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.