399 e-Letters

  • Comments on the article: “Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy”

    To the Editor
    We recently have read the article written by Dr. Daien et al. entitled published in Annals of the Rheumatic Diseases in 31th of May, 2022 (1). The study assessed the effect of different doses of ABX464 on clinical and laboratory features of patients with active rheumatoid arthritis (RA) and the rate of development of treatment-emergent adverse events in these patients. In this study, it was showed that each day 50 mg use of ABX464 could exert beneficial effects in the patients with acceptable safety and tolerability profile. This study provides fascinating evidence regarding the use of this first-in-class drug candidate for patients not responding to more frequently used treatment regimens; however, there are some points that we would like to address.
    The authors mentioned that patients with moderate to severe RA who had rheumatoid factor, anticitrullinated peptide antibody or bone erosions were recruited in the study. The study aimed at comparison of rate of response to the treatment and development of adverse events in each arm of the study. Although, it is generally considered that the randomized design of the clinical studies would produce comparable groups and result in unbiased assessment of the outcomes, different factors which were previously identified in the literature that could be in association with severity of rheumatoid arthritis or poor response to the treatment should had been considered in the quantitative analysis of this study....

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  • Leflunomide for lupus nephritis

    Leflunomide for lupus nephritis
    Mycophenolate mofetil and azathioprine are drugs with proven efficacy for lupus nephritis (LN) treatment. In excellent prospective, randomised, open-label trial, Fu et al.1 emphasize the competitive clinical response between azathioprine and leflunomide in 215 adult patients with biopsy-confirmed active LN after cyclophosphamide and glucocorticoids, as maintenance therapy during 36 months.
    Both kidney flares and their onset time were similar, as well as their proteinuria, serum creatinine and complement levels response, with similar adverse events. AEs leading to permanent treatment discontinuation were 2/108 patients treated with leflunomide (20 mg/d) and 5/107 in the azathioprine group (100mg/d). Authors, also mentioned that leflunomide is associated with some other advantages, such as easy accessibility, long-term safety profile and cost effectiveness, particularly in developing countries.
    In Mexico, most of rheumatologist have vast experience with leflunomide as monotherapy for rheumatoid arthritis or combined with other csDMARD’s, most of them with good pregnancy outcomes, as has been reported recently, with no significant difference in malformations rates between leflunomide exposed and unexposed pregnancies.2 The cost of leflunomide is lower than azathioprine, equivalent to $10 USD every 4 to 6 weeks.
    Additionally, the potential benefit of leflunomide as LN remission induction treatment has been reported. Wang...

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  • The unbearable lightness of low-dose glucocorticoid therapy for rheumatoid arthritis

    Glucocorticoid (GC) therapy is still the mainstay in managing rheumatoid arthritis (RA). The benefits of low-dose GC therapy are well established after decades of clinical experience in RA. Yet, it is essential to appoint the danger of exposure to chronic GC therapy.
    For many patients with RA and other inflammatory rheumatic musculoskeletal diseases (RMD), starting prednisolone means taking glucocorticoids for several years or decades, often indefinitely.1 The long-term complications of GC therapy are rarely emphasised by most clinical trials that usually run for only 1 or 2 years. In this regard, the GLORIA trial2 has illuminated both the harms and benefits of 2-year low-dose (5 mg daily) prednisolone in 451 elderly patients (≥65 years) with moderately active established RA. Indeed, there was an 11% increase in patients with at least one adverse event (AE) of special interest (mainly mild to moderate infections) in the prednisolone arm, accounting for a 1.24 (95% CL 0.4) fold higher risk compared to placebo, just within two years of treatment.2
    The likelihood of major osteoporotic fractures in GC users increases with the dosage, but more importantly, with the cumulative dose and duration of GC therapy.3 Moreover, low-dose GC therapy (≤5 mg/day) did not seem to be associated with a reduction of bone mineral density (BMD) in patients with inflammatory RMD and current or prior exposure to GC.4 However, while GC therapy effectively alleviates inflammation, it has...

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  • Correspondence on ‘Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial’ by Bandak et al. (2022)

    Bandak et al.[1] recently published a paper comparing the effect of an exercise and education program with an open-label placebo on a range of outcomes for people with knee osteoarthritis (OA). The exercise and education program consisted of two weeks of 1x1.5 hour education sessions/ week, then six weeks of 2x1 hour exercise sessions/ week. The open-label placebo involved four fortnightly knee intra-articular saline injections and arthrocentesis (if required).[1] The authors argued “open-label placebo provides an opportunity to compare exercise and education with an inert comparator and thereby mitigate some of the inbuilt challenges with blinded comparator groups in clinical trials of exercise and education.” However, the use of an open-label placebo does not attempt to facilitate any opportunity for blinding, and their ‘placebo’ intervention does not meet established placebo criteria.

    Placebo interventions should have no therapeutic effect, and should be perceived to be identical to the intervention of interest,[2] to control for the placebo effect; neither of these criteria has been met by Bandak et al.’s[1] placebo. Although saline injections are pharmacologically inert, they may have a real therapeutic effect particularly when coupled with arthrocentesis, as they may exert specific physical and chemical effects that could improve symptoms.[3] As such, it has been recommended that saline intra-articular injections not be used as placebo interventions in studi...

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  • The Impact of Clinical Setting on ANA Responses in SLE: Comment on the article by Choi et al.

    The Impact of Clinical Setting on ANA Responses in SLE: Comment on the article by Choi et al.
    David S. Pisetsky1 2 and Peter E. Lipsky3 4
    1 Medical Research Service, Durham VA Medical Center, Durham, North Carolina, USA
    2 Departments of Medicine and Immunology, Duke University Medical Center, Durham, North Carolina, USA
    3 RILITE Foundation, Charlottesville, Virginia, USA
    4 AMPEL BioSolutions LLC, Charlottesville, Virginia, USA

    In a recent paper in the Annals of the Rheumatic Diseases, Choi et al report data on the expression of antinuclear antibodies (ANA) in the sera of patients with systemic lupus erythematosus (SLE).(1) Using a large cohort of well characterized patients from the SLICC (Systemic Lupus International Cooperating Clinics) consortium, the authors show that ANA expression is almost invariable in SLE using three ANA assays (two immunofluorescence or IFA and one ELISA); over time, some changes can occur, with the ELISA showing a greater reduction in the frequency of positive responses than the IFA assays. In this study, patients were early in disease, with the first sample obtained on average 0.58 years after diagnosis.
    Choi et al are to be congratulated for this detailed and comprehensive study that includes longitudinal data. Most other studies on ANA expression in SLE have been cross-sectional in design or involved longitudinal data of relatively few patients.(2) Nevertheless, while consistent with data und...

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  • Secukinumab may not be satisfactory for Chinese Han refractory mucosal Behçet’s phenotype: a single-center experience in China

    We read the study by Fagni F et al. on the possible therapeutic effect of secukinumab for Behçet’s syndrome (BS).1 Fifteen BS patients with active mucosal and articular phenotypes participated in their study. Patients with polyarthritis started secukinumab at 300 mg/month; others initially received 150 mg/month, with dosage and frequency adjusted in patients responding poorly. After three months of follow-up, 9 (66.7%) patients achieved a partial or complete response; this proportion increased to 86.7% at six months and 100% at 24 months. The initial dose of 300 mg/month indicated a better therapeutic effect. As for the control of mucosal ulcers, the median number of oral ulcers in the last 28 days decreased significantly from 2 to 1 at three months and 0 at six months, indicating a promising effect of secukinumab for mucosal ulcers. Here, we report the efficacy and safety of secukinumab on refractory mucosal BS in the Chinese population.

    We enrolled six BS patients (two males and four females), fulfilling the 2013 International Criteria for BS, between October 2020 and March 2022 with a mean age of 33.8 ± 6.6 years and a median disease duration of 8 (IQR 3,10) years. At enrolment, they all presented with active oral/genital ulcers that responded inadequately to or were intolerant to conventional therapies or biologics. The combined immunosuppressants/immunomodulators were maintained for at least two or three months before evaluating their effectiveness; otherwise,...

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  • 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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