423 e-Letters

  • Is leflunomide non-inferiorior to azathioprine in the maintenance treatment of lupus nephritis?

    Dear Editor,
    We read with great interest the recent paper published in ARD by Fu et al.
    Based on their prospective open-label randomised control trial in 270 patients with active Class III/IV/V lupus nephritis, the authors conclude that the efficacy and safety profile of leflunomide is non-inferior to azathioprine for maintenance therapy of LN.
    Importantly, this study was designed as a non-inferiority trial with the non-inferiority margin set at 12% for the primary outcome (flare at 36 months of maintenance-phase follow-up), meaning that the lower bound of the two-sided 95% CI for the difference in flare rates between LEF and AZA (as reference) should exceed −12%. Unexpectedly for a non-inferiority trial, the difference between groups for all data was considered significant at p<0.05.
    Time to kidney flare was reported as not statistically different between the LEF group (17/108 patients, 15.7%; median time: 16 months) compared with that in the AZA group (19/107 patients, 17.8%; median time 14 months) during the 36 months of follow-up, yielding a Hazard Ratio (HR) of 0.89 (95%CI: 0.57-1.21), with the lower bound of the 95%CI below the non-inferiority margin (-12%) which should be interpreted as an inclusive non-inferiority trial.
    We therefore believe that the main conclusion of the authors is not supported by the data presented, and as leflunomide is currently not shown as non-inferior to azathioprine for the maintenance of LN.

  • What should be the threshold to initiate pharmacological treatment of hyperlipidaemia?

    The Editor, A R D
    This has reference to the EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including systemic lupus erythematosus and antiphospholipid syndrome [1]. These recommendations will help most of the practicing rheumatologists in getting actively involved the prevention of atherosclerotic cardiovascular disease in RMDs. However, I seek one clarification the answer of which, I did not find in this document. What exact measure/instrument should I be using to guide me for pharmacological intervention for appropriate lipid-control? Should I be only using any one of the ‘CVD 10-y risk prediction instruments’ (modified Framingham Risk score, ‘SCORE’, ‘QRISK3’) and using a cut-off of 10-year-risk of > 5% as a guide to initiate pharmacological intervention for lipid-control (besides life-style change recommendations)? Or should I use the widely endorsed recommendations/guidelines from different cardiology/cholesterol societies around the world? For example, presently most such recommendations suggest the formulae ‘total cholesterol minus_HDL-cholesterol’ or ‘total cholesterol/HDL-cholesterol ratio’ providing cutoff values (>120 or 130mg/dL/>3.5 to 5, respectively) above which pharmacological intervention for lipid-control must be initiated. Opinion of the experts will be highly appreciated.
    Yours Truly
    Anand N. Malaviya, Department of Rheumatology.
    ISIC Superspeciali...

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  • Authors' response to comments from Drs. Kardas and Küçük

    We appreciate Drs. Kardas’ and Küçük’s interest in the new 2022 ACR/EULAR Classification Criteria for ANCA-associated vasculitis (1-3) and will take this opportunity to respond to the points they raised. The key concept to reiterate and clarify is that the classification criteria are only intended for use as inclusion criteria for clinical research. Therefore, it is not appropriate to use the criteria as diagnostic tools in a clinical setting. These criteria were designed to be used when considering who to include within a clinical trial of a particular subtype of AAV only after a complex clinical assessment has taken place. Thus, application of these criteria assumes drug exposure, malignancy, infection, and many other conditions that could mimic vasculitis have been excluded.

    It is important to re-emphasize that inclusion and applications of weights for specific items in the criteria were based on rigorous data-driven methods and items were, in part, included to differentiate among the three forms of ANCA-associated vasculitis. Decisions about item selection and weighting were made keeping in mind the value of the items relative to other items through the regression methods used in the analyses. With these concepts in mind, it is easier to understand how items present in more than one type of vasculitis but in differing frequencies may be included in one but not another set of criteria. For example, pulmonary involvement incorporates multiple findings suc...

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  • Several points regarding 2022 ACR/EULAR classification criteria for ANCA-associated vasculitides

    We read with great interest the recently published classification criteria for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides [1–3]. As stated elsewhere, it is hoped these criteria will further allow more homogenous patients groups to be included in clinical studies [4]. Here we would like to make several points of interest.
    First, we believe the weight of laboratory criteria for granulomatosis with polyangiitis and microscopic angiitis is too high. Although it is stated in both the methodology and discussion sections that these criteria should only be applied after a diagnosis of small or medium vessel vasculitis has been made and vasculitis mimics have been excluded, this may not always be possible in a real-life setting. For instance, drug-induced [5] or paraneoplastic [6] vasculitis cases without overt clinical findings typically associated with microscopic polyangiitis (MPA) may inadvertently classified as primary MPA by the virtue of having perinuclear ANCA or anti-myeloperoxidase antibody positivity. We believe this may be prevented by lowering the point value of laboratory criteria or requiring the concomitant presence of both clinical and laboratory, imaging or biopsy criteria for classification, similar to other classification criteria used for other conditions such as systemic lupus erythematosus [7].
    Second, nearly one third of patients classified as granulomatosis with polyangiitis (GPA) were reported to have maximum eosinophil...

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  • Correspondence on ‘Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial’ by Bandak et al.

    Correspondence on ‘Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial’ by Bandak et al.

    Yang Li1, MD; Yiying Mai1, MD; Changhai Ding1, Prof; Zhaohua Zhu1,2, PhD

    Author Affiliations:
    1. Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China, 510280
    2. Department of Joint and Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China, 510280

    Corresponding Author: Zhaohua Zhu, PhD. Clinical Research Centre, Zhujiang Hospital, Southern Medical University. No.253 Industrial Avenue, Haizhu District, Guangzhou, Guangdong Province, China, 510280 (Email: zhaohua.zhu@utas.edu.au).

    Word count: 415

    We read with great interest the article by Bandak et al 1. The authors conducted an open-label, single centre randomised controlled trial involving 206 knee osteoarthritis (OA) patients in an attempt to discriminate the effect of exercise and education from a placebo control on joint symptoms. They reported that an 8-week exercise and education programme provided equivalent efficacies for improving OA symptoms and function to 4 intra-articular saline injections over 8 weeks. The findings question the recommendation of exercise and education as OA symptoms management strategies. However, we believe the effect of exercise and education cannot be negated, as some p...

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  • Correspondence on “Unexpected impact of COVID-19 lockdown on spinal mobility and health perception in spondyloarthritis” by De Mits S, De Craemer A-S, Deroo L, et al.

    We read with great interest the article reported by De Mits and colleagues [1] suggesting that lockdown during the COVID-19 pandemic decreased chest expansion but did not have any impact on spinal mobility or disease activity in patients with spondyloarthritis (SpA).
    We conducted a similar study in France during the first lockdown (17th March-10th May 2020), which included all patients with SpA from our centre, who received bDMARDs administered intravenously in the immunotherapy unit of our outpatient clinic. In this unit, a standardized procedure is applied to collect clinical, biological and if necessary, imaging data at each clinical visit. During this period of lockdown, patients had at least one clinical examination. The Visual Analog Scale (VAS) values for pain, asthenia and activity, as well as the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index) were collected and averaged from two clinical visits, one before (pre-lockdown) and one after (post-lockdown) and then compared with the data collected during lockdown. Fifty-nine patients ((mean ± SD) 52±12 years at the time of the study, 33 men, 26 women) were included during the study period. All patients had stable disease and none developed COVID-19 symptoms during this period. We also included a cohort of 50 patients (mean age of 62 years at the time of the study, 10 men, 40 women) with rheumatoid arthritis. The VAS values for pain, asthenia and...

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  • Response to: Correspondence on “Comparative analysis of SGLT-2 expression in renal vasculitis and lupus nephritis” by Tampe

    We thank Patoulias and colleagues for pointing out the relevance of clinical studies for the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in renal vasculitis and lupus nephritis.1 As discussed recently, relevant clinical evidence is missing because patients with autoimmune diseases were excluded from most renal outcome trials for SGLT-2 inhibitors.2-4 An exception for the use of SGLT-2 inhibitors in renal autoimmune diseases is the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial (DAPA-CKD, ClinicalTrials.gov Identifier: NCT03036150).5 In DAPA-CKD, the researchers evaluated the effects of SGLT-2 inhibitor dapagliflozin, along with angiotensin-blocking agents, on the progression of CKD, including those with immunoglobulin A nephropathy (IgAN).5 Overall, a 39% reduction in the primary outcome (≥50% decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes) was observed.5 Interestingly, patients with IgAN showed an unprecedented 71% reduction in the primary outcome, suggesting that CKD treatment may be equally beneficial in renal autoimmune diseases once the initial phase of remission induction is achieved and kidney function stabilized.6 Patients with renal vasculitis and lupus nephritis have a significantly increased risk for cardiovascular morbidity and mortality, with both inflammation and long-term use of immunosuppressants contributing to this risk.2 Therefore, SGLT-2 inhibitors could ultimately...

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  • Author's reply

    We thank Tsung-Yuan Yang and colleagues for their interest in our findings on survival after COVID-19 associated organ-failure among SLE population. They raised two interesting questions on the method that we used.
    First, they suspect a selection bias because we selected, for the unmatched analysis, patients still alive at D30 to measure the survival in the D30-D90 period while SLE patients had a lower mortality during the D0-D30 period. They stated that selecting patients based on what the next observation allocation is likely to be can lead to biased estimates. We agree with them, and, as we already wrote in the discussion section, “Such observation may be biased because patients with SLE are younger and more frequently female” which could explain the better prognosis during the D0-D30 period. Besides, we used D30 as a landmark not by choice, but because, in the matched analysis, (Figure 2) the Kaplan-Meier curves crossed at D30, and the proportional hazard assumption was therefore not respected. We did not drive conclusions from this unmatched analysis which was here mainly to show the importance of our matching procedure.
    Second, they raised the concern that “the baseline characteristics between the two groups were not defined in this study”. We partly disagree on this comment. As a matter of fact, we presented in Table 1 (unmatched analysis) and in Table 2 (matched analysis) the baseline characteristic of our studied populations. We presented all the data...

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  • Correspondence on “Factors Predicting Axial Spondylarthritis among First-Degree Relatives of Probands with Ankylosing Spondylitis: A Family Study Spanning 35 Years” from Jing-Xing Li

    Dear Editor,

    We read with interest the article by Sjef M van der Linden et al, in which factors predicting axial spondylarthritis (axSpA) was identified. We appreciate their delicate works and point out some issues which may improve the outcome of the study.

    First, a total of 1178 subjects were enrolled for completion of questionnaire and related physical examination and blood tests. Altogether 162 participants (123 probands and 360 first-degree relatives) have died during follow-up with unknown cause of death. However, only 485 participants were entered for statistically analysis. Although it is a long-period cohort study spanning 35 years, a high missing rate of data was still doubted. We suggested a second look on data retrieval and management.

    Second, the author took participants’ reply of having used topical corticosteroid as the proof the acute anterior uveitis (AAU), which is quite unreliable. Instead, medical record should be retrieved for all participants. The mainstay of treatment in uveitis is corticosteroid eyedrops, dexamethasone 0.1% and prednisolone 1% are the first choice among them. Depending on the course and progress of uveitis, subconjunctival, posterior sub-tenon, or intravitreal injection of steroids preparation was indicated, even with combination use of systemic corticosteroid, and corticosteroid-sparing agents comprising non-steroidal anti-inflammatory drugs (NSAIDs), anti-metabolites (methotrexate), cycloplegic drug (atropine...

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  • Correspondence on “Comparative analysis of SGLT-2 expression in renal vasculitis and lupus nephritis” by Hakroush et al.

    We really appreciated the results of the exploratory study by Hakroush and colleagues, which provides further insights into the potential role of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with lupus nephritis and renal vasculitis.1 Unfortunately, at present, relevant clinical evidence is missing.
    It has been formerly known that focal segmental glomerulosclerosis (FSGS) is considered as a distinct phenotype of lupus podocytopathy, which is associated with a severe tubulo-interstitial injury and a much lower complete remission rate, compared to other phenotypes, such as mimimal change and mesangial proliferation.2,3
    According to a recently published, post-hoc analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin compared to placebo resulted in a lower mean rate of estimated glomerular filtration rate decline among patients with baseline FSGS, although the result was not statistically significantly, possibly due to the small number of patients with FSGS (n = 104).4 Results of the EMPA-KIDNEY trial, which are anticipated within 2022, will provide more definitive answers on whether SGLT-2 inhibitors can play a crucial role in the therapeutic management of lupus nephritis the next years.5


    1. Hakroush S, Tampe D, Kluge IA, Baier E, Korsten P, Tampe B. Comparative analysis of SGLT-2 expression in renal vasculitis and lupus nephritis. Ann Rheum Dis. 2022...

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