We read with interest the recent manuscript by Neupane et al. (2023) (1) in Lupus Science and Medicine, which compared the efficacy of anifrolumab and belimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE). The study found that anifrolumab and belimumab are comparable in terms of SRI-4 response at 52 weeks using an indirect treatment comparison (ITC) analysis. The authors noted this was different from our ITC (Bruce et al. 2022) (2) findings where patients on anifrolumab were twice as likely to achieve an improvement in SRI-4 as belimumab.
The difference in the results between Neupane et al. and our study might not be an actual difference but explained by differences in data utilised in the ITC analyses.
First, different SRI-4 results were used. Neupane et al. utilised the SRI-4 results derived from pre-specified restricted medication rules for TULIP-1 whereas our study used results derived from amended medication rules (3). There was an error in the pre-specified restricted medication rules which were subsequently amended to ensure clinical appropriateness (3). As highlighted in our Letter in reply (6), the SRI-4 results derived from the amended rules were agreed to by the FDA and the EMA, and reported in the US Prescribing Information (5) and Summary of Product Characteristics (7). Regulators were aligned with the prespecified outcome definition used in TULIP-2 as well as the BLISS trials, thus they were the appropriate rules to use...
We read with interest the recent manuscript by Neupane et al. (2023) (1) in Lupus Science and Medicine, which compared the efficacy of anifrolumab and belimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE). The study found that anifrolumab and belimumab are comparable in terms of SRI-4 response at 52 weeks using an indirect treatment comparison (ITC) analysis. The authors noted this was different from our ITC (Bruce et al. 2022) (2) findings where patients on anifrolumab were twice as likely to achieve an improvement in SRI-4 as belimumab.
The difference in the results between Neupane et al. and our study might not be an actual difference but explained by differences in data utilised in the ITC analyses.
First, different SRI-4 results were used. Neupane et al. utilised the SRI-4 results derived from pre-specified restricted medication rules for TULIP-1 whereas our study used results derived from amended medication rules (3). There was an error in the pre-specified restricted medication rules which were subsequently amended to ensure clinical appropriateness (3). As highlighted in our Letter in reply (6), the SRI-4 results derived from the amended rules were agreed to by the FDA and the EMA, and reported in the US Prescribing Information (5) and Summary of Product Characteristics (7). Regulators were aligned with the prespecified outcome definition used in TULIP-2 as well as the BLISS trials, thus they were the appropriate rules to use for the analyses. The large difference in SRI-4 results between the two definitions – the odds ratio changed from favouring placebo to favouring anifrolumab (0.84 to 1.16) – would have impacted the Neupane et al results had the amended rules been used.
Second, Neupane et al. adjusted the baseline BILAG status from the BLISS trials to match the BILAG status at screening from the TULIP trials. In the TULIP trials, there was a difference in the BILAG status at screening (100% ≥ 1A or 2B) and at baseline (94.4% ≥ 1A or 2B), as expected of a disease with activity that fluctuates over time. Our study used baseline BILAG status from both the TULIP and BLISS trials. It was important to account for this to ensure a fair comparison across the trials.
We believe that these differences in data utilised contributed to the differences in results between the two publications. Had Neupane et al. used the TULIP-1 SRI-4 results derived from the amended medication rules and baseline BILAG status for both sets of trials, the results obtained would have been more consistent with our study.
Finally, Neupane et al. inaccurately claims that most or all differences in results can be explained by our study having insufficient data to undertake their approach. Neupane et al. highlighted the reduction of ESS (Effective Sample Size) to 71 in the Bruce et al. MAIC. However, it should be noted the MAIC in our study was only used as a sensitivity analysis. In the primary analysis with an STC, the sample size was not impacted (710), and results were consistent across both analyses. This showed that these results are robust. Also, the MAIC ESS reduction (90%) was within the range identified by a NICE review (4) where the reduction in ESS ranged from 57% to 98%.
In conclusion, we believe that our study is well-conducted and the results are robust. As we enter a new era of having more choice of therapies for our patients living with SLE, comparative analyses such as this will provide an additional layer of support to clinicians, patients and payers in their decision-making.
Sincerely,
Ian N Bruce MD FRCP
Professor of Rheumatology
Centre for Musculoskeletal Research,
Division of Musculoskeletal and Dermatological Sciences,
Faculty of Biology, Medicine and Health
University of Manchester
Manchester, UK
References:
1. Neupane, S., Sattar, A., Isenberg, D. A., et al. (2023). Belimumab versus anifrolumab in adults with systemic lupus erythematosus: an indirect comparison of clinical response at 52 weeks. Lupus Sci Med., 10(1), e000841.
2. Bruce IN, Golam S, Steenkamp J et al. Indirect treatment comparison of anifrolumab efficacy versus belimumab in adults with systemic lupus erythematosus. J. Comp. Eff. Res. doi:10.2217/cer-2022-0040 (2022).
3. Furie, R. A., Morand, E. F., Bruce, I. N., et al. (2019). Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol 2019; 1: e208–19.
4. Phillippo D, Ades T, Dias S et al. NICE DSU technical support document 18: methods for population-adjusted indirect comparisons in submissions to NICE. 2016.
5. SAPHNELO™ Prescribing Information. (2022). https://www.azpicentral.com/pi.html?product=saphnelo
6. Bruce IN, Golam S, Steenkamp K et al. Letter in reply: indirect treatment comparison of anifrolumab efficacy versus belimumab in adults with systemic lupus erythematosus
7. Summary of Product Characteristics – Saphnelo. https://www.ema.europa.eu/documents/product-information/saphnelo-epar-pr...
Ufuk Ilgen
Rheumatology, Ankara University, Ankara, Turkey
On behalf of all co-authors: Ufuk Ilgen, Mucteba Enes Yayla, Askin Ates, Ilyas Ercan Okatan, Emine Uslu Yurteri, Murat Torgutalp, Ayse Bahar Dincer Kelesoglu, Tahsin Murat Turgay, and Gulay Kinikli
Dear Editor,
We read the article by Bao S et al1 with interest. The authors cited our previous work2 by stating: “Prior research of aPL analysis in patients with JSLE did not include the other autoantibodies, and thus the results may not be convincing enough because the impact of the other autoantibodies was neglected in the disease course.” We have some concerns about the interpretation of our results:
1. Our study did not include patients with juvenile-onset SLE. As clearly stated in Methods, all were adult patients. Disease duration did not either date back to childhood (Table 1).
2. Potential impact of other autoantibodies on disease course was not neglected. As stated in Methods, all patients had a panel of 16 autoantibodies (against Sm, nucleosome, histone, PCNA, PO, SS-A 60 kDa, SS-A 52 kDa, SS-B, CENP-B, Scl-70, U1-RNP, Jo-1, PM/Scl, Mi-2, Ku, and dsDNA). However, none were found to be associated with antiphospholipid antibody status.
3. The aim of our study was not to determine a relationship between a general autoantibody profile and SLE manifestations at all. Patients with serial antiphospholipid antibody measurements were included in the study.
Some additi...
Ufuk Ilgen
Rheumatology, Ankara University, Ankara, Turkey
On behalf of all co-authors: Ufuk Ilgen, Mucteba Enes Yayla, Askin Ates, Ilyas Ercan Okatan, Emine Uslu Yurteri, Murat Torgutalp, Ayse Bahar Dincer Kelesoglu, Tahsin Murat Turgay, and Gulay Kinikli
Dear Editor,
We read the article by Bao S et al1 with interest. The authors cited our previous work2 by stating: “Prior research of aPL analysis in patients with JSLE did not include the other autoantibodies, and thus the results may not be convincing enough because the impact of the other autoantibodies was neglected in the disease course.” We have some concerns about the interpretation of our results:
1. Our study did not include patients with juvenile-onset SLE. As clearly stated in Methods, all were adult patients. Disease duration did not either date back to childhood (Table 1).
2. Potential impact of other autoantibodies on disease course was not neglected. As stated in Methods, all patients had a panel of 16 autoantibodies (against Sm, nucleosome, histone, PCNA, PO, SS-A 60 kDa, SS-A 52 kDa, SS-B, CENP-B, Scl-70, U1-RNP, Jo-1, PM/Scl, Mi-2, Ku, and dsDNA). However, none were found to be associated with antiphospholipid antibody status.
3. The aim of our study was not to determine a relationship between a general autoantibody profile and SLE manifestations at all. Patients with serial antiphospholipid antibody measurements were included in the study.
Some additional concerns are:
a. If patients with juvenile-onset SLE in the study by Bao S et al are divided into two groups based solely on the anti-U1-RNP status, the generated groups will exactly be the same as the cluster analysis results provided in Table 2. If a cluster analysis by just a single variable, the anti-U1-RNP status, is run, one will also have exactly the same result. Similar to antiphospholipid antibodies, the inclusion of autoantibodies other than the anti-U1-RNP to clustering would not have any impact on the results. So, the results provided in Table 3 may be interpreted as “clinical features associated with anti-U1-RNP antibodies”.
b. Some autoantibodies such as anti-dsDNA, anti-Sm, and anti-RNP have been known to have strong clinical associations, whereas some have little impact on disease phenotype and activity. Moreover, each may have somewhat differential impact on disease manifestation domains. As an example, positivity (including positive seroconversion) of anti-dsDNA has been known to be associated with nephritis which strongly contributes to disease activity, whereas anti-La positivity (including positive seroconversion) is associated with sicca which is not considered as a component of SLE disease activity in widely used disease activity indices such as SLEDAI. Putting all seroconversions in a single pool may cause losing fine clinical associations of particular autoantibodies. High rate of lupus nephritis in seroconverters in this study is not necessarily related to seroconversion itself, rather this may be related to high prevalence of baseline anti-Sm/RNP in the seroconverter group (Table 1). This point requires further analysis.
In conclusion, clustering based solely on autoantibody profile may not have a clinical translation other than established clinical associations of particular autoantibodies. Clinical associations of seroconversion should be interpreted for each particular autoantibody.
References
1. Bao S, Huang H, Jin Y, et al. Autoantibody-based subgroups and longitudinal seroconversion in juvenile-onset systemic lupus erythematosus. Lupus Science & Medicine 2023;10:e000834. doi:10.1136/ lupus-2022-000834
2. Ilgen U, Yayla ME, Ateş A, et al. Antiphospholipid antibodies and non-thrombotic manifestations of systemic lupus erythematosus. Lupus 2018;27:665-9. doi: 10.1177/0961203317734924
We have read with interest the study from Khawaja et al. entitled ''Loss of antiphospholipid antibody (aPL) positivity post-thrombosis in systemic lupus erythematosus (SLE)''(1). The authors described 31 patients with antiphospholipid syndrome (APS) associated with systemic lupus erythematosus who presented loss of antiphospholipid antibodies (aPL) positivity after thrombotic events.
They measured four types of aPL: IgM, IgG and IgA isotypes of anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). Complete disappearance after thrombosis was observed in 41% of APS patients for IgG aCL, 51% for those with IgM aCL, 50% for IgA aCL, and 20% for LAC. However, 60% of those who at the same time lost IgG aCL and 76% of those who became negative for LAC, reacquired the antibodies within five years. In contrast, only 37% and 17% of those who lost IgM or IgA aCL, reacquired the antibodies within five years, respectively. Finally, 14 (45%) patients never turned back positive during the follow-up period. They concluded that recurrence of aPL positivity is frequent in APS associated with SLE, after their disappearance in post-thrombotic states.
Until now, long term oral anticoagulation (OAC) is the cornerstone of treatment for thrombotic primary and SLE-associated APS (2). The decision to withdraw OAC in APS patients when aPL become "persistently" negative remains a matter of debate. In the light of results fro...
We have read with interest the study from Khawaja et al. entitled ''Loss of antiphospholipid antibody (aPL) positivity post-thrombosis in systemic lupus erythematosus (SLE)''(1). The authors described 31 patients with antiphospholipid syndrome (APS) associated with systemic lupus erythematosus who presented loss of antiphospholipid antibodies (aPL) positivity after thrombotic events.
They measured four types of aPL: IgM, IgG and IgA isotypes of anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). Complete disappearance after thrombosis was observed in 41% of APS patients for IgG aCL, 51% for those with IgM aCL, 50% for IgA aCL, and 20% for LAC. However, 60% of those who at the same time lost IgG aCL and 76% of those who became negative for LAC, reacquired the antibodies within five years. In contrast, only 37% and 17% of those who lost IgM or IgA aCL, reacquired the antibodies within five years, respectively. Finally, 14 (45%) patients never turned back positive during the follow-up period. They concluded that recurrence of aPL positivity is frequent in APS associated with SLE, after their disappearance in post-thrombotic states.
Until now, long term oral anticoagulation (OAC) is the cornerstone of treatment for thrombotic primary and SLE-associated APS (2). The decision to withdraw OAC in APS patients when aPL become "persistently" negative remains a matter of debate. In the light of results from Khawaja et al. (1), the discontinuation of OAC in patients with APS associated with SLE would not be advisable.
In a previous study (3), we described 11 patients with primary APS and low-risk aPL profile, who had their aPL persistently negative after thrombotic/obstetric morbidity manifestations, and in whom antithrombotic treatment was withdrawn. No new thrombotic events were observed after 20 months of follow-up.
We want to point out two different characteristics between the present study and ours: 1) our study did not include patients with SLE-associated APS; therefore, the population target of the two cohorts are not comparable; and 2) patients included in our study had low-risk aPL profile defined by the presence of only two positive aPL determinations pre-thrombosis or obstetric morbidity.
Zen et al. (4) described a small cohort of 16 patients with SLE-associated-APS in whom aPL became negative. Treatment with immunosuppressants was an independent predictor for negativization of aPL because they observed that seronegative patients received immunosuppressive therapy more frequently than patients with persistent positivity for aPL, suggesting downregulation of inflammatory pathways. Also, the immunomodulatory effect of antimalarials could contribute to aPL negativization during follow-up.
Further research is, therefore, needed to determine if discontinuation of OAC could be accepted in some patients with APS (i.e., those with primary APS and low-risk aPL profile, who had their aPL persistently negative after thrombotic/obstetric morbidity manifestations).
Declaration of conflicting interests
The authors declared no potential conflicts of interest concerning the research, authorship, and publication of this article.
Funding
The authors received no financial support for the research, authorship, and publication of this article.
References
1. Khawaja M, Magder L, Goldman D, Petri MA. Loss of antiphospholipid antibody positivity post-thrombosis in SLE. Lupus Sci Med. 2020;7(1):1–7.
2. Tektonidou MG, Andreoli L, Limper M, Amoura Z, Cervera R, Costedoat-Chalumeau N, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019;78(10):1296–304.
3. Coloma Bazán E, Donate López C, Moreno Lozano P, Cervera R, Espinosa G. Discontinuation of anticoagulation or antiaggregation treatment may be safe in patients with primary antiphospholipid syndrome when antiphospholipid antibodies became persistently negative. Immunol Res. 2013;56(2–3):358–61.
4. Zen M, Loredo Martinez M, Benvenuti F, Gatto M, Saccon F, Larosa M, et al. Prevalence, outcome and management of patients with SLE and secondary antiphospholipid antibody syndrome after aPL seroconversion. Rheumatology. 2020;1–8.
Dr Olsen and Karp have summarised data from several important papers on the use of novel diagnostic tests for earlier diagnosis of SLE. I agree in the importance of this problem, for the early exclusion of SLE in people with benign ANA positivity, and early intervention in people destined to develop SLE or related disease.
I also agree with the key challenges in such research. Previous studies have been limited by a retrospective design. Inclusion of patients with variable symptom duration or patient populations that were selected for certain clinical characteristics may bias findings by conditioning on the outcome. Also, putative biomarker results need to be appraised alongside routine diagnostic tests, not in isolation.
These challenges were met in our previous study into these questions[1]. We invited all ANA-positive referrals to our centre with an onset of the symptoms that triggered referral within the past 12 months to participate, ensuring an unbiased sample appropriate to the clinical question. We collected detailed data on clinical presentation, routine immunology assessments, patient and physician reported severity, and family history, and integrated these data into our biomarker evaluation. Our patients were recruited and followed up prospectively in a standardised schedule of visits with strict assessment of criteria and a "flare hotline" in case new symptoms developed.
By doing so, we were able to reliably demonstrate the value...
Dr Olsen and Karp have summarised data from several important papers on the use of novel diagnostic tests for earlier diagnosis of SLE. I agree in the importance of this problem, for the early exclusion of SLE in people with benign ANA positivity, and early intervention in people destined to develop SLE or related disease.
I also agree with the key challenges in such research. Previous studies have been limited by a retrospective design. Inclusion of patients with variable symptom duration or patient populations that were selected for certain clinical characteristics may bias findings by conditioning on the outcome. Also, putative biomarker results need to be appraised alongside routine diagnostic tests, not in isolation.
These challenges were met in our previous study into these questions[1]. We invited all ANA-positive referrals to our centre with an onset of the symptoms that triggered referral within the past 12 months to participate, ensuring an unbiased sample appropriate to the clinical question. We collected detailed data on clinical presentation, routine immunology assessments, patient and physician reported severity, and family history, and integrated these data into our biomarker evaluation. Our patients were recruited and followed up prospectively in a standardised schedule of visits with strict assessment of criteria and a "flare hotline" in case new symptoms developed.
By doing so, we were able to reliably demonstrate the value of interferon gene expression scores as independent predictors of progression suitable for exclusion of future SLE or early intervention at first clinic assessment. These biomarkers had previously been validated against disease activity in established SLE and shown to differentiate SLE and RA.
These results should therefore be considered alongside those cited in the review.
[1] Md Yusof et al. Ann Rheum Dis. 2018 Oct;77(10):1432-1439.
Dear editor;
We have read with great interest the article published by Haque et al. which was about association between atherosclerotic process, cardiovascular outocomes and systemic lupus erythematosus (SLE). It is reported that only SDI score, triglyceride level and cyclophosphamide exposure was predictive for future cardiovascular events and factors related with plaque progression were defined(1).
SLE is a multisystemic disorder and lupus nephritis is one of the main manifestions of the disease. It usually presents with proteinuria and deteriorated renal glomerular functions. Renin angiotensinogen antgiotensin system (RAAS) inhibitors are used in patients with lupus nephritis to reduce proteinuria and kidney function protection(3). Angiotensin II (AT II) has unfavorable effects on endothelial functions. AT II binds AT 1 receptors and promotes vasoconstriction and production of proinlammatory cytokines and proliferation factors. It is shown by several studies that RAAS inhibitors improves endothelial functions and induces the regression of atherosclerotic process(3).
Microalbuminuria (MAU) and proteinuria are related with worse cardiovascular outcomes. Microalbuminuria causes endothelial dysfunction and associated with accelerated atherosclerosis(4). MESA study demonstrated that coronary calcification is significantly higher in patients with microalbuminuria than counterparts without MAU. Not only presence but also amount of MAU is associated with insu...
Dear editor;
We have read with great interest the article published by Haque et al. which was about association between atherosclerotic process, cardiovascular outocomes and systemic lupus erythematosus (SLE). It is reported that only SDI score, triglyceride level and cyclophosphamide exposure was predictive for future cardiovascular events and factors related with plaque progression were defined(1).
SLE is a multisystemic disorder and lupus nephritis is one of the main manifestions of the disease. It usually presents with proteinuria and deteriorated renal glomerular functions. Renin angiotensinogen antgiotensin system (RAAS) inhibitors are used in patients with lupus nephritis to reduce proteinuria and kidney function protection(3). Angiotensin II (AT II) has unfavorable effects on endothelial functions. AT II binds AT 1 receptors and promotes vasoconstriction and production of proinlammatory cytokines and proliferation factors. It is shown by several studies that RAAS inhibitors improves endothelial functions and induces the regression of atherosclerotic process(3).
Microalbuminuria (MAU) and proteinuria are related with worse cardiovascular outcomes. Microalbuminuria causes endothelial dysfunction and associated with accelerated atherosclerosis(4). MESA study demonstrated that coronary calcification is significantly higher in patients with microalbuminuria than counterparts without MAU. Not only presence but also amount of MAU is associated with insulin resistence, hyperlipidemia and endothelial dysfunction(5). Cyclophosphamide is usually given when the patient has severe renal involvement so proteinuria may explain the relationship between cyclophosphamide exposure and future cardiovascular events.
To conclude; as most of medications were evaluated in the study, we think that it would be better either use of RAAS inhibitor was also assessed. Moreover, presence and the amount of proteinuria should give additional valuble information in the study population.
References;
1. Haque S, Skeoch S, Rakieh C et al. Progression of subclinical and clinical cardiovascular disease in a UK SLE cohort: the role of classic and SLE related factors. Lupus Sci Med. 2018 Nov 17;5(1):e000267.
2. Aziz F, Chaudhary K. Lupus Nephritis: A Treatment Update. Curr Clin Pharmacol. 2018;13(1):4-13.
3. Radenkovic M, Stojanovic M, Nesic IM et al. Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications. Indian J Med Res. 2016 Aug; 144(2): 154–168.
4. Nada DW, El Morsy S, Abu-Zaid MH et al. The role of microalbuminuria as a predictor of subclinical cardiovascular events in rheumatoid arthritis patients and its relation to disease activity. Clin Rheumatol. 2018 Mar;37(3):623-630.
5. Hyo Eun Park, Nam Ju Heo, Minkyung Kim, Su-Yeon Choi. Significance of Microalbuminuria in Relation to Subclinical Coronary Atherosclerosis in Asymptomatic Nonhypertensive, Nondiabetic Subjects. J Korean Med Sci. 2013 Mar; 28(3): 409–414.
Dear editor,
We read with interest the article of Idborg et al.1 who recently analyzed the role of several inflammatory mediators, and their usefulness as biomarkers in the measurement of activity of disease and the identification of clinical subphenotypes in systemic lupus erythematosus (SLE). Although interesting, these results may benefit of further discussion in light of systems medicine.
Authors concluded that the two main inflammatory mediators related with activity of SLE were TNF-α and p-albumin. However, previous studies have found that TNF-α and the TNF/IL-10 ratio were higher in patients with low activity of disease,2 and that TNF-α antagonists may induce SLE-like disease.3 These controversial data argues against a generalized model based on TNF-α as clinical activity biomarker, and advocate for the influence of other mediators in such a condition.
As shown by Idborg et al., IL-6, IL-10, IL-15, MCP-1, IP-10, MIP-1α, ESR, anti-dsDNA and U-albumin/creatinine were also positively correlated with activity of disease,1 suggesting that the exclusive role of TNF-α and p-albumin on activity of disease is unlikely. In fact, the pathological functions of these biomarkers are not isolate since they emerge from the interactions among them and between cells and tissues (i.e., systems medicine).4
In this sense, cytokine and autoantibody clusters (i.e., neutral, chemotactic/anti-phospholipid antibodies, and IFN-α/dsDNA) have been reported to be associat...
Dear editor,
We read with interest the article of Idborg et al.1 who recently analyzed the role of several inflammatory mediators, and their usefulness as biomarkers in the measurement of activity of disease and the identification of clinical subphenotypes in systemic lupus erythematosus (SLE). Although interesting, these results may benefit of further discussion in light of systems medicine.
Authors concluded that the two main inflammatory mediators related with activity of SLE were TNF-α and p-albumin. However, previous studies have found that TNF-α and the TNF/IL-10 ratio were higher in patients with low activity of disease,2 and that TNF-α antagonists may induce SLE-like disease.3 These controversial data argues against a generalized model based on TNF-α as clinical activity biomarker, and advocate for the influence of other mediators in such a condition.
As shown by Idborg et al., IL-6, IL-10, IL-15, MCP-1, IP-10, MIP-1α, ESR, anti-dsDNA and U-albumin/creatinine were also positively correlated with activity of disease,1 suggesting that the exclusive role of TNF-α and p-albumin on activity of disease is unlikely. In fact, the pathological functions of these biomarkers are not isolate since they emerge from the interactions among them and between cells and tissues (i.e., systems medicine).4
In this sense, cytokine and autoantibody clusters (i.e., neutral, chemotactic/anti-phospholipid antibodies, and IFN-α/dsDNA) have been reported to be associated with activity of SLE.5 Thus, data from Idborg et al. study could have been treated differently (i.e., cluster analysis) in order to obtain an interaction between the mediators evaluated and disease activity.
References
1 Idborg H, Eketjäll S, Pettersson S, et al. TNF-α and plasma albumin as biomarkers of disease activity in systemic lupus erythematosus. Lupus Sci Med 2018;5. doi:10.1136/lupus-2018-000260
2 Gomez D, Correa PA, Gomez LM, et al. Th1/Th2 cytokines in patients with systemic lupus erythematosus: is tumor necrosis factor alpha protective? Semin Arthritis Rheum 2004;33:404–13.
3 Williams VL, Cohen PR. TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with implications for treatment with alternative TNF alpha antagonists. Int J Dermatol 2011;50:619–25. doi:10.1111/j.1365-4632.2011.04871.x
4 Kirschner M. Systems Medicine: Sketching the Landscape. Methods Mol Biol 2016;1386:3–15. doi:10.1007/978-1-4939-3283-2_1
5 Pacheco Y, Barahona-Correa J, Monsalve DM, et al. Cytokine and autoantibody clusters interaction in systemic lupus erythematosus. J Transl Med 2017;15:239. doi:10.1186/s12967-017-1345-y
The Editor,
Lupus Science and Medicine
BMJ Journals
Dear Madam/Sir,
Our esteemed peer Dr. Boers has editorialised1 on our recently published study of associations of glucocorticoid use with damage accrual in SLE2, suggesting that studies of the type reported are ‘harmful’. As this is such a serious accusation, we feel compelled to respond, even though we suspect that in the end the views of the authors and of Dr Boers as serious physician-researchers are in fact highly aligned. Essentially, we do not resile from our view that long-term reliance on glucocorticoids for the control of inflammation in SLE carries harm, and that steroid-reducing regimens for SLE management are urgently needed. At no time in our report, and certainly not in our clinical practice, do we advise against the use of these drugs, though such an imprecation was implied (incorrectly) in Dr Boers’ editorial. Rather, it is our view that strategies to achieve control of disease activity with reduced reliance on glucocorticoids, such as improving the use of non-glucocorticoid agents or the introduction of novel therapies, are as urgently needed as ever – and that complacency about the chronic use of glucocorticoids in SLE is not an acceptable status quo.
As we stated in the opening remarks, ‘The objective of the present study was to quantify damage accrual in a prospectively followed cohort of patients with SLE and determine the association of glucocorticoid use with damage...
The Editor,
Lupus Science and Medicine
BMJ Journals
Dear Madam/Sir,
Our esteemed peer Dr. Boers has editorialised1 on our recently published study of associations of glucocorticoid use with damage accrual in SLE2, suggesting that studies of the type reported are ‘harmful’. As this is such a serious accusation, we feel compelled to respond, even though we suspect that in the end the views of the authors and of Dr Boers as serious physician-researchers are in fact highly aligned. Essentially, we do not resile from our view that long-term reliance on glucocorticoids for the control of inflammation in SLE carries harm, and that steroid-reducing regimens for SLE management are urgently needed. At no time in our report, and certainly not in our clinical practice, do we advise against the use of these drugs, though such an imprecation was implied (incorrectly) in Dr Boers’ editorial. Rather, it is our view that strategies to achieve control of disease activity with reduced reliance on glucocorticoids, such as improving the use of non-glucocorticoid agents or the introduction of novel therapies, are as urgently needed as ever – and that complacency about the chronic use of glucocorticoids in SLE is not an acceptable status quo.
As we stated in the opening remarks, ‘The objective of the present study was to quantify damage accrual in a prospectively followed cohort of patients with SLE and determine the association of glucocorticoid use with damage’; similarly, we concluded ‘our findings suggest the urgent need for a randomised study comparing the effect on damage accrual of usual care with that of a strategy that stringently limits glucocorticoid dosing’. That our report, like virtually all science that benefits from peer review, was improved in response to reviewers’ input is scarcely newsworthy. As peer reviewers we all collectively strive to help authors and readers achieve the best outcome from submitted work, be it through rejection or suggestions for improvement. Moreover, one of the longest paragraphs in our report was an assessment of the limitations of the data and its analysis, and we also clearly state the possibility that glucocorticoid dose is largely, though not completely, a surrogate measure of disease activity. We thank Dr. Boers for restating these in his editorial, although we would have preferred it to have been acknowledged that we had done likewise in our report.
While confounding by indication is a methodological concern in assessment of treatment effects using observational cohort data, there is no single standard dose of steroid applied universally for the treatment of each lupus manifestation. Furthermore, factors other than lupus activity such as musculoskeletal pain due to degenerative joint disease and fibromyalgia, often influence steroid tapering. Accordingly, in real-life cohort data sets, these variations in steroid dosing relative to disease activity score provide an opportunity to tease apart, albeit with limitation, some of the harmful effect of steroids from disease activity itself.
We accept neither the proposition that this study was fatally flawed or that its conclusions are harmful. Rather, we propose the possibility that chronic glucocorticoid exposure has hitherto-unexplored associations with harmful effects that contribute to negative outcomes in SLE above and beyond their largely metabolically-based ‘side-effects’. In unpublished studies on MRL/lpr lupus-prone mice, we have observed that glucocorticoid treatment was associated with accelerated mortality - the mechanism of this effect is as yet unknown, but glucocorticoids induce the release of macrophage migration inhibitory factor (MIF), a protein demonstrated clearly to be harmful in models of SLE by us and other groups3, 4. The most harmful thing we could do is fail to remain open to the possibility that independent of their confounding by indication, glucocorticoids are indeed causing undiscovered dose-related harmful effects with long-term use in SLE. We maintain our view that this is an area of medical science in need of deeper exploration.
D Apostolopoulos, M Nikpour, A Hoi, EF Morand.
1. Boers, M. 2017. Observational studies on glucocorticoids are harmful! Lupus Sci Med 4(1) e000219.
2. Apostolopoulos, D. et al. 2016. Independent association of glucocorticoids with damage accrual in SLE. Lupus Sci Med 3(1) e000157.
3. Hoi, A.Y. et al. 2006. Protection from crescentic glomerulonephritis in MIF-deficient MRL/lpr mice associated with reductions in macrophage recruitment and MCP-1. Arthritis Rheum 54(9) S283-S283.
4. Leng, L. et al. 2010. A small-molecule macrophage migration inhibitory factor antagonist protects against glomerulonephritis in lupus-prone NZB/NZW F1 and MRL/lpr mice. J Immunol 186(1) 527-538.
Geraldino-Pardillaet al.1 recently published an interesting article analysing one of the most important aspects of systemic lupus erythematosus (SLE): the risk of cardiovascular disease, a leading cause of death in SLE patients. Although there were no healthy control group to compare, and the SLE patient sample size was limited, their conclusions are clinically valuable and should be taken into consideration.
The usefulness of the corrected QT interval (QTc) as a marker of atherosclerosis risk is well-established in the general population and in some sub-groups with high cardiovascular risk. QTc prolongation is also linked to cardiovascular events and mortality during follow-up2-3. QTc interval prolongation in SLE patients has been described in previous studies4.However, no data on the clinical repercussions of this finding are available. Our research group recently published a paper on the positive correlation between QTc interval prolongation in SLE patients and higher arterial stiffness measured by pulse-wave velocity5. The association was independent of hypertension and age. Our data complement those published by Geraldino-Pardilla et al.1, suggesting an independent association between QTc interval prolongation and subclinical atherosclerosis. However, there is no evidence of the long-term clinical effects of this association. Prospective studies with large sample sizes and long follow-up periods are required to study the potential long-term effects. In any case...
Geraldino-Pardillaet al.1 recently published an interesting article analysing one of the most important aspects of systemic lupus erythematosus (SLE): the risk of cardiovascular disease, a leading cause of death in SLE patients. Although there were no healthy control group to compare, and the SLE patient sample size was limited, their conclusions are clinically valuable and should be taken into consideration.
The usefulness of the corrected QT interval (QTc) as a marker of atherosclerosis risk is well-established in the general population and in some sub-groups with high cardiovascular risk. QTc prolongation is also linked to cardiovascular events and mortality during follow-up2-3. QTc interval prolongation in SLE patients has been described in previous studies4.However, no data on the clinical repercussions of this finding are available. Our research group recently published a paper on the positive correlation between QTc interval prolongation in SLE patients and higher arterial stiffness measured by pulse-wave velocity5. The association was independent of hypertension and age. Our data complement those published by Geraldino-Pardilla et al.1, suggesting an independent association between QTc interval prolongation and subclinical atherosclerosis. However, there is no evidence of the long-term clinical effects of this association. Prospective studies with large sample sizes and long follow-up periods are required to study the potential long-term effects. In any case, this paper highlights the role that QT interval analysis could play in cardiovascular risk stratification in SLE patients.
References
1 Geraldino-Pardilla L, Gartshteyn Y, Piña P, et al. ECG non-specific ST-T and QTc abnormalities in patients with systemic lupus erythematosus compared with rheumatoid arthritis. Lupus Science & Medicine 2016;3.e000168.
2 Dekker JM, Crow RS, Hannan PJ, et al, ARIC Study. Heart rate-corrected QT interval prolongation predicts risk of coronary heart disease in black and white middle-aged men and women: the ARIC study. J Am Coll Cardiol 2004;43:565-71.
3 Panoulas VF, Toms TE, Douglas KM, et al. Prolonged QTc interval predicts all-cause mortality in patients with rheumatoid arthritis: an association driven by high inflammatory burden. Rheumatology (Oxford), 2014;53:131-7.
4 Cardoso CR, Sales MA, Papi JA, et al. QT-interval parameters are increased in systemic lupus erythematosus patients. Lupus 2005;14:846-52.
5 Rivera-López R, Jiménez-Jáimez J, Sabio JM, et al. Relationship between QT Interval Length and Arterial Stiffness in Systemic Lupus Erythematosus (SLE): A Cross-Sectional Case-Control Study. PLoS One 2016;11.e0152291.
After reading the article by Carli et al.(1) we would like to share
some thoughts that could be of practical use regarding vitamin D
supplementation in patients on low-dose glucocorticoids therapy.
In 2011, we published the results of a follow-up carried out in our
unit (located in a hospital in Granada, a sunny city in the south of
Spain) that included a cohort of 55 patients with systemi...
After reading the article by Carli et al.(1) we would like to share
some thoughts that could be of practical use regarding vitamin D
supplementation in patients on low-dose glucocorticoids therapy.
In 2011, we published the results of a follow-up carried out in our
unit (located in a hospital in Granada, a sunny city in the south of
Spain) that included a cohort of 55 patients with systemic lupus
erythematosus (SLE)(2); same as in the study by Carli et al., an important
percentage of patients had hypovitaminosis D (78.3% during summer and
90.6% during winter), and concentrations <15ng/ml in 39.1% of the
patients (throughout the whole year), despite the fact that 65.5% of them
were taking vitamin D supplementation (over 80% of the patients in the
study by Carli et al.). The authors of the above-mentioned article believe
the high prevalence of hypovitaminosis D could be explained by an
incorrect use of calcium and vitamin D supplements or a low compliance to
the medical indications. Other possible explanations that they argue are
the use of glucocorticoids or certain vitamin D receptor polymorphisms. In
subsequent studies, we found that in patients with different types of
autoimmune diseases treated with low doses of corticoids there is an
indirect correlation between corticoid dose and 25OHD levels(3); this
finding has been documented by other authors (4), as well as in a recent
meta-analysis (5). A realistic explanation for the low levels of 25OHD in
patients under glucocorticoid therapy is their effect on vitamin D
hydroxylation; experimental studies have shown that prednisolone
administration in rats inhibits the activity of vitamin D3 25-hydroxylase
(6). Furthermore, when our patients were given calcifediol, a lower
frequency of hypovitaminosis D was observed in comparison with those
patients treated with cholecalciferol (27.1% vs. 35%).
Calcifediol is sold in Spain, France, Italy, and Portugal; FDA approval
for its use in secondary hyperparathyroidism (SHPT) in patients with stage
3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency is
pending. We believe that in countries where it is available, its use in
patients on chronic glucocorticoid therapy can be a more physiological and
effective alternative to cholecalciferol.
1. Carli L, Tani C, Spera V, et al. Risk factors for osteoporosis and
fragility fractures in patients with systemic lupus erythematosus. Lupus
Sci Med 2016;3:e000098.
2. Lopez-Robles C, Rios-Fernandez R, Callejas-Rubio JL, Ortego-
Centeno N. Vitamin D deficiency in a cohort of patients with systemic
lupus erythematosus from the South of Spain. Lupus 2011;20:330-1.
3. Ortego-Jurado M, Callejas-Rubio JL, Rios-Fernandez R, et al. Oral
Calcidiol Is More Effective Than Cholecalciferol Supplementation to Reach
Adequate 25(OH)D Levels in Patients with Autoimmune Diseases Chronically
Treated with Low Doses of Glucocorticoids: A "Real-Life" Study. J
Osteoporos 2015;2015:729451.
4. Skversky AL, Kumar J, Abramowitz MK, Kaskel FJ, Melamed ML.
Association of glucocorticoid use and low 25-hydroxyvitamin D levels:
results from the National Health and Nutrition Examination Survey
(NHANES): 2001-2006. J Clin Endocrinol Metab 2011;96:3838-45.
5. Davidson ZE, Walker KZ, Truby H. Clinical review: Do
glucocorticosteroids alter vitamin D status? A systematic review with meta
-analyses of observational studies. J Clin Endocrinol Metab 2011;97:738-
44.
6. Khomenko AV. [Cholecalciferol hydroxylation in rat hepatocytes
under the influence of prednisolone]. Ukr Biokhim Zh (1999) 2013;85:90-5.
We read with great interest the article of Greloni et al, "Value of repeat
biopsy in lupus nephritis flares" and have some comments.
There is a high probability that what they call "histologic
transformation" is further evidence of the poor reproducibility of the
interpretation of the renal biopsy in lupus nephritis and no evidence that
there really been a change in the biological phenomenon o...
We read with great interest the article of Greloni et al, "Value of repeat
biopsy in lupus nephritis flares" and have some comments.
There is a high probability that what they call "histologic
transformation" is further evidence of the poor reproducibility of the
interpretation of the renal biopsy in lupus nephritis and no evidence that
there really been a change in the biological phenomenon observed. Before
checking the validity of the renal biopsy for diagnosis, prognosis or
prediction of response should have checked the reliability of the result
we receive. The reliability or accuracy refers to how similar are the
measurements the same phenomenon at different times or by different people
or methods.
Few studies attempt to assess the reliability of the interpretation
of the renal biopsy. The results of most reports show very poor or
moderate correlations at best. The results of the three largest and best-
methodological design studies are downright disappointing and disturbing
(1-3). In the study of Grootscholten et al(2)five experts
nephropathologist evaluated 126 renal biopsies of patients with lupus
nephritis and obtained an interrater agreement of 0.18 to diagnose the
histological class by current classification (ISN / RPS 2003) (4);
interrater agreement quietly rose to 0.25 when the outcome was simply to
establish whether it was a proliferative or not.
In addition to the poor reliability of most measurements that are
made during the reading of the biopsy, we believe that a critical factor
is the size of the sample obtained.A very important but often overlooked
point is the error inherent in any measurement. When we obtain a value for
a measure is essential to know the accuracy of the result observed. The
current classification states that the biopsy should contain at least 10
glomeruli for an accurate reading. In daily practice, usually the number
of glomeruli range from 5-20, and the publications about renal biopsies in
lupus usually do not give such information.
The problem of considering than 10 glomeruli is an acceptable number
is the inaccuracy of the value found for considering reflection of the
total population of renal glomeruli. As noted by Corwin et al., the number
of abnormal glomeruli present in a renal biopsy can be viewed as a
binomial distribution. Recognition of this fact permits a quantitative
assessment of the effect of biopsy sample size in renal biopsy
interpretation.
The confidence interval for any counting using only 10 glomeruli is
extremely broad. The probability of error in determining the histological
type are very high. With only 10 glomeruli altered the cumulative
probability of finding none (0 of 10) is 35% when the proportion of
glomeruli affected is 10%, and the cumulative probability of seeing 0-4
altered glomerular (and classified as class III) is 38% when in fact at
least 50% of glomeruli are altered, it actually corresponds to a class IV.
On the other hand, if 2 glomeruli were found with proliferation (out of 10
observed), the report must include the binomial confidence interval, in
this case is 0 to almost 60%, in which meet at least 3 different
histological categories (normal, <50%, =>50%).
Finally, but not least, although it appears that the new biopsies
were associated with changes in therapy or prognosis prediction, this is
not a justification for them because their marginal benefit should be
evaluated beyond what clinicians and multivariate mathematical models can
make or predict using all clinical and laboratory available information (6
-12) without invasive, costly and risky methods (13-14) such as renal
biopsy.
References
1. Furness PN, Taub N. Interobserver reproducibility and application of
the ISN/RPS classification of lupus nephritis-a UK-wide study. Am J Surg
Pathol. 2006 Aug;30(8):1030-5.
2. Grootscholten C, Bajema IM, Florquin S, Steenbergen EJ, Peutz-Kootstra
CJ, Goldschmeding R, et al. Interobserver agreement of scoring of
histopathological characteristics and classification of lupus nephritis.
Nephrol Dial Transplant. 2008 Jan;23(1):223-30.
3. Rao K, Ferrario F, Cook T, Bajema I, Bruijn JA, Noel L-H, et al. Lupus
Nephritis Histopathology Interobserver Agreement Between Local Pathologist
And An Expert Panel Of Nephropathologist In Belong. Ann Rheum Dis.
2012;71((Suppl3)):74.
4. Weening JJ, D'Agati VD, Schwartz MM, Seshan S V, Alpers CE, Appel GB,
et al. The classification of glomerulonephritis in systemic lupus
erythematosus revisited. Kidney Int. 2004 Feb;65(2):521-30.
5. Corwin HL, Schwartz MM, Lewis EJ. The importance of sample size in the
interpretation of the renal biopsy. Am J Nephrol. 1988 Jan;8(2):85-9.
6. Fries JF. Marginal Benefit of Renal Biopsy in Systemic Lupus
Erythematosus. Arch Intern Med. American Medical Association; 1978 Sep
1;138(9):1386.
7. Hao W, Rovin BH, Friedman A. Mathematical model of renal interstitial
fibrosis. Proc Natl Acad Sci U S A. 2014 Sep 15;111(39):14193-8.
8. Esdaile JM, Mackenzie T, Barr? P, Danoff D, Osterland CK, Somerville
P, et al. Can experienced clinicians predict the outcome of lupus
nephritis? Lupus. 1992 Aug;1(4):205-14.
9. Whiting-O'Keefe Q, Riccardi PJ, Henke JE, Shearn MA, Hopper J, Epstein
W V. Recognition of information in renal biopsies of patients with lupus
nephritis. Ann Intern Med. 1982 Jun;96(6 Pt 1):723-7.
10. Nossent JC, Bronsveld W, Swaak AJ. Systemic lupus erythematosus. III.
Observations on clinical renal involvement and follow up of renal
function: Dutch experience with 110 patients studied prospectively. Ann
Rheum Dis. 1989 Oct;48(10):810-6.
11. Jakez-Ocampo J, Arreola-Zavala R, Richaud-Patin Y, Romero-D?az J,
Llorente L. Lupus nephritis outcome with and without renal biopsy: a 5-
year comparative study. J Clin Rheumatol. 2004 Dec;10(6):289-94.
12. Melo AKG de, Avelar AB, Maegawa FKM, Souza BDB de. Avalia??o de 100
pacientes com nefrite l?pica acompanhados por dois anos. Rev Bras
Reumatol. Sociedade Brasileira de Reumatologia; 2009 Feb;49(1):8-19.
13. Torres Mu?oz A, Valdez-Ortiz R, Gonz?lez-Parra C, Espinoza-D?vila E,
Morales-Buenrostro LE, Correa-Rotter R. Percutaneous renal biopsy of
native kidneys: efficiency, safety and risk factors associated with major
complications. Arch Med Sci. 2011 Oct;7(5):823-31.
14. Chen TK, Estrella MM, Fine DM. Predictors of kidney biopsy
complication among patients with systemic lupus erythematosus. Lupus. 2012
Jul;21(8):848-54.
We read with interest the recent manuscript by Neupane et al. (2023) (1) in Lupus Science and Medicine, which compared the efficacy of anifrolumab and belimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE). The study found that anifrolumab and belimumab are comparable in terms of SRI-4 response at 52 weeks using an indirect treatment comparison (ITC) analysis. The authors noted this was different from our ITC (Bruce et al. 2022) (2) findings where patients on anifrolumab were twice as likely to achieve an improvement in SRI-4 as belimumab.
The difference in the results between Neupane et al. and our study might not be an actual difference but explained by differences in data utilised in the ITC analyses.
First, different SRI-4 results were used. Neupane et al. utilised the SRI-4 results derived from pre-specified restricted medication rules for TULIP-1 whereas our study used results derived from amended medication rules (3). There was an error in the pre-specified restricted medication rules which were subsequently amended to ensure clinical appropriateness (3). As highlighted in our Letter in reply (6), the SRI-4 results derived from the amended rules were agreed to by the FDA and the EMA, and reported in the US Prescribing Information (5) and Summary of Product Characteristics (7). Regulators were aligned with the prespecified outcome definition used in TULIP-2 as well as the BLISS trials, thus they were the appropriate rules to use...
Show MoreUfuk Ilgen
Rheumatology, Ankara University, Ankara, Turkey
On behalf of all co-authors: Ufuk Ilgen, Mucteba Enes Yayla, Askin Ates, Ilyas Ercan Okatan, Emine Uslu Yurteri, Murat Torgutalp, Ayse Bahar Dincer Kelesoglu, Tahsin Murat Turgay, and Gulay Kinikli
Dear Editor,
We read the article by Bao S et al1 with interest. The authors cited our previous work2 by stating: “Prior research of aPL analysis in patients with JSLE did not include the other autoantibodies, and thus the results may not be convincing enough because the impact of the other autoantibodies was neglected in the disease course.” We have some concerns about the interpretation of our results:
1. Our study did not include patients with juvenile-onset SLE. As clearly stated in Methods, all were adult patients. Disease duration did not either date back to childhood (Table 1).
2. Potential impact of other autoantibodies on disease course was not neglected. As stated in Methods, all patients had a panel of 16 autoantibodies (against Sm, nucleosome, histone, PCNA, PO, SS-A 60 kDa, SS-A 52 kDa, SS-B, CENP-B, Scl-70, U1-RNP, Jo-1, PM/Scl, Mi-2, Ku, and dsDNA). However, none were found to be associated with antiphospholipid antibody status.
3. The aim of our study was not to determine a relationship between a general autoantibody profile and SLE manifestations at all. Patients with serial antiphospholipid antibody measurements were included in the study.
Show MoreSome additi...
To the editor,
We have read with interest the study from Khawaja et al. entitled ''Loss of antiphospholipid antibody (aPL) positivity post-thrombosis in systemic lupus erythematosus (SLE)''(1). The authors described 31 patients with antiphospholipid syndrome (APS) associated with systemic lupus erythematosus who presented loss of antiphospholipid antibodies (aPL) positivity after thrombotic events.
They measured four types of aPL: IgM, IgG and IgA isotypes of anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). Complete disappearance after thrombosis was observed in 41% of APS patients for IgG aCL, 51% for those with IgM aCL, 50% for IgA aCL, and 20% for LAC. However, 60% of those who at the same time lost IgG aCL and 76% of those who became negative for LAC, reacquired the antibodies within five years. In contrast, only 37% and 17% of those who lost IgM or IgA aCL, reacquired the antibodies within five years, respectively. Finally, 14 (45%) patients never turned back positive during the follow-up period. They concluded that recurrence of aPL positivity is frequent in APS associated with SLE, after their disappearance in post-thrombotic states.
Until now, long term oral anticoagulation (OAC) is the cornerstone of treatment for thrombotic primary and SLE-associated APS (2). The decision to withdraw OAC in APS patients when aPL become "persistently" negative remains a matter of debate. In the light of results fro...
Show MoreDr Olsen and Karp have summarised data from several important papers on the use of novel diagnostic tests for earlier diagnosis of SLE. I agree in the importance of this problem, for the early exclusion of SLE in people with benign ANA positivity, and early intervention in people destined to develop SLE or related disease.
I also agree with the key challenges in such research. Previous studies have been limited by a retrospective design. Inclusion of patients with variable symptom duration or patient populations that were selected for certain clinical characteristics may bias findings by conditioning on the outcome. Also, putative biomarker results need to be appraised alongside routine diagnostic tests, not in isolation.
These challenges were met in our previous study into these questions[1]. We invited all ANA-positive referrals to our centre with an onset of the symptoms that triggered referral within the past 12 months to participate, ensuring an unbiased sample appropriate to the clinical question. We collected detailed data on clinical presentation, routine immunology assessments, patient and physician reported severity, and family history, and integrated these data into our biomarker evaluation. Our patients were recruited and followed up prospectively in a standardised schedule of visits with strict assessment of criteria and a "flare hotline" in case new symptoms developed.
By doing so, we were able to reliably demonstrate the value...
Show MoreDear editor;
Show MoreWe have read with great interest the article published by Haque et al. which was about association between atherosclerotic process, cardiovascular outocomes and systemic lupus erythematosus (SLE). It is reported that only SDI score, triglyceride level and cyclophosphamide exposure was predictive for future cardiovascular events and factors related with plaque progression were defined(1).
SLE is a multisystemic disorder and lupus nephritis is one of the main manifestions of the disease. It usually presents with proteinuria and deteriorated renal glomerular functions. Renin angiotensinogen antgiotensin system (RAAS) inhibitors are used in patients with lupus nephritis to reduce proteinuria and kidney function protection(3). Angiotensin II (AT II) has unfavorable effects on endothelial functions. AT II binds AT 1 receptors and promotes vasoconstriction and production of proinlammatory cytokines and proliferation factors. It is shown by several studies that RAAS inhibitors improves endothelial functions and induces the regression of atherosclerotic process(3).
Microalbuminuria (MAU) and proteinuria are related with worse cardiovascular outcomes. Microalbuminuria causes endothelial dysfunction and associated with accelerated atherosclerosis(4). MESA study demonstrated that coronary calcification is significantly higher in patients with microalbuminuria than counterparts without MAU. Not only presence but also amount of MAU is associated with insu...
Dear editor,
Show MoreWe read with interest the article of Idborg et al.1 who recently analyzed the role of several inflammatory mediators, and their usefulness as biomarkers in the measurement of activity of disease and the identification of clinical subphenotypes in systemic lupus erythematosus (SLE). Although interesting, these results may benefit of further discussion in light of systems medicine.
Authors concluded that the two main inflammatory mediators related with activity of SLE were TNF-α and p-albumin. However, previous studies have found that TNF-α and the TNF/IL-10 ratio were higher in patients with low activity of disease,2 and that TNF-α antagonists may induce SLE-like disease.3 These controversial data argues against a generalized model based on TNF-α as clinical activity biomarker, and advocate for the influence of other mediators in such a condition.
As shown by Idborg et al., IL-6, IL-10, IL-15, MCP-1, IP-10, MIP-1α, ESR, anti-dsDNA and U-albumin/creatinine were also positively correlated with activity of disease,1 suggesting that the exclusive role of TNF-α and p-albumin on activity of disease is unlikely. In fact, the pathological functions of these biomarkers are not isolate since they emerge from the interactions among them and between cells and tissues (i.e., systems medicine).4
In this sense, cytokine and autoantibody clusters (i.e., neutral, chemotactic/anti-phospholipid antibodies, and IFN-α/dsDNA) have been reported to be associat...
The Editor,
Lupus Science and Medicine
BMJ Journals
Dear Madam/Sir,
Our esteemed peer Dr. Boers has editorialised1 on our recently published study of associations of glucocorticoid use with damage accrual in SLE2, suggesting that studies of the type reported are ‘harmful’. As this is such a serious accusation, we feel compelled to respond, even though we suspect that in the end the views of the authors and of Dr Boers as serious physician-researchers are in fact highly aligned. Essentially, we do not resile from our view that long-term reliance on glucocorticoids for the control of inflammation in SLE carries harm, and that steroid-reducing regimens for SLE management are urgently needed. At no time in our report, and certainly not in our clinical practice, do we advise against the use of these drugs, though such an imprecation was implied (incorrectly) in Dr Boers’ editorial. Rather, it is our view that strategies to achieve control of disease activity with reduced reliance on glucocorticoids, such as improving the use of non-glucocorticoid agents or the introduction of novel therapies, are as urgently needed as ever – and that complacency about the chronic use of glucocorticoids in SLE is not an acceptable status quo.
As we stated in the opening remarks, ‘The objective of the present study was to quantify damage accrual in a prospectively followed cohort of patients with SLE and determine the association of glucocorticoid use with damage...
Show MoreGeraldino-Pardillaet al.1 recently published an interesting article analysing one of the most important aspects of systemic lupus erythematosus (SLE): the risk of cardiovascular disease, a leading cause of death in SLE patients. Although there were no healthy control group to compare, and the SLE patient sample size was limited, their conclusions are clinically valuable and should be taken into consideration.
The usefulness of the corrected QT interval (QTc) as a marker of atherosclerosis risk is well-established in the general population and in some sub-groups with high cardiovascular risk. QTc prolongation is also linked to cardiovascular events and mortality during follow-up2-3. QTc interval prolongation in SLE patients has been described in previous studies4.However, no data on the clinical repercussions of this finding are available. Our research group recently published a paper on the positive correlation between QTc interval prolongation in SLE patients and higher arterial stiffness measured by pulse-wave velocity5. The association was independent of hypertension and age. Our data complement those published by Geraldino-Pardilla et al.1, suggesting an independent association between QTc interval prolongation and subclinical atherosclerosis. However, there is no evidence of the long-term clinical effects of this association. Prospective studies with large sample sizes and long follow-up periods are required to study the potential long-term effects. In any case...
Show MoreDear Editor,
After reading the article by Carli et al.(1) we would like to share some thoughts that could be of practical use regarding vitamin D supplementation in patients on low-dose glucocorticoids therapy.
In 2011, we published the results of a follow-up carried out in our unit (located in a hospital in Granada, a sunny city in the south of Spain) that included a cohort of 55 patients with systemi...
Dear Editors,
We read with great interest the article of Greloni et al, "Value of repeat biopsy in lupus nephritis flares" and have some comments.
There is a high probability that what they call "histologic transformation" is further evidence of the poor reproducibility of the interpretation of the renal biopsy in lupus nephritis and no evidence that there really been a change in the biological phenomenon o...