reinvent clinical outcome assessment for use as a treatment response measure in SLE clinical trials: treatment response measure for SLE (TRM-SLE).2 A five-stage scientific protocol using Delphi and nominal consensus methods has been developed to lead to this novel outcome measure, which will subsequently be validated in clinical trial data both retrospectively and prospectively.
Connelly K, et al. Clinician-reported outcome measures in lupus trials: a problem worth solving. Lancet Rheumatol. 2021. doi:10.1016/s2665-9913(21)00119-3. Connelly K, et al. Towards a novel clinical outcome assessment for systemic lupus erythematosus: first outcomes of an international taskforce. Nat Rev Rheumatol. 2023 Jul 11. doi: 10.1038/s41584-023-00993-7. Epub ahead of print.
Increased understanding of the reasons for the lack of success of late-stage clinical trials in SLE Increased understanding of the limitations of current trial measures Awareness of a global project to develop and validate a new SLE clinical trial measure, TRM-SLE
Systemic lupus erythematosus (SLE) imposes a great burden on the lives of patients. Patients’ and physicians’ concerns about the disease diverge considerably. Physicians focus on controlling disease activity to prevent damage accrual, while patients focus on symptoms that impact on health-related quality of life (HRQoL). The existing clinician reported outcomes (ClinRO), such as disease activity indices, remission, low disease activity (LLDAS), response (SRI and BICLA) do not include the patient perspective.
Several investigations show that patients judged in remission by the treating physician, still report the presence of relevant clinical symptoms.1 2
Patients and physicians assess the disease differently (discordance up to 58% of cases) Patients tend to score disease activity higher than physicians Patients consider subjective manifestations as more relevant than physicians Physicians consider laboratory abnormalities as more relevant
It seems there is a discordance between patients and physicians when it comes to prioritising outcomes.
The best way to identify the patients’ priorities is through Patient Reported Outcomes (PROs). PROs allow us to capture aspects of the disease which have an impact on patients and constitute their burden of the disease. Ideally, the dialogue between doctor and patient should address the most bothersome symptoms for the individual patient. What is most bothersome for one might not be the same as for someone else and it most likely wont be the same priority as the doctor has. At the same time, some of the most bothersome symptoms are difficult (if not impossible) to manage with traditional SLE treatments. In these cases, the communication becomes even more important, and a communication gap can be detrimental to the HRQoL and overall care.3
Yen JC, et al. Discordance between patients and their physicians in the assessment of lupus disease activity: relevance for clinical trials. Lupus. 1999;8(8):660–70. doi: 10.1191/096120399680411362. Cornet A, et al. Living with systemic lupus erythematosus in 2020: a European patient survey. Lupus Sci Med. 2021 Apr;8(1):e000469. doi: 10.1136/lupus-2020-000469. PMID: 33849920; PMCID: PMC8051432. Cornet A, et al. Patient-doctor communication gap - results of a speed-shop on ‘lupus flare’ at lupus 2022 meetings. Ann Rheum Dis. 2023;82:309. POS0171.
Describe the burden of the disease from the patients perspective Explain the importance of patient-physician communication Distinguish between patient and physician priorities
Despite advances in understanding and managing systemic lupus erythematosus (SLE), patients continue to face significant challenges in receiving optimal care and support. The concept of a universal SLE patient charter, outlining the rights, needs and expectations of SLE patients, has emerged as a potential solution to address these challenges. However, the development and implementation of such a charter present several significant hurdles.
Firstly, there is a need for consensus among healthcare professionals, patient advocacy groups, researchers, and policymakers, regarding the content and scope of the charter. Standardizing care and efforts to ensure that the charter reflects evidence practices are crucial components in the development and implementation of a universal SLE patient charter. This requires robust communication and collaboration to guarantee that the charter encompasses the diverse needs and perspectives of the global SLE community.
Secondly, the inherent heterogeneity of SLE poses a challenge in creating a charter that can accommodate the unique experiences and requirements of individual patients. SLE manifests differently in each patient, making it crucial to strike a balance between specificity and inclusivity within the charter.1
Thirdly, the charter must address the barriers to access and equity in SLE care. Issues such as disparities in healthcare access, limited availability of specialized healthcare professionals, and high treatment costs need to be considered and addressed within the charter.2–6
In addition, the charter should emphasize the importance of patient education and empowerment to facilitate informed decision-making and self-management. Furthermore, the implementation and enforcement of the charter pose practical challenges. Adequate resources and infrastructure, along with legal and regulatory frameworks, are required to support the implementation of charter principles across different healthcare systems and jurisdictions. Additionally, the charter should encourage the integration of research and data collection efforts to advance our understanding of SLE. Despite these challenges, a universal SLE patient charter holds great potential in improving the quality of care and outcomes for SLE patients globally. It can serve as a guiding document to promote patient-centered care, raise awareness, and advocate for the rights of SLE patients.
Parra Sánchez AR, et al. Treat-to-target in systemic lupus erythematosus: advancing towards its implementation. Nat Rev Rheumatol. 2022 Mar;18(3):146–157. doi: 10.1038/s41584-021-00739-3. Peschken CA. Health disparities in systemic lupus erythematosus. Rheum Dis Clin North Am. 2020 Nov;46(4):673–683. doi: 10.1016/j.rdc.2020.07.010. Zirkzee EJ, et al. Health care in systemic lupus erythematosus (SLE): the patient’s perspective. Clin Rheumatol. 2014 Sep;33(9):1279–87. doi: 10.1007/s10067-014-2595-1. Williams EM, et al. Effective self-management interventions for patients with lupus: potential impact of peer mentoring. Am J Med Sci. 2017 Jun;353(6):580–592. doi: 10.1016/j.amjms.2017.01.011. Mendoza-Pinto C, et al. Improving access to SLE therapies in low and middle-income countries. Rheumatology (Oxford). 2023 Mar 29;62(Suppl 1):i30-i35. doi: 10.1093/rheumatology/keac530. Scofield L, et al. Employment and disability issues in systemic lupus erythematosus: a review. Arthritis Rheum. 2008 Oct 15;59(10):1475–9. doi: 10.1002/art.24113.
Recognize the potential of a universal SLE patient charter to address lupus care Identify significant barriers in developing and implementing the charter, including stakeholder consensus and defining key elements Appreciate the need to accommodate the heterogeneity of SLE and address barriers to access and equity in care Understand the importance of patient education and empowerment and the practical challenges of implementing and enforcing the charter across healthcare systems and jurisdictions
Although there is currently a need to adopt a treat to target approach in systemic lupus erythematosus (SLE), there are no clear descriptions of disease modifications to guide this approach. Recently van Vollenhoven et al reported a conceptual framework for defining disease modification in SLE in three epochs, year 1, years 2–5, and ≥5 years.1 They suggested criteria to define disease modification for each epoch including minimizing disease activity and slowing or preventing organ damage progression.1 Failure to achieve these disease modifications results in damage accrual either due to the disease or its treatment. Furthermore, damage accrual predicts increasing damage and mortality.2 3 Very few of the therapeutic agents currently available to treat SLE have been successful in disease modification in all three epochs either because their therapeutic effect is short lived, or they have not yet been used for ≥5 years or toxicity has precluded long term use.
Four medications merit mention at this time: corticosteroids, antimalarials, belimumab and anifrolumab. Corticosteroids are very effective anti-inflammatory/anti-immunologic agents, but should not be used long term because of their significant toxicities. One should use a dose required to achieve suppression of the acute inflammatory clinical disease BUT strive to wean to a dose of ≤5 mg prednisone by 3 months. Time to achieve the clinical response desired may vary depending on disease manifestations, but rapid weaning should remain the desired target. With complete remission weaning the last 5 mg prednisone is possible, using a slow taper schedule.4 Antimalarials used early and consistently have been shown to protect against damage accrual and mortality.2 3 Belimumab, the first biologic developed for the treatment of SLE, was first approved in 2011 and has now been shown to be disease modifying in each of the three epochs with minimal toxicity. Belimumab’s long term use has demonstrated a reduction in organ damage progression, a slowed rate of organ damage progression and reduction in the magnitude of year-to-year organ damage.5 Anifrolumab was approved by the FDA in 2021 but has data for 3 years of follow-up in an extension study that show the initial therapeutic responses persist. There is a lower cumulative corticosteroid dose in patients and there was no safety issue signal.6
van Vollenhoven R, et al. Conceptual framework for defining disease modification in systemic lupus erythematosus: a call for formal criteria. Lupus Sci Med. 2022 Mar;9(1):e000634. doi: 10.1136/lupus-2021-000634. Bruce IN, et al. Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the systemic lupus international collaborating clinics (SLICC) inception cohort. Ann Rheum Dis. 2015 Sep;74(9):1706–13. doi: 10.1136/annrheumdis-2013-205171. Rahman P, et al. Early damage as measured by the SLICC/ACR damage index is a predictor of mortality in systemic lupus erythematosus. Lupus. 2001;10(2):93–6. doi: 10.1191/096120301670679959. Tselios K, et al. Gradual glucocorticosteroid withdrawal is safe in clinically quiescent systemic lupus erythematosus. ACR Open Rheumatol. 2021 Aug;3(8):550–557. doi: 10.1002/acr2.11267. Epub 2021 Jul 10. Urowitz MB, et al. Organ damage in patients treated with belimumab versus standard of care: a propensity score-matched comparative analysis. Ann Rheum Dis. 2019 Mar;78(3):372–379. doi: 10.1136/annrheumdis-2018-214043. Kalunian KC, et al. A randomized, placebo-controlled phase iii extension trial of the long-term safety and tolerability of anifrolumab in active systemic lupus erythematosus. Arthritis Rheumatol. 2023 Feb;75(2):253–265. doi: 10.1002/art.42392. Epub 2022 Nov 11.
Describe a definition of disease modification in SLE Describe that failure of disease modification results in significant damage Explain how managing corticosteroids, antimalarials and two newer biologics may aid damage prevention
Although the concept of disease modification is well-established in several immune-mediated diseases, there is no widely accepted definition of disease modification in systemic lupus erythematosus (SLE). A group of international lupus experts recently proposed a framework for the definition of disease modification in SLE that includes minimizing disease activity with the fewest treatment associated toxicities and slowing/preventing organ damage progression.1 Achieving this goal in SLE will require a multifaceted approach including the use of therapies that target key immunologic pathways important to disease pathogenesis and shared decision making between patients and physicians to encourage therapeutic adherence.
The successful development and approval of two targeted biologic agents, belimumab and anifrolumab, will hopefully accelerate our ability to achieve disease modification in SLE. Both agents target key mechanisms that contribute to ongoing SLE disease activity and damage. Belimumab is a fully human IgG1l antibody against soluble B cell activating factor (BAFF) and anifrolumab is a fully human IgG1k against subunit 1 of the Type I Interferon receptor. In large scale international phase III trials of participants with SLE, both agents reduced disease activity across multiple organ domains and enabled tapering of glucocorticoids.2–5 The agents differ in kinetics of response, with anifrolumab demonstrating a faster time to response, particularly in people with cutaneous lupus manifestations. The availability of belimumab over the past decade has enabled studies demonstrating reduction in damage progression with belimumab compared to matched controls receiving conventional therapies. Such long-term studies are not yet available with anifrolumab. In terms of the critical issue of predictors of response, serologic activity predicts response to belimumab and to anifrolumab compared to conventional therapies. As a result of the distinct effects on pathways involved with host defence, the safety profile between belimumab and anifrolumab is quite distinct. Belimumab has consistently demonstrated a reassuring safety profile in comparison to conventional therapies with one exception being the increased risk of depression-related adverse events. In contrast, anifrolumab has been associated with an increased risk of mild-moderate infections, including herpes zoster and influenza. Thus, all patients should be strongly encouraged to receive appropriate vaccinations prior to start of therapy.
The pipeline of therapies for the treatment of SLE is full of promising agents targeting a variety of important immunologic pathways. An ongoing area of active investigation is learning how to select the right therapy for the right patient at the right stage of their disease. In this way, we will continue to make significant progress towards disease modification in SLE.
van Vollenhoven R, et al. Conceptual framework for defining disease modification in systemic lupus erythematosus: a call for formal criteria. Lupus Sci Med. 2022 Mar;9(1):e000634. doi: 10.1136/lupus-2021-000634. Navarra SV, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011 Feb 26;377(9767):721–31. doi: 10.1016/S0140-6736(10)61354-2. Furie R, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011 Dec;63(12):3918–30. doi: 10.1002/art.30613. PMID: 22127708; PMCID: PMC5007058. Morand EF, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 2020 Jan 16;382(3):211–221. doi: 10.1056/NEJMoa1912196. Furie RA, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019;1(4):E208-E219.Idoi:10.1016/S2665-9913(19)30076-1.
Describe the evolving framework for disease modification in SLE Distinguish the mechanisms of action of belimumab and anifrolumab Explain the key differences in efficacy and safety between belimumab and anifrolumab
Unlike many other autoimmune diseases, in systemic lupus erythematosus (SLE) there are only two targeted biological therapies approved to choose between, namely belimumab and anifrolumab. Each is approved for the treatment of moderate to severe active SLE, and the 2023 European Alliance of Associations for Rheumatology (EULAR), guidelines recommend consideration of biological therapy in first line treatment. But how are we to choose which one to use first in each patient? Assuming equal access and cost, our decisions are based largely on clinical trial and long-term extension data, with some additional information from investigator-initiated studies.
The case for using anifrolumab as first line biologic in SLE rests on several points of difference from belimumab. First, the available data suggest the potential for a fast onset of action for anifrolumab, with pooled data from the phase 3 trials showing separation between placebo and anifrolumab as early as 4 weeks in some domains.1 Secondly, anifrolumab was efficacious in mucocutaneous, musculoskeletal, and haematological domains, suggesting the potential for broad effects in SLE; importantly, efficacy in lupus nephritis has not yet been demonstrated.1 Thirdly, glucocorticoid sparing effects of anifrolumab were robustly demonstrated.2 Fourthly, anifrolumab is the only drug shown to increase attainment of remission in SLE; increased LLDAS was also demonstrated.3 Finally, the long-term extension study of anifrolumab, the first in SLE to include a long term placebo-control group, showed good tolerance, low rates of serious adverse events, and prolonged reduction in disease activity and glucocorticoid use; prolonged attainment of LLDAS has been reported in abstract form.4
Together these data suggest that anifrolumab treatment can induce broad, deep, and lasting effects on SLE disease activity and achieve steroid sparing.
Morand EF, et al. Efficacy of anifrolumab across organ domains in patients with moderate-to-severe systemic lupus erythematosus: a post-hoc analysis of pooled data from the TULIP-1 and TULIP-2 trials. Lancet Rheumatol. 2022;4(4): E282-E292. Bruce IN, et al. Sustained glucocorticoid tapering in the phase 3 trials of anifrolumab: a post hoc analysis of the TULIP-1 and TULIP-2 trials. Rheumatology (Oxford). 2023 Apr 3;62(4):1526–1534. doi: 10.1093/rheumatology/keac491. Morand EF, et al. Lupus low disease activity state attainment in the phase 3 TULIP trials of anifrolumab in active systemic lupus erythematosus. Ann Rheum Dis. 2023 May;82(5):639–645. doi: 10.1136/ard-2022-222748. Kalunian KC, et al. A randomized, placebo-controlled phase iii extension trial of the long-term safety and tolerability of anifrolumab in active systemic lupus erythematosus. Arthritis Rheumatol. 2023 Feb;75(2):253–265. doi: 10.1002/art.42392.
Increased understanding of the efficacy and safety data for anifrolumab in SLE clinical trials and long-term extension Increased awareness of key points of difference between anifrolumab and belimumab, potentially including onset of action and attainment of remission
Until recently, classification of antiphospholipid syndrome (APS) for clinical trials and studies was based on clinical and laboratory criteria described in the Sapporo classification criteria published in 1999,1 and revised in 2006.2
Given the limitations of the Sapporo criteria,3 and new data-driven and expert-based methodology available to develop classification criteria,4 an international effort jointly supported by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR), was initiated. The goal was to develop a new APS classification system, based on a more modern disease understanding, allowing for the weighting of individual criterion, and demonstrating excellent operating characteristics with the highest possible specificity. This international multidisciplinary effort included four phases: (1) criteria generation; (2) criteria reduction; (3) criteria definition, further reduction, and weighting via consensus-based multi-criteria decision analysis, and threshold identification; and (4) validation using independent adjudicators’ consensus as the ‘gold standard’.3 5
Novel clinical features of the new criteria include: (a) risk stratification of macrovascular events by traditional thrombosis risk factors; (b) well-defined microvascular domain items; (c) re-defined pregnancy morbidity definitions; and (d) the addition of cardiac valve disease and thrombocytopenia, to capture and quantify the magnitude of heterogeneous aPL manifestations. Novel laboratory features include: (a) quantifying single-, double-, and triple- antiphospholipid antibody (aPL) positivity based on different domains and weights; (b) separating anticardiolipin antibody (aCL)/anti-β2-Glycoprotein-I (aβ2GPI) IgG and IgM isotypes; and (c) defining two levels of aCL/aβ2GPI positivity that will be interpreted as clinically relevant by most investigators.5
In summary, the new (ACR/EULAR) APS classification criteria incorporate heterogenous aPL-related clinical and laboratory manifestations into a hierarchically clustered, weighted, and risk-stratified criteria reflecting current thinking about APS, providing high specificity and an improved foundation for APS research.
Wilson WA, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999 Jul;42(7):1309–11. doi: 10.1002/1529-0131(199907)42:7<1309::AID-ANR1>3.0.CO;2-F. Miyakis S, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb;4(2):295–306. doi: 10.1111/j.1538-7836.2006.01753.x. Barbhaiya M, et al. Development of a new international antiphospholipid syndrome classification criteria phase I/II report: generation and reduction of candidate criteria. Arthritis Care Res (Hoboken). 2021 Oct;73(10):1490–1501. doi: 10.1002/acr.24520. Epub 2021 Sep 2. Johnson SR, et al. Classification criteria in rheumatic diseases: a review of methodologic properties. Arthritis Rheum. 2007 Oct 15;57(7):1119–33. doi: 10.1002/art.23018. Erratum in: Arthritis Rheum. 2007 Dec 15;57(8):1574. Barbhaiya M, et al. 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Arthritis Rheumtol 2023 (in press).
Discuss the merits of the new APS classification system Describe the presentation of heterogenous aPL-related clinical and laboratory manifestations and how these reflect current thinking about APS Explain how the criteria provide an improved foundation for APS research
A patient pathway is the patient experience from the first symptom through the initial referral for diagnosis, treatment and follow-up, and includes diverse aspects of disease management, such as holistic support and prevention of complications. Among the most significant challenges in systemic lupus erythematosus (SLE) 1 are the excessive diagnosis delay and the lack of coordinated care. At our national reference center in Strasbourg (France), we have conducted a series of focus groups with healthcare professionals and SLE patients. Based on the collected data, the most impactful disruption points in SLE patient pathways were identified.2 A novel framework to improve individual patient pathways in SLE was developed, discussed and validated during a consensus meeting with representative stakeholders. Six main disruptions in optimal SLE patient pathways were identified: (1) appropriate and timely referral strategy for SLE diagnosis; (2) the need for a dedicated consultation during which the diagnosis of SLE would be communicated, and following which clarifications and psychological support offered; (3) individualized patient pathways with coordinated care based on organ involvement, disease severity and patient preference; (4) improved therapeutic patient education; (5) prevention of complications such as infections, osteoporosis and cancer; (6) and additional patient support. These disruption points are valuable knowledge, which may be used to improve individual patient pathways in SLE. These data may be of valuable interest to patients with SLE, their physicians, health organizations and policy makers.
Felten R, et al. 10 most important contemporary challenges in the management of SLE. Lupus Sci Med. 2019 Jan 10;6(1):e000303. doi: 10.1136/lupus-2018-000303. Schlencker A, et al. Improving patient pathways for systemic lupus erythematosus: a multistakeholder pathway optimisation study. Lupus Sci Med. 2022 May;9(1):e000700. doi: 10.1136/lupus-2022-000700.
Explain the key concept of patient pathways Describe how patient pathways can be mapped in systemic lupus Identify the main disruption points in lupus patient pathways Describe how to improve lupus patient pathways
The importance of interferons as a component of human antiviral host defense was first suggested by Isaacs and Lindenmann in 1957.1 It was not until the 1970s that a pathogenic role of interferons in systemic lupus erythematosus (SLE) was suspected.2 While it was recognized long ago that patients with systemic lupus were at increased risk of Herpes zoster reactivation (shingles), it was the phase 2 studies of sifalimumab and anifrolumab that highlighted the importance of this complication.3 4 Given the mechanism of action of sifalimumab and anifrolumab, namely their ability to dampen type I interferon pathway activation, it was no surprise that the incidence of Herpes zoster was as much as 8-fold higher in the treatment arms than in the placebo groups of the phase 2 and 3 SLE trials.4–6 In a post-hoc analysis of the phase II and the two phase III trials of anifrolumab, Tummala et al reported exposure-adjusted incidence rates (EAIR) per 100 patient-years of 6.9 and 1.5 in the 300 mg anifrolumab and placebo groups, respectively.7 Even higher frequencies of Herpes zoster were observed in the phase II anifrolumab trial in lupus nephritis with frequencies over the course of the study of 13.7% and 20.0% in the two treatment groups compared to 8.2% in the placebo group.8
Other drugs in development in SLE, such as litifilimab, daxdilimab, and deucravacitinib, also impact type I interferons. However, Herpes zoster was infrequent in these studies suggesting that the degree of inhibition of type I interferon pathway activation correlates with the risk of Herpes zoster. Despite a low basal incidence rate of Herpes zoster, vaccination with Zoster Vaccine Recombinant, Adjuvanted, is now recommended for adults aged ≥18 years who are or will be at increased risk for shingles because of immunodeficiency or immunosuppression caused by their underlying disease or therapy.
Isaacs A, Lindenmann J. Proceedings of the Royal Society of London. Series B, Biological Sciences 1957. Hooks JJ, et al. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med. 1979 Jul 5;301(1):5–8. doi: 10.1056/NEJM197907053010102. Khamashta M, et al. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016 Nov;75(11):1909–1916. doi: 10.1136/annrheumdis-2015-208562. Furie R, et al. Anifrolumab, an anti-Interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376–386. doi: 10.1002/art.39962. Furie RA, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019, 1(4), e208–e219. Morand EF, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020 Jan 16;382(3):211–221. doi: 10.1056/NEJMoa1912196. Tummala R, et al. Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials. Lupus Sci Med. 2021 Feb;8(1):e000464. doi: 10.1136/lupus-2020-000464. Jayne D, et al. Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis. Ann Rheum Dis. 2022 Apr;81(4):496–506. doi: 10.1136/annrheumdis-2021-221478.
Discuss the role of interferons in the pathogenesis of SLE Analyze SLE clinical trial data with respect to Herpes zoster incidence Describe strategies for prevention of Herpes zoster
Vaccination prevents infectious diseases by inducing/enhancing protective immunity, potentially translating into a lower rate of invasive infections and hospital admissions. Patients with autoimmune inflammatory rheumatic diseases (AIIRD), and particularly systemic lupus erythematosus (SLE) are at increased risk of vaccine-preventable infections, attributed to the underlying autoimmune disease, additional comorbidities and immunosuppressive therapies. Yet, this population of patients is generally sub-optimally immunized due to concerns about efficacy, immunogenicity, and safety of vaccines shared both by patients and their treating physicians. In this regard, vaccination may be less efficacious in subgroups of patients with AIIRD, such as SLE and could potentially be associated with temporal (usually mild) exacerbation of the underlying autoimmune disease. Immunization protocols which take into consideration the AIIRD itself, timing of immunization and the number of vaccines doses may enable safe and efficacious immunization.1–6
In recent years updated recommendations for immunization of AIIRD patients were issued. These recommendations comprise several overarching principles as: annual vaccination status assessment, shared decision-making, timing of vaccination (e.g. favoring vaccination during quiescent disease, preferably prior to initiation of immunosuppression), and avoidance of some live-attenuated vaccines both for patients and their household members. Additionally, new data suggest that increasing the doses of vaccine (e.g. anti-COVID vaccines) may overcome lower immunogenicity among SLE and other AIIRD patients.
Herein, an up-to-date guidance for immunization of SLE patients in 2023 will be reviewed.
Furer V, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2020 Jan;79(1):39–52. doi: 10.1136/annrheumdis-2019-215882. Furer V, et al. Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): a systemic literature review informing the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD. RMD Open. 2019 Sep 19;5(2):e001041. doi: 10.1136/rmdopen-2019-001041. Furer V, et al. Point of view on the vaccination against COVID-19 in patients with autoimmune inflammatory rheumatic diseases. RMD Open. 2021 Feb;7(1):e001594. doi: 10.1136/rmdopen-2021-001594. Scanzi F, et al. Are the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and the undifferentiated connective tissue disease (UCTD) related to each other? A case-control study of environmental exposures. Immunol Res. 2017 Feb;65(1):150–156. doi: 10.1007/s12026-017-8912-4. Tunitsky-Lifshitz Y, et al. The third dose of BNT162b2 COVID-19 vaccine is efficacious and safe for systemic lupus erythematosus patients receiving belimumab. Lupus. 2023 Apr;32(5):675–679. doi: 10.1177/09612033231164262. Kharouf F, et al. A deep look into the storm: Israeli multi-center experience of coronavirus disease 2019 (COVID-19) in patients with autoimmune inflammatory rheumatic diseases before and after vaccinations. Front Immunol. 2023 Mar 13;14:1064839. doi: 10.3389/fimmu.2023.1064839
Describe immunization protocols that may enable safe and efficacious immunization Discuss updated recommendations for immunization of AIIRD patients, in particular those with SLE Discuss plausible options to lower immunogenicity among SLE patients
Editor-in-Chief, Lupus Science and Medicine
In the past decade, the world of publishing has undergone rapid changes with the proliferation of online journals and the advances of the open access movement. Consequently, the roles of authors and reviewers, while unchanged in essence, have undergone shifts as well.
In this workshop we will discuss the changes in the world of publishing, share insights and tips for (aspiring) authors, and give recommendations for effective and rewarding peer review.
Explain the changes that have occurred and are occurring in the world of medical-scientific publishing, with special attention to the proliferation of on-line journals and the open access movement Discuss what journal editors and reviewers are looking for in a manuscript, and how to maximize the potential of your next submission Describe how to do an accurate, fair and insightful peer review should the opportunity arise
A 10-year-old girl presents with a prolonged fever and rash, most prominent around the eyes, with annular lesions encircling the periorbital regions. She is otherwise well, with normal blood pressure, a polymorphous rash, one aphthous ulcer on her lip and mild polyarthritis of the small joints of her hands.
Investigations show leukopenia (2.22x109/L), normocytic anemia (hemoglobin 9.5 g/dL), an elevated ESR (57 mm/hr) and C-reactive protein (36 mg/L), hypoalbuminemia (30 g/L), mild proteinuria (0.08 g/mmol), hematuria (29/hpf), pyuria (20/hpf), slightly elevated creatinine (88 µmol/L, giving an estimated GFR of 56 ml/min/1.73 m2). Eventually, urine culture returns positive for E. coli. She also has a positive Direct Coombs’ test, antinuclear antibodies, anti-RNP, anti-β2-glycoprotein IgG, anti-cardiolipin IgM. Her complement 3 (80 mg/dl) is slightly low, but she has a normal complement 4 level and negative anti-double stranded DNA. Ultrasound shows a dysplastic left kidney. A renal biopsy of the right kidney reveals an unexpected result. Come and see!
Describe the lesser-known cutaneous manifestations of lupus in children Describe renal involvement in lupus beyond the known classification of lupus nephritis Discuss the treatment of lupus nephritis
A 16-year-old girl presents with fever lasting one-month, extreme lethargy, loss of weight, alopecia and a facial rash. The diagnosis of systemic lupus erythematosus (SLE) is made with additional features of pancytopenia, positive direct Coombs’ test, positive ANA and anti-double stranded DNA, hypocomplementemia. She is started on oral prednisolone 30 mg twice daily and hydroxychloroquine. One day after initiation of therapy, she returns to the Emergency Department with severe abdominal pain and vomiting. An 18-year-old girl has received treatment for SLE since the age of 13 years old. She presented with cutaneous vasculitis and arthritis with cytopenia. Her current treatment included prednisolone 5 mg daily, mycophenolate mofetil 1 g twice daily and hydroxychloroquine. She has had persistent neutropenia for the last 2 years without infection and low complement 3 (75 mg/dl) without clinical features of lupus. She has had one month of abdominal bloating and abdominal pain following an acute food poisoning with another family member. While on a trip to Italy, the abdominal pain and nausea worsened and she was admitted to the Emergency Department. What could this be and what must be done?
Describe the treatment approach to abdominal pain in a patient with lupus Describe the clinical features and outcomes of acute pancreatitis in childhood lupus Explain the clinical features and outcomes of ‘lupus gut’ in childhood lupus Discuss the best practice for management of acute pancreatitis in lupus and ‘lupus gut’
A 35-year-old woman of Hispanic ancestry received a diagnosis of systemic lupus erythematosus (SLE) in June 2021, based on polyarthralgia/itis, malar rash, proteinuria of 1400 mg/24 h, positive antinuclear antibodies, anti-double-stranded DNA antibodies (anti-dsDNA), with hypocomplementemia. Lupus anticoagulant, anticardiolipin and anti-β2-Glycoprotein-I antibodies were negative. Her SLEDAI score was 16. A kidney biopsy was performed showing a focal proliferative glomerulonephritis (Class III), with a score of 12 and 0 of activity and chronicity, respectively. She was treated with hydroxychloroquine 400 mg/day, prednisone 20 mg/day, and mycophenolate mofetil 3000 mg/day as induction therapy.
In September 2021 she came to the emergency room due to persistent tachycardia, dyspnea on moderate exertion, and chest pain. At admission she presented elevated ESR and C-reactive protein level, normal kidney function tests, proteinuria of 350 mg/24 h, and positive anti-dsDNA, with low C3 and C4. During hospitalisation she presented fever, and worsening dyspnea, for which she required oxygen therapy. The electrocardiogram showed sinus tachycardia and the echocardiography a systolic dysfunction and a hypokinetic left ventricle (inferior and lateral walls) with an ejection fraction of 40%. Troponin T and brain natriuretic peptides were elevated. The SARS-CoV2 RT-PCR was positive. With the suspected diagnosis of acute myocarditis in the context of SARS-CoV2 infection, the patient was treated with methylprednisolone pulses, IVIG, and respiratory support.
Describe the different myocardial manifestations in a patient with SLE. Discuss complications and differential diagnosis with allied diseases. Discuss the treatment of myocarditis in a patient with SLE.
A 40-year-old female was diagnosed with systemic lupus erythematosus (SLE) at the age of 30 based on malar rash, arthritis, positive antinuclear antibodies, anti-double-stranded DNA antibodies, hypocomplementaemia, and biopsy-proven Class IV lupus nephritis. She was treated with glucocorticoids (GC), hydroxychloroquine (HCQ), and intravenous pulses of cyclophosphamide followed by mycophenolate mofetil (MMF) achieving complete remission 6 months later. Four years later, she suffered from a second SLE flare in the form of Class IV lupus nephritis as well as arthritis, receiving induction treatment with GC and MMF and achieving complete renal response 8 months later. She remained in lupus low disease activity for the next 5 years with prednisone 2.5 mg/day, HCQ 300 mg/day, and MMF 500 mg/12h. She was a current smoker, and her previous history included arterial hypertension and dyslipidaemia treated with enalapril 10 mg/day and atorvastatin 20 mg/day.
At the current admission, she presented at Emergency Department with thoracic pain and shortness of breath. She was diagnosed with myocardial infarction. Coronary angiography showed an atherosclerotic plaque in anterior descending coronary artery that required percutaneous coronary intervention and stenting. The patient was discharged without acute complications under treatment with dual platelet anti-aggregation.
What could we have done to avoid this outcome?
Discuss the general management of cardiovascular risk factors in patients with SLE Discuss the usefulness of different scoring tools to assess the atherosclerotic cardiovascular disease in SLE patients and the potential utility of imaging Discuss the objectives of treatment (primary prevention) of the different cardiovascular risk factors (hypertension, dyslipidaemia, tobacco) in SLE patients and the indications of aspirin in primary prevention
The therapeutic armamentarium of the lupologist is expanding, notably when faced with one of the most frequent severe systemic lupus erythematosus (SLE) organ manifestation: Lupus nephritis (LN). Based on real-practice case studies, we will address the latest guideline recommendations for the management of LN. With novel agents at hand, we will make a journey through several treatment strategies for LN and provide key learnings by interactive discussions.
A 20-year-old female with no significant pathological history presented with arthritis, facial rash and leg swelling. She was recently diagnosed SLE and treated prednisolone and hydroxychloroquine, calcium, and active vitamin D. Three months later she developed nephrotic syndrome and mild hypertension, her laboratory results showed a creatinine 123 mmol/L (1.5 mg/dL), positive antinuclear antibodies 1:1280, anti-double-stranded DNA 1230 U/mL and low C3 and C4. Her urine sediment showed glomerular erythrocyturia. A kidney biopsy was performed confirming active LN. After an interactive discussion on histopathological findings, a therapeutic decision must be made.
Describe at least four treatment goals for your LN patient Summarize three treatment options for induction of remission in LN Discuss three treatment options for preventing relapses in LN Explain the pathophysiology of glomerulonephritis in SLE
A 52-year-old female was diagnosed with systemic lupus erythematosus (SLE) in 1983. She had positive antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA) >666 IU/mL, C3 0.35 g/L, C4 0.07 g/L, CH50 20 IU/mL AI hemolytic anemia, lymphopenia, arthritis, probable lupus nephritis (LN) due to the presence of microhematuria, non-nephrotic proteinuria with preserved renal function, no renal biopsy was performed. She was treated with steroids, cyclophosphamide 6 x 500 mg, hydroxychloroquine 200 mg/d and subsequent maintenance with azathioprine 100 mg/d, prednisone 7.5 mg/d + calcium and vitamin D prophylaxis. Complete renal response was achieved after 18 months but with persistence of anti-dsDNA >600 and low levels of C3-C4. In 2006, she had clinical remission of SLE. GFR > 90 ml/min, inactive sediment and proteinuria 500 mg/d, persistently high anti-dsDNA titer and low C3-4 levels. The first renal biopsy revealed LN Class IIIC (IA 0/24, IC 2/12) and Grade 1 interstitial fibrosis and tubular atrophy. In 2012, she experienced a new flare. A renal biopsy revealed Class III (AC) (IA 6/24, CI 3/12. Complete renal remission was achieved after 1 year of treatment with steroids plus sodium mycophenolate, but persistent immunological activity. On March 2021 she experienced a new flare, with proteinuria up to 2.5 g/d, microhematuria, AKI 1, arthritis, malar rash and positive AAF. Renal biopsy showed LN Class IV (AC) AI: 10/24 CI: 4/12. Triple therapy with steroids, mycophenolate mofetil and belimumab was started. The response to triple therapy in this grumbling disease is discussed, from a renal and immunological point of view.
A 22-year-old woman, diagnosed with SLE at 18 years, presented with deep vein thrombosis, a study was carried out, revealing positive ANA, anti-dsDNA >666 IU/mL, positive IgG anti-β2-Glycoprotein-I and lupus anticoagulant, and low C3, C4 and CH50, microhematuria and proteinuria of 2 g/d, with normal renal function. Renal biopsy showed LN Class III, AI 4/24, IC 0/12. Steroids, mycophenolate mofetil and hydroxychloroquine, as well as anticoagulation with Vitamin K antagonists were initiated. Despite treatment, the patient presented progressive worsening of proteinuria up to 6 g/d. A new biopsy was performed 6 months later. The light micrograph showed LN Class IV-G (AC) IA 11/24 and IC 2/12 with immune deposits (IF and EM) compatible with associated membranous nephropathy. A sequential regimen of steroids plus cyclophosphamide 3 g (total dose) was started and later triple therapy with MMF-tacrolimus-steroids was continued due to persistent proteinuria in nephrotic range.
A third renal biopsy was performed for control of proteinuria stagnant in 3.5 g, revealing LN III + V with AI 4/24 and CI 3/12, IFTA ≥15%. Treatment with rituximab 1 g x 2 and nephroprotective treatment with losartan 50 mg/12 h were initiated. Under this treatment, a progressive decrease in anti-dsDNA titers up to 125 IU/mL and partial improvement in C3-C4 levels was confirmed, but there was an increase in proteinuria up to 4.5 g/d. In view of these findings and the high burden of immunosuppression administered, nephroprotective treatment was prioritized by sequentially adding dapagliflozin 10 mg/d and spironolactone 50 mg/d, achieving resolution of the nephrotic syndrome, with stable renal function and residual proteinuria of 1 g/d.
Currently, effective antiproteinuric treatments are available and they act by multiple mechanisms. The importance of establishing an adequate clinical correlation between the trajectory of immunological activity and proteinuria will be discussed in order to obtain better clinical results in LN.
Describe clinical and histological findings that identify challenging cases of proliferative LN Explain the current role of therapy with anti-BAFF biologics in LN Discuss principles and strategies in the management and prevention of organ damage and preservation of kidney function in the long term
A 14-year-old Caucasian girl presented to her physician with malar and trunk photosensitivity rashes in Summer 2010. In October 2010, she developed fever, pleurisy, polyarthritis and mild proteinuria (<0.5 g/day). Laboratory tests showed positive antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA, anti-U1RNP, anti-Sm and decreased C3. A diagnosis of systemic lupus erythematosus (SLE) was made and she was treated with IV pulses of methylprednisolone (MPN), 500 mg x 3, then oral prednisone starting from 25 mg/day, then tapered to 5 mg per day plus hydroxychloroquine (HCQ) 400 mg/day. After almost one-year prednisone was withdrawn due to clinical remission1; unfortunately, in 2017–2018, she experienced three episodes of SLE articular and skin flares; thus, prednisone was reintroduced (25 mg/day than tapered to 15 mg/day always plus HCQ). It must be mentioned that she experienced recurrent genital herpes simplex, 1–2 episodes/year, starting from 2015. In June 2018, she had a new hospital admission due to polyarthritis (DAS28 7.16), fever, malar rash, fatigue and lymphadenopathy, and muscular weakness. She had high C-reactive protein (CRP) 18.3 mg/l, lymphopenia 700/mm3, C3 0.83 mg/dl, increased anti-dsDNA 1.096 KIU/L and creatin kinase (CK) 965 U/L. Muscular MRI showed mild oedema at proximal muscle of the limbs. At that time, she was on prednisone 25 mg/day and HCQ 400 mg/day. [The best therapeutic options in this case will be discussed with the participants at the workshop.] However, we increased the daily dosage of prednisone and we added belimumab.2 3 After belimumab initiation we observed a progressive decline in SLEDAI-2K score and in DAS-28 score, a decrease in the prednisone dose taken by the patient, a decrease in anti-dsDNA serum levels and an increase in C3 and C4 serum levels. Regarding safety, we did not observe infusion reactions.
Zen M, et al. Defining the targets in SLE management: insights and unmet gaps. Ann Rheum Dis. 2022 Nov;81(11):1483–1485. doi: 10.1136/ard-2022-222991. Epub 2022 Aug 25. PMID: 36008131. Zen M, et al. Early and late response and glucocorticoid-sparing effect of belimumab in patients with systemic lupus erythematosus with joint and skin manifestations: results from the belimumab in real life setting study-joint and skin (BeRLiSS-JS). J Pers Med. 2023 Apr 20;13(4):691. doi: 10.3390/jpm13040691. Gatto M, et al. Early disease and low baseline damage as predictors of response to belimumab in patients with systemic lupus erythematosus in a real-life setting. Arthritis Rheumatol. 2020 Aug;72(8):1314–1324. doi: 10.1002/art.41253. Epub 2020 Jun 12.
A 32-year-old Caucasian female started to complain fever and headache in July 2010. In August 2010, she developed subacute lupus on upper arms, leukopenia and thrombocytopenia, arthritis, with mild arthritis at hands and wrists. Blood tests showed leukopenia (WBC 3,467/mm3), low C3 (0.79 g/L), increase gamma-globulins (24.2%), positive ANA, anti-dsDNA, anti-SSA, anti-P-ribosomal, and rheumatoid factor. The diagnosis of SLE was made and she was treated with prednisone 25 mg per day, progressively tapered to 5 mg/day, and HCQ 400 mg with improvement of her clinical manifestations. She went well until 2014, with the exception of mild but persistent inflammatory arthralgias.1 In May 2015 she developed skin and joint flares with subacute cutaneous lupus and arthritis at hands and wrists with mild Jaccoud’s deformities, leukopenia (WBC 2.320/mm3), increase in anti-dsDNA (199 KIU/L), decrease in C3. Notably, she had SLEDAI-2K: 7, CLASI activity: 10, DAS28: 4.58, SLICC-DI: 1. At that time she was on prednisone 25 mg and HCQ 400 mg. The best therapeutic options in this case will be discussed with the participants at the workshop. We increased the prednisone dose and started belimumab in June 2015. In May 2017 she developed a new flare with diffuse subacute lupus on upper arms, chest and back after sun exposition and persistent arthritis, leukopenia (WBC 3.722/mm3), increased anti-dsDNA (134 KIU/L), decreased complement levels (C3 0.79 g/l). She had SLEDAI-2K: 10, CLASIa: 11, DAS28: 4.52, SLEDAS:2 5.96, SLICC-DI: 0, PGA: 1.3. We continued belimumab and added mycophenolate mofetil (2 g/day) and this approach was effective. In august 2020 at the time of the 70th belimumab administration she presented mild skin involvement (few little red lesions on left arm), a worsening of Jaccoud’s joint deformities with inflammatory arthralgias and right wrist arthritis, positive anti-dsDNA (96 KUI/L), and leukopenia (WBC 2900 mm3); C3 and C4 within normal range; SLEDAI-2K 5; SLEDAS 8.05; CLASIa 2; DAS28 3.56; SLICC-DI 1 (no new damage). She was on prednisone 5 mg/day, belimumab 640 mg IV every 4 weeks, chloroquine 250 mg/day, MMF 2 g/day. Since she was not at target according to the treat-to-target strategy,1 3 in September 2020 we administered rituximab with a good result and in February 2021 we restarted belimumab.
Gatto M, et al. New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol. 2019 Jan;15(1):30–48. doi: 10.1038/s41584-018-0133-2. Jesus D, et al. Derivation and validation of the SLE disease activity score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity. Ann Rheum Dis. 2019 Mar;78(3):365–371. doi: 10.1136/annrheumdis-2018-214502. Epub 2019 Jan 9. Jesus D, et al. Systemic lupus erythematosus disease activity score (SLE-DAS) enables accurate and user-friendly definitions of clinical remission and categories of disease activity. Ann Rheum Dis. 2021 Dec;80(12):1568–1574. doi: 10.1136/annrheumdis-2021-220363. Epub 2021 Aug 18.
Discuss the different treatment approach in SLE patients with relapsing-remitting or persistent arthritis Discuss how to treat patients with arthritis to the target and how to manage biologic treatment in SLE
In the management of cutaneous lupus erythematosus (CLE), topical calcineurin inhibitors have recently been established as the first-line treatment according to the S2k guidelines for the treatment of CLE.1 2 This recommendation is further supported by the 2019 European League Against Rheumatism (EULAR) recommendations, which state that topical calcineurin inhibitors should be considered as a primary choice for treating cutaneous lesions in patients with systemic lupus erythematosus (SLE).3 A randomized, controlled trial demonstrated tacrolimus 0.1% ointment to be significantly more effective than placebo in treating CLE.4 Additionally, facial lesions showed a better response to tacrolimus ointment 0.1% compared to lesions on the body, particularly when the lesions had been present for less than 6 months. In summary, tacrolimus ointment 0.1% is recommended primarily for treating facial lesions in CLE and can serve as an alternative to topical glucocorticoids. In cases where the disease is widespread and/or there is a risk of scarring, concurrent treatment with antimalarials is recommended.
A 34-year-old female patient diagnosed with SLE presented with confluent erythematous, edematous papules and plaques, known as ’malar rash’, on the left side of her face. She received treatment with antimalarial agents and mycophenolate mofetil; however, over the past month, she had developed skin lesions after sun exposure. After 28 days of treatment with tacrolimus ointment 0.1%, her skin lesions had completely resolved. No recurrence of skin lesions was observed after 84 days of treatment with 0.1% tacrolimus ointment.4
Kuhn A, et al. S2k guideline for treatment of cutaneous lupus erythematosus - guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol. 2017 Mar;31(3):389–404. doi: 10.1111/jdv.14053. Worm M, et al. S2k guideline: Diagnosis and management of cutaneous lupus erythematosus - Part 2: Therapy, risk factors and other special topics. J Dtsch Dermatol Ges. 2021 Sep;19(9):1371–1395. doi: 10.1111/ddg.14491. Fanouriakis A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019 Jun;78(6):736–745. doi: 10.1136/annrheumdis-2019-215089. Kuhn A, et al. Efficacy of tacrolimus 0.1% ointment in cutaneous lupus erythematosus: a multicenter, randomized, double-blind, vehicle-controlled trial. J Am Acad Dermatol. 2011 Jul;65(1):54–64, 64.e1-2. doi: 10.1016/j.jaad.2010.03.037.
Discuss the topical and systemic treatment options in CLE Describe the preventive strategies in CLE Discuss the therapeutic guidelines of CLE Describe the RCLASI as validated activity and damage score of CLE
Skin lesions can be very heterogeneous in systemic lupus erythematosus (SLE). Clinicopathological correlation is crucial to identify the type of cutaneous lesion since it provides prognostic and therapeutic implications. Blistering lesions are rare in lupus erythematosus; however, they can be difficult to characterize and the cutaneous differential diagnosis is wide. The term ‘bullous lupus’ can be confusing since it may even reflect different immune mechanisms that need specific management.
A 42-year-old with a 10-month history of hand arthritis and positivity for antinuclear antibodies (ANA), anti-RNP and anti-Sm, presented with a 2-month history of cutaneous lesions affecting her upper trunk and upper limbs. Vesicle and blisters were observed on the aforementioned sites. She had been treated with non-steroidal anti-inflammatory drugs and short pulses of prednisone that improved partially her skin lesions. The lesions resolved without scarring but leaving hypopigmentation.
Demonstrate the clinical differential diagnosis of blisters in SLE Describe the main immunopathologic findings of blistering eruptions in SLE Explain the main features of bullous systemic lupus erythematosus Discuss the extracutaneous associations of blistering eruptions in SLE Describe the treatment of bullous systemic lupus erythematosus
Hand lesions are relatively common in patients with SLE. Since these lesions are not always biopsied (especially those of the digits) a correct characterization may be lacking. These lesions can appear in patients with or without SLE. The differential diagnosis includes vasculitis, vasculopathy, chilblain lupus and palmoplantar lupus. Although localized, they are usually painful with functional impairment of loss of quality of life. Among them, the most common lesions are chilblain lupus. Response to topical treatment and antimalarials is typically poor. Chilblain lupus may not respond as well to systemic therapy compared to other visceral manifestations of SLE, hence being a treatment challenge both for rheumatologists and dermatologists.
A 40-year-old woman, with an 8-year history of cutaneous lesions in the face and arms (diagnosed of cutaneous lupus erythematosus by biopsy), arthritis and ANA+, treated with hydroxychloroquine and variable doses of prednisone, was admitted in the rheumatology department due to headache and visual loss with bilateral papilledema. Magnetic resonance imaging was normal but the ophthalmological exploration showed inferior branch retinal vein thrombosis in the left eye. The autoimmunity study showed ANA 1/1280 and positivity for anti-dsDNA, anti-RNP and anti-Sm. With the possible diagnosis of SLE-related pseudotumor cerebri, prednisone dose was increased, hydroxychloroquine was maintained and acetazolamide was added, with progressive vision recovery. Two months after discharge, she started to progressively present papulosquamous lesions on the back, neckline, back of the hands and fingertips, the latter being painful.
Describe the differential diagnosis of hand lesions in SLE Understand the prognostic implications of hand lesions in SLE Discuss how cutaneous manifestations may not respond to systemic treatments aimed at controlling active SLE Explain chilblain lupus and its treatment Describe available treatments strictly directed to the cutaneous component of lupus erythematosus
Systemic lupus erythematosus (SLE) is a very complicated and heterogeneous disease, and the popular saying is that no two lupus patients are the same. This of course also means that the treatment and planning of care can be very complicated and needs to be adjusted to the individual patient.
One of the best ways to achieve this goal is through shared decision making. If the patient feels like they have a voice in the treatment plans the probability of treatment adherence increases substantially. On average the SLE patient is more aware of their own symptoms, disease progression and medication than patients with less complicated or less heterogeneous diseases. They need to become experts in their disease because they are the ones living with the symptoms and can often ‘feel’ a flare coming on before the laboratory results show it. Health-related-quality of life (HRQoL) when living with a chronic disease like SLE very much depends on how you self-manage; living a healthy life, keeping active, prioritising everyday tasks according to energy-level etc. The engaged and informed patient can be both a help and a burden when it comes to the physicans disease management. It helps if the patient has the right medical information and respects that the physician has the expertise to decide what is best for them.1 A patient needs to know that not every symptom is because of lupus and that they might not be flaring, even though they feel like they are.
This ‘complicated’ care of an SLE patient often takes more than one health care professional. Apart from a multidisciplinary team of physicians each specialised in their own manifestations (like kidneys, lungs, heart etc.) it is often beneficial to involve other areas such as specialised nurses, physiotherapists, psychologists, occupational therapists etc. This multidisciplinary team of course requires a good coordination, which should not be put exclusively on the patient.
Cornet A, et al. Patients expectations, and what we (can) do about it. Lupus Sci Med.2020;7:doi:10.1136/lupus-2020-eurolupus.7.
Explain the importance of involving patients in shared-decision-making Describe how a multidisciplinary team can be used in the SLE care Describe the role of the informed patient in their own care
Lupus (Latin term for wolf) was used, since the Middle Ages to describe several types of diseases characterized by ulcerous lesions, mainly in the lower limbs. The true turning point in its history occurred at the beginning of the 19th century, with the distinction between lupus vulgaris and cutaneous lupus in its modern sense.1
Today, systemic lupus erythematosus (SLE/lupus) is described as a chronic systemic autoimmune disease of variable severity and course, distinguished by a tendency for flare. It is clinically and serologically, a diverse autoimmune disease that can affect any organ or system of the body and display a wide spectrum of manifestations.2
Evidently, due to the chronic relapsing-remitting nature of SLE,3 a holistic approach, involving a multi-disciplinary team (Physician, Rheumatology/Lupus Nurse Specialist, Physiotherapist etc) is essential to providing high quality care to lupus patients.
The pathway to becoming a Rheumatology/Lupus Nurse Specialist, requires a Registered Nurse undergoing additional specialised education and training, that allows them to provide autonomous advanced care and tasks to meet the patient’s clinical needs (i.e., facilitating screening, initiating, monitoring and reviewing treatment and providing specialty education and timely accessible health advice to patients) in order to ensure effective disease management.4
As early the 1980s, Rheumatology nursing (roles include Rheumatology Clinical Nurse Specialist, Rheumatology Nurse Practitioner), was recognised as a distinct nursing speciality in the UK and USA.5
The Rheumatology Nurse has since remained a significant member of the multi-disciplinary team, in the management of patients with systemic lupus erythematosus.
Felten R, Lipsker D, Sibilia J, et al. The history of lupus throughout the ages. J Am Acad Dermatol 2022;87:1361–9. doi:10.1016/j.jaad.2020.04.150. Hinojosa-Azaola A, Sanchez-Guerrero J : Overview and Clinical Presentation : Dubois’ Lupus Erythematosus and Related Syndromes (Ninth Edition) 2019, Ch 32, Pages 389–394 (Available online 7 November 2018, Version of Record 7 November 2018). Zen M, Iaccarino L, Gatto M, et al. Prolonged remission in Caucasian patients with SLE: prevalence and outcomes. Ann Rheum Dis 2015;74:2117–22. doi:10.1136/annrheumdis-2015-207347. Mounce, K., Ryan, S (2001). The historical development of extended clinical roles in rheumatology. In: Carr, A. (Ed.), Defining the Extended Clinical Role for Allied Health Professionals in rheumatology. Arthritis Research Campaign, Chesterfield, pp. 9–10. American Nurses Association, 1983. Outcome Standards for Rheumatology Nursing Practice. American Nurses Association Publications.
Explain the role of the Rheumatology Nurse Describe the pathway to becoming a Rheumatology Nurse Describe the benefits of a Rheumatology Nurse to the rheumatology/lupus patient
The European Reference Networks (ERNs) were launched by the European Commission in 2017 with the mission to improve quality, safety and access to highly specialised and sustainable healthcare to European patients with rare, low-prevalence and complex diseases.1
ERN ReCONNET is the European Reference Network on Connective Tissue and Musculoskeletal Diseases and covers 10 musculoskeletal and connective tissue diseases (rCTDs): antiphospholipid syndrome (APS), Ehlers-Danlos syndromes (EDS), idiopathic inflammatory myopathies (IIM), IgG4-related diseases (IgG4), mixed connective tissue diseases (MCTD), relapsing polychondritis (RP), Sjögren’s syndrome (SS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and undifferentiated connective tissue diseases (UCTD). ERN ReCONNET currently has 55 Full Members and 9 Affiliated Partners (APs) from over 23 European countries.
ERN ReCONNET can be viewed as an infrastructure where all the stakeholders (health care professionals, patients, families, health care systems, hospital managers, private sectors, etc.) meet and work together to achieve common goals.
One major objective of ReCONNET is to promote a partnership with patients (patients’ advocates – ePAGs). Since 2017 this objective has been pursued by starting to ensure and promote patients’ representation and their active involvement in all the ERN activities. In fact, the ePAG advocates have been involved in different levels of the network’s governance: the Steering Committee, the respective Disease Groups where they collaborate to plan and implement activities, and more recently in the Working Groups (WG) where they act as co-chairs in three WGs. ePAG representatives provide patients’ opinions and input in the different ERN activities, collaborate in the evaluation of the ERN actions, contribute to research, participate to dissemination activities, and ensure that patient’s rights and choices are considered in decision-making.
Thanks to this collaboration, the opinions, needs and priorities of the ePAG advocates and of their communities have been integrated into the activities of ERN ReCONNET. ePAG advocates and patients’ representatives have participated to research activities, co-authored many ReCONNET publications, participated actively as speakers to ERN meetings and in the first ERN ReCONNET congress held in Brussels in 2023, and have disseminated ERN ReCONNET activities at international meetings including EULAR.
All these activities are promoting the culture of an effective and solid patient-clinician partnership and are triggering a cultural change in the healthcare ecosystem at international level.
European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases Website. https://reconnet.ern-net.eu . Accessed July 2023.
Explain the value of ERN ReCONNET’s infrastructure in supporting patients, their families and healthcare professionals in working together to achieve common goals Discuss the value of patient representation and their active involvement in all the ERN activities to ensure patients’ rights and choices are considered in clinical decision making.
The concept of disease modification is well-established in diverse diseases such as rheumatoid arthritis (RA), Alzheimer’s disease, and asthma. In RA, the concept was initially introduced to distinguish the effects of acetylsalicylic acid and non-steroidal anti-inflammatory drugs, which had been shown to ameliorate joint pain but not to prevent erosive damage to the joint structures, from those of a heterogeneous group of medications that were able to accomplish both goals and were henceforth designated ‘disease-modifying antirheumatic drugs (DMARDs)’. While gold compounds were initially the main drugs in this category, methotrexate eventually was established as the main DMARD for RA.
In the other diseases, the concept of disease modification was defined differently, based on the characteristics of that disease. Therefore, it was of interest to investigate the commonalities between these definitions, with a view to develop an evidence- and consensus-based definition of disease modification for treatments in lupus.1
Based on a systematic review of the literature and extensive discussions, an international task force arrived at such a definition, the main ingredients of which are demonstrated efficacy with respect to established disease activity indices, as well as with respect to organ damage outcomes.
The task force believes that establishing a definition of disease modification in systemic lupus erythematosus will help to clarify which treatments can be considered disease modifying. This will help to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes.
van Vollenhoven R, et al. Conceptual framework for defining disease modification in systemic lupus erythematosus: a call for formal criteria. Lupus Sci Med. 2022 Mar;9(1):e000634. doi: 10.1136/lupus-2021-000634.
Explain the concept of disease modification as they are applied to other diseases Discuss the proposed definition of disease modification in SLE Describe the potential utility of a definition of disease modification in SLE
Glucocorticoids (GC) have long been one of the cornerstones of the treatment of systemic lupus erythematosus (SLE). However, it is now a well-established fact that GC are a major cause of irreversible damage.1 Therefore, strategies to decrease GC load without compromising the adequate control of disease activity are essential in the management of SLE.
Hydroxychloroquine (HCQ) should be considered the main GC-sparing drug in lupus. Its continued use has been associated to a myriad of beneficial effects, including the prevention of damage accrual and the improvement of survival, but also to a better control of lupus activity and, thus, a reduced need for GC use. Also, immunosuppressive drugs such as cyclophosphamide, azathioprine and methotrexate, have been extensively used throughout different clinical scenarios in order to decrease GC doses.2 Although clinical trials with this group of drugs are few, their use has long been validated by clinical practice. More recently, biologic agents approved for SLE such as belimumab and anifrolumab have also been shown to allow a good control of disease activity whilst reducing the dose of GCs.3 4
However, it is my view that the best GC-sparing drugs are...GCs. Pulses of methyl-prednisolone (MP), 125–500 mg/d, given for short periods of time (usually 3 days) have been shown to be the most effective way of rapidly controlling lupus flares through the activation of the non-genomic pathway.5 6 Therefore, the use of MP in the induction of remission, not only in life-threatening scenarios, combination therapy with HCQ and immunosuppressive drugs and a rapid tapering with a slow withdrawal of prednisone is our proposal for the successful management of SLE. In cases in which this scheme fails to adequately control lupus activity, the addition of biologic drugs should be considered.
Ugarte-Gil MF, et al. Impact of glucocorticoids on the incidence of lupus-related major organ damage: a systematic literature review and meta-regression analysis of longitudinal observational studies. Lupus Sci Med. 2021 Dec;8(1):e000590. doi: 10.1136/lupus-2021-000590. Pego-Reigosa JM, et al. Efficacy and safety of nonbiologic immunosuppressants in the treatment of nonrenal systemic lupus erythematosus: a systematic review. Arthritis Care Res. (Hoboken). 2013 Nov;65(11):1775–85. doi: 10.1002/acr.22035. Touma Z, et al. Belimumab use, clinical outcomes and glucocorticoid reduction in patients with systemic lupus erythematosus receiving belimumab in clinical practice settings: results from the OBSErve Canada Study. Rheumatol Int. 2017 Jun;37(6):865–873. doi: 10.1007/s00296-017-3682-9. Epub 2017 Mar 9. Bruce IN, et al. Sustained glucocorticoid tapering in the phase 3 trials of anifrolumab: a post hoc analysis of the TULIP-1 and TULIP-2 trials. Rheumatology (Oxford). 2023 Apr 3;62(4):1526–1534. doi: 10.1093/rheumatology/keac491. Ruiz-Irastorza G, et al. Prolonged remission in SLE is possible by using reduced doses of prednisone: an observational study from the lupus-cruces and lupus-bordeaux inception cohorts. Autoimmun Rev. 2019 Sep;18(9):102359. doi: 10.1016/j.autrev.2019.102359. Epub 2019 Jul 16. Ruiz-Irastorza G, Bertsias G. Treating systemic lupus erythematosus in the 21st century: new drugs and new perspectives on old drugs. Rheumatology (Oxford). 2020 Dec 5;59(Suppl5):v69-v81. doi: 10.1093/rheumatology/keaa403.
Describe the concept and the need for sparing GC Describe different drugs used to treat SLE with a GC-sparing effect Discuss results from recent studies on the efficacy and toxicity of therapeutic schemes using methyl-prednisolone pulses followed by lower doses of prednisone in active lupus Describe practical guidelines for using glucocorticoid-sparing drugs in the different settings of active lupus
The treatment of lupus nephritis (LN) in recent decades has relied on combined treatment with corticosteroids and either mycophenolate mofetil (MMF) or intravenous boluses of cyclophosphamide. In recent years the therapeutic possibilities for LN have expanded remarkably, thanks to the completion of several landmark randomised controlled trials (RCT) that have demonstrated the efficacy of new drugs. Drugs that have shown efficacy in the initial treatment of LN include calcineurin inhibitors (CNI). Several small local trials with cyclosporine and tacrolimus showed that these CNI increase the achievement of remission and have a strong antiproteinuric effect. Recently, the AURORA-1 study confirmed that voclosporin, a new CNI, added to corticosteroids and MMF was superior to placebo in obtaining complete remission with a good safety profile.1 Longer-term follow-up of patients suggests that voclosporin does not share the nephrotoxic effect of other CNIs. Belimumab, a drug that blocks BLyS (a stimulator of B lymphocyte proliferation), had shown efficacy in improving different extrarenal manifestations of systemic lupus erythematosus (SLE) and decrease immunological activity. The BLYS-LN study demonstrated that belimumab, added to corticosteroids and MMF, induces a significantly higher number of LN remission than placebo, with a satisfactory safety profile.2 Obinutuzumab, a newer anti-CD20 drug, has also shown encouraging preliminary data as initial therapy for NL. It is important to highlight that all these recent RCT compare triple therapy (corticosteroids plus MMF and the new drug under evaluation) with double therapy (corticosteroids plus MMF and placebo), so the addition of a CNI or belimumab for refractory cases or the use of triple therapy regimens from the onset for patients with high-risk profiles are recommended in recent guidelines.3 Conversely, new renoprotective and cardioprotective drugs, such as SGLT2 inhibitors, are starting to show their importance in the non-immunosuppressive treatment of LN.4 Despite these important successes in improving the initial treatment of LN, more studies are needed to determine the optimal maintenance treatment and criteria to personalize treatment duration in patients who achieve remission.
Rovin BH, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021 May 29;397(10289):2070–2080. doi: 10.1016/S0140-6736(21)00578-X. Epub 2021 May 7. Erratum in: Lancet. 2021 May 29;397(10289):2048. Furie R, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020 Sep 17;383(12):1117–1128. doi: 10.1056/NEJMoa2001180. Rojas-Rivera JE, et al. Consensus document of the Spanish group for the study of the glomerular diseases (GLOSEN) for the diagnosis and treatment of lupus nephritis. Nefrologia (Engl Ed). 2023 Jan-Feb;43(1):6–47. doi: 10.1016/j.nefroe.2023.05.006. Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020 Oct 8;383(15):1436–1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.
Describe studies about the use of calcineurin inhibitors in LN Describe the use of belimumab in LN Discuss the option of triple versus double therapy as initial treatment in LN Discuss different treatment options according to a patients disease profile Discuss newer non-immunosuppressive treatments for renal and cardioprotection in LN
In the 1970s, Hooks et al . at the National Institutes of Health noted the presence of interferon in the blood of approximately 70% of patients with active systemic lupus erythematosus (SLE). They concluded that interferon may play a role in the pathogenesis of SLE.1 Additional evidence linking interferon and SLE emerged in the form of isolated case reports.2 With the introduction of the interferon gene signature in the early 2000s, interferon science evolved to even greater heights.3 4 The burning clinical question was whether the interferon pathway could be inhibited and whether this would impact lupus disease activity. With the success of the anifrolumab development programme, additional strategies to subdue interferon pathway activation were explored.5–7 The plasmacytoid dendritic cell (pDC), a mass producer of type I and III interferons, was a very compelling target. Abundant in the skin as well as other organs in patients with SLE, development programs evolved with litifilimab and daxdilimab. The former monoclonal antibody binds blood cell dendritic antigen 2 (BDCA2), a protein selectively expressed on pDCs.8 BDCA2 ligation results in the suppression of type I and III interferon production as well as other proinflammatory cytokines and chemokines. Building upon the successes of the phase 2 programme,9 10 litifilimab is currently in phase III studies of both SLE and cutaneous lupus. Daxdilimab, a cytolytic antibody that targets Immunoglobulin-like transcript 7 (ILT7), is also in development for the treatment of SLE.11 Strategies to dampen SLE disease activity are incredibly eclectic, and the interferon pathway is no exception. Regardless of which approach rises to the top, the future is bright for our patients with SLE.
Hooks JJ, et al. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med. 1979 Jul 5;301(1):5–8. doi: 10.1056/NEJM197907053010102. Rönnblom LE, et al. Possible induction of systemic lupus erythematosus by interferon-alpha treatment in a patient with a malignant carcinoid tumour. J Intern Med. 1990 Mar;227(3):207–10. doi: 10.1111/j.1365-2796.1990.tb00144.x. Bennett L, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003 Mar 17;197(6):711–23. doi: 10.1084/jem.20021553. Baechler EC, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2610–5. doi: 10.1073/pnas.0337679100. Furie R, et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376–386. doi: 10.1002/art.39962. Furie RA, et al. Trial of anti-BDCA2 antibody litifilimab for systemic lupus erythematosus. N Engl J Med. 2022 Sep 8;387(10):894–904. doi: 10.1056/NEJMoa2118025. Furie RA, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019, 1(4), e208–e219. Morand EF, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020 Jan 16;382(3):211–221. doi: 10.1056/NEJMoa1912196. Pellerin A, et al. Anti-BDCA2 monoclonal antibody inhibits plasmacytoid dendritic cell activation through Fc-dependent and Fc-independent mechanisms. EMBO Mol Med. 2015 Apr;7(4):464–76. doi: 10.15252/emmm.201404719. Werth VP, et al. Trial of anti-BDCA2 antibody litifilimab for cutaneous lupus erythematosus. N Engl J Med. 2022 Jul 28;387(4):321–331. doi: 10.1056/NEJMoa2118024. Karnell JL, et al. Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus. Sci Transl Med. 2021 May 26;13(595):eabf8442. doi: 10.1126/scitranslmed.abf8442.
Discuss the role of interferons in the pathogenesis of SLE Describe strategies to inhibit interferons with a particular emphasis on plasmacytoid dendritic cells Analyze litifilimab and daxdilimab SLE clinical trial data
Cellular immunotherapy (particularly chimeric antigen receptor (CAR) T-cell therapy) has become a consolidated therapeutic reality in hematologic neoplastic diseases, but it is mainly seen as having a promising future. Considered advanced therapy medicinal products, their development has so far originated from proposals made by academic centers and later gaining market authorization by large pharmaceutical companies, which are defining the distribution and implementation of these products in patients from whom the T cells are obtained and subsequently incorporated with the chimeric antigen receptor. This unidirectional model of academic development and industrial implementation has clear advantages but also evident drawbacks.
At the Hospital Clíic of Barcelona, we have developed a second-generation CAR-T (with 4-1BB as a co-stimulatory motif) targeting CD19 (ARI0001 or varnimcabtagene autoleucel), which is fully publicly funded and has received authorization for use under the hospital exemption regulation. It is the first academic and European CAR-T approved worldwide for acute lymphoblastic leukemia B and is currently undergoing evaluation under the Priority Medicines (PRIME) designation by the European Medicines Agency (EMA), trying to obtain centralized marketing authorization. Alongside ARI0001, we are also close to obtaining ‘hospital exemption’ for ARI0002h (cesnicabtagene autoleucel), an anti-BCMA CAR-T for multiple myeloma. Obviously, all these academic products meet the same quality requirements as commercial products and must also demonstrate effectiveness within the ranges of commercial products in clinical trials for approval. Possibly, with these Barcelona products, we are paving the way to enable academic production to provide treatment options in cases where pharmaceutical companies are not interested in developing these products (such as rare diseases like pediatric tumors or even autoimmune diseases to low frequent autoantigens). Beyond cancer, other immune-mediated diseases (such as autoimmune disorders and systemic lupus erythematosus) are probably the next challenges for CAR-T immunotherapies.
]]>Systemic lupus erythematosus (SLE) is a heterogeneous disease characterised by abnormalities in cellular and humoral immunity. There is evidence that abnormalities of B lineage cells (B and plasma cells) and imprints of type I interferon are key drivers in this disease. However, these findings are not found uniquely in each SLE patient which has implications for translational research: Delineation of molecular SLE endotypes have been identified that may allow better prediction of treatment response. Recent discoveries of gain-of-function mutations in toll-like TLR7 signalling in certain patients suffering from monogenetic SLE indicate the role of this pathway as potential treatment target.1 Targeting enhanced cytokine signalling, in particular Jak/STAT continuous to be of interest as recent data of upadacitinib2 and deucravacitinib.3 were promising, although development of baricitinib4 5 has not been continued.
Clinical experiences with belimumab provide evidence that indirectly blocking B cell survival can change the clinical course of the disease, including prevention of damage accrual. Advanced B cell targeting following the concepts of deeper tissue depletion overcoming the status of anergic B cells6 and co-targeting plasma cells has been studied recently. These include more profound targeting by second generation anti-CD20 modalities (obinutuzumab),7 CD19-CART8 or employing other immune targets, such as CD38 (daratumumab),9 BAFFR (ianalumab)10 or the use of immune proteasome inhibition (zetomipzomib).11 As more defined immune abnormalities in SLE may be identified as targets for treatment, use of bispecific antibodies12 may hold promise to improve selective immune therapy with at least similar or even better efficacy/safety compared to current strategies.
Brown GJ, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature. 2022 May;605(7909):349–356. doi: 10.1038/s41586-022-04642-z. Epub 2022 Apr 27. Merrill JT, et al. Efficacy and safety of ABBV-599 high dose (elsubrutinib 60 mg and upadacitinib 30 mg) and upadacitinib monotherapy for the treatment of systemic lupus erythematosus: a phase 2, double-blind, placebo-controlled trial. Ann Rheum Dis. 2023;82:91–92. OP0139. Morand E, et al. Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: a phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2023 Feb;75(2):242–252. doi: 10.1002/art.42391. Epub 2022 Nov 11. Petri M, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II). Lancet. 2023 Mar 25;401(10381):1011–1019. doi: 10.1016/S0140-6736(22)02546-6. Epub 2023 Feb 24 Morand EF, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I). Lancet. 2023 Mar 25;401(10381):1001–1010. doi: 10.1016/S0140-6736(22)02607-1. Epub 2023 Feb 24. Weißenberg SY, et al. Identification and characterization of post-activated B cells in systemic autoimmune diseases. Front Immunol. 2019 Sep 24;10:2136. doi: 10.3389/fimmu.2019.02136. Furie RA, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022 Jan;81(1):100–107. doi: 10.1136/annrheumdis-2021-220920. Epub 2021 Oct 6. Mackensen A, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124–2132. doi: 10.1038/s41591-022-02017-5. Epub 2022 Sep 15. Erratum in: Nat Med. 2022 Nov 3. Ostendorf L, et al. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. N Engl J Med. 2020 Sep 17;383(12):1149–1155. doi: 10.1056/NEJMoa2023325. Cortés-Hernández J, et al. Safety and efficacy of subcutaneous (S.C.) dose ianalumab (VAY736; anti-BAFFR mAb) administered monthly over 28 weeks in patients with systemic lupus erythematosus (SLE). Ann Rheum Dis. 2023;82:275–276. POS0120. Saxena A, et al. Zetomipzomib (KZR-616) treatment results in clinically meaningful renal responses in patients with lupus nephritis. Ann Rheum Dis; 2023;82:891–892. POS1128. Dang VD, et al. B- and plasma cell subsets in autoimmune diseases: translational perspectives. J Invest Dermatol. 2022 Mar;142(3 Pt B):811–822. doi: 10.1016/j.jid.2021.05.038. Epub 2021 Dec 24.
Discuss the translational concepts of the SLE key signatures: type I IFN (convergence of various activated pathways) and B lineage abnormalities (plasmablasts including CD19-CXCR5- pre-plasmablasts, anergic B cells) Explain the impact of targeting type IFN abnormalities by blocking Jak/STAT and TL/signaling Discuss new concepts with deeper depletion of tissue-resident B cells and partial targeting of bone marrow plasma cells Develop the concept that bispecific antibodies may have value in treating SLE
Patients with autoimmune encephalitis can present with a variety of neurological symptoms such as short-term memory loss, behavioral changes, abnormal movements, seizures or focal deficits.1 2 These complex and severe disorders have become increasingly recognized in the past 15 years, thanks to the discovery and characterization of neural autoantibodies that cause autoimmune encephalitis.3 They can affect people of all ages and the clinical progression is acute or subacute, from days to weeks, in contrast to neurodegenerative disorders. Evaluation for infectious or other alternative conditions is of high clinical relevance as a first approach. Cerebrospinal fluid studies, magnetic resonance imaging and appropriate detection of neural antibodies have a key role in the diagnosis and management of patients with autoimmune encephalitis.4 5 A rapid identification is crucial, as these diseases are treatable. Neural antibodies associate with specific clinical syndromes, different comorbidities (such as tumours), and show different responses to immunotherapy and prognosis. These novel antibody-mediated syndromes have changed dramatically the field of neurology, with impact in other disciplines such as pediatrics, psychiatry, or infectious diseases.
Graus F, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016 Apr;15(4):391–404. doi: 10.1016/S1474-4422(15)00401-9. Epub 2016 Feb 20. Armangue T, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018 Sep;17(9):760–772. doi: 10.1016/S1474-4422(18)30244-8. Epub 2018 Jul 23. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med. 2018 Mar 1;378(9):840–851. doi: 10.1056/NEJMra1708712. Venkatesan A, et al. Acute encephalitis in immunocompetent adults. Lancet. 2019 Feb 16;393(10172):702–716. doi: 10.1016/S0140-6736(18)32526-1. Epub 2019 Feb 14. Armangue T, et al. Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study. Lancet Neurol. 2020 Mar;19(3):234–246. doi: 10.1016/S1474-4422(19)30488-0. Epub 2020 Feb 10. Erratum in: Lancet Neurol. 2020 Apr;19(4):e4.
Describe the general clinical features of autoimmune encephalitis and the diagnostic and therapeutic approach Explain the difference between cell-surface and intracellular neural antibodies and their implications Discuss the role of potential triggers of paraneoplastic and post-infectious syndromes
Interstitial lung diseases (ILD) encompass a broad group of more than 200 parenchymal pulmonary disorders in which the lung tissue is comprised. Connective tissue disease related ILD comprise almost 20% of all ILD, rheumatoid arthritis and systemic sclerosis (SSc) making up the largest proportion of CTD-ILD.1 Some CTD-ILD may have an acute course, such as anti-MDA5 positive rapidly progressive amyopathic dermatomyositis related ILD, others may have a chronic course. CTD-ILD are frequently progressive bringing along an as dismal disease course as idiopathic pulmonary fibrosis. Several challenges are related to CTD-ILD. One of the challenges concerning is firstly to think of them. The second challenge is to screen for them. The third challenge is the optimal management. In this way only for SSc related ILD we have generally adopted screening/monitoring strategies as well as several randomised controlled trials to evaluate the efficacy of immune suppressive and antifibrotic drugs.2 Multidisciplinary approach in diagnosis and management of CTD-ILD is paramount.
Wijsenbeek M, et al. Interstitial lung diseases. Lancet. 2022 Sep 3;400(10354):769–786. doi: 10.1016/S0140-6736(22)01052-2. Epub 2022 Aug 11. Volkmann ER, et al. Systemic sclerosis. Lancet. 2023 Jan 28;401(10373):304–318. doi: 10.1016/S0140-6736(22)01692-0. Epub 2022 Nov 25.
Capillary leak syndrome (CLS) is a rare, life-threatening disorder characterized by recurrent episodes of fluid leaking from the blood vessels into the surrounding tissues, hypotension, oedema, haemoconcentration and hypoalbuminemia.1 CLS can be idiopathic (Clarkson’s disease) or secondary to various conditions and treatments.1 Secondary CLS typically results from, systemic autoimmune disorders, viral infections, malignant haematological diseases and treatments such as chemotherapies and therapeutic growth factors.1 Diagnosis of idiopathic CLS is made by exclusion of secondary diseases, especially as a serum monoclonal immunoglobulin is present, or when there is a relapsing disease, no initial lung involvement or preserved consciousness despite low blood pressure.1 Prophylactic treatment of Clarkson’s disease with intravenous immunoglobulin may reduce the frequency and severity of attacks and may improve survival.
Duron L, et al. Syndrome de fuite capillaire idiopathique et formes secondaires : une revue systématique de la littérature [Idiopathic and secondary capillary leak syndromes: A systematic review of the literature]. Rev Med Interne. 2015 Jun;36(6):386–94.
Describe the clinical presentation of systemic CLS, including symptoms, signs, and complications Discuss the diagnosis of systemic CLS, including diagnostic tests and criteria. Discuss treatment options for systemic CLS, including both acute and chronic management
Demographic factors such as sex, socioeconomic position and migration status may be associated with poor health care outcomes. Measures implemented by health care providers aiming to reduce these disparities are not always successful. The present study provides empirical insights from Germany focusing on patients with systemic connective tissue disorders and illustrates the need for evaluated diversity-sensitive measures.
The analysis is based on a 10% random sample of routine data on completed rehabilitative treatments among patients with systemic connective tissue disorders (ICD-10 M30-M36) in Germany during 2006–2016 (n=1.819). Of these, 2.6% had polyarteritis nodosa and related conditions (M30), 10.4% had other necrotizing vasculopathies (M31), 19.0% had systemic lupus erythematosus (M32), 6.0% had dermatopolymyositis (M33), 10.4% had systemic sclerosis (M34) and 51.0% had other systemic involvement of connective tissue (M35). The outcome of interest was the persistence of impairment after treatment. It was compared between sex, nationality and occupational/employment groups used as SES measures. Logistic regression was applied to adjust for other demographic confounders. Differences in disparities over time and diagnostic groups were examined by means of interaction analysis.
As compared to German nationals, non-Germans had a 81% higher chance of impairment despite treatment (adjusted odds ratio [aOR]=1.81; 95%-CI=1.17–2.78) (
The study illustrates disparities in health care outcomes associated with different diversity characteristics, which likely result from different obstacles some disadvantaged population groups encounter in the health system. This heterogeneity must be taken into account through strategies of diversity-sensitive health care provision.
Results of the multivariable logistic regression model with persistence of mental and physical impairment after rehabilitation as the dependent variable. Adjusted odds ratios (aOR) and 95% confidence intervals [95%-CI] (10% random sample of patients with systemic connective tissue disorders who completed medical rehabilitation in the years 2006–2008, 2010–2014 and 2016 granted by the German Statutory Pension Insurance Scheme; n=1.819). Main effects model. No interaction effects included
The current commonly used definitions of flare may not be able to capture patients with a persistently active disease (PAD) course. This study sought to identity the frequency and determinants of flare and PAD in an Asia-Pacific cohort.
Data from Asia-Pacific SLE patients collected between 2013 and 2020 were included. Flare was assessed using the SELENA-SLEDAI flare index (SFI) and PAD was defined as a SLEDAI-2K score of >4, excluding serology, on >2 consecutive visits. Data from 2013 to 2015 were used to model flare and PAD in 2016 through logistic regression and model properties were tested for prediction of flare and PAD in 2020 using the data from 2017 to 2019.
During median 2.5 (1.0–5.1) years, 53.1% (2180/4106) of patients experienced at least one episode of flare (flare incidence 0.49 per patient-year). 1786 (43.5%) patients experienced PAD including 368 patients (9.0%) who did not achieve the definition of flare. In the predictive model for flare, being from a country with GDP<$20,000, current smoking, prior mucocutaneous involvement, arthritis, nephritis and low complements were risk factors, and achieving low disease activity state (LLDAS) for ≥50% of follow-up time during the previous three years was a protective factor. Prior nephritis and higher time-adjusted SLEDAI score in the previous three years were predictors for subsequent PAD while spending ≥50% of follow-up time in LLDAS during the previous three years was protectively associated with PAD (
Both flare and PAD were common disease activity patterns in SLE, with 9% of patients having PAD that was not captured by the SFI definition. Our predictive models may help identify patients at high risk of flare or PAD and enable targeted interventions to achieve better outcomes.
Multivariate logistic regression analysis for the predictors of flare and persistently active disease (PAD) in 2016 from the data of 2013–2015
There is an urgent need to identify novel biomarkers for lupus nephritis (LN) in disease diagnosis, assessment, monitoring, and prognosis prediction. Here, we report a new non-invasive urinary biomarker, L-selectin, in two independent multiple-ethnicity SLE cohorts from three centers.
Urinary L-selectin (uL-selectin) was tested cross-sectionally in a Chinese-based cohort (n=255) and a US-based cohort (n=223) of SLE patients and controls using ELISA. A longitudinal cohort includes eighteen active Chinese LN patients who were followed up for a minimum of 6 months.
In the Chinese cross-sectional cohort, uL-selectin was significantly increased in active lupus nephritis (aLN) patients compared with active non-renal SLE patients (aNR), inactive LN patients (iLN), inactive non-renal SLE patients, chronic kidney disease (CKD) patients, and healthy controls (HC) (all p < 0.0001) (
uL-selectin is a novel biomarker of clinical disease activity and renal histopathology in LN across multiple ethnicities. It also reflects treatment response in LN patients during follow up.
Comparison of uL-selectin levels among subject subgroups in Asian (all were Chinese) (A), non-Hispanic Caucasian (B), non-Hispanic African American (C) and Hispanic (D) subjects. uL-selectin in LN patients correlated with AI (E) and CI (F) by Spearman correlation analysis in Chinese subjects. (G) Correlation matrix for comparison of uL-selectin and conventional metrics (serum C3, C4, anti-dsDNA and 24h proteinuria) with renal pathology AI, CI and their component attributes. Urinary L-selectin levels were compared in active LN patients at the endpoints of follow up and those at baseline in the remission group (CRR+PRR) (H) and the non-remission group (NR) (I, J) The forest plot summarizes results from univariate and multivariate logistic regression analysis for high renal pathology CI (CI>3)
Demographic and clinical characteristics of study subjects from the Chinese cohort (n=255)
A decline of urine protein-to-creatinine ratio (UPCR) to < 0.5 is associated with better long-term preservation of kidney function in lupus nephritis (LN). UPCR < 0.5 defines complete response in guidelines and clinical trials when achieved after 1 or 2 years. Biomarkers of early response are needed to guide early treatment changes. We studied longitudinal urine proteomic profiles in LN to identify early predictors of proteinuric response.
We quantified 1200 biomarkers (Kiloplex, RayBiotech) in urine samples collected on the day of (73%) or within 3 weeks (27%) of kidney biopsy and week 12, 24, or 52 in LN patients (ISN class III, IV, V, or mixed) with proteinuria > 1 g/d. Response was defined at one year from renal biopsy: Complete = UPCR < 0.5, serum creatinine (sCr) < 125% of baseline, prednisone ≤ 10mg/d; Partial = UPCR < 50% from baseline but >0.5, sCr < 125% of baseline, but prednisone allowed to 15 mg/d; Non responder = not meeting previous definitions.
A total of 127 patients were included: 48 (38%) with pure proliferative LN (class III or IV), 41 (32%) with mixed LN (III or IV +/- V), and 38% (30%) with pure membranous LN. Response was complete in 34 (27%), partial in 29 (23%), and none in 64 (50%). There were no urinary biomarkers at baseline that predicted response. We then analyzed the changes in urinary proteins at 3 months compared to baseline. Patients who responded at 1 year showed an early decline in 51 urinary proteins led by CD163, IL-16, and CD206 (macrophage mannose receptor) (
An early decline in urinary biomarkers of histological activity is associated with proteinuric response at 1 year. These findings indicate that effective immunosuppression induces by three months an immunological response in the kidney that can be noninvasively monitored in the urine. Biomarkers of immunological response outperformed early decline of UPCR, the standard of care, in predicting 1-year proteinuric response, especially in proliferative LN. Because biomarkers of immunological response parallel intrarenal activity, they could detect early treatment response/failure and allow early treatment changes. They could serve as surrogate endpoints in clinical trials. Longitudinal studies are needed to confirm that this immunological response is a better predictor of long-term kidney function preservation than proteinuric responses.
(A) Volcano plot of the changes of the urinary proteomic profile of treatment responders at 3 months after kidney biopsy compared to time of biopsy. (B) Correlation of urinary biomarkers at time of biopsy the NIH Activity Index. (C) Area under the curve (AUC) of the 1yr response prediction of the change of a biomarker at 3 months. (D) ROC curves comparing the performance of 3-months biomarker decline. FDR, false discovery rate. q, adjusted p value, UPCR, urine protein-to-creatinine ratio
Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator with a role in B cell development. We have previously demonstrated increased EZH2 expression in peripheral blood mononuclear cells isolated from lupus patients, and that pharmacological inhibition of EZH2 alleviates lupus-like disease in mouse models. The goal of this study was to evaluate the role of B cell EZH2 overexpression in lupus pathogenesis.
Using CRISPR/Cas9 technology, we generated an MRL/lpr mouse with floxed Ezh2, which was crossed with CD19-Cre mice. Autoantibody production, proteinuria, and kidney histology were evaluated. Flow cytometry, single cell RNA sequencing, and single cell B cell receptor sequencing were used to investigate compositional and functional changes of B cell subsets. In vitro B cell culture with/without an XBP1 inhibitor was performed. EZH2 and XBP1 mRNA levels in CD19+ B cells isolated from SLE patients and healthy controls were analyzed.
Ezh2 deletion in B cells decreased autoantibody production and improved glomerulonephritis in MRL/lpr mice. B cell development and differentiation were altered in the bone marrow and spleen in EZH2-deficient mice. Differentiation of germinal center (GC) B cells and plasmablasts was impaired. XBP1, a key transcription factor in B cell development, was downregulated in the absence of EZH2, and inhibiting XBP1 in vitro impairs plasmablast differentiation similar to EZH2-deficient mice. Single cell B cell receptor RNA sequencing revealed defective immunoglobulin class switch recombination in EZH2-deficient mice. In human lupus B cells, there was a strong correlation between EZH2 and XBP1 mRNA expression levels.
Our results suggest that EZH2 overexpression in B cells contributes to disease pathogenesis in lupus. EZH2 enhances GC B cell development and the differentiation of plasmablasts via upregulating XBP1. Inhibiting B cell EZH2 expression impairs B cell development and immunoglobulin class switch recombination, and might provide a novel therapeutic approach in lupus.
Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis.1 2 In a phase 2 trial in SLE patients on background standard therapy, deucravacitinib demonstrated efficacy vs placebo across multiple endpoints, including SRI(4) at week 32 (primary endpoint) and at week 48 (secondary endpoint), as well as BICLA at week 48 (secondary endpoint).3 This post-hoc analysis further evaluated efficacy and time to response with deucravacitinib vs placebo in these responses in the phase 2 trial.
This 48-week, double-blind trial (NCT03252587) randomized 363 patients with active SLE 1:1:1:1 to placebo or deucravacitinib 3 mg BID, 6 mg BID, or 12 mg QD. Endpoints included the proportions of patients achieving SRI(4), BICLA, and simultaneous (dual) SRI(4)/BICLA responses at weeks 32 and 48, proportions of patients with sustained responses through week 48 (responder at every visit from week 32 through week 48), and time to onset of responses. BICLA response, and therefore dual response, were measurable at the first visit after steroid taper completion (week 24 [day 168]). Analyses were descriptive.
At weeks 32 and 48, SRI(4), BICLA, and dual response rates were numerically higher with deucravacitinib vs placebo (
Deucravacitinib treatment elicited higher and faster SRI(4), BICLA, and dual responses compared with placebo. Patients were more likely to sustain their treatment responses from weeks 32 through 48 with deucravacitinib treatment vs placebo. These data support the robust efficacy of deucravacitinib across multiple SLE response indices.
SRI(4), BICLA, and dual responses at weeks 32 and 48
SRI(4), BICLA, and dual SRI(4)/BICLA: responses at week 32, sustained responses, and time to responses
Armstrong A, et al. J Am Acad Dermatol. 2023;88(1):29–39. Strober B, et al. J Am Acad Dermatol. 2023;88(1):40–51. Morand E, et al. Arthritis Rheumatol. 2022; Nov 11 (Epub ahead of print).
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by aberrant lymphocyte activation and autoantibodies. Formation and tissue deposition of immune complexes lead to auto-inflammatory reactions and release of further autoantigens, fueling a perpetual autoimmune process, ultimately leading to organ damage and tissue destruction.1 Cenerimod, a highly selective S1P1 receptor modulator with a biased signaling, has the potential to target SLE pathogenesis due to its multifaceted immunomodulatory effects on lymphocytes, inflammation, and autoantigen transport.
The impact of cenerimod on leukocyte distribution, autoantibody titers, inflammation, and antigen transport was assessed in a murine model of SLE and Sjögren’s Syndrome (MRL/lpr mice), in a proof-of-mechanism murine model for antigen transportation, and in two phase 2 clinical studies (NCT02472795 and NCT03742037), using flow cytometry, ELISA, and histology.
In MRL/lpr mice, therapeutic treatment with cenerimod significantly decreased tissue-infiltrating lymphocytes, autoantibodies, and inflammation, resulting in reduced kidney histopathological score, improved organ function, and increased survival.2 3 Furthermore, antigen transportation to draining lymph nodes was reduced. In a 12-week phase 2a clinical trial, treatment with cenerimod resulted in reduction of circulating T and B lymphocytes, antibody-secreting cells, autoantibodies, and IFN-α.2 4 These results were confirmed in a 12-month phase 2b clinical trial.5 which additionally showed that cenerimod 4 mg reduced pro-inflammatory cytokines and improved clinical disease activity (measured by SLEDAI-2K score modified to exclude leukopenia [mSLEDAI-2K] and SRI-4). Cenerimod is therefore hypothesized to act on three key aspects of SLE pathogenesis: autoreactive lymphocytes, general inflammation, and continuous autoimmune priming with new autoantigens (
Preclinical and clinical evidence suggests that cenerimod is a promising immunomodulatory drug candidate targeting several aspects of SLE pathogenesis. The ongoing confirmatory Phase 3 program OPUS (NCT05648500, NCT05672576) will further evaluate the safety and efficacy of 4 mg cenerimod in adults with SLE.
Cenerimod treatment targets three key interconnected aspects of SLE pathogenesis by S1P1receptor modulation
Kaul A, et al. Systemic lupus erythematosus. Nat Rev Dis Primers 2016;2:16039. Strasser DS, et al. Preclinical to clinical translation of cenerimod, a novel S1P1 receptor modulator, in systemic lupus erythematosus. RMD Open 2020;6(2):e001261. Gerossier E, et al. Cenerimod, a selective S1P1 receptor modulator, improves organ-specific disease outcomes in animal models of Sjögren’s syndrome. Arthritis Res Ther 2021;23(1):289. Hermann V, et al. First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomized, placebo-controlled, proof-of-concept study. Lupus Sci Med 2019;6(1):e000354. Askanase A, et al. Efficacy and safety of cenerimod in patients with moderate to severe systemic lupus erythematosus (SLE): a multicenter, randomized, parallel-group, double-blind, placebo-controlled, dose-finding phase 2b trial. Arthritis Rheumatol 2022;74(suppl 9):3293–7.
Zetomipzomib is a first-in-class selective inhibitor of the immunoproteasome that offers anti-inflammatory properties without significant immunosuppression.1 2
The MISSION study is a Phase 1b/2, open-label study to evaluate safety, tolerability, and exploratory efficacy of zetomipzomib in patients with active systemic lupus erythematosus (SLE) ± lupus nephritis (LN). The Phase 1b portion included multiple dose escalation cohorts to evaluate the safety and tolerability of zetomipzomib in patients with SLE ± LN. The Phase 2 portion studied patients with active LN (Class III/IV ± V) to assess the efficacy and safety of zetomipzomib. Study schematics and endpoints are detailed in
In the Phase 1b portion (47 patients enrolled, 35 patients completed study), zetomipzomib demonstrated a favorable safety/tolerability profile and resulted in improvement across multiple exploratory disease activity measures (
In the MISSION study, treatment with zetomipzomib in SLE/LN patients reduced proteinuria and improved biomarkers of disease activity, with lowered glucocorticoid dosing and without serious/opportunistic infections. Zetomipzomib has the potential to be a steroid-sparing immunomodulatory therapy for patients with SLE/LN.
MISSION Phase 1b/2 open-label study schematics and endpoints
Select exploratory efficacy outcomes in the MISSION study
Kisselev AF, Groettrup M. Curr Opin Chem Bio. 2014;23(16–22). Parikh et al. 2022 ASN Kidney Week. Furie et al. 2021 EULAR Virtual Congress.
Evidences suggest mesenchymal stem cells (MSC)-derived secretome (secretome) exert anti-inflammatory properties and could be used for the treatment of autoinflammatory diseases. This study aimed to investigate the efficacy of secretome on murine and human systemic lupus erythematosus (SLE).
Fifty-two NZB/W F1 mice were randomly assigned into 4 groups (untreated, methylprednisolone, MSC, and secretome (n=13 for each group). The amount of proteinuria and histological damages, as well as renal deposition of immune-complexes was assessed. Serum cytokines and anti-dsDNA levels were determined by ELISA. Helper T (Th) cell, dendritic cell, macrophage, and plasma cell markers were analyzed using flow cytometry. CD4+ T cells from SLE patients were cultured with secretome to identify the effect of secretome ex vivo.
Mice treated with methylprednisolone, MSC, and secretome exhibited diminished proteinuria, improved renal injury, and reduced renal deposition of immune-complexes compared to untreated mice. Regarding Th cell subsets, the proportion of Th1 and Th2 cells decreased and regulatory T cells (Tregs) increased in splenocytes from secretome treated mice. In addition, expression of mature dendritic cells and plasma cells in splenocytes, as well as M1 macrophages in the peritoneum decreased following secretome treatment. Secretome treatment resulted in a decrease of serum cytokines of interferon-, interleukin (IL)-17A, and anti-dsDNA, whereas IL-10 level was increased. No toxic effect of secretome was shown in mice. Treatment of CD4+ T cells isolated from SLE patients with secretome induced an increase of Tregs.
Our results suggest secretome could be a promising therapeutic agent for SLE.
Systemic lupus erythematosus (SLE) has been well known to be associated with B cell hyperactivation with overexpression of B cell-activating factor of the TNF family (BAFF). Belimumab (anti-BAFF therapy) was approved as the first targeted biological drug for SLE. We investigated dynamic feature of immune cells over the Belimumab treatment using longitudinal single-cell transcriptome data.
We conducted single-cell RNA sequencing (scRNA-seq) along with T cell receptor (TCR) and B cell receptor (BCR) repertoire from serial longitudinal PBMC samples (0, 2 weeks, 1, 3, 6 and 12 months after Belimumab) from four Korean patients with SLE.
We profiled more than 130,000 PBMC from the four patients at six distinct time points during Belimumab treatment. The mean SELENA-SLEDAI score from the patients decreased from 12.5 at baseline to 3.5 at 12 months. We observed the dynamic changes of several B cell components during Belimumab treatment; decrease of naïve B cells at one month followed by progressive decline in plasmablasts at six months (
We identified dynamic changes of immune cell components along with transcriptomic signatures during Belimumab treatment, suggesting that therapeutic effects of Belimumab occurs through its effect on T cell lineage as well as its effect on B cell lineage.
Dynamics of circulating immune cells in SLE patients after anti-BAFF treatment. (A) UMAP visualization of 26 cell types. (B) UMAP visualization of T cells. (C) UMAP visualization of B cells. (D) Bar graph comparing the frequency of B cell subtypes at different timepoints. (E) Bar graph comparing the frequency of T cell subtypes at different timepoints. (F) IFN- related genes compared by CD4+ T cell subtypes
Lupus nephritis (LN) is characterized by glomerular and tubulointerstitial (TI) inflammation that presumably must resolve with treatment to achieve remission. Here we sought to document the trajectory of histologic resolution using protocol kidney biopsies during LN treatment.
A cohort (n=110) of proliferative LN patients was prospectively followed during treatment with standard (glucocorticoids plus MMF or cyclophosphamide) therapy. Patients underwent a diagnostic kidney biopsy (Bx1), a biopsy within the first treatment year (Bx2, 9.7 months), and a biopsy after ≥3 years of total immunosuppression (Bx3, 42.6 months). At each biopsy NIH activity and chronicity indices (AI, CI) were calculated.
Patients were followed for a median of 109 months. Treatment was successful. At last follow-up only 2 patients had ESKD and only 5 developed new CKD (eGFR <60 ml/min/1.73m²). AI decline was biphasic, rapidly falling immediately after starting treatment and then slowing (
The most inflammatory LN lesions respond rapidly to conventional immunosuppression, but EH and HD are more resistant. Complement deposition resolves quickly, but IgG can persist in glomeruli for years. Despite rapid improvement in inflammation, chronic damage accumulates early
The change in the activity index/chronicity index (A), and prevalence of activity index (B) and chronicity index (C) histologic components over time during successful treatment of lupus nephritis
Systemic lupus erythematosus (SLE) is an inflammatory disease with complex genetic underpinnings. SLE association at 2p22.3 is one of the most consistently replicated SLE signals. We reported [Sun et al. 2016, Nat Genet] that multiple intronic variants near RasGrp3 (RAS Guanyl Releasing Protein 3) could explain this genetic signal in Asians. However, the underlying causal variant and molecular mechanisms for increasing SLE susceptibility are largely unknown.
First, we used in silico bioinformatics to prioritize the potential regulatory candidate variants. Next, we applied a combination of molecular biology experiments to assess the allele-specific regulatory potential of the candidate variants in B-cell lines. Finally, we validated the effector gene function by CRISPR-based genome editing.
Comprehensive bioinformatics predicted that rs1338573, located in an active chromatin region, is a strong eQTL, and it has the potential to be a dual enhancer/promoter. Luciferase assays demonstrated significant (p<0.005) allele-specific enhancer and promoter activities with the risk allele (T) at rs13385731. DNA pulldown and EMSA suggested allele-specific bound protein ~100 kDa, which was identified as PARP1 protein by Mass Spectrometry and later confirmed by Super-shift and Western blot. We also verified the differential allele-specific binding to H3K27Ac, H3K3Me1, P300, PARP1, and IRF1 against rs13385731 using ChIP-qPCR (
Taken together, our data suggest that over-expression of RasGRP3 could dysregulate the ERK signaling pathway that might be associated with increased SLE risk. We provide mechanistic insights into how a non-coding functional variant, rs13385731, increases underlying SLE risk at the 2p22.3 locus.
The significant allelic effect at rs13385731 and enhancer effect on RasGrp3 expression level. (A) ChIP-qPCR assays for determining allele-specific DNA-protein interactions with H3K27ac, H3K4me1, H3K4me3, p300, and poly(ADP-ribose) polymerase 1 (PARP-1) at R and NR homozygous cell lines. (B) Levels of RasGrp3 mRNA expression between WT and KO cells, based on 3 biological replicates. ** p<0.005, * p<0.05
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease and its heterogeneity means that many cohorts and clinical trials do not collect the same data, making comparative studies difficult. We aimed to ascertain what data is commonly collected in SLE registries/trials. Our ultimate goal is to generate a core minimal dataset for future SLE studies.
We designed and distributed a questionnaire to members of the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) as well as additional research active centres in China. Our survey included 26 questions about the types of data that are routinely collected for research. Data collected by ≥ 75% of participating centres was used as a threshold for concordance.
Eighteen centres; eight from USA/Canada, five from China and five from Europe responded.
An initial set of commonly collected data was identified. This forms the basis to start to consider a core minimum dataset for SLE. Development and further refinement of this dataset is needed, as will common definitions of each data field to allow widespread use.
Data that ≥ 75% centres collected
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease that leads to significant worsening of quality of life and mortality. The enormous molecular heterogeneity of SLE is reflected in different clinical manifestations, disease progression and also in a different drug efficacy across patients.1Lupus nephritis (LN) is the most severe SLE manifestation with the potential of rapidly evolving into irreversible chronic kidney disease. Mycophenolate mofetil (MMF) is the most widely used first-line treatment for LN, being ineffective in 15–30 percent of the patients.2 Reasons for non-response are still unknown and low or moderate drug efficacy may lead to aggravation of the disease. The development of new, more effective therapies to treat LN is an urgent unmet need.3 The objective of this work is to define the cellular and molecular immune landscape behind non-response to MMF to finally apply this knowledge within routine clinical practice.
A longitudinal cohort comprising gene-expression and clinical data of 97 MMF responder and 28 non-responder samples was retrospectively analyzed (
A robust signature comprising 41 differentially expressed genes defined non-response to MMF and cellular profiles that favor the response to the drug in the patients were revealed (
Blood cell subtypes and genes mediating non-response to MMF were revealed, opening a new scenario for the development of new therapeutic strategies for LN.
Gene-signatures behind response to MMF
Characteristics of responder and non-responder patients of SLE
Toro-Domínguez D, Martorell-Marugán J, Martinez-Bueno M, López-Domínguez R, Carnero-Montoro E, Barturen G, et al. Scoring personalized molecular portraits identify systemic lupus erythematosus subtypes and predict individualized drug responses, symptomatology and disease progression. Brief Bioinform. 2022 Sep 20;23(5):bbac332. Chan TM, Li FK, Tang CSO, Wong RWS, Fang GX, Ji YL, et al. Efficacy of Mycophenolate Mofetil in Patients with Diffuse Proliferative Lupus Nephritis. N Engl J Med. 2000 Oct 19;343(16):1156–62. Guthridge JM, Wagner CA, James JA. The promise of precision medicine in rheumatology. Nat Med. 2022 Jul;28(7):1363–71.
Measurement of treatment effects in systemic lupus erythematosus (SLE) randomised controlled trials (RCTs) remains challenging. Current RCT endpoints are not based on contemporary outcome assessment methodology. We report the current status of a global academic-industry-patient partnership aiming to develop a novel, patient-centred clinical outcome assessment (COA) for SLE RCTs: Treatment Response Measure for SLE (TRM-SLE).
We convened a global Taskforce of clinical-academic, metrology and regulatory experts, patient representatives and experts from ten pharmaceutical companies. A study protocol outlining a structured process for COA development was drafted and refined by TRM-SLE Taskforce members (
A panel of 45 Taskforce members representing key stakeholder groups formulated the conceptual definition and context of use for TRM-SLE. Moderated discussion and multiple rounds of voting resulted in high agreement (81–100%,
A global academic-industry-patient partnership has completed the first steps towards developing a novel SLE COA that is a quantitative measure of treatment response. Subsequent steps will combine consensus techniques with evaluation of supporting evidence, to determine the final set of concepts and associated measurements to be included in TRM-SLE. These measures will be integrated as a multi-domain COA in an SLE RCT endpoint that will be validated in clinical trials.
Steps in the development of a novel COA for SLE clinical trials
High level measurement goals for the TRM-SLE COA
To investigate the alterations of eye sign and functional magnetic resonance imaging (fMRI) in patients with neuropsychiatric systemic lupus erythematosus (NPSLE) and to explore the performance of combining eye sign and MRI in diagnosing NPSLE.
In phase 1, SLE patients were consecutively recruited Sep 2017 to Sep 2018 including NPSLE patients and non-NPSLE patients. Eye sign examination for bulbar conjunctival microvascular were performed for all SLE patients and fMRI scanning for NPSLE patients. Demographic and clinical data were compared between two groups and to identify potential predictors for NPSLE by using multivariable logistic regression analysis. In phase 2, NPSLE patients in phase 1 were enrolled, and a new diagnostic algorithm including predictors and changed fMRI indexes was designed with the 1999 NPSLE ACR classification as comparasion. Expert opinion was considered as golden standard. Double-blind clinical diagnosis from expert were recorded using new algorithm and reference standard. Area under the curve (AUC) under receiver operating characteristic (ROC) curve, sensitivity and specificity were calculated and compared between these two diagnostic methods.
120 SLE patients were recruited (32.99±1.03 years) including 45 NPSLE and 90 non-NPSLE. NPSLE had higher disease activity (reflected as SLEDAI and ESR). Compared with Non-NPSLE group, fMRI showed changed fALFF and ReHo in brain regions relevant to cognition and emotion (p<0.01). Eye sign examination showed NPSLE group had significantly higher scores of ramified loops, vascular tone, microangioma, wound point and had higher total scores than non-NPSLE group (p<.001). In multivariable logistic analysis, SLEDAI, ramified loop, microangioma, wound point and presence of antiphospholipid antibodies were predictors of NPSLE (
This proposed new algorithm showed not to be inferior to the 1999 ACR classification and need to be confirmed in further studies.
ROC curve of potential predictors in diagnosing NPSLE
Multivariable logistic regression analysis of predictors for developing NPSLE
Thrombocytopenia is a common complication of antiphospholipid syndrome (APS). It is a main concern for hemorrhage risk on the current standard treatment of low dose aspirin (LDA) and low molecular weight heparin (LMWH) in obstetric APS (OAPS). This study assesses the possible relationship between the different levels of thrombocytopenia and adverse pregnancy outcomes (APOs) in OAPS patients.
A retrospective study was conducted at Peking University People’s Hospital, Beijing, China. The demographic, clinical, immunologic, and pregnancy outcomes of the OAPS patients were collected. Univariate and multivariate logistic regression analyses were applied to assess the association between APOs and thrombocytopenia, especially severe thrombocytopenia (<30x109/L).
A total of 206 participants were included in the analysis. There were 30 with mild to moderate thrombocytopenia (30–100x109/L) and 19 with severe thrombocytopenia (<30x109/L) among 176 OAPS patients in pregnancy. The rate of the hypocomplementemia in severe thrombocytopenia group (36.84%) was higher than that in the non-severe group (20.00%) and in control group (9.57%) (P = 0.005). Severe thrombocytopenia was associated with a higher APOs of OAPS, such as preterm delivery before 34 weeks (Model I: OR, 16.09; 95%CI, 3.69–70.10, P = 0.0002; Model II: OR, 10.33 ;95%CI, 2.02–52.88, P = 0.0051), uteroplacental insufficiency (Model I: OR, 3.35;95%CI, 1.14–9.85, P = 0.028; Model II: OR, 5.98;95%CI, 1.62–22.14, P = 0.0074), and gestational hypertension (Model I: OR, 5.26;95%CI, 1.16–23.82, P = 0.031; Model II: OR, 9.45;95%CI, 1.43–62.45, P = 0.0198), but not the mild to moderate thrombocytopenia after adjusting for demographic and laboratory factors. After adding medication adjustments, these factors above become insignificant (p > 0.05).
The risk of APOs depends on the different levels of thrombocytopenia in OAPS patients. Only severe thrombocytopenia is associated with adverse pregnancy outcomes. The effective OAPS treatments may improve pregnancy outcomes.
Type I interferon (IFN) plays a vital role in the pathogenesis of systemic lupus erythematosus. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that recognizes dsDNA and creates cGAMP to activate STING-mediated type I IFN production. The activation of STING induces lupus disease in Fcgr2b deficient mice through the differentiation of dendritic cells. In contrast, Cgas deficient mice could be generated more autoantibody production and proteinuria in pristane-induced lupus (PIL). These data suggested that the other dsDNA sensors could be involved in lupus development mechanisms.
This study aimed to identify the cGAS-mediated mechanisms contributing to lupus pathogenesis in PIL. The Cgas-deficient and WT mice were induced with lupus disease by pristane injection. The lung tissues were analyzed with the expression profiles by RT-PCR and western blot. The bone marrow-derived macrophages were stimulated with inflammasome activators and observed pyroptosis.
The Cgas-/- mice developed more severe pulmonary hemorrhage and autoantibody production than WT mice. The activated dendritic cells, IFN-g-, and IL-17a-producing T helper cells, and infiltrated macrophages in the lung were detected in Cgas-/- mice higher than in WT mice. We observed an increase in expression of Aim2, Casp11, and Ifi16 in the lung and serum IL-1a but IL-1b in pristane-injected Cgas-/- mice. The rise of Caspase-11 in the lung of pristane-injected Cgas-/- mice suggested noncanonical inflammasome activation. The activation of AIM2 and NLRP3 inflammasomes in bone marrow-derived macrophages (BMDMs) enhanced the number of dead cells in Cgas-/- mice compared with WT mice. Activation of the inflammasome significantly induced pyroptosis in Cgas-/- BMDMs. The dsDNA level, but not mitochondrial DNA, increased dramatically in pristane injected Cgas-/- mice suggesting the dsDNA could be a ligand activating inflammasomes. The cGAS agonist-induced BMDM
These findings suggested that cGAS hampers the unusual noncanonical inflammasome activation through other DNA sensors.
With the improvement in survival, the prevention of cumulative organ damage has become a major goal in the management of systemic lupus erythematosus (SLE). Patients with autoimmune disease suffered from an increasing risk of cardiovascular disease (23·3 events per 1000 patient-years1). Although antiphospholipid (aPLs) antibodies, including anticardiolipin antibodies, anti-β2 glycoprotein I, and lupus anticoagulant, were associated with vascular events in antiphospholipid syndrome, the role of APLs in SLE patients was not yet determined. Based on the Chinese SLE treatment and research (CSTAR) multi-center prospective study, we aimed to identify the predictive value of high-risk aPLs on cumulative organ damage progression in SLE.
Demographic characteristics, autoantibody profiles, clinical manifestations, disease activity status, and organ damage were collected at baseline. High-risk aPLs profile was defined according to 2019 EULAR recommendations for APS2 (the presence of lupus anticoagulant, or double or triple aPL positivity, or the presence of persistently high aPLs titers).
A total of 2132 SLE patients with full follow-up data were recruited and 424 (19.9%) showed high-risk aPLs profiles. 453 (21.2%) patients developed new organ damage during a mean follow-up of 4.40±2.64 years, and 143(31.6%) are cardio-cerebral vascular damage. At baseline, patients with high-risk aPLs profile have a higher rate of neurological involvement (12.5% vs 7.6%, p=0.001). As shown in
SLE patients with high-risk aPLs profile warrant more care and surveillance of cardio-cerebral vascular events during follow-up.
(A). Cumulative probability of new-onset organ damage in patients with or without high-risk aPLs profile. (B). Cumulative probability of cardio-cerebral vascular damage in patients with or without high-risk aPLs profile. (C). Risk factors of cardio-cerebral vascular damage in SLE patients
Conrad N, et al. Lancet 2022;400(10354):733–43. Tektonidou MG, et al. Ann Rheum Dis 2019;0:1–9.
Antiphospholipid antibodies (aPLs) are the leading causes of adverse pregnancy outcomes (APO). Women with persistently aPLs positive present heterogeneous clinical manifestations and APO. We applied cluster analysis to identify specific phenotypes among these patients to manage risk stratification during pregnancy and improve prognosis.
This was a prospective study of persistent aPLs-positive women cohort to PUMCH between July 2009 and February 2022. Demographic characteristics, clinical manifestation, previous pregnancy history and antibodies profiles were recorded. Hierarchical cluster analysis and Chi-square test were performed.
A total of 209 patients with 477 pregnancies were enrolled in this study. β2GPI was the most frequently found in persistent aPLs-positive women. The live birth rate improved from 17.29% before enrollment to 75.64% dramatically (
Our study identified three clinical subtypes of aPLs-positive women with APO. Cluster 1 contains patients with a predisposition to SLE. Patients in cluster 2 majorly present PI combined with aPLs-IgG subtype, while cluster 3 present EM with aPLs-IgM subtype. The individualized risk stratification assessment of these patients will help to develop different treatment strategies and improve the pregnancy outcome.
Study flowchart, hierarchical clustering analysis of 209 persistent aPLs-positive women and representative HE staining of three clusters
Comparison of pregnancy outcomes before and after enrollment
The metabolic disturbances that underlie antiphospholipid syndrome (APS) are currently unknown. The goal of this study is to utilize high-throughput metabolomics screening to identify new biomarkers and dysregulated pathways in primary APS patients.
Fasting serum samples were collected from 20 primary APS patients and 17 healthy controls. High-throughput metabolomics screening of 247 small molecule metabolites were performed via gas chromatography coupled mass spectrometry. Multiple variate analysis, principal components analysis (PCA), partial least squares discriminant analysis (PLS-DA), and pathway analysis were completed. SYTOX Green NETosis assay was performed utilizing freshly prepared healthy donor neutrophils with various stimulants including PMA, PMA+DPI, normal human IgG, antiphospholipid antibodies (aPL), sphingosine-1 phosphate (S1P), and aPL plus various concentration of S1P.
50 circulating small molecule metabolites were significantly different between primary APS patients and healthy controls. PLS-DA modeling was performed and demonstrated a clear separation between primary APS patients and healthy controls. 15 metabolic biomarkers that made the biggest contribution to the differentiation of primary APS patients and the healthy controls assessed by variable importance on projection score were identified. Pathway analysis revealed that sphingosine metabolism was the most enriched pathway among primary APS patients. To further elucidate the role of sphingosine metabolism in APS, we examined the effect of S1P, the product of sphingosine metabolism, on aPL mediated NETosis. aPL mediated NETosis was significantly potentiated by S1P in a concentration dependent manner. S1P did not trigger NETosis by itself (
This study comprehensively profiled the serum metabolites of primary APS patients and identified metabolic biomarkers that have the potential to be used as a diagnostic tool for differentiating APS from healthy controls. The APS metabolome analysis also revealed a potential significant role of S1P/S1PR axis in APS pathogenesis.
The effect of S1P on aPL mediated NETosis. aPL mediated NETosis was significantly potentiated by S1P in a concentration dependent manner. S1P did not trigger NETosis by itself.
This study aimed to demonstrate the potential of Activated Leukocyte Cell Adhesion Molecule (ALCAM), hemopexin, and peroxiredoxin (PRDX) 6 as urine biomarkers for systemic lupus erythematosus (SLE).
We collected urine samples from 138 patients with SLE from Ajou Lupus Cohort and 39 healthy controls (HC). The concentrations of urine biomarker levels were analyzed by enzyme-linked immunosorbent assay kits specific for ALCAM, hemopexin and PRDX 6, respectively, according to the manufacturer’s protocols. Receiver operating characteristic (ROC) curve analysis was performed to evaluate diagnostic utility and Pearson’s correlation analysis was conducted to assess the relationships among the disease activity and urine biomarkers.
Patients with SLE showed a 5.7-fold increase in urinary ALCAM levels compared to HCs (6,760.5 pg/ml vs. 1,192.6 pg/ml, p < 0.001). In urinary hemopexin and PRDX6, the average levels were also significantly higher in patients with SLE compared to HCs (hemopexin, 649.8 ng/ml vs. 202 ng/ml, p < 0.001; PRDX6, 0.78 ng/ml vs. 0.17 ng/ml, p = 0.003). ALCAM, hemopexin, and PRDX6 showed more significant diagnostic value, especially for lupus nephritis (LN), and the area under the receiver operating characteristic curve for LN was 0.850 for ALCAM (95% CI, 0.778–0.921), 0.781 for hemopexin (95% CI, 0.695–0.867), and 0.714 for salivary S100A8 (95% CI, 0.617–0.812). In correlation analysis, all were significantly associated with anti-double stranded DNA (ALCAM, r = 0.350, p < 0.001; hemopexin, r = 0.346, p < 0.001; PRDX6, r = 0.191, p = 0.026) and SLEDAI (ALCAM, r = 0.526, p < 0.001; hemopexin, r = 0.479, p < 0.001; PRDX6, r = 0.262, p = 0.002).
Urinary ALCAM, hemopexin and PRDX 6 were highly expressed patients with SLE compared to HCs. Thus, we suggest that urinary ALCAM, hemopexin and PRDX 6 can be potential biomarkers for SLE, especially valuable in the diagnosis of LN.
Lupus Low Disease Activity State (LLDAS) permits serological activity and activity in several organs including joint, muscle, and mucocutaneous activity, provided SLEDA4-2K is <=4 and other LLDAS criteria are met.
Patients in the Asia-Pacific Lupus Collaboration cohort who were recruited and followed up between 2013 and 2020 who had been in LLDAS at least once were included. However, visits which fulfilled both LLDAS and DORIS remission criteria was excluded. Multivariable Cox regression was used to compare flare (SELENA Flare Index) and damage (SLICC-DI increase >=1) in those with serologic and those with neither serologic nor clinical activity, compared with those in LLDAS who had clinical activity.
2701 patients were included with median 3.5 (1.3–5.9) years of follow-up and 14239 visits in LLDAS but not DORIS remission. These visits included 1280 (9.0%) with clinical activity, 7461 (52.4%) visits with serological activity only, and 5498 (38.6%) visits with neither clinical nor serological activity. The most common presentation of visits with clinical activity was mucocutaneous (38.2%). Among the 2701 patients, 539 (20.0%) had at least one episode of LLDAS with clinical activity (clinical-group), 1481 (54.8%) had LLDAS with serological activity only (serologic-group), and 681 (25.2%) had LLDAS without any clinical or serological activities (neither-group). Multivariable cox regression analysis adjusted for demographic variables showed both types of LLDAS without clinical activity are protectively associated with flares, while LLDAS without clinical or serology activity had the strongest protective association with flare (HR 0.67, 95% CI 0.56–0.80, p<0.0001) (
80% of patients in LLDAS did not have any clinical activity according to SLEDA-2K. LLDAS without clinical or serologic activity is most desirable given the strongest protective association with flare.
Association of LLDAS subtypes with subsequent flares and damage accrual by cox regression analysis
Systemic Lupus Erythematosus (SLE) patients experience frequent hospitalizations; lupus flares and infections have been shown to be the two most common causes. The aim of this study is to describe the main causes and predictors of first hospitalizations due to disease activity and infections in SLE patients.
SLE patients from GLADEL, a multi-ethnic, multi-national Latin-American (LA) cohort were studied. The first hospitalization during these patients’ follow-up due to either infection and/or SLE disease activity was examined. Baseline sociodemographic, clinical, damage (SDI) and treatments were evaluated as possible predictors. First, descriptive analyses were performed. Predictors of infection or SLE disease activity associated hospitalization were identified using univariate and multivariate logistic.
A total of 1341 patients were included; 1201 (89.6%) were female. Their median interquartile range (IQR) age at diagnosis was 27 (20–37) years and their median IQR follow up time 27.5 (4.7–62.2) months; 456 (34.9%) patients were hospitalized; 344 (75.4%), 85 (18.6%) and 27 (5.9%) were hospitalized for disease activity, infections, or both, respectively, as depicted in graph 1. In the multivariable analysis, arthritis was associated with hospitalizations due to infection. Serositis, disease activity and damage were associated with hospitalizations due to disease activity. Older age, higher socioeconomic status and antimalarial use were found to be protective, as depicted in
In this large LA lupus cohort, one third of the patients had at least one hospitalization; of them, three quarters were due to SLE disease activity. Our findings call attention for controlling disease activity and preventing damage using antimalarials early in the disease course disease to prevent the first hospitalization.
Reason for the first hospitalization
Univariable and multivariable logistic regression analysis of predictors of hospitalization due to disease activity and infections in patients with SLE
Frailty is associated with adverse health outcomes in systemic lupus erythematosus (SLE). We aimed to assess the agreement between two frailty measures, the SLICC Frailty Index (SLICC-FI) and the FRAIL scale, for identifying frailty among SLE patients. We also evaluated differences in characteristics between frail and non-frail SLE patients according to each frailty definition.
This was a cross-sectional study of consecutive adult SLE patients assessed in the Lupus Clinic at a single academic medical centre from December 2020-November 2021. At a single visit, participants were assessed for disease activity, organ damage, comorbidities, medications, and health-related quality of life (HRQoL). A SLICC-FI score was calculated for each patient. The 5-item FRAIL scale was administered at the same visit. Agreement between the SLICC-FI and the FRAIL scale was evaluated. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal threshold SLICC-FI value based on agreement with the FRAIL scale.
The 181 SLE patients were mostly female (90.1%) with mean (SD) age 54.6 (14.3) years. Mean (SD) baseline SLICC-FI score was 0.17 (0.08), with 57 patients (31.5%) classified as frail (SLICC-FI >0.21). Based on the FRAIL scale, 31 patients (17.1%) were classified as frail (≥3/5 items). There was moderate correlation between the FRAIL scale and the SLICC-FI (r=0.639; p<0.0001). Agreement occurred in 84.5% of cases (=0.591; p<0.0001). The ROC curve analysis yielded an AUC of 0.936 (
There is moderate agreement between the SLICC-FI and the FRAIL scale for identifying frailty in SLE patients. Each frailty metric may have distinct advantages in different settings.
Receiver operating characteristic (ROC) curve for SLICC frailty index (SLICC-FI) values, based on agreement with frailty status as determined by the FRAIL scale
Clinical and laboratory characteristics of SLE patients based on frailty status (n=181)
Identifying clinical and serological associations of Latent tuberculosis infection (LTBI) in lupus may be important in preventing progression to overt TB. This study aimed to assess prevalence of LTBI, its association with clinical and serological parameters in SLE.
This is a single center prospective observational study. SLE patients with no prior TB were recruited (n=219). Demography and disease parameters were noted at baseline, 6 and 12 months. LTBI was assessed using TB-IGRA (IFN- release assay) and SLE cases were divided into IGRA positive and negative groups. Correlation of disease activity was assessed with IFN- levels in unstimulated tube of TB IGRA (for baseline immune activation).
Among 219 patients, prevalence of LTBI was 18.7%. Average disease duration was 3.5 years. Proportion of Ro 52 was higher in IGRA positive (43.9%) than negative group(25.3%) (p=0.014) and anticardiolipin IgM antibody higher in IGRA negative group (12.9%) than positive group (2.4%) (p=0.032). Comparison of clinical features yielded no statistically significant difference. Serology revealed greater proportion of low C4 in IGRA negative as compared to the positive group(p=0.036). There was no correlation of SLE disease activity with the IFN- levels in the unstimulated tube of TB IGRA. Follow up data was available for 56% at 1 year and 39% at 6months. There was no significant difference in flares among IGRA positive and negative groups
Prevalence of LTBI in SLE cases was 18.7%, much lesser than general population (40%). Higher association of anti-Ro 52 antibody in IGRA positive group along with higher anticardiolipin IgM and low C4 in IGRA negative group were found whose clinical significance is unknown. IFN- levels in unstimulated tube of TB IGRA did not correlate with SLE disease activity. IGRA status did not seem to have an impact on disease flares in SLE.
Systemic lupus erythematosus (SLE) is a complex disease with heterogenous manifestations.1 Clinical subphenotypes have been reported, but limited studies have evaluated their long-term impact.2 This study utilized the data from the Asia Pacific Lupus Collaboration (APLC) cohort to evaluate subphenotypes in SLE and differences in long term outcome.3
Patient data from the APLC cohort collected between 2013 and 2020 were included. Two-step cluster analysis was conducted based on serological features (anti-dsDNA, anti-Sm, anti-phospholipid antibodies, direct coomb’s test, and hypocomplementemia). Clinical characteristics, LLDAS-50 attainment, and risk of damage accrual were compared.
Three clusters with distinct clinical and serological characteristics were identified (
Over a median of 2.5 years, damage accrual occurred in 20.8% patients and the risk was highest in cluster one (cluster 1 vs cluster 2: OR 1.34, P=0.008; cluster 1 vs cluster 3: OR 1.28, P=0.041). LLDAS-50 was most frequently achieved in cluster three (cluster 1: 49.6%, cluster 2: 48.7%, cluster 3: 59.1%) (
Three distinct subphenotypes were confirmed and associated with different risks of damage accrual. LLDAS-50 was an attainable target and associated with reduced risk of damage accrual across three clusters.
Percentage of patients with LLDAS-50 across three clusters
Cluster analyses based on autoantibody profile of 3614 SLE patients
Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, et al. Systemic lupus erythematosus. Nat Rev Dis Primers. 2016;2:16039. Li PH, Wong WH, Lee TL, Lau CS, Chan TM, Leung AM, et al. Relationship between autoantibody clustering and clinical subsets in SLE: cluster and association analyses in Hong Kong Chinese. Rheumatology (Oxford). 2013;52(2):337–45.
The molecular and cellular heterogeneity of human Lupus Nephritis (LN) at the kidney tissue level makes it challenging to identify key disease drivers and therapeutic targets. Single-cell transcriptomics (scRNA-Seq) has advanced our understanding of LN pathogenesis, but tissue dissociation eliminates all spatial information and several rare cell types (such as podocytes) are under-represented using droplet-based scRNA-Seq protocols.
Using the CosMx Spatial Molecular Imager (Nanostring), we performed spatial transcriptomics on 8 pediatric Class III/IV LN patients and 2 health controls. This platform generated 1000-plex gene expression data at single cell resolution using archived clinical biopsy tissue.
After data QC and cell segmentation, we identified a total of 447,892 cells, which were assigned to 33 reference cell types (
Spatial transcriptomics is a powerful tool to uncover the heterogeneity of LN. The identification of new pathogenic mechanisms may inform the development of new targeted therapies.
(A) UMAP projection of immune and renal cell subsets in LN. (B) Spatial relationships with each dot indicating a single cell. Arrows denote glomeruli and infiltrating tubulointerstitial immune cells. (C) Left: Illustration showing major glomerular cell types. Right: Glomerular cell types are spatially confined to glomerular structures (dashed circle), with podocytes (red) predominantly located peripherally outside mesangial and endothelial cells. Grey dots: unlabeled cells
Patients with SLE experience substantial health disparities. Studying the effect of spatial context on health outcomes has become a focus in health disparities research. The CDC Social Vulnerability Index (SVI) identifies communities where social determinants lead to higher levels of morbidity and mortality. We sought to understand the level of social vulnerability where patients with SLE reside and determine if specific dimensions of social vulnerability were associated with disease activity and prednisone utilization.
272 consented subjects who met either ACR or SLICC classification criteria for SLE were enrolled and longitudinally assessed from April 2014 to August 2020 (demographics in
There was no correlation between cumulative SVI and disease activity (OR 1.15, 95% CI=0.67–1.99). Compared to patients with invulnerable cumulative SVI, vulnerable patients were 2.31 times as likely to have higher dose of prednisone (1.36–3.92). Of the specific SVI dimensions, socioeconomic status (2.47, 1.43–4.27) and household composition (2.21, 1.28–3.83) associated with higher prednisone dose, whereas race/ethnicity/language (1.57, 0.92–2.68) and housing/transportation (1.08, 0.65–1.80) had no statistically significant association.
Patients who live in more socially vulnerable areas are more likely to be prescribed higher doses of prednisone, specifically patients vulnerable in terms of socioeconomic status and household composition. This is worrisome as this likely will contribute to a higher burden of damage. These data highlight that access to social determinants is associated with health inequities.
Patient demographics
There are limited population-based data on morality in juvenile Systemic Lupus Erythematosus (SLE). Here, we examine standard mortality rate (SMR) in juvenile SLE and compare with young- and adult-onset subsets in a large population-based SLE cohort.
The population-based cohort included all SLE patients who were resident in Southeast Norway 1999 – 2017, had SLE diagnosis confirmed by chart-review and met the 1997 ACR criteria for SLE. Cases with new-onset disease 1999–2017 were defined as inception cases. We stratified the cohort by age at diagnosis, with juvenile SLE diagnosed age <16, young-onset age 16–29 and adult-onset age ≥30. Lupus nephritis (LN) was defined by 1997 ACR criteria for SLE. We compared ratios with X2-test, estimated risk of death by SMR using 15 controls per SLE case (individually matched to case by age, sex and ethnicity) and survival in juvenile inception cases by Kaplan-Meier.
The cohort included 1300 SLE cases; of whom 93 (7%) were diagnosed at age<16, 461 (35%) at age 16–29 and 746 (57%) at age≥30 (
The SMR was significantly higher in juvenile and young adult-onset than in adult-onset, with highest SMR in juvenile-onset (
Early disease-onset greatly increase SMR in SLE to a maximum of 7.2 in juvenile-onset, twice as high as in juvenile type-1 Diabetes.1 We find no sex-specific differences in SMR, but juvenile-onset with LN has the highest SMR.
Patient demographic and mortality in Systemic Lupus Erythematosus; stratified by age at diagnosis
Gagnum V, Stene LC, Sandvik L, Fagerland MW, Njølstad PR, Joner G, et al. All-cause mortality in a nationwide cohort of childhood-onset diabetes in Norway 1973–2013. Diabetologia. 2015;58(8):1779–86.
SLE more commonly affects non-White populations who suffer higher disease activity and damage accrual. We aimed to describe differential response of moderate-to-severe SLE by ethnic group.
Patients commencing rituximab (RTX), belimumab or a standard-of-care medication (SoC) for SLE in the BILAG-BR were analysed over 12-months. Major clinical response (MCR) was defined as a SLEDAI-2K ≤4 at 12 months. Deprivation was measured using English indices of deprivation-2019 decile (EID, 1= most deprived, 10=least). MCR was compared using multivariate logistic regression (adjusted for age, gender and EID).
1601 SLE patients commenced therapy from Sept-2010-Sept-2022 (RTX: N=1177, belimumab: N=193, SOC: N=231). 905 (56.5%) were White, 233 (14.6%) were Black, 197 were Indo-Asian, 81 (5.1%) were Chinese/East Asian, and 60 were of mixed background and 125 (7.8%) preferred not to say (
MCR was achieved in 901 (56.3%) patients at 12 months. Black patients had a higher SLEDAI-2K at baseline compared with White individuals (
In patients receiving RTX, Black (adjusted OR 0.36 [95%CI 0.25–0.52]) and Indo-Asian (0.42 [0.18–0.96]) patients were less likely to achieve MCR. In patients receiving belimumab, Black (0.65 [0.44–0.96]) and Indo-Asian patients (0.29 [0.09–0.93]) were also less likely to have MCR. Absolute reduction in SLEDAI-2K was similar for each ethnic group.
Although absolute reduction in disease activity was similar across ethnic backgrounds, obtaining a MCR following treatment was lower in Black and Indo-Asian patients, in part reflecting higher baseline disease activity, but not explained by level of social deprivation; an observation not confined to a single treatment. There is a need for investigation into the drivers of these inequitable outcomes and reappraisal of treat-to-target strategies in these populations.
Mean SLEDAI-2k at baseline, 3, 6 and 12 months, in A) Rituximab (n=1089), B) Belimumab (n=179) and C) SoC (n=208) treated patients
Demographic and clinical data by ethnic background. EID, English indices of deprivation 2019 decile; SoC, standard of care. Data presented as median (IQR) or N (%), with respective p values computed with chi2 or Kruskall-Wallis test
Lupus nephritis (LN) leads to end stage kidney disease (ESKD) in 17–33% after 10 years. The prevalence of chronic kidney disease stage IV (eGFR=15–29ml/min/1.73m2) is not known. Our objective was to determine the impact of time to remission and number of flares on the development of advanced CKD in LN.
Patients with LN were retrieved from the Toronto Lupus Clinic database. Individuals with advanced CKD at baseline were excluded. All patients were followed for ≥ 5 years. Primary outcome: advanced CKD (eGFR&x2266;29ml/min/1.73m2). Remission: proteinuria<0.5g/24h, no active urinary sediment, serum creatinine ≤120% baseline. Flare: proteinuria >0.5g/day after remission. Death was treated as competing risk in survival analysis.
Of 418 eligible patients, 50% achieved remission within the first year, 24.4% within the 2nd/3rd years, 16.7% after 3 years and 8.9% never achieved remission. Sixty-six patients (15.8%) developed advanced CKD after 9.5 years on average (29 with CKD IV, 37 with ESKD). At baseline, these patients had a higher SLICC/Damage Index, lower eGFR, higher prevalence of hypertension, more proliferative nephritis and more often treated with angiotensin converting enzyme inhibitors or receptor blockers. Other variables did not differ significantly. Remission rates, flares and exposure to immunosuppressives after remission shown in
Patients who achieved remission within one year from diagnosis demonstrated significantly better outcomes compared to all other groups (p <0.0001,
Complete remission within the 1st year from LN diagnosis strongly protects against the development of advanced CKD. Flares significantly affect prognosis. Longer time on immunosuppressives after remission is associated with decreased risk for advanced CKD. These findings emphasize the importance of achieving early remission as well as flare prevention with immunosuppressives to maximize renal survival.
Kaplan-Meier curve for the outcome of advanced CKD according to the time to complete remission
Remission rates, flares and exposure to immunosuppressives after remission
Disease modification is an important concept for minimizing disease activity with the fewest treatment-associated toxicities when managing SLE . Belimumab has been used as a maintenance therapy for SLE; however, data on its disease-modifying effects are scarce. Therefore, we aimed to investigate the disease-modifying effects of belimumab in SLE patients.
This single-centre retrospective cohort study included SLE patients treated with belimumab at our institution. We analysed the changes in flare-free ratio, lupus low disease activity state (LLDAS) achievement ratio, glucocorticoid dosage, SLICC/ACR damage index (SDI) score, and drug retention rate after belimumab initiation.
Of the 567 patients with SLE followed up in our hospital, 95 used belimumab and to 92 were included in the study.
Fifty-two weeks after initiating belimumab, the flare rate decreased (82.6% to 14.1%) (p<0.01). At week 52 and day 1,000 after initiation of belimumab, >70% and approximately 90% of the patients achieved LLDAS, respectively. Belimumab administration also significantly decreased glucocorticoid demands, and at the end of the study period, 68.5% of patients achieved prednisolone ≤5 mg/day and 22.8% achieved glucocorticoid discontinuation. Furthermore, most patients were free of SDI progression (week 52, ±95%; end of study period, almost 90%), and belimumab showed a high drug retention rate (week 52, 90%; day 1000 after initiation >80% ).
Most patients on belimumab achieved LLDAS, decreased flare rate and glucocorticoid demand, and a stable trend of SDI after its induction. Furthermore, belimumab had a high drug retention rate. Therefore, the introduction of belimumab may be a key element in disease modification.
We aimed to determine the effect of antimalarial agents (AMA) and different doses and pharmaceutical forms of belimumab on preventing renal flares in patients with systemic lupus erythematosus (SLE) treated for active extra-renal disease.
We pooled data from the BLISS-52, BLISS-76, BLISS-SC and BLISS-Northeast Asia (NEA) randomised clinical trials of belimumab (N=3225), that included seropositive, active SLE patients with no active severe lupus nephritis (LN). Participants were allocated to receive intravenous (IV) belimumab 1 mg/kg (N=559), IV belimumab 10 mg/kg (N=1033), subcutaneous (SC) belimumab 200 mg (N=556) or placebo (N=1077) in addition to standard therapy. The outcome of the present post-hoc analysis was development of renal flares, defined according to the analysis plan within the BLISS programme. The hazard of renal flare was assessed with Cox proportional hazards regression models, adjusted for age, sex, ethnicity, previous renal involvement, baseline proteinuria and glomerular filtration rate, and use of glucocorticoids and immunosuppressants.
Demographic and clinical characteristics are shown in
Belimumab in combination with AMA prevent against renal flares in patients treated for extra-renal SLE. The prominent effect of low-dose belimumab warrants investigation of the efficacy of intermediate doses.
BLM: belimumab; UPCR: urine protein/creatinine ratio
First multicenter study in clinical practice in SLE patients treated with BLM in Spain.
Descriptive, retrospective, multicenter study in patients diagnosed with SLE according to EULAR/ACR 2019, SLICC and/or ACR 1997 diagnostic criteria. Data regarding SLE patients treated with BLM were collected from medical records (2011–2022). Demographic features, efficacy, analytical variables, SLEDAI, renal involvement, steroid dose, administration routes and safety were assessed.
Baseline characteristics of patients are summarized in
A total of 462 patients (36 hospitals) were included, 50.9% were on intravenous (IV), 34% on subcutaneous (SC) and 15.1% switched from IV to SC route. The median number of pre-BLM csDMARD use was 2.0 (2.0–3.0), being hydroxychloroquine (HCQ) the most frequently used (94.5%). Fifty-two patients were treated with IV cyclophosphamide with a median of 6 bolus received. At the time of BLM start, 443 patients were on prednisone with a median dose of 6.2 mg (5.0–10.0). A statistically significant decrease in prednisone dose, SLEDAI and DNA was observed from baseline until the last visit, whereas complement C3 and C4 values raised (p<0.001) (
In our cohort BLM has been effective, safe and seems to be a good choice for patients with not severe renal involvement.
Prednisone time-dependent evolution
Baseline characteristics of patients included in Belimumab Spanish registry
Limited data exist on quality of life (QoL) improvement in patients with SLE who were organ-specific responders per SELENA-SLEDAI. Here we explore the association between organ-specific SELENA-SLEDAI treatment response and 36-item Short Form Survey version 2 (SF-36v2) components and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scores in adults with SLE.
This post hoc analysis (GSK Study 217382) used data from four belimumab trials (BLISS-52, NCT00424476; BLISS-76, NCT00410384; BLISS-SC, NCT01484496; EMBRACE, NCT01632241). Differences in mean changes in SF-36v2 and FACIT-Fatigue scores were compared with published group-level minimum important difference (MID; as defined in
At baseline, BLISS-52, BLISS-76, BLISS-SC, and EMBRACE included 864, 818, 834, and 496 patients, respectively. As indicated in
Being an organ responder is associated with QoL benefits experienced by patients with SLE that were more often observed among belimumab-treated patients. Statistical significance was interpreted with caution owing to small sample sizes.
GSK
Summary of differences between SELENA-SLEDAI organ system responders* and non-responders in mean QoL score change (baseline to Week 52).* Responder defined as a patient with decrease from baseline in SELENA-SLEDAI score at a post-baseline visit. BLISS-52, NCT00424476; BLISS-76, NCT00410384. BLISS-52, NCT00424476; BLISS-76, NCT00410384; BLISS-SC, NCT01484496; EMBRACE, NCT01632241. Note: Differences in mean score changes ≥MID are indicated in bold; statistically significant (p<0.05) differences between organ responders and non-responders are in grey. R, responder; NR, non-responder
In 2017, Belimumab (BEL) was approved in subcutaneous (SC) version.1 The effectiveness after switching from intravenous (IV) to SC and patient satisfaction in daily clinical practice has not been studied. During the pandemic, patient follow-up and treatment were significantly affected, including the administration of IV biologic therapies. In some patients, a change from IV to SC, including BEL therapy, was required.2 Our aim was to evaluate in daily clinical practice satisfaction to BEL SC therapy in patients previously treated IV BEL. We hypothesized that SC BEL in SLE patients previously treated with IV BEL was similar in effectiveness and conferred higher satisfaction.
Observational, multicenter study, conducted in 7 reference centres in Catalonia (Spain). Inclusion criteria: Stable SLE patients (EULAR/ACR 2019) on treatment with BEL SC and previous use of BEL IV (at least 3 months of treatment with BEL IV before switching).
Since there are no well-validated tools for SC BEL treatment satisfaction, we used RASQ-SC, validated in patients with lymphoma who switched from Rituximab IV to SC treatment,3 modified for BEL treatment.
Twenty-seven patients were included. Demographic and general characteristics are summarized in
Overall satisfaction, satisfaction with via of administration and satisfaction with the time taken to receive BEL were higher for SC BEL treatment. A switching SC strategy is a reasonable alternative for BEL patients.
RASQ-SC modified for belimumab
Demographic and disease characteristic
Stohl W, Schwarting A, Okada M, et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fiftytwo-week randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2017;69(5):1016–1027. doi:10.1002/art.40049 Mucke J, Brinks R, Fischer-Betz R, Richter JG, Sander O, Schneider M, Chehab G. Patient satisfaction and disease control in patients with systemic lupus erythematosus is not affected by switching from intravenous belimumab to subcutaneous injections. Patient Prefer Adherence. 2019;13:1889–1894 Theodore-Oklota C, Humphrey L, Wiesner C, Schnetzler G, Hudgens S, Campbell A. Validation of a treatment satisfaction questionnaire in non-Hodgkin lymphoma: assessing the change from intravenous to subcutaneous administration of rituximab. Patient Prefer Adherence. 2016;10:1767–1776
Monogenic lupus is a rare, inherited entity, and the precise prevalence is unknown. It demonstrates great heterogeneity in etiopathogenesis and phenotypes. To date, there is no standardized definition or criteria for identifying monogenic lupus.
To report the phenotypic characteristics, and identify the spectrum of genetic variants related to monogenic lupus from a single tertiary lupus clinic.
A descriptive, observational, cross-sectional study was conducted. Data was retrospectively collected on patients with lupus manifestations and genetic variants seen between 1997 and 2022. Data comprised the clinical findings, including family history and consanguinity, and laboratory findings. Genetic testing, including Whole exome sequencing (WES), was performed on all monogenic lupus patients.
Among the 256 patients with childhood systemic lupus erythematosus (cSLE) seen in our lupus clinic at King Faisal Specialist Hospital & Research Center (KFSHRC)-Riyadh, 30 patients (11.7%) (16 females) were identified as having monogenic lupus. All patients included in the study were of Arab origin, with 70% having early-onset disease. The most frequent features were fever (100%), musculoskeletal (93.3%), and mucocutaneous lesions (86.7%). Renal, cardiac, and pulmonary involvement were seen at 33.3%, 30%, and 26.7%, respectively. Thirteen patients (43.3%) experienced recurrent infections. Complement deficiency was the most frequent genetic variant (40%), followed by DNase variants (23.3%). Interestingly, genetic analysis revealed 12 novel gene variants. All patients were treated aggressively with corticosteroids and sequential conventional immunosuppressive drugs. Twenty-eight patients received biologic agents (14 belimumab, 12 rituximab, and 2 JAK inhibitors), while 23 received IVIG. Most of them showed a poor response to treatment. There were five deaths related to serious infections.
This report expands the pathogenic variants and the clinical spectrum of monogenic lupus. Patients with various variants share clinical characteristics. The outcome is guarded by a high mortality rate. Unfortunately, to date, there is no effective standard treatment.
Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are the prototypes of autoimmune diseases, for which many genetic loci have been identified using genome-wide association studies (GWAS) for recent decades. This study aims to establish genomic prediction models for autoimmune diseases using machine learning (ML) techniques, which can classify the patients with RA or SLE from healthy controls.
We obtained SNPs data (N=446,097) from Korean Chip (Affymetrix Axiom™ KOR) for 3,145 RA, 1,870 SLE, and 3,635 controls, enrolled from Hanyang University Hospital for Rheumatic Diseases. After quality control (N=428,380), we selected the significant associated SNPs with each disease (RA or SLE) using univariate test (p< 5.0e-8) and imputed by SHAPEIT2, IMPUTE4, Eagle v2, Minimac3. We conducted ML, support vector machine (SVM) and extreme gradient boosting (XGB). Contribution of SNPs for classification was calculated with importance (or gain) values.
A total of 2,458 SNPs were selected and used as inputs for ML models. Each group of RA, SLE, and controls was randomly divided into training (70%) and testing (30%) subsets. Both SVM and XGB approaches showed high prediction performance to discriminate autoimmune diseases of RA or SLE from controls (
We identified ML based genomic prediction models that could distinguish between autoimmune diseases (RA or SLE) and healthy controls in the Korean population, while suggesting the need for more research for differentiating RA from SLE. These results suggest that ML approach using genomic data might be useful to predict the risk of autoimmune diseases.
Feature importance of top 30 SNPs of machine learning models.
Statistics of machine learning models
The Asia-Pacific League of Associations for Rheumatology (APLAR) recently published consensus recommendations, including overarching principles, general management, and specific treatment strategies for SLE in Asia. The use of hydroxychloroquine (HCQ) in all SLE patients was recommended unless contraindicated (statement 7).1 We evaluated the current therapeutic practice with respect to anti-malarial use in the Asia Pacific region against this recommendation.
We used data from the Asia Pacific Lupus Collaboration (APLC) cohort, collected from SLE patients (meeting either ACR or SLICC criteria) between 2013 and 2020. Disease activity (SLEDAI-2K) and medication details were captured at enrolment and at routine visits. We defined medication categories based on glucocorticoid (GC), anti-malarial (AM) and immunosuppressant (IS) use at each visit and examined them in relation to clinical and serological disease activity.
We analysed 4,086 patients and 41,653 visits of data. Patients had no disease activity (i.e. SLEDAI-2K=0) in 25.5% of visits; clinical activity alone in 12.7% of visits; serological activity alone in 34.8% of visits, and both clinical and serological activity on 27% of visits. Regardless of disease activity, 78% of all patient visits were on GC, 67% on AM and 61% on IS. These proportions varied significantly among countries (
AM use was suboptimal and varied significantly across Asia Pacific countries There are disparities between current practice and Asia-Pacific SLE management guidelines, highlighting the need for knowledge dissemination.
Proportions of prednisolone (PNL), anti-malarials (AM) and immunosuppressants (IS) use, stratified by the APLC-participating countries. AU = Australia, CH=China, HK=Hong Kong, ID = Indonesia, JP = Japan, KR = Republic of Korea, MY = Malaysia, NZ = New Zealand, PH = Philippines, SG = Singapore, LK = Sri Lanka, TW = Taiwan, TH = Thailand
Mok CC, Hamijoyo L, Kasitanon N, Chen DY, Chen S, Yamaoka K, et al. The Asia-Pacific League of Associations for Rheumatology consensus statements on the management of systemic lupus erythematosus. The Lancet Rheumatology. 2021;3(7):E517-E531.
Belimumab and low dose IL2 (Ld-IL2) has been identified effective in the treatment of systemic lupus erythematosus (SLE). However, the application of combined therapy for SLE has not been documented in the real-life clinical setting. This study aims to determine the efficacy and safety of belimumab plus Ld-IL2 in patients with SLE.
A randomized clinical trial was designed as SLE patients regularly received 10 mg/kg belimumab (n=10), 1 million IU Ld-IL2 (n=10) and combined utilization (n=10). Notably, belimumab was intravenously administered once a month for 48 weeks. Ld-IL2 was injected subcutaneously every other day to week 12, subsequently once a week to week 24 as one cycle and then treated for another cycle to week 48. During the therapy, we evaluated clinical parameters every three months and detected immunological variants monthly.
Data showed that the serum IgG, anti-dsDNA and AnuA levels witnessed a substantial decline at week 48 after Belimumab combined with Ld-IL2 treatment (
Ld-IL2 synthesis with Belimumab regulated the immune balance in patients with SLE without increasing the risk for severe advents. We provide the novel insights into the favorable effect of the combined therapy in clinical practice.
The decline in clinical activity after combined treatment
Combined treatment improved the distribution of circulating T and B cell subsets in SLE patients
To evaluate belimumab (BLM) effectiveness in SLE patients from a Spanish multicenter registry.
A longitudinal retrospective multicenter cohort including SLE patients treated with belimumab. Data collection at baseline, 6, 12 months and in the last visit available. Changes in SLEDAI-2K; LLDAS and DORIS-2021 states and response according to physician were compared between visits; also changes in damage and glucocorticoids used. T-test was used for numerical variables and the Fisher’s test for categorical variables.
324 patients: 295 (91%) females with a mean (±SD) age of 42.4 (±12.9) years. Mean follow-up was 3,8 (±2.7) years and mean time with BLM was 2.7 (±2.4) years. Baseline mean SLEDAI-2K was 10.4 (±5.25). BLM was initiated with another DMARD in 67.9% of patients.
SLEDAI-2K significantly reduced in all visits. Rates of LLDAS, DORIS and clinical response according to physician criteria, significantly increased from baseline to the successive evaluations. Anti-dsDNA antibodies and inflammatory markers (ESR, CRP), significantly decreased over the time. (
107 (45,9%) patients discontinued GC. Mean (±SD) prednisone dose was significantly reduce over the visits: 12.3 (±12.16) and 4.7 (±3.7) mg/day at baseline and in the last visit, respectively (
Our data confirm belimumab efficacy in real world, reducing clinical and serological activity in the short and medium-term. BLM leads to high rates of LLDAS and DORIS at 6 months, that continue increasing over time. BLM has an important GC sparing effect and prevents organ damage accrual. BLM is useful to achieve the therapeutic goals of a T2T strategy.
Clinical response and changes in GC dose
Povetacicept (ALPN-303) is an Fc fusion protein of a variant, engineered TACI domain, which mediates significantly more potent inhibitory activity than WT TACI-Fc or BAFF- or APRIL-specific monoclonal antibodies, with enhanced pharmacokinetic (PK) and immunomodulatory properties versus WT TACI-Fc in preclinical studies. Povetacicept may therefore significantly improve clinical outcomes in systemic lupus erythematosus (SLE) and other B-cell-related diseases. This study was designed to evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of povetacicept in adult healthy volunteers (HV).
In this first-in-human study (NCT05034484), 66 adult HV were randomized 4:2 into single ascending dose cohorts of intravenous (IV) or subcutaneous (SC) povetacicept or placebo. Participants were followed to assess safety and PK, circulating immunoglobulins (Ig), and circulating leukocyte populations.
Povetacicept has been well tolerated in all cohorts evaluated as single IV or SC doses of up to 960 mg. Overall, it exhibits dose-related PK and expected PD effects, including dose-related reductions in serum IgA, IgM, IgG (
To date, povetacicept has demonstrated acceptable safety and tolerability and exhibits expected PD effects on circulating Ig. These findings support future clinical development of povetacicept in patients with SLE and/or other B-cell- and/or autoantibody-related diseases.
Povetacicept Dose-Dependently Reduces Circulating Immunoglobulins. Effects generally appear saturated ≥ 80 mg for ≥ 4 weeks
Treatment-Emergent Adverse Events
Patients with systemic lupus erythematosus may develop secondary warm autoimmune hemolytic anemia (wAIHA). wAIHA is a rare condition characterized by the premature destruction of red blood cells (RBCs) mainly in the presence of pathogenic immunoglobulin G (IgG) autoantibodies that preferentially bind to RBCs at 37°C, resulting in extravascular hemolysis of these RBCs in the spleen (or liver). Nipocalimab is a high affinity, fully human, aglycosylated, effectorless monoclonal antibody that targets the neonatal Fc receptor (FcRn) to lower circulating IgG levels, including pathogenic autoantibodies. Here we describe the rationale and study design of ENERGY, an ongoing, adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study that will evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of nipocalimab compared with placebo in patients with wAIHA (NCT04119050).
Subjects ≥18 years of age who have been diagnosed with primary idiopathic or secondary wAIHA and are currently receiving treatment for wAIHA or have previously received treatment for wAIHA will be included in the study. Stable doses of corticosteroids or immunosuppressants will be allowed. Approximately 111 patients will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, patients may enter an open-label extension period to receive nipocalimab for 144 weeks with a follow-up period of 6 weeks after last assessment.
ENERGY will include over 170 sites across nearly 20 countries. The primary endpoint is percentage of participants achieving durable response of improvement in hemoglobin (Hgb). The secondary endpoints include change from baseline in the total score from the Functional Assessment of Chronic Illness Therapy-Fatigue Scale, corticosteroid dose reduction from baseline, and normalization of hemolytic markers.
The results of ENERGY have the potential to identify a novel treatment option to address the significant unmet needs of patients with wAIHA. Enrollment is ongoing in this clinical trial.
Calprotectin, mainly secreted by neutrophils and monocytes in the condition of inflammation, has been found elevated in many autoimmune disease patients. However, there has been no study focusing on calprotectin in antiphospholipid antibodies (aPLs) positive patients. In this study, we aimed to identify the clinical associations of calprotectin in aPLs positive patients.
Consecutive patients with persistent aPLs positivity (detected at least 12 weeks apart) referred to Peking Union Medical College Hospital and age, sex-matched health controls (HCs) were included. Clinical data and aPLs profile of patients were collected. Serum calprotectin was measured using Enzyme-linked immunosorbent assay (ELISA) (Elabscience). The cutoff value was defined as mean + 2 standard deviation (SD) of HCs.
A total of 467 patients were included in the study. The median age was 34.74 [30.28, 42.50] years old, and 77.3% were female. 38 HCs were included in the study. The median age was 35.00 [32.75, 39.00] years old, and 78.9% were female. Serum calprotectin in aPLs positive patients was much higher than it in HCs (484.62±149.37 ng/ml) regardless of systemic lupus erythematosus (SLE) (p<0.001). Patients without SLE (640.98±259.96 ng/ml) had relative lower serum calprotectin than patients with SLE (690.49±268.22 ng/ml) (p=0.047,
Serum calprotectin elevates in aPLs positive patients, and could be a novel marker of microangiopathy in antiphospholipid syndrome patients. More studies are required to explore the association between calprotectin and microangiopathy in APS patients, as well as the clinical application value of calprotectin in the future.
Comparison of serum calprotectin between HCs, aPLs positive patients with and without SLE
Demographic and clinical characteristics of patients with positive and negative serum calprotectin
Incomplete systemic lupus erythematosus (iSLE) is a condition of patients with clinical and immunological signs of lupus who do not fulfill classification criteria for SLE.
Methods iSLE(n=58) was defined by rheumatologists as clinical diagnosis, not fulfilling ACR or SLICCcriteria and had no classification or specific symptoms of other rheumatic diseases. The majority of the iSLE patients were female (98%), aged 38[27–48]years.
The median age of iSLE diagnosis was 34[25–43]years. Positive family history of autoimmune rheumatic disease was in 9% of iSLEpts. In the most patients, there were no connection with any provoking factors-57%, in 16%pts the iSLE onset was associated with pregnancy, 7% each-with infection and combined oral contraceptives use, 5%-with insolation. The median disease duration was 13[2–42]months, 12(21%)pts had a disease duration of ≥5 years.
At the onset of iSLE diagnosis, the most patients had clinical and immunological signs-76%, clinical only-15%, immunological only-9%pts. The clinical manifestations were as follows: fever-29%, acute cutaneous lupus-21%, subacute-7%, discoid-2%, panniculitis-3%, non-scarring alopecia-10%, Raynaud phenomenon-5%, oral ulcers-9%, joint involvement-55%, serositis-9%, nephritis-10%, psychosis-5%, migraine-17%, leukopenia-21%, thrombocytopenia-14%, autoimmune hemolysis-7%. Autoantibody profiles revealed the presence of ANA in 83%cases, anti-dsDNA – in 47%, anti-Sm – none, antiphospholipid antibodies(aPL)-in 36% of patients. Eighteen patients (31%) exhibited low complement.
Evolution of iSLE to SLE occurred in 15(26%) of these patients, 2(3%)-to antiphospholipid syndrome, 2(3%)-to osteoarthritis, 1(2%)-to Sjögren’s syndrome, 9(16%)-to none-rheumatic diseases, with a median interval of 19[8–48]months between iSLE onset and the other definite diagnosis. Twenty six patients(45%) continue to be observed by a rheumatologist with a diagnosis of iSLE.
The most commonly clinical features in patients with iSLE are joint involvement(55%), fever(29%), hematological manifestations(28%) and cutaneous lupus(24%); among immunological disorders are positive ANA and anti-dsDNA, more than a third of iSLE patients had aPL and hypocomplementemia. Only quarter of iSLEpts were diagnosed with definite SLE within 19months.
Previous US study presented a claims-based algorithm, consisted with comorbidities and medication information, to classify systemic lupus erythematosus (SLE) severity as mild, moderate or severe. We aimed to validate algorithms to measure SLE activity in Korean claims data.
We identified SLE patients in a single academic hospital between October 2014 and August 2020. To measure SLE disease activity, we set five algorithms using diagnostic codes for comorbidities and medications: (1) previously suggested algorithm consisted of SLE-related comorbidities, immunosuppressant including rituximab, cyclophosphamide, etc., and oral glucocorticoid, (2) modified (1) by adding intravenous glucocorticoid, (3) modified (1) by adjusting glucocorticoid criteria with 55mg to differentiate between moderate and severe SLE, (4) modified (1) by adjusting glucocorticoid criteria with 5mg to differentiate between mild and moderate SLE, (5) combined algorithm (3) with (4), We assessed SLE Disease Activity Index-2000 (SLEDAI-2K) score at each visit over a year per person, and calculated average SLEDAI-2K for 1 year as gold standard. After categorizing moderate to severe ≥ 3 of SLEDAI-2K, sensitivity, specificity, positive predictive values (PPV), and negative predictive values for the algorithms to detect patients with moderate to severe SLE were estimated.
We included 151 patients with SLE. Their mean age was 34.5 ± 8.8, and 94.7% were female, presenting initial SLEDAI-2K score of 3.8 ± 3.2. For classifying moderate to severe SLE, the PPV of claims-based algorithm ranged from 75.86 to 77.19%. The algorithms (4) and (5) improved PPV up to 77.19%. However, the algorithms modifying glucocorticoid dose to differentiate between moderate and severe SLE or considering any prescriptions of intravenous glucocorticoid did not increase the PPV.
The algorithm using diagnostic codes for comorbidities and medications demonstrated PPV of 77.19% to detect moderate to severe SLE. It may be a useful for classifying SLE severity in Korean claims database studies.
We employed urine proteomics to define the molecular signatures associated with the histological features quantified by the NIH activity and chronicity indices.
We employed urine proteomics to define the molecular signatures associated with the histological features quantified by the NIH activity and chronicity indices.
Glomerular and interstitial lesions in lupus nephritis were quantified (scored 0–3) based on the revised 2018 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification for lupus nephritis and the modified NIH scoring system by a central renal pathologist (JH). Urinary proteins (1200 biomarkers, RayBiotech Kiloplex) were quantified in urine samples collected on the day of (73%) or within 3 weeks of (27%) the diagnostic kidney biopsy. Proteomic signatures of each lesion were defined based on Spearman correlations of each urine protein with each pathologic lesion.
Ninety-one biopsies were included: 32 (35%) with pure proliferative LN, 33 (36%) with pure membranous LN, and 26 (29%) with mixed LN. The 5 most correlated urinary proteins and each pathologic feature are summarized in Figure 1A-B. Most lesions in the activity or chronicity indices shared a similar signature within their respective index. In contrast, fibrous crescents displayed an inflammatory signature (CD73, MMP9, MIP1b, and IL-8) despite being part of the NIH chronicity index. Hierarchical clustering based on proteomic signatures revealed that fibrous crescents were more similar to activity-related lesions (
To examine B-cell subsets in peripheral blood of patients (pts) with systemic lupus erythematosus (SLE), and to analyze the association between the B-cell subsets and SLE activity.
Peripheral blood of 20 healthy donors, 21 SLE pts (16F/5M, Me(IQR) age 33 (29–40) years, disease duration 6,0 (0,2–12,0) months, SLEDAI-2K 6 (4–9), SDI 0 (0–1)) were assessed for B-cell subpopulations. CD19+B cells, memory B cells (CD19+CD27+), non-switched memory B cells (CD19+IgD+CD27+), switched memory B cells (CD19+IgD-CD27+), naïve (CD19+IgD+CD27-), double negative (CD19+IgD-CD27-), transitional (CD19+IgD+CD10+CD38++CD27-) B cells, and plasmablasts (CD19+CD38+++IgD-CD27+CD20-) were assessed by multicolor flow cytometry.
In pts with SLE, compared to healthy donors was found the higher percentage and abs level of memory B cells (14.4 (12.8–23.3) vs 2.15 (1.05–2.95) and 0.016 (0.007–0.03) vs 0.0025
(0.01–0.007)), the higher percentage of non-switched memory B cells (11 (8.7–19.4) vs7.35 (3.7–11.05)), the higher percentage and abs level of plasmatic cells (2.8 (1.3–4.7) vs 0.1 (0.1–0.2) and 0.002 (0.001–0.006) vs 0.0002 (0.00009–0.0004) and higher percentage and abs level of transitional cells (17.1 (9.0–30.0) vs 0.1 (0.0–0.1) and 0.019 (0.009–0.03) vs 0.0001 (0.0–0.00025)), p<0.05 for all cases.
In pts with SLE we found a significant correlation between the percentage of CD19+B cells and La-SSB (r=0.54), abs memory B cells and La-SSB (r=0.53); abs negative correlation between non-switched memory B cells and C3 (r=0.67) and C4 (r=0.66), p<0.05 for all cases.
Patients with SLE showed an increase in the percentage and absolute levels of memory B cells, non-switched memory B cells, plasmatic cells and transitional cells. We found a positive correlation between the B-cell subsets and autoantibody levels and negative correlation with the level of compliment components.
In Systemic Lupus Erythematous (SLE) patients, various anemia types are found, among others autoimmune hemolytic anemia, iron deficiency anemia (IDA) or anemia of chronic disease. Since Indonesia is located in the thalassemia belt area, thalassemia trait among SLE may exist. Therefore, this study aimed to identify the possibility of thalassemia trait among SLE patients living in Bandung, West Java, Indonesia.
This was an observational study, including complete blood count data of all female SLE patients registered in the Lupus Registry at Dr. Hasan Sadikin General Hospital throughout 2022. Erythrocyte index Shine & Lal (MCV*MCH*MCH/100) was calculated in those with low MCV value (<80 fl) and/or low MCH (<27 pg) to determine whether anemia was due to IDA (>1530) or thalassemia trait (<1530).
In total, 298 data of female SLE patients (mean aged 38+10.6 years old) were collected and the mean SLE onset was 29+9.6 years old. Low Hb (<12 mg/dl) was found in 49% (n146) of whom 23.5% were mild, 7% were moderate and 18.5% were severe anemia. Moreover, 26% (n78) had low MCV (microcytic anemia) and/or low MCH (hypochromic anemia). Interestingly, low Shine & Lal index were found in 10.7% these patients, indicating thalassemia trait.
About 10% of SLE patients in our study have been considered to carry thalassemia trait, similar to data in the general population in Indonesia. Hb-electrophoresis followed by DNA examination need to be performed to confirm this finding. Since most of SLE patients are female, and they have been mostly diagnosed as SLE in young adult age, thalassemia carrier screening is of great importance for future family planning.
Agents such as cyclosporine A(CSA) and tacrolimus(TAC) have long been used in SLEpatients. A new therapeutic approach of lupus nephritis(LN) is a multitarget therapy: calcineurin inhibitors with mycophenolate mofetil(MMF).
Here is a case report of lupus nephritis (class V) and infectious complication in a SLE patient treated with low-dose combination of CSA and MMF.
A 40-year-old woman(caucasoid), the disease debut at the age of 25, duration 16 years(since 2006), the diagnosis of SLE was established in 10.2011(full picture after childbirth). History: LN (class IV, with nephrotic syndrome, azotemia – 2011), nervous system (migraine with aura, sensorimotor polyneuropathy of the lower extremities, dysuria – 2011), arthritis and Raynaud’s phenomenon (2006, 2010), thrombocytopenia (2011), positive anti-ds-DNA, anti-Sm, ANA, hypocomplementemia (2011). In 2011, therapy was carried out with high doses of prednisolone(max 40mg/day), cyclophosphamide (total 5000mg, 2011–2012years), rituximab (1000 mg No. 2, 2012–2013years), MMF 2.5–1 g/day (2012 -2017years), hydroxychloroquine(HCQ). Low disease activity was achieved in 2016–12.2020years: therapy with prednisolone 5mg/day and HCQ 200mg/day.
In 12.2020 there was a disease relapse – isolated persistent proteinuria 1.3g/day. Repeated nephrobiopsy was performed: membranous glomerulonephritis(class V) was revealed. The dose of prednisolone was increased from 5 to 30mg/day, MMF 2 g/day was added, HCQ. After 5 months of this therapy, proteinuria did not decrease – 1.2g/day. A decision was made to switch to multitarget therapy: a combination of MMF 1g/day and CSA 150mg/day (2 mg/kg/day) from 06/14/2021, but on 07/16/2021 panaritium of the 2nd toe of the foot developed. Resumption of multitarget therapy 08/12/2021. By September 2021 proteinuria decreased to 0.6g/day, but on 09/28/2021, purulent bursitis of the right elbow joint developed. The patient was transferred to monotherapy of MMF 1–2 g/day, prednisone10–7.5mg/day, HCQ 200mg/day, proteinuria 0.18 g/day from 03.2022
Multitarget therapy with CSAandMMF is effective in treating LN(classV), but can lead to purulent infectious complications.
Serum uric acid (SUA) is a risk factor for the development of renal involvement in systemic lupus erythematosus (SLE), but the effect of SUA on renal involvement in specific genders and ages is not well known. We evaluated the association between SUA and the development of renal involvement in premenopausal female SLE patients.
We retrospectively reviewed 155 premenopausal female patients with newly diagnosed SLE in a tertiary medical center. Baseline characteristics including SUA were compared between those who did (n = 48) or did not (n = 107) develop renal involvement. Patients without baseline renal involvement were followed up to identify factors affecting future renal involvement. Time-averaged SUA was divided into four categories of increasing levels (Q1, Q2, Q3, and Q4).
At baseline, patients with renal involvement showed higher SUA than patients without renal involvement (mean, 6.3 vs. 4.2 mg/dL, p < 0.001). Among 107 patients without baseline renal involvement (median follow-up of 6.6 years), 28 (26.2%) patients developed renal involvement. Although baseline SUA did not differ between both groups, patients with developing renal involvement showed higher time-averaged SUA (median, 4.4 vs. 4.1 mg/dL, p = 0.001) and higher last SUA (median, 4.9 vs. 3.8 mg/dL, p < 0.001) than those without developing renal involvement. The incidence of developing renal involvement in each time-averaged SUA quartile was as follows; 7.1% in Q1, 14.3% in Q2, 38.5% in Q3, and 40.6% in Q4 (
In premenopausal female SLE patients, high baseline SUA is associated with renal involvement at diagnosis. In addition, high time-averaged SUA may contribute to developing future renal involvement in patients without baseline renal involvement.
Incidence of developing renal involvement according to time-averaged serum uric acid level in premenopausal female patients with systemic lupus erythematosus. Q1: < 3.9 mg/dL (n = 28), Q2: 3.9–4.1 mg/dL (n = 21), Q3: 4.2–4.6 mg/dL (n = 26), and Q4: ≥ 4.7 mg/dL (n = 32), respectively.
Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus (SLE), with 10–30% progressing to end-stage renal disease (ESRD) and requiring dialysis. Kidney transplantation (KT) is also a treatment option, but long-term graft survival remains controversial. The aim of this study is to compare the disease phenotype in patients with LN undergoing KT and RRT in comparison to that of SLE patient without LN and to estimate graft survival in a United Arab Emirates cohort who underwent renal transplantation.
10 adult LN patients with ESRD who had KT or were list for KT were age and gender matched to 15 SLE patients without LN. All patients in both groups were female.
The mean age of SLE diagnosis in patients who developed LN was 24, and the mean age of LN development was 25. The mean age of SLE diagnosis was 28.7 years, older in SLE patients without LN. At a mean age of 29 years, 50% of LN patients were started on intermittent hemodialysis. In four patients, the mean time between starting hemodialysis and having a kidney transplant was seven years. The mean age of kidney transplant recipients was 38 years old. In four patients, the mean time between diagnosis of LN and kidney transplant was 13 years. The mean duration of post-kidney transplant follow-up was 7 months. Prednisolone was used by 90% of patients with lupus nephritis and KT and 66.6% of patients with SLE without LN.
Patients with LN presented at a younger age and patients with LN undergoing kidney transplantation in the UAE remain an understudied population with sparse data, highlighting the need for additional large-scale studies of the region.
Comorbidity profile of the patients with SLE without LN and LN with ESRD who underwent or awaiting KT.
Time to complete remission, subsequent flares and time on immunosuppressives after remission are major determinants of the progression to advanced chronic kidney disease (CKD) in lupus nephritis (LN). However, the impact of these factors on the rate of glomerular filtration rate (GFR) deterioration is not known. Our objective was to determine their impact on the estimated GFR in LN.
Patients with LN based on biopsy or abnormal proteinuria (>0.5g/day) for two consecutive visits were retrieved from the Toronto Lupus Clinic database. Individuals with advanced CKD at baseline (eGFR&x2266;29ml/min/1.73m2) were excluded. All patients were followed for ≥ 5 years. The primary outcome was the annual eGFR decrease (slope). Remission: proteinuria<0.5g/24h, inactive urinary sediment, serum creatinine (SCR) &x2266;120% of baseline. Flare: abnormal proteinuria (>0.5g/day) or SCR increase from normal to abnormal or >120% of baseline after remission.
Of 418 eligible patients, 209 (50%) achieved remission within the first year, 102 (24.4%) within the 2nd/3rd years, 70 (16.7%) after 3 years and 37 (8.9%) never achieved remission. Regarding flares, 82 patients (19.6%) never flared, 75 (18%) had one flare and 261 (62.4%) had ≥2 flares. The total number of flares was 1159; 203 (17.5%) were characterized by an eGFR decrease of ≥10ml/min/1.73m2. The trajectory and annual slope of eGFR according to time to remission and number of flares is shown in the Figure.
Complete remission after 3 years or no remission is associated with a significant eGFR decrease, while remission during the 2nd/3rd year from LN diagnosis is not associated with any significant eGFR decrease over time. Patients with one flare did not have any significant impact on their renal function over time. Patients with ≥2 flares had a significant eGFR decrease over 20 years, after adjustment for other covariates. Time on immunosuppressives after complete remission is protective against eGFR decline.
Trajectory and annual slope of eGFR according to time to remission and number of flares.
Regression analysis (linear mixed model) for the outcome of eGFR
Mesangial lupus nephritis is considered benign with minimal potential for developing advanced chronic kidney disease (CKD). However, some patients still develop advanced CKD and end-stage renal disease (ESRD). Our objective was to describe the factors associated with the development of CKD stage IV or worse in patients with LN II.
Patients with mesangial LN and ≥ 1 year follow-up were retrieved from the Toronto Lupus Clinic. Biopsy was performed because of proteinuria (n=55), rising serum creatinine (n=24), active urinary sediment (n=6) and generalized lupus activity (n=6). Patients with ESRD at baseline were excluded. Individuals were followed over time for the development of advanced CKD.
Of 91 eligible patients, 10 developed advanced CKD during follow-up, 7 CKD stage IV and 3 ESRD. Baseline characteristics in
In 81/91 patients, there was no significant deterioration of the renal function after 16.8 years. Proteinuria was mild (1.17±0.89g). Fifteen patients had a repeat biopsy; histologic transformation was demonstrated in 10 (7 proliferative nephritis, 2 membranous, 1 advanced glomerulosclerosis). Sixty-three patients (67.7%) had normal renal function while 19.4% had CKD stage III (eGFR=30–59ml/min/1.73m2) at last visit.
Seven patients developed CKD IV (4 had impaired kidney function at baseline). Proteinuria was mild (<1g/day). Four had a repeat biopsy; 2 developed membranous nephropathy. Renal function remained stable (eGFR=24.2±4.3ml/min/1.73m2) after a mean of 18.5 years.
Three patients developed ESRD after 8.6, 10.3 and 16.8 years respectively. Two had a repeat biopsy demonstrating histologic transformation (proliferative nephritis, advanced glomerulosclerosis).
Advanced CKD developed in 11% of LN II patients but the progression was slow. In most cases, kidney function was impaired at diagnosis while proteinuria was mild. These findings imply that mesangial disease can occasionally lead to CKD and underlines the need for close monitoring. Treatment should not be based on the level of proteinuria alone.
Baseline characteristics of the patients (only the statistically significant differences are displayed)
Systemic lupus erythematosus (SLE) often mimics the symptoms of other diseases, and the interval between symptom onset and diagnosis remains long in these patients. The aim of this study is to examine the variables associated with a delay to diagnosis and their impact in damage accrual and mortality in patients with SLE.
GLADEL a multi-ethnic, multi-national Latin-American SLE inception cohort was studied. Patients were recruited based on the physicians’ diagnosis but 97% fulfilled the ACR criteria. Delay to diagnosis was defined as ≥6 months from the first ACR criterion to SLE diagnosis. Socio-demographic, clinical/laboratory, disease activity, damage and mortality were compared using descriptive statistical tests. Multivariable Cox regression (HR) model with damage accrual and mortality as the end points were performed.
Of the 1437 included in this analysis, the median delay to diagnosis was 5.9 months (Q1-Q3 2.4–16.1) and 721 (50.2%) had ≥6 months delay in SLE diagnosis. Patients with delay in diagnosis were more frequently of female gender, older age at diagnosis, mestizo ethnicity and without medical insurance. The characteristics of patients according to delay in diagnosis are depicted in
In the GLADEL cohort, delay to diagnosis was associated to sex, age, thrombosis, sicca syndrome, cutaneous and neurological involvement. Furthermore, delay to diagnosis had no apparent negative impact on disease outcome (damage accrual and mortality). Early referral when there are suspicious clinical manifestations of SLE is crucial to reduce the diagnostic delay.
Comparison between the two patient groups in relation at the time to SLE diagnosis.
Systemic lupus erythematosus (SLE) is heterogeneous autoimmune disease. Identification of patient clusters may be useful for the management of the disease. The aim of this study is to describe different SLE clusters according to sociodemographic, clinical and serological characteristics.
GLADEL 2.0 is an ongoing Latin-American observational cohort initiated in 2019. Variables chosen at cohort entry to stratify patients and construct clusters were selected from sociodemographic and cumulative clinical and serological variables. Hierarchical cluster analyses were performed by the Ward method on a distance matrix using the Gower’s method.
A total of 560 SLE patients were included in this analysis. Three clusters were identified. Cluster 1 (n=269) was characterized by more cutaneous, articular, renal and serosal involvement; serological manifestation was positive anti-dsDNA. Cluster 2 (n=194) was represented by patients who rarely had renal involvement and the most frequent clinical manifestations were cutaneous and hematological; the most frequent serological manifestations were the presence of antiphospholipid antibodies (aPLs). Cluster 3 (n=97) was characterized by a lower frequency of clinical and serological involvements, with the exception of neurological domain. Clusters 1 and 2 share hematologic manifestations and hypocomplementemia (
In this cohort, three clusters were identified. Cluster 1 patients were characterized by renal, articular, cutaneous and serositis involvement, anti-dsDNA antibodies and hypocomplementemia, Cluster 2 patients were characterized by hematologic, cutaneous involvement, aPLs and hypocomplementemia. Cluster 3 patients presented fewer serological findings but a higher frequency of neurological involvement. Follow up of these patients will allow for elucidation of relationship of these clusters with SLE outcomes.
Clustering of GLADEL 2.0 SLE patients based on sociodemographic, serological and clinical characteristics
Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis.¹–² Deucravacitinib demonstrated efficacy across multiple outcome measures, including achievement of ≥50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity score (CLASI-50), in a phase 2 trial in patients with systemic lupus erythematosus (SLE)3 and is being investigated in two phase 3 trials (NCT05617677; NCT05620407). Patients with discoid and/or subacute cutaneous lupus erythematosus (DLE/SCLE) have elevated expression of Type I interferons (IFN).4 Deucravacitinib mediates signaling of Type I IFN, IL-12, and IL-23 and may be an effective treatment for patients with DLE/SCLE.5 Results of this ongoing phase 2 trial (NCT04857034) will characterize the efficacy and safety of deucravacitinib compared with placebo in patients with active DLE/SCLE with or without SLE.
This phase 2, global, randomized, double-blind, placebo-controlled trial is enrolling adults (aged 18–75) with biopsy-confirmed clinical diagnosis of DLE/SCLE. Key eligibility criteria and study design are depicted below (
Planned enrollment is 75 total patients (25 per double-blind treatment group) in 8 countries in North and South America, Europe, and Asia-Pacific regions.
This phase 2 trial will characterize the efficacy, safety, and tolerability of deucravacitinib in patients with active DLE/SCLE.
Trial design
Primary and secondary endpoints assessed at week 16
Armstrong A, et al. J Am Acad Dermatol 2023;88(1):29–39. Strober B, et al. J Am Acad Dermatol 2023;88(1):40–51. Morand E, et al. Arthritis Rheumatol 2022 Nov 11 (Epub ahead of print). Braunstein I, et al. Br J Dermatol 2012;166(5):971–975. Burke JR, et al. Sci Transl Med 2019;11(502):eaaw1736.
Belimumab in conjunction with mycophenolate mofetil has been proven to be effective for treating systemic lupus erythematosus (SLE) in several randomized controlled trials. Usefulness of calcineurin inhibitors has also been reported in controlling the activity of SLE. However, the safety and effectiveness of belimumab-calcineurin inhibitor combination therapy have not been addressed. Therefore, we conducted a single-center retrospective study to analyze the safety/efficacy profile of belimumab-tacrolimus (B-T) combination therapy in patients with SLE.
Patients with SLE administered belimumab and tacrolimus during their treatment were included in the study, and samples collected were analyzed for the drug retention rate/SLE flare rate/infection incidence rate/glucocorticoid-sparing effect of the B-T combination therapy.
Thirty-three patients with SLE were treated with B-T combination therapy at our institution. Four patients discontinued the treatment because of insufficient response/adverse events. The drug retention rate was over 90% at week 52 and approximately 80% at day 1000. Only one patient developed serious infection.
The lupus low disease activity state (LLDAS) achievement ratio was 9.1% on the day of initiation and improved to 64.0% at 52 weeks after initiation.
SLE flares were observed in only three patients (9.1%) in the first 52 weeks after initiation, and in five patients (15.2%) throughout the study period. A glucocorticoid-reducing effect was also observed in patients treated with B-T combination therapy.
In most patients with SLE, B-T combination therapy was well tolerated, and showed a good efficacy profile and glucocorticoid-reducing effect. Thus, B-T combination therapy can be a feasible option for patients with refractory lupus.
Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis.¹ ² Deucravacitinib binds the unique TYK2 regulatory domain, conferring greater functional selectivity vs JAK inhibitors, which bind the catalytic domain. Deucravacitinib showed superior efficacy vs placebo in a phase 2 trial in SLE (NCT03252587).3 This analysis assessed the pharmacokinetics (PK), selectivity profile compared to JAK inhibitors, and exposure-response (E-R) relationship for efficacy and safety of deucravacitinib in SLE.
In the phase 2 trial, patients with active SLE were randomized 1:1:1:1 to placebo or deucravacitinib (3 mg BID, 6 mg BID, 12 mg QD). PK analysis included pooled concentration data from 266 SLE patients and 328 phase 1 participants. IC50 was determined by in vitro whole blood assays and plotted against PK profiles. E-R analyses included data from 356 patients. Logistic regression analyses assessed the relationship between deucravacitinib exposure and probability of achieving efficacy endpoints and safety events at weeks 32 and 48.
Deucravacitinib PK in SLE patients was not meaningfully different from that in phase 1 participants. At 12 mg QD, deucravacitinib Cmax was 8-fold lower than JAK 1/3 IC50 and 47-fold lower than JAK 2/2 IC50 (
Deucravacitinib PK in SLE patients is not meaningfully different from that in phase 1 participants. At clinically relevant exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 vs JAK 1/2/3. The deucravacitinib E-R relationships are well characterized for various efficacy endpoints and safety events.
Plasma concentration-time profile of deucravacitinib, baricitinib, tofacitinib, and upadacitinib along with their respective whole blood IC50 curves
Armstrong A, et al. J Am Acad Dermatol 2023;88(1):29–39. Strober B, et al. J Am Acad Dermatol 2023;88(1):40–51. Morand E, et al. Arthritis Rheumatol 2022 Nov 11 (Epub ahead of print).
Aberrant toll-like receptor (TLR) 7/8 activation is thought to be involved in both lupus pathogenesis and glucocorticoid resistance. Enpatoran, a selective and potent dual inhibitor of TLR7/8 that is in development for cutaneous and systemic lupus erythematosus (CLE/SLE), was well tolerated by healthy participants and patients hospitalized with COVID-19 pneumonia. We report evaluation of the glucocorticoid-sparing effect of enpatoran and a trial design to assess its efficacy and safety in patients with SLE and/or CLE.
Cytokine concentrations and gene expression changes were measured in stimulated human peripheral blood mononuclear cells (PBMCs) from healthy donors after treatment with dexamethasone, TLR7/8 inhibitor, or both. A Phase II basket design, proof-of-concept, dose-finding, randomized, double-blind, placebo-controlled 24-week study in patients with SLE and/or CLE (WILLOW; NCT05162586), which will also assess glucocorticoid sparing, was designed.
In healthy donor PBMCs, synergy was observed between TLR7/8 inhibitor and dexamethasone. Combination treatment inhibited cytokine release (interleukin-6) with greater potency than either treatment alone and reduced the expression of nuclear factor-kappa B and interferon-regulated genes. Glucocorticoid sparing will be evaluated by a mandatory tapering schedule in the WILLOW study, which has two cohorts (
Enpatoran is a novel TLR7/8 inhibitor and may enable glucocorticoid dose reduction in patients with SLE and CLE. The WILLOW study incorporates multiple novel elements including a basket design and evaluation of glucocorticoid sparing.
WILLOW study design
Wide-ranging placebo responses challenge SLE trials. This analysis aims to identify predictors of SOC+PBO response in patients with SLE.
Analyses used the SOC+PBO arm of the phase 2b trial of dapirolizumab pegol (NCT02804763), a polyethylene glycol conjugated antigen-binding fragment lacking a functional Fc domain, which inhibits CD40-CD40L interaction.¹ Response was assessed by BILAG-based Composite Lupus Assessment (BICLA) response at Week 24.² Univariate/multivariate analyses were performed, with 22 previously determined potential predictors. Stepwise multivariate analysis included univariate predictors with p<0.25, using p≤0.10 as entry/stay criteria. Disease activity at screening was defined using BILAG 2004 item level scores as acute flare (worsening/new symptoms) or persistent (symptoms the same) based on the past 4 weeks compared with the prior 4 weeks; low C3/C4 was defined as below the lower limit of normal at screening. Results were supported by additional biologic clinical trial datasets.
Univariate analysis found the following significant predictors of BICLA non-response at Week 24 (p<0.05): persistent disease (vs acute flare; p=0.003), low C3 and/or C4 (vs normal; p=0.007), low C4 (vs normal; p=0.007), low C3 (vs normal; p=0.042), and SLEDAI-2K score ≥10 (vs <10; p=0.044) (
To explore the impact of identified predictors, subgroup analyses showed a higher proportion of patients with acute flare without low C3/C4 (n=10) achieved BICLA response at Week 24 vs patients with acute flare and low C3/C4 or persistent disease activity (n=33) (80.0% vs 24.2%; p=0.005 for OR vs acute flare without low C3/C4).
Acute flare with normal complement predicted high placebo response in this analysis. Recent medical history should be considered when defining SLE study populations.
Univariate analysis of predictors of BICLA response at Week 24 in patients who received SOC+PBO. Anti-dsDNA: anti-double-stranded deoxyribonucleic acid; BICLA: BILAG-based Composite Lupus Assessment; BILAG: British Isles Lupus Assessment Group; CLASI: Cutaneous Lupus Erythematosus Disease Area and Severity Index; m: months; PBO: placebo; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000; SOC: standard of care.
Furie RA. Rheumatology (Oxford) 2021;60:5397–407. Wallace D. Arthritis Rheum 2011;63(Suppl 10):S885.
The ‘skin-deep resilience’ hypothesis suggests that Black Americans from disadvantaged backgrounds who persevere and attain academic or professional success despite various social obstacles may nevertheless suffer from poorer underlying physical health. This study examined the ‘skin-deep resilience’ phenomenon among Black American women with systemic lupus erythematosus (SLE).
Data were from the Black Women’s Experiences Living with Lupus (BeWELL) Study, which recruited largely from a population-based sample of Black women living with SLE in metropolitan Atlanta, GA, USA (n=438). Multivariable linear regression models were specified examining SLE disease activity measured using the patient-reported Systemic Lupus Activity Questionnaire (SLAQ), in relation to educational attainment, adverse childhood experiences (ACEs), and experiences of racial discrimination in adulthood. We examined whether associations between racial discrimination and disease activity differed by educational attainment and ACEs, particularly for those who achieved high levels of education despite greater childhood adversity—an indicator of resilience.
We found a significant three-way interaction between educational attainment, ACEs, and racial discrimination, consistent with the skin-deep resilience hypothesis (F(26,399)=2.92, p=.02). As expected, racial discrimination was positively associated with disease activity (b=1.89, 95% Confidence Interval [CI] [1.19, 2.59], p<.001). However, this relationship was strongest among those who experienced greater childhood adversity and attained a graduate degree, in other words, those who were highly resilient. There was no interaction between education attainment and racial discrimination among those who experienced low childhood adversity.
Findings suggest that ‘highly resilient’ Black women living with SLE (those who achieved a graduate degree despite high childhood adversity), were the most physically impacted by experiences of high racial discrimination. This study challenges traditional conceptualizations of resilience by demonstrating the unintended physical health tolls of ‘building resilience’ without addressing other social and structural inequities stemming from racism.
To investigate the prevalence and level of agreement between remission according to physician and patient criteria and to evaluate the impact of remission on HRQoL in patients with SLE.
Prospective study of patients included in RELESSER-PROS, a multicenter register of SLE patients, protocol previously described.1 Remission according to physician was defined in agreement with DORIS 2021 criteria.2 Remission according to patient was defined as SLAQ (Systemic Lupus Activity Questionnaire) question 1 with no flare in the last 3 months (score 0).
Patients were classified in three groups according to remission status (DORIS, SLAQ, both). Level of agreement was assessed using kappa statistics, considered acceptable if kappa>0.60.
1102 patients, with a follow-up of at least 2 years (data from 3 visits available) were included. Patient characteristics according remission status at baseline are presented in the
Our results reflect low level of agreement between physician and patients in terms of remission status with increasing disagreement in the follow-up. Patients in remission by DORIS shows better results in EQ-5D and LIT.
Patient characteristics according remission status at baseline
Rúa-Figueroa I, et al. Reumatol Clin. 2014;10(1):17–24. van Vollenhoven RF, et al. Lupus Sci Med. 2021;8(1):e000538.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibody production and follicular helper T cells (Tfh) play a crucial role in this process. A recent study revealed that a rare genetic variant in the myocytes enhancer factor 2D (MEF2D) gene is found in a subgroup of Swedish SLE patients and is strongly associated with autoantibodies. Considering that the MEF2D transcription factor is known to negative regulator in neuronal synapse formation, we hypothesized that MEF2D expression in CD4 T cells controls Tfh differentiation and humoral (auto)immunity by regulating B:T synapse formation.
MEF2D expression was measured in total peripheral blood CD4 T cells of healthy individuals and SLE patients and was compared with the magnitude of autoimmune features. The function of Mef2d in Tfh differentiation and humoral immunity was investigated with murine antigen (Ag)-specific CD4 T cells in the context of protein immunization.
CD4 T cells of SLE patients had significantly downregulated MEF2D expression compared to those of healthy individuals with robust negative associations with circulating Tfh (cTfh) cell frequency and autoimmune parameters of SLE. Ectopic Mef2d expression in murine Ag-specific CD4 T cells led to profound defects in germinal center (GC)-Tfh differentiation and GC formation after NP-OVA immunization by directly suppressing the Sh2d1a gene that encodes SAP. Consequently, Mef2d overexpressed CD4 T cells exhibited lower conjugate formation with cognate Ag-presenting B cells compared to those of control. Mef2d deficiency in CD4 T cells, on the contrary, resulted in a spark increase in GC-Tfh differentiation with enhanced SAP expression implying that Mef2d expression in CD4 T cells is associated with abnormal Tfh cell generation.
These data provide important implications for the regulatory function of MEF2D (Mef2d) in modulating (aberrant) Tfh differentiation and TD humoral (auto)immunity.
The antinuclear antibody (ANA)-positive asymptomatic individuals are at higher risk of developing systemic lupus erythematosus (SLE). However, the genetic burden for SLE in preclinical ANA-positive phase remains largely unknown. In this study, we analyzed SLE-specific polygenic risk scores (PRSs) from a prospective cohort comprising Korean individuals with preclinical autoantibodies, SLE, or none of these conditions to understand the effect of SLE-risk genetic variants on the development of ANA.
The PRS for SLE was calculated from genome-wide variants data obtained from 349 individuals with preclinical autoimmunity, 2,057 patients with SLE, and 33,596 healthy controls based on the known risk effects of 180 SLE-risk variants. Preclinical autoantibodies-positive individuals who were diagnosed by rheumatologists, tested positive for at least one among ANA, rheumatoid factor (RF), or anti-cyclic citrullinated peptide autoantibody (anti-CCP). Differences in PRSs among phenotypic groups were assessed using ANOVA with adjustment for genotypic principal components and sex while controlling for the family-wise error rate.
There was a significant increase in the SLE PRS in the preclinical ANA-positive group (ANA titers ≥ 1:160) compared to healthy controls (p=2.69x10–5) and the preclinical ANA-negative group with preclinical autoimmunity (positive for RF or anti-CCP) (p=2.42x10–²), although their SLE genetic burden was significantly weaker than patients with SLE (p=7.48x10–²5). In addition, SLE PRSs were gradually increased according to the level of ANA titers in a stratified analysis (p=2.38x10–3,
This study demonstrated that the genetic burden for SLE contributes to the preclinical development of ANA.
Polygenic risk scores (PRSs) for SLE were plotted based on the following phenotypes: healthy controls, preclinical autoimmunity, and SLE. The individuals with preclinical autoimmunity were divided into four groups according to antinuclear antibody (ANA) titers
The Cutaneous Lupus Disease Activity and Severity Index (CLASI) is a responsive outcome instrument with high inter- and intra-rater reliability in patients with cutaneous lupus erythematosus (CLE). Recently, there has been discussion about the activity alopecia and mucous membrane components of the CLASI. Overlap of these elements with non-lupus etiologies poses the question if alopecia and mucous membrane signs are important to capture.
In this retrospective study of our prospectively collected data, we examined whether the CLASI could capture a similar degree of clinical change with the removal of these components. 171 patients with alopecia and/or oral activity, two consecutive visits, and a CLASI activity (CLASI-A) ≥4 were selected for this study and grouped according to alopecia involvement. Percent change in CLASI-A scores before and after removal of alopecia and mucous membrane components were compared for each patient. Statistical analysis was performed using Paired Wilcoxon Signed Rank Test.
Following removal of these components, there was a -1.39% median difference (IQR 49.18, p=0.457) in CLASI-A percent change for patients with recent hair loss or mucous membrane lesions (n=34), -2.08% median difference (IQR 137.66, p=0.013) for patients with diffuse hair loss (n=26), and -11.76% median difference (IQR 42.13, p=0.002) for patients with focal/patchy alopecia in one or more quadrants (n=111). The percentage difference change was most significant for patients with focal/patchy alopecia compared to patients with diffuse alopecia and recent hair loss.
Exclusion of alopecia and mucous membrane involvement from the CLASI-A score limits capturing valuable objective clinical information on disease activity. This is problem given that activity alopecia greatly impacts quality of life for patients with CLE. These components should be retained and continued to be scored, as supported by the extensive validation of the CLASI.
To study the relationship between the 2019 EULAR/ACR classification criteria and organ damage in patients with SLE
Patients involved in a cross-sectional validation study of the EULAR/ACR criteria and judged by a panel to be clinical SLE were studied. Those who fulfilled the EULAR/ACR criteria (last visit) were stratified into 2 groups based on a cut-off score of 20. The last SLICC organ damage index (SDI) was compared between these two groups. Relationship among the domains of the EULAR/ACR criteria and SDI in all patients was studied by Spearman’s rank correlation.
562 SLE patients were studied (93.6% women; age 36.5±14.1 years; disease duration 11.6±6.6 years). The mean and median EULAR/ACR criteria scores in those fulfilling the EULAR/ACR criteria (N=542) was 24.6±7.3 and 24 (IQR 19–30), respectively. 392 patients had EULAR/ACR scores of ≥20 (group 1) and 150 patients had scores of 10–19 (group 2). Group 1 had significantly higher prevalence of fever, alopecia, oral ulcers, acute lupus skin lesions, arthritis, serositis, seizure, hemolytic anemia, leukopenia and renal disease, and so were the anti-dsDNA, anti-Sm, antiphospholipid antibodies and low complement state. Organ damage (SDI score of ≥1) occurred in 232 (42.8%) patients. Patients in group 1 had significantly higher SDI scores in the renal, cardiovascular, dermatological and gonadal domains than group 2. The renal, neuropsychiatric and aPL antibodies domain scores of the EULAR/ACR criteria correlated positively with the total SDI. The renal domain of the EULAR/ACR criteria had the strongest correlation with renal damage (Rho 0.30; p<0.001). Patients who scored 10 points in the renal domain had significantly higher renal damage score than those scored 8 points or 4
In addition to disease classification, the EULAR/ACR SLE criteria may have a role in.
Signaling driven by nucleic acid sensors participates in interferonopathy-mediated autoimmune diseases. NLRP12, a pyrin-containing NLR protein, is a negative regulator of innate immune activation and type I interferon (IFN-I) production.
SLE patients enrolled in this study will be analyzed the NLRP12 and IFNA expression in their Peripheral blood mononuclear cells (PBMCs), and their corresponding serological markers were recorded to determine the correlation between level of NLRP12 expression and serological markers. Regulation of NLRP12 expression was analyzed with the luciferase reporter assay, and the specific transcription factor on the NLRP12 promoter was determined with the chromatin immunoprecipitation assay (ChIP) in SLE PBMCs. The spontaneous activation of SLE PBMCs and the hyperresponsiveness of SLE PBMCs to nucleic acid stimulation toward cytokine production was analyzed. Nlrp12 deficient mouse was applied to confirm the role of NLRP12 in the pathogenesis of lupus progression.
PBMCs derived from systemic lupus erythematosus (SLE) patients expressed lower levels of NLRP12, with an inverse correlation with IFNA expression and high disease activity. NLRP12 expression was transcriptionally suppressed by runt-related transcription factor 1–dependent (RUNX1-dependent) epigenetic regulation under IFN-I treatment, which enhanced a negative feedback loop between low NLRP12 expression and IFN-I production. Reduced NLRP12 protein levels in SLE monocytes were linked to spontaneous activation of innate immune signaling and hyperresponsiveness to nucleic acid stimulations. Pristane-treated Nlrp12–/– mice exhibited augmented inflammation and immune responses; and substantial lymphoid hypertrophy was characterized in NLRP12-deficient lupus-prone mice. The NLRP12 deficiency mediated- increase of autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and the deterioration of kidney function were bound to IFN-I signature-dependent manner in the mouse models.
These findings highlight a relationship between low NLRP12 expression and SLE progression with implications as a treatment target. We also suggest the level of NLRP12 expression on homeostasis and immune resilience.
Tripartite motif-containing protein (TRIM) 21 is an E3 ubiquitin-protein ligase, involved in the ubiquitin-dependent proteolysis pathway of various proteins including factors related to type I interferon pathways. Although the presence of autoantibodies against TRIM21 in various autoimmune diseases suggests potential pathogenetic roles, no studies have clarified its exact implications, especially in lupus. We aimed to elucidate the functions of TRIM21 in the dysregulation of type I interferon signals in lupus.
To investigate the effects of TRIM21 dysfunction in lupus pathogenesis, two independent lupus animal models, the R848-induced model and the B6/lpr mice model were performed using TRIM21 knockout mice, and their phenotypes and immunological profiles were determined. In addition, we investigated the degree of TRIM21 dysfunction and therapeutic effects of in vivo delivery of TRIM21 in MRL/lpr mice. To evaluate the E3 ubiquitin ligase activity of TRIM21 for targeted proteins in type I interferon pathways, we performed a specialized immunoblot assay.
The R848 induced model and the B6/lpr model both presented with more severe lupus-like phenotypes such as nephritis, lymphadenopathies, and inflammatory immune cell profiles in TRIM21 knockout mice than in control mice. TRIM21 deficiency resulted in activation of intracellular factors related to type I interferon pathways such as STING, TBK1, and IRF3 in both models. MRL/lpr mice presented with activation of type I interferon pathways including STING, TBK1, and IRF3, and decreased expressions of TRIM21. Overexpression of TRIM21 attenuated the disease phenotypes in MRL/lpr mice. Using immunoblot assay, we observed E3 ubiquitin ligase activity of TRIM21 directly targeting STING via the proteasome pathway.
TRIM21 dysfunction induces dysregulation of STING-type I interferon pathways and exacerbates the disease in lupus animal models. Targeting TRIM21-STING-type I interferon axis can be a novel therapeutic strategy in lupus treatment.
Heterozygous STAT1 gain-of-function (GOF) mutations result in a predisposition to early-onset humoral autoimmunity, including lupus-like disease. Since multiple STAT1-dependent cytokines are implicated in lupus pathogenesis, we hypothesized that insights into STAT1 GOF disease mechanisms might inform our understanding of polygenic SLE.
We performed multiparameter CyTOF immunophenotyping of human STAT1 GOF syndrome (8 pediatric STAT1 GOF patients and 9 age-matched controls). In parallel, we generated an inducible knock-in mouse strain allowing lineage-specific expression of the pathogenic STAT1 R274Q human mutation.
STAT1 GOF subjects exhibited dysregulated CD4+ T cell and B cell activation, including expansion of Th1-skewed CXCR3+ circulating T follicular helper (cTFH) cells and CXCR3+ activated B cells. These expanded B and T cell populations correlated with autoantibody titers, suggesting a mechanistic link with breaks in tolerance. Notably, STAT1 GOF B cells downregulated CXCR5, reminiscent of extra-follicular B cell activation in SLE.
To gain mechanistic insights, we used our new murine model to study the cytokine signals driving STAT1 GOF autoimmunity, focusing on STAT1-dependent Type 1 and Type 2 interferon (IFN) receptors. As predicted, Stat1 GOF transgenic mice developed spontaneous lupus-like autoimmunity. However, in contrast to the prevailing Type 1 IFN-centric model for STAT1 GOF and lupus autoimmunity, Stat1GOF mice lacking the type 1 IFN receptor (IFNAR) were only partially protected from STAT1-driven systemic inflammation, whereas loss of Type 2 IFN (IFN-) signals abrogated autoimmunity. Finally, we show that pathogenic mutations promote increased total STAT1 protein levels, while IFN- receptor deletion normalized total STAT1 expression across immune lineages.
We identify IFN- as the critical driver of feedforward STAT1 elevation and humoral autoimmunity in STAT1 GOF syndrome. These data implicate a similar STAT1-dependent mechanism in lupus pathogenesis, by driving the extra-follicular activation of autoreactive B cells.
To study the effect of COVID-19 infection on disease flares and herpes zoster (HZ) reactivation in patients with SLE
We identified patients who fulfilled the SLICC criteria for SLE and had documented COVID-19 infection (Omicron and its variants) between Feb-Nov 2022 and SLE controls who did not have COVID-19 randomly matched for age, sex and the period of COVID infection in a 1:2 ratio. The primary outcomes of interest were SLE flares and HZ infection within 90 days of COVID-19 infection. SLE flares were assessed by the SELENA flare instruments, with modifications. The rates of SLE flares and HZ reactivation were compared between the two groups
91 SLE patients with COVID-19 infection (age 48.6±14.0 years; 95.6% women; SLE duration 14.2±8.3 years; 53% history of lupus nephritis) and 182 matched SLE controls not infected by COVID-19 were studied. 11/90 (12.2%) COVID-infected patients had serious manifestations (oxygen requirement, use of mechanical ventilator, lung infiltrates on imaging studies or admission to the ICU). One (1.1%) patient died and 7(7.7%) patients developed severe complications. Within 90 days of COVID-19 infection, 14 (15.4%) patients developed mild/moderate SLE flares and 2 (2.2%) patients had severe SLE flares, and the rate of any flares was significantly higher than those not infected with COVID (17.6% vs 5.5%; p=0.001). Among COVID-19 infected patients, those with SLE flares had significantly lower C3 values (p=0.004). HZ reactivation occurred in 2 patients (2.2%) with COVID-19 infection, which was numerically higher than those not infected with COVID (2 patients, 1.1%; p=0.48)
Clinical flares within 90 days were significantly more frequent in SLE patients infected with COVID-19 than age/gender matched non-infected SLE controls. HZ reactivation occurred at a numerically higher rate after COVID-19 infection in SLE patients than controls.
Although many studies have been conducted within COVID-19, there are still unanswered questions regarding breakthrough infections (BTIs), particularly in patients with systemic lupus erythematosus (SLE). We aimed to determine the occurrence of breakthrough COVID-19 infections in patients with SLE versus other autoimmune rheumatic diseases (AIRDs), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HCs).
The study was based on data from the COVAD questionnaire which amassed a total of 10,783 complete responses from patients with SLE, AIRD, or nrAIRD, and HCs. After exclusion of individuals who were unvaccinated, those who received one vaccine dose only, and those with uncertain responses regarding the vaccine doses, a total of 9,595 patients formed the study population of the present investigation. If a COVID-19 infection occurred after the initial two vaccine doses and at least one booster dose (herein termed full vaccination), it was considered a BTI. Data were analysed using multivariable regression models.
Among SLE patients, 867/1,218 (71.2%) were fully vaccinated. BTI frequencies in fully vaccinated SLE patients were comparable to those of other AIRDs (OR: 1.0; 95% CI: 0.8–1.3; p=0.447) and nrAIDS (OR: 0.9; 95% CI: 0.6–1.3; p=0.856) but higher compared with HCs (OR:1.2; 95% CI: 1.0–1.6; p=0.022). Compared with HCs (OR: 10.6; 95% CI: 1.2–93.0; p=0.032) and other AIRDs (OR: 3.5; 95% CI: 1.08–11.5; p=0.036), SLE patients showed higher frequencies of hospitalisation.
COVID-19 BTIs occurred in nearly 1 every 6th fully vaccinated patient with SLE. Moreover, BTIs in SLE patients were more severe compared with BTIs in HCs or patients with AIRDs other than SLE, resulting in a greater need for hospitalisation. These insights call for greater attention to vaccination in the vulnerable group of SLE patients, with appropriate risk stratification towards optimised vaccination strategies.
Corticosteroid (CS) is effective for controlling inflammatory reactions in SLE, but may have been known to increase risk of avascular necrosis (AVN) in patients with Systemic lupus erythematosus (SLE). This population-based study aims to investigate the association between cumulative dose of CS and the incidence of AVN in newly diagnosed SLE patients.
We conducted a nested case-control study using Korean National Health Insurance claims database from 2002 to 2018. Cohort of incident diagnosis of SLE (ICD10, M32) with rare intractable disease code (V136) were identified during 2007~2018. Cases, who were diagnosed for any reason with AVN (M87.0x, M87.1x, M87.3x, M87.8x, M87.9x, M90.5x (ICD-10)), were matched up to 10 controls based on gender, age (±5yrs), and date of SLE diagnosis (±6 months). Conditional logistic regression analysis was performed to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of AVN occurrence associated with cumulative dose of CS [prednisolone-equivalent dose (PED)] from the date of SLE diagnosis to the index date, with adjusting for hypertension, dyslipidemia, immunosuppressants and so forth. Cumulative CS dose was categorized into 3 groups (0≤ < 4g, 4≤ <8g and 8g≤) based on distribution in the study population.
Among the 12,375 SLE patients who were newly diagnosed during the inclusion period, a total of 358 AVN patients were identified. Controls without AVN (N=3,276) were identified. In terms of cumulative CS dose, used after first diagnosis of SLE, compared with cumulative CS dose less than 4g, ORs associated with 4≤ <8g and 8g≤ group were 2.48 (95% CI 1.70 – 3.64) and 6.14 (95% CI 4.20 – 8.93), respectively.
The trend of association between higher cumulative CS dose and risk of AVN may provide evidence for monitoring patients with continuous use of CS for SLE management, especially in aspect of cumulative dose of CS.
Ianalumab (VAY736; defucosylated, human IgG1 anti-BAFF-receptor mAb), provides both antibody-dependent cellular cytotoxicity-mediated B cell depletion and BAFF-receptor signaling blockade. We report here ianalumab safety and efficacy in patients with active SLE.
Placebo-controlled, randomized, parallel group, double-blind treatment cohort within a multi-center platform trial. Patients with ANA ≥1:80 and meeting ≥4/11 ACR 1997 SLE classification criteria, with SLEDAI-2K score ≥6 and BILAG-2004 ≥1A or ≥2B, including activity in either mucocutaneous and/or musculoskeletal domains were enrolled. We report interim analysis for the first 48 patients enrolled into the ianalumab-treatment cohort (active=22, placebo=26) completing the 28-week (w) blinded treatment period, comprised of ianalumab 300mg or placebo monthly s.c. injections. Outcomes were measured at baseline and every 4w till w28. Primary outcome was proportion patients meeting composite endpoint: achieving w28 SRI-4 and tapering predniso(lo)ne to ≤5 mg/d or ≤baseline dose, whichever was lower, by w16 and remaining so to w28. Secondary/exploratory outcomes included safety, incidence moderate/severe flare (BILAG-2004 ≥1A or ≥2B), LLDAS, SLEDAI-2K, BILAG-2004, and physician/patient global VAS.
Ianalumab was safe/well-tolerated with no drug-related SAE or dropouts and one pandemic-related discontinuation in placebo arm. Mean age=40y; 7 males (placebo=5, ianalumab=2). Baseline mean(range) for ianalumab and placebo was: SLEDAI-2K, 12.4(6–32) and 11.6(4–21), and predniso(lo)ne 11.3mg(3–30) and 11.4mg(3–28). Proportion ianalumab or placebo patients achieving w28 SRI-4 (
Treatment of SLE with ianalumab was safe, well tolerated, and more patients achieved composite primary endpoint SRI-4 with sustained steroid reduction vs. placebo arm, with other evidence for clinical improvement, including reductions in moderate/severe flares and LLDAS.
Proportion patients attaining SRI-4 and achieving w28 composite endpoint
Hydroxychloroquine is one of the major treatment of SLE, but its effectiveness is impaired by non-adherence, reported to range from 3% to 85% in SLE patients. Our objective was to assess the associations of severe non-adherence to HCQ, objectively assessed by HCQ serum levels, and risks of SLE flares, damage, and mortality over 5 years of follow-up.
The SLICC Inception Cohort is a multicenter initiative (33 centers; 11 countries). Serum of patients taking HCQ for at least 3 months, sampled at enrolment or during the first-year follow-up visit, were analyzed. Severe non-adherence was defined by a serum HCQ level <106 ng/ml or <53 ng/ml, for daily HCQ doses of 400 or 200 mg/d, respectively. Association with the risk of a flare (defined as a SLEDAI-2K increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) was studied with logistic regression, and association with damage (first SLICC/ACR Damage Index (SDI) increase ≥1 point) and mortality were studied with separate Cox proportional hazard models.
Of 1849 cohort subjects, 660 patients (88% women) were included. Median [interquartile range] serum HCQ was 388 ng/ml (244–566); 48 patients (7.3%) had severe HCQ non-adherence. No factors were clearly associated with severe non-adherence. Severe non-adherence was independently associated with flare (OR 3.38; 95% CI 1.80–6.42) and of an increase in the SDI within each of the first 3 years (HR 1.92 at 3 years; 95% CI 1.05–3.50). Eleven patients died within 5 years, including 3 with severe non-adherence (HR 5.41; 95% CI 1.43–20.39).
Severe non-adherence was independently associated with the risk of an SLE flare in the following year, with early damage and 5-year mortality. Our results suggest the benefits of testing of detecting severe non-adherence and dedicating more resources and more time to these patients, to improve their long-term prognosis.
Pregnant SLE women are at high risk of pre-eclampsia. Aspirin reduces its risk but is used only in a minority of SLE pregnancies. This randomized controlled trial evaluated a specifically-designed educational tool on pre-eclampsia knowledge, aspirin use and adherence in SLE pregnancies. We present interim results.
We recruited pregnant SLE women up to 16 gestational weeks at 5 Canadian SLICC centres. Participants were randomly assigned to the educational tool (intervention) or standard of care (control). At every pregnancy visit, participants completed pre-eclampsia questionnaire, aspirin survey, and modified Adherence to Refills and Medications Scale (ARMS). We performed Student’s t-test and univariate linear regression to assess pre-eclampsia knowledge, and estimated 95% CI for difference in proportion of aspirin users using the Wilson procedure. We evaluated mean ARMS score difference with Student’s t-test and Mann-Whitney U test.
Thirty-eight women were included, with 20 exposed to the intervention. Baseline characteristics were well-balanced. The difference in mean pre-eclampsia knowledge scores between 1st and 2nd trimester visits in the intervention group was 5.0 points (95% CI 1.4, 8.6) and 1.1 points (95% CI -3.1, 5.4) in the control group when all women were included regardless of fetal loss. The mean difference in scores for those receiving the educational tool was 4.1 points higher (95% CI 0.4, 7.9) than those receiving standard of care. There was a trend of higher aspirin use in the intervention group. Aspirin adherence was high regardless of intervention status.
Midway into the trial, pre-eclampsia knowledge improved from 1st to 2nd trimester visits in pregnant SLE women who received the tool compared to those who did not. There was a trend of higher aspirin use in women receiving the educational tool. The trial is well-poised to provide a new evidence-based approach to improve pre-eclampsia knowledge and potentially optimize aspirin use and pregnancy outcomes.
Some studies have reported an increased risk of major congenital malformations (MCM) associated with hydroxychloroquine (HCQ), but others find no increased risk. We aim to assess the risk of MCM associated with 1st-trimester HCQ exposure in the offspring of women with lupus.
We conducted a population-based cohort study of pregnancies (2006–2020) with a singleton birth among women with prevalent lupus in Sweden. Prevalent lupus was defined as having ≥ two ICD-coded visits in the National Patient Register before pregnancy, with ≥ one with a lupus specialist. HCQ exposure was defined as filling ≥ one HCQ prescription during the 1st trimester (Prescribed Drug Register). MCM was assessed at birth by any ICD code in the Swedish Medical Birth Register. Inverse probability of treatment weighting (IPTW) was applied to adjust for confounding. Risk ratios and 95% confidence intervals (RR 95%CI) were estimated using modified Poisson regression models with robust variance estimation.
We included 407 exposed births and 520 unexposed births. The risks of MCM in the full cohort, the exposed, and the unexposed were 2.3%, 2.7%, and 1.9%, respectively (unadjusted RR 1.42, 95%CI 0.60–3.28). The IPTW-adjusted population achieved a good balance across patient characteristics. The IPTW-adjusted RR was 1.59 (0.67–3.75). The adjusted risk difference was 0.01 (-0.01–0.03). When the exposure was defined as having ≥ one HCQ dispensation from three months preconception to the end of the 1st trimester, the IPTW-adjusted RR was 1.56 (0.69–3.54).
Our findings show an increased, but not statistically significant, risk of MCM at birth among births born to women with lupus exposed to HCQ during the 1st trimester compared to those without HCQ exposure. Future studies are warranted and should utilize a longer follow-up for MCM ascertainment (i.e., within one year of birth). For managing lupus during pregnancy, the benefits of HCQ may still outweigh the risks.
While COVID-19 vaccination has been shown to be safe in patients with systemic lupus erythematosus (SLE), data on vaccine-associated adverse events (AEs) during the antenatal and lactation period are scarce, justifying the present investigation.
A total of 9201 complete responses were extracted from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) database, a global e-survey involving 157 collaborators from 106 countries. Among respondents, 6787 (73.8%) were women. We identified 70 (1.1%) women who were exposed to at least one COVID-19 vaccine dose during pregnancy, among those 11 with SLE.
The age of patients ranged from 28 to 39 years; 5/11 women were of Asian origin. None of these patients reported major vaccine AEs, change in the status of their autoimmune disease, hospitalisation, or special treatment requirement. Six women experienced minor vaccine AEs; two of them had active disease prior to vaccination. Four patients reported COVID-19 infection; two of them while they were pregnant and post-vaccination and two prior to pregnancy and vaccination. All four patients experienced symptoms of their disease, but no overt SLE flare was reported. All patients reported their general health to be good/excellent. Importantly, no adverse pregnancy outcomes were reported. No post-vaccination thrombotic events were recorded. Although minor AEs were common, they did not impair daily functioning, and the symptoms resolved in all patients after a median of 3 (IQR: 2.5–5.0) days.
Our report adds evidence concerning the sensitive issue of COVID-19 vaccine AEs and flares in SLE patients during the antenatal and lactation period. Based on the present data, the risk/benefit ratio of COVID-19 vaccination appears favourable, with vaccines both providing passive immunisation to the fetus and active immunisation to the mother with no signals of exacerbation of the mother’s autoimmune disease.
The dysregulation of enhancers has been observed in many autoimmune diseases, but it is still a big challenge to identify the function, the target genes, and the pathogenic roles of the dysregulated enhancers. Here, we intend to dissect the enhancer regulatory landscape of a SLE critical microRNA in different cell lineages and identify the SLE-associated enhancers, which would be intervened by CRISPR as possible therapeutic targets.
Epigenomic analysis and 4C-seq study were carried out to identify candidate enhancers of miR-146a. CRISPR-dCas9-VP64 mediated activation was adopted to map the functional enhancers. The chromatin accessibility of different immune cell subpopulations from the healthy control and SLE patients was analyzed to identify SLE-dysregulated enhancer. The transcription factor binding was analyzed to dissect the mechanism that mediates enhancer dysfunction. The SLE-associated enhancer was targeted to intervene in the disease phenotype in SLE patients‘ PBMCs through CRISPR activation approach.
The cell-type-specific and shared enhancers of miR-146a were identified in different cell lineages. An enhancer, 32.5 kb away from the downstream of miR-146a, is dysregulated in SLE, with lower chromatin accessibility than the healthy control. The chromatin openness of this enhancers was positively correlated with the miR-146a expression and negatively correlated with SLEDAI scores of SLE patients. Moreover, the decreased expression of CEBPA mediated the dysregulation of this enhancer. Furthermore, CRISPR-based activation targeting this enhancer attenuated ISGs expression in SLE patients’ PBMCs.
We developed an integrative approach to establish the enhancer landscape of the SLE critical gene, and dissect the mechanism that mediates the enhancer dysfunction in SLE. Our work reveals a possible therapeutical target for SLE treatment.
Cellular immune responses are phenotypically and functionally perturbed in patients with lupus nephritis (LN), leading to severe renal tissue inflammation. Although multiple gene expression landscapes have been identified for LN development, longitudinal cell type-specific immune responses and prognostic signatures during treatment of LN remain largely unknown.
To uncover transcriptome changes during treatment and identify immune markers to predict treatment response, we performed sequential single-cell RNA sequencing using peripheral blood mononuclear cells (PBMCs) obtained from patients with biopsy-proven LN who received mycophenolate mofetil in combination with glucocorticoids. Single-cell libraries were generated using a commercially available droplet method, the Chromium System from 10x Genomics, Inc. (Pleasanton, CA, USA).
We profiled ~239,000 PBMCs from 10 female patients with LN. After receiving standard therapy for 1 year, number of individuals with complete response (CR) and non-response (NR) according to ACR response criteria was 5 each. Peripheral blood B cells in patients with NR showed a significant expansion of double-negative switched memory cells (DN2), a distinct subset expressing T-box transcription factor T-bet, at renal flare and the increased proportion was maintained after immunomodulatory treatment. Next, we directly compared myeloid cells between CR and NR groups. Analysis of differentially expressed genes revealed that NR was characterized by up-regulation of various interferon-stimulated genes (ISGs), including IFITM1, IFI44, and ISG15. Both IFN-α and IFN- responsive genes were enriched. Patients with CR were accompanied by repression of inflammatory pathways across all types of myeloid cells, with noticeable down-regulation of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3)-inducible signatures.
We provide the first evidence of comparative transcriptional signatures depending on the treatment response in patients with LN. Our results highlight that detailed analysis on immune cells and a dissection of type I IFN-driven inflammatory features enhance the understanding of treatment response dynamics, which might guide the selection of optimal therapeutics for LN.
Pulmonary arterial hypertension (PAH) is one of the most important complications that seriously threatens the prognosis of patients with systemic lupus erythematosus (SLE). We aim to investigate candidate biomarkers and targeted therapy for the early diagnosis and timely treatment of SLE-PAH patients.
1) In order to screen susceptible genes of SLE-PAH, a number of 150 peripheral blood from SLE-PAH patients were subject to whole-exome sequencing (WES), and genome-wide association study (GWAS) was performed by comparing with 934 healthy controls.
2) The transcriptional expression levels of the above screened genes on peripheral blood of SLE-PAH patients were examined by RT-qPCR for further validation.
3) Intervention experiments on pulmonary artery endothelial cells (PAEC) were performed to figure out the potential pathogenesis of the selected gene in vitro. RNA-seq and gene ontology were applied to identify downstream pathways.
4) Established by pristane injection and hypoxia induction, SLE-PAH mice model was established. Pulmonary arterial pressure (PAP) was measured by right heart catheterization with/without tail-intravenous injection of therapeutic vectors.
1) The tumor necrosis factor receptor-associated factor 5 (TRAF5) was identified as a susceptible gene of SLE-PAH based on WES and GWAS.
2) The significant reductions of TRAF5 on transcriptional level in peripheral blood of SLE-PAH patients were identified, indicating clinical diagnosis values.
3) Knockdown of TRAF5 significantly increased early apoptosis of PAEC and triggered the pathogenesis of PAH through distinct pathways.
4) SLE-PAH mouse model was successfully established since they showed phenotypes of lupus and the mean PAPs were measured as over 40mmHg. Tail-intravenous injection of TRAF5-overexpression vector attenuated PAH phenotypes.
Lack of TRAF5 triggers the pathogenesis of PAH in SLE patients through inducing abnormal apoptosis of PAEC. TRAF5 is a susceptible gene of SLE-PAH and it could be a candidate biomarker for diagnosis and therapy for SLE-PAH patients.
Transcolbalamin2 (TCN2) is a vitamin B12 transport plasma protein that facilitates cellular uptake of cobalamin. TCN2 deficiency displays a metabolic disorder with immunodeficiency disease. However, its functions in autoimmunity diseases remain unknown. We attempt to investigate the effects of TCN2 on immune cells in systemic lupus erythema (SLE).
TCN2 expression change in SLE was detected by analyzing our RNA-seq data and microarray from the GEO database and further examined by qPCR. TCN2-KO mice were developed and induced to lupus via pristane injection. The anti-dsDNA and urine protein level, skin, and renal involvement were assessed by ELISA, urine-protein test strips, hematoxylin-eosin (HE), PAS, and immunofluorescent staining. The frequency of immune cells in blood and kidney was investigated via flow cytometry.
We identified increased TCN2 expression in the blood and kidneys of SLE and confirmed upregulated expression of TCN2 in CD19+ B cells and CD4+ T cells in lupus patients and lupus-like mice compared to healthy controls. Then we successfully knocked out TCN2 in C57B/L6. Further studies demonstrated that downregulated expression of TCN2 ameliorated lupus symptoms, which displayed lower dsDNA levels, miler urine protein, and less mesangial hypercellularity and IgG deposition in the glomerulus. Flow cytometry results showed that inhibition of TCN2 remarkably reduced the frequency of B cells and CXCR5+ ICOS+ Tfh cells in the spleen and kidney of lupus-like mice.
These results substantiate the involvement of TCN2 in SLE development. Inhibition of TCN2 overexpression alleviated renal injury by reducing Tfh and B cell infiltration. Our findings imply that cobalamin metabolism might be associated with aberrant germinal center responses and provide a novel target for SLE treatment.
The phenotypic, signaling and metabolic diversities of leucocytes of systemic lupus erythematosus (SLE) impede comprehensive identification of immunopathologically-relevant alterations in leucocytes associated with active SLE. We aimed to identify these alteration signatures in leucocytes from patients with active SLE by an integrated platform comprising high-dimensional flow cytometry, cytometry by time of flight (CyTOF) and RNA sequencing (RNA-seq).
Peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy subjects were subjected to high-dimensional flow cytometry and CyTOF for studying alterations of myeloid cells and lymphocytes. Bulk RNA-seq was conducted for 8 sorted cell populations. Data were subjected to integrative analyses with Cytozoom that identified cellular signatures of active SLE. Differences in T-cell and B-cell receptor clonalities, cellular signaling and metabolic reaction pathways were studied based on SLE activity.
SLE patients with active disease had significantly lower CD14+CD16highCD86+HLA-DR+ and higher circulating CD3+CCR4+CXC3CR1+CD45RO+CD27+cells in their PBMCs (See
An integrated analytical platform comprising high-dimensional cytometric analyses and RNA-seq demonstrated signatures that highlight the concerted and complex pathogenic signatures of non-classical monocytes, tissue-homing memory T cells and altered signaling/metabolic pathways of lymphocytes and myeloid cells in patients with active SLE.
The paradigms in searching for flare-related cell types in Myeloid (A-L) and T/NK (M-Y) lineages, presented with UMAP and PAGA plots, and Leiden clustering
Follicular helper T (TFH) cells induce germinal center response to produce high affinity antibodies against a specific pathogen. Excessive formation of TFH cells are closely associated with the onset of antibody-mediated systemic autoimmune diseases, such as systemic lupus erythematosus (SLE). Our previous study has shown that ETV5 promotes murine TFH cell differentiation. However, its role in human TFH cell differentiation and the pathogenesis of SLE has not been investigated.
We analyzed the autoimmune phenotype and cell population in ETV5 deficient lupus mouse models. Autoimmunity was evaluated by checking autoantibody levels, immune cell infiltration into non-lymphoid organs, and kidney IgG deposition. The frequency of TFH, TFR, and GC B cells was measured by flow cytometry. The expression levels of ETV5 in human samples were analyzed by qRT-PCR and western blot.
The frequency of TFH cells is decreased in the spleen of T cell-specific ETV5 null mice compared with control mice. In addition, ETV5 deficiency in T cells substantially suppresses autoimmunity in lupus mouse models. TFH cells have higher levels of ETV5 than non-TFH cells in humans as well as in mice. ETV5 overexpression also promotes human TFH cell differentiation. Furthermore, ETV5 levels are significantly higher in CD4 T cells from SLE patients than in those from healthy control, suggesting that ETV5 may be an SLE-promoting factor.
In this study, we show that ETV5 is a transcription factor that promotes the pathogenesis of lupus autoimmune disease via enhancing TFH cell differentiation. We are currently investigating the molecular mechanism of how ETV5 promotes TFH cell differentiation.
Systemic lupus erythematosus (SLE) is an autoimmune disease in which defective T cells, immune complex deposition, and other immune system alterations contribute to pathological changes of multiple organs and organ systems. Our aim was to investigate the effects of 1,25-(OH)2 vitamin D3 (VitD3) on the activation of myeloid dendritic cells (mDCs) by autologous DNA immune complex (DNA-IC), and the effects of VitD3 on immune system balance during SLE.
We purified DNA-ICs from SLE patients and isolated peripheral blood mDCs before and after histone deacetylase3(HDAC3) gene interference by siRNA. mDC was stimulated by DNA-ICs and/or VD3.The expression of NF-B subunit RelB detected by WB. TNF-α,IL-10 secretion was detected by ELISA respectively. The immune balance of Treg/Th17 cells was determined after the co-culture of homologous CD4+T lymphocytes with different stimulators primed-mDCs.
Our in vitro studies indicated that DNA-ICs were internalized and consumed by mDCs. Further analysis indicated that VitD3 blocked the effects of DNA-ICs on RelB, IL-10, and TNF-α in mDCs. Co-culture of mDCs and CD4+T cells indicated that VitD3 inhibited multiple processes mediated by DNA-ICs, including the proliferation of mDCs, downregulation of IL-10, and upregulation of TNF-α. Additional co-culture experiments indicated that VitD3 reversed the effects of DNA-ICs in regulating the percentages of CD4+CD127-Foxp3+ T cells and CD4+IL17+ T cells.
Our results indicated that autologous DNA-ICs stimulated activation of mDCs during SLE, and that VitD3 inhibited the stimulatory effects of DNA-ICs and maintained the Treg/Th17 immune cell balance. These results suggest that VitD3 may have therapeutic value for treatment of SLE.
Thrombocytopenia is a common manifestation associated with the presence of antiphospholipid antibodies (aPLs). A specific guideline for management of aPLs associated thrombocytopenia is still absent.
This is a single-center observational prospective study. Patients with aPLs associated thrombocytopenia were recruited. Patients with systemic lupus erythematosus (SLE) related major organ involvement were excluded. Treatment response, adverse effects, bleeding events were monitored.
A total of 61 patients were enrolled with a median treatment duration of 22 months. The overall response rate in this cohort was 80.3% (n = 49), including 49.2% of complete responses (n = 30) (
This study suggests that tacrolimus has adequate efficacy and is well tolerated for aPLs associated thrombocytopenia. Patients with mild to moderate SLE might benefit the most from tacrolimus treatment.
Percentages and mean platelet count of patients with different treatment response during follow-up
Response characteristics of the studied patients
Emerging evidences indicate that a distinct CD11c+T-bet+ B cell subset termed age/autoimmune-associated B cells (ABCs) is the major pathogenic autoantibody producer in lupus. Human lupus is associated with significant metabolic alterations, but how ABCs orchestrate their typical transcription factors (TFs) and metabolic programs to meet specific functional requirements is unclear. Our goal is to characterize the metabolism of ABCs and identify the regulators of metabolic pathways for developing new therapies for ABC-mediated autoimmunity.
We developed a T-bet-tdTomato reporter mouse strain to trace live T-bet+ B cells and adoptively transferred CD4+ T cells from Bm12 mice to induce lupus. Then CD11c+tdTomato+ B cells were sorted and conducted RNA sequencing and extracellular flux assay. Metabolic restriction to constrain ABC formation was tested on human and mouse B cells. The metabolic intervention was conducted in the Bm12-induced lupus model.
ABCs exhibited a hypermetabolic state with enhanced glycolytic capacity. The increased glycolytic rate in ABCs was promoted by IFN-Y signaling. T-bet, a downstream TF of IFN-Y, regulated the gene program of the glycolysis pathway in ABCs by repressing the expression of Bcl6. Functionally, glycolysis restriction could impair ABC formation. The engagement of glycolysis promoted survival and terminal differentiation of antibody-secreting cells. Administration of glycolysis inhibitor ameliorated ABCs accumulation and autoantibody production in Bm12-induced lupus model.
T-bet can couple immune signals and metabolic programming to establish pathogenic ABC formation and functional capacities. Modulating ABC favored metabolic program could be a novel therapeutic approach for lupus.
Disruption of B-cell homeostasis and subsequent dominance of effector B-cell subsets are critical for the development of systemic lupus erythematosus (SLE). Revealing the key intrinsic regulators involved in the homeostatic control of B cells has important therapeutic value for SLE. This study aims to uncover the regulatory role of the transcription factor Pbx1 in B-cell homeostasis and to provide new targets for SLE treatment.
We constructed mice with B-cell-specific deletion of Pbx1. T-cell-dependent and independent humoral responses were induced by intraperitoneal injection of NP-KLH or NP-Ficoll. The regulatory effects of Pbx1 on autoimmunity were observed in a Bm12-induced lupus model. Mechanisms were investigated by combined analysis of RNA-sequencing, Cut&Tag, and Chip-qPCR assay. B-cells from SLE patients were transduced with Pbx1 overexpression plasmids to explore the in vitro therapeutic efficacy.
Pbx1 was specifically downregulated in autoimmune B-cells and negatively correlated with disease activity. The deficiency of Pbx1 in B-cells resulted in excessive humoral responses following immunization. In a Bm12-induced lupus model, mice with B-cell-specific Pbx1 deficiency displayed enhancements in germinal center responses, plasma cell differentiation, and autoantibody production. Pbx1-deficient B-cells gained a survival advantage upon activation. Pbx1 regulated genetic programs by directly targeting critical components of the proliferation and apoptosis pathways. In SLE patients, PBX1 expression was negatively correlated with effector B-cell expansion and enforced PBX1 expression attenuated the survival capacity of SLE B-cells.
Our study reveals the regulatory function and mechanism of Pbx1 in adjusting B-cell homeostasis and highlights Pbx1 as a therapeutic target in SLE.
Progesterone-induced blocking factor 1 (PIBF1), a protein produced by maternal lymphocytes upon exposure to progesterone during pregnancy, acts as an immunomodulator by suppressing several immune pathway cytokines including Th1-based cytokines. Considering the female susceptibility to systemic lupus erythematosus, we aimed to determine the role of recombinant PIBF1 in the alleviation of lupus nephritis (LN) in MRL/MpJ-Faslpr/J (MRL/lpr) mice.
MRL/lpr mice were ovariectomized at 6 weeks of age, and recombinant PIBF1 was administered intraperitoneally from 8 to 26 weeks of age (twice a week). Serum anti-dsDNA level was examined every 2 weeks from 8 to 24 weeks of age. The levels of serum cytokines at 16 and 24 weeks of age and urine albumin/creatinine (uACR) at 26 weeks of age were measured. At 26 weeks, the mice were sacrificed, and kidney biopsy was performed. Pathologic grading of disease activity and chronicity was performed by an animal pathologist according to the criteria of the NIH activity and chronicity indices. Additionally, splenocytes were analyzed by flow cytometry.
Serum anti-dsDNA level was increased in MRL/lpr mice that underwent ovariectomy; however, recombinant PIBF1 treatment attenuated the increase in anti-dsDNA autoantibodies (statistical significance after 18 weeks, p <0.05). uACR at 26 weeks was significantly decreased in the PIBF1-treated ovariectomy group compared with the PIBF1-untreated ovariectomy group (p <0.05). Furthermore, interstitial inflammation, global glomerulosclerosis, total activity index, and chronicity index scores were significantly decreased in PIBF1-treated mice compared with non-treated mice (
Administration of recombinant PIBF1 attenuated the laboratory and histologic scores of LN-prone mice. Therefore, PIBF1 may function as an immunomodulator in LN.
Kidney tissues of MRL/lpr mice at 26 weeks. (A) Activity index. (B) Chronicity index. OVX, ovariectomy, *p < 0.05, **p < 0.01, ***p < 0.001
Lupus nephritis (LN) is one of the most common organ-specific injury of systemic lupus erythematosus (SLE) and has great influence on patients’ prognosis. Some research showed that interleukin (IL) -22 was enriched in the kidney tissue of MRL/lpr mice, and it was related to kidney lesions. The proportion of Th22 cells and IL-22 in periphery blood mononucleated cell (PBMC) and kidney tissue of LN patients were found increased, suggesting that IL-22/Th22 may be participated in the development of LN. About seventy-five percent of SLE patients showed significantly up-regulated of serum IFN-α (the main active component of IFN-I) and increased transcription of IFN-α-regulated genes in PBMC. Injected with IFN-α showed lupus phenotype increased in MRL/lpr mice.
The effect of IFN-I on Th22 cell differentiation and the related key intracellular signaling pathway were investigated by in vitro cell experiments and in vivo animal model intervention, to explore whether IFN-I affects IL-22 production and Th22 differentiation.
Complement 3 levels were lower and SLEDAI-2K were higher in the LN group than in the non-LN group. Comparison of IL-22/IL-22R1 immunohistochemical (IHC) images in kidney between healthy control (HC) and LN patients, and the quantitative levels of IL-22/IL-22R1 in the LN group were quite higher than in the HC group. Similar results could be found in comparison between premortem (8 weeks) and postmortem (27 weeks) NZB/W F1 mice. Flow cytometry showed the high concentration of IFN-α could be inhibitor of the differentiation of Th22 cell.
IL-22/Th22 could be participated in the development of LN, and IFN-I may play a significant role in activating the IL-22/Th22 pathway.
B-cells expressing B-cell receptors (BCRs) specific for self-antigens are normally eliminated, or made anergic, through negative selection during B-cell development. VH4-34 is an intrinsically autoreactive antibody (and BCR) heavy chain variable region that includes a hydrophobic patch in framework region 1 (FR1). Autoantigens recognized by VH4-34-encoded antibodies include N-acetyl lactosamine chains displayed on red blood cells. In healthy individuals, <1% of B cells express VH4-34-encoded BCRs but during the loss of self-tolerance, the hydrophobic region in FR1 reacts to self-antigen, erroneously driving B-cell activation and expansion.
Expansion of VH4-34+ B cells and increased serum concentrations of auto-reactive VH4-34 antibodies have been reported in autoimmune disorders, including systemic lupus erythematosus (50%) and virtually all cases of cold agglutinin disease. To date, there have been no successful therapies against VH4-34 due to challenges of specifically targeting VH4-34 while avoiding other VH regions.
We applied Hummingbird Bioscience’s Rational Antibody Discovery approach to develop anti-VH4-34 antibodies that bind to a computationally predicted and lineage conserved epitope in the FR1 of VH4-34 antibodies. In vitro, the ability of HMBD-011 to specifically bind VH4-34+ cell lines was determined using flow cytometry. Potency of HMBD-011, to eliminate circulating VH4-34 antibodies and VH4-34+ cells in vivo, was measured using serum ELISA and IVIS Spectrum In Vivo Imaging System respectively.
The lead antibody, HMBD-011, demonstrates selective and high affinity binding to tested VH4-34 antibodies, with no off-target binding to a panel of other VH antibodies. The binding epitope of HMBD-011 was confirmed by mutagenesis to be within the FR1 of VH4-34. Further, HMBD-011 shows selective binding to cells that endogenously and exogenously express VH4-34 BCRs. In vivo, HMBD-011 treatment results in specific elimination of VH4-34 auto-antibodies and depletion of VH4-34+ B cells.
HMBD-011 represents a promising new precision therapy for patients with VH4-34 autoimmune disorders.
Systemic lupus erythematosus (SLE) is 9 times more prevalent in females than in males, suggesting a possible role for X-linked genes in disease onset and progression. Toll-like receptor (TLR7) is an X-encoded innate immune sensor that detects RNA degradation products to promote inflammatory cytokine and interferon production during viral infection. While aberrant TLR7 activity has long been implicated in the aetiology of systemic autoimmunity, a recent study published in Nature has now definitively linked gain-of-function mutations in TLR7 with human lupus.1 There are currently no approved therapeutic inhibitors of TLR7, making this an urgent unmet need. We have developed novel synthetic, RNA-like trimeric oligonucleotides that bind to TLR7 with low nanomolar potency to effectively block its activation by RNA.
Daily application of Aldara cream, containing the TLR7 agonist Imiquimod, induces an inflammatory skin phenotype in mice that resembles psoriasis or cutaneous lupus erythematosus (CLE). Aldara cream was applied topically to the back and ear of C57/BL6J mice directly following, or not, application of TLR7-inhibitory trimeric oligonucleotides formulated in F127 Pluronic gel. Mice were scored daily for the appearance and severity of skin inflammation. After four days, mice were humanely euthanised for multiplex ELISA and qPCR analysis of serum cytokines and inflammatory gene signatures in the skin, respectively.
Topical treatment with the TLR7-inhibitory trimeric oligonucleotides greatly ameliorated disease severity (measured by scaling and redness on the back and ear, as well as dermal thickening of the ear) and also led to a significant reduction in both NF-B-dependent and Type I interferon-stimulated genes in the skin.
Our novel TLR7-inhibitory trimeric oligonucleotides represent a promising new class of therapeutics for the treatment of TLR7-driven inflammation in skin manifestations of autoimmunity, for example, psoriasis and CLE.
Brown et al. Nature 2022;605:349–356.
The NKT-like cells were known to play a role of the suppression in many chronic inflammatory diseases. This study was designed to investigate both of the expression and the possible role of NKT-like cells in SLE patients.
79 patients with SLE together with 30 age- and sex-matched healthy controls were enrolled. Flow cytometric determination of peripheral NKT-like cells was carried out for all participants by detecting the absolute counts (Abs) and percentage (%) of CD3+CD16+CD56+ cells. Disease activity index, laboratory parameters and clinical manifestations were collected. The correlation between the cells and these parameters were analyzed.
SLE patients had, with respect to controls, considerably decreased values of NKT-like cells (P < 0.001 in both absolute number and percentage). The absolute number of NKT-like cells were found to have positive correlations with WBC, RBC, PLT, C3, C4, IgM and negative correlations with the disease duration, SLEDAI-2K, anti-dsDNA, anti-nucleosome, anti-ribosomal protein, and CRP, ESR. Meanwhile, it was found that the percentage values of NKT-like cells decreased in SLE patients with nephritis which was correlated with anti-ribosomal protein and CRP in comparison to SLE patients without nephritis. Moreover, an increase in the NKT-like cell counts was also observed in the patients with a clinical response to the treatment.
The absolute counts and frequencies of NKT-like cells decreased in SLE patients significantly, which correlated to disease activities and could recover to normal after the treatment. The NKT-like cells may play an important role in the pathogenesis of SLE and could be a useful marker in the disease assessment.
The prevention of catastrophic antiphospholipid syndrome (CAPS), a rare complication of antiphospholipid syndrome (APS), is a major goal. The role of precipitating factors in CAPS development is well known. However, little is known about the specific role of anticoagulant treatment as a potential precipitating factor for CAPS. We analyzed precipitating factors of CAPS in a large series of patients, and we focused on anticoagulation immediately before CAPS episodes.
We retrospectively analyzed patients in the French multicenter APS/systemic lupus erythematosus database with at least one CAPS episode. Then we compared each patient with known APS before CAPS with two non-CAPS APS patients matched for age, sex, center and APS phenotype.
We included 112 CAPS patients (70% female, mean age 43±15 years). At least one standard precipitating factor of CAPS was observed for 67 patients (64%), mainly infections (n=28, 27%), pregnancy (n=23, 22%), and surgery (n=16, 15%).
Before the CAPS episode, 67 (60%) patients already had a diagnosis of APS. Of the 61 treated with anticoagulants, 32 (48%) received vitamin K antagonists (VKA), 23 (34%) heparin, and 2 (3%) a direct oral anticoagulant. They were less likely than their matched APS patients without CAPS to receive VKA (48% vs 66%, P=0.001). Among those treated with VKA, 72% had a subtherapeutic INR < 2, versus 28% in APS patients without CAPS (P<0.001). Finally, if we excluded pregnant patients (n=14) for whom the effect of treatment versus pregnancy is impossible to differentiate, among the 47 remaining cases, 32 (68%) had either a recent introduction of DOAC (n=2), a planned bridging therapy (n=9) or a VKA treatment with INR <2 (n=21).
These results strongly suggest that suboptimal anticoagulation management is a trigger of CAPS in patients with thrombotic APS.
Conventional serological markers do not always correlate with clinical activity in lupus nephritis (LN). CD44 is a transmembrane glycoprotein that is widely expressed in immune and non-immune cells, and is implicated in tissue inflammation and fibrosis. CD44 also serves as a cell receptor for hyaluronan (HA), a glycosaminoglycan that contributes to inflammatory and fibrosis processes. This study investigated clinico-pathological associations of circulating CD44 level.
Serial serum samples from patients with biopsy-proven Class III/IV LN were collected at intervals of 3–4 months over 3 to 4 years. Sera from sex- and age-matched patients with non-renal SLE or non-lupus chronic kidney disease (CKD) or healthy subjects served as Controls. Serum CD44 level was measured by ELISA
Six hundred and sixty-seven sera from 41 patients with LN (31 female and 10 male, age 38.78±12.02 years) were included. Serum CD44 level was significantly higher in active LN compared to remission, non-renal SLE, CKD, or healthy subjects (P<0.001, for all). Serum CD44 level correlated with SLEDAI-2K and renal SLEDAI-2K scores, anti-dsDNA antibody titre, proteinuria, and serum HA level, and inversely correlated with eGFR and C3 level (P<0.001, for all). Serum CD44 level increased at the time of nephritic flare and decreased after treatment with immunosuppression. A temporal relationship was observed between CD44 level and SLEDAI-2K or renal SLEDAI-2K scores, anti-dsDNA antibody and C3 levels, and proteinuria. ROC analysis showed that serum CD44 level distinguished active LN from healthy subjects (sensitivity 98.31%, specificity 100.00%), from quiescent LN (sensitivity 86.44%, specificity 98.31%), from non-renal SLE (sensitivity 98.31%, specificity 95.24%), and from non-lupus CKD (sensitivity 98.31%, specificity 100.00%) (P<0.0001, for all).
Active LN is associated with increased serum CD44 level. Further studies are required to determine whether CD44 can serve as a clinically useful biomarker in the diagnosis and monitoring of LN activity.
Tyrosine kinase 2 (TYK2) mediates signaling of key cytokines (eg, Type 1 IFNs, IL-23, and IL-12) involved in lupus pathogenesis. Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis.1 2 Deucravacitinib was efficacious in a phase 2 trial in patients with active SLE (PAISLEY; NCT03252587).3 This analysis evaluated the effect of deucravacitinib on biomarkers of TYK2-mediated pathways, B cell pathways, and serological biomarkers in patients in the phase 2 PAISLEY SLE trial.
The 48-week PAISLEY trial randomized 363 patients with SLE 1:1:1:1 to placebo or deucravacitinib 3 mg twice daily (BID), 6 mg BID, or 12 mg once daily (QD). Whole blood transcripts, serum proteins, blood cell subsets, and antibody profiles were measured by immunoassays and flow cytometry.
With deucravacitinib treatment, significant reductions were observed in IFNα (at week 48) and IFN (week 2 through week 48), and IFN was numerically lower after week 12. Deucravacitinib, but not placebo, reduced IFN-regulated gene (IRG) expression as well as expression of cytokines and chemokines downstream of IFN activity, including BAFF, CXCL10, and MCP2 (
Deucravacitinib suppressed IFN production, IRG expression, IFN-inducible proteins, B cell pathway markers, and serological biomarkers, consistent with clinical symptom improvements in SLE patients treated with deucravacitinib. Suppression of both IFN and B cell pathways suggests a broad reduction in lupus pathophysiology. These results provide a molecular framework for understanding how deucravacitinib modifies molecular networks in SLE.
Deucravacitinib, but not placebo, reduced biomarkers of IFN activity and lupus pathophysiology
Armstrong A, et al. J Am Acad Dermatol. 2023;88(1):29–39. Strober B, et al. J Am Acad Dermatol. 2023;88(1):40–51. Morand E, et al. Arthritis Rheumatol. 2022 Nov 11 (Epub ahead of print).
Systemic lupus erythematosus (SLE) is chronic inflammatory disease caused by the production of various autoantibodies such as antinuclear antibodies and anti-dsDNA.. Previous studies have shown that genetic and environmental factors influence onset, but the exact cause of SLE is unclear. The SLE is diagnosed with various clinical and immunologic indicators. We focused on finding biomarkers for a diagnosis of SLE.
We compared the serum of normal (NC) and patients with SLE through screening, and selected highly expressed TCP1 antibodies as a candidate for SLE-specific biomarker. We produced GST-fusion TCP1 as a TCP1 antigen using SF9 cell and used RPLP 0, 1, 2 known as lupus autoantibodies as controls. We confirmed the possibility of TCP1 autoantibody as a SLE-specific biomarker using sera of the NC patients with SLE or other autoimmune disease through Dot blot assay.
TCP1 antibody was expressed high in the most of SLE (n=10) patients as compared with the NCs (n=5). We performed Dot blot analysis using serum from NC (n=50), patients with SLE (n=100), and patients with other autoimmune disease including rheumatoid arthritis (n=25), systemic sclerosis (n=30), and Bechet’s disease (n=15). As a result, the TCP1 antibody were detected 79 out of 100 patients with SLE and it was more commonly expressed compared with NC and other autoimmune diseases. The sensitivity of TCP1 antibody in SLE patients was 79%, and the specificity was 90%.
Therefore, TCP1 antibody is the potential to be a specific biomarker of SLE and is expected to be a new biomarker for the diagnosis of SLE.
Complement activation is a hallmark of SLE pathophysiology. We previously found that iC3b/C3 ratios associated with active disease and clinically meaningful changes in SLE disease activity. Since SLE is more severe in nonwhite populations, we hypothesized that iC3b/C3 ratios would be a more sensitive marker of disease activity in nonwhite populations. Thus, we examined the relationship of iC3b/C3 ratios between African-American (AA) and White subjects with classified SLE seen at the Washington University.
159 adult SLE patients were enrolled in this observational study. 83 patients with 3–7 study visits were used for this longitudinal analysis. C3 and C4 were measured by nephelometry; iC3b by a lateral flow assay using an investigational medical device. SLE disease activity was measured using the SLEDAI 2K Responder Index-50 instrument. Statistical analyses were performed using SAS v9.4. Multilevel regression models examined associations for SLE disease activity. Ordinal logistic regression models with generalized estimating equation modeling (GEE) examined associations for clinically meaningful changes since the outcome variable is ordinal. Odds ratios and 95% confidence intervals were estimated using Proc GLIMMIX and Proc GENMOD.
iC3b/C3 ratios and C3 associated with active disease in AA and White SLE subjects, with the association of the iC3b/C3 ratio in AA was stronger (
iC3/C3 ratios better correlated with active disease in AA compared to Whites. Furthermore, iC3b/C3 ratios correlated with clinically meaningful changes in disease activity only in AA.
Univariate regression analysis of the association of biochemical variables with active SLE. Red (AA) and pink (whites) whiskers represent statistically significant variables, while grey (white) and black (AA) represent non-significant variables
Exposure to air pollutants is associated with an increased risk of pulmonary and cardiovascular disease and death. Because few studies have investigated the effects of air pollution on systemic lupus erythematosus (SLE), we investigated the association between exposure to air pollutants, including particulate matter (PM), and disease activity over 1 year in a prospective, longitudinal cohort of Korean patients with SLE.
The study enrolled 386 patients from three metropolitan regions in Korea. The daily average PM10, PM2.5, NO2, CO, SO2, and O3 concentrations were measured using portable air quality monitors and data from the National Ambient Air Monitoring System. Disease activity was evaluated using the SLE Disease Activity Index 2000 (SLEDAI-2K) and Physician Global Assessment (PGA), every 3 months for 1 year. Lupus flares, a damage index, and 36-Item Short Form Health Survey (SF-36) scores were also assessed. A generalized estimating equation was used to evaluate the impact of air pollutants on clinical outcomes, including disease activity.
Changes in PM10 and PM2.5 were significantly associated with changes in SLEDAI-2K scores of > 8 over 1 year in SLE patients (β = 0.097, 95% confidence interval [CI]: 0.048–0.146, p < 0.001; β = 0.100, 95% CI: 0.054–0.146, p < 0.001, respectively). Changes in PM10 and PM2.5 were also significantly associated with the development of lupus flares (β = 1.603, 95% CI: 1.067–2.408, p = 0.023; β = 1.777, 95% CI: 1.048–3.011, p = 0.033, respectively). However, there were no significant associations between the changes in NO2, CO, SO2, and O3 and lupus activity.
In this study, PM10 and PM2.5 exposure increased disease activity and the risk of lupus flares in SLE patients living in metropolitan regions.
To optimize medication adherence and outcomes of patients with systemic lupus erythematosus (SLE), we developed an adherence intervention that encourages providers to review real-time pharmacy refill data and use effective communication techniques with patients to collaboratively overcome adherence barriers (
We audio recorded clinic encounters between clinicians and patients seen at an academic lupus clinic and included patients with 90-day medication possession ratio (MPR) <80% for SLE-specific medications. We coded which intervention components clinicians performed, quality of patient-provider communication, and time spent discussing adherence. We assessed change in 90-day MPR after the intervention visit. We also conducted audio-recorded semi-structured interviews with patients and clinicians about their experiences with the intervention and analyzed the data using applied thematic analysis.
We recorded and analyzed 25 patient encounters (median age 39, 100% female, 72% Black) among six clinicians. Clinicians performed the majority of intervention components in most of encounters (
Our findings suggest that this intervention can be performed with high fidelity in a short amount of time and encourages high quality patient-provider communication. Future work will focus on optimizing provider training and testing the intervention in a larger controlled setting.
Adherence intervention workflow with screenshot of pharmacy refill
Intervention components performed and quality of patient-provider communication during 25 recordings of the adherence intervention
Updated information regarding the epidemiology and survival of SLE in the last decade is scanty. We aimed at estimating the incidence, prevalence, and survival of SLE in northeastern Italy over the period 2012–2020.
A retrospective population-based study was conducted in Veneto Region (4.9 million people) using the Population Registry, an administrative health database where all residents are recorded, which was linked with healthcare copayment exemption database, hospital discharge records, and mortality records. Between 2012 and 2020, SLE cases were defined by a healthcare copayment exemption for SLE (national registry code 028) or any hospital diagnosis of SLE (ICD-9-CM 710.0), whichever came first. Standardized incidence and prevalence were reported by age and gender; trends during the follow-up were analyzed through Poisson regression models. SLE mortality rates (MRs) and standardized mortality ratios (SMRs) were calculated. MRs per 1,000 were stratified by year, sex, and age. SMRs were derived by comparing MRs of the general regional population.
We identified 4,283 SLE patients (85% female), with 1,092 incident cases. Across the study period, SLE standardized point prevalence increased from 66.7 (95% CI 64.3–69.0) to 72.9 per 100,000 residents (95%CI 70.5–75.3, p<0.0001,
Over the last decade, SLE prevalence has increased, and incidence has declined. Survival since SLE diagnosis is good, however mortality is still higher in SLE patients compared with the general population.
Adverse childhood experiences (ACEs) have been linked to poorer adult health outcomes. ACEs may be a risk factor for heightened disease activity among Black American women living with systemic lupus erythematosus (SLE), who experience worse outcomes compared to their White counterparts. However, there is a paucity of research on the role of ACEs in the pathogenesis of SLE, and in particular, mechanisms through which childhood adversity may impact disease activity. This study sought to examine if ACEs (e.g., physical/sexual abuse, household incarceration, etc.) and other traumas experienced in the lifecourse are associated with disease activity among Black American women living with SLE.
Participants were from the Black Women’s Experiences Living with Lupus (BeWELL) Study, which recruited Black women (n=418) with a validated diagnosis of SLE living in metropolitan Atlanta, GA, USA, largely from a population-based registry. Multivariable cross-sectional regression models were specified examining patient-reported disease activity, measured using the Systemic Lupus Activity Questionnaire (SLAQ), in relation to the ACE Questionnaire and the Trauma History Screen.
Controlling for sociodemographic and health-related covariates, ACE score was significantly associated with disease activity (β=1.52, SE=0.35, p<.001). Trauma was found to mediate this relationship (Sobel test z=4.77, p<.001). In the final model, the association between ACE and SLAQ was attenuated and not significant (β=0.72, SE=0.38, p=.06). Additional analyses restricting items to trauma specifically in adulthood resulted in substantively similar conclusions.
Consistent with the stress proliferation theory, results suggest that childhood adversity increases the risk of traumas experienced in later developmental periods, including in adulthood. Adversities experienced at various developmental periods across the lifecourse increase SLE severity among Black American women, and may contribute to racial inequities in SLE outcomes. Importantly, findings suggest that the impact of childhood adversity on adult disease activity may be reversible through interventions aimed at preventing subsequent traumas.
Patients with systemic lupus erythematosus (SLE) present greater severity of SARS-CoV-2 infection compared to the general population. High disease activity and some immunosuppressants have been associated with worse outcomes. The aim of this study was to describe the characteristics of SARS-CoV-2 infection in patients with SLE in Argentina from the SAR-COVID registry and to establish factors associated with a worse outcome.
Observational study. Patients diagnosed with SLE with confirmed SARS-CoV-2 infection (RT-PCR and/or positive serology) from the SAR-COVID registry were included. Data was collected from August 2020 to March 2022. The outcome of the infection was measured using the World Health Organization – ordinal scale (WHO-OS). Severe COVID-19 was defined as an WHO-OS value ≥5. Descriptive analysis, Student’s T test, Mann Whitney U, ANOVA, Chi2 and Fisher. Multiple logistic regression.
A total of 399 patients were included, 93% female, with a mean age of 40.9 years (SD 12.2), 39.6% had at least one comorbidity. At the time of infection, 54.9% were receiving glucocorticoids, 30.8% immunosuppressants, and 3.3% biological agents. SARS-CoV-2 infection was mild in most cases, while 4.6% had a severe course and/or died. The latter had comorbidities, used glucocorticoids and had antiphospholipid syndrome (APS) more frequently and higher disease activity at the time of infection. In the multivariate analysis, high blood pressure (OR 5.1, 95%CI 1.8–15.0), the diagnosis of APS (4.7, 95%CI 1.2–15.8), and the use of glucocorticoids (10 mg/day or more: OR 5.5, 95%CI 1.6–20.5) were associated with severe hospitalization and/or death from COVID-19 (WHO-EO≥5).
In this cohort of SLE patients with confirmed SARS-CoV-2 infection, most had a symptomatic course, 22.1% were hospitalized, and 5% required mechanical ventilation. Mortality was close to 3%. The diagnosis of APS, having high blood pressure, and the use of glucocorticoids were significantly associated with severe COVID-19.
In a multiethnic U.S cohort compared to White patients., Black patients developed systemic lupus erythematosus (SLE) at a younger age, had more severe disease, and had worse outcomes. Patients of Asian ancestry developed SLE were similar but also had more frequent autoantibodies. Black and Asian SLE patients have not been directly compared across nations.
The Georgia Lupus Registry (GLR) is a population-based registry of validated SLE patients in Atlanta of those with ≥4 ACR criteria or 3 ACR criteria with a final diagnosis of SLE by a rheumatologist. The Hanyang BAE Cohort is comprised of SLE patients meeting ACR and/or SLICC criteria from a single center. A total of 248 Black patients from 2002–04 (GLR) and 395 Korean patients from 2002–13 (BAE) with incident disease (<1 year) were compared. The outcomes of end-stage renal disease (ESRD) and mortality were evaluated for cumulative incidence over time and by multivariable Cox proportional hazard regression. Causes of death were derived from national databases.
A total of 248 U.S. Black patients were compared with 395 Korean patients. The cause-specific hazard ratio (GLR vs. BAE), adjusted by age of SLE onset, sex, and total number of ACR criteria, was 6.42 (2.40–17.16) for ESRD and 2.7 (1.40–5.21) for mortality. The most frequent causes of death in the U.S. Black population were SLE (33%), other (29.5%, of which 42.3% were neoplasms), and cerebrovascular disease (23.9%). In the Korean population, it was SLE (57.1%), infection (21.4%), and others (14.3%).
U.S. Black and Korean SLE patients showed significant differences clinically in the first year of disease. Despite similar frequencies of renal involvement at baseline, there was a notable over six-fold increased risk in U.S. Black patients to progress to ESRD. These comparisons and contrasts are opportunities to better explore biological as well environmental differences in disease expression and outcomes.
Add-on intravenous pulse methylprednisolone (IVMP) is a strategy to reduce cumulative glucocorticoids (GCs) doses for treating proliferative lupus nephritis (LN). However, the benefit is still under debate. This study compares the efficacy and safety of add-on IVMP versus GCs alone in Thai patients with proliferative LN receiving monthly intravenous cyclophosphamide (IVCY).
This study enrolled 63 biopsy-proven proliferative LN who underwent induction therapy in Songklanagarind hospital, from January 2009 to December 2019. 18 patients in add-on IVMP and 45 patients in medium to high dose GCs alone were reviewed and analysed. Both groups received monthly IVCY for the induction phase. The primary outcome was the remission rate, and the secondary outcomes were a 6-month proteinuria decline from baseline> 50%, renal survival, time to achieve remission, cumulative GCs dose, and proteinuria < 0.5 gm.
The remission rate in our study was 79.4%, which was no significant difference between add-on IVMP and GCs alone (66.7% vs. 84.5%, p= 0.214). The secondary outcomes were not different between groups demonstrated as renal survival (83.3% vs. 97.8%, p=0.067), median time (IQR) to achieve remission [180 (120,215) vs. 138 (103,237.2), p=0.962], proteinuria decline from baseline> 50% (66.7% vs. 86.7%, p=0.085), proteinuria < 0.5 gm (27.8% vs. 40.0%, p=0.535), and cumulative GCs dose. However, the 6-month renal function was significantly improved in add-on IVMP (72.2% vs.57.8%, p= 0.002). We compared the subgroups of 11 add-on IVMP with medium GCs and 45 GCs alone; the overall outcomes were similar, but the mean (SD) 6-month cumulative GCs dose tended to lower in add-on IVMP [3.7(1.2) vs. 4(1), gm, p= 0.052].
The remission rate was not different between add-on IVMP and GCs alone but significant improvement of renal function in add-on IVMP in proliferative lupus nephritis who monthly IVCY.
The effectiveness and safety of sirolimus for the treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN) have been shown in some studies. However, a comparison of sirolimus with standard of care (SoC) for LN patients has not been reported. We conducted the study to compare the efficiency and safety of sirolimus versus mycophenolate mofetil (MMF) for LN treatment.
A real-world cohort study based on the Chinese SLE Treatment and Research (CSTAR) registry was conducted. LN patients who were prescribed sirolimus or MMF were enrolled. Patients who achieved LLDAS (lupus low disease activity state) or remission at baseline were excluded. Propensity score matching was used to ensure equivalent disease conditions and background medications. SLE disease activity indices, serological parameters, steroid doses, renal efficacy, and adverse events were compared between the two groups at 3-month, 6-month, and 12-month follow-up visits.
Data from 53 patients in each group were analyzed. The clinical effectiveness of sirolimus, including the proportion of patients with LLDAS/remission, or clinical response (SLEDAI-2K reduction≥4 and PhGA increase <0.3), the change of Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, physician’s global assessment (PhGA) scores, the remission of lupus nephritis, the change of 24 hours urine protein level, and the steroid tapering effect, were equivalent to those of MMF at all follow-up timepoints (all P≥0.05). Greater improvements in complement levels were observed in the sirolimus group than the MMF group at 3, 6, and 12 months. Ten adverse events in the sirolimus group and one in the MMF group were recorded. None was severe or led to drug discontinuation.
Sirolimus was as effective as MMF in the treatment of LN and glucocorticoid tapering. Sirolimus had better effects on serological improvement. Sirolimus was well tolerated in LN patients.
Lupus nephritis (LN) has been identified as a major risk factor for the mortality in patients with systemic lupus erythematosus (SLE). We investigated the predictors of end-stage renal disease (ESRD) and death among LN patients.
This study enrolled Korean patients with biopsy-proven LN, from a prospective BAE lupus cohort between January 1998 and December 2018. Baseline demographics, histological, and clinical features were collected, and the disease activity measured by the SLE Disease Activity Index 2000 (SLEDAI-2K) and organ damage determined by the Systemic Lupus International Collaborating Clinics Damage Index (SDI) score were annually assessed.
In total, 599 patients with proliferative LN (class III and IV/±V) and membranous LN (class V) were included and followed for a mean of 10.7 ± 6.7 years. 42 (7.0%) LN patients developed ESRD. In a multivariate logistic regression model, anti-phospholipid (aPL) antibodies [odds ratio (OR) 2.94, CI 1.1–7.87, p=0.032] and higher activity index score at renal biopsy [OR 1.12, CI 1.01–1.26, p=0.048] were independent predictors of ESRD after adjusting for age, sex, and disease duration (
We identified key predictors of the worst long term outcome, ESRD and death, in patients with lupus nephritis, emphasizing the importance of strict disease activity control to prevent death in high-risk groups of ESRD progression.
Kaplan-Meier analysis with log-rank test to measure survival rate between ESRD and non-ESRD patients with lupus nephritis. X-axis displays the time in years, and Y-axis displays the patient survival rate. ESRD: end-stage-renal-disease. p< 0.05 is the threshold for significance
Baseline clinical characteristics and multivariate logistic analysis of variables associated with end-stage renal disease in 599 patients with lupus nephritis
Each lupus nephritis (LN) flare causes nephron loss that equals a decade or more of reduction in renal function lifespan. Identification of readily available signals of imminent flare is therefore expected to improve prognosis. In light of observed cases of de novo LN during belimumab treatment, we evaluated predictors of de novo renal flare occurrence in patients with systemic lupus erythematosus (SLE) and no prior history of renal disease undergoing standard therapy (ST) with or without add-on belimumab in clinical trial settings.
Data from five clinical trials of belimumab in SLE (BLISS-52 NCT00424476; BLISS-76 NCT00410384; BLISS-NEA NCT01345253; BLISS-SC NCT01484496; EMBRACE NCT01632241) were utilised. The study population comprised 1932 patients with a baseline renal British Isles Lupus Assessment Group (BILAG) score E. De novo renal flares were defined as a change from renal BILAG E to A or B within a 52-week follow-up. Predictors of renal flare occurrence were investigated using Cox regression analysis.
De novo renal flares were documented in 146 (7.6%) patients. In multivariable Cox regression analysis adjusting for age, sex, ethnicity, serum creatinine, and variables that differed significantly in univariable analysis, Asian ancestry was associated with imminent de novo renal flare (HR: 1.60; 95% CI: 1.03–2.49; p=0.036). Notably, use of belimumab 1 mg/kg by intravenous (IV) infusion yielded a nearly 3 times decreased hazard of renal flare (HR: 0.37; 95% CI: 0.20–0.68; p=0.001), whereas IV belimumab 10 mg/kg and belimumab 200 mg administered subcutaneously (SC) displayed no clear protection.
Asian patients appeared particularly susceptible to new-onset renal involvement, corroborating the substantial vulnerability of Asian SLE populations to renal affliction. Discrepant results between low and high/approved belimumab doses warrant in-depth mechanistic exploration of underlying reasons e.g., potential effects of belimumab on B cell subsets that acquire regulatory properties.
Renal relapse has known to be a poor prognostic factor of renal function impairment in patients with lupus nephritis (LN). However, there was few studies that identified the risk factors of renal relapse. Therefore, we conducted a study based on 35 years of experience at a single center to find predictors of renal relapse.
Among 401 patients of LN treated at Seoul St. Mary’s hospital from 1985 to 2019, 296 patients who reached complete remission were enrolled. We retrospectively analyzed the clinical, laboratory, pathologic and therapeutic parameters. The timing and cumulative risk of renal relapse were identified by Kaplan-Meier methods. The independent risk factors for renal relapse were examined by Cox proportional hazards regression analyses.
The median follow-up time after the diagnosis of LN was 131 months. Renal relapse had occurred in 157 patients, and 139 patients maintained complete remission. Renal relapse had occurred in 38.2%, 57.6% and 69.2% of patients within 5-year, 10-year, and 20-year after achievement of complete remission, respectively. Age of onset of SLE and LN were significantly younger in patients with renal relapse (26.3 vs 29.7, p=0.006 and 28.1 vs 31.7, p=0.004, respectively), and the ratio of absence of immunosuppressive maintenance treatment was also higher (p=0.002) in patients with renal relapse. In Cox proportional hazards regression analyses, age at onset of LN (HR 0.987, p=0.016) and absence of immunosuppressive maintenance therapy (HR 1.819, p=0.004) were identified to independent risk factors of renal relapse.
We found that LN onset at an earlier age and absence of immunosuppressive maintenance treatment independently predicted renal relapse in patients with LN who achieved complete remission.
Identification of patients at risk of developing renal flares is imperative to optimise management in systemic lupus erythematosus (SLE). We aimed to identify predictors of renal flares in patients receiving treatment for active extra-renal SLE.
Data from BLISS-52 (NCT00424476), BLISS-76 (NCT00410384), BLISS Northeast Asia (NCT01345253), and BLISS-SC (NCT01484496) were used. The trials included patients with active, seropositive SLE and excluded active severe renal SLE. Participants were assigned to belimumab or placebo, on top of non-biologic standard therapy. We investigated baseline levels of traditional biomarkers in blood and urine as potential predictors of renal flares during a 52–76-week follow-up. We used adjusted Cox regression models to estimate hazards of renal flares.
Out of 3225 participants, 192 developed a renal flare after a median follow-up time of 197 days. Baseline serum albumin (HR 0.9; 95% CI: 0.9–0.9), proteinuria (HR: 1.3; 95% CI: 1.2–1.4), and low C3 levels (HR: 1.8; 95% CI: 1.3–2.5) were robust determinants of renal flares in the pooled study population, as well as in the belimumab and placebo subgroups. Furthermore, we observed an association between anti-dsDNA positivity and renal flares in univariable models, which attenuated in multivariable models (
High baseline proteinuria levels, hypoalbuminaemia, and C3 consumption were robust determinants of imminent renal flares. Beyond anti-dsDNA, anti-ribosomal P and aCL antibody positivity may prove valuable early signals of imminent renal flares in belimumab-treated patients, whereas anti-Sm antibody positivity may predict renal flares in patients treated with non-biological standard therapy.
Early complete remission (within 12 months) is considered an important protective factor against development of chronic kidney disease (CKD) in lupus nephritis (LN). However, a certain proportion of such patients still develop advanced CKD. Our objective was to describe the factors associated with the development of CKD stage IV or worse in LN patients who achieved early complete remission.
Patients with LN based on biopsy or abnormal proteinuria (>0.5g/day) and/or urinary sediment for two consecutive visits in the absence of other plausible explanation were retrieved from the Toronto Lupus Clinic database. Individuals with advanced CKD at baseline (eGFR&x2266;29ml/min/1.73m2) were excluded. All patients achieved complete remission (proteinuria<0.5g/24h, inactive urinary sediment and serum creatinine &x2266;120% of baseline) within 12 months. Patients were followed for at least 5 years after LN diagnosis.
Of 273 eligible patients, 21 (7.7%) developed advanced CKD after a median of 5.8 years from the time of remission (range 0.7–31.7 years). At baseline, these patients had higher SCR (124.9±71.9 vs. 80.7±25.8μmol/L, p<0.001); other baseline characteristics were not significantly different. Multivariate survival analysis for predictors of advanced CKD is shown in
Patients with impaired kidney function, low complement C3 at baseline and histopathologic features of chronic irreversible damage (interstitial fibrosis/tubular atrophy), are at risk for CKD despite early remission and should be followed closely. The importance of maintenance therapy should be communicated to prevent non-compliance and subsequent flares.
Multivariate survival analysis for predictors of advanced CKD
Abnormalities of type I interferon signaling and production can initiate lupus development. Disturbances of nucleic acid-sensing molecules triggered autoreactivity in lupus mouse models. Stimulator of interferon genes (STING) showed various effects in different lupus mouse models, which could be due to the diverse background of the lupus models and Sting-deficient mice. We aim to confirm the function of Sting/Tmem173 in pristane-induced lupus and identify the role of STING/TMEM173 variants in SLE susceptibility.
Pristane-induced lupus model was introduced in the Sting-deficient mice (ENU-induced Goldenticket mutant mice). Autoantibody, histopathology, and immunophenotypes were analyzed after pristane injection for six months. Isolated DNA from 302 SLE patients and 173 healthy donors were tested for STING genotyping. We calculated the Odd Ratios of each STING variant and the inheritance patterns that significantly increased SLE susceptibility. Then, we analyzed the associations between STING genotypes and lupus phenotypes.
The absence of STING signaling in the Goldenticket mutant mice reduced the autoantibody production and severity of glomerulonephritis in pristane-induced lupus. The human STING mutation at p.R284S (gain-of-function) significantly increased the SLE risk in autosomal dominant pattern [OR = 64.0860 (95%CI = 22.8605–179.6555), p < 0.0001], while the mutation at p.R232H (loss of function) reduced the SLE risk in autosomal recessive pattern [OR = 0.2515 (95%CI = 0.1648–0.3836), p < 0.0001]. The combination of STING variants in a specific inheritance pattern increased the higher OR than a single variant. The patient who had p.R284S with p.R232H showed milder disease activity than those who had p.R284S alone at the time of diagnosis.
The inhibition of STING rescued autoimmune phenotypes in pristane-induced lupus. Gain-of-function STING mutation increased SLE susceptibility and severity of the disease. These data suggested the critical function via STING-mediated signaling in SLE. Targeted at STING may provide a favorable outcome in SLE patients.
NLRP12 (NOD-like receptor family (NLR) pyrin domain containing 12) is an innate immune check-point in regulating type I IFNs expression. Since NLRP12 may participate in the pathogenesis of lupus, its role in lupus nephritis remained unknown.
Wild type C57BL/6 and Nlrp12-/- mice in 12-week-old age were injected intra-peritoneally with a single dose of 500μl of pristane (2,6,10,14-tetramethylpentadecane, TMPD), and mice were sacrificed from 1st to 9th months after injection. Serum were collected for evaluation autoantibodies and renal functions. Kidneys sections were collected for immunoglobulin (IgG) evaluation and periodic-acid-Schiff (PAS) staining. Lupus prone mice with C57BL/6-Faslpr and C57BL/6- Faslpr-Nlrp12-/- mice were harvested and collected from 7th to 11th months.
Among animal models, both pristane induced mice and Faslpr mice revealed increasing autoantibodies production and severity of glomerulonephritis in Nlrp12-/- group in comparison with Nlrp12+/+ ones. Immunofluorescence staining for IgG revealed more profound deposition from 1st to 9th months after pristane injection group, with renal glomerulus damage from PAS staining. For Faslpr-Nlrp12-/- mice, more IgG deposition was noted. The CD43 staining revealed similar trend of both animal models. In serological evaluation, the dsDNA antibody in both animal model revealed significantly increased titer in Nlrp12-/- deficient ones (both group P < 0.01). Proteinuria analysis and serum creatinine all showed worsened presentation in Nlrp12-/- deficient mice.
Animal models revealed Nlrp12 deficiency could exacerbate the lupus disease severity and progression of lupus nephritis in 2 different mouse models, both in histologic examinations and serological changes, reflecting the importance of Nlrp12 in controlling lupus pathogenesis.
Cutaneous lupus erythematosus (CLE) and dermatomyositis (DM) are autoimmune diseases with characteristic cutaneous rashes. Both are histopathologically characterized by interface dermatitis and they are difficult and sometimes impossible to differentiate based on skin biopsies. The specific pathogenesis of both conditions remains enigmatic.
Punch biopsies were obtained from lesional skin from patients with CLE (n=6) or DM (n=5), and control skin (n=6). Equal volumes of tissue were microdissected within the CLE and DM dermal inflammatory infiltrates and control dermis. Proteomic database was constructed using nano-LC tandem mass spectrometry. Qiagen Ingenuity pathway analysis was performed, and identified canonical pathways were compared between CLE, DM, and controls.
Comparing CLE vs controls we identified 246 pathways, while 51 of them were enriched (threshold p<0.05). Comparing DM vs controls 200 pathways were identified, 72 enriched. Canonical pathways enriched in both CLE and DM were those involved in antigen presentation, protein ubiquitination, acute phase response, interferon signaling, GP6 signaling, tRNA charging, and B cell development. Analysis of CLE vs DM showed 237 pathways, 70 of them enriched (p<0.05). The top differentially enriched canonical pathways in CLE compared to DM included EIF2 signaling, complement system, LXR/RXR and FXR/RXR activation, acute phase response signaling, mTOR and granzyme A signaling, clathrin mediated endocytosis signaling, and coagulation system.
Canonical pathways enriched in both CLE and DM skin are associated with activation of innate and adaptive immune systems, including the interferon system. A major difference between CLE and DM was that the EIF2 pathway, involved in cellular stress and induction of cell death, was enriched in CLE. Enhanced granzyme A signaling in CLE coincides with the top upregulated cytokine in the CLE proteomics being IL-16,1 majorly expressed by CD8 T lymphocytes. Further, results indicate differentially activated metabolic pathways and deposition of complement and coagulation components in CLE dermal infiltrate.
Niewold TB, Meves A, Lehman JS, et al. Proteome study of cutaneous lupus erythematosus (CLE) and dermatomyositis skin lesions reveals IL-16 is differentially upregulated in CLE. Arthritis Res Ther 2021;23:132. doi:10.1186/s13075-021-02511-0
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the overproduction of autoantibodies. Recent studies showed that CD11c+ extrafollicular (EF) B-cells plays a central role for the development of lupus. We investigated the role of mitochondria in CD11c+ EF B cells and autoimmune plasmablasts in lupus.
We investigated EF B cells, CD11c+ plasmablasts in B6 mice stimulated with CpG-Oligodeoxyribonucleotides (ODN) every other day for 10 days. Immune cell subtypes were analyzed by flow cytometry. Mitochondria membrane potential and mass were measured by JC-1, MTDR, and MTG. Generation of autoimmune plasmablasts were evaluated by measuring serum anti-dsDNA antibody by ELISA and anti-dsDNA antibody secreting cells by ELISPOT. Furthermore, mouse spleen B cells and human peripheral blood B cells from lupus patients were stimulated with CpG-ODN for 3 days and generation of EF B cells and mitochondria were evaluated by FACS. Mitochondria were inhibited by IM156 (complex I inhibitor), and CB-839 (GLS1 inhibitor) with in vivo or in vitro CpG-ODN stimulation.
In vivo injection of CpG-ODN induced anti-DNA antibody in mice. Mitochondria membrane potential and mass of EF B cells and plasmablasts were increased by CpG-ODN. Autoimmune plasmablasts measured by anti-dsDNA antibody ELISPOT were increased in bone marrow from CpG-ODN injected mice. CpG-ODN induced EF B cells and plasmablasts in in vitro culture condition with mouse splenic B cells and lupus B cells. Furthermore, CpG-ODN also increased mitochondria membrane potential and mass in in vitro culture condition. IM156 or CB-839 inhibited EF B cells and autoimmune plasmablasts in vivo and in vitro.
This study demonstrated that the central role of mitochondria in generation of autoimmune plasmablasts in lupus. CpG-ODN induced autoimmune plasmablasts while IM156, or CB-839 inhibited autoimmune plasmablasts by suppression of mitochondria.
GWAS have linked loss-of-function mutations in phagocytic NADPH oxidase complex (NOX2) genes, including NCF1 and NCF2, to lupus pathogenesis. The prevailing model holds that reduced NOX2 promotes SLE via defective efferocytosis, the immunologically silent clearance of apoptotic cells. We previously showed that defects in endolysosomal flux increase B cell TLR signals, resulting in humoral autoimmunity.1–3 Since NCF1/NCF2 are known regulators of myeloid endosomal trafficking, we hypothesized that a parallel B cell-intrinsic mechanism contributes to lupus risk.
We tested the impact of NOX2 family gene deletion on B cell TLR signaling using in vivo animal models, primary murine B cells, NCF1-null human B cell lymphoma lines, and CRISPR-edited primary human B cells.
NOX2-deficient mice exhibited increased humoral responses to nucleic acid-containing antigens, findings which correlate with enhanced B cell signals downstream of endosomal TLRs. In keeping with important roles for B cell TLRs in lupus pathogenesis, B cell-intrinsic NADPH oxidase deletion promoted humoral autoimmunity in mice. To understand the underlying mechanisms, we quantified TLR-induced intracellular trafficking in B cells using live cell microscopy. Following CpG stimulation, NADPH oxidase activation promoted trafficking of TLR-containing endosomes to lysosomes, resulting in TLR signal termination. Whereas initial uptake and aggregation of fluorescent CpG in early endosomes was preserved in NCF1-null B cell lymphomas, loss of NADPH oxidase activity limited signal degradation resulting in enhanced downstream NFkB activation. Finally, CRISPR-mediated disruption of NCF1 in primary human B cells confirmed a direct role for NOX2 in regulating endosomal TLR signaling in B cells. Following TLR9 activation in vitro, NCF1-deficient human B cells exhibited increased differentiation into IgM- and IgG-producing plasma cells, supporting a mechanistic link between B cell NADPH oxidase activity and human lupus pathogenesis.
Loss of function NCF1/NCF2 variants exert a B cell-intrinsic contribution to lupus pathogenesis.
Acharya M., F. Raso, S. Sagadiev, E. Gilbertson, L. Kadavy, Q.Z. Li, M. Yan, L.M. Stuart, J.A. Hamerman, A. Lacy-Hulbert. B Cell alphav Integrins Regulate TLR-Driven Autoimmunity. J Immunol 2020;205:1810–1818. Acharya M., A. Sokolovska, J.M. Tam, K.L. Conway, C. Stefani, F. Raso, S. Mukhopadhyay, M. Feliu, E. Paul, J. Savill, R.O. Hynes, R.J. Xavier, J.M. Vyas, L.M. Stuart, A. Lacy-Hulbert. alphav Integrins combine with LC3 and atg5 to regulate Toll-like receptor signalling in B cells. Nat Commun 2016;7:10917. Raso F., S. Sagadiev, S. Du, E. Gage, T. Arkatkar, G. Metzler, L.M. Stuart, M.T. Orr, D.J. Rawlings, S.W. Jackson, A. Lacy-Hulbert, M. Acharya. alphav Integrins regulate germinal center B cell responses through noncanonical autophagy. J Clin Invest 2018;128:4163–4178.
Neutrophil gelatinase-associated lipocalin (NGAL) is an acute-phase glycoprotein increased by inflammatory stimuli, oxidative stress, and tissue injury. Although NGAL is associated with global and renal disease activity in systemic lupus erythematosus (SLE), it is not known whether particulate matter (PM) affects NGAL levels and lupus activity in these patients. Thus, we investigated the mediating role of NGAL in the association between PM10 and PM2.5 exposure and lupus activity in a prospective, longitudinal cohort.
The study enrolled 386 patients from three metropolitan regions in Korea. The daily average PM10 and PM2.5 concentrations were measured using portable air quality monitors and based on data from the National Ambient Air Monitoring System. Urinary NGAL (uNGAL) was measured at the time of enrollment and at 12 months, and disease activity was evaluated using the SLE Disease Activity Index 2000 (SLEDAI-2K) every 3 months for 1 year. Mixed Cox proportional hazard regression was performed to evaluate the associations of PM10 and PM2.5 with uNGAL and SLE disease activity.
Changes in PM10 and PM2.5 were associated with changes in uNGAL (β = 1.038, 95% confidence interval [CI]: 1.017–1.059, p < 0.001; β = 1.030, 95% CI: 1.001–1.045, p = 0.013, respectively), and with changes of SLEDAI-2K scores of > 8 over 1 year in SLE patients (β = 0.097, 95% CI: 0.048–0.146, p < 0.001; β = 0.100, 95% CI: 0.054–0.146, p < 0.001, respectively). In addition, changes in uNGAL were significantly associated with changes in SLEDAI-2K scores of > 8 (β = 1.000, 95% CI: 1.000–1.002, p = 0.043).
The association between PM exposure and SLE disease activity may be partially explained by uNGAL levels.
Sphingolipids involved in regulating signal pathways in cell growth, differentiation, and apoptosis are increasingly recognized as playing an important role in the pathophysiology of chronic inflammatory diseases. This study aimed to evaluate the serum profile of sphingolipids in systemic lupus erythematosus (SLE) and to investigate the association between serum sphingolipids and disease activity.
Levels of sphingolipids in plasma of women with SLE were assessed by liquid chromatography tandem mass spectrometry. The diagnostic value of plasma sphingolipids was analyzed using the area under the receiver operating characteristic curve (ROC). Pearson’s correlation coefficient was used to analyze the relationship with disease activity markers.
Serum samples were collected from 38 women with SLE, including 11 lupus nephritis, and 30 controls. There were increases in concentration ceramide (Cer) and Cer to sphingosine-1-phosphate (S1P) ratio subspecies in patients with SLE, while the levels of sphingomyelins were decreased compared to the controls. The ratio of Cer16:0 to S1P showed a particularly strong increase in patients with lupus nephritis, with an area under the curve 0.739 (95% confidence interval, 0.581–0.898) to discriminate lupus nephritis in the control group. Furthermore, Cer16/S1P levels were correlated with disease duration, anti-double stranded DNA antibody, SLE disease activity index 2000, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index.
Our data indicate that serum sphingolipids can be a good candidate for SLE diagnostic markers. In particular, we identified that Cer16 to S1P could be useful for diagnosing lupus nephritis.
Little has been known regarding the biomarker to predict the treatment response in lupus nephritis. This study aimed to identify potential biomarkers that predict treatment response in lupus nephritis (LN).
In this prospective longitudinal study, 66 active LN patients were included and underwent renal biopsy at the time of enrollment. Patients were divided into two groups according to one-year response: 50 responders and 16 non-responders. Serum and urine samples were collected at 0, 12, 24, and 48 weeks after induction therapy. Twelve serum and urine biomarkers were measured by the multiplex immunofluorescence assay.
Urine (VDBP, MCP-1, IL-6, and IP-10) and serum (IP-10 and IL-23) levels of 12 biomarkers sampled one year after treatment differed significantly between responders and non-responders. Compared with the baseline, their levels in one year were significantly higher in non-responders than in responders. Urine VDBP was significantly correlated with proteinuria (rho=0.62, p< 0.0001), creatinine (rho=0.37, p=0.0025), and renal activity index (rho=0.35, p=0.0042).
The change in urine IL-6 and IL-23 levels during three months after induction treatment could predict the treatment response in lupus nephritis with an AUC of 0.70 (p=0.025) and 0.71 (p=0.018), respectively. A model incorporating these two predictors into complement C3 and C4, which are significant clinical factors for treatment response, showed increased predictive value with an AUC of 0.78.
Urine VDBP, MCP-1, IL-6, IP-10, and serum IP-10 and IL-23 after one year of treatment differed significantly between responders and non-responders. Moreover, our predictive model composed of urine IL-6, 23, and complement showed increased discriminative ability between responders and non-responders in patients with LN.
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a common manifestation of systemic lupus erythematosus (SLE), with high mortality and disability rate. The lack of effective diagnostic methods, such as biomarkers, makes it difficult to diagnose and treat NPSLE. Metabolomics studies in autoimmune diseases shed new light on the identification of biomarkers beyond autoantibodies and cytokine profiling. This research aimed to explore the unique metabolomic profile, and discover novel molecular biomarkers and pathways for NPSLE.
Cerebrospinal fluid samples from 26 NPSLE patients, 9 SLE controls, 7 connective tissue disease (CTD) controls and 9 nervous system disorder (NSD) controls were analysed to identify metabolomic signatures, significant pathways and biomarkers in the discovery cohort, using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Next, the potential biomarkers were verified in an independent validation cohort including 22 NPSLE patients, 11 SLE controls and 4 NSD controls.
The metabolite profiles of cerebrospinal fluid (CSF) samples allowed significant differentiation of NPSLE patients from other disease controls. β-alanine metabolism and inositol phosphate metabolism pathways were significantly perturbed in NPSLE group. In the discovery cohort, 44 CSF metabolites with variable importance in projection (VIP) scores >1.5 and p < 0.05 were considered as the most differential metabolic biomarkers, including β-alanine amino acid and inositol. The diagnostic value of inositol was verified in the validation cohort, with the greatest specificity of 95.45% and the sensitivity of 60.00% for NPSLE. The CSF inositol level was higher in NPSLE patients with neuropsychiatric damage, cranial neuropathy and cerebrovascular disease.
CSF metabolomic profile of NPSLE patients is unique from other disease controls. The pathway perturbations are involved in β-alanine metabolism and inositol phosphate metabolism. Inositol is a promising biomarker for the diagnosis and neuropsychiatric damage evaluation of NPSLE, and has potential relationships with specific NPSLE manifestations.
Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most serious complications of systemic lupus erythematosus (SLE), lacking efficient diagnostic biomarkers. Previous studies have shown that anti-ubiquitin carboxyl hydrolase L1(UCH-L1) autoantibody is a promising cerebrospinal fluid (CSF) biomarker for NPSLE diagnosis. The purpose of this study is to explore the serum autoantibodies against different UCH-L1 epitopes and investigate the potential diagnostic value of serum autoantibodies against different UCH-L1 epitopes in NPSLE.
The epitopes of UCH-L1 protein were predicted in DNAStar software. The serum levels of different UCH-L1 epitope autoantibodies in 40 NPSLE patients, 32 SLE patients without neuropsychiatric symptoms and 21 healthy controls were determined by enzyme-linked immunosorbent assay (ELISA). Data were analysed using Pearson correlation analysis, ROC curve analysis, nonparametric Mann-Whitney test, t-test and 2 test.
We screened three candidate epitopes of UCH-L1 protein. The autoantibody against amino acid 58 to 69 of UCH-L1 (UCH58-69) showed highest diagnostic power in distinguishing NPSLE patients from SLE patients without neuropsychiatric symptoms (p=0.0038). The ROC analysis showed that the specificity and sensitivity of anti-UCH58-69 were 92.3% and 37.5%, respectively. In addition, increased serum anti-UCH58-69 levels were associated with increased SLEDAI, CSF microprotein, CSF leukocyte count, ESR, AnuA, anti-dsDNA, IgG and IgM but with decrease of C3 in SLE patients.
The serum levels of anti-UCH58-69 significantly increased in NPSLE patients compared with SLE patients without neuropsychiatric symptoms and were correlated with disease severity. Anti-UCH58-69 autoantibody may become a novel serum biomarker for NPSLE non-invasive diagnosis, which might be applicable for NPSLE early screening and diagnosis.
Interleukin-6 (IL-6) is a Pro-Inflammatory cytokine with many biological activities. IL-6 is mainly involved in immunity and inflammatory process. It induces the terminal differentiation of B lymphocytes into antibody-forming cells and the differentiation of T cells into effector cells. Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by antibodies to nuclear and cytoplasmic antigens, multisystem inflammation, protean clinical manifestations, and relapsing course. We designed a study to establish the correlation between IL-6 and the severity of SLE.
About 52 SLE-diagnosed patients were recruited based on the 1997 Updated American College of Rheumatology Revised Criteria for Classification of SLE in our centre. Their venous blood was taken and centrifuged at 4500RPM for about 5mins, and the serum was collected. ELISA test was done on these sera, and the data obtained was recorded in the form of a scatter plot and statistics, in which any ‘P’ value of >0.05 was significant. The severity of the subject’s SLE was quantified using BILAG Index. The index allocates alphabetic scores to each of the ten organ-based systems, and then a total score is calculated.
We found a direct correlation between the level of IL-6(statistically significant P=0.005) and the severity of the SLE. The IL-6 mean value was taken as 132.6pg/ml, while a linear scatter plot was obtained. Pearson correlation coefficient showed a linear correlation between the two variables. Thus, the higher the IL-6 levels, the higher the BILAG score.
Serum IL-6 levels can be used to screen, diagnose, and act as a prognostic factor in the development and progression of SLE. These findings may open the opportunity for a new horizon in the early detection and treatment of SLE patients, which will greatly implicate the disease’s complications and the cost of treating it.
Systemic lupus erythematosus (SLE) is becoming a public health concern because of increasing disease and economic burdens. However, epidemiological data on SLE, especially its incidence rate, were limited in China. We aimed to investigate the incidence, prevalence, and cost burdens of SLE in urban Chinese.
We conducted a population-based study using national databases, Urban Employee Basic Medical Insurance and Urban Resident Basic Medical Insurance, in China between 2013 and 2017. Data from over 380 million patients were analyzed, and a total of 132,258 SLE patients (mean age 43.03 years, 81.34% female) were identified. Incident cases were individuals with a diagnosis of SLE with a 3-year disease-free period. Prevalent cases were patients with at least 1 insurance claim record with the diagnosis of SLE. Primary outcomes, including overall, age-, gender-, and region-specific incidence and prevalence rates of SLE, were estimated by a two-stage approach assuming a Poisson distribution. Associated annual costs and hospital visit times were also calculated.
The crude incidence and prevalence of SLE in China in 2017 were 14.96 (95%CI, 12.69–17.43) and 50.37 (95%CI, 44.19–56.95) per 100,000 person-years, suggesting incident and prevalent populations of 0.21 and 0.71 million (
Rapidly expanding SLE population and increasing costs associated with SLE have placed considerable burdens on health systems in China. Enhanced efforts are needed to make long-term care more accessible and cost-effective for SLE patients, especially young population.
Figure Incidence and prevalence of SLE in urban China from 2013 to 2017 A: Crude and standardized incidence of SLE (the standardized incidence is based on 2010 China census data) in 2016 and 2017. B: Age- and gender-stratified incidence of SLE in 2017. C: Crude and D: Standardized prevalence of SLE (the standardized prevalence is based on 2010 China census data) from 2013 to 2017. E: Age-stratified prevalence of SLE in female and F: male from 2013 to 2017
The association between cigarette smoking and the risk of developing systemic lupus erythematosus (SLE) remains a matter of debate. The aim of this study is testing the hypothesis that there is a larger proportion of smokers among SLE patients at symptom debut compared to controls.
Two hundred and fifty five SLE patients fulfilling the ACR classification criteria responded to a questionnaire regarding smoking in 2010. The year of symptom development was registered. Juvenile SLE was defined as onset before 16 years of age. All men, participants below 16 years, and patients born before 1920 were excluded due to lack of proper matches in the control group. Each of the remaining 200 SLE patients had three age-matched controls. The control group consisted of 1050 females who answered a questionnaire of various health issues including smoking habits in 2012. The smoking status in the SLE patients at onset of symptoms was compared with controls. The Cochran-Mantel-Haenszel (CMH) test was used to determine the association between smoking and SLE.
The pooled odds ratios (OR), 95% confidence intervals for OR as well as p-values for test of the hypothesis that OR = 1 are shown in the
In this study of 200 women with SLE and age-matched controls, current smoking was associated with a modestly elevated risk of SLE (OR 1.49, p<0,03). This corresponds with a previous meta study on SLE.1 However, smoking is complex phenomenon where cultural and socioeconomic factors play a part. The relationship between cigarette smoking and SLE should be addressed in a prospective manner.
Odds ratio of SLE patients smoking versus not smoking at onset of disease compared with controls
Costenbader KH, Kim DJ, Peerzada J, et al. Cigarette smoking and the risk of systemic lupus erythematosus: a metaanalysis. Arthr Rheum 2004;50:849e57.
Patients with systemic lupus erythematosus (SLE) have increased mortality related to cardiovascular disease (CVD) and the age is one of important risk factors for the development of CVDs. However, the comparative risk of CVDs in patients with older onset SLE has not been well studied. This study aimed to compare the CVD risk in patients with SLE occurred after the age of 40 compared to those with diabetes mellitus (DM).
Incident SLE patients aged over 40 years and age-sex matched (1:4:4) controls with DM or general population were identified from the nationwide claims database in Korea between 2008 and 2018. We defined CVD risk as ischemic heart disease, stroke, and cardiac death. The incidence rate (IR), incidence rate ratio (IRR), and adjusted hazard ratio (HR) of CVDs were calculated using generalized estimating equation models.
We identified 4,272 SLE, 17,003 DM, and 17,088 general population patients aged over 40 years. Their mean age was 53.1 (±9.7) and 87.1% of them were female. The IR per 1,000 person-years (PYs) of CVDs for SLE, DM, and general population were 16.8, 11.7, and 5.7, respectively. Compared to general population, patients with SLE (IRR 3.27, 95% CI 2.78–3.85) and DM (IRR 2.77, 95% CI 2.02–2.56) showed higher CVD risk compared to general population. Increased risk of CVDs in SLE patients was highest in their forties (IRR 4.13, 95% CI 3.06, 5.59). After adjusting confounders, the CVD risk of SLE (HR 1.99, 95% CI 1.66–2.38) was higher than DM (HR 1.39, 95% CI 1.22–1.58) patients.
Older onset SLE patients had increased CVD risk compared to general population. Even after adjustment for confounders, older onset SLE patients showed higher CVD risk than DM patients in Korea.
The long-term morbidity and mortality of childhood-onset SLE (cSLE) after transition to adult care is not well-documented. The present study aims to fill this knowledge gap by analyzing outcomes in a large province-wide cSLE cohort. Our objectives were to: 1) determine all-cause and cause-specific mortality rates, adverse renal event rates, cardiovascular event and cancer rates; and 2) determine baseline characteristics associated with higher rates of transition between 3 different states: event-free, adverse renal event, and death.
Clinical data were abstracted for cSLE patients diagnosed between January 1990 and March 2011 after contacting all pediatric and adult rheumatologists and nephrologists in Ontario. Data were linked to administrative healthcare databases at ICES to determine the outcomes of interest. We examined descriptive summaries of major outcomes including death, end-stage kidney disease [ESKD] requiring chronic dialysis and renal transplant, cardiovascular events and cancer. We used a multi-state Cox model to determine baseline characteristics associated with higher rates of transition between the 3 states (
There were 37 deaths in a cohort of 601 patients at a mean follow-up time of 14 years. The all-cause mortality rate was 3.43 per 1000 person-years. The rates for ESKD requiring chronic dialysis and renal transplant were 5.34 and 2.16 per 1000 person-years, respectively. The rates for any type of cardiovascular event and cancer were 6.32 and 3.13 per 1000 person-years, respectively. The multi-state model indicated that the non-white ethnic group (HR, 2.15; 95% CI, 1.14–4.08) and the presence of renal involvement at baseline (HR, 2.15; 95% CI, 1.17–3.95) were significantly associated with higher rates of transition from event-free to adverse renal event.
In this large multi-ethnic cSLE cohort, ethnicity was associated with adverse outcomes including renal events and death. Further analyses will help inform risk for adverse outcomes to improve clinical care for the highest risk patients.
Accumulating evidence suggests that differentially expressed circular RNAs (circRNAs) play critical roles in immune cells of SLE patients. Hsa_circ_0000479 has been studied in the field of cancer and infection, whereas a few researches in autoimmune disease. The aim of this study was to discuss the roles and clinical value of hsa_circ_0000479 in SLE.
Reverse-transcription real-time quantitative polymerase chain reaction (RT-qPCR) was conducted to detect the expressions level of hsa_circ_0000479 in PBMCs (HC: n = 8; SLE: n = 8) and in neutrophils (HC: n = 45; SLE: n = 80). The relationships between hsa_circ_0000479 levels in neutrophils and the clinical features and laboratory parameters in SLE were analyzed.
The expressions level of hsa_circ_0000479 in SLE patients were higher than that in healthy controls. Even the expressions of hsa_circ_0000479 of neutrophils were significant obvious than that of PBMCs of patients with SLE. Moreover, the expressions level of hsa_circ_0000479 on neutrophils in SLE patients were negatively related to absolute neutrophils count (r = -0.323, P = 0.004) and complement 3 (C3) (r = -0.346, P = 0.002), whereas positively correlated with anti-dsDNA (r = 0.394, P = 0.001) and anti-nucleosome antibodies (r = 0.384, P = 0.001). Additionally, the increased level of hsa_circ_0000479 was associated with several clinical manifestations, including mucocutaneous vasculitis involvement, anemia, arthritis, lupus nephritis, neuropsychiatric involvement, and pulmonary involvement of SLE.
Hsa_circ_0000479 in neutrophils probable was one of factors which involved in the pathogenesis and had potential clinical value in SLE.
The association between major histocompatibility complex (MHC) regions and systemic lupus erythematosus (SLE) has been widely established.
To refined the most significant independent MHC loci with SLE susceptibility and clinical manifestations in Chinese Han population, we conducted stepwise conditional analysis 7,342 SLE cases and 7,185 control subjects of Chinese Han population based on the genotyped MHC region in Genome-wide association studies data by the Han-MHC reference panel in 1000 Genomes Project phase 3. Meta-analysis was performed in part of those independent loci with other ethnic populations from published studies. The correlation between the independent variants and SLE clinical feature was assessed by chi-square test.
A total of 1427 HLA variants significantly associated with SLE were identified(P<5x10–8): amino acid residue at position 233 in HLA-DRB1 (P=2.99x10–4, OR 0.81), HLA-DRB1*15:01(P=2.46x10–5, OR 1.37) and rs3135393(P=1.74x10–4, OR 0.71) contributing the strongest signal. Stepwise conditional analysis revealed 20 independent variants including 15 novel loci with most strongly statistically association signal.
Meta-analysis of different ethnic groups confirmed 3 alleles shown consistent role to disease predisposed effects in multiple races and HLA-DQB1*03:01 present slightly different in different race. In a sub-phenotype comparative analysis, a link between 7 alleles, 5 amino acid residue and 3 SNP of HLA independent variant were detected strongly signal with different clinical manifestations of SLE.
Our study emphasized the genetic value of the MHC region in the predisposition and its clinical feature of SLE in Chinese Han population. This funding provided a new perspective for early diagnosis, prevention, intervention among autoimmune diseases.
Despite recent advances in systemic lupus erythematosus (SLE) genetics, genetic contribution to development of neuropsychiatric SLE (NPSLE), which is one of the devastating complications of SLE, has yet to be defined. We investigated genetic contributions to NPSLE using a genome-wide association study (GWAS).
We recruited 1,205 SLE patients from Hanyang BAE lupus cohort (enrollment from 1998 to June 2021; June 2022 as final follow-up) and performed GWAS using Korean Chip with imputation using 1KG reference panels. The 271 patients with NPSLE (22.5%) were defined using Ainiala Criteria that did not include minor NP events (headaches, anxiety), a revised version of American Colleague of Rheumatology (ACR) case definitions for 19 NP syndromes. The association of GWAS data with Ainiala NPSLE or each major event (seizure, psychosis) were analyzed using logistic regression by adjusting for clinical factors.
Across all analyses groups, we identified 30 significant genetic loci at suggestive level (P <1x10–6). rs4508395 and rs191085932 were top SNPs in analyses of Ainiala NPSLE and SLE with seizure, respectively (OR [95% CI] = 1.96 [1.51–2.54], P = 3.49x10–7 and OR = 8.26 [3.71 – 18.37], P = 3.51x10–7). In the Ainiala NPSLE analysis group, we mapped 53 genes using variants with P <1x 10–5 and observed that those were significantly associated with differentially expressed genes in nerve tissue and in parts of the brain (adjusted P = 0.044 and 0.040, respectively,
We identified genetic variants associated with Ainiala NPSLE which may be functionally related to nerve and brain, providing new ideas for molecular pathogenesis of NPSLE.
Functional analyses for genetic risk loci of NPSLE. Tissue implicated by genetic associations with NPSLE from (A) GTEx data expression data v7, (B) GTEx data expression data v6. (C) Result of gene set enrichment test using genetic associations with NPSLE
Systemic lupus erythematosus (SLE) is a complex autoimmune and hereditary disease. We found that the mutation rs13306575 located in NCF2 is associated with the lupus phenotype, and we aim to explore its relationship with SLE.
Transcriptome analysis was performed using public databases on the transcriptome of various tissues in lupus. Blood samples were collected and qPCR was used to verify the expression of NCF2 in peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls (HC). The rs13306575 mutant (NCF2 R395W mutation) cell lines of NCF2 was constructed. Co-immunoprecipitation was used to observe the binding of NCF2 to its ligand. The effects of NCF2 on inflammation were detected by fluorescence microscopy, ELISA, Western Blot and qPCR.
NCF2 expression was decreased in PBMCs and lupus nephritis kidneys in SLE patients compared with HC. Similar to NCF2-cells, NCF2 R395W mutation reduced the function of NADPH oxidase and the ability to produce reactive oxygen species (ROS). Meanwhile, the mutation reduced the binding of NCF2 to NCF4. Under different stimuli, NCF2- and mutant cells showed decreased expression of NETs and altered expression of p38MAPK signaling pathway to varying degrees.
In conclusion, the missense mutation rs13306575 lead to decreased expression of NCF2 and declined function of NADPH oxidase, which may be involved in SLE through multiple mechanisms.
The B cell-activating factor (BAFF) promotes the maturation, differentiation, and survival of B lymphocytes, which play an important role in the pathogenesis of systemic lupus erythematosus (SLE). This cytokine has been associated with SLE disease activity, hence TNFSF13B gene, which encodes BAFF, along with its diverse single-nucleotide polymorphisms (SNPs) might also be associated with more severe SLE activity. The aim of this study was to explore the association between TNFSF13B genetic polymorphisms with disease activity, as well as serum soluble BAFF (s-BAFF) levels in SLE patients.
This cross-sectional study included SLE patients in rheumatology clinic and in-patient wards of Dr. Hasan Sadikin General Hospital, Bandung, between February 2020 -March 2022. One single nucleotide rs9514828 (C>T -871) polymorphism in the 5’ regulatory region of the TNFSF13B gene were identified by PCR-sequencing. Serum BAFF levels were measured by ELISA and disease activity was measured by MEX-SLEDAI score. The active disease was determined by MEX-SLEDAI 2. The statistical analysis was performed using Mann-Whitney, Chi-Square, and Spearman test for the correlation.
There were 107 SLE patients, all female with median age of 32 years old (interquartile range [IQR], 15–64). The median disease duration was 5 years (IQR 0.5–22), whereas the median s-BAFF levels was 846.9 pg/mL (IQR 185–6979.88). The s-BAFF levels were significantly elevated in active disease patients compared to inactive disease (953.17 pg/ml vs 781.4 pg/mL; p 0.008). There was a weak positive correlation between s-BAFF levels and disease activity (r 0.311; p 0.001). There were no differences in genotype TNFSF13B polymorphisms with the disease activity.
Although the rs9514828 (C>T -871) of TNFSF13B gene promoter does not seem to be related with SLE activity, s-BAFF levels is, however, correlated with disease activity. Further study to explore other polymorphisms in TNFSF13B gene is of great interest.
Prognosis of systemic lupus erythematosus (SLE) has been improved during past decades. However, some clinical features which might be associated with poor prognosis persist or increase. This study aimed to identify changes of clinical features and mortality between late and early cohort.
Among 1,448 SLE patients, 621 defined to inception cohort. They divided into early (1998–2007, n=317) and late (2008–2017, n=304) cohort and followed for 10 years until 2008 and 2018, respectively. They were compared with ACR criteria, SLEDAI, Adjusted Mean SLEDAI (AMS), SDI, and mortality. Mortality data were collected by linking with data from the Korean National Statistics Office. Poisson Cox hazard model was used to investigate risk factors for mortality.
Mean age at enrollment was 28.5 ± 10.9 years and women were 92.3% in overall inception cohort. Baseline demographic characteristics and the number of ACR criteria during follow-up were not different between two cohorts (all P>0.05). SLEDAI at enrollment (P<0.001) and AMS (P=0.03) were lower in late cohort than early cohort. There was no difference in SDI accrual (P=0.546). However, most common organ damage in early cohort was musculoskeletal (12.3%), followed by neuropsychiatric (8.2%) and renal (7.3%), whereas in late cohort, musculoskeletal (11.5%), followed by pulmonary (6.6%) and skin (5.6%). Renal damage was less in late cohort (7.3% and 2.6%, P=0.013). Mortality was not different between them [n=10 (3.2%) and n=8 (2.6%), P=0.882]. Risk factors for mortality in early cohort was no use of hydroxychloroquine (P=0.017) and neuropsychiatric damage (P=0.024), whereas in late cohort pulmonary damage (P=0.028).
Prognosis of late cohort have been improved regarding to disease activity and renal damage. Mortality was not different, but risk factors for mortality in late cohort have been changed from neuropsychiatric to pulmonary damage, which could be a target to improve outcomes for SLE patients diagnosed recently.
New Zealand became a member of the Asia Pacific Lupus Collaboration (APLC) group in 2018. The APLC treat-to-target (T2T) LLDAS study is an ongoing, prospective longitudinal study (n = 4,106).
The aim of this study was to: (1) assess SLE epidemiology from the Auckland cohort of APLC T2T LLDAS study, and (2) examine if there are ethnic differences in association with the ability to achieve LLDAS, with emphasis on lupus nephritis.
All patients fulfilled either the ACR or SLICC lupus criteria. At each study visit (3 to 6 monthly), patients are assessed for flares using SLEDAI-2K. Information on medication and laboratory data are collected. Patients are assessed annually for SLE damage.
144 patients from 3 Auckland hospitals were recruited during 2018–2020. The ethnic breakdown was Asian 42%, European 33%, Pacific Island (PI) 19% and Maori 4.9%. Arthritis (n=115, 80%), was the most common clinical feature. 41 patients (28%) had renal disease.
The incidence of SLE in Auckland is 6.32 per 100,000. Asian (n=23/60, 38%) and PI patients (n=9/28, 32%) had more renal disease (p=0.03). PI patients had proportionally more proliferative (Class III/IV) lupus nephritis that can potentially lead to long term renal damage compared to the other ethnic groups (n=8/9, 89%; p =0.046). 76% (n=109) of patients achieved LLDAS on at least one occasion. 90% (n= 129) of patients were on hydroxychloroquine. The mean SDI damage score is 0.4.
This is the first NZ study to provide prospective data on SLE disease activity and damage. There are ethnic differences in lupus nephritis with over representation in Asian and PI patients.
Self-efficacy for managing chronic conditions assesses the confidence an individual has on her/his ability of successfully performing specific tasks related to a chronic condition in several different situations. It is considered a modifiable behavior in educational interventions in SLE patients. The aim of this study was to evaluate the association between self-efficacy and damage accrual in SLE patients.
We evaluated SLE patients from the Almenara Lupus Cohort. Self-efficacy was ascertained with six instruments of the Patient-Reported Outcomes Measurement Information System® (PROMIS®) Self-efficacy for Managing Chronic Conditions. For PROMIS instruments, a score of 50 is the average for a clinical population (people with a chronic condition), the higher score, the greater self-efficacy. Damage was assessed with the SLICC/ACR damage index (SDI). Generalized estimating equations were performed, using as the outcome any increase in the SDI and the self-efficacy instrument in the previous visit; multivariable models were adjusted for possible confounders measured at the same visit as the self-efficacy instrument. OR was reported per 5 units increase per self-efficacy instrument component.
A total of 209 patients (563 visits) were included. At baseline, mean general self-efficacy was 47.2 (10.4), self-efficacy for managing emotions was 44.6 (8.0), for managing symptoms was 47.7 (8.2), for managing daily activities was 45.5 (7.5) for managing social interactions was 42.9 (7.9) and for managing medications and treatment was 43.9 (7.0). During the follow-up visits, 41 (19.6%) patients accrued damage once and 2 patients (1.0%) accrued damage twice. In the multivariable models, a better self-efficacy for managing symptoms and daily activities was predictive of less damage accrual (
A better self-efficacy mainly in managing symptoms and daily activities domains is predictive of a lower risk of damage accrual, even after adjustment for possible confounders. Strategies to improve self-efficacy in SLE patients should be encouraged to improve patients’ outcomes.
The predictive value of self-efficacy on damage accrual in SLE patients
Anti-dsDNA antibody-targeting peptide mimic ALW has been reported to be a potential strategy in attenuating lupus-like disease in MRL/lpr mice. However, the therapeutic effect of peptide has been hampered due to its unstable architecture and non-renal targeting. Here, we describe a strategy of D-amino acid modified peptide and further engineered it by nanoparticle delivery system to overcome the obstacles in lupus nephritis therapy.
The binding efficiency of D-form mimic peptide (D-ALW) to anti-dsDNA antibodies was assessed in vitro by surface plasma resonance and enzyme-linked immunosorbent assay (ELISA). The inhibition capacity of D-ALW affinity to autoantigens, mesangial cells and glomeruli was determined by inhibitory ELISA, flow cells, and glomerular binding assay. The proteolysis resistance of D-ALW was measured by high-performance liquid chromatography. The peptide D-ALW engineered by PEG-PLGA nanoparticles was injected into BALB/c mice to determine its attenuation in blood and biodistributions in tissue. Polyethylene glycol coated poly lactic-co-glycolic acid was used for the preparation of D-ALW nanoparticles, which were then administered to MRL/lpr mice. The serum anti-dsDNA IgG, complement 3 (C3), proteinuria, renal histopathologic, and renal IgG deposition were analyzed accordingly.
D-ALW, but not L-form ALW, can efficiently resist the proteolysis and possess a higher ability of binding to anti-dsDNA antibody IgG isotypes and blocking the binding of the anti-dsDNA antibody to multiple antigens, mesangial cells or glomeruli in vitro. In vivo studies showed that, compared to D-ALW, D-ALW nanoparticles with specific diameter and charge largely enhanced half-life in sera and accumulation in kidneys. D-ALW nanoparticles even improved the renal IgG deposition and glomerular fibrosis in MRL/lpr mice, accompanied by prolonged life-span.
This study demonstrated that D-form ALW peptide possesses high efficiency and stability. D-ALW nanoparticles with special kidney-targeting ability can ameliorate the nephritis in MRL/lpr mice, possibly through inhibiting pathogenic renal IgG deposition and fibrosis.
SLE is linked to an elevated risk of MACEs. CVD remained the leading cause of death among SLE patients. Management of CVD risk in SLE patients cannot be applied as the general population and must be implemented as soon as SLE is recognised. Our meta-analysis aims to evaluate and provide evidence of the correlation between traditional and SLE-related disease risk factors and CIMT as an early predictor of MACEs in SLE patients
Relevant literatures were obtained from CENTRAL, PubMed and Google Scholars. The primary outcome was correlation of traditional and SLE related risk factors with CIMT in SLE patients were presented as correlation coefficients (r). Random-effect model was used on the analysis in order to represent population better. Risk of bias was assessed by using funnel plot
Out of 1657 studies found, six full-text studies met the inclusion criteria. Total of 615 patients from six studies were included. Our meta-analysis showed traditional risk factors age [r = 0.45, 95% CI (0.35, 0.56), p < 0.0001] and BMI [r = 0.29, 95% CI (0.16, 0.42), p < 0.0001] are correlated with CIMT. SLE related disease like SLE duration [r = 0.21, 95% CI (0.05, 0.37), p = 0.01], SLICC score [r = 0.27, 95% CI (0.12, 0.42), p = 0.0005], and CRP [r = 0.25, 95% CI (0.02, 0.48), p = 0.03] also significantly correlated with CIMT based on random effect model
We found significant correlation between CIMT and age, BMI, SLE duration, SLICC score, and CRP as a predictor of MACEs in SLE. By pointing out the role of CIMT, we hope that future guidelines will place more emphasis on them. SLE patients should be viewed as high-risk individuals and risk factors should be aggressively modified as soon as SLE is recognised
Previous studies have described improved survival in systemic sclerosis (SSc) associated pulmonary arterial hypertension (PAH), yet it is unclear whether survival of systemic lupus erythematosus (SLE) associated PAH has also improved.
A multi-center cohort of SLE-PAH patients diagnosed by right heart catheterization (RHC) was established and divided into cohort A (2011.6-2016.5) and cohort B (2016.6-2021.5) according to the date of their baseline RHC. Another single-center cohort of idiopathic pulmonary arterial hypertension (IPAH) was consecutively recruited as control to describe the baseline characteristic and survival of SLE-PAH patients simultaneously. Disease characteristics and all-cause mortality were compared between cohort A and B. Multivariable cox regression was used to analyze association between treatment goal achievement and survival.
A total of 610 SLE-PAH and 104 IPAH patients were enrolled. Overall, SLE-PAH patients were younger, had lower NT-proBNP level, better function status, better hemodynamic, and higher overall survival than IPAH (81.2% vs 56.0%, p<0.001). Compared with cohort A, patients in cohort B showed lower mPAP and PVR, higher CI, and were more likely to receive extensive immunosuppressants and PAH-targeted medication. 5-year survival rate was also higher in cohort B than cohort A (88.1% vs 72.9%, p=0.01). In multivariable Cox regression, treatment goal achievement of PAH (HR 0.31, 95%CI 0.12–0.81, p=0.017) and reaching lupus low disease activity state (LLDAS) (HR 0.23, 95%CI 0.08–0.67, p=0.007) were independently associated with a lower mortality.
This largest muti-center prospective SLE-PAH cohort showed that survival has improved significantly for SLE-PAH in the last 5 years, and for the first time, demonstrated achieving LLDAS for SLE is associated with reduced mortality for SLE-PAH patients.
We aimed to characterise the all-cause mortality rate (MR) and the incidence of cancer in SLE patients receiving biologic and standard of care (SoC) therapies.
Patients recruited to the BILAG-BR 2010–2021 were included. Demographic and clinical data were recorded at recruitment. Mortality and malignancy data were collected from study centres, the UK Office of National Statistics and the National Cancer Register. Cox regression models were used to estimate risk in biologic-treated patients compared to SoC. Mortality models were adjusted for age, gender, co-morbidity, SLICC damage index (SDI) and hydroxychloroquine (HCQ) use.
During follow-up, (1463 patients with 5,962 person years [pys]), 32 incident cancers occurred in 31 individuals, a median (IQR) of 1.31 (0.63–3.36) years after registration. Compared to the UK general population, the SIR (95% CI) was 1.21 (0.85–1.72). Using SoC as the comparator, the age and gender adjusted HR was 1.49 (0.57–3.92) for rituximab and 2.47 (0.57–10.58) for belimumab. Across the whole cohort, associated risk factors (
Following registration, 54 deaths occurred after a median of 1.8 (0.8–3.3) years. The standardised MR was 4.74 (3.63–6.19). The most common causes of death were infection (22, 40.7%), SLE (11, 20.3%) and cancer (6, 11.1%). MR was 3.3 (1.3–8.9) per 1000 py in the SoC, 11.3 (8.5–15.0) in the rituximab and 2.5 (0.4–17.9) in the belimumab group. Risk factors included age at recruitment (HR 1.07 [1.05–1.09]) and SDI (HR 1.34 [1.08–1.67]. HCQ use was protective (HR 0.30 [0.14–0.65]). In multivariate analysis, compared to SoC, risk was similar in rituximab (HR 2.36 [0.69–8.10) and belimumab groups (HR 1.41 [0.14–14.14]).
Although overall numbers are low, mortality rate and incidence of cancer appears to be broadly similar in SoC, rituximab and belimumab treated patients.
Risk factors associated with risk of cancer and death in a cohort of patientswith moderate-severe SLE
Cardiovascular disease (CVD) is a major cause of mortality in systemic lupus erythematosus (SLE). Role of conventional risk scores which look at cardiovascular events, in assessing subclinical atherosclerosis in SLE is not fully established. This study aims to assess performance of QRESEARCH database risk score-3 (QRISK3), systemic coronary risk evaluation (SCORE) and WHO (World Health Organization) CVD scores in subclinical atherosclerosis and determine clinical associations of the same.
This is a single center cross-sectional analytical study which enrolled 79 patients with SLE (without CVD) and 76 healthy controls. Demography, disease activity, autoantibodies, steroid dose were noted. Subclinical atherosclerosis (carotid plaque or abnormal carotid intima media thickness cIMT) and CVD risk (QRISK3, SCORE and WHO scores) were assessed. Agreement between scores was determined using kappa coefficient.
Subclinical atherosclerosis was seen in 52% SLE (abnormal cIMT-47% and plaque- 8%) and 53% healthy controls (abnormal cIMT-47% and plaque 12%). Mean age of cohort was 45±6 years, mean SLE duration 96±64 months, SLEDAI 1 ±2.3 and median SLICC ACR DI of 1 (0–2). SCORE, WHO and QRISK3 had sensitivity of 0%, 10% and 28% in detecting subclinical atherosclerosis in SLE, 20%, 22% and 5% in controls while specificity was 0%, 82% and 79% in SLE and 97%, 91% and 100% in controls respectively. Kappa agreement was 0 for SCORE with other scores, between QRISK3 and WHO 68% and 15% for plaque in SLE and controls, 31% for cIMT in SLE and controls respectively. Anticardiolipin IgG (14.6% vs 2.6%) was numerically higher in SLE with atherosclerosis but not statistically significant.
Sensitivity of conventional CVD scores in detecting subclinical atherosclerosis was very poor in SLE with QRISK3 and WHO score having good specificity. Hence, until further scores are validated, screening for subclinical atherosclerosis using carotid ultrasound remains gold standard.
Objective: To determine the risk factors associated with the development of cardiovascular events (CVE) in a multi-ethnic Asian cohort of Singapore Systemic Lupus Erythematosus (SLE) patients
We analysed patients in a prospective SLE cohort Tock Seng Hospital (TTSH) in Singapore during the period 2002 to 2017. Patients without prior CVE at baseline visit (V0) who subsequently developed CVE during the follow-up were identified from this registry. Clinical information on traditional, SLE-associated, and treatment-associated risk factors were collected at baseline and at follow up. Predictors associated with development of CVE were analyzed using Chi-squared test and student’s t test.
Out of 1000 patients recruited, 132 were excluded due to prior CVE before V0 and/or withdrew consent. Of the remaining 868 patients, 42 (4.8%) developed a CVE (16 angina/acute myocardial infarction/ischaemic heart disease, 17 cerebrovascular accidents, 11 arterial thrombosis/peripheral vascular disease) after a median (Interquartile range IQR) time of 6.18 (2.70 – 9.13) years. Of those who developed CVE, the median (IQR) age of SLE diagnosis was 34.75 (25.89 – 44.95) years and median (IQR) SLE duration was 10.66 (4.31 – 15.45) years before CVE onset. The risk factors for development of CVE (p<0.05) include onset of SLE at an older age, longer disease duration, longer exposure to corticosteroids, less usage of hydroxychloroquine, presence of hypertension, hyperlipidemia, antiphospholipid syndrome and lower creatinine clearance at time of enrolment into the study.
Besides traditional risk factors, age, disease duration and corticosteroid use are predictors of CVE in this prospective study. The use of hydroxychloroquine appear to be protective.
Kidney biopsies provide useful information to guide management in lupus nephritis (LN). Standard histopathology report includes ISN/RPS class, as well as Activity Index (AI) and Chronicity Index (CI) scores representing inflammation and fibrosis, respectively. We analyzed the clinical attributes associated with histopathologic class, AI and CI scores in patients with LN.
We reviewed the medical records of LN patients seen at the University of Santo Tomas (UST, Manila Philippines) who underwent kidney biopsies from 2015 to 2022. Correlations between SLE disease characteristics at time of biopsy with ISN/RPS class, AI and CI scores were analyzed using Pearson correlation coefficient.
Of 44 patients (95.5% females), 13 and 29 patients had Class III and Class IV LN respectively, 1 each with co-existing Class V. Two patients had pure Class V, there were no patients in the other classes. Mean age was 25.1±10.3 years at LN diagnosis, with average disease duration of 2.4±3.7 years from diagnosis to biopsy. 70.5% had mild to moderate disease (SLEDAI<12) at biopsy. Average serum creatinine was 1.4±0.87 mg/dL, eGFR 71.8±37.7 mL/min, UPCR 2.6±1.4, and SLEDAI 10.6±4.4. Of renal parameters, only hypertension was associated with higher CI (r=0.417,p=0.002); although there was a trend for higher UPCR (r=0.144,p=0.176) and serum creatinine (r=0.221,p=0.075) correlating with higher AI, this was not statistically significant. Extra-renal features of oral ulcers (r=-0.368,p=0.007), arthritis (r=-0.461,p=0.001), and serositis (r=-0.301,p=0.023) were associated with lower CI scores. There was no correlation of individual disease parameters with ISN/RPS class.
This study demonstrated a significant correlation of hypertension with higher chronicity index scores among LN patients. Extra-renal disease activity features of oral ulcers, arthritis and serositis had lower CI scores. Aside from early aggressive management of active LN, strict sustained blood pressure control must be reinforced throughout the disease course in order to prevent renal damage.
Genetic factors play key roles in the pathogenesis of systemic lupus erythematosus (SLE). In the last one and half decade, genome-wide association studies (GWAS) have seen enormous successes, revealing nearly 200 associated loci. However, for large number of loci, the causal variant(s), the association mechanism(s) are unclear. For some, the target gene(s) are unknown or controversial. Lack of functional understanding is the major challenge for translating genetic findings into clinical applications.
In this study, we compared the association signals for SLE with the associations from 14 other autoimmune diseases, using linkage disequilibrium and conditional analyses to identify the shared and specific association signals. We annotated these signals using genomic resources such as eQTL, histone marks, chromatin accessibility, TF binding, and promoter interaction. Relevant cell types and signaling networks are constructed and compared among these diseases.
Analyzing the association signals between SLE and other autoimmune diseases and genomic annotations allow us to have a better grip on the causal genes and association mechanisms. Specific associations are identified for SLE even when the locus is shared with other diseases, including in IKZF1, ETS1, IL12A, DUSP22, IL12RB2, and CD40. Specific target genes, distinct cell types and signaling networks are detected for SLE. The differences suggested by these analyses raise intriguing questions on the shared and unique mechanisms of these autoimmune diseases.
Genetic analysis and genomic annotations of associated loci for SLE in comparison with associations with 14 other autoimmune diseases facilitate the identification of the causal genes and the association mechanisms for SLE. The signals that are shared, or SLE-specific, or lack thereof shed new light on this prototype autoimmune disease from different angles.
Tyrosine kinase 2 (TYK2) mediates cytokine pathways (eg, Type I IFN) linked with SLE pathogenesis. Deucravacitinib is a first-in-class, oral, selective, allosteric TYK2 inhibitor approved for the treatment of adults with plaque psoriasis.1 2 Deucravacitinib was efficacious in a phase 2 SLE trial.3 We developed a customized IFN 5-gene signature score, assessed the pharmacodynamic effects of deucravacitinib on the IFN score, and evaluated the score’s association with SLE disease activity and clinical response in the phase 2 trial.
Patients were randomized equally to placebo or deucravacitinib (3 mg BID, 6 mg BID, or 12 mg QD). DxTerity chemical ligation-dependent probe amplification was used to measure 51 immune system-related genes from whole blood. IFN genes were selected based on distribution, correlations, hierarchical clustering, and consistency of k-means clusters. Serum proteins, blood cell subsets, and antibodies were measured by immunoassays and flow cytometry. SRI(4) and BICLA were measured at weeks 32 and 48.
An IFN 5-gene (MX1, HERC5, IFIT1, RSAD2, and EIF2AK2) signature score was identified and used to classify patients into IFN-high or IFN-low subgroups (
These data support the IFN 5-gene signature score as a biomarker to classify patients with SLE into IFN-high or IFN-low subgroups; however, clinical response by IFN score was inconsistently improved (
IFN 5-gene signature score with k-means clustering-derived cutpoint in the PAISLEY trial
Clinical response at week 32
Armstrong A, et al. J Am Acad Dermatol. 2023;88(1):29–39. Strober B, et al. J Am Acad Dermatol. 2023;88(1):40–51. Morand E, et al. Arthritis Rheumatol. 2022; Nov 11 (Epub ahead of print).
Single-cell RNA-sequencing (scRNA-seq) has been recently applied in systemic lupus erythematosus (SLE) to define distinct cellular composition and transcriptional signatures, greatly expanding our understanding of SLE pathogenesis. However, since most of the studies were cross-sectional approach from a single moment in time, dynamic feature of immune cells over the disease course is yet to be revealed.
We analyzed serial longitudinal PBMC samples (N=19) obtained at various time points of SLEDAI ranged from 4 to 19 in lupus nephritis (N=6) and from controls (N=33) using scRNA-seq (10X Chromium 5’, TCR sequencing).
SLE showed different cellular composition; reduction of CD4+ T, monocytes, cDC, pDC, and increases of CD8+ T and B cells compared to controls. Expression of type 1 IFN signatures were increased in the most cell clusters. Cell to cell interaction analysis revealed activated CD8+ T cells were the most interactive cell population. Further analysis of CD8+ T cell showed increased T cell exhaustion markers and highest cytotoxicity in GZMH+ CD8+ Tem population in SLE. We also observed significantly decreased CD8+ T cell TCR diversity in SLE. To investigate dynamic transformation of immune cells during flare, especially CD8+ T cells, we analyzed selected paired samples before and after flare of lupus nephritis (N=12). In flare state, GZMH+ CD8+ Tem were expanded, displaying increased cytotoxicity with reduction of TCR diversity. We also observed expression of T cell exhaustion markers, but reduced Type 1 IFN signalling in flare state. Interestingly, the paired TCR repertoire and mitochondrial mutation analysis reveals expanded effector CD8+ T cell clonotypes are heterogeneous in each flare from the same patient, directing towards unique antigen convergence in flare stage.
These results uncover dynamic transition of peripheral blood immune cells during flare of lupus nephritis, especially in CD8+ T cell population, suggesting its pivotal roles in SLE pathogenesis.
The development of lupus low disease activity state (LLDAS) as a treat-to-target endpoint for SLE patients has been validated. Its attainment has been associated with improved outcomes. This study aims to show whether a machine learning model can yield good results in predicting whether a patient will achieve LLDAS on their succeeding assessment.
A total of 42,355 records of patients were retrieved from the APLC longitudinal study database. Three machine learning models – XGBoost, Random Forest, and Naive Bayes – were tested for their predictive power. Eighty percent of the data was used to train the models while thirty percent was used for validation. The data were normalized and all models were subjected to 10-fold cross-validation to prevent overfitting. Additionally, we compared the top ten most significant features of each model.
Various metrics were used to measure the model’s predictive power. The results of our study showed that the Random Forest model scored the highest for specificity, PPV, and accuracy with 0.8450, 0.8182, and 0.8338, respectively. The XGBoost model topped the NPV metric with 0.8559 while the Naive Bayes model got the highest score for sensitivity with 0.8986. It is good to note that the score difference of Random Forest with the top sensitivity and NPV scores were only 0.0629 and 0.0085, respectively.
For the significant features, only two features were present on all three models, namely the current LLDAS and proteinuria level. Three additional features were important for two models—whether the patient is taking prednisolone; time adjusted mean (TAM) SLEDAI score; and SLEDAI score.
The study showed and compared various machine learning models on their predictive power in determining whether a patient will achieve LLDAS on their next visit. The results determined that the current LLDAS, proteinuria levels, SLEDAI score (and TAM SLEDAI),
Many SLE patients develop lupus nephritis (LN) and receive mycophenolate mofetil (MMF), a teratogenic drug. Guidelines recommend azathioprine (AZA) in SLE pregnancy without providing guidance on pharmacogenetic testing and therapeutic monitoring although these may help personalize therapy (e.g., identifying ‘shunters’, non-adherence). We evaluated practice patterns pertaining to SLE women with LN in preconception and gestational periods, focusing on pharmacogenetic testing and drug monitoring.
In 02/2022, we distributed an electronic survey to 39 Systemic Lupus International Collaborating Clinics (SLICC) members. Physicians were queried about number of LN patients seen for pregnancy planning, wait time physicians recommend preconception after renal response, choice of pregnancy-compatible immunosuppressive when switching from MMF, pharmacogenetic testing before AZA initiation, and therapeutic monitoring.
Response rate was 74%. On average, respondents saw 7.2 (standard deviation 6.6) LN patients in the preceding year for pre-pregnancy counselling. Most (93%) recommended waiting for a minimal time after achieving renal response on MMF before transitioning to a pregnancy-compatible immunosuppressive (19% suggested ≤ 6 months, 44% 6–11 months, 30% 12–23 months). In patients with inactive LN for ≥ 2 years, 86% switched immunosuppressives, while 14% discontinued MMF without switching. First choice of pregnancy-compatible immunosuppressive was AZA (90%). Tacrolimus (TAC) was preferred over cyclosporine (CsA) by 96% as second option. When initiating AZA, 38% never assessed thiopurine methyltransferase (TPMT) genotype and/or phenotype and 97% never tested for nudix hydrolase 15 (NUDT15) gene. When switching MMF to AZA preconception, 14% measured 6-mercaptopurine (6-MP) levels. Most (56%) faced barriers to 6-MP testing related to access, cost, and wait times. When patients were on TAC or CsA, 48% monitored drug each trimester, while 44% never did.
There is low use of pharmacogenetic testing and therapeutic monitoring when transitioning MMF to a pregnancy-compatible drug preconception. We identified potential care gaps, which could be addressed by future pragmatic trials.
Systemic lupus erythematosus (SLE),APL, SSc, RA, affects women of child bearing age and is associated with several negative outcomes in pregnancy that includes preterm births, hypertensive disorders and increased risk for Cesarean delivery
This was a retrospective descriptive cross-sectional study based on data from the patients’ records. The study was conducted at KNH. The study involved a cohort of women managed for rheumatic disease (SLE, APL, rheumatoid arthritis, and scleroderma) in pregnancy at KNH, 2010–2022. The targeted sample size was 41, but only 30 patients met the criteria for inclusion in this study.
Records of 1200 women with rheumatic diseases seen between 2010 and October 2022 were retrieved. Only 30 patients met the eligibility criteria. The mean maternal age was M = 31.7 years. Prevalence of the rheuatic diseases were as follows: SLE at 63.33% (N = 19), APL, 26.67% (N = 8), RA 20.0% (N = 6), mixed connective tissue disease (MCTD) 6.67% (N = 2) and SSc 3.33% (N = 1).
Maternal outcomes were as follows: post-delivery admission (70.0%, N = 21); pre-eclampsia with severe features (50.0%, N = 15); pre-delivery admissions (46.7%, N = 14) and flaring in (36.7%, N = 11), CS delivery 40.0% (N = 12), premature rupture of membranes 26.7% (N = 8), ICU admissions 23.3% (N = 7), and post-partum hemorrahge20.0% (N = 6).
The main adverse perinatal outcomes noted included fetal loss (including stillbirth) 46.7%, (N = 14), prematurity 23.3% (N = 7), fetal growth restriction 20.0% (N = 6), and new born critical care admission 16.7% (N = 5).
The study established that SLE, antiphospholipid and rheumatoid arthritis are the main three rheumatic diseases among pregnant mothers managed with RDs at the KNH. There is significant pregnant morbidity in these patients.
Systemic Lupus Erythematosus (SLE) is predominant in women of childbearing age. Careful family planning is required because SLE disease activity and SLE therapy affect the risk of adverse pregnancy outcomes (APOs). This study investigates prevalence and risk factors of APOs (Pre-term birth (PB), pre-eclampsia/eclampsia).
We conducted a cohort study of pregnancies in women with SLE using the National Health Insurance Service (NHIS) database of Korea (2002–2018). SLE was defined as having both ICD-10 codes (M32.0) and rare intractable disease registration codes (V136). Pregnancies from 2005 to 2017 of women aged 15–49 with SLE-related visits at least a year before the Last Menstrual Period (LMP) were included. Logistic regression models for APOs were conducted, including age, SLE-related clinical characteristics before pregnancy (SLE treatments during 3 months before LMP, number of SLE-related outpatient visits or hospitalization), use of immunosuppressants (mycophenolate mofetil (MMF)/methotrexate (MTX)/cyclophosphamide (CYC)) during pregnancy, comorbidities, parity, and obstetric complications.
In 5,044 total pregnancies, mean age was 32.4 years (standard deviation 4.3). PB and pre-eclampsia/eclampsia were 11.0% and 4.3%, respectively. Only 42.3% were prescribed hydroxychloroquine (HCQ) during pregnancy, and 2.8% were prescribed MMF/MTX/CYC during 1st trimester. PB was associated with more than 10 SLE-related visits (Adjusted Odds Ratio [AOR] 2.15, 95% Confidence Interval [CI] 1.64–2.81) in previous year and pre-eclampsia/eclampsia (AOR 2.02, 95% CI 1.42–2.85). The risk of pre-eclampsia/eclampsia was associated with MMF/MTX/CYC use during the first trimester (AOR 3.55, 95%CI 1.32–9.57), hypertension (AOR 2.70, 95%CI 1.93–3.77), and steroids use during 3 months before LMP (≥7.5mg AOR 1.89, 95%CI 1.28–2.79 vs. 0mg).
The limited use of HCQ during pregnancy was observed in study period. PB was associated with higher number of SLE visits before pregnancy and pre-eclampsia/eclampsia. Pre-eclampsia/eclampsia was associated with MMF/MTX/CYC use during the first trimester, hypertension, and steroid use, reflecting the effects of maternal comorbidities and SLE disease activity.
Obstetric morbidity (OM) is higher in Systemic Lupus Erythematosus (SLE) women than in healthy ones. Few data on SLE pregnancy outcomes in Latin America (LA) have been reported. The aim of this study was to assess SLE pregnancy outcomes in LA.
GLADEL 2.0 is an observational prevalent/incident cohort started in 2019.1 To date, 43 centers from 10 LA countries have enrolled 1030 SLE patients, ≥18 years, 1982/1997 ACR or SLICC criteria. Women with at least one pregnancy were included. Past and ongoing (6, 12, 24 months follow-up) OM (miscarriages, fetal deaths, pre-eclampsia, prematurity, neonatal lupus) were evaluated.
At inclusion, 329 women have had at least one pregnancy [median (IQR): 2 (1–3)]:
In GLADEL 2.0 cohort, around half of the women studied presented OM, being frequently related to APS. Miscarriages, prematurity, pre-eclampsia, and fetal deaths were the most common fetal-maternal complications. The incidence of neonatal lupus was lower than previously reported (16%).2
Pregnancy outcome during 2-year follow-up (6, 12 and 24 months
Sociodemographic, clinical and treatment characteristics among SLE women with at least one pregnancy at cohort inclusion related to obstetric morbidity
A longitudinal multiethnic study of biomarkers in systemic lupus erythematosus: Launching the GLADEL 2.0 Study Group. Gómez-Puerta JA, Pons-Estel GJ, Quintana R, Nieto R, Serrano Morales RM, Harvey GB, Wojdyla D, Scolnik M, Funes Soaje C, Alba Moreyra P, Novatti E, Arizpe F, Berbotto GA, González Lucero L, Porta S, Pérez N, Rodriguez AM, Appenzeller S, de Oliveira E Silva Montadon AC, Monticielo OA, Cavalcanti FS, Machado Ribeiro F, Borba EF, Torres Dos Reis-Neto E, Neira O, Chahuán JM, Mimica M, Aroca Martínez G, Tobón GJ, Vásquez G, Quintana-Lopez G, Moreno Alvarez MJ, Saavedra MÁ, Cristobal MP, Fragoso-Loyo H, Amezcua-Guerra LM, González-Bello YC, Abud-Mendoza C, Esquivel-Valerio JA, Duarte M, Acosta Colman I, Mora-Trujillo C, Reátegui-Sokolova C, Calvo Quiroz AA, Muñoz-Louis R, Cairoli E, Rosas I, Rebella M, Cardiel MH, García de la Torre I, Catoggio LJ, Alarcón GS, Pons-Estel BA. Lupus. 2021 Jan 28:961203320988586. Cimaz R, Spence DL, Hornberger L, Silverman ED. Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-Ro autoantibodies. J Pediatr 2003;142:678–83.
Two Phase 2 studies investigating once-daily cenerimod, a selective sphingosine 1-phosphate 1 receptor modulator, in adults with SLE were recently completed: CARE (NCT03742037) and ID-064A203.
The CARE study was previously described.1 Adults with moderate to severe SLE were randomised to placebo or cenerimod (0.5, 1, 2 or 4 mg). At Month (M) 6, patients receiving cenerimod 4 mg were re-randomised to placebo or cenerimod 2 mg for M7-12; patients from other groups continued their initial treatment to M12. The primary endpoint was change from baseline to M6 in SLEDAI-2K score modified to exclude leukopenia (mSLEDAI-2K).
ID-064A203, performed in Japan, randomised adults with moderate to severe SLE to 2 or 4 mg cenerimod for 3 months with end-of-study at M9. The primary endpoint was occurrence of treatment-emergent adverse events (AEs), serious AEs and AEs of special interest. The secondary endpoint was change from baseline to each post-baseline assessment (PBA) until M9 in total lymphocyte count. Exploratory endpoints included change from baseline to each PBA until M9 in mSLEDAI-2K, physician’s global assessment and biomarkers.
In both studies, patients continued their SLE background therapies, and oral corticosteroid (OCS) dose should have been maintained stable for ≥15 days before randomisation. It was preferable for OCS dose to be maintained stable until M3 in ID-064A203, and to the end of M6 in CARE.
Results from ID-064A203 will be available in 2023.
CARE results were presented;1 the primary endpoint was not met after adjustment for multiplicity (nominal p=0.0291 for cenerimod 4 mg versus placebo), although reduction in disease activity at M6 was observed.
These Phase 2 clinical trials increase our knowledge of the efficacy, safety and pharmacodynamics of cenerimod in SLE. Two Phase 3 trials of 4 mg cenerimod in patients with SLE are underway (OPUS, NCT05648500, NCT05672576).
In recent years, many studies have demonstrated an important role of gut microbiota in the development of various illnesses including autoimmune diseases. A number of evidence have also been found that alterations of gut microbiota affect the host immune system, resulting in changes in autoimmunity, which contributes significantly to the development of systemic lupus erythematosus (SLE). Therefore, we aimed to elucidate discover the gut microbiotas influential to SLE and investigate their association with disease activities.
Fecal samples were provided in the same protocol from 38 patients with SLE in Ajou Lupus Cohort and 52 age and sex-matched healthy controls (HCs). The components of the gut microbiota in feces were investigated via 16S rRNA next-generation sequencing, and alpha and beta diversities were evaluated. Clinical, laboratory, and medication data of SLE patients were obtained through medical records, and the correlation between disease activity and gut microbiota was also analyzed.
The gut microbiota of SLE group exhibited a significant decrease in species richness in the beta diversity analysis by NMDS plots compared to controls. Taxonomic composition differences between the two groups were also found at phylum, genus, species levels. At the species level, the relative abundance of 7 kind of bacteria was significantly higher and another 7 bacterial taxa were significantly lower in the SLE group compared with HCs, suggesting that reduction in Faecalibacterium prausnitzii and Prevotella copri (p=0.001 and p=0.001, respectively) played an important role in SLE. In clinical correlation analysis, there was a significant positive correlation between complement 3/4 and Faecalibacterium prausnitzii (r=0.44 and r=0.49, respectively), and total lymphocytes and Prevotella copri (r=0.45).
The composition of gut microbiota was different between SLE patients and HCs in Korean population. Among them, Faecalibacterium prausnitzii and Prevotella copri, which are significantly reduced in SLE patients, are expected to provide potential targets for new treatment.
Previous studies have reported that gut dysbiosis is observed in systemic lupus erythematosus (SLE) and linked to the diseases. However, the relation with the pathogenesis remains unclear. We explored gut microbiota in patients with SLE and investigated the association with the onset and activity of disease and clinical findings
Stool samples were collected from 25 patients with new-onset SLE (noSLE), 30 patients with SLE in remission (remSLE) and 30 healthy controls (HC). Stool samples from 23 patients with noSLE were collected at 3, 6 and 12 months after the treatment started. Microbial composition was determined by bacterial 16S rRNA analysis to examine α- and β- diversities and abundances of phylum, family, genus and species.
Patients with noSLE displayed altered α -diversity, decreases in butyrate-producing bacteria including Eubacterium rectale, Lachnospira pectinoshiza, Anaerostipes hadrus, Fusicatenibacter saccharivorans, and Anaerobutyricum halli, and increases in Hungatella efuluvii, Intestinibacter barrtletti, and Eisenbergiella tayi. Some had correlation with SLEDAI, while the others did not. Furthermore, the abundance of specific bacterial species was correlated with involved organs and the positivity of autoantibodies.
Butyrate plays a role in the homeostasis of gut and regulation of immune cells, and therefore a decrease in butyrate-producing bacteria may be involved in the pathogenesis of the disease. Our study suggests that the gut microbiota possibly contributes to the activity and clinical findings of SLE.
Genome-wide association studies (GWAS) have discovered thousands of genetic loci associated with various autoimmune diseases and significantly improved our understanding of their pathogenesis. Many loci are associated with multiple autoimmune diseases. However, whether they share the same association mechanisms in these cases has not been well studied.
In this study, we conducted a comprehensive analysis of the association signals for the 15 most common autoimmune diseases using data from the GWAS catalog. In particular, we defined shared and independent association signals based on linkage disequilibrium (LD) among the genetic variants and examined the distinction between locus-sharing and signal-sharing for these diseases. Using genomic resources such as eQTL, histone modification, chromatin accessibility, TF binding, and 3D enhancer-promoter interactions, we annotated these signals and further analyzed the functional implications of these signals.
Our analysis identified 353 loci associated with at least two autoimmune diseases (pleiotropic loci) out of a total of 620 loci for all 15 autoimmune diseases. While locus-sharing is common, only 325 signals are shared by multiple autoimmune diseases (pleiotropy), with 1261 signals being disease-specific, suggesting differences in the putative causal genes and/or context-dependent regulation mechanisms. The functional analysis sheds new light on the target genes and association mechanisms, especially on the specific pathways and cell types involved in these diseases.
Detailed analyses of shared and specific association signals among the 15 most common autoimmune diseases shed new light on the putative effector genes, relevant cell types, or context-specific regulatory mechanisms for these diseases, and open a window for facilitating further functional characterizations, drug repurposing and discovering novel drug targets.
Breakdown of the blood-brain barrier (BBB) integrity is required for the development of psychiatric manifestations in SLE (NPSLE), especially in lupus psychosis for the direct attack by autoantibodies against neurons. The aim of this study is to investigate the direct effect of anti-Smith antibody (anti-Sm) on BBB integrity via matrix metalloproteinase (MMP)-2 and evaluate the effect of captopril, a MMP-2 inhibitor on preventing BBB breach.
Human umbilical vein endothelial cells (HUVEC) were stimulated with monoclonal anti-Sm or anti-RNP antibody (anti-RNP). BBB integrity was evaluated with claudin-5 expression, the tight junction composing protein by q-PCR, and western blot. MMP-2 activity was measured by gelatin zymography.
Antibody stimulation with anti-Sm or anti-RNP did not affect the expression of MMP-2 and claudin-5 at mRNA level. However, Claudin-5 protein expression was significantly reduced by anti-Sm stimulation compared to isotype control (p=0.004), but not by anti-RNP (p=0.496) (
Anti-Sm reduced claudin-5 expression in HUVEC through up-regulation of active MMP-2 expression. Our results suggest that Captopril can be protective for BBB breaches mediated by anti-Sm in patients with NPSLE.
Claudin-5 and active MMP-2
Vaccines are widely credited for their role in reducing the incidence and the severity of various infections. The aim of the COVID-19 and Influenza Vaccine In Lupus (CIVIL) study was to compare the perception and safety profile between COVID-19 vaccine and influenza vaccine in Korean patients with systemic lupus erythematosus (SLE).
We conducted a cross-sectional study based on a 34-question web-based survey on COVID-19 and influenza vaccination in 207 confirmed SLE patients. Patients were recruited from 12 academic hospitals affiliated with Korean society of SLE research (KSSR) from DEC 2022 to JAN 2023. The primary outcome was the perception of patients and physicians on the vaccines, and the occurrence of side effects including flare.
94.1% of two hundred respondents were females aged in 20’s (19.8%), 30’s (24.3%), 40’s (27.7%), 50’s (16.8%), and 52% was treated more than 10 years. More than 50% of patients were in stable condition for recent 6 months (below 20mm in 100mm visual analogue scale with lower than 10mg prednisolone equivalent dose). COVID-19 vaccine and influenza vaccine were completed in 77.7% and 87.6% of SLE patients, respectively. Reasons for willing not vaccinated included fear of lupus flare (56.3% vs 24.5%), worried about side effects (52.1% vs 26.6%), and not recommended from physicians (35.4% vs 7.4%) on COVID-19 and influenza vaccines, respectively. Adverse events (AEs) occurred much higher in COVID-19 vaccine (65.8%) than influenza vaccine (12.4%). However, only 4.4% of patients experiencing AEs from COVID-19 vaccine required hospitalization. Most common AEs were pain/redness on injection site, myalgia and/or arthralgia, fatigue, febrile sense. 10.3% of patients taking COVID-19 vaccine experienced lupus flare (arthralgia, skin rash, hair loss, and deterioration of proteinuria/laboratory parameter), which lead to medication change or hospitalization.
COVID-19 vaccine has a worse perception and higher adverse events compared to influenza vaccine in Korean SLE patients.
To investigate factors associated with severe COVID-19 in people with rheumatic disease.
Demographic data, clinical and laboratory characteristics and COVID-19 outcome severity of adults with rheumatic disease were collected from a single center in China from December 10, 2022 to January 31, 2023. A three-point ordinal COVID-19 severity scale was used to measure the severity of the disease. Multivariable ordinal logistic regression was used to estimate the odds ratios.
A total of 190 cases were included in the study. The most common rheumatic diseases were systemic lupus erythematosus (33.5%), rheumatoid arthritis (31.02%), Sjögren’s syndrome (10.7%), systemic sclerosis (6.42%), idiopathic inflammatory myopathy (5.88%), and vasculitis (8%). More than half of the cases (52.3%) were hospitalized, and 12 (6.3%) died. Over 60% of patients were on a stable stage of disease, and more than 18% were on biologics. Additionally, over 60% had not been vaccinated against COVID-19. The mortality rate for those without the COVID-19 vaccine is significantly higher than for those who have been vaccinated (9.5% vs.1.4%, P =0.03). Patients with pneumonia who died had significantly lower levels of lymphocytes than those who survived ( (0.45±0.07x
10^9/L vs. (0.99±0.12) x10^9/L), P=0.01). Logistic regression analysis also revealed that older age, lymphopenia was associated with more severe COVID-19.
Older age, low lymphocyte levels and no vaccination are risk factors for severe disease in COVID 19 in rhematic diseases.
Juvenile onset Systemic Lupus Erythematosus (jSLE) is a rare multisystem autoimmune disease with variable clinical features and severity. jSLE is a common cause of secondary antiphospholipid syndrome (APS). Our aim is to describe the clinical characteristics, treatment, and outcomes of jSLE with secondary APS in our cohort.
A retrospective descriptive study of all jSLE patients with APS from January 2013- December 2022 (10 years) seen at the Paediatric Rheumatology Unit, Selayang Hospital, Malaysia. Clinical, laboratory, treatment and outcome data were collated from hospital electronic medical records.
We identified 11 patients with total of 14 thrombotic events. The mean age of SLE diagnosis: 11.0 years (8.9–14.9) and mean age of first APS diagnosis: 13.9 years (10.2–21.3). The majority were Malays (36%) and Indians (36%) and the female-to-male ratio was 10:1. Most were venous thrombosis (79%) predominantly lower limb deep vein thrombosis (73%). Arterial thrombosis occurred in 14%, affecting the internal carotid and central retinal artery; while one (7%) had a mixed arterial (splenic infarct) and venous thrombosis (bilateral pulmonary artery). Of those tested, positive antiphospholipid antibodies include lupus anticoagulant (80%), beta 2-glycoprotein (56%) and anticardiolipin antibody (22%). Risk factors included obesity (4/11), overweight (4/11), hypertension (3/11) and high cholesterol (3/11). The mean SLEDAI score was 7 at time of thrombosis (range 0–22). Eight patients had a prior diagnosis of jSLE and were receiving Prednisolone (100%), Hydroxychloroquine (75%), Mycophenolate mofetil (38%), Azathioprine (25%) or Cyclophosphamide (13%). All received heparin during the acute phase (10/11 sc Enoxaparin) followed by warfarin. One required surgical intervention (transcatheter embolectomy and inferior vena cava filter insertion). All patients survived with complete clinical resolution of thrombotic episodes.
Antiphospholipid-associated thrombosis in juvenile SLE is predominantly venous, sometimes recurrent and occurs during active SLE disease. Unlike adults, traditional risk factors are uncommon in jSLE and the overall prognosis is good.
Antiphospholipid syndrome (APS) is acquired thrombophilia characterized by the presence of antiphospholipid antibodies (aPL). Its main manifestations are vascular thromboses and pregnancy complications. Despite apparently adequate anticoagulation, the risk of recurrent thrombosis remains high.
The aim. To evaluate the relationship between aPL and recurrent thrombosis in patients with primary APS (PAPS).
The study included 52 patients with PAPS: 30 (58%) – women and 22 (42%) – men. The mean age of the patients was 38.5 [31.5–43.5] years, duration of the disease – 9.0 [3.1–13.0] years. Recurrent thromboses had 34 (65%)/52 patients and no recurrent thromboses had 18 (35%)/52. The study of aPL involved the determination of IgG/IgM antibodies to cardiolipin (aCL), IgG/IgM antibodies to β2 glycoprotein 1 (anti-β2GP1) and IgG/IgM antibodies to phosphatidylserine-prothrombin complex (aPs/Pt) by enzyme immunoassay (ELISA), IgG/IgM/IgA aCL, IgG/IgM/IgA anti-β2GP1, IgG antibodies to domain I β2 glycoprotein 1 (IgG anti-β2GP1DI) by chemiluminescence assay (CLA).
IgM aCL and IgM anti-β2GP1 were not associated with recurrent thrombosis, in contrast to IgG aPL (ELISA/CLA); figure 1. There was an association between recurrent thrombosis and «extra»-criteria aPLs: IgG aPs/Pt, IgA aCL, IgG anti-β2GP1DI.
Combination of IgG aCL+IgG anti-β2GP1+IgG aPs/Pt (ELISA) was 34/52 (65%) patients and thrombosis recurred in 27 (79%)/34; p=0.008. Thirty-six (69%)/48 patients had a combination of IgG aCL+IgG anti-β2GP1+IgG anti-β2GP1DI (CLA). Recurrent thromboses had 29 (81%)/36; p=0.0003. . Relationship between antiphospholipid antibodies and recurrent thrombosis in patients with primary antiphospholipid syndrome is shown in
Recurrent thrombosis was associated with triple IgG aPL positivity in any combination Patients with positive IgG aPL (ELISA/CLA) and IgA aCL were significantly more likely to have recurrent thrombosis. The highest relationship was observed with IgG anti-β2GP1DI (CLA) and IgG anti-β2GP1.
Relationship between antiphospholipid antibodies and recurrent thrombosis in patients with primary antiphospholipid syndrome
Immunoglobulin gamma-3 subclass, also called the immunoglobulin gamma 3 chain C (IGHG3), normally comprises 5%–8% of all IgG in humans. The salivary IGHG3 was increased in Korean patients with systemic lupus erythematosus (SLE). This study tried to assess the levels of IGHG3 in serum, saliva, and urine in patients with SLE.
Serum, saliva, and urine samples were collected from 181 patients with SLE and 99 age- and sex-matched healthy controls (HCs) with clinical data. The levels of IGHG3 in each body fluid were measured and analyzed to assess their associations with clinical manifestations and disease activity of SLE.
Serum IGHG3 was 478.1 ± 160.9 and 364.4 ± 97.9 μg/mL (p<0.001) in patients with SLE and HCs. Salivary IGHG3 was 3,078.9 ± 2,473.8 and 1,413.6 ± 1,075.3 ng/mL (p<0.001), and urinary IGHG3 was 64.0 ± 74.5 and 27.1 ± 16.2 ng/mL (p<0.001) in patients with SLE and HCs, respectively. Area under the receiver operating characteristic curve for diagnosis of SLE was 0.737 for serum IGHG3 (95% confidence interval (CI), 0.673–0.8), 0.755 for salivary IGHG3 (95% CI, 0.694–0.815), and 0.733 for urinary IGHG3 (95% CI, 0.67–0.795). Serum IGHG3 was correlated with leukocyte count (r=-0.219, p=0.003), lymphocyte count (r=-0.221, p=0.03), anti-dsDNA antibody (r=0.22, p=0.003), C3 (r=-0.23, p=0.002), salivary IGHG3 was correlated with ESR (r=0.173, p=0.024), and urinary IGHG3 was correlated with hemoglobin (r=-0.183, p=0.021), erythrocyte sedimentation rate (r=0.204, p=0.01), anti-dsDNA antibody (r=0.262, p=0.001), C3 (r=-0.202, p=0.011), and SLE disease activity index (r=0.332, p<0.01). In addition, urinary IGHG3 was higher in patients with nephritis compared in those not (119.55 ± 110.0 vs. 49.8 ± 54.4, p<0.01).
The levels of IGHG3 were significantly increased in serum, saliva and urine of patients with SLE, and urinary IGHG3 level was associated with disease activity and renal involvement of SLE.
The presence of anti-U1RNP is associated with the features of different systemic rheumatic diseases (SLE, SSc, etc.), and it is also included in the criteria of the mixed connective tissue disease (MCTD). It is important to note that the MCTD may evolve into other rheumatic diseases over time and only a third of patients have a stable clinical picture for many years. The frequency of detection of anti-U1RNP in SLE according to various studies varies from 13 to 40%. Our aim was to study the frequency of SLE among patients positive for anti-U1RNP.
The study included 60 patients (pts) who were positive for anti-U1RNP: 54 women and 6 men, mean age 52±10 years, duration of the disease 10.6±8 years. All pts were examined according to guidelines.
In study group all pts were positive for ANAs, anti-U1RNP and met the criteria of MCTD (R. Kasukawa, 1987). The frequency of anti-DNA was 42%, anti-Ro – 38%, RF in 31%, anti-Sm 11%, anti-La – 8%. The detection of anti-DNA was correlated with the presence of overlap syndrome (r=0.3, p<0.05), the median indicator was 16.7 (5.2; 29.5), the range of values ranged from 0.1 to 300 IU/ml, while high values were detected in pts with a cross with SLE. Leukopenia was detected in 8 pts (14%), anemia – 2 pts (3%), hypocomplimentemia – 9 pts (15%), arthritis/arthralgia – 37 pts (62%), malar rash – 14 pts (24%). It turned out that 18 out of 60 (30%) pts with MCTD, it was possible to simultaneously establish the diagnosis of SLE (SLICC, 2012), thus the patients met the criteria for two different rheumatic diseases.
30% of patients positivity for anti-U1RNP simultaneously met the SLE criteria. This fact requires further study of this group of patients as a separate subtype of SLE.
Autoantibodies are a hallmark of lupus nephritis (LN). While there is known heterogeneity in autoantibody expression among LN patients, the association of autoantibodies with LN subtypes and the implications of longitudinal changes in LN are not entirely understood. In this study, we quantified circulating autoantibodies in the Accelerating Medicines Partnership (AMP) LN longitudinal cohort to identify novel serum biomarkers of LN classification and treatment response and to provide insights into the pathogenesis of LN.
SLE patients meeting ACR or SLICC criteria (n=268) indicated for kidney biopsy by a urine protein/creatinine (UPCR) >0.5 were recruited for this study as part of the AMP. Kidney biopsies were evaluated by a renal pathologist according to ISN/RPS classification, and serum samples were collected at the time of diagnostic kidney biopsy and 3-, 6-, and 12-months post-biopsy. Serum autoantibodies against dsDNA, chromatin, ribosomal-P, Ro, La, Sm, SmRNP, RNP, Jo-1, Scl-70, and centromere-B were measured using the BioPlex 2200® ANA kit (Bio-Rad Technologies, Hercules, CA), while anti-C1q positivity was determined by ELISA (QUANTA Lite®, Werfen, Bedford, MA). Clinical response was determined at 12 months using the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study definitions for patients with ISN/RPS class III, IV, V, or a combination thereof and a baseline UPCR ratio >1.0.
Most LN patients exhibited autoantibodies against chromatin (78%) dsDNA (70%), SmRNP (63%), C1q (56%), RNP (54%), and Sm (52%) (
LN patients exhibit heterogeneous autoantibody profiles associated with ISN/RPS classification. Specifically, levels of autoantibodies against dsDNA, C1q, chromatin, and ribosomal P may serve as noninvasive biomarkers of proliferative LN. In patients with proliferative but not membranous LN, a decline in the titers of several autoantibodies, including many not routinely measured over time, such as anti-Sm, was associated with treatment response, suggesting a possible role in LN pathogenesis. In addition, these autoantibodies may serve as early biomarkers of treatment response.
In SLE, anti-dsDNA often exists together with autoantibodies against other chromatin components, like histones and nucleosomes. These antibodies can induce cytokines including interferon-alpha.
We have measured ANA specificities and investigated their associations to inflammatory biomarkers. We included 93 Sudanese and 480 Swedish SLE patients. Serum levels of autoantibodies against dsDNA, Sm, the Sm/U1RNP complex, U1RNP, SSA/Ro52, SSA/Ro60, SSB/La, ribosomal P, PCNA and histones were quantified with a bead-based multiplex immunoassay. In the Swedish cohort also anti-nucleosome antibodies were investigated. Relative levels of 73 plasma biomarkers were determined with Proximity Extension Assay technique or ELISA. Adjusted p values were considered significant when <0.05.
Among Sudanese patients, levels of 5/73 biomarkers showed significant associations to ANA-associated antibodies. Anti-histone antibodies showed the strongest positive correlations with interferon-inducible factors MCP-1 and IP-10, and with MCP-3 and S100A12, and negative correlation with stem cell factor. Also anti-dsDNA antibodies associated with MCP-3, IP-10 and S100A12, but when combined in the same regression model, anti-dsDNA associations but not anti-histone lost significance.
Validation analyses among Swedish patients for MCP-1, IP-10, SA100A12 also demonstrated significantly stronger associations to anti-histone and anti-nucleosome antibodies respectively, compared to anti-dsDNA and other ANA specificities, and in combined regression models, anti-histone/nucleosome showed the strongest associations. When excluding anti-histone or anti-nucleosome positive patients, the associations between interferon-inducible factors MCP-1/IP-10 and anti-dsDNA and were lost. In contrary, when excluding anti-dsDNA positive patients, associations with anti-histone and anti-nucleosome respectively remained significant. SA100A12 associations with anti-dsDNA antibodies remained significant after exclusion of anti-histone positive patients but lost significance when excluding anti-nucleosome positive patients.
Levels of mainly IFN-induced inflammatory biomarkers correlate stronger with anti-histone and anti-nucleosome antibodies compared to other ANA specificities including anti-dsDNA. Our results suggest that autoantibodies against DNA-complexes or DNA-associated proteins rather than anti-dsDNA induce the interferon signature in SLE.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown etiology, characterized by the hyperproduction of autoantibodies to various components of the cell nucleus and the resulting immune-inflammatory damage to tissues. Current trends of personalization therapy require the search for new serum markers, the production of which reflects aberrant activation of the immune system with further formation of autoimmunity. These are cytokines, chemokines and their receptors. Our aim was to determine the levels of interleukin (IL)-1b and soluble IL-2 receptor (sIL-2R) in patients with SLE, to evaluate their association with clinical and laboratory disease manifestations.
The study included 26 patients (21 women, 5 men) with a diagnosis of SLE meeting the criteria of SLICC 2012 and EULAR/ACR 2019. The mean age of the patients was 33±11 years and the median disease duration was 14 [4;144] months. Examination of patients included standard laboratory and instrumental diagnostics. Disease activity was assessed using the SLEDAI-2K index. Serum levels of IL-1b and sIL-2R were determined by enzyme immunoassay (Invitrogen, Australia).
In the study cohort median IL-1b and sIL-2R levels were 3,3 [2,5;4,6] ng/mL and 0,0065 [0,005;0,008] pg/mL, respectively. Only negative correlation of IL-1b level with glomerular filtration rate was found (R=-0,48, p<0,01). sIL-2R level was associated with SLEDAI-2K (R=0,53, p<0,005), anti-dsDNA (R=0,55, p<0,003), C3 (R=-0,56, p<0,003) and ferritin level (R=0,47, p<0,05), CRP (R=0,45, p<0,002), urinary casts (R=0,46, p<0,01), leukocyturia (R=0,42, p<0,03). There were no statistically significant differences in the concentrations of both studied immunological markers between patients with lupus nephritis (LN) (n=18) and without LN (n=8).
The concentration of sIL-2R correlates with laboratory indicators of SLE, SLEDAI-2K and urine sediments, suggesting its promising potential for SLE activity evaluation. In turn, IL-1b levels may reflect renal function, which requires further study in a larger cohort of patients with SLE.
stress factors (SF), anxiety-depressive spectrum disorders (ADSD) in patients with rheumatic disorders (RD) are related to stress vulnerability
110 patients (62 – SLE, 48 – PAPS), mostly women (85 (77,3%)), mean (M±SD) age 37,5±12,2 years, were consecutively enrolled in the study. ADSD were diagnosed in accordance with ICD-10. PSS-10 scale was used.
The majority of patients suffered ADSD (100 (90,9%)), that were mostly related to SF and developed earlier than RD in 48 (77.4%) SLE and 31 (63.3%) PAPS patients.
SF in childhood (0–11 years) (58 (93,5%) vs 33 (68,8%) p=0,001), first of all parental deprivation in 0–3 years (44 (70.9%) vs 17 (35,4%), p=0,0001) were found more often in SLE than PAPS patients.
SF in adolescence (11–16 years) were more commonly found among SLE but not PAPS patients (34 (54.8%) vs 17 (35,4%), p=0,03) with more often social maladjustment in SLE (15 (24,2%) vs (4 (8,33%), p=0,02).
SF during few months before the RD onset were experienced by 45 (72.6%) SLE, 31 (64.5%) PAPS patients. SLE patients also were significantly more likely to be exposed to multiple stress factors before RD than PAPS (29 (46.8%) vs 9 (18.8%), p=0.002).
As a result, SLE were more vulnerable to stress factors compared to PAPS patients, according to PSS-10: 28,7±6,25 vs 26,2±6,68, p=0,05.
SF in childhood are related to social maladjustment and predispose to ADSD and SLE onset.
Bisphosphonates (oral alendronate and risedronate, and intravenous zoledronate) are effective agents for glucocorticoid-induced osteoporosis (GIOP). Zoledronate is a convenient and highly compliant treatment compared to other bisphosphonates. In this study, we aimed to compare the efficacy, patient satisfaction, and preference of zoledronate with other bisphosphonates.
We included 50 patients diagnosed with GIOP during treatment for autoimmune diseases including systemic lupus erythematosus (SLE). All patients had new fractures or persistent osteoporosis in follow-up bone densitometry after taking oral bisphosphonates for at least 1 year. After 1 year of treatment with zoledronate, a face-to-face survey was conducted on patients’ preference and satisfaction. The treatment efficacy was analyzed by comparing the changes in bone density and fractures with patients maintaining oral bisphosphonates as controls.
Patients with SLE and rheumatoid arthritis were included, with a mean age of 64.1 years (96% were female), and the mean duration of GIOP of 5.5 years. There was no difference in the cumulative glucocorticoid doses of the two groups. There were no significant differences in the treatment efficacy between zoledronate and oral bisphosphonate; annualized percentage change in bone density in the lumbar spine (1.9±3.91g/cm2 vs. 1±5.3g/cm2, p=0.355), femur neck (-0.91±6.31g/cm2 vs. 0.41±5.07g/cm2, p=0.264), and hip (0.29±2.91g/cm2 vs. 0.41±5.07g/cm2, p=0.888). The incidence of new fractures was two in each of the two groups, showing no difference. As a result of the survey, 39 patients (78%) preferred intravenous zoledronate over oral bisphosphonates and had higher satisfaction, and the most common reasons were administration interval and convenient regimen. The infusion-related adverse events of zoledronate were only 2 patients (4%).
The patient reported preference and satisfaction of zoledronate were significantly higher than that of oral bisphosphonates, and the treatment efficacy for osteoporosis was similar. Therefore, zoledronate is recommended as a proper treatment for GIOP in patients with autoimmune disease including SLE.
Systemic lupus erythematosus (SLE) and atopic dermatitis (AD) are both immune disorders that can lead to significant physical complications. There have been several reports of coexistence or association of the two diseases. In cases of concurrence of SLE and AD, patients may require more comprehensive therapeutic strategies for proper control of both diseases’ activities. In addition, physical trauma such as excoriation can exacerbate or initiate cutaneous lupus erythematosus lesions, so called Koebner phenomenon.
Herein, we report 12 patients with SLE accompanied with AD. They commonly presented with eczematous lesions or lichenification of the flexural areas with marked itching. They all showed elevation of immunoglobulin E (IgE) level, thus satisfying the diagnostic criteria for AD. Additionally, ANA titer and Anti-dsDNA antibody were elevated in laboratory tests. Also, they satisfied other diagnostic criteria for SLE, such as acute or chronic cutaneous lupus erythematosus. Under the diagnosis of concurrent AD and SLE, they were successfully controlled for both cutaneous lupus erythematosus and chronic pruritic eczema.
If patients with SLE suffer from severe itching that is incompatible with the activity of SLE, it can be helpful to measure IgE levels. Elevated IgE levels may indicate their underlying allergic disorders, especially AD. It is important to screen for other diagnostic criteria for AD in addition to measuring IgE levels. Understanding the coexistence of both conditions allows the physician to provide optimal treatment for the patient. Herein, we report a case series of SLE patients with concurrent AD who show elevated IgE level.
A 22 year old-female SLE patient with hematological, nephritis, mucocutaneous and arthritis manifestations presented with complaint of painful and enlarged of abdomen area since 2 weeks before admission. On the previous hospital, an ascites was suspected as the cause and a total of 1100cc reddish liquid was evacuated. No analysis or cytological examination of the fluid was carried out. Patient was then referred to Sardjito Hospital. Patient also had pancytopenia problems related to her SLE. Moderate normocytic anemia (Hemoglobin: 8.3 g/dL), leukopenia (AL: 2.3x103/uL), and severe thrombocytopenia (AT: 12,000/uL) were revealed. An abdominal ultrasound was performed and found a complex cyst in the right parametrium with thick septations and a solid component with mural nodules leading to a picture of malignancy. Examination of Ca-125 showed an increased result = 42 U/mL, CEA examination showed normal results = 3.58 ng/mL. A multisliced abdominal CT-scan was conducted and revealed a colorectal duplication cyst accompanied by a duplication cyst fistula at the level of the rectum with the urinary bladder. Grade 2 right hydronephrosis and hydroureter, hepatomegaly, and bilateral pleural effusion were also revealed. During treatment, there began to be a change in the patient‘s urine where feces material started to appear. A multidiscipline surgery procedure for the duplication cyst and fistule complication was planned. Despite adequate treatments of intravenous crystalloid, norepinephrine, Meropenem, PRC and platelet transfusions, patient died due to urosepsis shock before surgery could be carried out.
Gastrointestinal tract duplication is a rare congenital anomaly that can form anywhere along the gastrointestinal tract. Its occurrence in SLE patients makes its cases increasingly rare. This case was reported because of problems in making a diagnosis due to the rare incidence causing a lack of suspicion towards the diagnosis, as well as symptoms and investigations that resemble other diseases.
Systemic lupus erythematosus (SLE) is associated with lipid metabolism disorders.
To determine lipid spectrum and cholesterol (C) content in circulating immune complexes (CICs) in the blood of SLE patients and control group
SLE patients were divided into two groups: the 1st group – 37 patients with new-onset SLE (median age 29[22;39] years), the 2nd group – 35 patients receiving low-dose glucocorticoid therapy (<7,5mg/day) for a long time (at least 5 years) (median age 34[21;44] years, median disease duration 14[5;28] years. SLADAI 2K was higher in patients of group 1 (21[12;39]) compared to patients of group 2 (2[0;8], p<0,05). The control group was composed of 30 women (48[45;57]years) without autoimmune and cardiovascular diseases.
Dyslipidemia occurred in 38% of the 1st group and 34% in the 2nd group. Average lipids levels of the SLE and control groups are presented in the (
C percentage increase in CICs, immune mediator circulating in SLE patients’ blood and presumably affecting atherosclerosis progression in SLE, appear to be the characteristic of blood serum lipid spectrum of the 2nd group patients and a distinguishing feature of the 2nd group patient’ serum samples in contrast to the 1st group.
Objective: To compare the incidences of overweight, abdominal obesity, hyperleptinemia and insulin resistance (IR) in women with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
The study included 96 patients (age 18–65 years): 46 women with SLE and 50 – with RA, matched by age and diseases duration. Exclusion criteria: pregnancy and lactation, a history of diabetes, fasting hyperglycemia (≥ 6.1 mmol/L) and/or hypoglycemic drugs taking. The concentration of leptin (ELISA) and insulin (electrochemiluminescent analysis) was determined in all patients, and the HOMA-IR index was calculated. Hyperleptinemia was diagnosed at leptin concentrations >11.1 ng/ml, IR – at HOMA-IR values ≥2.77, abdominal obesity (AO) – at waist circumference (WC) ≥80cm.
Leptin concentrations, insulin levels, HOMA-IR were higher, and CRP was lower in SLE than in RA (p≤0,001 for all). Hyperleptinemia was found in 34 (74%) SLE and 23 (46%) RA patients (p=0.005), IR – in 10 (22%) and 5 (10%) women, respectively (p=0.2). WC, body mass index (BMI), the frequency of AO (35% vs 40%) and BMI≥25 kg/m2 (43% vs 38%) in the groups did not differ (p>0,05 for all). Glucocorticoids (GC) were received by 38 (85%) patients with SLE and 18 (36%) – with RA (p<0.0001), daily doses were 10 [7.5;10] mg and 5[5;10] mg, respectively (p=0.001).
In women with similar anthropometric parameters, hyperleptinemia, but not IR incidences, was more common in SLE than in RA, which may be due to both less expression of inflammation and differences in GC regimens.
Objective: To find out the rate of various overweight phenotypes based on body mass index and insulin resistance (IR) in women with systemic lupus erythematosus (SLE).
A total of 46 women with SLE (40[31;48] years old) without diabetes mellitus or hyperglycemia were enrolled in the study. The median SLE duration was 3,0[0,9;9,0] years, SLEDAI-2K was 5[2;8]. SLE pts were treated with glucocorticoids (GC) (83%), hydroxychloroquine (76%), immunosuppressive drugs (22%) and biological agents (11%). IR was defined as Homeostasis Model Assessment of Insulin Resistance index (HOMA-IR) ≥2,77. There were three main phenotypes of obesity/overweight: 1.’classic or metabolic unhealthy obesity/overweight’ – body mass index (BMI) ≥25kg/m2 + IR, 2.’metabolically healthy obesity/overweight ‘ – BMI ≥25kg/m2 without IR, 3.’latent or metabolic unhealthy non-obesity’ – BMI <25kg/m2 + IR.
The classic phenotype was found in 15%, metabolically healthy phenotype – in 28%, latent phenotype – in 7%, normal weight without metabolic disturbances – in 50% women. HOMA-IR negatively correlated with SLEDAI-2K (r= -0.35, p=0.02), and positively – with waist circumference (r=0.57, p<0.0001). Patients with normal weight without metabolic disorders were younger (p=0.02), had a lower concentration of uric acid (p=0.03) than women with the classical phenotype, received lower daily dose of GC for the entire period of SLE than these with latent phenotype (p=0.05). The healthy overweight phenotype had a higher diastolic blood pressure than patients with normal weight without IR (p=0.02), and a tendency to a greater age (p=0.06).
A combination of BMI ≥25 kg/m2 and IR was used to separate the phenotypes of obesity/overweight, since its existence did not coincide in 35% of patients with SLE. The metabolically healthy phenotype was the most frequent, the latent phenotype was the rarest. The formation of a specific phenotype seems to be influenced by age, disease activity and the intake of GC.
Childhood-onset systemic lupus erythematosus is considered a multisystemic, inflammatory autoimmune disease with a wide spectrum of organs involvement. The clinical presentation can vary from cutaneous involvement to nephritis, hematological, neuropsychiatric or macrophage activation syndrome and generally require a more aggressive treatment than for adult population.
We present a series of two cases of pediatric systemic lupus erythematosus.
First case is of a girl 17 years old who presented with malar rash and discoid lesions on photo-exposed aria with histopathological picture relevant for chronic discoid lupus erythematosus. The immunological screening revealed positive antinuclear antibodies, positive anti DNAdc antibodies and decreased complement (C3 and C4). The investigations also showed lymphocytopenia but no other organ involvement (no proteinuria and no echographic cardiac changes). She also complained about different skin rashes, non-specific for lupus, which were resolved only by oral corticosteroids administration. Currently she is on hydroxychloroquine with a favorable course but we close monitoring her by rheum-derma team.
The second case is also a girl 13 years old who is known with a single discoid lesion on the right cheek for about 3 years treated with dermato-corticosteroids and lasers with no improvement. Furthermore, she developed also atrophic aria on the same spot and another two round lesions on the malar area and on the scalp. She also had photosensitivity together with positive antinuclear antibodies and anti DNAdc antibodies. We performed a biopsy relevant for discoid lupus and begun hydroxychloroquine treatment(200mg/day). Despite the treatment the lesions did not show significative improvement. We added mycophenolate mofetil and local calcineurin inhibitor with a good cutaneous and immunological response.
The two cases presented prove that childhood-onset systemic lupus erythematosus need an intense multidisciplinary approach because of its aggressive course and disease flares associated with higher morbidity.
To evaluate treatment satisfaction in the patients with chronic rheumatic diseases.
This cross-sectional study was performed from September 2021 through December 2021 using treatment satisfaction questionnaire for medication (TSQM).
Two hundred fifteen patients (RA patients n=114, SLE patients n=101) were enrolled in this study. 82.3% were female (73.7% of RA, 92.1% of SLE, p < 0.001). The mean of age was 52.8 years (57.8 years vs. 47.2 years, p < 0.001), of disease duration was 9.1 years (6.8 years vs. 11.8 years, p < 0.001), of duration of education was 11.5 years (11.0 years vs. 12.0, p=0.010). Mean of DAS28-ESR was 2.0, of DAS28-CRP was 1.8, of SLEDAI was 1.8, and of EQ5D- VAS was 68.6. Mean of TSQM summary scores; 1) treatment effectiveness 64.5 (66.5 vs. 62.3, p=0.028), side effects 97.6 (97.9 vs. 97.3, p=0.726), convenience of administration 67.7 (66.9 vs. 68.7, p=0.268), and global satisfaction 65.2 (66.2 vs. 63.9, p=0.307). There were good correlations between TSQM and demographic data in age at symptom onset, duration of education, global assessment of patient or physician, ESR, CRP, DAS28-ESR/CRP, and SLEDAI. The score 80 or more of global satisfaction was defined as ‘satisfied’. 80 or more group (n=36, 16.7%) showed longer duration of education, higher income, lower global assessment of patients or physician, and higher EQ5D-VAS (all, p< 0.05) compared to 80 or less group. However, SLE patients with 80 or more score showed just a trend in the household income per month (p=0.054). Among EQ-5D questionnaires, the level of pain/discomfort and anxiety/depression were significantly difference between 80 or more and less group.
Factors associated with global satisfaction ‘satisfied’ were duration of education, household income per month, pain/discomfort, or anxiety/depression in this study. Although most of them were stable disease status, patients with SLE showed lower treatment satisfaction than RA patients.
This study aimed to investigate the clinical characteristics, outcomes, and risk factors of patients with a rare but fatal manifestation of systemic lupus erythematosus (SLE), diffusive alveolar hemorrhage (DAH), stratified by infection status in a national representative cohort.
This single-center retrospective study included 124 consecutive patients with SLE-DAH in a tertiary care center between 2006 to 2021. The diagnosis of DAH was made based on a comprehensive evaluation of clinical manifestations, laboratory and radiologic findings, and bronchoalveolar lavage. Demographics, clinical features, and survival curves were compared between patients with bacterial, non-bacterial, and non-infection groups. Univariate and multivariate logistic regression analysis were performed to determine the factors independently associated with bacterial infection in SLE-DAH.
Fifty-eight patients with SLE-DAH developed bacterial infection after DAH occurrence, thirty-two patients developed fungal and/or viral infection, and thirty-four patients were categorized as non-infection. The bacterial infection group have a worse prognosis (OR 3.059, 95%CI 1.469–6.369, p=0.002) compared with the other two groups, with a mortality rate of 60.3% within 180 days after DAH occurrence. Factors independently associated with bacterial infections in SLE-DAH included hematuria (OR 4.523, 95%CI 1.068–19.155, p=0.040), hemoglobin drop in the first 24 hours after DAH occurred (OR 1.056, 95%CI 1.001–1.115, p=0.049), and anti-Smith antibody (OR 0.167, 95%CI 0.052–0.535, p=0.003). Glucocorticoid pulse therapy and cyclophosphamide were administered in more than 50% of patients regardless of their infectious status. According to clinical experience at our hospital and in previous studies, we recommended a comprehensive management algorithm for SLE-DAH based on infection stratification.
Infection, especially bacterial infection, is a severe complication and prognostic factor of SLE-DAH. Comprehensive management strategies, including diagnosis, evaluation, treatment, and monitoring, based on infection stratification may fundamentally improve outcomes of patients with SLE-DAH.
Comprehensive management algorithm for SLE-DAH. SLE, systemic lupus erythematosus; DAH, diffusive alveolar hemorrhage; HgB, hemoglobin; BALF, bronchoalveolar lavage fluid; Anti-Sm: anti-Smith antibodies; CTX, cyclophosphamide.
Juvenile systemic lupus erythematosus (jSLE) has more severe and aggressive clinical features than adult onset SLE. We investigated the risk factors related with long-term outcome among initial parameters at diagnosis.
The study was designed for patients initially diagnosed with jSLE below 18 years old between January 2009 and December 2021. We excluded patients with previous diagnosis, transferred from another hospitals, clinical findings related with infection or post-transplantation, and underlying diseases. We reviewed retrospectively electronic medical records for initial laboratory data, and clinical manifestations including SLE disease activity index-2K (SLDAI-2k). We analyzed parameters associated with survival and events including flare, complications, and new organ involvement.
Total 109 patients were enrolled in this study. The mean age was 14.4 ± 2.3 years old, and the female to male ratio 7.4:1. Twenty-eight patients (25.7%) were diagnosed at pre-pubertal period. The overall survival rate was 92.9% (median: 5 years, range: 0 ~ 13 years). The causes of death were intractable macrophage activation syndrome, disease related state, and sepsis. The related factors for survival were initial C-reactive protein (CRP, P =0.017, HR: 2.396, 95% CI: 1.165 ~4.926) in multi-variate analysis, although there were associated with CRP, SLEDAI, and false positivity for syphilis (P < 0.05) in univariate analysis. The event free survival was 10.4% and related with SLEDAI, anti-smith antibody, false positivity for syphilis, and ANCA (P<0.05) in univariate analysis. In multivariate analysis, factors associated with event were SLEDAI-2K (P=0.035, HR: 2.82, 95% CI: 1.078 ~7.375), anti-Smith antibody (P=0.019, HR: 3.262, 95% CI: 1.218 ~ 8.741).
These results suggested that initial SLEDAI and markers for immune response were related with survival and events during follow-up. We have to concern disease activity and laboratory parameters for long-term outcome in jSLE.
The efficacy of methylprednisolone pulse therapy is well-established however, the gold standard of treatment is quite expensive and associated with significant infectious complications. Currently, there are no published study comparing the effect of methylprednisolone pulse therapy versus dexamethasone pulse therapy. Hence, this research aims to compare the current standard of care (methylprednisolone) versus the alternative regimen (dexamethasone pulse therapy).
The study employed descriptive cross-sectional study. The participants included are patients with Systemic Lupus Erythematosus (SLE) treated with either high-dose dexamethasone or methylprednisolone therapy. Data were collected via retrospective review of medical charts.
A total of 45 patients were included in the study, 98% of which are female and 62% were treated with dexamethasone. The most common presenting features of SLE were hematologic (87%) and nephritis (44%). There is no significant difference in any of the characteristics, presenting features and outcomes between dexamethasone and methylprednisolone-treated patients (all p’s>0.05) except for neurologic manifestations. The most common indication for methylprednisolone pulse and dexamethasone pulse therapy for all patients in the study is nephritis (38%). In our study, neuropsychiatric lupus is the most common indication for methylprednisolone pulsing-treated patients (53%) whereas, nephritis and anemia are the common indications for dexamethasone pulse therapy.
The characteristics of patients treated with dexamethasone and methylprednisolone were similar except for neurologic manifestations. In addition, the clinical outcomes of dexamethasone patients were comparable to methylprednisolone. Dexamethasone is less expensive than methylprednisolone which is a good alternative option for patients that belongs to low-income group; however, Randomized Controlled Trials should be performed to provide higher level of evidence in terms of efficacy and safety.
Manifestations of neuropsychiatric lupus are highly variable. Neuroimage such as magnetic resonance imaging (MRI) has been used extensively for evaluating neuropsychiatric lupus. Here we reported a patient with neuropsychiatric lupus and positive anti-ribosomal P antibody in acute confusion status underwent MRI evaluation, which revealed bilateral pallidal lesions.
This 24-year-old woman was diagnosed with systemic lupus erythematosus ( joint pain, positive ANA, low complement, anti-dsDNA, and anti-ribosomal P antibody) and had regular follow-ups at our rheumatology clinic. According to her mother, the patient had consciousness disturbance with anxiety and bad dreams ten days before ER visit. Three days before ER visit, incoherent speech and unstable gait were noted. She was brought to our clinic and then referred to ER. At ER, a fever up to 38.9 degree Celsius and tachycardia of 111 per minute with Glasgow coma scale E4M6V5 were recorded. Blood pressure was 132/76 mmHg, and SpO2 was 97%. Chest roentgenography or urine analysis showed no evidence of infection. EKG was normal. Methylprednisolone 20 mg every 12 hours was given. The brain MRI data showed symmetric T2 hyperintensity without diffusion restriction in bilateral globus pallidi (
The neuroimage of bilateral pallidal necrosis in the patient with SLE provides a direction for elucidating the pathogenesis of neuropsychiatric lupus.
T2-weighted-Fluid-Attenuated Inversion Recovery (T2-FLAIR) image showed bilateral globus pallidi hyperintensity with normal diffusion-weighted image (DWI).
A 32-year old Indonesian female patient of lower socioeconomic status with an urban background was admitted to our hospital with seizures three hours before hospital admission. She was just diagnosed with SLE three months ago after having recurrent seizures days prior to diagnosis, and at the time of our hospital admission she was under 48 mg/day of methylprednisolone (tablet) in divided doses. At the time of SLE diagnosis, she was brought by her family to our satellite hospital with seizures as a chief complaint, and the in-charge doctor recognized discoid rash on her face. At that time, the patient was unconscious, but her family told the doctor that she had reddish rash on her face for many years before, and also had occasional arthralgia on her hands, both considered not a big problem by the patient and her family. At the time of admission to our hospital, the patient was conscious but had slurred speech and occasional anger outbursts. Physical examination showed non-scarring alopecia, and decreased muscle strength and hypotonia in all four extremities. The patient also complained of having an increased sense of pain in the whole body, especially in the cervical region and trunks. The laboratory examination showed elevated levels of anti-dsDNA, C-reactive protein, and lactate dehydrogenase, and low levels of complement components 3 and 4. MRI showed multiple small hyperintense lesions in bilateral white matter frontal lobes. Following the exclusion of other possible diseases, neuropsychiatric lupus was diagnosed.
This case showed a common condition of delay in autoimmune diagnosis in Indonesia, even in urban areas, which is not surprising to happen in rural areas. Therefore, community education is needed so that more people are aware of autoimmune diseases’ signs and symptoms.
To investigate the dietary patterns and life-styles of patients with lupus gastrointestinal (GI) involvement and the possible role of diet in the organ-specific involvement of systemic lupus erythematosus (SLE).
Patients with SLE complicated with gastrointestinal involvement (SLE-GI) admitted to the Peking Union Medical College Hospital (PUMCH), as well as the corresponding healthy people with age- and sex-matched as control from January 2010 to September 2021 were enrolled and matched at a ratio of 1:2. A questionnaire survey was distributed to the patients and healthy controls (HC) to collect dietary and lifestyle information.
The questionnaire survey results showed the SLE-GI group had a higher proportion of vegetarians (p=0.014), traditional Chinese medicine (TCM) (p=0.018) taken, and less in fried/pickled food (p=0.042), dietary supplements (p=0.024) than in the HC group. Ten patients (10/24, 41.7%) in the SLE-GI group and 7 (7/48, 14.6%) in the HC group had reported undergone surgery (p=0.014).
The dietary patterns, life-styles, medication history of SLE-GI patients differed greatly from those of healthy control people. These factors may integrate and contribute to the susceptibility of autoimmunity and the predilection of gastrointestinal involvement in SLE.
Despite the advances in the management of systemic lupus erythematosus (SLE), mortality rate among patients with SLE significantly remained higher compared to non-SLE over time. Serious infections (SIs) were likely one of the leading causes of death in SLE patients over the last few years. The aim of this study was to evaluate the incidence and identify predictive factors of SIs over time in Thai patients with SLE.
We evaluated SLE patients followed up at Lupus Clinic of Royal Thai Army (LUCRA) between March 2018 and September 2022. SIs were defined as ones that received intravenous antibiotic, required hospitalization, or led to death. Multivariable regression analyses were performed to identify factor predicting of SIs.
Of the 237 patients included, 22 (9.28%) had SIs at least once during the follow-up time. The median (interquartile range) onset of SIs after enrollment was 29.75 (4.25–34) months. The incidence rate of SIs was 2.4 events per 100 person-years. Pneumonia caused by gram-negative pathogens was the most common cause of SIs. Multivariable analysis revealed that predictive factors of SIs were prednisolone intake (hazard ratio (HR): 1.06; 95% confidence interval (CI): 1.01–1.11; p=0.15), doses of prednisone >7.5 mg/day (HR: 3.08; 95%CI: 1.34–10.77; p=0.012), and > 10 mg/day (HR: 3.61; 95%CI: 1.21–10.80; p=0.021). In addition, use of mycophenolic acid was independent factor associated with increased risk of SIs when adjusting prednisolone > 5 mg/day (HR: 2.95; 95% CI: 1.01–8.58; p=0.047). The other factors predicted SIs included hypertension (HR: 3.45; 95% CI: 1.28–9.34; p=0.015), and damage accrual (HR: 3.34; 95% CI: 1.92–5.83; p< 0.012).
Prednisone had a dose-dependent effect on increasing risk of SIs. Moreover, use of mycophenolic acid, underlying hypertension, and damage accrual influenced SIs in SLE patients over time.
We aimed to evaluate the effect of Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) and Definition Of Remission In SLE (DORIS) remission state on damage accrual in SLE.
We defined SLE patients from Lupus Clinic of Royal Thai Army (LUCRA) cohort based on Index and Boolean-based SLE-DAS and DORIS for remission state. Those who were not in any remission definitions were defined as non-remission status. Sustained remission was defined as those with prolonged remission state for ≥ 1 year. Regression analysis models were constructed to identify predictors of the Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) during follow up.
There were 198 patients identified: 98 patients met at least 1 definition of sustain remission state and 100 patients in non-remission group. Of 98 patients, 97 patients were achieved Index-based definitions, 75 patients achieved Boolean-based definition, and 55 patients were achieved Doria definition. The mean ± SD of follow up was 4.77 ± 0.6 years. The changes in SDI over time were non-significant lower in patient who met any definition of remission compared with those who not. Multivariable analysis revealed that predictive factors of increased SDI were age (HR 1.03, p = 0.01) and baseline SDI ≥ 1 (HR 2.54, p = 0.01). However, Index, Boolean, and Doria-based definition of remission had no significant relative risk reduction on SDI compared with non-remission group (HR 0.7, p= 0.27; HR 0.73, p =0.37; HR 0.8, p= 0.55, respectively).
To achieve sustained remission state based on definitions of SLE-DAS and DORIS showed relative protective effect on damage accrual compared to non-remission status, but not statistically significant. These definitions had a comparable effect and could be used as the treatment goal of treat to target strategies in SLE.
Jesus D, Matos A, Henriques C, Zen M, Larosa M, Iaccarino L, Da Silva JAP, Doria A, Inês LS. Derivation and validation of the SLE Disease Activity Score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity. Ann Rheum Dis 2019 Mar;78(3):365–371. Jesus D, Larosa M, Henriques C, Matos A, Zen M, Tomé P, Alves V, Costa N, Le Guern V, Iaccarino L, Costedoat-Chalumeau N, Doria A, Inês LS. Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) enables accurate and user-friendly definitions of clinical remission and categories of disease activity. Ann Rheum Dis 2021 Dec;80(12):1568–1574.
Pseudo-pseudo Meigs Syndrome (PPMS) or Tjalma Syndrome is characterized by ascites, pleural effusion, increased CA-125 marker, and a diagnosis of Systemic Lupus Erythematosus (SLE) with no evidence of any gynecologic tumors. It is a rare diagnosis of exclusion from Meigs syndrome and Pseudo-Meigs syndrome which are associated with benign and malignant tumors respectively. We are presenting an interesting case of PPMS which is an initial manifestation in a patient with lupus. Literature search through Pubmed, Google scholar, Scopus, Medline, and HERDIN (Health Research and Information Development Network), revealed only 18 reported cases worldwide. Since it was first described in 2005, this is the first reported case in the Philippines.
A 26-year-old gravida 1 para 1 (1001) Filipino female was admitted due to abdominal distention associated with undocumented intermittent fever, nausea, epigastric pain, easy fatigability, dizziness and arthritis. Physical findings revealed pallor, malar rash, decreased breath sounds on the right lower lung field, distended abdomen and grade two bipedal edema. Immunologic markers were positive (ANA, DsDNA, Coombs test, low C3) thus fulfilling a diagnosis of SLE based on SLICC criteria. CA- 125 was also elevated. Transvaginal ultrasound revealed normal sized anteverted uterus and no evidence of pelvic mass. Whole abdomen computed tomography scan revealed loculated exudative massive ascites. Colonoscopy revealed non-specific colitis and mixed hemorrhoids. Paracentesis and peritoneal fluid biopsy revealed negative for malignancy and tuberculosis. Treatment with glucocorticoids and hydroxychloroquine resulted in disease remission. At one month‘s follow up, there is normal CA 125 level with resolution of ascites and pleural effusion.
PPMS associated with SLE is a rare manifestation which needs thorough investigation and prompt management. This rare clinical entity is still new in the medical literature thus a physician must have a high index of clinical suspicion when ruling out other disease entities.
Discoid lupus erythematosus (DLE) is one of the LE-specific skin diseases on the scalp, and some cases induce scarring alopecia. In systemic LE (SLE), variable nail changes not specific to LE can occur, including leukonychia, longitudinal ridges, and partial onycholysis. However, there are insufficient reports that investigate the characteristics and relationship of hair and nail changes in LE patients.
This was a retrospective study that included 113 CLE patients who visited the Department of Dermatology at Hanyang University Seoul Hospital in Korea between October 2021 and October 2022. Patient medical records, demographic information, and clinical photographs were reviewed, and all patients were examined for scalp and fingernail involvement, Raynaud phenomenon, and laboratory findings.
Among the 113 CLE patients, 69 (61.1%) showed hair loss and 19 (16.8%) showed fingernail involvement. The CLE patients with hair loss exhibited earlier disease onset (p=0.001) and were more frequently accompanied by SLE (p<0.001), facial CLE lesions (p=0.012), and fingernail changes (p=0.012). Of the 69 CLE patients with hair loss, 59 (85.5%) showed DLE alopecia. In the DLE alopecia group, patients with fingernail changes showed a higher incidence rate of additional CLE lesions on extremities (p=0.049) and the Raynaud phenomenon than those without fingernail changes (p=0.009). There were significant differences in positivity for antinuclear antibody between CLE patients with DLE alopecia and other patients (p=0.04).
This study reviewed the clinical features of scalp and nail apparatus involvement in Korean CLE patients and is the first study to demonstrate significant correlations between these clinical findings and the laboratory findings. Involvement of the scalp and nails in CLE patients is an important disease manifestation, and proper understanding could be essential for diagnosis and efficient management.
Recently, vitamin D has been shown to play an important role in the immune responses, increasing evidence that it can contribute to the pathogenesis of systemic lupus erythematosus (SLE) as well as affect disease course and activity. Therefore, this study aims to determine whether there is a correlation between seasonal vitamin D levels and clinical manifestations or disease activity.
Seasonal measurements of serum 25(OH)D3 were performed in December to February in winter time and in July to September in summer time. We included patients with SLE who measured serum 25(OH)D3 from 2013 to 2016, with 407 patients measured during winter and 375 patients measured during summer. Vitamin D-deficient groups were classified based on 20ng/ml, 25ng/ml, and 30ng/ml for each summer and winter. The relationship between vitamin D concentrations and clinical manifestations or disease activity was analyzed using logistic regression analysis.
There were seasonal differences in the reference concentration of vitamin D, which affects disease activity or clinical manifestations, and the values were 20ng/ml and 30ng/ml in winter and summer, respectively. In the winter vitamin D-deficient group (less than 20ng/ml), the erythrocyte sedimentation rate was 23.9mm/hr, which was marginally higher than that in the vitamin D-sufficient group (22.4mm/hr, p = 0.08). In addition, oral ulcer was significantly less frequent in winter vitamin D-sufficient group (Odds ratio [OR] 0.530, p = 0.047). In summer, oral ulcer (OR 0.278, p = 0.019) and skin rash (OR 0.221, p= 0.015) were significantly less common in vitamin D-sufficient group with cut off of 30ng/ml.
In conclusion, this study suggests that seasonal variations in serum vitamin D may affect the clinical manifestations of SLE, and that vitamin D-deficiency leads to increased oral ulcer, skin rash, and inflammatory marker.
Cutaneous lupus erythematous (CLE) is amanifestation of systemic lupus erythematosus (SLE) that may have no systemic symptoms. SLE is known to affect a heterogeneous group of patients, and drug treatment response differs between each affected organ. Extracellular vesicles (EVs) have attracted attention as new communication tools between cells, that encapsulate various substances and deliver them rapidly throughout the body. We hypothesized that EVs might support disease specific inflammation in CLE and SLE.
EVs were isolated from the plasma of 5 healthy controls, 6 CLE patients, and 17 dermatomyositis patients using sequential ultracentrifugation and size-exclusion chromatography (SEC). Surface markers were detected by MACSPlex bead flowcytometry. Protein content of the EVs was analyzed by mass spectrometry using LC-MS/MS.
EVs in blood are mainly derived from platelets, endothelial cells, and antigen-presenting cells. EVs from CLE patients’ blood contained 4 unique proteins:, Mimecan, Interferon alpha-inducible protein 27, Fibulin-2, and Small nuclear ribonucleoprotein-associated proteins B and B’ (antigens of anti-Sm antibodies). A number of these proteins were increased in patients with a high SLEDAI (SLE Disease Activity Index). 18 significantly upregulated and 15 downregulated proteins were detected in CLE EV compared with HC. A number of upregulated proteins demonstrated a positive correlation with the SLEDAI (r=0.79), but not with the cutaneous lupus erythematosus disease area and severity index (CLASI) (r=0.21). Of the 18 proteins increased in CLE EVs, lysozyme C and hyaluronan-binding protein densities were positively correlated with CLASI (r=0.74 and r=0.86 respectively), but not with SLEDAI (r=0.52,
EVs in the blood of CLE were abundantly derived from antigen-presenting cells, and contained disease-specific proteins such as anti-Sm antigens and pro-inflammatory proteins. The concentration of some of the proteins contained in EV of CLE blood correlated with CLASI rather than SLEDAI, suggesting that the content of EV’s are different in SLE and CLE.
Systemic lupus erythematosus (SLE) is an important cause of secondary warm-antibody autoimmune hemolytic anemia (AIHA). The prevalence of AIHA has been estimated to range from 5% to 30%, but severe AIHA is comparatively less frequent in SLE patients. The severity of AIHA has rarely been studied in SLE patients;1–3 we thus have examined the predictors of severe AIHA using the extensive database of a large Latin American inception cohort.
In patients with a recent diagnosis of SLE (≤ 2 years), factors associated with the occurrence of severe AIHA (hemoglobin level <7 g/dl) were examined by Cox proportional univariable and multivariable hazards regression analyses.
Of 1,349 patients, 103 (7.6%) developed AIHA over 5.4 (3.8) years. Of them, 49 (47.6%) patients were classified as having severe AIHA (Mestizos 44.9%, Caucasians 40.8%, and African-Latin American 14.3%). The median time from the first clinical SLE manifestation to the occurrence of severe AIHA was 3.7 months (IQR 1.4–15). In the univariable analyses, male sex and disease activity at diagnosis were associated with a shorter time to severe AIHA occurrence while malar rash and photosensitivity were associated with a longer time. By multivariable analysis and after adjusting for age at SLE diagnosis, gender, and ethnicity, male sex, and higher disease activity at diagnosis remained associated with a shorter time to the occurrence of severe AIHA. The results are shown in the Table below.
Severe AIHA occurred in 3.6% of our cohort and it is an early manifestation of lupus. In Latin American patients with SLE, male sex represents more than a two-fold higher risk of experiencing severe AIHA at a faster pace. A higher level of disease activity at SLE diagnosis is also an independent predictor of the occurrence of severe AIHA in a shorter time.
Durán S, Apte M, Alarcón GS, et al. Features associated with, and the impact of, hemolytic anemia in patients with systemic lupus erythematosus: LX, results from a multiethnic cohort. Arthritis Rheum 2008; 59:1332–1340.6. Sultan SM, Begum S, Isenberg DA. Prevalence, patterns of disease, and outcome in patients with systemic lupus erythematosus who develop severe hematological problems. Rheumatology (Oxford) 2003;42:230–234. 28. Moysidou GS, Garantziotis P, Nikolopoulos D, Katsimbri P, Fanouriakis A, Boumpas DT. Relapses are common in severe hematologic systemic lupus erythematosus and may be prevented by early institution of immunosuppressive agents: A real-life single-center study. Lupus 2022 Dec 9:9612033221144425. DOI: 10.1177/09612033221144425. Epub ahead of print. PMID: 36490217.
We investigated the 2-year outcomes of belimumab (BEL) additive on standard of care (SoC) in patients with SLE in the real-world setting.
Sixty-four SLE patients treated with BEL additive to SoC for 2 years (BEL+SoC) and 341 patients treated with SoC were recruited. The patient backgrounds were adjusted with propensity score matching; 11 items including age, sex, disease activity, glucocorticoid (GC) dose, rash, alopecia, arthritis, anti-dsDNA antibody, hypocomplementemia, urinary and blood cell count abnormality, and 33 patients in each group remained for analysis. Disease activity was measured by SLE disease activity scale (SLEDAS).
The median SLEDAS at 2 years was significantly decreased from baseline in BEL+SoC (2.08 to 1.12, p<0.001) but not in SoC (2.09 to 2.03, p=0.058). Low disease activity was achieved with significant difference in BEL+SoC compared to SoC (29 (88.8%) vs 17 (51.5%), p=0.023) without difference in remission rate (72.7% vs. 51.5%, p=0.127). Median daily prednisolone (PSL) dose at 24 weeks significantly decreased in both treatment groups from baseline (BEL+SoC; 6.0 to 3.5 mg/day, p<0.001, SoC; 5.0 to 4.0 mg/day, p<0.001) without a statistical difference (p=0.112). However, absolute reduction was significant in BEL+SoC (-3.0mg) compared to SoC (-1.0mg) (p=0.004). Disease recurrence occurred in 5 (15.2%) patients in BEL+SoC and 4 (12.1%) in SoC (p=0.714). All recurrences in patients with BEL+SoC were experienced after 10 months and later during PSL tapering. Whereas those in SoC occurred from one month and later, which did not always relate to PSL tapering.
Add-on treatment with BEL was effective to achieve low disease activity during PSL tapering which would lead to reducing GC related organ damages. However, recurrence was observed in both groups indicating the need for GC tapering strategies in an individual setting.
Libman-Sacks (LS) endocarditis is one of the major cardiac involvement of systemic lupus erythematosus (SLE) and can manifest with neuropsychiatric events including stroke. However, data on the clinical features of LS endocarditis in comparison with infective endocarditis are limited. Thus, we compared SLE patients with LS endocarditis and those with infective endocarditis and analyzed the long-term clinical outcomes.
We reviewed the medical records of SLE patients who were diagnosed with LS endocarditis or infective endocarditis between 1990 and 2021. Poor outcomes were defined as the occurrence of stroke, transient ischemic attack, or seizure during follow-up.
A total of 47 patients with LS endocarditis were compared with 5 patients with infective endocarditis. Patients with LS endocarditis were less likely to have fever, chest pain, and vegetation (40.4% vs. 100%, p=0.019) and had smaller vegetation size (median, 0 mm, vs. 12 mm, p=0.008) compared with those with infective endocarditis. Of the 37 patients with LS endocarditis who were followed for more than one year, 11 patients had poor outcomes, who had a significantly higher rate of vegetation (63.6% vs. 29.2%, p=0.048) and a lower rate of pericardial effusion (27.3% vs. 66.7%, p=0.039) than those without poor outcomes. The presence of vegetation and pericardial effusion were significantly associated with the development of poor outcomes.
Patients with LS endocarditis had different clinical features compared with those with infective endocarditis. Neuropsychiatric outcomes occurred in approximately 30% of patients with LS endocarditis during follow-up, and the presence of vegetation and pericardial effusion were significant factors for the development of poor outcomes.
To study the effect of osteoporosis on MACEs in a longitudinal cohort of patients with SLE.
Patients who fulfilled ≥4 ACR criteria for SLE and had a DEXA scan performed were followed longitudinally. The incidence of MACEs documented by imaging studies was evaluated. Osteoporosis/fracture at baseline was defined as a T score of <-2.5 or Z score <-2.0 at the hip/femoral neck/spine, or old fragility fractures. The effect of osteoporosis on incident MACEs was studied by Cox regression, adjusted for confounders.
383 SLE patients were studied (age 40.5±13 years; 94% women). Osteoporosis/fractures was present in 113 patients at baseline. Over 153±41 months, 44 MACEs (acute coronary syndrome [n=19]; ischemic stroke [n=19]; peripheral vascular disease with digital gangrene [n=6]) developed in 42 patients. The incidence of MACEs was significantly higher in patients with osteoporosis/fracture than those without (1.59 vs 0.63/100 patient-years; p=0.001). The cumulative risk of MACEs by KM plot was significantly higher in the osteoporosis than non-osteoporosis groups (p=0.002). Cox regression revealed osteoporosis/fracture was an independent risk factor for MACEs after adjustment for age, sex, vascular risk factors, past MACE, aPL antibodies, and the use of immunosuppressive drugs, aspirin/warfarin, statins, vitamin D and bisphosphonates (HR 2.41[1.25–4.67];p=0.009). 62(16%) patients succumbed and osteoporosis/fracture at baseline was associated with vascular mortality (HR 11.1[1.02–120]; p=0.048) but not with all-cause mortality after adjustment for the same confounders.
Osteoporosis increases the risk of MACEs and vascular mortality in patients with SLE, which is not accounted by traditional vascular risk factors.
To study the prevalence and risk factors of fragility fractures in patients with SLE.
383 patients who fulfilled ≥4 ACR criteria for SLE and had a DEXA scan performed (baseline) were longitudinally followed for new fragility fractures. Osteoporosis/fracture was defined as a DEXA T score <-2.5 or Z score <-2.0 at the hip/femoral neck/spine or a history of old fractures. The cumulative incidence of new fractures was studied by Kaplan-Meier’s analysis and risk factors by Cox regression, adjusted for confounders.
383 SLE patients were studied (age 40.5±13 years; 94% women). Patients with osteoporosis/fracture at baseline (n=113) were more likely to have childhood onset disease (<18 years), longer SLE duration and higher prevalence of hematological or neuropsychiatric manifestations than those without. Use of glucocorticoids (GCs) and MMF/AZA, BMI≤18kg/m2, premature menopause (<45 years) were also more frequent in the osteoporosis/fracture group. However, no difference in the SLEDAI scores was observed. Over 153±41 months, new symptomatic fragility fractures developed in 34(8.9%) patients (vertebral [n=19], hip [n=2], limbs (non-hip) [n=6], digital/rib [n=7]; incidence 0.69 per 100 patient-years). The cumulative risk of fragility fractures was significantly higher in the osteoporosis than non-osteoporosis group (p<0.001). Cox regression showed that increasing age (HR1.08[1.03–1.12]), osteoporosis/fracture (HR3.47[1.59–7.59]) and a family history of fracture (HR4.31[1.41–13.2]) were independently associated with new fractures after adjustment for SLE duration, childhood onset disease, other osteoporosis risk factors, clinical manifestations, GCs and immunosuppressive medications. No relationship between the daily dosage of GCs and fractures was observed.
In this longitudinal cohort of SLE, new fragility fracture developed in 8.9% of patients. Increasing age and severe osteoporosis at baseline was major risk factors.
Clinical manifestations of SLE in male patients tend to be more severe with a worse prognosis. Generally, SLE in male patients involves kidney and serological abnormalities such as hypocomplementemia and anti-dsDNA autoantibodies. In addition, cardiovascular complications are more common in men with SLE, which contributes to an overall increase in organ damage. Case illustration A 18-year-old male patient suffered from back pain 6 months ago. He complained of low urine output (urinating 3–4 times a day with a total output of approximately 400 mL), dyspnea, and swelling in both legs. Pericard effusion was discovered, and pericardiocentesis was performed. Physical examination showed the patient was hemodynamically stable. We found malar rash, rash in the plantar pedis and plantar manus also decreased vesicular sounds with rales in both lungs. Laboratory examination showed leukopenia, thrombocytopenia, hypoalbuminemia, hyperuricemia, and a glomerular filtration rate of 94 mL/min/1.73 m2. Urinalysis showed proteinuria, hematuria, and leukocyturia. Blood gas analysis found metabolic alkalosis. ANA IF test was positive for anti-Smith, anti-RNP-Smith, and anti-dsDNA antibodies. The patient was given methylprednisolone pulses dose (1000 mg/day) for 3 days, followed by methylprednisolone 125mg/12h for 3 days, 62.5mg/12h for the next 3 days and tapered-off to 8mg/day. The patient also received mycophenolic acid (500mg/8h), hydroxychloroquine (200mg/day) per oral, and Captopril 12.5mg/8h per oral during hospitalization. The patient showed clinical improvement and was discharged after 11 days. Subsequent follow-up at rheumatology policlinic showed the patient had improved both clinically and laboratory.
The patient‘s condition in this case is consistent with the theory, where the patient is experiencing lupus nephritis and pericardial effusion. Establishing an accurate diagnosis of SLE in male patients is crucial. Early diagnosis leads to better outcomes.
Serious infections contribute significantly to morbidity and mortality in systemic lupus erythematosus (SLE)
We undertook a retrospective analysis of all SLE patients enrolled in the Australian Lupus Registry & Biobank admitted to hospital with infection between 2009–2020. Comparisons of length of stay (LOS) according to different patient and disease characteristics and clinical decisions regarding corticosteroids (CS), immunosuppression (IS) and anti-microbial therapy were performed using ANOVA (Kruskal Wallis test). Cox and related regression models were used to identify associations between hospital LOS and clinical variables.
53 patients with 85 separate hospitalisations were identified. Patients had a mean (SD) age of 44.6 (14.8) years. Mean hospital LOS was 15.4 (19.7) days. Admission to the Intensive Care Unit (ICU) occurred in 11.8% of cases. IS was withheld during 29.4% of infections. There was considerable variation in whether CS were modified from a patient’s baseline dose. Use of pulse CS and weaning baseline CS during infection were strongly associated with longer LOS. Unsurprisingly, ICU admission, intravenous anti-microbial use and nosocomial infections were also linked with increased LOS. Withholding immunosuppression during infection did not reduce LOS. Patient factors including age, Charlson Co-Morbidity Index (CCI), preceding disease activity and pre-admission immunosuppression did not influence LOS.
From this single centre study hospital LOS was primarily influenced by factors relating to the severity of infection. Factors possibly relating to inadequately controlled SLE, such as attempted tapering of usual CS dose and administering pulse CS – commonly used to treat severe disease flares, also significantly prolonged infection admissions. Further research is required to identify the optimal approach towards modifying baseline CS and immunosuppression when managing infections in SLE patients.
Chilblain lupus erythematosus(CHLE) or Perniosis is a rare and chronic form of lupus involving the toes, fingers, nose, and ears precipitated by cold exposure. The prevalence is 3–20%, affecting mostly women and can be divided into primary and secondary. The primary or idiopathic form is not associated with an underlying disease, while the secondary form is associated with an underlying condition such as connective tissue disease, monoclonal gammopathy, cryoglobulinemia, or chronic myelomonocytic leukaemia. It is often associated with other forms of cutaneous lupus, and about 20% of patients develop systemic lupus erythematosus(SLE). The patient usually comes with symptoms of purple plaques or nodules and oedematous skin, mainly around the acral regions of the body. Histologic features are identical to those of discoid lupus erythematosus. The damaged skin gives a Positive fluorescent band test picture. CHLE is defined by the Mayo Clinic criteria, which include two major and four minor. Diagnosing a patient requires two major and at least one minor criterion. Patients with chilblain lupus erythematosus may also display hypergammaglobulinaemia, positive rheumatoid factor, antinuclear antibody, antiphospholipid or anti-Ro antibodies. They are usually negative for anti-double-stranded DNA antibodies. The first-line treatment for mild and localised symptoms is topical corticosteroids. Second-line systemic treatments consist mainly of immunomodulators and immunosuppressants. Studies have shown benefits from the use of topical tacrolimus and pimecrolimus. We want to report a case of a young lady that presented to our centre with CHLE.
Chilblain lupus erythematosus is a rare and chronic disease mainly affecting women. Although it is not as severe as Systemic Lupus Erythematosus(SLE), it may be the sentinel sign of a range of underlying auto-immune diseases. Physicians should be vigilant in dealing with CHLE as their symptoms may be subtle and mimic other similar pathologies.
The presence of antinuclear antibody (ANA) is usually considered a hallmark of Systemic Lupus Erythematosus (SLE). However, a small group of SLE patients had the typical clinical manifestation of SLE with negative ANA tests. Segmental hyalinizing vasculitis is an orphan disease associated with various diseases including SLE. We report a case of a 29-year-old female presented with a painful skin ulcer on both her upper and lower extremities for 2 weeks. She also noted joint pain, fever, and shortness of breath. The symptoms were accompanied by multiple redness and pus-filled skin ulcer on both arms, thighs, and legs. The remainder examination revealed hair loss, pale conjunctiva, crackles in chest examination, ascites, and edema in both feet. There were also redness and tenderness on both hand at Distal Interphalangeal(DIP), Proximal Interphalangeal(PIP), and Metacarpophalangeal(MCP). Laboratory studies showed anemia, elevated erythrocyte sedimentation rate, and positive LE cell. The antinuclear antibody immunofluorescence (ANA IF) test was negative. A skin biopsy revealed segmented hyalinizing vasculitis suitable for Lupus. A transthoracic echocardiogram showed mildly abnormal left ventricular systolic function with an ejection fraction 45%, moderate mitral regurgitation, and mild aortic regurgitation. Chest X-ray showed signs of pulmonary edema and right pleural effusion. The conditions fulfilled the clinical criteria of SLE, and the patient was diagnosed with ANA-negative SLE. The patient underwent treatment with hydroxychloroquine 200 mg twice daily, methylprednisolone 16 mg twice daily, and desoximethasone cream. The patient showed significant clinical improvement and her ulcer completely resolved after 6 months of treatment, and there is no recurrent ulcer.
Case report of a 29-year-old woman diagnosed with ANA-negative SLE with segmental hyalinizing vasculitis and valvular heart disease as the main manifestation of SLE. Early recognition and aggressive SLE therapy of this rare subset of SLE disease showed clinical improvement and completely resolved skin ulcers.
COVID19 pandemic likely has had significant influence on the presentation, management and outcome of Systemic Lupus Erythematosus (SLE). A single-centre experience of managing SLE during the 3rd wave of COVID19 pandemic in Sri Lanka is presented.
New and follow up patients with SLE seen at Peradeniya University Teaching Hospital from the 1st of July to the 31st of August 2021 were audited. Those with moderate to severe disease (assessed by British Isles Lupus Assessment Groups 2004/BILAG score1) requiring intensification of immunosuppression, were identified. Possible effects of the pandemic on the clinical presentation, and treatment outcome were assessed.
Of 45 patients with SLE seen during this period, eleven had moderate to severe flares (female:male 10:1). Four were new diagnoses during the study period. Of the seven follow-up patients, six had well-controlled disease over the preceding 24 months, while one had intermittent flares.
9 out of 11 patients were BILAG-A in at least one domain and two were BILAG-B. All needed aggressive immunosuppression. Remission was induced in ten patients while one succumbed to severe disease and sepsis.
In 72.7% of patients (n=8), effects of COVID19 were evident. These were possible causal association (n=1), disease flare concomitant with COVID19 infection (n=2), COVID19 complicating immunosuppression (n=1) and delayed presentation leading to requirement of aggressive immunosuppression (n=4).
Diagnosing and managing SLE is challenging due to variable clinical presentation, multi-system involvement and complex treatment decisions.2 The on-going pandemic has increased these challenges several-fold. COVID19 probably has a causative relationship with autoimmune disease.3 Delayed presentation can cause unfavourable outcomes during the pandemic.
Very limited and old data regarding the epidemiology of juvenile-onset SLE (jSLE) are available. Our aim was to estimate jSLE incidence and mortality rate in incident cases over the period 2012–2020. In addition, we also assessed point prevalence of pediatric SLE in 2020.
This is a retrospective population-based study conducted using the Veneto Region Population Registry, an administrative health database where all residents are recorded (4.9 million people), which was linked to the mortality register. SLE cases were identified by any hospital diagnosis of SLE (ICD-9-CM 710.0), or a healthcare copayment exemption for SLE (national registry code 028), whichever came first, between 2021 and 2020. All SLE diagnoses in subjects <19 years-old were considered. Standardized incidence rate (IR) was reported by gender. Standardized point prevalence of pediatric SLE was assessed considering prevalent SLE cases aged <19 years-old in 2020.
During the study period, among 1,092 incident SLE cases, 68 (6.2%) were jSLE (54 females, 79.4%). IR (95%CI) over the study period was 0.94 overall: 0.38 (0.23–0.63) x 100,000 residents in males, and 1.54 (1.18–2.01) x 100,000 in females. This incidence rate was significantly lower than those observed in other age groups (age groups 19–44, 45–60, 60–75, >75 years). Incidence was 4-folds higher in females (female-to-male IR ratio: 4.09, 95% CI 2.27–7.36, p<0.0001). No death occurred among the incident cases of jSLE. In 2020, 34/3,472 prevalent SLE patients were <19 years-old (1%); point prevalence of pediatric SLE was 3.9 (2.6–5.2) per 100,000 residents, significantly lower than that of adults SLE (71.2, 68.8–73.5). No death occurred among the incident cases of jSLE.
Between 2012 and 2020, jSLE incidence was 1:10,000 residents, confirming that pediatric SLE is a rare condition, as reported in older studies in other European countries. Over the last decade, early jSLE mortality has been negligible.
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease requiring a long-term therapeutic approach. Low compliance with medication leads to the worsening of the disease. Evaluating medication compliance rates and factors associated with low compliance are important to design further compliance interventions.
We conducted a cross-sectional analysis of adult individuals with SLE from Tittari Community, Surakarta. Patient completed the 5-item version of Compliance Questionnaire for Rheumatology (CQR5), Quick Systemic Lupus Activity questionnaire (Q-SLAQ), and Hamilton Anxiety Depression Rating Scale (HADS). Association between compliance and demographic, disease-related characteristics, and medication characteristics were explored.
A total of 78 individuals with SLE participated in the study, 76 (96.4%) were female with a mean age of 36±10.9 years. The Majority of SLE patients reported disease duration >5 years (52.7%), were prescribed <5 drugs (52.7%) and had side effect complaints in 28 (35.89%). Low compliance was found in 29.49% of patients. In logistic regression analysis, having mental health issues such as anxiety (OR 4.3, CI 95% 0.6–28.7), depression (OR 3.7, CI 95% 0.9–14.1), or both anxiety and depression (OR 2.6, CI 95% 0.5–13.5) tend to increase the risk of low compliance. Other factors associated with low compliance were disease duration of 1–3 years (OR 4.9, CI 95% 0.5–47.7), and the presence of medication adverse events (OR 1.7, CI 95% 0.6–5.1).
The prevalence of low medication compliance among SLE patients was high. SLE patients with anxiety and/or depression who had been living with the disease for 1–3 years, or experienced medication adverse events were found to have a higher risk of low compliance.
It is not clear how well administrative data identify incident disease in complex chronic disorders like Systemic Lupus Erythematosus (SLE). We aimed to clarify accuracy of ICD-10-coding in incident SLE by comparing incidence-rates from code-based case-definitions and confirmed SLE diagnosis by expert clinical assessment in a defined population.
From administrative data, we identified all individual cases registered with a SLE-specific ICD-10 code (M32) during 1999–2017 in three Southeast Norway counties(2.1 million). All cases were manually chart-reviewed to confirm SLE diagnosis. To prevent against admixture of prevalent cases, we defined incident by presence of M32 in 2004–2017, but not in 1999–2003. Incidence-rates were estimated from five case-definition; (a-c) first occurrence of one-, two- and three or more M32-codes 2004–2017, (d) SLE diagnosis confirmed by chart-review and (e) SLE classified by 1997 ACR classification criteria. To define accuracy, we applied incidence-rate ratios obtained from dividing M32-derived incidence-rates to those from SLE diagnosis.
Of 1975 unique cases registered with a M32-code 1999–2017, chart-review confirmed SLE diagnosis in 936 cases (45%), while 1033 (52%) had conditions other than SLE.
Of 936 cases with confirmed SLE diagnosis, 323 (34%) were incident 2004–2017 (
Case-definitions based solely on ICD-10 code gave incidence-rates of SLE twice as high as when cases were defined by expert clinical assessment, with a maximum discrepancy of seven times more in elderly (70–79 years of age) to no discrepancy before 25 years of age.
a-c) Age-distribution of estimated incidence of Systemic Lupus Erythematous (SLE) in study area 2004–2017 by different case-definitions; for all (a), women (b), men (c). d) Age distribution of incidence rate-ratios comparing SLE defined by two or more ICD-codes of SLE to SLE diagnosis confirmed by individual chart-review (i.e. accuracy of ICD-code); stratified by sex.
Relationship between clinical parameters and length of stay in SLE patients with serious infection
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by a multi-systemic presentation.1 Patients with SLE will often see multiple providers operating within different healthcare networks, meaning that pieces of important data related to patients’ disease course may be spread across disparate electronic health records2 (EHR). One method for integrating EHR data from multiple sites leverages clinical data research networks (CDRNs), such as the Chicago Area Patient Centered Outcomes Research Network (CAPriCORN),3 which includes data from 11 healthcare sites.
These results highlight the importance of linking information across multiple healthcare sites in the context of complex diseases such as SLE, as disease-specific information can be gained through data aggregation. Systems such as CAPriCORN may have important applications in improving recruitment for clinical trials, clinical decision-making for rheumatologists, and population-level surveillance of SLE.
Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD. Manifestations of systemic lupus erythematosus. Maedica 2011;6(4):330. Walunas TL, Jackson KL, Chung AH, Mancera-Cuevas KA, Erickson DL, Ramsey-Goldman R, et al. Disease outcomes and care fragmentation among patients with systemic lupus erythematosus. Arthritis care & research. 2017;69(9):1369–76. Kho AN, Hynes DM, Goel S, Solomonides AE, Price R, Hota B, et al. CAPriCORN: Chicago Area Patient-Centered Outcomes Research Network. Journal of the American Medical Informatics Association 2014;21(4):607–11.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with various ranges of organ damages, so that patients with SLE might face to considerable medical costs in their early disease courses. We aimed to estimate the progression of direct healthcare costs before and after diagnosis of SLE and to compare healthcare costs by disease severity in Korean patients with SLE.
Incident patients with SLE were identified between 2008 and 2018 using the Korean National Health Insurance databases. Annual direct healthcare costs for five years before and after the diagnosis of SLE were estimated and we compared them with those of age-, sex-, and calendar months-matched controls (1:4). Direct healthcare costs of patients with SLE were compared by disease severity using inverse probability-weighted regression analysis.
A total of 11,173 incident SLE patients and 45,500 subjects without SLE were identified. Annual direct healthcare costs per person in SLE group was increasing one year before SLE diagnosis, and reached the highest at the first year of SLE diagnosis, resulting 7.7-fold greater than comparators ($5,694 vs. $736 a year, respectively). Among patients with SLE, having severe SLE resulted in 4.39 times (95% Confidence Interval [CI] 4.123–4.673) higher cost over a period of 1 year. Older age (aged 70–79, 1.455 times, 95% CI 1.304–1.623), having comorbidities such as lupus nephritis (1.89 times, 95% CI 1.801–1.983), avascular necrosis (5.482 times, 95% CI 3.977–7.668), chronic kidney diseases (1.783 times, 95% CI 1.601–1.985), and interstitial lung diseases (1.542 times, 95% CI 1.346–1.765) were associated with higher annual direct healthcare costs of the first year.
Patients with SLE incurred significantly high direct healthcare costs compared to subjects without SLE, especially during the first year after diagnosis. Disease severity as well as comorbidities were associated with increased costs of illness in patients with SLE.
The course and evolution of the SLE depends on the affected organ, adherence to treatment and accumulated organ damage, but ethnicity plays a fundamental role, leading to worse results in the non-Caucasian population. Our goal was to describe the demographic, clinical and serological characteristics of a cohort of patients diagnosed with SLE, treated at a private center in the City of Cali, Colombia.
Descriptive analytical study of a cohort of patients older than 18 years, diagnosed with Systemic Lupus Erythematosus who met the SLICC 2012 classification criteria and who were treated at a Private Center in the City of Cali, Colombia between January 2016, and January 2023.
Categorical variables were expressed in percentages and 95% confidence intervals (95% CI). Continuous variables were expressed as means with standard deviations (SD) and medians with interquartile ranges (IQR).
848 patients were included. The mean age of the patients attended was 48.4 years (SD: 15.34). 92.2% correspond to the female gender. The median follow-up (time between the first and last visit) was 24.9 months (IQR: 10.0–38.28). The ANA titer that we found most frequently was 1/1280 in 21.77% of the cases followed by 1/640 in 18.08% and 1/160 in 17.34%. The anti-DNA was positive in 42.61% of the cases. Regarding antiphospholipid antibodies, the presence of IgG-anticardiolipin (ACL) was positive in 21.37%, IgM-ACL positive in 18.92%, IgG-B2GP (Beta 2 glycoprotein) in 10% and IgM-B2GP in 5.45% of the cases. Lupus anticoagulant was positive in 5.88% of the cases. Regarding disease activity, most patients (53.47%) presented a SLEDAI of 0 (remission), 32.04% a SLEDAI between 1 and 4 (low activity), 12.86% between 5 and 10 (moderate activity) and only 1.63% a SLEDAI greater than 10 (high activity).
The results are similar to the data published in different national and international studies.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies to various nuclear antigens and high serum cholesterol levels. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors has been shown to have exhibited anti-inflammatory effects in several clinical trials. We conducted this study to evaluate the effect of rosuvastatin on inflammatory responses in MRL/lpr mice, a representative model of human SLE.
MRL/lpr mice were intraperitoneally injected with rosuvastatin (10 mg/kg, n = 4) or vehicle [2% dimethyl sulfoxide (DMSO), n = 4] five times a week from 13 to 17 weeks of age. The serum levels of low-density lipoprotein (LDL) cholesterol and autoantibodies were measured, as well as the urine levels of albumin. Renal tissues were stained with HE and PAS for histopathological analysis. Concentrations of key inflammatory cytokines in serum were measured, and messenger RNA (mRNA) levels in target organs (kidney, spleen, and lymph nodes) were evaluated.
Rosuvastatin treatment significantly decreased serum LDL-cholesterol concentration in MRL/lpr mice. However, the treatment of rosuvastatin did not improve clinical manifestations nor the titers of autoantibody. In addition, serum inflammatory cytokines and proteinuria were not changed with treatment of rosuvastatin. Furthermore, histopathological analysis of the kidneys did not improve with rosuvastatin treatment. When assessing the expression of mRNA, the treatment with rosuvastatin decreased tumor necrosis alpha in spleen and kidney tissue, and interleukin-17 concentration in the kidney and lymph node of MRL/lpr mice.
The treatment of rosuvastatin is insufficient to improve disease activity of SLE, although it can decrease inflammatory cytokines in the lymphoid organs and kidneys of MRL/lpr mice.
Rationale: Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by autoantibody production by hyper-activated B cells. Although mesenchymal stem cells (MSCs) ameliorate lupus symptoms by inhibiting T cells, whether they inhibit B cells has been controversial. Here we address this issue and reveal how to prime MSCs to inhibit B cells and improve the efficacy of MSCs in SLE.
We examined the effect of MSCs on purified B cells in vitro and the therapeutic efficacy of MSCs in lupus-prone MRL.Faslpr mice. We screened chemicals for their ability to activate MSCs to inhibit B cells.
Mouse bone marrow-derived MSCs inhibited mouse B cells in a CXCL12-dependent manner, whereas human bone marrow-derived MSCs (hMSCs) did not inhibit human B (hB) cells. We used a chemical approach to overcome this hurdle and found that phorbol myristate acetate (PMA), phorbol 12,13-dibutyrate, and ingenol-3-angelate rendered hMSCs capable of inhibiting IgM production by hB cells. As to the mechanism, PMA-primed hMSCs attracted hB cells in a CXCL10-dependent manner and induced hB cell apoptosis in a PD-L1-dependent manner. Finally, we showed that PMA-primed hMSCs were better than naïve hMSCs at ameliorating SLE progression in MRL.Faslpr mice.
Conclusion: Taken together, our data demonstrate that phorbol esters might be good tool compounds to activate MSCs to inhibit B cells and suggest that our chemical approach might allow to improve the therapeutic efficacy of hMSCs in SLE.
Advances in single cell genomics have illuminated aberrant cells with striking transcriptional differences in patients with systemic lupus erythematosus compared to healthy individuals. However, it is not clear whether the aberrant cells are directly responsible for pathology or bystanders that have become aberrant in response to an inflammatory environment. This is an important distinction because safer and more effective treatments rely on identifying and eliminating pathogenic cells. The goal of this study was to molecularly characterise the cells that produce pathogenic autoantibodies and determine how they differ to their normal counterparts.
A multi-omics approach was employed to identify pathogenic autoreactive B-cells, which linked mass spectrometry sequencing of serum autoantibody with massively parallel sequencing of immunoglobulin expressed by circulating B-cells. Single cell sequencing was performed to compare gene expression and mutation in pathogenic and normal B-cells.
Rare circulating B-cells making pathogenic autoantibodies were found to comprise clonal trees accumulating mutations in immunoglobulin regions. The pathogenic cells had a distinct gene expression profile similar to that previously observed in CD21-low atypical memory B-cells.
The detailed analysis of pathogenic B-cells reveals insights into disease pathology and therapeutic targets for precision medicine approaches.
Administration of cytotoxic and immunosuppressive agents are well established treatment of systemic lupus erythematosus. However, the usage of these drugs shows frequent side effects. Therefore, finding new treatment option are necessary. Mucus secretion from snail (Achatina Fulica) contain glycosaminoglycans including heparan and acharan sulfate, which known to accelerate the inflammatory process and replace the damaged glomerular filtration membrane in renal interstitial fibrosis. This study aimed to determine the effect of snail mucus on levels of heparan sulfate in mice model of lupus nephritis.
Experimental study uses posttest-only group design. The control group was male Balb/C mice injected with 0.5 cc NaCl 0.9% I.P, while mice model of nephritis lupus injected with 0.5 cc Pristane I.P. Nephritis lupus mice grouped into group I (received oral methylprednisolone 0.5mg/kgBW/day), group II (received oral 0.5 cc snail mucus/day) and group III (combination of standard therapy and snail mucus). The treatment administered for 4 weeks. Detection of heparan sulfate on blood serum taken 4 months after therapy. Statistical analysis used anova test and post hoc test.
There was an increase in heparan sulfate levels in the snail mucus group (12.13 +1.27 mg/dL; p = 0.277), and the methylprednisolone group (11.79 +0.97 mg/dL; p = 0.230) compared to the lupus group (11.27+1.20 mg/dL). The snail mucus group also showed higher level of heparan sulfate compared to control group, although not statistically significant (p = 0.257).
Achatina fulica mucus may increase heparan sulfate level in mice model of lupus nephritis.
Carvalho O, dos S, Teles HM, Mota EM, Mendonca CLGF, de Lenzi HL. Potentiality of Achatina fulica Bowdich, 1822 (Mollusca: Gastropoda) as intermediate host of the Angiostrongylus costaricensis Morera & Céspedes 1971. Rev. Soc. Bras. Med. Trop 2003;36:743–745. Collins LE, Troeberg L. Heparan sulfate as a regulator of inflammation and immunity. J Leukoc Biol 2019;105:81–92 Dharmezier, Bawazier LA. Diagnosis Dan Penatalaksanaan Nefritis Lupus. Dalam : Simadibrata M, Syam AF, Setiati S, Setyohadi B, Alwi I. (editors). Buku Ajar Ilmu Penyakit Dalam Jilid III Edisi VI. Jakarta : Interna Publishing FK UI; hal 2014;3378–85. Gesteira TF, Coulson-Thomas VJ, Ogata FT, Farias EHC, Cavalheiro RP, de Lima MA, Cunha GLA, Nakayasu ES, Almeida IC, Toma L, Nader HB. A novel approach for the characterisation of proteoglycans and biosynthetic enzymes in a snail model. Biochimica et Biophysica Acta (BBA) – Proteins and Proteomics 2011;1814: 1862–1869 Guilermo J, Alarcon GS, Scofifield L, Reinlib L, Cooper GS. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritits Rheum 2010;39:257–9. Kim HJ, Hong Y-H, Kim Y-J, Kim H-S, Park J-W, Do J-Y, Kim K-J, Bae S-W, Kim C-W, Lee C-K. Anti-heparan sulfate antibody and functional loss of glomerular heparan sulfate proteoglycans in lupus nephritis. Lupus 2016;0:1–10.
Recent advances in the treatment of systemic lupus erythematosus (SLE) have focused on inducing specific immune tolerance to avoid complications from the long-term use of immunosuppressive drugs. Dendritic cells (DCs) are the most potent antigen-presenting cells that have multifaceted functions in the control of immune activation and immune tolerance. Since altered tolerogenicity of DCs contributes to the development and pathogenesis of SLE, DC-targeted therapies aimed at inducing self-tolerance have become of great importance for the treatment of SLE and autoimmune diseases. Our current study developed a new nanoparticle (NP) containing PDMAEMA-PLGA copolymer for target-oriented delivery to DCs in situ.
The in vitro tolerogenic effects of PDMAEMA-PLGA NPs and dexamethasone-incorporated PDMAEMA-PLGA NPs (Dex-NPs) were tested in conventional DCs generated from murine bone marrow (BM-cDCs) using FLT3L and GM-CSF in comparison with pure dexamethasone. The uptake of PDMAEMA-PLGA NPs by DCs was investigated in vivo and the in vivo therapeutic efficacy of Dex-NPs was observed in Fcgr2b-/- lupus-prone mice.
PDMAEMA-PLGA NPs provided sustained drug release profiles and exhibited immunosuppressive activity in BM-cDCs. PDMAEMA-PLGA NPs strengthened the dexamethasone capability to convert wild-type and Fcgr2b-/- BM-cDCs from immunogenic to tolerogenic state, and BM-cDCs treated with Dex-NPs efficiently mediated Treg expansion in vitro. PDMAEMA-PLGA NPs were actively captured by DCs in vivo probably in a particle size-dependent manner. Furthermore, Dex-NPs potentially ameliorated lupus activity in Fcgr2b-/- mice by reducing renal inflammation, anti-double-strand DNA antibodies, serum IL-6, serum creatinine, and proteinuria. Dex-NP therapy markedly enhanced Foxp3+ Treg expansion in an antigen-specific manner in Fcgr2b-/- mice.
These findings substantiate the superior efficacy of our Dex-NPs and provide further support for clinical development as a potential therapy for SLE. Furthermore, Dex-NPs may be a versatile platform for DC-targeted therapy to induce antigen-specific immune tolerance to unwanted immune responses that occur in autoimmune diseases.
Macrophage activation syndrome (MAS) is a rare and life-threatening disease, characterized by inappropriate activation of lymphocytes and histiocytes, leading to a cytokine storm, haemophagocytosis and multi-organ damage. Our previous studies demonstrated that the leukocyte immunoglobulin-like receptors A3 (LILRA3) plays a pathogenic role in multiple autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and antiphospholipid syndrome. However, the role of LILRA3 in MAS has not been investigated. This study was undertaken to examine the in vivo role of LILRA3 in MAS model.
To functionally study the role of LILRA3 in MAS pathogenesis, we generated a novel LILRA3 knock-in (LILRA3-KI) mouse. Human LILRA3 gene (Gene ID: 11026) was inserted into Rosa26 allele in C57BL/6 (B6) mice based on Cas9/sgRNA system. The MAS-like disease model was induced by repeated intraperitoneal injection of CpG-ODNs in either B6 wild-type (B6-WT) or LILRA3-KI mice. Mice were assessed for the development of splenomegaly, hematological indices, immune cellular response, cytokine expression, and spleen pathology.
Compared with untreated B6-WT control mice, both B6-WT and LILRA3-KI treated mice displayed decreased haemocytes; inappropriate activation of lymphocytes; increased organ damage; and elevated levels of cytokines. Notably, compared with CpG-ODN treated B6-WT mice, the treated LILRA3-KI mice displayed a less pronounced MAS-like phenotypes and immune responses, including an increase of erythrocytes, hemoglobin, and platelets; an expansion of CD4+ and CD8+ T cells; decreased spleen enlargement; less disorganized spleen architecture and inflammatory cell infiltration; and reduced serum levels of cytokines (IL-6, IL-10, IL-12p70, IL-18 and IFN-).
Our data indicate that LILRA3 plays a protective role in MAS-like disease probably through suppressing the inappropriate activation of both CD4+ and CD8+ T cells, and subsequently leading to decreased production of cytokines, less haemophagocytosis and reduced spleen impairment.
Age-associated B cells (ABCs) are a particular population of B cells that CD11c and T-bet double positive, rarely observed in healthy young individuals. These atypical B cells are from an extrafollicular (EF) response, unlike T cell-dependent germinal center (GC) response that produces long-lived, high-affinity antibody-secreting B cells. Since ABCs not going through GC response, somatic hypermutation or class-switching poorly happens, and they secrete pathogenic autoantibodies. ABCs expansion and chronic autoimmune disease correlation are well-established, especially in systemic lupus erythematosus (SLE). Some individuals with active SLE display abnormal expansion of ABCs regardless of age, but how ABCs impact the disease remains unclear. Not just aged or autoimmune disease individuals, the infectious condition could increase the ABCs differentiation. In such case, IL-21 drives extrafollicular CD11c+ B cells. It means IL-21, which plays a multifunctional role in B cell differentiation, could influence the expansion of ABCs also in aged and autoimmune diseases. Therefore, we experimented to confirm whether ABCs can express autoimmune disease phenotypes and whether IL-21 is related with ABCs.
We inspected the ABCs expansion in Aged (> 60 weeks) and Young (6 weeks) mice without autoimmune disease and collected the spleen and lymph nodes. The organ samples are used in comparing ABCs-inducing inflammatory phenotypes between two groups. Furthermore, measured the titer of autoantibodies from serum.
The extrafollicular (CD23-CD21-) ABCs (CD11c+ T-bet+) are dramatically increased in aged mice, and some inflammatory reactions are observed.
We confirmed the inflammatory phenotype by ABCs in aged mice without autoimmune diseases. These results represent that ABCs could affect the autoimmune disease phenotype. Recently we revealed the transcription factor ‘Mef2d’ could regulate the cytokine IL-21. To figure out the mechanism of ABCs expansion in aged and autoimmunity, we will investigate whether the differentiation of ABCs can also be controlled by regulating IL-21 through Mef2d expression.
Systemic lupus erythematosus is a chronic-systemic autoimmune disease that may affect different organ and organ system. Pathogenesis of SLE is not well understood but high inflammatory response of innate and adaptive immunity were thought to be main hallmark of the disease. IL-6 cytokines, which mainly secreted by Th-1 activation, were responsible to the pro-inflammatory response that affect inflammation and correlated with lupus disease activity. Meanwhile, IL-17 cytokines, secreted by Th-17 cells, also cytokines that believed to maintain the regulatory of immunity. This study is aimed to determining the correlation between serum of IL-6 with ratio of IL-6 and IL-17 cytokines on active SLE patients.
SLE patients with active disease activity were recruited as subject of this study. Diagnosis criteria of SLE was using American College of Rheumatology (ACR) 1997 revised and MEX-SLEDAI was using to measured disease activity of lupus, which score >2 was considered as active disease activity. IL-6 and IL-7 was measured using ELISA methods and correlation of IL-6 and ratio of IL-6/IL-17 cytokines was performed using computerised statistical analysis program, with p<0,05 considered as significant correlation.
On this study, there were 50 SLE patients that included as subject of our study. Correlation analysis study was performed using computerised statistical analysis which we found that there was significant correlation between Il-6 cytokine serum with ratio of IL-6/IL-17 in SLE patients with p = < 0,05, r = 0,995
There is significant correlation between cytokines of IL-6 and ratio of IL-6/IL-17 cytokines serum on active lupus patients. From this study, it’s important to determine the ratio of these inflammatory cytokines serum on blood peripheral to assess disease progression and response to the treatment, in addition to using existing disease activity instruments such as SLEDAI2K or MEX-SLEDAI.
Background: neutrophil extracellular traps (NETs) are released by activated neutrophils. It has been shown that NETs play a role in the pathogenesis of different autoimmune diseases, including systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (PAPS). The aim: evaluate levels of NETs observed in blood smears and their association with clinical variables in SLE, SLE+APS, and PAPS.
The study included 54 patients with SLE (SLICC criteria, 2012), 37 with PAPS (Sydney criteria, 2006), 42 with SLE+APS, and 27 healthy controls without acute infections. NETs were investigated in standardized thin blood smears produced from citrated whole blood and stained by the Giemsa method. NETs percentage to the number of neutrophils was calculated (%NETs).
Neutrophils in PAPS, SLE+APS, and SLE released significantly more NETs than neutrophils in the control group (p=0.023). When comparing the groups in pairs, we found that the level of NETs% was higher in PAPS, SLE+APS, and SLE compared to controls (p<0.05). There were no significant differences between the levels of NETs among patients (p>0.05). NETs levels was not associated with SLE activity. Patients with glomerulonephritis in SLE and SLE+APS had significantly lower NETs capacity (4 [2.6; 5.6] versus 6.6 [2.6; 11.1], p=0.04). The levels of NETs did not differ significantly in patients with PAPS and SLE+APS depending on antiphospholipid (aPL) positivity (single, double, triple positivity), history of thrombosis or obstetric pathology.
NETs levels were higher in SLE, SLE+APS, and PAPS compared to controls. SLE patients with renal involvement had significantly lower NETs levels. This study was prepared as a part of the fundamental scientific theme 1021051402790.
Single cell RNA sequencing (scRNA-seq) of kidney tissues in patients with lupus has led to landscape of complete cellular composition and states for immune and non-immune cells. These studies suggested type I interferon (IFN) signatures prime inflammatory responses. However, there is a lack of knowledge regarding the characteristics of subsets of IFN stimulating genes (ISG) high expressed cells. Here we investigated immune cell compositions between peripheral blood mononuclear cells (PBMCs), skin and kidney tissues in patients with lupus using scRNA-seq. We characterized a subset of ISG high CD4 T cells, which are commonly expressed across PBMCs, skins and kidneys of lupus but not skins of healthy
scRNA-seq dataset of PBMCs, skin and kidney tissues in patients with lupus were collected. We integrated and analyzed immune cell compositions from this scRNA-seq dataset. We focused on subset of ISG high expressed CD4 T cells and characterized top 200 genes of this subset.
There is one subset of ISG high expressed CD4 T cells in the lupus PBMCs, kidneys, and skins but not in the healthy skins. This ISG high expressed CD4 T cells have the greatest number of type I interferon signatures and gasdermin D gene, which is related to pyroptosis of cells, among top 200 genes. We further investigated pyroptosis pathway genes in the subsets of CD3 T cells. Interestingly, the subset of ISG high expressed CD4 T cells have most increased pyroptosis related upstream regulating genes including IRF1, GBP1, CASP4 and CASP1. Furthermore, this subset highly expressed inflammasome gene such as NLRC5 not NLRP3.
There are ISG high expressed CD4 T cells across tissues of lupus. Those cells highly expressed pyroptosis pathway related genes. Further investigation is needed to characterize association between ISG and pyroptosis.
Leukocyte immunoglobulin-like receptor A3 (LILRA3) is the soluble protein of LILRs family. LILRA3 exhibits a 6.7-kb deletion variation among individuals. The deletion removes all of four Ig-like domains, resulting in a ‘non-functional LILRA3’. Our research group identified the functional LILRA3 as a novel genetic risk for systemic lupus erythematosus. The aim of this study was to functionally characterize the impact of LILRA3 in the pathogenesis of SLE.
We constructed a humanized LILRA3 knock-in (LILRA3-KI) mouse in C57BL/6 (B6) mice background. The lupus-like disease was induced by repeated epicutaneous stimulation with Toll-like receptor (TLR)-7 agonist imiquimod (IMQ) on both ears of mice. All of the mice were euthanized four weeks after the initiation of treatment. The spleen and serum samples were collected. Immunocyte populations were determined by staining with fluorescently-conjugated antibodies and analysed by flow cytometry. Serum antibodies were detected by enzyme-linked immunosorbent assay (ELISA).
The mice developed lupus-like disease following 4 weeks of treatment with imiquimod. LILRA3-KI mice exposed to imiquimod showed increased innate and adaptive immune response, including splenomegaly (p < 0.05) and elevated levels of serum anti-dsDNA IgG (p < 0.05), compared to WT mice. The frequencies of M1 macrophage, M2 macrophage, T follicular helper cells (Tfh), germinal center (GC) B, and plasma B cells were increased in KI mice (p < 0.05).
Our data demonstrated that LILRA3 promoted the TLR7-driven lupus autoimmunity with the excessive expansion of macrophages, Tfh, GC B, and plasma B cells.
Id3 is a member of the inhibitor of DNA binding (Id) family which is a helix-loop-helix protein acting as a transcriptional regulator. Previous studies have reported that Id3 plays an essential role in the development and function of regulatory T cells in lupus. However, its role in B cells remains unclarified.
To investigate the role of Id3 in B cells, we generated C57BL/6 mice with a CD19Cre-mediated B cell-specific depletion of Id3 as well as mice (Id3-/-) with a conventional knockout of Id3. In these mice, we evaluated the presentation of lupus-mimicking phenotypes and changes in immune cell populations. Additionally, we assessed the influences of B cell-specific Id3 depletion in lupus-induced mice by R848.
In Id3-/- mice, proportions of effector T cells such as Th1, Th2, and Th17 cells were elevated whereas those of regulatory T cells were lower than in control mice. Furthermore, proportions of plasma cells were significantly elevated in Id3-/- mice. These mice presented with increased inflammation in kidney tissues, resembling lupus nephritis. An elevated proportion of plasma cells was replicated in mice with B cell-specific Id3 depletion. Induction using R848 exacerbated lupus-like manifestations including increased proteinuria and higher serum immunoglobulin levels in B cell-specific Id3-depleted mice than in control mice. In an in vitro study, CD19+ B cells from Id3-/- mice were more differentiated into plasma cells than those from control mice. In contrast, there were no significant differences in other B cell subsets.
Genetic suppression of Id3 in murine models exacerbated lupus-like phenotypes with aberrant B cell differentiation. These findings may imply a potential role of Id3 in the pathogenesis of lupus.
The study of the ability of monocytes to activate associated with the clinical activity of immunological markers of inflammation in systemic lupus erythematosus (SLE) will provide important and fundamentally new information on the involvement of these cells in the development of autoimmune rheumatic diseases.
To study macrophage activation in untreated systemic lupus erythematosus (SLE) patients (pts).
A total of 21 active SLE pts (female/male 15/6) were enrolled in the study (median age was 35[24; 41] years; disease duration was 8 [2; 14] months; SLADAI-2K was 7 [6;16]). The control group consisted of 29 volunteers (23F/6M, median age 38 [35; 48] years).
Isolation of monocytes was carried out according to the standard procedure for obtaining a leukocyte fraction in a Ficoll gradient and subsequent selection of CD14 + cells using magnetic separation. After isolation, the cells were cultured in X-Vivo medium. To assess the degree of monocyte activation, cells were stimulated by the addition of LPS. The value of monocyte activation was expressed as a ratio of the level of secretion of proinflammatory cytokines by monocytes cultured with and without LPS addition. Secretion levels were determined by ELISA. The belonging of the isolated cells to CD14 + monocytes was additionally confirmed by flow cytometry.
Macrophage activation was 4.8 (2.8;7.3) in SLE pts and 10,2(3.5;11,6) in control group, p>0,05. In SLE pts macrophage activation was independent of age, sex, body mass index, traditional risk factors (arterial hypertension, overweight, smoking, family history of cardiovascular diseases), SLADAI-2K. No association was found between macrophage activation and levels of ANA, C3, C4, and anti-dsDNA.
No differences in macrophage activation were found in SLE pts and control group. Macrophage activation was independent of age, sex, traditional risk factors, and SLE-related parameters.
Double negative B cells represent a heterogeneous compartment and expansion has been linked to systemic lupus erythematosus (SLE) in previous studies.1–3 Previously we found a novel CXCR5-CD19low subset in the DN compartment. Thus, we aimed to further characterize this population phenotypically and functionally.4
For this study, we collected peripheral blood from a total of 79 patients with SLE and 80 healthy individuals as reference. We investigated baseline surface marker expression and Syk phosphorylation kinetics upon B cell receptor (BCR) stimulation of peripheral B cells and specifically the CXCR5-CD19low subset using flow cytometry. To check the subset for its capability of secreting antibodies, cell cultures were performed and soluble immunoglobulins were detected using a bead-based flow cytometry assay. Additionally, targeted RNAseq was performed.
We found that the subset of CXCR5-CD19low B cells can be found among DN and CD27+ memory B cells and was increased in SLE. Frequencies correlated with PBs frequencies. Surface marker expression of CD38, CD95 and CD71 and IgA and IgG suggest an activated and antigen experienced phenotype. BCR stimulation show a reduced responsiveness similar to the kinetic of PBs. The capacity to secret IgA ex vivo suggests that CXCR5-CD19low B cells are antibody secreting cells which was further supported by the finding of elevated transcriptional expression of PRDM1, XBP-1 and IRF4, transcription factors known to regulate plasmablasts (PB) differentiation.
Summing up, besides bimodal expression of CD27 the subset of CXCR5- CD19low B cells shared various characteristics with PBs such as phenotype and functionality like antibody secretion and reduced BCR responsiveness. CXCR5- CD19low seemed to be related to plasmacytosis as suggested by the correlation with PB frequencies. Our data suggest that CXCR5-CD19low B cells are precursors of PBs and targeting this subset in SLE may have therapeutic value.
Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 2000;165(10):5970–9. Jenks SA, Cashman KS, Zumaquero E, Marigorta UM, Patel AV, Wang X, et al. Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus. Immunity 2018;49(4):725–39.e6. Ruschil C, Gabernet G, Lepennetier G, Heumos S, Kaminski M, Hracsko Z, et al. Specific Induction of Double Negative B Cells During Protective and Pathogenic Immune Responses. Front Immunol 2020;11:606338. Szelinski F, Stefanski AL, Schrezenmeier E, Rincon-Arevalo H, Wiedemann A, Reiter K, et al. Plasmablast-like Phenotype Among Antigen-Experienced CXCR5-CD19(low) B Cells in Systemic Lupus Erythematosus. Arthritis Rheumatol 2022;74(9):1556–68.
Despite optimal treatment, lupus nephritis (LN) remains associated with irreversible kidney damage1. A better understanding of the mechanisms underlying LN pathogenesis is needed to develop better treatment targets. As part of the Accelerating Medicines Partnership (AMP), we discovered that urinary PR3, a neutrophil degranulation product, correlated with histological activity implicating neutrophil/monocyte degranulation in proliferative LN, the most aggressive type2. PR3 is a serine protease that can mediate kidney damage. Mature neutrophils with classical polylobate nuclei are rare in LN kidney biopsies. However, recent evidence displayed how immature, degranulating myeloid cells have been implicated in the pathogenesis of LN3, but their role in mediating kidney damage is not completely understood. We aimed to investigate PR3+ cells in LN kidney and their association with histopathological features, and define their immunophenotype.
We performed multiplexed histology using serial immunohistochemistry (sIHC)4 on archival LN kidney biopsies to quantify the expression of PR3 and multiple cell lineage markers (20-plex). Image analysis including deconvolution, cell segmentation, glomerular annotation, and quantitative histology was performed using Indica HALO. The analysis was limited to renal cortex.
A total of 11 patients with LN who underwent a clinically indicated kidney biopsy were enrolled: 6 (55%) with pure proliferative LN (ISN/RPS class III or IV) and 5 (45%) with pure membranous LN. PR3+ cells were identified in all LN biopsies (range 343–7625 per sample). Most PR3+ cells did not show a polylobate nucleus. The majority of PR3+ cells were in the tubulointersitium (
PR3+ cells are abundant in LN. PR3+ cells are increased in proliferative LN and are strongly associated with histological activity thereby characterizing a more aggressive phenotype. This population densely infiltrated the glomeruli emphasizing a potential role in the endothelial pathogenic process. In preliminary analysis, kidney infiltrating PR3+ cells were not polymorphonucleated, did not express neutrophil elastase, and variably expressed CD14 suggesting a phenotype consistent with degranulating monocytes or an immature myeloid population. We previously showed the association between urinary PR3 and histological activity suggesting that intrarenal PR3+ cells are actively degranulating and, therefore, likely inducing kidney damage. These findings nominate PR3+ cells as a potential therapeutic target. Spatial transcriptomics and proteomic studies are ongoing to define the lineage and function of these cells.
(A) PR3+ cell density per mm2 of cortical area according to location and LN class. PR3+ cell density within glomeruli (B) and tubulointerstitium (C). (D) Pearson’s correlation between NIH Activity Index and glomerular PR3+ cell density. (E) Original and deconvoluted IHC images on the same representative glomerulus. Arrows indicate 3 same representative cells. Markers indicated at the bottom with matching false colors.
Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations and unpredictable outcome. We aimed to identify the genetic contributions on clinical and serological manifestations in Korean patients with SLE.
The patients with SLE were enrolled including a discovery cohort and a replication cohort from the Korean population (n = 1,655). Weighted genetic risk score (wGRS) were calculated by SLE risk loci [112 well-validated non-HLA SNPs and HLA-DRB1 haplotype] based on genome-wide association study. Individual wGRS was tested for associations with clinical sub-phenotypes of SLE by using multivariable linear regression or logistic regression.
Increasing wGRS was significantly associated with more diverse manifestation of SLE, regardless of onset age, sex and disease duration. The SLE patients with high wGRS-quartile were significantly associated with the risk of renal disorder (HR=1.74; p=2.2x10–8) and anti-Sm antibody production (HR=1.85; p=2.8x10–5) compared to patients with low wGRS-quartile.
We found that wGRS influenced on the development of proliferative lupus nephritis (LN) [class III or IV (HR=1.98, p=1.6x10–5)] and membranous LN [class V (HR=2.79, p=1.0x10–3)]. Moreover, increasing wGRS had the strongest effect on the development of LN class V in anti-Sm positive SLE (AUC=0.681, p= 1.8x10–4).
The higher wGRS, which implicated in pathogenesis of SLE, increased the risk to develop lupus nephritis and anti-Sm antibody production. Our study provided that genetic risk loads could predict the clinical outcome in SLE.
Mutations, both activating and inactivating ones, continue to be identified in human diseases, including systemic lupus erythematosus (SLE). One emphasis is on mutations in transcription factors and their impact on the genome, leading to disease. Here I discuss experimental approaches, genome-editing coupled with next-generation sequencing-based technologies, that provide a framework to provide insight into the function of mutant proteins in disease. The JAK/STAT (Janus kinase/Signal Transducer and Activator of Transcription) signaling cascade transduces cytokine signals in normal development and disease. Dysregulation of cytokine action on immune cells plays a key role in the initiation and progression of autoimmune diseases including systemic lupus erythematosus (SLE). Elevated levels of phosphorylated (activated) STAT5 are detected in conventional CD4 T cells and activated regulatory T cells of SLE patients. However, the contribution of protein-altering mutations in STAT5 in the etiology of the disease have not been investigated. Mutations in the SH2 domain of STAT5B, which is essential for its dimerization and biological activation, have been identified in patients with T cell leukemias.
The Y665F mutation has been identified in patients with T cell large granulocyte lymphocytic leukemia (T-LGLL) using whole genome sequencing. To understand the molecular consequences of this mutation we introduced it into the mouse genome using CRISPR/Cas9 genome editing and deaminase base editing.
Using ChIP-seq and RNA-seq, we identified activity and formation of STAT5-dependent regulatory elements and expression of target genes that are altered by mutations. These findings provide insight into the initiation and progression of hematopoietic disease. Single cell RNA-seq and flow cytometry explored the impact of the STAT5B mutation on different immune cell populations and their genetic programs.
Our study offers insights into pathogenic molecular immune mechanism elicited by STAT5 mutations. Our experimental approach provides a blueprint to investigate and understand mutations in autoimmune disease including lupus.
IKZF1 (Ikaros), IKZF2 (Helios) and IKZF3 (Aiolos) are candidate genes for Systemic Lupus Erythematosus (Pmeta<5x10–8). The proteins are members of the Kruppel zinc finger family of transcription factors (TF). These three TFs are important regulators of haematopoesis and lymphocyte function, making good functional candidates for lupus. Helios-deficient mice acquire an auto-inflammatory phenotype in later life, resulting in increased numbers of activated CD4+ and CD8+ T-cells and germinal centre B-cells, culminating in autoantibody production. Murine knockouts of Ikzf1 and Ikzf3 also exhibit problems with immune function. The underlying mechanism(s) for the genetic associations are currently unknown.
We used ChIP-Seq to determine the DNA binding sites of Ikaros, Helios and Aiolos in the GM12878 EBV-lymphoblastoid cell line and for Helios in Jurkat T-cells by implementing the uniform processing pipeline for TF ChIP-Seq (ENCODE Phase 3). We compared the unique binding sites of each Ikaros transcription factor using MAnorm2 and identified biological pathways enriched for target-genes using EnrichR.
21,334 high-confidence peaks were called for Aiolos, 9,027 for Ikaros, 13,583 for Helios in B-cells and 5,070 peaks for Helios in T-cells. Ikaros and Aiolos target-genes share a similar pattern of enrichment within immune-related pathways. There was a distinct tissue-specific pattern of enrichment for Helios binding sites in T-cells compared with B-cells within immune-related pathways for: Chemokine signalling- CCL27 (C-C Motif Chemokine Ligand 27); Regulation of Toll-like receptor signalling- SQTM1 (Sequestosome 1), SIGIRR (single immunoglobulin IL-1R-related receptor; IL1 signalling- SQTM1, TRAF6 (TNF Receptor-Associated Factor 6); IL17 signalling- IL17RE (Interleukin 17 Receptor E), TRAF3IP2 (TRAF3 Interacting Protein 2) and TRAF6.
Our study describes the first comprehensive analysis of Ikaros transcription factors in SLE using ChIP-Seq. The cell-type specific differences of Helios target-genes in B-cells compared with T-cells suggest separate immune-functions in these two cell-types.
Systemic lupus erythematosus (SLE) is a female predominant autoimmune disorder. X chromosome contains the largest number of immune-related genes of entire human genome. The number of X chromosomes in an individual has been recognized as having a ‘dose effect’ in the proclivity of developing SLE. We investigate the proportion of individuals with Klinefelter syndrome (KS) karyoptype 47, XXY and karyotype 47, XXX with SLE compared with SLE in the general population.
Multicenter retrospective cohort study utilizing a global federated research network database of electronic health records. Using ICD-10 codes, patients with KS karyotype 47, XXY and karyotype 47, XXX who developed SLE at any given time were identified and compared with proportion of SLE in general population from 1/1/2013 to 12/31/2022.
A total of 125,757,374 patients were queried on 1/16/2023 on the Global Collaborative Network. A total of 1,774 patients have KS; 2,582 patients have XXX; and 259,841 patients have SLE (224,230 or 86% female; 35,611 or 14% male with F:M ratio was 6:1 for all comers). A total of 21 patients with KS were found to have SLE; 19 patients with XXX have SLE. KS has a 41-fold increase in having SLE when compared with male SLE patients in the general population; and a 6.8-fold increase in SLE when compared with female SLE patients in general population. Karyotype 47, XXX patients have a 4.2-fold increase in SLE when compared with female SLE patients in general population.
This real world, real-time cohort study showed a 6.8-fold increase in SLE in Klinefelter syndrome karyotype 47, XXY and a 4.2-fold increase in SLE in karyotype 47, XXX when compared with female SLE patients in the general population. Extra X chromosome in KS and XXX appear to have a non-proportional, synergistic effect on the risk of developing SLE.
Cyclophosphamide, an immunosuppressant in patients with lupus nephritis, aims to prevent recurrence and is a steroid-sparing agent. The clinical response (efficacy and toxicity) of lupus nephritis patients receiving cyclophosphamide varied.1 Cyclophosphamide is a pro-drug metabolized by hydroxylation via the CYP2C19 and CYP2B6 enzymes and detoxification via the glutathione-S-transferase (GST) enzyme.2 The most common type of mutation that occurs is single nucleotide polymorphism (SNP). Several SNPs from previous studies associated with cyclophosphamide response, metabolism, and toxicity in patients with lupus nephritis, namely rs3957356 in the GSTA1, rs4244285 in the CYP2C19, rs7254579 and rs4802101 in the CYP2B6.3 Therefore, detecting and screening SNP genotypes in lupus nephritis patients can help analyze cyclophosphamide response variation. This study aims to develop a method for detecting the genotypes of the four target SNPs and several surrounding SNPs using PCR-Sanger sequencing.
The gene polymorphism analysis method was optimized before taking patient samples at the hospital. PCR and Sanger sequencing methods are used for gene polymorphism analysis because they produce chromatograms with target amplicon base lengths and several SNPs that can be analyzed simultaneously.
The analysis results of the four target SNPs of the GSTA1, CYP2C19, and CYP2B6 (rs3957356, rs4244285, rs7254579, and rs4802101) showed one synonymous SNP and three SNPs (regulatory and intergenic). We have developed an SNP detection assay using four fragments from the GSTA1, CYP2C19, and CYP2B6 that can detect 15 SNPs simultaneously (
PCR-sanger sequencing is a reliable, accurate, and simple method for determining SNP genotypes from blood samples.
Chromatogram depicting four genotypes SNP target and adjacent SNP simultaneously
Mok CC, et al. The Asia-Pacific League of Associations for Rheumatology consensus statements on the management of systemic lupus erythematosus. Lancet Rheumatol 2021;3:e517–e531. Alamilla Sanchez ME, Alcala-Salgado MA, Alonso-Bello CD, & Fonseca Gonzalez GT. Mechanism of Action and Efficacy of Immunosupressors in Lupus Nephritis. Int. J. Nephrol. Renovasc. Dis 2021;14:441–458. Helsby, N. A., Yong, M., van Kan, M., de Zoysa, J. R. & Burns, K. E. The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes. Br. J. Clin. Pharmacol 2019;85:1925–1934.
Neonatal lupus was developed in infants born from mother with autoimmune disorders through transplacental autoimmune antibodies. Macrophage activation syndrome (MAS) occur in autoimmune diseases and is fatal complication that led to death if not promptly diagnosed and treated appropriately. MAS in neonatal lupus is very rare.
A 33 days-old female was admitted due to fever with pancytopenia. Her skin was showed multiple erythema marginatum like rash on whole body. She was born from primipara mother without any autoimmune disorders. She was admitted at another hospital due to skin rash at post-natal 5 days and diagnosed with neonatal lupus because her mother auto immune study had positive anti-nuclear antibody (ANA) and anti-SSA (+), SSB (+). On admission, laboratory data were shown as 5.6 g/dL hemoglobin, 1,100/μL white blood cells (absolute neutrophil count: 110/μL), and 71,000/μL platelet. Inflammatory biomarkers showed C-reactive protein was 9.17mg/dL, and procalcitonin 1.88 ng/mL, and ferritin 1,507 ng/mL. DIC profiles were showed that INR of prothrombin time was over 5, aPTT over 120 seconds, and antithrombin III 64.2%, fibrinogen 401 mg/dL. We began empirical antibiotics for septicemia and high dose methylprednisolone (mPD) therapy for MAS. She received supportive care with packed red cell transfusion, fresh frozen plasma, and anti-thrombin. Body temperature decreased 3 days later after mPD treatment, and we changed to oral dexamethasone. We got results for decreased NK cell activity and high-level of soluble IL-2 (5,187 U/ml). Her auto-immune study showed ANA (1:320), anti-SSA (+3), and anti-SSB (+3). She was diagnosed with MAS in neonatal lupus. Her condition and laboratory data were recovered and discharged. Her clinical findings and auto-antibodies were disappeared at 9 month-of age.
Our case suggested that we should consider neonatal lupus if there was neonatal fever and erythematous rash in infants born to mother even without autoimmune history.
Patient, 60 years old. In 2018, symmetrical non-erosive arthritis of the hand joints appeared. According to tests: ACCP, RF, ESR, CRP – normal, ANA – negative. Seronegative rheumatoid arthritis (DAS28 4.7) was diagnosed and methotrexate (MT) 22.5 mg/week was prescribed with a positive effect. Due to arthritis recurrence two years later, methylprednisolone (MP) 4 mg/day, hydroxychloroquine (HCQ) 200 mg/day and MP IV total 1250 mg were prescribed. Then MT dose was increased to 25 mg/week, HCQ to 400 mg/day. In January 2022, the patient had mild COVID-19 confirmed by RT-PCR. On 23/01/22, she was treated with a combination of monoclonal antibodies against SARS-CoV2 surface S-protein (Bamlanivimab 700 mg + Etesivimab 1400 mg). In March 2022, examination revealed arthritis, urtic rash. There were laboratory abnormalities: CRP 6.2mg/L(0–5), ANA 1/320cytopl, anti-dsDNA 200IU/ml(0–25), anti-C1q 24.4IU/ml(0–10), C3 0.83g/L(0.9–1.4). Echocardiography showed no pathology. Given the chronological relationship with the administration of monoclonal antibodies, the late age of onset and the absence of visceral organ involvement, drug-induced lupus (DIL) with skin involvement (anti-C1q vasculitis) was initially diagnosed. Therapy: MP IV 1500 mg total, oral MP 8 mg/day, HCQ 400 mg/day, MT 20 mg/week with positive effect – reduction of arthritis and rash elements. However, considering the persistence of immunological abnormalities (anti-dsDNA 800IU/ml, anti-C1q 27.9IU/ml, C3 0.756g/L) by November 2022, the diagnosis is revised in favor of systemic lupus erythematosus (SLE), SELENA-SLEDAI 4 without clinical manifestations.
There are known cases of the development of DIL/SLE against the background of therapy with monoclonal antibodies, mainly TNF-α inhibitors. However, SLE after therapy with Bamlanivimab and Etesivimab are not described in the literature. Dynamic monitoring of the patient allowed to establish a final diagnosis and to prescribe an adequate and effective therapy.
In our studies of the relationship of the association of Epstein-Barr virus (EBV) infection with SLE we have also found an association of the anti-EBV Epstein-Barr Nuclear Antigen 1 (EBNA1) with SLE.1 Previously, we found that the anti-60kd Ro/SSA and anti-Sm B/B’ autoantibody responses were initiated at autoantigenic epitopes that cross-reacted with antigenic epitopes from EBNA1. Anti-Sm D and anti-C1q also bind EBNA1, constituting two additional examples in SLE. The structure of EBNA1 is unique in the known biological universe and profoundly inhibits the anti-EBNA1 CD8 T cell response, providing a basis for considering specific effects of this antigen on the human host immune response.
Literature search and combining available data to present summary results.
Recent studies establish that not only was anti-GlialCAM autoimmunity pathogenic in multiple sclerosis (MS) but also show that these autoantibodies bound EBNA1.2 A literature search revealed three EBNA1 cross reacting autoantigens in MS: αB crystallin, myelin basic protein, and anoctamin 2. In addition, accessible serologic data are consistent with anti-EBNA1 being increased in MS relative to EBV-infected controls, as they are in SLE, therefore, in aggregate suggesting that our model extends to MS. There is also evidence for a potential EBNA1 binding by anti-citrullinated peptide antibodies of rheumatoid arthritis by citrullinating Arginines of EBNA1.
These and other observations have led to a theory for the etiology and initiation of autoantibodies in SLE in which the anti-EBNA1 heteroimmune response constitutes the usual initiating humoral immune response for SLE autoantibodies. With two such different disorders potentially originating from the anti-EBNA1 response, one wonders whether such a mechanism may operate in other disorders. These findings present a possible human host immune response basis for the origin of lupus.
Laurynenka V, et al. Front Immunol 2022;13:830993. Lanz TV, et al. Nature 2022;603:321.
Although the safety profile of COVID-19 vaccines was shown to be acceptable in the clinical trials, risk and benefit of the vaccines in patients with systemic lupus erythematosus (SLE) are not known, as these patients have been excluded in the trials. The aim of the COVID-19 Vaccine In Lupus (C1VIL) study was to assess the risk and benefits of COVID-19 vaccines in on patients with systemic lupus erythematosus (SLE).
Information regarding COVID-19 vaccination and COVID-19 infection were collected from 207 SLE patients seen at 12 academic medical centers, affiliated with the Korean society of SLE research (KSSR) by patient self-reported, descriptive questionnaire from DEC 2022 to JAN 2023. Primary outcomes included status of COVID-19 vaccination/infection, vaccination-related adverse events (AEs), and disease flares after COVID-19 vaccination/infection.
As of JAN 2023, 77.5% of patients had received at least 1 shot of the COVID-19 vaccine. Overall, vaccine-related AE occurred in 66% of the patients, and 4.5% of the patients had serious vaccine-related AE requiring hospitalization. The most common AE pain/redness on the injection site, followed by myalgia, and/or arthralgia. COVID-19 was confirmed in 156 patients, and 3.2% of the infected patients required hospitalization. The incidence of Covid-19 was higher in the age group of >40 years (p=0.049), but not significantly different between vaccinated and never-vaccinated groups (69.9% vs 55.6%, p=0.489). Disease flare requiring medication change or hospitalization occurred in 10.3% of patients after COVID-19 vaccination, whereas in 14.9% of patients after COVID-19 infection. Disease flare also occurred more frequently in the age group of >40 years (p=0.046).
Vaccine hesitancy was observed in Korean patients with SLE, although vaccine-related AEs were mild to modest and disease flares were more frequent after COVID-19 infection than vaccination. Our data suggest that benefit of the COVID-19 vaccines appears to outweigh the risk in patients with SLE.
Coronavirus disease 2019 (COVID-19) pandemic, had posed a huge impact among patients with deranged or dysregulated immune systems, these include autoimmune rheumatic diseases, specifically lupus and Human Immune deficiency Virus or Acquired Immune Deficiency Syndrome (HIV-AIDS). These subsets of patients, eg. SLE and People living with HIV (PLWH) are unique populations considering the risk for them of contracting COVID-19 infection and its outcomes. Here, we report a rare case of a 22-year-old Filipino male, who was diagnosed to have SLE pre-pandemic. His presentations included progressive easy bruisability with persistent bicytopenia (anemia and thrombocytopenia), malaise, arthralgia and ill-defined flat, non -pruritic, erythematous lesions on his legs and dry cough. On work up he was found to have interstitial lung disease, high titers ANA and positive anti-dsDNA. He was given prednisone, hydroxychloroquine and mycophenolate moefetil which offered significant improvement. He was lost follow up until pandemic set in. He experienced crampy abdominal pain, rashes on his legs, weight loss, diffuse alopecia, low grade fever and bicytopenia. Work up revealed positive HIV test, low CD4 count, and positive for RTPCR for Covid. Neoplastic process was ruled out. Given his condition, his antimalarial and mycophenolate were temporarily held. He was managed according to COVID 19 guidelines and eventually referred to treatment hub for HIV-AIDS therapy.
This case illustrates the unfathomable relationship of infections and immune system. Identifying the clinical symptoms described as the presenting signs of a specific infection or a flare of lupus or one of the HIV associated clinical syndromes has remained a challenge for clinicians. A high index of suspicion must be kept in mind for appropriate and timely diagnosis. Management options must be tailored for the patient’s best outcomes.
Systemic lupus erythematosus (SLE) is a heterogeneous chronic autoimmune rheumatic disease characterized by a hyperproduction of autoantibodies to nuclear antigens and a wide spectrum of clinical manifestations. SLE Disease Activity Index-2000 (SLEDAI-2k) and SLE-disease activity state (SLE-DAS) are currently used to assess the activity of SLE. SLE-DAS covers a greater number of clinical manifestations of SLE, and it includes Coombs-positive hemolytic anemia, Liebman-Sachs endocarditis, the variability of vasculitis. Achieving definition of remission in SLE (DORIS) or lupus low disease activity state (LLDAS) is the main goal of therapy for patients with SLE. The aim of the study was to compare the activity of SLEDAI and SLE-DAS and to identify the correspondence of DORIS and LLDAS in SLE-DAS.
The study included 228 patients with SLE (204 women and 24 men). The age was Me=36.0 [28.0–45.0] y.o. and the disease duration – Me=6.0 [2.0–14.0] years. All patients were assessed for disease activity using the activity indices – SLEDAI-2k and SLE-DAS.
Patients were divided into 5 groups according to SLEDAI-2K (
Receiver operating characteristic (ROC) curves comparing the performance of SLE-DAS and SLEDAI-2K to detect DORIS и LLDAS are shown in (
Remission of SLE by DORIS corresponded to SLE-DAS≤1.1 points, for the detection of low activity, according to LLDAS, SLE-DAS was ≤2.08. In assessing the remission of SLE by DORIS, SLEDAI-2k has greater specificity (89%) compared to SLE-DAS (79%), however, ROC analysis shows a good clinical informativeness of SLE-DAS (AUC=0.901). Greater specificity of SLE-DAS for LLDAS was noted (80%) compared to SLEDAI 2k (59%) with similar sensitivity (73% and 76%, respectively).
Receiver operating characteristic (ROC) curves comparing the performance of SLE-DAS and SLEDAI-2K to detect DORIS и LLDAS
SLE activity according to SLEDAI-2K and SLE-DAS.
While lupus nephritis (LN) is more common with higher severity and mortality in children than in adult-onset disease, data regarding long-term outcome of childhood-onset LN is rare.
Long-term renal outcome and their treatment were assessed in 57 Korean childhood-onset LN patients diagnosed between 1999 and 2020 from a tertiary single center in Korea.
Median age at diagnosis of LN was 14.5 (range 7.8–17.8) years. Median follow-up period was 135 (30–266) months. 26.3% (15/57) of patients progressed to chronic kidney disease (CKD) stage 3–5 (CKD stage 3: 6 patients, stage 4: 1 patient, stage 5: 8 patients). 10-year renal survival was 100% in patients diagnosed after 2011, compared to 80.3% in patients diagnosed before 2011 (p=0.049). Comparing the two eras, there were no clear difference between the laboratory finding at diagnosis, the drug used, and the cumulative dose of cyclophosphamide or hydroxychloroquine, except that primary renal response rate was higher at the latter era (55.2% vs 82.1%, p=0.029), and the diagnosis age was slightly younger in the earlier era (median 13.5 vs 14.6, p=0.056). Hydroxychloroquine use was significantly associated with maintaining renal estimated glomerular filtration rate (eGFR) higher than 60ml/min/m2 at 10 years (95.2% vs 77.2%), and 20 years (68.6% vs 16.1%), respectively (p= 0.033).
Early diagnosis and timely adequate treatment, and the use of hydroxychloroquine are important in the long-term kidney prognosis of childhood-onset LN.
4 CASES with clinical manifestations of systemic lupus erythematosus (SLE) and proteinuria in nephrotic range. Case 1, a 30-year-old woman with multiple sclerosis history, using β1 interferon for 16 years, present dyspnea, delirium, edema in the lower limbs, hypertension, lymphopenia, thrombocytopenia, active sediment, 2.8 g/24 hrs. proteinuria, hypocomplementemia, ANA and anti-DNA+. Case 2, a 40-year-old woman with no medical history, arthritis, non-scarring alopecia, oliguria, and emergency hemodialysis criteria, anemia, hypocomplementemia, 0.5 g/24 hrs. proteinuria, ANA, and anti-DNA +. Case 3, a 46-year-old woman with no previous history, high blood pressure, leukocytoclastic vasculitis, edema in the lower limbs, anemia, thrombocytopenia, active sediment, 0.6 g/24 hrs. proteinuria, ANA, lupus anticoagulant, and SSA +. Case 4, a 39-year-old woman with no medical history, non-scarring alopecia, malar erythema, emergency hemodialysis criteria, lymphopenia, anemia, hypocomplementemia, 4.1 g/24 hrs. proteinuria, ANA, and anti-DNA +. The clinical manifestations are summarized in (
Glomerulopathy in SLE is a frequent and severe manifestation, so timely treatment is necessary. However, the role of renal biopsy becomes important despite the clinical characteristics, where its performance shows us that in the clinical spectrum of glomerulopathies not everything is Lupus.
Clinical manifestations according to SLE EULAR/ACR 2019 classification criteria
The standard treatment of lupus nephritis is based on immunosuppressive therapy using mycophenolate mofetil or cyclophosphamide and with glucocorticoids, however, these treatments are not consistently effective. Tacrolimus (TAC), a novel calcineurin inhibitor with immunosuppressive effects, has recently become increasingly interested in its role as a potential therapeutic agent in SLE. We aimed to evaluate the efficacy of TAC as a treatment for LN.
A total 170 patients with biopsy proven LN were enrolled by reviewing the medical records of patients with LN in Ajou Lupus cohort. The clinical response of TAC treatment was evaluated by proteinuria, estimated glomerular filtration rate (eGFR), anti-double-stranded DNA (anti-dsDNA) antibody, complement 3 (C3), complement 4 (C4), and renal SLE disease activity index (SLEDAI). Complete renal response was defined as urine protein to creatinine ratio <0.5, normal serum creatinine or, if normal at baseline, not increased by ≥15%, and partial renal response was defined as a normal or near-normal GFR with a ≥50% reduction in proteinuria to sub-nephrotic levels. The definition of poor outcomes was determined by end stage renal disease or death.
The baseline clinical manifestations between 92 TAC group and 87 non-TAC group showed no significant differences. Most of TAC group received multi-target therapy with other immunosuppressants, while the non-TAC group usually used monotherapy. After 5 years, there were no statistically significant differences in proteinuria, eGFR levels, anti-dsDNA, serum C3/C4, and renal SLEDAI. The overall (complete and partial) renal response rate was not significantly different (TAC group versus non-TAC group=72.9% versus 85.5%; p=0.1). The poor outcomes were similar in both groups (log-rank p=0.837).
TAC is an effective maintenance therapy for LN, and may be a reasonable option for patients with refractive LN or LN who have not reached remission. In conclusion, TAC can help patients with LN achieve a renal response and slow progression.
Tacrolimus, mycophenolate mofetil (MMF), and azathioprine (AZA) have all shown considerable effectiveness as maintenance therapy for lupus nephritis in randomized controlled trials (RCTs), but their relative efficacy and safety in patients with lupus nephritis are still unknown. The objective of this research was to compare the relative effectiveness and safety of tacrolimus, MMF, and AZA as maintenance therapies for lupus nephritis.
RCTs examining the efficacy and safety of tacrolimus, MMF, and AZA as maintenance therapies in patients with lupus nephritis were included. We performed a Bayesian random-effects network meta-analysis to combine the direct and indirect evidence from RCTs.
Nine RCTs comprising 815 patients were included in the study. Although the difference was not statistically significant, MMF showed a trend toward a lower relapse rate compared with AZA (OR 0.73, 95% CrI 0.44 – 1.30). Similarly, tacrolimus showed a trend toward a lower relapse rate compared with AZA (OR 0.92, 95% CrI 0.24 – 2.84). Ranking probability based on the surface under the cumulative ranking curve indicated that MMF had the highest probability of being the best treatment based on the relapse rate, followed by tacrolimus and AZA. The incidence of leukopenia in the tacrolimus and MMF groups was significantly lower than that in the AZA group (OR 0.11, 95% CrI 0.02 – 0.56; OR 0.12, 95% CrI 0.03 – 0.32). Fewer patients with infections were observed in the MMF group than in the AZA group, although the difference was not statistically significant. The analysis of withdrawal due to adverse events showed a similar pattern.
Lower relapse rates combined with a more favorable safety profile suggest that tacrolimus and MMF are superior to AZA as maintenance treatments in lupus nephritis patients.
Lupus nephritis (LN) affects up to 60% of patients with systemic lupus erythematosus. Complete renal response (CRR) at 12 months is recommended as a treatment target. Remission or low disease activity in extra-renal domains also contributes to one of the important treatment goals. This study evaluated the usefulness of Lupus Low Disease Activity State (LLDAS) as a treatment target in LN.
Patients with a biopsy-proven active LN during the period of 2010–2020 were included. CRR was defined as proteinuria ≤0.5g/day (or equivalent) and normal estimate glomerular filtration rate (eGFR); partial renal response (PRR) was defined as a reduction of proteinuria by ≥50% with near-normal eGFR. The attainment of CRR, PRR, and LLDAS was evaluated at 12 months post-treatment. LN relapse was defined as worsening of proteinuria/serum creatinine and confirmed activity in repeat renal biopsy. The frequency of relapse was evaluated in patients who have achieved ≥50% proteinuria reduction to sub-nephrotic range post-treatment.
143 LN patients were included with a median follow-up duration of 10.4 years. Most patients (74%) had class III/IV (±V) histological subtypes (
LLDAS is an attainable target in LN and is associated with a lower risk of relapse. This study advocates the potential role of LLDAS as a complementary target to renal response in LN patients.
CRR=complete renal remission; LLDAS=lupus low disease activity state; NR=no response; PRR=partial renal response
C3=complement 3; C4=complement 4; CKD=chronic kidney disease; dsDNA=double stranded DNA; eGFR=estimated glomerular filtration rate; RNP=ribonucleoprotein; Sm=smith; UPCR=urinary protein-creatinine ratio; 24huP= 24-hour urine protein. eGFR calculated by MDRD formula
The neutrophil-to-lymphocyte ratio (NLR) is known to be associated with a poor outcome in patients with chronic kidney disease (CKD). Several studies have reported that NLR is closely related to the presence and activity of systemic lupus erythematosus (SLE). However, little is known about the prognostic role of NLR in patients with lupus nephritis (LN). Thus, the aim of this study was to determine whether NLR can predict progression to CKD in LN patients.
We enrolled 175 LN patients with available clinical data at the time of renal biopsy from the longitudinal SLE cohort. We divided LN patients into three groups based on NLR levels (T1, < 2.43; T2, 2.43–4.75; T3, > 4.75), and compared their demographic, clinical, histological and laboratory findings, and long-term prognosis among the groups. Univariate and multivariable Cox proportional hazard regression models were used to identify independent risk factors for CKD in LN patients.
Patients in the highest NLR tertile were older and had a higher SLEDAI score, lower eGFR, and higher white blood cell and platelet counts than those in the lowest tertile. During a mean follow-up of 100.8 ± 65.6 months, development of CKD and end-stage renal disease (ESRD) was more frequent in patients in the highest tertile (p < 0.001, p = 0.026). Finally, the highest NLR tertile was associated with an increased risk of development of CKD (adjusted hazard ratio (HR) = 2.972, 95% CI (1.429–6.182)).
Our results demonstrated that a higher NLR in LN patients had higher disease activity and showed more rapid decline of kidney function from the onset of LN. Therefore, NLR can be used as a prognostic marker for predicting CKD and and ESRD in LN patients.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune-mediated neurologic disorder that targets the peripheral nerves and nerve roots which can cause progressive weakness and sensory loss, described as gradual to chronic progression of symmetric, proximal and distal weakness. It is often misdiagnosed due to its presentation as it can mimic different kinds of peripheral neuropathies. CIDP can also be associated with systemic lupus erythematosus (SLE), Human Immunodeficiency Virus (HIV), diabetes mellitus or thyroid disorders. CIDP is said to be an uncommon manifestation of SLE and Diabetes Mellitus.
CIPD patients usually respond to a loading dose of IVIg 2 g/kg/day infusion for 5 days and often repeat infusions of either 0.5 g/kg/day 2 to 5 days every 2 weeks; 1 g/kg/day for 2 to 5 days every 3 weeks or 2 g/kg/day for 5 days every month, for a total of 2 or 3 months. IVIg must then be tapered down or discontinued and must be determined if continuous use is still needed.
IVIg has proven to be a safe and more effective treatment compared to steroids in a short-term prospective randomized controlled trials for CIDP; especially for those with pure motor CIDP.
In conclusion, there is a need for diagnostic vigilance as there is no proven diagnostic test to highly prove the diagnosis of CIDP, it is highly dependent on physical examination, neurologic evaluation, Electromyography – Nerve Conduction Velocity (EMG-NCV) test, lumbar puncture and lastly nerve biopsy. Early diagnosis and treatment of CIDP and its underlying cause is beneficial to patients. For cases of CIDP, it is treatable and responds to IVIg and steroids as well as compared to those suffering from diabetic polyneuropathy. Identification and reporting of this case can benefit physicians to establish a diagnosis and treatment in order to prevent progression of the disease.
Neuropsychiatric systemic lupus erythematosus (NPSLE) presenting with mood disorder, headache, psychosis, and cognitive impairment appears within 1 year of SLE diagnosis in more than half of cases.1–2 Most studies have focused on the epidemiology of neuropsychiatric manifestations in patients with established SLE.3 Therefore, diagnosing NPSLE in patients who have visited the hospital with psychiatric symptoms is challenging. Although some studies have conducted anti-nuclear antibody (ANA) screening in psychiatric patients, none have occurred in an Asian population.4–5 We aimed to determine the benefits of ANA screening for NPSLE in patients admitted to the department of psychiatry in Korea.
We investigated patients admitted to the department of psychiatry who underwent ANA testing between January 2015 and December 2021 at a single tertiary center in Korea. Patients diagnosed with SLE before admission were excluded from this study. Electronic medical records, including ANA titer, extractable nuclear antigen (ENA) were reviewed retrospectively. Diagnosis at psychiatric hospitalization was classified according to the International Classification of Diseases (ICD)-10.
Throughout the study period, 2523 patients were hospitalized, 1355 of whom underwent ANA testing. The median age of all patients was 40 (27–58), and 897 (66.2%) were female. Of the 1355 patients, 96 (7.1%) were positive with a titer of ≥1:80. Among the 17 patients who underwent ENA testing, 1 was positive for anti-Ro and anti-La, eventually diagnosed with Sjogren’s syndrome. According to the diagnostic classification of admission, there was no significant difference in the ANA positivity rate (p=0.205).
There was no difference in the positivity rate of ANA in the general population when testing was performed for screening purposes on patients admitted to the psychiatric department. Additionally, none of the 1355 patients were diagnosed with NPSLE after undergoing ANA screening. Thus, the benefits of performing routine screening appear to be limited.
Arthritis Rheum 1999 Apr;42(4):599–608 Neurol Clin. 1999 Nov;17(4):901–41 Semin Arthritis Rheum 2012 Oct;42(2):179–85 Arthritis Care Res (Hoboken) 2022 Mar;74(3):427–432 Medicine (Baltimore) 2016 Nov;95(47):e5288 2
The prognosis of Sjögren’s syndrome (SS) is generally better than that of systemic lupus erythematosus (SLE). But, if SLE develops later in SS patients, it could be one of the factors that increase the mortality of SS. Therefore, we determined the impact of demographic factors, clinical manifestations, disease activity, and serological tests at baseline on future SLE development in SS patients.
This retrospective study assessed 1,082 SS patients without other autoimmune diseases at baseline who visited our hospital between January 2012 and March 2021. We analyzed demographic features, extra-glandular manifestations (EGMs), clinical indices, and laboratory values at baseline between the two groups divided per future SLE development (SS/SLE group vs. SS group). The probability and predictors of SLE development in SS patients were estimated using the Kaplan-Meier method and Cox proportional hazards models.
The median follow-up duration was 1083.5 days. Forty-nine patients (4.5%) developed SLE that met the 2012 Systemic Lupus International Collaborating Clinics or 2019 EULAR/ACR classification criteria. The baseline EULAR SS disease activity index (ESSDAI) score was significantly higher in the SS/SLE group (p<0.001). The SS/SLE group had more lymphadenopathy and renal involvement (p=0.015 and p=0.017, respectively). Shorter SS disease duration (<3 years) (hazard ratio [HR]=2.61, p=0.012), high ESSDAI (HR=3.04, p=0.024), leukopenia (HR=2.20, p=0.017), hypocomplementemia (HR=17.40, p<0.0001), and positive for anti-dsDNA (HR=19.93, p<0.0001), anti-ribonucleoprotein (RNP) (HR=2.96, p=0.025), and anti-ribosomal P (HR=2.74, p=0.048) at baseline were SLE development predictors in SS patients.
Shorter disease duration and higher disease activity of SS at baseline may be risk factors for future SLE development. Serologic predictors of SLE development are hypocomplementemia, leukopenia, and positivity for anti-dsDNA, anti-RNP, and anti-ribosomal P antibodies. If the above factors are observed, close monitoring will be necessary during the follow-up period, considering the possibility of future SLE development.
Clinically evident kidney disease eventually occurs in up to one-half of SLE patients. The aim of this study is to describe sociodemographic, clinical, serological and treatment characteristics of a multicenter and multiethnic Latin American SLE cohort of patients with or without lupus nephritis (LN).
GLADEL 2.0 is an ongoing observational cohort. Patients were categorized according to renal involvement: Group I (LN never); Group II (prevalent renal involvement currently inactive); Group III (prevalent renal involvement, currently active) and Group IV (incident renal involvement). Demographic, clinical manifestations, treatments, disease activity were examined at baseline. A descriptive cross-sectional analysis was performed.
A total of 991 SLE patients were included, 884 (89.2%) female and 656 (68.3%) Mestizos (Amerindian and European ancestry). Median (IQR) age at cohort entry was 35 (28–45) years and disease duration were 67 months (18–139). Patients with incident LN had a higher proportion of males, were younger, had shorter disease duration and were more frequently Mestizos. Pericarditis and anti-dsDNA were less frequent in group I and MMF in groups I and IV (
Baseline characteristics of GLADEL 2.0 well characterized lupus patients’ cohort with or without LN are described with distinct demographic, clinical and laboratory patterns that will allow both centralized laboratory evaluation of urinary biomarkers and exploratory biomarker analyses including transcriptome and their impact on the outcome of these patients.
Sociodemographic and clinical characteristics and treatment at cohort entry
Due to oral bleeding, a 34-year-old male patient was admitted to the hospital. Additionally, he developed hematochezia as a result of an anal fissure brought on by a hard stool. In the months prior, he had experienced persistent diarrhoea and a biopsy during a colonoscopy revealed non-specific colitis treated afterwards with mesalazine. He also had a history of acute coronary syndrome. Hyperpigmented malar rash, and plaques in both ears, hands, and feet were notable physical findings. The findings of the laboratory tests showed proteinuria, microscopic hematuria, anaemia, thrombocytopenia, normal creatinine levels, and low albumin level. The participation of multiple systems casts doubt on SLE. Results from the ANA IF and ANA profile further support the diagnosis of SLE. The patient showed a good response to methylprednisolone given in the pulse dose. Despite the tapering of steroids, the patient has continued to improve after being given azathioprine and hydroxychloroquine.
1. The diagnosis of SLE should be entertained despite male gender in those presented with multi-systems involvement;
2. Unlike the majority of men with SLE, this male patient has responded favourably to treatment
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterized by production of autoantibodies. The anti-double stranded DNA (anti-dsDNA) autoantibodies are diagnostic biomarkers of SLE. A subset of anti-dsDNA antibodies can enter living cells and induce cytokine secretion. Our previous studies have reported that internalizable anti-DNA IgG localize to the cytosol and trigger secretion of IL-8 and TNF-a in primary human CD14+ monocytes. In this study, we detected the presence of antibodies that localized to the cytosol in monocytes obtained from the patients with SLE.
Cytosolic localization of IgG in CD14+ monocyte gated from PBMC of healthy controls (n=65) and SLE patients (n=160) was analyzed using a FACSCanto II flow cytometer. The Alexa Fluor 488 fluorescence intensity resulting from Igs existence ( and chain of Ig) within the CD14+ monocyte population was then quantified as the mean fluorescence intensity (MFI). The presence of cytosolic IgG was determined by the ratio of permeabilization (P) to non-permeabilization (NP). [formula: Ratio of P:NP = (P – Control P)/(NP – Control NP)]
We show a statistically significant association between cytosolic localization of antibodies (ratio of P:NP) and disease activity in the patients with SLE. Compared with healthy controls (MFI=1.082), SLE patients had higher levels in active (MFI=1.245) and inactive (MFI=1.328) disease.
Antibodies in the patients with SLE highly localize to the cytosol of monocytes, depending on the disease activity defined by SLE disease activity index (SLEDAI).
Myocarditis is a rare presentation of systemic lupus erythematosus (SLE) and its diagnosis can be challenging as its non-specific clinical presentation varies greatly from being asymptomatic to life-threatening. Nonetheless, prompt and early identification of lupus myocarditis can reduce morbidity and mortality. Timely administration of high dose corticosteroids may pose favorable outcome for the patient. This paper aims to present a case of 43-year-old female who presented with polyarthritis, shortness of breath, intermittent fever and orthopnea. Diagnostics revealed pancytopenia, positive direct Coombs test, elevated LDH, proteinuria and hematuria. Chest radiographs and computed tomography showed alveolar edema. The initial 2D echocardiography showed low ejection fraction (EF) of 35% by Simpson with depressed systolic function, global hypokinesia with normal left ventricular dimensions, left atrial size, and volume index. Her ANA is positive with homogenous pattern hence was diagnosed with acute lupus myocarditis. She was admitted at the intensive care unit and was intubated. She received methylprednisolone pulse therapy with guidelines directed medical therapy for heart failure. Repeat 2D echocardiography a day after pulse therapy showed marked improvement of systolic function with EF of 66% by Simpson, adequate wall motion, contractility, systolic, and diastolic function. She had full recovery and returned to her normal function after one month.
Timely diagnosis and prompt initiation of treatment for Lupus Myocarditis by giving high dose steroids together with guidelines directed medical therapy for heart failure led to favorable clinical outcomes.
To compare the prognosis of SLE patients who achieve clinically quiescent following treatment, with or without serologically active.
We categorized SLE patients from Lupus Clinic of Royal Thai Army (LUCRA) cohort based on disease activity status (DAS): serologically active clinically quiescent (SACQ), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) without serological domain = 0, positivity of anti-dsDNA or low complement; serologically and clinically quiescent (SQCQ) patients, SLEDAI-2K = 0. Prednisolone ≤ 5 mg/day, immunosuppressive drugs and antimalarials were allowed. Those who were not in any remission definitions were defined as non-remission status. Outcomes included flare (any new clinical feature of the SLEDAI-2K) and increase in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) overtime. Regression analysis models were constructed to identify predictors of the outcomes.
A total of 197 patients with SLE were evaluated between March 2017 and November 2022. Sixty-eight SACQ patients, 57 SQCQ patients, and 72 non-remission patients were identified. The mean ± SD of follow up was 4.79 ± 0.63 years. The percentage of flares over 3 years after achieving SACQ status was 50% versus 26.3% in SQCQ (p = 0.007), and over 5 years was 57.4% versus 35.1%, respectively (p = 0.013). However, the changes in SDI over 5 years were similar between SACQ, SQCQ, and non-remission patients (22.9%, 24.8%, and 21.5%, respectively), p= 0.87. In addition, multivariable analysis revealed that SACQ status was not independent risk factor for increasing flare event compared with SQCQ group when adjusting for confounding factors (HR 1.65; 95% CI:0.94–2.89; p=0.083).
To attain serologically remission in patients with clinically quiescent SLE had similar effects on flare event and damage accrual compared to serologically active. This supports treating SLE with a treat-to-target strategy for achieving clinical remission, irrespectively of serological activity.
Monitoring disease activity of patients with systemic lupus erythematosus (SLE) is essential in treatment decision-making, but is challenging due to the scarcity of sensitive biomarkers. The aim of this study was to investigate new biomarkers to monitor disease activity in SLE.
The study included 34 SLE patients attending Hokkaido University Hospital from 2020 to 2021 and 15 healthy controls (HC). Clinical and laboratory data, including SLE Disease Activity Index (SLEDAI), were recorded. Serum samples were collected and inflammation-associated proteins were measured by Olink Explore 384 Inflammation panel using proximity extension assay technology. Peripheral blood mononuclear cells were also isolated and the proportion of peripheral immune cell types was evaluated by flow cytometry. The correlation between protein expression, SLEDAI, and the proportion of the immune cells were analyzed.
Of 34 patients, 31 were females, median age 40 years old and median SLEDAI 6.0. In serum samples, 368 inflammation-associated proteins were detected. Eighty-two proteins showed significant differences between SLE patients and HC, including 14 positive (r>0.4) and 4 negative (r<-0.4) correlations with SLEDAI. Cytoskeleton-associated protein 4 (CKAP4) exhibited the highest positive correlation with SLEDAI (r=0.54) and we focused on this protein. CKAP4 induces NF-B pathway through transduction of Dickkopf-1 signal. Serum CKAP4 levels were higher even in SLE patients with low disease activity (SLEDAI≤4) than in HC (p<0.01). Moreover, in SLE patients, serum CKAP4 levels correlated with the population of Tph17 (r=0.68), Tfh17 (r=0.59), activated CD4 (r=0.68) and activated CD8 (r=0.51) T cells, which were increased in SLE patients compared with HC. Cytokine analysis showed correlations between serum levels of CKAP4 and those of TNFα (r=0.81), IL-6 (r=0.77) and IFN (r=0.67).
Serum CKAP4 levels were upregulated in SLE and positively correlated with SLEDAI. Serum CKAP4 could be a potential novel biomarker in SLE.
Digital ulcers and gangrene are common cutaneous manifestations of connective tissue diseases. They are frequently seen in systemic sclerosis, but are relatively rare in systemic lupus erythematosus (SLE). There are only 0.2% SLE patients who initially present as digital gangrene.
We report a case of a 35-year-old woman presented with pain and necrosis of finger tips. She has been diagnosed with SLE for 2 years and was taking immunosuppressant regularly but quit the medication 6 month prior to admission and experience recurring Raynaud phenomenon. There is no history of infections, drug addiction, trauma, diabetes, miscarriage, or vascular disease. A diagnosis of SLE with digital gangrene has been established based on clinical appearance (
We reported a case of A 35-year-old woman with a rare peripheral gangrene in Systematic Lupus Erythematosus. The patient shown clinical improvement after using corticosteroid, methotrexate, and sildenafil.
Peripheral gangrene on both hands of a 35-years-old female with systemic lupus erythematosus
Nowadays, clinicians have realized that a great portion of lupus patients had suffered from psychiatric symptoms. Regardless of attribution, neuropsychiatric symptoms are reported to reduce quality of life and increase organ damage. The prevalence of NPSLE was 18,8 – 21,7 per 100.000 SLE patients, and psychosis is one of the rarest manifestations where the prevalence is only 2 – 11%.
We report a case of a 19 year old female with psychosis symptoms in the form of visual and auditory hallucinations since 2 months ago, history of seizure and complaint of fever which she has experienced since the last 2 months. On physical examination found febris, pale conjunctiva, malar rash, hair loss, mouth ulcers, and arthritis. Based on laboratorium examination, there was anemia, lymphopenia, increased CRP, and positive immunoserological results (RNP/Sm, SS-A native, Ro-52 recombinant, dsDNA, and nucleosome), and decreased C3 C4 complement. Urinalysis examination showed proteinuria and haematuria. Also on chest examination found cardiomegaly and bilateral pleural effusion. For Brain MSCT found normal, so after being identified according to the SLICC criteria, multiple target organs were found, the diagnosis leading to systemic lupus erythematosus with neuropsychiatric manifestations (NPSLE). During treatment the patient experienced maximal improvement after being given combination therapy with high-dose corticosteroid therapy, immunosuppressants, and antidepressants as adjuvant therapy.
Case report of a 19-year-old woman with a history of psychosis and history of seizure as first manifestations of NPSLE. Based on anamnesis, physical examination, and supporting examinations, she was diagnosed with SLE with clinical manifestations of neuropsychiatry, improved with combination of high doses of corticosteroids, immunosuppressants and antidepressants as an adjuvant therapy. There is no difference in the standard therapy for NPSLE, each patient is treated based on the symptoms and manifestations they experience, the same as the management of SLE in general.
Discoid Lupus Erythematosus (DLE) was the most common Cutaneous lupus erythematosus (CLE) subtype diagnosed. Cutaneous manifestation occur in Systemic Lupus Erytematosus (SLE) patients. The incidence of CLE was 4,3/100.000. We reported a 33-year-old woman admitted to the hospital with injuries to her face, head, hands and feet since 6 months ago starting with black spots on her legs, redness on both cheeks accompanied by sores in her mouth, then getting worse in the last 1 month. The patient has a history of SLE since 6 months ago. On physical examination of the facial region showed erythematous macules, hyperpigmentation, multiple well-defined plaques with fine scales. Plaque erythema (butterfly rash). Crust in the right supraorbital region. The extensor anterbracium region shows discoid lesions, hyperpigmented plaques with crusts. Pedis and plantar pedis appear vascultilis. Laboratory finding showed RNP/Sm +++. Sm ++. RIB +++. Anti dsDNA < 10, C3 complement 107,8, and C4 complement 16,1. The patient treated with steroid, methotrexate, folic acid, calcium hydrogen phosphate, and cholecalciferol, and showed clinical improvement in 4 months.
We report a case of 33-year-old woman with Progressive Discoid Lupus Related Severe Vasculitis as a rare case report and improved after treated with corticosteroid and methotrexate.
To study the condition of patients, the assessment of disease activity and cumulative damage to internal organs, the degree of their influence on the prognosis of the course of patients with SLE in the Kazakh population.
The study included 30 women with systemic lupus erythematosus. The average age of the studied patients was 36.33±7.928. The average duration of the disease varied from 1.5 to 8 years, and averaged 5 years.
We used Spearman’s correlation coefficient. The Spearman correlation coefficient equal to 0 indicated the absence of a connection between the signs, up to <0.5 – a weak connection, from 0.5 to <0.7 – a medium one, and from 0.7 to 1.0 – a strong connection
According to the SELENA-SLEDAI, low activity was detected in 3 (10%) patients, moderate and high in 15 (50%) and 12 (40%). Signs of arthritis were observed in 14 (46.7%) patients, myositis in 17 (56.7%), skin rashes in 15 (50%), mucosal ulcers in 10 (33.3%) and alopecia in 9 (30% ) patients.
By SLICC/ACR, there were low damage in 2 (6.7%), medium in 18 (60%), high in 9 (30%) patients. The average score for the SELENA-SLEDAI was 10 points (from 2 to 19 points), for the SLICC/ACR-3.6 points (from 0 to 9 points). Among the most frequent injuries were changes in the organs of vision and cognitive impairment, noted in 11 (36.7%), peripheral neuropathy in 9 (30.0%) patients.
A strong correlation was found between SELENA-SLEDAI and SLICC/ACR (r=0.701, p<0.0001). A moderate correlation between the duration of SLE disease and SELENA-SLEDAI (r=0.619, p<0.0001) and SLICC/ACR (r=0.592, p=0.001).m
Conclusions revealed the relationship between the activity of SLE and the degree of damage to internal organs. It depend on the duration of SLE disease. SELENA-SLEDAI and SLICC/ACR reliably reflect indicators of cumulative disease activity.
Tjalma Syndrome (Pseudo-Pseudo Meigs Syndrome) is a rare clinical condition that can occur in patients with systemic lupus erythematosus (SLE). This syndrome is characterized by massive ascites, pleural effusions and increased CA-125 levels without related to benign or malignant tumors. Tjalma Syndrome is a rare condition reported in the literature and currently there are only 14 reports of this condition.
A 31-year-old woman had a major complaint of massive ascites for 3 months. She had fatigue, hair loss, joints pain, shortness of breath and lower legs edema. Her laboratory revealed positive ANA 1: 10.000, speckled patterns, lymphopenia, proteinuria with urine protein creatinine ratio of 1.773 mg/gr, and she fulfilled the SLE classification criteria based on ACR/EULAR 2019 with mucocutaneous, musculoskeletal, renal involvement and serositis. Analysis of the ascites fluid and pleural effusion showed the exudate and negative results for tuberculosis nor malignant cells. Her CA-125 was markly increased, with no benign or malignant tumors found on either imaging or anatomic pathology examination. Based on these findings, the patient was diagnosed as SLE and Tjalma Syndrome. She was given methylprednisolone pulse dose 500 mg for 3 consecutive days, followed by oral methylprednisolone 0.8 mg/kg daily, mycophenolic acid 720 mg twice daily, hydroxychloroquine 200 mg/d, ramipril 5 mg/d, furosemide 40 mg/d, calcium carbonate 500 mg twice/d and therapeutic ascites punctuation. Patient was discharge in better condition.
Tjalma Syndrome is a rare clinical condition, but can be revealed as main presentation of SLE. This case report shows that Tjalma Syndrome could be one of the differential diagnosis of patients with ascites, pleural effusions, and increased CA-125 levels in SLE patients. Possible malignancy should be ruled out, and Tjalma syndrome should be considered so that the patient with this condition can get the proper management and avoid unnecessary surgical examination.
Immune thrombocytopenia (ITP) is a common hematologic manifestation in systemic lupus erythematosus (SLE). Thrombocytopenia can persist for more than one year, which is defined as chronic thrombocytopenia. This study aimed to identify the clinical characteristics and risk factors for the chronic thrombocytopenia in SLE-ITP.
We retrospectively reviewed patients who were diagnosed with SLE-ITP at a tertiary hospital between January 2000 and December 2021. The clinical and laboratory characteristics were analyzed according to the progression of chronic thrombocytopenia. Factors associated with chronic thrombocytopenia were evaluated by logistic regression analysis.
Of 121 SLE patients with ITP, 29 (24.0%) patients progressed to chronic thrombocytopenia lasting more than 1 year. The mean initial platelet count was lower in patients with chronic thrombocytopenia than those without (29.7 vs. 49.3 x 109/L, P < 0.001). Multivariable analysis showed that body mass index (BMI) (adjusted odds ratio [aOR] = 1.194, 95% confidence interval [CI] = 1.014–1.406), severe thrombocytopenia (< 20 x109/L) (aOR = 3.974, 95% CI = 1.290–12.240), and recurrence of thrombocytopenia within 1 year (aOR=10.052, 95% CI=3.177–31.803) were significantly associated with the risk of chronic thrombocytopenia.
Approximately one-quarter of the patients progressed to chronic thrombocytopenia in SLE. High BMI, severe thrombocytopenia, and recurrence of thrombocytopenia within 1 year were risk factors for the development of chronic thrombocytopenia in patients with SLE-ITP.
A 29 year old patient presented with progressive dyspnea (mMRC grade 3) over 4 months. Her 2D Echocardiogram revealed moderate pulmonary hypertension with right ventricular dilatation. She had a history of inflammatory polyarthritis and constitutional symptoms. Her ANA was 1: 80 (Homogenous pattern). HRCT-Chest, CTPA, bubble contrast study and serology tests including APLS screening were all negative. A diagnosis of pulmonary arterial hypertension (PAH) was made. She also had an incidental detection of diffuse splenic calcification which is a rare association of SLE. She was treated with immunosuppressants and vasodilators for which she had a symptomatic improvement.
A 31 year old patient presented with progressive abdominal pain, distention and diarrhea for 2 weeks duration. She underwent an exploratory laparotomy which revealed gross ascites and dilated small intestinal loops. Subsequent Abdominal CT showed small intestinal wall ischemia involving multiple arterial territories. She also reported on alopecia and gave a history of ITP during her pregnancy in 2016. With positive ANA (1:1280 titer), low complement levels, negative APLS screening and exclusion of other causes, SLE with mesenteric vasculitis was confirmed.
A 40 year old patient presented with a 2 week history of fever, nonproductive cough, inflammatory type polyarthritis and bilateral axillary lymphadenopathy. She later developed a pancytopenia and alopecia. Her ANA was 1:10000; Diagnosis of SLE was made. Axillary lymph node biopsy showed necrotizing lymphadenopathy and immunohistochemistry was strongly positive for CD68 favoring Kikuchi disease.
Initial clinical presentations of SLE can be highly variable; can mimic infections and malignancies and may lead to delays in diagnosis. Therefore the clinicians should be vigilant on rare presentations of SLE such as PAH, mesenteric vasculitis and necrotizing lymphadenopathy to initiate timely treatments. Timely management in mesenteric vasculitis is crucial to prevent the possible catastrophic complications like necrotic bowel, perforation and sepsis.
Chronic and latent infections like tuberculosis (TB) are known triggers for developing autoimmunity. It is not known the consequences of latent TB infection (LTBI) in individuals who are genetically predisposed to develop autoimmune disease. Although several studies reported autoantibodies in first-degree relatives (FDR) of SLE, association between LTBI and these antibodies is not clear. This study focused on the prevalence of autoantibody levels in FDRs of SLE and assess any association with LTBI.
This is a single center cross sectional study. FDRs of SLE who were apparently healthy and without past h/o TB were recruited (n=167). Demography, comorbidity and various autoantibodies (antibodies to beta-2 glycoprotein, cardiolipin, thyroid peroxidase, cyclic citrullinated peptide, glutamic acid decarboxylase, antinuclear antibody) were measured. LTBI was assessed using TB-IGRA (IFN- release assay). Based on results of TB-IGRA and seropositivity to antibodies, FDR were divided into 4 groups- Autoantibody positive and negative groups with and without LTBI. Basal IFN- and mycobacterium tuberculosis antigen specific IFN- levels were assessed in the unstimulated and stimulated tubes respectively.
In FDRs, overall prevalence of LTBI 25.7% (n=43) which is lesser than prevalence in the general population (40%). Prevalence of LTBI was numerically higher among FDRs positive for any autoantibody compared to the negative group (32.6% vs 21.8%), but without statistical significance. Seropositivity of various autoantibodies was comparable between those with and without LTBI. Basal and stimulated IFN- levels was lower in IGRA and autoantibodies positive group(p=0.014) compared to IGRA positive antibody negative group.
This study showed higher prevalence of LTBI in antibody positive FDRs of SLE. Basal and stimulated IFN- levels were lower in antibody positive group, in contrast to SLE patients who have higher basal IFN-. Further longitudinal studies would be required to see the effect of these autoantibodies on LTBI and risk of progression to TB.
Belimumab has shown ability to reduce flare rates in systemic lupus erythematosus (SLE), but little is known about its potential benefits in neuropsychiatric (NP)SLE. We investigated predictors of NP flares in SLE patients under standard therapy with or without add-on belimumab.
Data from five clinical trials of belimumab in SLE (BLISS-52, BLISS-76, BLISS-NEA, BLISS-SC, EMBRACE) were utilised (N=3638). Flares were defined using the British Isles Lupus Assessment Group (BILAG) activity index. Predictors of flares were investigated throughout a 52-week follow-up using univariable and multivariable Cox regression. A subgroup analysis in patients with baseline NP BILAG E was performed to determine predictors of de novo NP flare. Organ damage was assessed using the SLICC/ACR Damage Index (SDI).
In total, 105 (2.9%) NP flares were documented. In multivariable analysis, male sex (HR: 2.37; 95% CI: 1.31–4.28; p=0.004), baseline NP BILAG B-D (HR: 5.91; 95% CI: 3.86–9.06; p<0.001), and high baseline SDI score (HR: 1.35; 95% CI: 1.21–1.50; p<0.001) were highly associated with NP flare development. Belimumab use yielded no clear protection. In a separate analysis of SDI domains, the NP domain (HR: 3.25; 95% CI: 2.72–3.88; p<0.001) was the strongest predictor of NP flare, with cognitive impairment (HR: 14.29; 95% CI: 9.22–22.14; p<0.001), transverse myelitis (HR: 21.89; 95% CI: 5.40–88.72; p<0.001), and neuropathy (HR: 8.87; 95% CI: 5.59–14.09; p<0.001) mainly driving this association. In the subgroup analysis of the NP BILAG E population, male sex was the strongest predictor of de novo NP flare (HR: 3.26; 95% CI: 1.51–7.04; p=0.003).
Current or former NPSLE activity and established organ damage in the NP domain at baseline were the strongest predictors of NP flare. Whether belimumab treatment protects against NP events remains unclear.
Little is known about depression in SLE. To evaluate the prevalence of depression and associated factors in a large, multicenter SLE cohort (RELESSER-PROS).
Prospective longitudinal study of SLE patients answering positively to the depression question of the Lupus Impact Tracker (LIT) questionary (question number 7, LITQ7 ‘I was depressed’) over 5 consecutive annual visits (V1 to V5). Self-perceived depression was answered from 0 (‘none of the time’) to 4 (‘most of time’). Covariates with potential impact in depression were considered. Friedman test and GEE models were used.
1463 patients were included. Mean age 55 years, 90% female. Mean disease duration: 14 years. Fibromyalgia was present in 5.7%. Glucocorticoids use ranged from 49.4% to 57%, depending on the visit. SLEDAI ranged from 0 to 2 and SDI from 1 to 2. Prevalence of ‘depression any time’ was 89.9% and ‘most of time’ in 34.6%. Up to 26.5% answered to LITQ7 ‘depression most of time’ in the five visits. 89.7% perceived themselves as depressed at least in 2 out of 5 visits. Only 6.9% of the patients with previous diagnosis of depression answered ‘0’ (‘none of the time’) to LITQ7. SLEDAI, SDI, Charlson and glucocorticoids use showed statistically significative changes during the follow up. Patients with ‘depression any time’ developed more damage at V5 than patients without depression (p=0.009). In the GEE binomial analysis, fibromyalgia (OR 2.79), unemployment (OR 1.95) and glucocorticoids use (OR 1.88) were significantly associated with ‘depression any time’. The best model displayed a significant association with fibromyalgia (OR 2.90) and glucocorticoids (OR 1.85). Neither SDI nor unemployment reached significance (
The prevalence of self-perceived depression is high in SLE. Our study suggests causal relationship between glucocorticoids use, fibromyalgia and self-perceived depression.
Best multivariable GEE model
Pulmonary arterial hypertension (PAH) is a rare but severe manifestation of systemic lupus erythematosus (SLE). It is important to suspect the development of PAH in time and prescribe treatment.
The study included 6 patients with PAH associated with SLE, all 6 were women. All patients met the SLICC 2012 criteria for SLE. PAH was verified by right heart catheterization (RHC). Excluded were other forms of PH. Functional class (FC) of PAH was determined by the NYHA scale. Prior to the development of PAH, all patients (pts) were taking corticosteroids and immunosuppressants.
The mean age at diagnosis of PAH was 30,8±3,8 years. The mean duration of SLE up to PAH 9.3 years. In 5 patients, no other lesion of internal organs was detected, except for PAH, 1 patient had moderately severe glomerulonephritis. The ds-DNA antibodies were detected in 3 pts, Sm in 5, RNP-70 in 3, Ro-52 in 5, La in 2, nucleosomes in 2, ACL in 1 pts. The distance in the 6-minute walk test was 449±112 m, dyspnea on the Borg scale was 3.3±1.4. FC of PAH averaged 2.5 ± 0.5, 50% of patients each had FC I and FC II. All patients had chronic heart failure NYHA I or II. During RHC the mean PAP was 49.5±8.9 mm Hg, mean PAWP 5.5±1.2 mm Hg, PVR 9.79±2.4 units Wood. After the diagnosis of PAH, each patient was prescribed one specific drug (sildenafil, bosentan, macitentan or riociguat) with a positive result.
PAH in SLE proceeds relatively favorably. Reception of immunosuppressants and glucocorticoids does not stop the development of PAH. Timely detection of this condition and the appointment of specific therapy lead to an extension of patient survival and an improvement in the quality of life.
In recent decades, there is an advancement in systemic lupus erythematosus (SLE) therapy and survival rates, however morbidity caused by organ damage remain problematical. The aims of this study were to evaluate the irreversible damage resulting from systemic lupus erythematosus (SLE) disease activity and its treatment by using Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI) and to establish factors that influence damage in SLE.
Two hundred-eleven SLE patients were included in a retrospective cohort study. Participants were divided into 2 groups, SDI = 0 (without damage) or SDI ≥ 1 (with damage), then the two groups were compared using factors that affecting SDI. Statistical analysis was by chi2 test, Fisher’s exact test, Mann-Whitney test, and multivariable logistic regression.
There were 127 (61.2%) participants who had damage index ≥ 1. Most of the participants had renal damage (29.38%), followed by neuropsychiatric damage (14.69%) and ocular damage (14.22%). Factors that significantly associated with damage were relapse rate ≥ 1 (p<0.001), hypertension (p=0.007), exposure to cyclophosphamide (p<0.001), mycophenolic acid (p=0.016), high serum creatinine (p=0.003) and positive protein urine (p<0.005). By using multivariable logistic regression, we found that, relapse rate ≥ 1 (p=0.008, OR 2.414 (1.255–4.642)), High serum creatinine (p=0.034, OR 9.573 (1.192–76.852)) and exposure to cyclophosphamide (p=0.017, OR 2.926 (1.213–7.057)) were significantly associated with damage.
Damage in SLE is significantly associated with relapse rate and high serum creatinine suggesting that controlling disease activity to prevent relapse and comorbidity is very important to prevent further damage. This study also reveals that cyclophosphamide administration was associated with increased risk of damage, probably related to the more active organ involvement (renal and cerebral) who received cyclophosphamide.
Neuropsychiatric systemic lupus erythematosus (NPSLE) comprises of various neurological and psychiatric conditions in patients with SLE. The frequencies, clinical manifestations and prognosis may vary significantly among different disease entities.
Clinical records of 431 Chinese SLE patients were reviewed. Manifestations of NPSLE were defined based on the 1999 American College of Rheumatology (ACR) nomenclature.1 ‘Common’ neuropsychiatric events (anxiety, headache, mild depression, mild cognitive dysfunction, and polyneuropathy without electrophysiological confirmation) described by the Ainiala’s criteria were excluded.2 Other neuropsychiatric evens in the absence of alternative contributing factors were attributed to SLE. The frequencies of different NPSLE manifestations were reported. Clinical features of patients with central nervous system (CNS) diseases and peripheral nervous system (PNS) diseases were described and compared.
Among 431 Chinese SLE patients, 396 (91.9%) were female and the median age of SLE onset was 26 (IQR 15) years. NPSLE occurred in 88 (20.4%) patients, including 77 and 11 patients with CNS and PNS diseases, respectively. The most frequent manifestations were mood disorder (26/431; 6.0%), seizure disorder (15/431; 3.5%), acute confusion (11/431; 2.6%), mononeuritis (7/431; 1.6%), and myelopathy (6/431; 1.4%). The median time from SLE diagnosis to onset of NPSLE was 6 (IQR 16) years and 10 (IQR 7.5) years for CNS and PNS diseases, respectively. Compared to CNS diseases, patients with PNS diseases had older age at SLE diagnosis (PNS 39 years vs CNS 25 years, p=0.04) and older age at NPSLE onset (PNS 47 years vs CNS 34 years, p=0.02). The 10-year survival rates were 96.1% and 100% for CNS and PNS diseases, respectively.
PNS diseases are important manifestations in patients with long-standing SLE, especially in patients with older age at SLE diagnosis. The outcome is favorable compared with patients with CNS diseases. Prospective studies are needed to confirm these findings.
The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42(4):599–608. Ainiala H, Hietaharju A, Loukkola J, Peltola J, Korpela M, Metsanoja R, Auvinen A, Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation. Arthritis Rheum 2001;45(5):419–23.
Patients with systemic lupus erythematosus (SLE) should be more proactive with the administration of the COVID-19 vaccine, as their systemic conditions are prone to developing severe outcomes. However, there are concerns that immunosuppressive agents used in SLE patients could reduce the immune response. Previous data demonstrates that total B-cell depletion impairs the humoral response in patients treated with Rituximab, but there is very limited information about Belimumab. Thus, we aimed to assess the immunogenicity and safety of COVID-19 vaccine in SLE patients treated with Belimumab.
Patients with SLE receiving B-cell targeted therapy with Belimumab were recruited from December 14, 2021, to June 17, 2022. We reviewed the patients’ immunization history and measured the antibody titers of patients who had completed their third dose of COVID-19 vaccine. SARS-CoV-2 antibody titers were determined through semiquantitative anti-SARS-CoV-2 S enzyme immunoassay.
A total of 21 patients with SLE receiving Belimumab treatment were surveyed, out of which 10 patients had completed 3 doses of COVID-19 vaccinations. The mean duration between the last (3rd) vaccination date and the date of sample acquisition was 22.5 weeks, and there was no patient with side effects other than mild myalgia. The antibody titers were positive in all 10 patients, with 8 patients showing high antibody titers of 250 U/mL or more. The other 2 patients measured relatively low antibody titers of 117 U/mL and 112 U/mL, with a treatment history with Rituximab within one year and current treatment with hydroxychloroquine, respectively.
Our findings suggest that Belimumab does not compromise the antibody production from the vaccination. SLE patients with Belimumab need not be reluctant to get COVID-19 vaccines in regard to humoral response impairment.
To compare disease manifestations and outcomes of juvenile-onset SLE (jSLE) and adult-onset SLE (aSLE) patients using a nested case control study of patients in a Singapore cohort.
A prospective cohort of SLE patients was established at Tan Tock Seng Hospital from 1st January 2002 to 31st December 2017. Sociodemographic, clinical, laboratory and treatment data were collected according to a standardised protocol. jSLE patients (≤18 years old) were selected from this cohort and matched for gender and disease duration in a 1:1 ratio with aSLE patients. Data from the enrolment visit (V0) and last visit (VL) were analysed in this study.
There were 148 jSLE patients with sufficient information for analysis who were matched with 148 aSLE patients. Fever and lymphadenopathy (p<0.001) and hypocomplementemia (p=0.002 at V0) were significantly more common in jSLE, while cardiovascular manifestations were significantly more common in aSLE patients (p=0.008 at VL). Disease activity measured by the SLE Disease Activity Index (SLEDAI) was higher in the jSLE group at V0 (median SLEDAI 4 vs 2, p=0.05) and at VL (median SLEDAI 2.5 vs 0, p=0.007). A significantly higher proportion of jSLE patients received immunosuppressants (intravenous cyclophosphamide, mycophenolate mofetil, azathioprine and ciclosporin) (p=0.003 at V0, p<0.001 at VL) and intravenous methylprednisolone (p<0.001 at V0 and VL) compared to aSLE patients.
A higher proportion of jSLE patients have fever, lymphadenopathy, hypocomplementemia; more active disease requiring greater use of immunosuppressants compared to aSLE patients. Early diagnosis and treatment of jSLE may prevent development of major organ involvement, in particular renal and neuropsychiatric disease.
We report a case of a 26 year old female, Gravida 2 Para 1 (G2P1) 30 weeks age of gestation (AOG), with shortness of breath and chest discomfort. History revealed 4 years prior, patient has been experiencing chronic urticaria in the face, abdomen and extremities aggravated by sunlight. Upon consult, she was given Prednisone 20mg twice daily and Chlorphenamine 4mg daily but was lost to follow up. Four years later, she was hospitalized due to joint pains, butterfly rashes and shortness of breath. Using the SLICC criteria (cutaneous, serositis, synovitis, FANA), patient was managed as SLE. Antiphospolipid and cardiolipin panels were negative. She was started on Hydroxychloroquine 200mg twice daily, Prednisone 20mg daily and Mycophenolate 1gram daily. However, discontinued her medications upon pregnancy. Few months later, she was readmitted for chest discomfort, shortness of breath and uterine contractions. She has red raised patched rashes on extremities, periorbital edema, saddle nose, and cauliflower ears. Hence, Relapsing Polychondritis on top of SLE, G2P1 30 weeks AOG on preterm labor was entertained. 2D echocardiogram revealed normal left ventricular size with normal systolic/diastolic function, ejection fraction of 64%, dilated left atrium with trivial pericardial effusion o 0.5cm. She was started on Dexamethasone 6mg every 12 hours for 4 doses, Nifedipine 10mg thrice daily, Hydroxycholoroquine 200mg daily, Enoxaparin 40mg every 12 hours and Colchine 0.5mg daily. Symptoms improved and preterm labor was controlled. She was discharged with the following medications: Hydroxychloroquine 200mg daily, Prednisone 20mg daily, Azathrioprine 50mg daily, and Aspirin 80mgdaily. After a few weeks, she successfully delivered a live term baby boy with no complications.
Systemic Lupus Erythematosus with Relapsing Polychondritis overlap during pregnancy carry a high maternal and fetal risk. Thus, a multidisciplinary approach with close medical, obstetric, and neonatal monitoring is necessary to optimize both maternal and fetal outcome.
Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, approved in multiple countries for the treatment of adults with plaque psoriasis.¹ ² Deucravacitinib demonstrated efficacy across the primary endpoint and all key secondary endpoints in a phase 2 trial in patients with systemic lupus erythematosus (SLE).3 Here, we describe 2 phase 3 trials currently underway to assess the efficacy and safety of deucravacitinib in patients with active SLE. These phase 3 trials have been designed to replicate the successful elements of the phase 2 trial, including its glucocorticoid-tapering strategy and rigorous management structure.3
In these phase 3, randomized, double-blind, placebo-controlled, global trials (POETYK SLE-1 [NCT05617677], POETYK SLE-2 [NCT05620407]), adults (aged 18–75) with active SLE on background standard-of-care treatment will be randomized (1:1) to placebo or deucravacitinib for 52 weeks of double-blind treatment (
Planned randomization in each trial includes 490 patients (245 per treatment group) in 27 countries across North and South America, Europe, and Asia-Pacific.
The phase 3 POETYK SLE trials will further evaluate the efficacy and safety of deucravacitinib, an oral, selective, TYK2 inhibitor, in patients with active SLE.
POETYK SLE-1 and POETYK SLE-2 Trial Design
Primary and Secondary Endpoints Assessed at Week 52
Armstrong A, et al. J Am Acad Dermatol 2022;S0190-9622(22)02256-3. Strober B, et al. J Am Acad Dermatol 2022;S0190-9622(22)02643-3. Morand E, et al. Arthritis Rheumatol 2022;Nov 11 (Epub ahead of print). doi: 10.1002/art.42391.
Litifilimab is a humanized IgG1 monoclonal antibody targeting BDCA2, a receptor predominantly expressed on plasmacytoid dendritic cells (pDCs). In Part A of the Phase 2 LILAC study (NCT02847598), administration of litifilimab at a dose of 450 mg was superior to placebo in reducing the total active joint count at Week 24 and resulted in a greater frequency of SLE Responder Index 4 (SRI-4) responses versus placebo.¹ Two multicenter, Phase 3, randomized, double-blind, placebo-controlled studies (TOPAZ-1, NCT04895241; TOPAZ-2, NCT04961567), described here, are ongoing to further evaluate litifilimab efficacy and safety in patients with SLE.
Eligible participants are randomly assigned to receive either subcutaneous litifilimab (at a high or low dose) or placebo at Weeks 0 and 2, then Q4W until Week 48 (
Both studies are currently recruiting, aiming to enroll 540 participants each; estimated primary completion dates are April 2025 (TOPAZ-1) and June 2025 (TOPAZ-2).
Data from the TOPAZ studies will help characterize the efficacy and safety of litifilimab in SLE, a disease in need of greater treatment options.
TOPAZ-1 and TOPAZ-2 study design
Furie RA, et al. N Engl J Med 2022;387:894–904
Current mainstay treatment of cutaneous lupus erythematosus (CLE) include topical corticosteroids, sun protection, and systemic treatment. Various non-medical alternative/adjunctive treatment have been reported such as cryotherapy, and laser therapy. Several studies have shown the efficacy of pulsed dye laser (PDL) for discoid lupus erythematosus (DLE). Additionally, there was a case report showing the efficacy of fractional photothermolysis for reminiscent scar of DLE.
This was a retrospective study which included 20 CLE patients who visited the Department of Dermatology at Hanyang University Seoul Hospital in Korea between November 2016 and December 2022. Patient medical datas and clinical photographs were reviewed.
Of the 20 CLE patients, 15 (75%) underwent PDL, 7 (35%) underwent fractional laser, 9 (45%) underwent long-pulse neodymium-doped yttrium aluminium garnet (Nd:YAG), 4 (20%) underwent 532-nm Nd: YAG, and 2 (10%) were treated with intense pulsed light (IPL). The majority of patients had been taking hydroxychloroquine for several years. After a mean number of 2.4 sessions of PDL, patients showed improvement of telangiectasias and erythema, and there was mild improvement of atrophic and pigmented lesions. After a mean number of 3.1 sessions of fractional laser, there was improvement of scarring lesions of DLE. All treatments were well tolerated, and all patients did not show any worsening of disease. Also, none of our patients experienced any long-lasting side effects, such as photosensitivity, disease reactivation, or pigmentary defects.
In general, laser treatments are still regarded as harmful in patients with underlying immunologic deficiency or autoimmune connective tissue disorder, since wound healing in these patients may be impaired. None of our patients, however, showed any worsening of skin lesion or side effects. It seems reasonable and safe to use laser treatments as an adjunctive treatment for cosmetic purpose to patients who achieve stable disease activity.
Belimumab, a human IgG1 monoclonal antibody, inhibits the binding of soluble B lymphocyte stimulator to B cells. It is approved for renal and non-renal SLE and as an add-on therapy. Belimumab was only made available in Singapore in Jan 2022, and we hope that it will be a potential disease-modifying and disease-remitting lupus biologic therapy.
We reviewed and analysed our initial experience with belimumab therapy in 6 SLE patients as an add-on and/or sequential therapy after rituximab since the start of Jan 2022 till Jan 2023
All 6 patients were female, age range 21–64 years old, with 3 Chinese, 1 Malay, and 2 Cambodian. Disease duration ranged from few months to 4 years. 2 had renal
Involvement, and one patient has SLE/APS.
Concomitant medications includes prednisolone(6 patients). tacrolimus( 4 patients), mycophenolate ( 2 patients), baricitinib ( 4 patients), hydroxychloroquine ( 4 patients). 3 patients had sequential rituximab -belimumab therapy.
IV belimumab infusion was very well tolerated without any adverse events
Number of infusions completed ranged from 2–11( average 7).
Disease stability, reduction of steroid doses and severity of flares were observed in this small case series of patients.
Belimumab is a useful disease-modifying and disease-remitting therapy that can be added-on to the standard lupus therapy with minimal adverse effects. More patients and longer follow-up period will be needed to gain a wider clinical patient experience.
JA Singh, et al. Belimumab for systemic lupus erythematosus. Cochrane Database Syst Rev 2021 Feb 25;2(2):CD010668 Urowitz, et al. Impact of Belimumab on Organ Damage in Systemic Lupus Erythematosus. Arthritis Care Res (Hoboken) 2022 Nov;74(11):1822–1828 M Shipa, et al. Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus : A Randomized Controlled Trial. Ann Intern Med 2021 Dec;174(12):1647–1657
Serologically active clinically quiescent (SACQ) is a clinical state of systemic lupus erythematosus (SLE) characterized by high levels of serologic markers without clinical activity. The outcome and treatment strategy after SACQ achievement remains unclear. After achieving the treatment goal, maintaining low-dose glucocorticoids has always been both a blessing and a curse.1 2 In this multi-center prospective study, we aimed to identify the risk of flares, organ damage accumulation, and the glucocorticoids discontinuation feasibility of SLE patients who achieved the clinical state as SACQ.
This study was conducted based on data from the Chinese SLE treatment and research (CSTAR) registry. Demographic characteristics, autoantibody profiles, clinical manifestations, organ damage, and treatment profile were collected at recruitment and during follow-up. SACQ was defined as persistent serologic activity (positive anti-dsDNA antibody, and/or hypocomplementemia), and without clinical activity. Serologically quiescent clinically quiescent (SQCQ) was defined as a persistent serologic and clinical quiescent stage. Organ damage is principally assessed using the SLICC damage index (SDI).
Of 4107 SLE patients, 1889 reached the clinical quiescent stage (990 achieved SACQ, and 899 achieved SQCQ). Among SACQ patients, 364 (36.7%) underwent flares, 163(16.5%) showed organ damage, 47 (4.7%) developed renal damage, and 21 (2.1%) died during a mean follow-up of 7.30 years. Compared with SQCQ, SACQ patients were at a higher risk of flares (HR=1.47, 95% CI 1.25–1.73, p<0.001) and renal damage accumulation (HR=2.02, 95% CI 1.23–3.33, p=0.004). Furthermore, 224 (22.6%) SACQ patients withdraw glucocorticoids and 125 (55.8%) of them did not flare. Glucocorticoids discontinuation was a favorable factor of survival (HR=0.22, 85% CI, 0.05–0.96, P=0.044). As shown in the figure, withdrawing glucocorticoids can reduce organ damage (p=0.0075), especially renal damage accumulation (p=0.045), even experience flares after discontinuation.
Glucocorticoids withdrawal under tight survallance could be considered after achieving the clinical state as SACQ to prevent the accrual of renal damage.
Apostolopoulos D, et al. The Lancet Rheumatology 2020;2(1):e24-e30. Mathian A, et al. Ann Rheum Dis 2020;79(3):339–46.
Belimumab is the only biologic agent approved for systemic lupus erythematosus (SLE). In cornerstone clinical trials, belimumab demonstrated SRI-4 response in patients with moderate disease activity, and real-world studies showed consistent findings.1–3 However, most previous studies have been conducted in patients with use of steroids, with mean prednisolone-equivalent dose of approximately 10 mg/day (1¬3). Therefore, the effect of belimumab has been focused on the steroid sparing. Here, we aimed to identify the effect of belimumab in SLE patients treated with minimal or no steroid with mild-to-moderate activity.
We retrospectively reviewed the electronic medical records of patients (age ≥ 18 years) who first received belimumab from May 2021 to June 2022 and maintained use at least 6 months. We only included patients who received prednisolone-equivalent ≤5mg or without steroid (for more than 1 year). The primary endpoint was SRI-4 response at 6 months, and secondary endpoint was improvement in serology at 6 months. Analysis Of Variance (ANOVA) with Bonferroni’s post hoc analysis were performed to compare the continuous variables.
In total, 31 patients were included, with 12 minimal steroid users and 19 non-steroid users. The mean age was 39.2 (±11.4) years, and 90.3% were female. Baseline SELENA-SLEDAI was 6.0 (4.0¬9.0). The primary endpoint was seen in 32.3% (10/31). Anemia (p=0.025), C4 level (p<0.001), and SELENA-SLEDAI (p=0.016) showed significant improvement over time during treatment. Univariable analysis showed baseline SELENA-SLEDAI and arthritis were significantly associated with SRI-4 response at 6 months, and SELENA-SLEDAI only remained significant in multivariable logistic regression analysis.
In our cohort study, belimumab was shown to be effective in improving SELENA-SLEDAI, anemia and low C4 in patients who did not use or did use minimal dose of steroids. Therefore, the effect of belimumab can be expected even in patients not taking steroids.
Lancet 2011 Feb 26;377(9767):721–31 J Autoimmun 2018 Jan;86:1–8 Autoimmun Rev 2017 Apr;16(4):343–351.
Systemic lupus erythematosus (SLE) is an immune system disease characterized by immune system activation, which leads to exaggerated B cell and T cell responses and loss of immune tolerance against self-antigens. We presented a case of SLE presented with autoimmune hemolytic anemia occurring in a 49-year-old Chinese female patient. She was failed in the first and sceond line treatment, including methylprednisolone pulse, immunosuppressants (monotherapy or combination therapy), intravenous gammaglobulin, two courses of rituximab with each course consisting of four 200mg intravenously, and plasmapheresis. However, the patient’s condition was always clinically unstable. Surprisingly, after being treated with rituximab (500mg d 0) plus bortezomib (2.5mg d 1, 4, 8, 11), the immune status of the patient was improved gradually and all indexes returned to normal ranges. Half a year later, rituximab (100mg d 0) plus bortezomib (2.5mg d 1, 4, 8, 11) was applied. Ultimately, the patient was in remission without recurrence until now. Additionally, we summarized the available literature and explained the possible mechanism. Rituximab combined with bortezomib was more effective for depleting B cells and plasmocytes, which was accompanied by decreases in antibodies. Finally, although there were no adverse effects in this patient, we pointed out that rituximab plus bortezomib might cause infection and peripheral neuropathy. Therefore, monitoring safety is required.
Our case shows that rituximab combined with bortezomib is effective in treating SLE patients with refractory hemolytic anemia, but safety should be monitored.
Baseline profile of systemic lupus erythematosus patients on treatment with Belimumab of a Spanish multicenter cohort.
Multicenter retrospective and longitudinal cohort study. Data was collected at baseline, 6, 12 months and in the last visit available. Different periods (2010–2015/2016–2021) were compared.
324 patients (91% female) were enrolled. Mean (±SD) age at diagnosis: 31.8 years (±11.9); mean disease duration of 8.7 years (±9.07). At baseline, mean SLEDAI-2K score was 10.4 (±5.25); 152 (47.5%) patients had damage with a mean SDI score of 0.83 (±1.2). 289 patients (89.2%) had received DMARDs before BLM: cDMARDS in 282 (87%) and bDMARDs in 74 patients (22.8%); 164 (51.9%) had received more than one cDMARDs, methotrexate being the most frequently used (44.4%) and Rituximab the most frequent bDMARDs used (80%). Antimalarials were used in 83,2% and glucocorticoids (GC) in 91.2%, with a mean dose of 12.3 mg/day. 67.9% of patients were receiving more than 5 mg/day and 58.4% more than 7.5 mg/day of prednisone. BLM was used in monotherapy in 30.5% of subjects. Reasons of prescription: disease activity in 95% of patients and/or as a GC sparing agent in 59%. Only a few patients received BLM just for maintenance (4/322) or save GC (8/322). At baseline, 6 patients (1.9%) were in DORIS-21-remission and LLDAS. The main reasons of prescription for ongoing activity were arthritis (65.4%), cutaneous (40.7%) or both (81%). No differences were observed in prescription reasons between periods.
Belimumab was mainly prescribed after the use of other DMARDs and more than 50% had received at least 2 DMARDs and were receiving GC at medium doses. Most patients received BLM due to active disease and/or as GC sparing agent. Activity in articular and cutaneous domains were the main reasons of indication. No changes in prescription habits were identified.
Systemic lupus erythematosus (SLE) is a chronic, complex autoimmune disease characterized by pathogenic autoantibodies and tissue damage to multiple organ systems. Nipocalimab is a novel high affinity, fully human, aglycosylated, effectorless IgG1 monoclonal antibody that selectively blocks the neonatal Fc receptor (FcRn). Nipocalimab has demonstrated rapid and durable serum IgG and pathogenic autoantibody reductions (NCT02828046; NCT03896295). Here we describe the protocol of a Phase 2 study evaluating the efficacy and safety of nipocalimab in patients with active SLE (NCT04882878).
Phase 2, multicenter, randomized, placebo-controlled, double-blind, parallel-group study enrolling adults with active, autoantibody-positive SLE with an inadequate response to one or more standard of care treatments. The study consists of a ≤6-week screening period, a 52-week double-blind treatment period, and a 6-week follow-up period (
The primary efficacy endpoint is the percentage of participants achieving an SLE Responder Index (SRI)-4 composite response at Week 24. Secondary efficacy endpoints assessed at Week 24 include the percentage of participants achieving: ≥50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity score (CLASI), ≥50% reduction in active joints, ≥4 points improvement in SLE Disease Activity Index 2000 (SLEDAI 2K), and British Isles Lupus Assessment Group Composite Lupus Assessment response (BICLA); time to first disease flare; and reduction in corticosteroid use. Percentage of participants achieving an SRI-4 composite response at Week 52 will also be assessed. Safety endpoints include adverse events (AEs), serious AEs, AEs of special interest (severe infections, grade ≥3 hypoalbuminemia), and AEs leading to treatment discontinuation through Week 58.
This ongoing phase 2 study will evaluate the safety and efficacy of nipocalimab in adults with active SLE.
Study design
Low-dose IL-2 supplementation is a promising treatment of SLE. However, in most of current studies, lack of appropriate control groups lead to uncertainty on its efficacy. We conducted a randomized double-blinded placebo controlled trial to determine the efficacy of low-dose IL-2 on various organ involvement in SLE and the response predictors for this therapy.
SLE patients received either IL-2 (n=30) or placebo (n=30) with standard treatment for 10 weeks. The clinical responses, laboratory features and dynamics of immune cell subsets and molecular profile were determined. The association between these parameters and response to IL-2 treatment was analyzed.
The SRI-4 response rate of IL-2 group was significantly higher than that of placebo group from week 6 to week 10. The most obvious improvement on organ involvement was observed in the renal domain. Both of the complete remission tate and partial remission rate of lupus nephritis (LN) in IL-2 group were significantly higher (P<0.05). Arthritis was more improved in IL-2 group than the placebo group. Other organ involvements were all imporved in IL-2 and placebo group, without significant difference. Our further analysis showed that decreased Treg ratio in SLE patients before treatment showed good ability for predicting SRI-4 response with IL-2 treatment. Serum anti-IL-2 autoantibody was increased and associated with disease severity in SLE, but it was not induced by IL-2 treatment and did not predict the clincial response to IL-2 therapy. Our in vivo and in vitro analysis also showed that IL-2 may synergize with glucocorticoid treatment to further promote Treg survial and functions in SLE patients and accelerate the decrease of disease activity.
Low-dose IL-2 might be most efficient in treatment of lupus nephritis and synergize with conventional treatment such as glucocorticoid. Low baseline Treg ratio might be an indicator to apply this novel treatment.
Systemic Lupus Erythematosus (SLE) is an autoimmune disease caused by disturbance in immune tolerance to self-antigens, leading to multiorgan inflammation. SLE causes a high risk of tuberculosis (TB) infection in SLE. In SLE pathogenesis, T cells play a major role to amplify inflammation by secreting pro-inflammatory cytokines. Interferon- release assay (IGRA) is commonly used to diagnose latent TB infection (LTBI). Many immunosuppressive agents are potent inhibitors of T cells and may impair the interferon- response. This study was aimed to determine the effect of steroid therapy on the performance of IGRA in SLE.
This experimental study included 50 female SLE. Data such as age, disease duration, SLE disease activity index (SLEDAI), steroid therapy doses, and Body Mass Index (BMI) were obtained. Steroid therapy doses were categorized as high-dose (≥7.50 mg) and low-dose steroids (<7.50 mg). Patients were excluded if they had history of TB or current active TB. Each group underwent IGRA testing using the QuantiFERON-TB Gold Plus kit. Data analysis was performed using SPSS.
There were 50 (100%) female SLE with average age 32.64 (±8.16) years old, mean disease duration 5.78 (±3.99) years, mean SLEDAI score 2.64 (±3.19), mean steroid therapy doses 8.47 (±8.35) mg/day, and median of BMI 21.7 (16.4–36.0). In high-dose steroids group (n=20), IGRA result was 5% positive, 15% indeterminate, and 80% negative. In low-dose steroids group, 3.3% was positive and 96.7% was negative. There was no significant association between steroid therapies and IGRA results (p=0.084).
Steroid therapy causes dysregulation of immune response and has tendency to influence IGRA result in SLE. In our study steroid therapy is not associated with IGRA result. Further study to explore latent tuberculosis infection and steroid therapy in SLE is of great interest.
Often, patients present with clinical symptoms and immunologic abnormalities suggestive of systemic lupus erythematosus(SLE), while not meeting classification criteria yet. This is referred to as incomplete SLE(iSLE). Timely treatment, however, is important to limit disease progression, and prevent organ damage and mortality. The aim of the study was to evaluate the therapy administered to patients diagnosed with iSLE.
Methods iSLE(n=60) was defined by rheumatologists as clinical diagnosis, not fulfilling ACR or SLICCcriteria and had no classification or specific symptoms of other rheumatic diseases. The majority of the iSLE patients were female (97%), aged 38[26–47]years. The median age of iSLE diagnosis was 33[25–42]years, disease duration was 12[2–39]months, 12(20%)pts had a disease duration of ≥5 years. The median SLEDAI-2K was 2[1–5] score, SDI – 0[0–0] score.
A large proportion of iSLE patients (55%) were prescribed hydroxychloroquine at a dose of 200 mg/day and oral corticosteroids (42%), the maximum dose of prednisolone was 15[6–40]mg/day. Five (8%) patients with iSLE were taking immunosuppressants: sulfasalazine-2(4%), methotrexate-1(2%), azathioprine-1(2%), and cyclophosphamide -1(2%). Six (10%) iSLE patients were taking biology: rituximab -1(2%), IL-6 inhibitor – 1(2%), intravenous human immunoglobulin – 4(7%). Other medicines: NSAIDs – 28%, vitamin D – 27%, course of antibiotics – 18%, low dose aspirin – 17%, anticoagulants – 10%, antipsychotics – 5%, eltrombopag and antihistamines – 2% each of patients.
Although iSLE is sometimes considered a mild form of lupus, the clinical manifestations of iSLE can be significant. This may explain why many iSLE patients are treated with immunomodulatory medications.
Background: Psoriasis is a chronic disease of the skin that often affects joints and IL17 has a pathogenetic role. It has been reported that interleukin-17 (IL-17) and Th17 cells play important roles in the pathogenesis of SLE: amplifies the immune response by inducing the local production of chemokines and cytokines, recruiting neutrophils and monocytes, augmenting the production of autoantibodies, and aggravating the inflammation. Secukinumab is an anti-IL17 monoclonal antibody with approval for use in AS and Psoriatic arthritis. There are few reports on interleukin-17-targeted therapy in SLE. Objectives: We report a case SLE overlapped with psoriatic arthritis, successfully treated with Secukinumab.
32 y.o.man diagnosed with psoriasis on 2016, started having arthralgia on 2018 simultaneously with a new facial rash. Skin biopsy revealed lupus erythematosus tumidus. Gradually he developed fatigue, photosensitivity, low back pain and arthritis of hand, feet hip joints. Laboratory profile: ANA 1/160 homogeneous, antidsDNA neg, C3, C4 normal, lupus anticoagulant positive, all the other autoantibodies negative.
X-rays showed MCP MTP hand DIP stenosis, and sacroilitis. PASI score 3
First he was treated with Plaquenil and Medrol with improvement in lupus rash and failure both in arthritis and psoriasis. We then added methotrexate and subsequently cyclosporine but all combinations failed to control arthritis.
After one year of treatment failures we offered him a combination of Plaquenil, sc Methotrexate and Secukinumab 300 mg/4 weeks. After six months with Secukinumab treatment SLE is inactive and psoriatic arthritis has low disease activity. PASI score 1. No adverse events were observed in terms of SLE.
Although recent studies have begun to shed light on the role of IL-17 in the pathogenesis of SLE, there is no experience in real world yet. This case report adds on to our experience on results and safety of Secukinumab in Lupus.
Methylprednisolone (mPSL) pulse therapy is an essential option for patients with active systemic lupus erythematosus, but there is a risk of adverse events related to microcirculation disorders, including idiopathic osteonecrosis of the femoral head (ONFH). Recent studies have revealed that excessive neutrophil extracellular traps (NETs) are involved in microcirculation disorders. This study aimed to demonstrate that mPSL pulse could induce NETs in lupus mice and identify the factors contributing to this induction.
Six mice with imiquimod (IMQ)-induced lupus-like disease and six normal mice were intraperitoneally injected with mPSL on days 39 to 41, and five mice with IMQ-induced lupus-like disease and six normal mice were injected with phosphate-buffered saline. Pathological examinations were conducted to evaluate the ischaemic state of the femoral head and tissue infiltration of NET-forming neutrophils. Proteome analysis was performed to extract plasma proteins specifically elevated in mPSL-administered mice with IMQ-induced lupus-like disease, and their effects on NET formation were assessed in vitro.
Mice with IMQ-induced lupus-like disease that received mPSL pulse demonstrated ischaemia of the femoral head cartilage with tissue infiltration of NET-forming neutrophils. Proteome analysis suggested that prenylcysteine oxidase 1 (PCYOX1) played a role in this phenomenon. The reaction of PCYOX1-containing very low-density lipoproteins (VLDL) with its substrate farnesylcysteine (FC) induced NETs in vitro. The combined addition of IMQ and mPSL synergistically enhanced VLDL-plus-FC-induced NET formation.
PCYOX1 and related factors are worthy of attention to understand the underlying mechanisms and create novel therapeutic strategies for mPSL-mediated microcirculation disorders, including ONFH.
This study aimed to investigate the clinical significance of exostosin 1 (EXT1) in confirmed and suspected lupus membranous nephropathy (LMN).
EXT1 was detected in 67 renal tissues of M-type phospholipase A2 receptor (PLA2R)-negative and ANA-positive membranous nephropathy by immunohistochemistry, and cases were divided into confirmed LMN and suspected LMN. The clinicopathological data were compared among the above groups, as well as EXT1-positive group and EXT1-negative group.
Twenty-two cases (73.3%) of confirmed LMN and six cases (16.2%) of suspected LMN exhibited EXT1 expression on the glomerular basement membrane and/or mesangium area, showing a significant difference (p<0.001). Concurrently, lupus nephritis (LN) of pure class V demonstrated a lower frequency of EXT1 positivity compared with mixed class V LN in the confirmed LMN group (31.8% vs 68.2%, p=0.007). EXT1-positive patients in the confirmed and suspected LMN group showed significant differences in some clinicopathological data comparing with EXT1-negative patients (p<0.05). Follow-up data revealed that a greater proportion of patients in the EXT1-positive group achieved complete remission post-treatment (p<0.05). Cox regression analysis showed that EXT1 positivity was significantly correlated with complete remission across the entire study cohort (HR 5.647; 95% CI, 1.323 to 12.048; p=0.019). Kaplan-Meier analysis indicated that the EXT1-positive group had a higher rate of accumulated nephrotic remission compared with the EXT1-negative group in the whole study cohort (p=0.028).
The EXT1-positive group exhibited a higher active index and a more favourable renal outcome than the EXT1-negative group. It would be better to recognise suspected LMN with EXT1 positivity as a potential autoimmune disease and maintain close follow-up due to its similarities with confirmed LMN.
Comparison of oral corticosteroid (OCS) use in patients with SLE in a US rheumatology network pre- and post-belimumab initiation.
This retrospective cohort study (GSK Study 214140) used data from the Patient-Important Outcomes Data Repository (PIONEER)-Rheumatology database. Eligible adults with SLE initiated belimumab between 1 January 2012 and 30 June 2021, and had available data for >180 days pre- and >360 days post-belimumab initiation. The index was the date of belimumab initiation. Changes in OCS use were measured by: proportion of patients receiving OCS; mean total OCS dose/patient; mean total number of OCS days supplied/patient; mean daily OCS dose for days supplied/patient; the proportion of patients with OCS doses of ≤5 mg/day and ≤7.5 mg/day for days supplied. These changes were assessed between period (P)1 (6 months pre-index) and P2 (first 6 months post-index) and P3 (second 6 months post-index) in patients with OCS use in P1 who persisted with belimumab at each assessed period.
Overall, 608 patients received belimumab for 180 days (full analysis set (FAS)) and 492 for 360 days. Most patients were female (92.8%); 70.4% had moderate SLE. In P1, 56.3% of FAS patients and 54.5% of patients who persisted with belimumab for 360 days received OCS.
Among patients receiving OCS in P1, significantly fewer patients received OCS in P2 (78.4%) and P3 (64.9%) vs P1 (100.0%). Significant reductions from P1 were observed in P2 and P3 in the mean total OCS dose/patient, the mean OCS daily dose for days supplied and the proportions of patients with OCS dose of ≤5 mg/day and ≤7.5 mg/day, and the mean total OCS days supplied/patient in P3 only.
This analysis showed significant reductions in OCS dose and use in patients with SLE who persisted with belimumab, providing more real-world evidence for belimumab’s steroid-sparing effect.
The longitudinal Systemic Lupus Erythematosus Prospective Observational Cohort Study (SPOCS) aims to assess SLE disease course overall and according to type I interferon 4 gene signature (IFNGS). Here, we describe SPOCS patient characteristics by IFNGS and baseline disease activity.
SPOCS (NCT03189875) is an international study of patients with SLE according to Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) criteria. Enrolled patients from 135 centres in 8 countries were followed biannually for ≤3 years from June 2017 to November 2022. Baseline demographics, disease characteristics, organ system involvement/damage and flares were analysed descriptively according to SLE Disease Activity Index-2000 score (SLEDAI-2K <10/≥10) and IFNGS status (high/low).
The study population (n=823) was 93.2% female, with mean (SD) age 45.3 (13.9) years and 11.1 (9.2) years since diagnosis; 52.4% had baseline SLICC/ACR Damage Index score ≥1. Patients with SLEDAI-2K scores ≥10 (241 of 584, 41.3%) vs <10 were younger (mean 42.8 (13.7) vs 46.6 (14.2) years; nominal p=0.001), had shorter SLE duration (10.4 (8.6) vs 12.4 (9.6) years; nominal p=0.012) and more severe flares (12.9% vs 5.3%; nominal p=0.001). IFNGS-high patients (522 of 739, 70.6%) were younger than IFNGS-low patients at first SLE manifestation (30.0 (12.7) vs 36.8 (14.6) years; nominal p<0.001). Proportions of IFNGS-high patients differed according to race (nominal p<0.001), with higher proportions among Asian (83.3%) and black (86.5%) versus white patients (63.5%). Greater proportions of IFNGS-high versus IFNGS-low patients had haematological (12.6% vs 4.1%), immunological (74.4% vs 45.6%) or dermal (69.7% vs 62.2%) involvement.
We identified key characteristics of patients with high disease activity and/or elevated type I IFN signalling, populations with SLE with high unmet needs. Baseline SLEDAI-2K ≥10 was associated with shorter disease duration and more severe flares. IFNGS-high patients were younger at diagnosis and had distinct patterns of organ involvement, compared with IFNGS-low patients.
To assess the efficacy of anifrolumab, a type-1 interferon receptor subunit-1 monoclonal antibody, in treating refractory cutaneous lupus erythematosus (CLE) and lupus non-specific mucocutaneous manifestations in patients with systemic lupus erythematosus (SLE).
A case series comprising four SLE patients with refractory CLE received anifrolumab (300mg) as add-on therapy. Medical history, serological markers and images were collected. Cutaneous Lupus Erythematosus Disease Area and Severity Index–Activity (CLASI-A) was assessed at baseline and post-treatment visits.
Patient 1: Anifrolumab effectively treated refractory chronic cutaneous lupus erythematosus with lupus panniculitis and calcinosis cutis.
Patient 2: Anifrolumab demonstrated rapid improvement in generalised discoid lupus, achieving a substantial reduction in CLASI-A from 40 to 8.
Patient 3: Switching from belimumab to anifrolumab led to notable improvement in photosensitivity and tumid lupus.
Patient 4: Anifrolumab effectively managed refractory subacute cutaneous lupus erythematosus, resulting in remarkable cutaneous improvement and successful tapering of prednisone and mycophenolate mofetil.
Anifrolumab demonstrates efficacy in treating refractory CLE subtypes and lupus non-specific mucocutaneous manifestations in SLE patients. Further studies are needed to establish response rates, optimal dosing, and long-term outcomes.
Manifestations of SLE can be categorised as type 1 (classic signs and symptoms of SLE) or type 2 (fatigue, widespread pain and brain fog with an unclear relationship to inflammation). While measures of type 1 SLE activity exist, most current physician-reported measures do not encompass type 2 SLE manifestations. To better evaluate type 2 SLE symptoms, we developed and psychometrically evaluated a physician-reported measure of type 2 symptoms, the Type 2 Physician Global Assessment (‘Type 2 PGA’).
The Type 2 PGA was developed and evaluated by six rheumatologists practising in the same academic lupus clinic. The study began with a roundtable discussion to establish consensus guidelines for scoring the Type 2 PGA. Following the roundtable, the Type 2 PGA was psychometrically evaluated using data prospectively collected from 263 patients with SLE enrolled in the Duke Lupus Registry.
There was strong intra-rater and inter-rater reliability (intraclass correlation coefficient=0.83), indicating the Type 2 PGA scores were consistent within a rheumatologist and across rheumatologists. The Type 2 PGA was correlated with patient-reported symptoms of polysymptomatic distress (r=0.76), fatigue (r=0.68), cognitive dysfunction (r=0.63), waking unrefreshed (r=0.62) and forgetfulness (r=0.60), and weakly correlated with the Type 1 PGA and the Systemic Lupus Erythematosus Disease Activity Index.
The Type 2 PGA performed well as a physician-reported measure of type 2 SLE symptoms. The incorporation of the Type 2 PGA into a routine rheumatology visit may improve patient care by bringing the provider’s attention to certain symptoms not well represented in conventional measures of disease activity.
Lupus nephritis (LN) is one of the most severe manifestations of SLE; however, we know little about the lived experience of LN. This research investigates patient experiences and perspectives of (1) LN diagnosis; (2) living with LN; and (3) LN healthcare and treatment.
Patients aged ≥18 years with biopsy-proven pure or mixed International Society of Nephrology/Renal Pathology Society class III, IV or V LN were purposefully recruited from a Canadian lupus cohort to participate in semistructured in-depth interviews.
Thirty patients with LN completed the interviews. The mean (SD) age was 42.1 (16.4) years, and 86.7% were female. Participants described challenges seeking, receiving and adjusting to a LN diagnosis, and some reported that their diagnosis process took weeks to years. While 16 participants were provided resources by healthcare providers to help them through the process of diagnosis, the need for accessible LN-specific information at diagnosis was highlighted (n=18). Participants also described the unpredictability of living with LN, particularly related to impacts on physical and mental health, relationships, leisure activities, employment and education, and family planning. While most (n=26) participants reported a positive impression of their care, the side effects of LN medications and the need to increase patient and societal awareness/understanding of LN were highlighted in the context of healthcare and treatment.
The unpredictability of living with LN, the heavy treatment burden and a lack of patient/societal awareness substantially affect the lived experience of LN. These findings will inform the development of LN-specific patient resources to increase understanding of LN and improve well-being for patients.
To examine the efficacy and safety of telitacicept in the treatment of patients with SLE in everyday clinical practice.
Seventy-two patients with active SLE who received telitacicept for more than 24 weeks at multiple centres in China between 2019 and 2022 were retrospectively identified. Twenty-one of these patients received 52 continuous weeks of treatment with telitacicept. Treatment outcomes were analysed separately according to whether patients had renal or haematological abnormalities. Trajectory analysis was performed to identify patients with a limited response. Factors contributing to a limited response were explored by multivariable logistic regression analysis.
After treatment with telitacicept for 4, 12, 24 and 52 weeks, 22.22%, 54.17%, 72.22% and 80.95% of patients, respectively, achieved an SLE Responder Index 4; 8.33%, 26.39%, 34.72% and 47.62% achieved a Lupus Low Disease Activity State; and 0%, 4.17%, 8.33% and 23.81% achieved remission. Significant decreases in serum IgA, IgG and IgM levels were observed at 4 weeks and showed a downward trend at 12, 24 and 52 weeks. The median 24-hour urinary protein declined from 1323.5 mg to 224.0 mg in patients with lupus nephritis after treatment with telitacicept for 52 weeks. Furthermore, a large proportion of patients (10 of 13) with haematological abnormalities recovered after 52 weeks of treatment with telitacicept. No severe adverse events were reported during the observation period. Age appeared to have a negative impact on treatment efficacy.
Telitacicept demonstrated favourable efficacy and safety in patients with active SLE and improved the renal and haematological manifestations of the disease.
The study aims to investigate the impact of gene polymorphisms on blood hydroxychloroquine (HCQ) concentrations in patients with SLE and provide guidelines for individualised care.
489 Chinese patients with SLE taking HCQ for more than 3 months were collected in this study. The blood HCQ, desethylhydroxychloroquine (DHCQ) and desethylchloroquine concentrations were measured. The optimal blood concentration of HCQ was determined by receiver operating characteristic curve analysis. Single nucleotide polymorphisms of metabolic enzymes involved in HCQ metabolism were genotyped and the associations with treatment effects were investigated.
The cut-off value of HCQ was 559.67 ng/mL, with sensitivity and specificity values of 0.51 and 0.89, respectively. The TC and CC genotypes of CYP2C8 (rs7910936) were significantly related to the increase in blood HCQ concentrations, and the CYP2C8 (rs10882521) TT genotype was associated with lower blood HCQ concentrations. The DHCQ:HCQ ratio was highest in patients with the GG genotype of the CYP2D6*10 (rs1065852) polymorphism and lowest in those with the AA genotype. Patients with the CYP2C8 (rs7910936) CC genotype were more likely to achieve the optimal blood concentration (p=0.030) in HCQ 200 mg/day group and patients with the CYP2D6*10 (rs1065852) GG genotype were more likely to reach the optimal blood concentration (p=0.049) in 400 mg/day group.
Our results suggest that the optimal blood concentration of HCQ measured approximately 12–18 hours after the last dosage may be between 500 and 600 ng/mL in Chinese patients with SLE. The observed variations in HCQ concentrations between individuals can potentially be attributed to genetic polymorphisms in CYP2D6*10 (rs1065852) and CYP2C8 (rs7910936 and rs10882521). Genotypical testing of patients and regular monitoring of blood levels are recommended for optimising HCQ dosage management in Chinese patients with SLE.
ChiCTR2300070628.
In this study, we investigated the in vivo ameliorative effects of vitamin E in a hydralazine-induced lupus model, which closely resembles SLE in humans. We aim to shed light on its potential as a therapeutic agent for managing SLE.
Forty BALB/c mice were used in this study. Hydralazine hydrochloride was orally administered in a concentration of 25 mg/kg to the five mice groups once weekly for a period of 5 weeks to induce a lupus-like condition. The untreated group was the normal control group. To confirm the development of lupus, an ANA test was conducted. After the mice tested positive for ANA, drug treatments commenced. The negative control group did not receive any drug treatment. The treatments included prednisolone, methotrexate and vitamin E, all administered at a concentration of 25 mg/kg, with a higher dose of vitamin E (50 mg/kg) also administered.
Notably, on day 35, after drug treatment, we observed that mice that received vitamin E at a dosage of 50 mg/kg (3.01±0.100) had a slight decrease in lymphocyte hydrogen peroxide radicals when compared with the group receiving 25 mg/kg of vitamin E (3.30±0.100) (p<0.05). This finding suggests that the scavenging potential of vitamin E is dose dependent.
This study suggests that vitamin E supplementation, especially at a higher dose (50 mg/kg), holds promise in ameliorating lupus-like conditions. These findings warrant further exploration and may offer a potential avenue for improving the disease status of patients experiencing SLE.
Anti-dsDNA antibodies (anti-dsDNA) are a component of all classification schemes in SLE and comprise one of the domains in validated activity indices. Anti-dsDNA is frequently measured commercially by an enzyme immunoassay (EIA) or Crithidia luciliae immunofluorescence test (CLIFT). To address the clinical impact of measuring these antibodies by two different assays, this study leveraged a well-phenotyped multiethnic/racial cohort.
All patients fulfilled the classification criteria for SLE by at least one of the validated schemes: American College of Rheumatology, Systemic Lupus Erythematosus International Collaborating Clinics and/or American College of Rheumatology/European League Against Rheumatism classification criteria. Patients with one or more simultaneously paired anti-dsDNA by multiplex EIA and CLIFT were identified. Analysis of concordance or discordance, titre comparability of assays and association with hybrid SLE Disease Activity Index score, prevalence of lupus nephritis (LN), ability to predict a flare and classification criteria was performed.
207 patients were simultaneously tested by EIA and CLIFT at least once for anti-dsDNA, generating 586 paired results. 377 pairs were concordant and 209 were discordant. 41 of 207 patients always had discordant paired results and 39 patients always had results with titre discordance. In 100 patients with LN, 60 were positive by EIA and 72 by CLIFT. Sensitivities and specificities for patients with LN versus patients without LN were EIA 60% and 47%, and CLIFT 72% and 37%, respectively. 42 patients had flare assessment within 90 days of their paired result. Six of seven patients with mild flares and all four patients with severe flares had concordant positive results.
Our data demonstrate that discordance of positivity between both assays for anti-dsDNA is relatively common, occurring in a fifth of patients overall and a third of visits. EIA positivity is associated with LN less often than CLIFT positivity. With the significant discordance of results between anti-dsDNA assays, obtaining both CLIFT and EIA assays may be beneficial for classification and routine monitoring of SLE.
To explore the effects of anti-ribosomal P protein (anti-P) and anti-N-methyl-D-aspartic acid receptor subunit 2 (anti-NR2) autoantibodies on depression and cognitive dysfunction and their relationships with functional brain connectivity in SLE.
This cross-sectional study included adult patients who fulfilled the American College of Rheumatology/European Alliance of Associations for Rheumatology 2019 SLE criteria. Anti-P and anti-NR2 were quantified using ELISA. A 1-hour battery of neuropsychological testing interpreted by a neuropsychologist explored depressive symptoms (Center for Epidemiologic Studies Depression Scale, CES-D), cognitive domains and quality of life (SF-12). Resting-state functional connectivity (rs-fc) MRI analysis was performed within 1 month, and region-of-interest to region-of-interest (ROI-to-ROI) analyses with the graph theory were performed.
Thirty-three patients with SLE (9% male) were enrolled, mean age (SD) of 43.5 (14) years and median disease duration of 10.4 years (2.9–25.4). Anti-P was positive in 6 (18.2%) and anti-NR2 in 14 (42.4%) patients. Depressive symptoms were found in 14 (42.4%) patients using the CES-D (range 0–51). After correction for age, disease duration, disease activity and white matter lesion load, the CES-D score was independently associated with anti-P serum level (β=0.32; p=0.049) and prednisone daily dose (β=0.38; p=0.023). Nineteen patients (57.6%) showed at least a cognitive test alteration, but no significant association with autoantibodies was found. The rs-fc MRI analysis revealed an independent association between the anti-P serum levels and many altered brain ROI properties but no anti-NR2 and prednisone effects on the cerebral network.
Anti-P was associated with brain network perturbation, which may be responsible for depressive symptoms in patients with SLE.
No study evaluated the impact of low muscle strength and mass on the Sarcopenia-related Quality of Life (SarQoL) in women with SLE.
This cross-sectional study recruited 145 women with SLE consecutively; muscle strength was measured with a calibrated Jamar handheld dynamometer, muscle mass was measured with appendicular muscle mass index (Tanita MC-780 MAP body impedance analyser) and health-related quality of life with SarQoL Questionnaire. The cut-off points for low muscle strength, low muscle mass and sarcopenia were derived from the Asian Working Group on Sarcopenia 2019. Statistical analysis was conducted with a t-test for mean difference, and logistic regression was used to evaluate for low muscle strength contributing factors.
There was a significant difference in the mean total score of SarQoL in individuals with normal compared with low muscle strength (74.36 vs 64.85; mean difference 9.50; 95% CI 2.10 to 5.33; p<0.001). On the other hand, there was no difference in individuals with normal compared with low muscle mass (71.07 vs 70.79; mean difference 0.28; –5.18 to 5.74; p=0.91). After minimally adjusted with age, we found moderate-severe joint pain (B –9.280; p<0.001) and low muscle strength (B –6.979; p=0.001) to be independently associated with low mean SarQoL total score.
There was a lower total SarQoL score in individuals with low muscle strength but not with low muscle mass.
Antidouble-stranded DNA (dsDNA) antibodies are essential for diagnosis and follow-up of systemic lupus erythematous (SLE). To ensure the best diagnostic approach, most healthcare laboratories opt for a combination of highly sensitive methods, such as solid-phase immunoassays, and highly specific methods, such as the Crithidia luciliae indirect immunofluorescence test (CLIFT). Even so, discordant results are common, thus hindering the diagnostic process. Therefore, this study aimed to characterise a cohort of patients with discrepant results for a dsDNA fluorescence enzyme immunoassay (FEIA) and CLIFT during 2016–2018 and to follow patients up until December 2021.
We performed an observational, longitudinal and retrospective study on 417 samples from 257 patients who had been referred for suspected connective tissue diseases or followed up after diagnosis. All of them were positive for antinuclear antibodies (ANAs) using an indirect immunofluorescence assay (IFA) on Hep-2 cells, the entry criterion in our laboratory, and positive for FEIA dsDNA. Samples were then tested with CLIFT according to our routine protocol, which includes CLIFT testing after FEIA dsDNA results ≥10 UI/ml. After the assessment of data quality, the final analysis was based on 222 patients.
Eighty-three patients (37.4%) had positive results in both tests and met the diagnostic criteria for SLE. However, 139 patients (62.6%) had discrepant results (FEIA+, CLIFT–). Of these, 58 patients (41.7%) had a diagnosis of SLE, with 47 (33.8%) having been previously diagnosed and under treatment. The remaining 11 patients (7.9%) had a new diagnosis of SLE, which was made up within 4 years of the initial screening. A total of 81 of the 139 patients (57.5%) with discrepant results did not meet lupus criteria during the follow-up period.
The study showed that CLIFT could be negative in both treated and newly diagnosed SLE, thus underlining the importance of follow-up of dsDNA-positive results using solid-phase tests. Therefore, quantitative tests such as FEIA could add value to the diagnosis and management of patients with suspected SLE.
Despite treatment, one-third of patients with lupus nephritis (LN) show a decline in renal function. Prognostic markers of poor outcome as well as novel therapeutic targets are therefore highly sought. We showed that p16INK4a, a marker of cellular senescence, is observed in baseline kidney biopsies from patients with LN, and is associated with renal disease. Here, we set out to assess for whether these findings are recapitulated in the B6.NZMSle1/Sle2/Sle3 (B6.Sle1.2.3) mouse model of spontaneous lupus.
We evaluated the occurrence and time of onset of p16Ink4a staining by immunohistochemistry on kidney sections, and tested for its association with multiple renal and systemic disease parameters, fibrosis and CD8+ T cell infiltration, in two cohorts of B6.Sle1.2.3 mice.
The presence of p16Ink4a-positive cells in kidney was significantly associated with increased urine albumin/creatinine ratio, histopathological scores, CD8+ T cell infiltration and fibrosis, in both B6.Sle1.2.3 cohorts. In contrast, p16Ink4a staining was not associated with systemic disease parameters. A time course showed that systemic disease parameters as well as glomerular IgG deposits appeared in B6.Sle1.2.3 mice by 4 months of age; the appearance of p16Ink4a-positive cells occurred later, by 8 months of age, overlapping with renal disease.
We report, for the first time, the presence of p16Ink4a-positive cells, a marker of cellular senescence, in the B6.Sle1.2.3 kidney, and their association with renal disease severity. This provides a preclinical model in which to test for the role of cellular senescence in the pathogenesis of LN, as a potential kidney-intrinsic disease mechanism.
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterised by venous thrombosis (VT) or arterial thrombosis (AT) and/or pregnancy morbidity and the presence of antiphospholipid antibodies. Direct oral anticoagulants (DOACs) hold several advantages to vitamin K antagonists (VKAs) for prevention of thrombosis and we wish to evaluate DOACs compared with VKAs in secondary prevention of thromboembolic events in patients with APS.
We conducted searches of the published literature using relevant data sources (MEDLINE, Embase and Cochrane CENTRAL), and of trial registers for unpublished data and ongoing trials. We included randomised trials examining individuals >18 years with APS classified according to the criteria valid when the trial was carried out. Randomised controlled trials had to examine any DOAC agent compared with any comparable drug. We tabulated all occurrences of events from all eligible randomised trials. Due to few events, ORs and 95% CIs were calculated using the Peto method.
5 randomised trials comprising 624 patients met the predefined eligibility criteria. The primary outcome measure was new thrombotic events, a composite endpoint of any VT or AT, during the VKA-controlled phase of treatment. According to the I2 inconsistency index, there was evidence of statistical heterogeneity across the studies (I2=60%). Across trials, 29 and 10 thrombotic events were observed in 305 and 319 patients with APS treated with DOAC and VKA, respectively, corresponding to a combined Peto OR of 3.01 (95% CI 1.56 to 5.78, p=0.001). There was a significantly increased risk of AT while treated with DOACs compared with VKA (OR 5.5 (2.5, 12.1) p<0.0001), but no difference in the risk of VT (p=0.87). We found no significant difference in risk of bleeding.
DOACs were associated with a significant increase in the risk of a new thrombotic event, especially AT, favouring standard prophylaxis with warfarin.
CRD42019126720.
Rhupus is a rare disease that shares characteristics of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). While several studies have explored the clinical and immunological profiles of patients with rhupus, the underlying cause of the disease remains unknown due to its complex pathogenesis. The objective of this study was to investigate the role of tumour necrosis factor (TNF) in the production of inflammatory molecules by peripheral blood mononuclear cells (PBMCs) from patients with rhupus.
The study involved five healthy controls, seven patients with rhupus and seven patients with SLE. PBMCs were obtained from each participant and stimulated with recombinant human TNF for 24 hours. The levels of various molecules secreted by the cells, such as cytokines and chemokines, were measured using immunobead-based assays on xMAP technology.
The production levels of some molecules were higher in TNF-stimulated PBMCs from patients with rhupus and SLE than in unstimulated cells. In addition, the levels of certain molecules, including gp130/sIL-6Rb, a proliferation-inducing ligand (APRIL), interferon-β, matrix metalloproteinase-3 and interleukin (IL)-12, were higher in PBMCs from patients with rhupus even without TNF stimulation. Similarly, the levels of gp130/sIL-6Rb and APRIL were higher in TNF-stimulated PBMCs from patients with rhupus than in healthy controls. These results were further validated against patients with RA using enzyme-linked immunosorbent assay.
These findings suggest that the spontaneous production of molecules by cells from patients with rhupus may contribute to the development of the disease, and that TNF may play a role in this process by regulating the secretion of gp130/sIL-6Rb and APRIL.
Tissue damage in lupus nephritis (LN) is mediated by activation of the classical complement pathway. Complement-mediated upregulation of endothelial cell adhesion molecules is seen in dermal blood vessels of non-lesional skin of patients with active lupus. In diseases with systemic complement activation, extensive microvascular C5b-9 deposition is seen in non-lesional skin. In this study, we assess the presence of systemic complement pathway activation as determined by non-lesional skin microvascular C5b-9 deposition in patients with LN.
Eight patients with active LN and eight patients without active LN underwent non-lesional skin biopsies. Using a diaminobenzidine technique, specimens were evaluated for microvascular C5b-9 consistent with systemic complement pathway activation.
Five of eight patients with active LN and one of eight patients without active LN demonstrated positive C5b-9 staining in non-lesional skin (p=0.04). Positive non-lesional C5b-9 staining has greater specificity, 87.5%, for active LN than pyuria, low complements, elevated double-stranded DNA (dsDNA) and proteinuria. Urine protein creatinine ratio was significantly higher in patients with positive non-lesional C5b-9 deposition (5.18 vs 1.20; p=0.04). C5b-9 deposition was not associated with a higher NIH Activity Index, interstitial fibrosis, dsDNA or lower complements.
This is the first study to demonstrate evidence in non-lesional skin of microvascular C5b-9 indicative of systemic complement pathway activation in LN. C5b-9 deposition is statistically more common and demonstrated greater specificity than most historical biomarkers for active LN. The findings support a potential role for microvascular C5b-9 assessment in non-lesional skin as a biomarker for LN activity.
To assess the application and utility of algorithms designed to detect features of SLE in electronic health record (EHR) data in a multisite, urban data network.
Using the Chicago Area Patient-Centered Outcomes Research Network (CAPriCORN), a Clinical Data Research Network (CDRN) containing data from multiple healthcare sites, we identified patients with at least one positively identified criterion from three SLE classification criteria sets developed by the American College of Rheumatology (ACR) in 1997, the Systemic Lupus International Collaborating Clinics (SLICC) in 2012, and the European Alliance of Associations for Rheumatology and the ACR in 2019 using EHR-based algorithms. To measure the algorithms’ performance in this data setting, we first evaluated whether the number of clinical encounters for SLE was associated with a greater quantity of positively identified criteria domains using Poisson regression. We next quantified the amount of SLE criteria identified at a single healthcare institution versus all sites to assess the amount of SLE-related information gained from implementing the algorithms in a CDRN.
Patients with three or more SLE encounters were estimated to have documented 2.77 (2.73 to 2.80) times the number of positive SLE attributes from the 2012 SLICC criteria set than patients without an SLE encounter via Poisson regression. Patients with three or more SLE-related encounters and with documented care from multiple institutions were identified with more SLICC criteria domains when data were included from all CAPriCORN sites compared with a single site (p<0.05).
The positive association observed between amount of SLE-related clinical encounters and the number of criteria domains detected suggests that the algorithms used in this study can be used to help describe SLE features in this data environment. This work also demonstrates the benefit of aggregating data across healthcare institutions for patients with fragmented care.
To investigate the association of medication copayment and treatment adherence to hydroxychloroquine and immunosuppressants for SLE.
We conducted a retrospective analysis of health claims data using Optum’s de-identified Clinformatics Data Mart Database. Individuals with SLE continuously enrolled for 180 days from 1 July 2010 to 31 December 2019 were included. Adherence was defined as the proportion of days covered ≥80%. Copayment for a 30-day supply of medication was dichotomised as high (≥$10) or low (<$10). We examined the association between copayment and odds of adherence in multivariable-adjusted logistic regression models, including age, sex, race or ethnicity, comorbidities, educational attainment and household income.
We identified 12 510 individuals (age 54.2±15.5 years; 88.2% female sex), of whom 9510 (76%) were prescribed hydroxychloroquine and 1880 (15%) prescribed hydroxychloroquine and an additional immunosuppressant (azathioprine, methotrexate or mycophenolate mofetil). Median (IQR) 30-day copayments were $8 (4–10) for hydroxychloroquine, $7 (2–10) for azathioprine, $8 (3–11) for methotrexate and $10 (5–20) for mycophenolate mofetil. High copayments were associated with OR of adherence of 0.61 (95% CI 0.55 to 0.68) for hydroxychloroquine, OR 0.44 (95% CI 0.30 to 0.66) for azathioprine and OR 0.69 (95% CI 0.49 to 0.96) for mycophenolate mofetil. For methotrexate, the association was not significant.
In a large, administrative health claims database, we identified that high copayments were associated with reduced adherence to commonly prescribed medications for SLE. Incorporating awareness of the burden of copayments and its consequences into healthcare is essential to promote optimal medication adherence.
Patients with SLE have higher cardiovascular (CV) risk compared with healthy controls (HC) and are characterised by accelerated atherosclerosis; intima media thickness (IMT), marker of subclinical atherosclerosis, is higher in patients with SLE than in HCs. Retinal microvascular impairment detected through optical coherence tomography angiography (OCTA) was investigated as a marker of systemic vascular involvement in SLE.
The aim of the study was to evaluate the relationship between retinal vascular impairment and IMT in SLE.
Cross-sectional study recruiting patients with SLE and HCs. Data of the study population were collected. CV risk was evaluated through the American College of Cardiology/American Heart Association (ACC/AHA) guidelines, Framingham and QRESEARCH risk estimator V.3 (QRISK3) scores. Both groups underwent OCTA and carotid ultrasound with IMT assessment.
Statistical analysis was accomplished using Pearson/Spearman, t-test/Mann-Whitney or 2 test. Variables statistically significant at univariate regression analysis were tested in an age-corrected and sex-corrected multivariate regression model.
43 patients with SLE and 34 HCs were recruited. Patients with SLE showed higher triglycerides (p=0.019), Triglycerides-Glucose (TyG) Index (p=0.035), ACC/AHA guidelines (p=0.001), Framingham Risk Scores (p=0.008) and a reduced superficial (p<0.001) and deep (p=0.005) whole retinal vessel density (VD) compared with HCs.
In SLE univariate analysis, deep whole VD showed a negative correlation with IMT (p=0.027), age (p=0.001), systolic blood pressure (p=0.011), QRISK3 Score (p<0.001), Systemic Lupus International Collaborating Clinics Damage Index (p=0.006) and apolipoprotein B (p=0.021), while a positive correlation was found with female sex (p=0.029). Age-adjusted and sex-adjusted multivariate analysis confirmed QRISK3 Score (p=0.049) and IMT (p=0.039) to be independent risk factors for reduced retinal VD.
Patients with SLE showed lower retinal VD and higher CV risk indicators compared with HCs. Among patients with SLE, QRISK3 Score and IMT were found to be independent risk factors for retinal vascular impairment, suggesting a role of OCTA in evaluating preclinical CV involvement in SLE. Moreover, TyG Index could represent a biomarker of CV risk in patients with SLE compared with HCs.
Data concerning SARS-CoV-2 in patients affected by SLE are contradicting.
The aim of this study was to investigate disease-related differences in COVID-19 prognosis of patients affected by rheumatic diseases before vaccination; we tested the hypothesis that patients with SLE may have a different outcome compared with those with rheumatoid arthritis (RA) or spondyloarthritis (SPA).
We analysed data from the national CONTROL-19 Database with a retrospective, observational design, including rheumatic patients affected by COVID-19. The principal outcome measure was hospitalisation with death or mechanical ventilation. Differences between SLE, RA and SPA were analysed by univariable and multivariable logistic regression models.
We included 103 patients with SLE (88.2% female, mean age 48.9 years, 50.4% active disease), 524 patients with RA (74.4% female, mean age 60.6 years, 59.7% active disease) and 486 patients with SPA (58.1% female, mean age 53.2 years, 58% active disease).
Outcome prevalence was not different between patients with SLE and those with RA (SLE 24.5%, RA 25.6%), while patients with SPA showed a more favourable outcome compared with those with SLE (SPA 15.9%); data from the multivariable analysis confirmed this result.
In SLE, age >65 years (OR 17.3, CI 5.51 to 63.16, p<0.001), hypertension (OR 6.2, CI 2.37 to 17.04, p<0.001) and prednisone (PDN) use (OR 3.8, CI 1.43 to 11.39, p=0.01) were associated with severe outcomes, whereas hydroxychloroquine use was found to be protective (OR 0.3, CI 0.14 to 0.91, p=0.03).
Our data suggest that patients with SLE and RA do not show a different COVID-19 outcome, while patients with SPA have a more favourable disease course compared with those with SLE. Risk of hospitalisation with ventilation or death was associated with age >65 years, hypertension and PDN use in patients with SLE.
B cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile.
Female patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina’s Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases.
Double-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 –/– (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/– or –/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048).
High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.
An important clinical question is whether the use of immunosuppressants or corticosteroids increases the risk of incident COVID-19 disease among patients with SLE. To address this question, we examined the incidence of COVID-19 infection in a large SLE cohort.
This study was based on a single-centre cohort of patients with SLE seen quarterly from March 2020 to August 2022. Clinical information from these visits was augmented with information on COVID-19 infections and vaccinations obtained from the electronic medical records and by patient self-report. We compared treated and untreated patients with respect to the incidence of COVID-19 infection per person month. Statistical significance was assessed based on logistic regression models.
We observed 339 incident cases of COVID-19 experienced over 24 614 person-months of follow-up from 1052 different patients. The risk of infection per person-month of follow-up was similar among those not on prednisone (1.37%), on moderate doses of prednisone (<7 mg/day) (1.44%) and those on higher doses (1.52%) (p=0.87 for difference). We observed an elevated risk among those taking belimumab, however, after adjustment for potential confounding variables, the increased risk was not statistically significant (rate ratio 1.4, 95% CI 0.88 to 2.24, p=0.16) There was no evidence of an increased risk among those taking mycophenolate, methotrexate or azathioprine.
It is reassuring that there was not strong evidence of an increased risk of infection among those taking prednisone or other immunosuppressants. However, given the range of our CIs, moderate effects of these medications on COVID-19 risk cannot be completely ruled out.
This study sought to elucidate the molecular impacts of belimumab (BEL) treatment on T-cell immune profiling in SLE.
We used mass cytometry with 25 marker panels for T-cell immune profiling in peripheral blood T cells (CD3+) from 22 patients with BEL-treated SLE and 20 controls with non-BEL-treated SLE. An unsupervised machine-learning clustering, FlowSOM, was used to identify 39 T-cell clusters (TCLs; TCL01–TCL39). TCLs (% of CD3+) showing significant (p<0.05) associations with BEL treatment (BEL-TCL) were selected by a linear mixed-effects model for comparing groups of time-series data. Furthermore, we analysed the association between BEL treatment and variations in regulatory T-cell (Treg) phenotypes, and the ratio of other T-cell subsets to Treg as secondary analysis.
Clinical outcomes: BEL treatment was associated with a decrease in daily prednisolone use (coef=–0.1769, p=0.00074), and an increase in serum CH50 (coef=0.4653, p=0.003), C3 (coef=1.1047, p=0.00001) and C4 (coef=0.2990, p=0.00157) levels. Molecular effects: five distinct BEL-TCLs (TCL 04, 07, 11, 12 and 27) were identified. Among these, BEL-treated patients exhibited increased proportions in the Treg-like cluster TCL11 (coef=0.404, p=0.037) and two naïve TCLs (TCL04 and TCL07). TCL27 showed increased levels (coef=0.222, p=0.037) inversely correlating with baseline C3 levels. Secondary analyses revealed associations between BEL treatment and an increase in Tregs (coef=1.749, p=0.0044), elevated proportions of the fraction of Tregs with inhibitory function (fTregs, coef=0.7294, p=0.0178) and changes in peripheral helper T cells/fTreg (coef=–4.475, p=0.0319) and T helper 17/fTreg ratios (coef=–6.7868, p=0.0327). Additionally, BEL was linked to variations in T-cell immunoglobulin and mucin domain-containing protein-3 expression (coef=0.2422, p=0.039).
The study suggests an association between BEL treatment and variations in T cells, particularly Tregs, in SLE pathologies involving various immune cells.
SLE is a common multisystem autoimmune disease with chronic inflammation. Many efficacy evaluation indicators of randomised clinical trials (RCTs) for SLE have been proposed but the comparability remains unknown. We aim to explore the preference and comparability of indicators reporting response rate and provide basis for primary outcome selection when evaluating the efficacy of SLE pharmaceutical treatment.
We systematically searched three databases and three registries to identify pharmacological intervention-controlled SLE RCTs. Relative discriminations between indicators were assessed by the Bayesian hierarchical linear mixed model.
33 RCTs met our inclusion criteria and we compared eight of the most commonly used indicators reporting response rate. SLE Disease Activity Index 4 (SLEDAI-4) and SLE Responder Index 4 were considered the best recommended indicators reporting response rate to discriminate the pharmacological efficacy. Indicator preference was altered by disease severity, classification of drugs and outcome of trials, but SLEDAI-4 had robust efficacy in discriminating ability for most interventions. Of note, BILAG Index-based Combined Lupus Assessment showed efficacy in trials covering all-severity patients, as well as non-biologics RCTs. The British Isles Lupus Assessment Group response and Physician’s Global Assessment response were more cautious in evaluating disease changes. Serious adverse event was often applied to evaluate the safety and tolerability of treatments rather than efficacy.
The impressionable efficacy discrimination ability of indicators highlights the importance of flexibility and comprehensiveness when choosing primary outcome(s). As for trials that are only evaluated by SLEDAI-4, attention should be paid to outcome interpretation to avoid the exaggeration of treatment efficacy. Further subgroup analyses are limited by the number of included RCTs.
CRD42022334517.
To evaluate the performance of Systemic Lupus Erythematosus Risk Probability Index (SLERPI) in patients with SLE using a Chinese cohort.
The Chinese cohort included 352 patients with and 385 without SLE (control group). The clinical data of patients, including demographic data, clinical findings and serological profiles, were collected. Patients with an SLERPI score >7 were classified as SLE. The performance of the American College of Rheumatology (ACR)-1997, Systemic Lupus International Collaborating Clinics (SLICC)-2012 and European League Against Rheumatism (EULAR)/ACR-2019 criteria were used as references.
Of these four classification criteria, SLERPI has the highest sensitivity (98.3% (95% CI 96.3% to 99.4%)), but lowest specificity (89.4% (95% CI 85.8% to 92.2%)). In the control group, patients eligible for the classification criteria for SLE were mainly those with primary Sjogren’s syndrome (pSS) and undifferentiated connective tissue disease (UCTD), which adversely affected the specificity of the classification criteria. Moreover, significantly more patients with pSS and UCTD met SLERPI than those who met other classification criteria. After excluding patients with pSS and UCTD from the control group, the specificity and accuracy of SLERPI improved to 94.3% (95% CI 91.0% to 96.6%) and 96.5% (95% CI 95.0% to 97.9%), respectively, and both outperformed the EULAR/ACR-2019 criteria. The time to SLERPI classification was the same as their clinical time to diagnosis in 261 patients, earlier than the clinical diagnosis in 23 patients and later than the clinical diagnosis in 9 patients. A total of 280 patients had the same time to SLERPI classification as EULAR/ACR-2019, 8 patients had earlier than EULAR/ACR-2019 and 1 patient had later than EULAR/ACR-2019.
SLERPI performed well in patients with SLE, particularly for the earlier diagnosis of SLE.
Dysregulation of interferon-alpha (IFN-α) is considered central to the immunological abnormalities observed in SLE. Short-term mortality during high disease activity in lupus is up to 30%. Adenovirus vector-introduced IFN-α into a lupus-prone mouse causes the development of glomerulonephritis and death within weeks. We studied serum IFN-α as a biomarker of in-hospital mortality in patients of SLE with high disease activity.
Serum IFN-α (ELISA) was measured in patients hospitalised for acute severe lupus in a tertiary care rheumatology unit in India and the levels were compared between survivors and non-survivors. Serum IFN-α was compared with traditional clinical and serological markers associated with disease activity to assess which better prognosticates survival.
In a cohort of 90 patients with a mean Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) of 19.3 (±5.5), the mean serum IFN-α was 88±144 pg/dL. Levels were undetectable in patients with inactive disease. SLEDAI, anti double stranded DNA (dsDNA) antibody titres and serum IFN-α levels were higher and serum complement (C3) lower in non-survivors (p=0.003, p=0.017, p<0.001, p=0.029, respectively). Serum IFN-α level of 140 pg/mL had a sensitivity of 86.7%, specificity of 94.6%, positive predictive value of 76% and negative predictive value of 83.3% (p<0.001) in predicting mortality. The area under the curve for predicting in-hospital mortality was 0.25 for C3, 0.72 for dsDNA, 0.77 for SLEDAI and 0.92 for serum IFN-α.
Serum IFN-α was better in predicting in-hospital mortality compared with conventional measures of disease activity such as anti-dsDNA, complements and SLEDAI.
To characterise the safety and efficacy of anifrolumab in active lupus nephritis (LN) through year 2 of the phase II randomised, double-blind Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-LN trial (NCT02547922) of 2 anifrolumab dosing regimens versus placebo.
Patients received intravenous anifrolumab 900 mg for the first 3 doses followed by 300 mg anifrolumab (intensified regimen (IR)), 300 mg anifrolumab (basic regimen (BR)) or placebo every 4 weeks throughout. To continue into Year 2, patients must have achieved at least partial renal response and a glucocorticoid tapering target.
Of 147 randomised patients, 101 completed Year 1 study treatment; of these, 75 (74%) continued into Year 2 (anifrolumab IR: n=29, BR: n=23 and placebo: n=23). During Year 2, 72% of patients reported ≥1 adverse event (AE); serious AEs were reported in 6.9%, 8.7% and 8.7% of patients (anifrolumab IR, BR and placebo, respectively); 3 patients discontinued treatment due to an AE (anifrolumab IR: n=2 and placebo: n=1) and herpes zoster was reported in 2 patients (anifrolumab IR: n=1 and BR: n=1). The study was ongoing at the start of the pandemic, but no COVID-19 cases were reported. Of the 145 patients receiving treatment, more patients on the IR attained complete renal response at Week 104 compared with those on BR or placebo (27.3% vs 18.6% and 17.8%) and simultaneously achieved sustained glucocorticoid tapering (IR: 25.0%; BR: 18.6% and placebo: 17.8%). The improvements in estimated glomerular filtration rate were numerically larger in both anifrolumab groups versus placebo.
The safety and tolerability profile through Year 2 of TULIP-LN was generally consistent with Year 1, with promising efficacy results for the anifrolumab IR regimen. Collectively, the results support further investigation of an anifrolumab intensified dosing regimen in larger populations of patients with active proliferative LN.
Anti-β2GPI-domain I (β2GPI-DI) antibody is pathogenic in patients with antiphospholipid syndrome (APS), but its additional clinical associations and diagnostic value are controversial.
A total of 378 patients were included, of which 119 patients diagnosed with primary APS, 50 with APS secondary to SLE (SAPS group), 209 with SLE without APS (SLE group). Serum anti-β2GPI-DI IgG was measured using chemiluminescent immunoassay. Extra-criteria manifestations were analysed, including thrombocytopenia, autoimmune haemolytic anaemia, valvular lesions, APS nephropathy and non-vascular neurological manifestations.
In 169 patients with APS, 55 (32.5%) were positive for anti-β2GPI-DI IgG, accounting for 77.5% of those with anti-β2GPI IgG positivity. It is shown that 96.4% of those with anti-β2GPI-DI IgG also showed triple positivity in classic antiphospholipid antibodies (aPLs). The positivity of anti-β2GPI-DI IgG was significantly associated with recurrent thrombosis before APS diagnosis (p=0.015), microvascular thrombosis (p=0.038), but not with pregnancy morbidity (PM). Notably, patients with extra-criteria manifestations showed significantly higher positivity (p=0.001) and titres (p<0.001) in anti-β2GPI-DI IgG, especially for thrombocytopenia and APS nephropathy. In multivariable analysis, anti-β2GPI-DI IgG positivity (OR 2.94, 95% CI 1.29 to 6.70), secondary APS, arterial hypertension and Coombs’ test positivity independently predicted extra-criteria manifestations (C-index 0.83, 95% CI 0.77 to 0.90). After a median follow-up of 25 months, patients with anti-β2GPI-DI IgG also showed a tendency of more extra-criteria events, but not thrombotic events. Anti-β2GPI-DI was positive among 8.1% of the SLE controls, and showed high specificity (91.9%) in diagnosing SAPS among patients with SLE as compared with classic aPLs.
Anti-β2GPI-DI IgG was associated with extra-criteria manifestations in patients with APS. Further studies are warranted to validate its predictive values and potential role in daily practice.
Patients with lupus erythematosus (LE) are at heightened risk for clinical events, chiefly heart attacks and strokes, from atherosclerotic cardiovascular disease (ASCVD). We recently proposed new guidelines to assess and manage ASCVD event risk specifically in LE. Here, we examined current cardiovascular management in light of these new recommendations.
We studied our entire UPenn Longitudinal Lupus Cohort of patients with cutaneous LE, without (CLE-only) or with (CLE+SLE) concurrent systemic LE, for whom we had full access to medical records (n=370, LE-ASCVD Study Cohort).
Of our LE-ASCVD Study Cohort, 336 out of 370 (90.8%) had a designated primary-care physician. By the new guidelines, the most recent low-density lipoprotein (LDL) levels were above-goal for 249 out of 370 (67.3%). Two-hundred sixty-six (71.9%) had hypertension, which was undertreated or untreated in 198 out of 266 (74.4%). Of current smokers, 51 out of 63 (81.0%) had no documented smoking cessation counselling or referrals. Diabetes and triglyceridaemia were generally well managed. Of the cohort, 278 qualified for two widely used online estimators of ASCVD event risk in primary prevention: the ACC-ASCVD Risk Estimator Plus and QRisk3. We also stratified these 278 patients into our recently defined categories of ASCVD event risk in LE. These three methods for estimating ASCVD event risk showed clinically meaningful discordance for 169 out of 278 (60.8%). The documented rate of ASCVD events in the first 10 years after enrolment was 13.5% (95% CI 8.9%, 17.9%), similar between CLE-only and CLE+SLE, indicating an at-risk population despite the preponderance of women and an average age at enrolment of only 47 years.
Patients with CLE-only or CLE+SLE are undertreated compared with the new guidelines and, accordingly, they experience a significant burden of ASCVD events. Moreover, it is unclear how to accurately assess their future ASCVD event risk, except that it is substantial. Efforts are underway to improve ASCVD event risk estimation and guideline implementation in patients with lupus.
SLE is a chronic autoimmune disease that places a great burden on human society. T follicular helper (Tfh) cells play a critical role in the pathological process of SLE. Therefore, elucidating the mechanism of Tfh cell differentiation will contribute to SLE treatment. Dopamine receptors (DRDs) are members of the family of G protein-coupled receptors and are primarily divided into D1-like and D2-like receptors. Previous studies have found that DRDs can regulate differentiation of immune cells. However, there is currently a lack of research on DRDs and Tfh cells. We here explore the relationship between DRDs and Tfh cells, and analyse the relationship between DRD expression on Tfh cells and the course of SLE.
We first detected plasma catecholamine concentrations in patients with SLE and healthy controls by mass spectrometry, followed by reverse transcription-quantitative PCR (RT-qPCR) to detect DRD messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells, and flow cytometry to detect DRD expression in Tfh cells. Finally, in vitro experiments and RNA sequencing (RNA-seq) were used to explore the possible pathway by which DRDs regulate Tfh cell differentiation.
The plasma dopamine concentration in patients with SLE was significantly increased, and abnormal mRNA expression of DRDs was observed in both PBMCs and CD4+ T cells. The results of flow cytometry showed that D1-like receptors were highly expressed in Tfh cells of patients with SLE and associated with disease activity. In vitro induction experiments showed that differentiation of naïve T cells into Tfh cells was accompanied by an increase in D1-like receptor expression. RNA-seq and RT-qPCR results indicate that D1-like receptors might promote Tfh cell differentiation through the Phosphatidylinositol3-kinase (PI3K)/protein kinase B (AKT)/Forkhead box protein O1 (FOXO1)/Kruppel-like factor 2 (Klf2) pathway.
Tfh cells in patients with SLE highly express D1-like receptors, which correlate with disease activity. D1-like receptors may promote Tfh cell differentiation through the PI3K/AKT/FOXO1/Klf2 pathway.
To determine vitamin D levels in patients with SLE and evaluate their relationship to bone mineral density (BMD) and the disease course.
The study included 101 patients with SLE and 29 individuals in the control group. The study participants were tested for vitamin D level, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), interleukin (IL)-6, osteocalcin (OC) and collagen type I C-terminal telopeptide (CTX), and the dual-energy X-ray absorptiometry was provided to assess BMD in the lumbar spine and the hip.
The mean serum vitamin D level was 18.98±0.88 ng/mL, and women had 25.42% lower vitamin D levels than men (p<0.05). There was no correlation between vitamin D levels and patient’s age or disease course. There was a significant inverse correlation between vitamin D levels and cumulative dose of glucocorticoids (r=–0.26) and serum inflammatory markers, particularly CRP (r=–0.39), IL-6 (r=–0.37) and ESR (r=–0.15). Vitamin D level was associated with the bone turnover markers (BTMs). In women of reproductive age with vitamin D deficiency, BMD of the lumbar spine and the hip was 9.5–23.1% higher than in those with no vitamin deficiency, respectively, and the mean lumbar spine Z-score in women of reproductive age with vitamin D insufficiency and deficiency was significantly 2.0 and 2.9 times lower than in patients with normal vitamin D level.
Hypovitaminosis D is quite common in patients with SLE and is associated with high inflammatory activity (SLE Disease Activity Index, ESR, CRP, IL-6), severity of organ damage (Damage Index), cumulative dose of glucocorticoids, BTM changes (decrease in OC, increase in CTX) and BMD decline. Vitamin D status was not associated with the patient’s age or disease course.
Frailty is a risk factor for adverse health in adults with SLE, including those <65 years. Emergency department (ED) utilisation is high in adults with SLE, but to our knowledge, whether frailty is associated with ED use is unknown. In a large administrative claims dataset, we assessed risk of ED utilisation among frail adults with SLE ≤65 years of age relative to non-frail adults ≤65 years of age with SLE.
Using the MarketScan Medicaid subset from 2011 to 2015, we identified beneficiaries 18–65 years with SLE (≥3 SLE International Classification of Diseases, Ninth Revision codes ≥30 days apart). Comparators without a systemic rheumatic disease (SRD) were matched 4:1 on age and gender. Frailty status in 2011 was determined using two claims-based frailty indices (CFIs). We compared risk of recurrent ED utilisation among frail and non-frail beneficiaries with SLE using an extension of the Cox proportional hazard model for recurrent events data.
Of 2262 beneficiaries with SLE and 9048 non-SRD comparators, 28.8% and 11.6% were frail, respectively, according to both CFIs. Compared with non-frail beneficiaries with SLE, frail beneficiaries with SLE had significantly higher hazard of recurrent ED use (HR 1.75, 95% CI 1.48 to 2.08).
Frailty increased hazard of recurrent ED visits in frail adults ≤65 years of age with SLE relative to comparable non-frail adults with SLE. Frailty is a potential target for efforts to improve quality of care in SLE.
Up to 83% of patients with SLE stop taking hydroxychloroquine (HCQ) within the first year due to knowledge gaps regarding the survival benefits of HCQ versus inflated fears of rare toxicity. Thus, there is a need for a shared decision-making tool that highlights HCQ’s significant benefits versus rare harms to improve patients’ understanding and align treatments with their values. The objective of this study was to describe development and piloting of a decision aid (HCQ-SAFE) to facilitate HCQ adherence, and safe, effective use by engaging patients in therapeutic decision-making.
HCQ-SAFE was developed via a collaborative process involving patients, clinicians, implementation scientists and health literacy experts. The initial prototype was informed by Agency for Healthcare Research and Quality (AHRQ) low literacy principles and key themes about HCQ use from six prior patient and clinician focus groups, with iterative expert and stakeholder feedback to deliver a final prototype. We implemented HCQ-SAFE in four clinics to examine usability and feasibility on Likert scales (0–7) and net promoter score (0%–100%).
The final HCQ-SAFE shared decision-making laminated tool organises data using pictograms showing how HCQ use reduces risk of organ damage, early death and blood clots versus low risk of eye toxicity.
HCQ-SAFE was reviewed in all eligible patient visits (n=40) across four clinics on an average of ~8 min, including 25% non-English-speaking patients. All patients scored 100% on the knowledge post-test; no decisional conflicts were noted after using HCQ-SAFE. HCQ-SAFE garnered high clinician and patient satisfaction with 100% likelihood to recommend to peers.
HCQ-SAFE is a stakeholder-informed feasible shared decision-making tool that enhances communication and can potentially improve knowledge, clarify misbeliefs and engage patients in treatment decisions, including those with limited English proficiency.
Recently, a new subtype of granzyme B (GrB)-producing Breg cells has been identified, which was proven to be involved in autoimmune disease. Our recent report demonstrated that GrB-producing Breg cells were correlated with clinical and immunological features of SLE. However, the effect of GrB-producing Breg cells in lupus mice is unclear.
GrB expression in naïve and lupus mouse B cells was analysed using flow cytometry, PCR, ELISA and ELISpot assays. To study the role of GrB-producing B cells in a lupus model, GrB knockout (KO) and wild-type (WT) mice were intraperitoneally injected with monoclonal cells from the mutant mouse strain B6.C-H-2bm12 (bm12) for 2 weeks. In addition, the function of GrB-producing Breg cells in naïve and lupus mice was further explored using in vitro B cells-CD4+CD25– T cell co-culture assays with GrB blockade/KO of B cells.
B cells from the spleens of WT C57BL/6 (B6) mice could express and secret GrB (p<0.001). GrB-producing Breg cells from WT mice showed their regulatory functions on CD4+CD25– T cell. While the frequency of GrB-producing Breg cells was significantly decreased (p=0.001) in lupus mice (p<0.001). Moreover, GrB-producing Breg cells in lupus mice failed to suppress T cell-mediated proinflammatory responses, partially due to the impaired capacity of downregulating the T cell receptor-zeta chain and inducing CD4+CD25– T cell apoptosis.
This study further revealed the function and mechanism of GrB-producing Breg cells in regulating T cell homeostasis in lupus mice and highlighted GrB-producing Breg cells as a therapeutic target in SLE.
Since molecularly targeted therapies are emerging for treating lupus nephritis (LN), this study aimed to assess the immunohistochemical findings of the cytokines in renal tissue and their pathological and clinical relevance in LN.
Fifty patients with proliferative LN formed the case group; 5 with LN class II, IgA nephropathy and 10 with idiopathic haematuria were enrolled as controls. Immunohistochemical analysis for CD3, CD20, interferon (IFN)-α, interleukin (IL)-12/p40 and B-cell activating factor (BAFF) was performed by scoring the number of positive cells/area of the cortex. All immunohistochemical investigations were performed on formalin-fixed paraffin-embedded renal tissue. Proliferative LN cases were grouped by the dominant expression of IFN-α, IL-12/p40 and BAFF, and subsequently, clinicopathological features were compared.
Clinical data of patients with proliferative LN included urine protein creatinine ratio, 2.2 g/gCre; anti-double-stranded DNA antibody, 200.9 IU/mL; total complement activity (CH50), 21.9 U/mL and SLE Disease Activity Index, 19.8 points. Proliferative LN cases, including class III (n=18) and IV (n=32), were classified into three subgroups according to the immunohistochemical score based on the dominancy of IFN-α (n=17), IL-12 (n=16) and BAFF group (n=17) proteins. Hypocomplementaemia and glomerular endocapillary hypercellularity were significantly increased in the IFN-α group, whereas chronic lesions were significantly higher in the IL-12 group (p<0.05). The IFN-α group had a poorer renal prognosis in treatment response after 52 weeks.
The immunohistochemistry (IHC) of IFN-α, IL-12 and BAFF for proliferative LN enabled grouping. Especially, the IFN-α and IL-12 groups showed different clinicopathological features and renal prognoses. The results indicated the possibility of stratifying cases according to the IHC of target molecules, which might lead to precision medicine.
To assess real-world treatment regimens and patterns in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE) cohorts, including similarities in treatments, duration of use and adherence.
This retrospective study utilised data from Merative L.P. MarketScan Research Databases (USA). Index date was the date of first SLE diagnosis (2010–2019). Patients aged <18 years (cSLE) and ≥18 years (aSLE) at index date with confirmed SLE diagnosis and ≥12 months continuous enrolment during pre-index and post-index periods were included. The cohorts were stratified based on the presence (existing) or absence (new) of pre-index SLE. Primary outcomes (post-index period) included treatment regimens (all patients), and adherence (proportion of days covered (PDC)) and discontinuation of therapies initiated within 90 days of diagnosis (new patients). Univariate comparisons between cSLE and aSLE cohorts were performed using Wilcoxon rank-sum and 2 (or Fisher’s exact) tests.
cSLE cohort included 1275 patients (mean age=14.1 years) and aSLE cohort included 66 326 patients (mean age=49.7 years). Antimalarials and glucocorticoids were commonly used among new (cSLE=64.4%/62.0%; aSLE=51.8%/49.7%) and existing (cSLE=68.6%/58.9%; aSLE=63.8%/51.3%) patients in both cohorts. Median oral glucocorticoid dose (prednisone equivalent) was higher in cSLE vs aSLE (new=22.1 vs 14.0 mg/day; existing=14.4 vs 12.3 mg/day; p<0.05). Mycophenolate mofetil use was higher in patients with cSLE vs aSLE (new=26.2% vs 5.8%; existing=37.6% vs 11.0%; p<0.0001). Compared with aSLE, more patients used combination therapies in cSLE (p<0.0001). Median PDC was higher in cSLE vs aSLE for antimalarials (0.9 vs 0.8; p<0.0001) and oral glucocorticoids (0.6 vs 0.3; p<0.0001). Treatment discontinuation was lower in cSLE vs aSLE for antimalarials (25.0% vs 33.1%; p<0.0001) and oral glucocorticoids (56.6% vs 71.2%; p<0.0001).
Management of cSLE and aSLE includes the same medication classes; differences include more intensive use of therapy in cSLE, warranting the need for approved safe medications for cSLE.
Cognitive dysfunction (CD) is detectable in approximately 40% of patients with SLE. Despite this high prevalence, there are no approved pharmacological treatment options for this detrimental condition. Preliminary murine studies show potential for targeting microglial activation as a treatment of SLE-CD, which may be ameliorated with centrally acting ACE inhibitor (cACEi) and angiotensin receptor blocker (cARB) use. The aim of this study is to determine if there is an association of cACEi/cARB use with cognitive function in a human SLE cohort.
The American College of Rheumatology neuropsychological battery was administered to patients with consecutive SLE at a single academic health centre at baseline, 6 and 12 months. Scores were compared with sex-matched and age-matched control subjects. Clinical and demographic data were gathered at each visit. The primary outcome was CD defined as dysfunction in two or more cognitive domains. The primary predictor was a total cumulative dose of cACEi/cARB in milligrams per kilogram, recorded as an equivalent ramipril dose. Odds of CD with respect to cACEi/cARB use were determined through generalised linear mixed modelling.
A total of 300 patients, representing 676 visits, completed this study. One hundred sixteen (39%) met the criteria for CD. Fifty-three participants (18%) were treated with a cACEi or cARB. Mean cumulative dose was 236 mg/kg (calculated as equivalent ramipril dose). Cumulative cACEi/cARB dose was not protective against SLE-CD. Caucasian ethnicity, current employment status and azathioprine cumulative dose were each associated with reduced odds of SLE-CD. Increasing Fatigue Severity Scale score was associated with increased odds of CD.
In a single-centre SLE cohort, cACEi/cARB use was not associated with absence of CD. Many important confounders may have influenced the results of this retrospective study. A randomised trial is required to accurately determine if cACEi/cARB is a potential treatment for SLE-CD.
There is a lack of data on the use of telemedicine (TM) in SLE. SLE outcome measures remain complex, and clinicians and clinical trialists have raised concerns about the accuracy of virtual disease activity measures. This study evaluates the level of agreement between virtual SLE outcome measures and face-to-face (F2F) encounter. Here, we describe the study design, virtual physical examination protocol and demographics for the first 50 patients evaluated.
This is an observational, longitudinal study of 200 patients with SLE with varying levels of disease activity from 4 academic lupus centres serving diverse populations. Each study participant will be evaluated at a baseline and a follow-up visit. At each visit, participants are evaluated by the same physician first via a videoconference-based TM and then a F2F encounter. For this protocol, virtual physical examination guidelines relying on physician-directed patient self-examination were established. SLE disease activity measures will be completed immediately after the TM encounter and repeated after the F2F encounter for each visit. The degree of agreement between TM and F2F disease activity measures will be analysed using the Bland-Altman method. An interim analysis is planned after the enrolment of the first 50 participants.
This study has been reviewed by the Columbia University Medical Center Institutional Review Board (IRB Protocol #: AAAT6574). The full results of this study will be published after the final data analysis of 200 patients. The abrupt shift to TM visits due to the COVID-19 pandemic disrupted clinical practice and clinical trials. Establishing a high level of agreement between SLE disease activity measures obtained with videoconference TM and F2F at the same time point, will allow for improved assessment of disease activity when F2F data cannot be acquired. This information may guide both medical decision-making and provide reliable outcome measures for clinical research.
To determine whole-brain and regional functional connectivity (FC) characteristics of patients with neuropsychiatric SLE (NPSLE) or without neuropsychiatric manifestations (non-NPSLE) and examine their association with cognitive performance.
Cross-recurrence quantification analysis (CRQA) of resting-state functional MRI (rs-fMRI) data was performed in 44 patients with NPSLE, 20 patients without NPSLE and 35 healthy controls (HCs). Volumetric analysis of total brain and specific cortical and subcortical regions, where significant connectivity changes were identified, was performed. Cognitive status of patients with NPSLE was assessed by neuropsychological tests. Group comparisons on nodal FC, global network metrics and regional volumetrics were conducted, and associations with cognitive performance were estimated (at p<0.05 false discovery rate corrected).
FC in patients with NPSLE was characterised by increased modularity (mean (SD)=0.31 (0.06)) as compared with HCs (mean (SD)=0.27 (0.06); p=0.05), hypoconnectivity of the left (mean (SD)=0.06 (0.018)) and right hippocampi (mean (SD)=0.051 (0.0.16)), and of the right amygdala (mean (SD)=0.091 (0.039)), as compared with HCs (mean (SD)=0.075 (0.022), p=0.02; 0.065 (0.019), p=0.01; 0.14 (0.096), p=0.05, respectively). Hyperconnectivity of the left angular gyrus (NPSLE/HCs: mean (SD)=0.29 (0.26) and 0.10 (0.09); p=0.01), left (NPSLE/HCs: mean (SD)=0.16 (0.09) and 0.09 (0.05); p=0.01) and right superior parietal lobule (SPL) (NPSLE/HCs: mean (SD)=0.25 (0.19) and 0.13 (0.13), p=0.01) was noted in NPSLE versus HC groups. Among patients with NPSLE, verbal episodic memory scores were positively associated with connectivity (local efficiency) of the left hippocampus (r2=0.22, p=0.005) and negatively with local efficiency of the left angular gyrus (r2=0.24, p=0.003). Patients without NPSLE displayed hypoconnectivity of the right hippocampus (mean (SD)=0.056 (0.014)) and hyperconnectivity of the left angular gyrus (mean (SD)=0.25 (0.13)) and SPL (mean (SD)=0.17 (0.12)).
By using dynamic CRQA of the rs-fMRI data, distorted FC was found globally, as well as in medial temporal and parietal brain regions in patients with SLE, that correlated significantly and adversely with memory capacity in NPSLE. These results highlight the value of dynamic approaches to assessing impaired brain network function in patients with lupus with and without neuropsychiatric symptoms.