446 e-Letters

  • Correspondence on “Stage-specific roles of microbial dysbiosis and metabolic disorders in rheumatoid arthritis” by Cheng et al.

    Cheng et al. recently reported the changes in fecal microbiota and peripheral blood metabolites in patients with rheumatoid arthritis (RA) across four stages of the disease. In addition, they performed 16S rRNA sequencing and identified bacteria in synovial fluid of RA. and successfully isolated and identified many microbes in synovial fluid samples of RA patients at the stage 4 (RAS4). Moreover, substances shaped like bacteria in rod-like or spherical forms were also observed under scanning electron microscopy.1 This is the first time that bacteria were successfully isolated from the synovial fluid of RA and this finding deserves attention.
    First, it is always an interesting question whether bacteria are actually present in the synovial fluid of RA. Up to date, several studies have reported the presence of microbial DNA in joint effusion of RA by 16S rRNA gene sequencing technology (Table 1). However, there is no direct evidence on isolation of bacteria from RA synovial fluid. The synovial fluid is usually sterile, and RA is a kind of chronic non-infectious arthritis induced by autoimmune disorder.2 It was indeed reported that bacteria were found in the synovial fluid of RA, however, this was mainly because of multiple arthroscopic washouts and joint injections. Unfortunately, the history information of repeated arthroscopy or arthrocentesis was missing in RAS4 of which bacteria were isolated from synovial fluid in this article. Thus, it is uncertain if these isolat...

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  • Biologics targeted to skin in psoriasis patients can prevent psoriatic arthritis: killing two birds with one stone?

    The question of whether the use of biologic disease-modifying antirheumatic drugs (bDMARDs) can prevent psoriatic arthritis (PsA) in psoriasis (PsO) patients may be confusing. Some observational studies reported that biologic therapies were associated with a decreased risk of PsA1-2, but other studies did not3-5.
    We read with great interest the recent article published in Annals of the Rheumatic Diseases by Gisondiet and colleagues regarding the impact of biologic therapy on development of PsA1. This study is very interesting and important; however, we would like to share with the authors our perplexities about the conclusions drawn from this report.
    First and foremost, Gisondiet et al identified that treatment with bDMARDs was significantly associated with a lower risk of incident PsA in moderate-to-severe PsO (aHR 0.27, 95%CI 0.11 to 0.66) compared with nb-UVB phototherapy. However, we noted that this association was reversed if HRs were calculated using propensity score matching (PSM) data (aHR 2.07, 95%CI 0.87 to 4.93, Supplementary Table 2), and the explanation provided by the authors may be related to the limited sample size after PSM. In fact, these well-known risk factors, including age, scalp psoriasis, nail psoriasis, psoriasis duration, and family history of PsA, showed larger effect values after PSM even with smaller sample sizes. Thus, we reckon that, rather than a smaller sample size, this discrepancy is more likely the consequence of the pre-matc...

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  • Consultation on additional analysis for the post hoc analysis of TULIP-1 and TULIP-2.

    I read with interest the post hoc analysis of pooled data from two phase III trials by Vital et al. [1]. 73.0% (267/366) and 67.5% (243/360) of patients treated with placebo and anifrolumab, respectively, were taking antimalarials at the time of randomisation of the trial [2, 3]. I would like to know if there was a difference in achievement of the outcomes with or without the drug at baseline, as antimalarials have an inhibitory role against type 1 interferon [4], which may have attenuated the effect of anifrolumab.

    1. Vital EM, Merrill JT, Morand EF, et al. Ann Rheum Dis 2022;81:951-61.
    2. Furie RA, Morand EF, Bruce IN, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol 2019;1:e208-19
    3. Morand EF, Furie R, Tanaka Y,et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med 2020;382:211-21.
    4. Sacre K, Criswell LA, McCune JM. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther 2012; 14:R155

  • Correspondence on “Tumour necrosis factor inhibitor use during pregnancy is associated with increased birth weight of rheumatoid arthritis patients’ offspring” by Smeele et al.

    The article by Smeele et al.[1] investigated influence of biologics on infants and pregnancy outcomes. We would like to raise some concerns on this important study.

    Regarding measurement of depression, we suggest the use of Beck Depression Inventory (BDI), Geriatric Depression Scale (GDS) or other clinically used indexes might have better information. Besides, life style and habbit were important information on pregnance outcomes.[2] We suggested that Baecke Questionnaire or Pregnancy Physical Activity Questionnaire (PPAQ) would provide a good insight for us in this field. Moreover, some residudal confounders should be considered, such as alcohol and nutritioan status.[3, 4]

    In terms of comparator group selection, the authors compared participants with TNFi and without TNFi use during pregnancy. However, this could cause confounding-by-indication because that those who didn’t use TNFi might originally have mild symptom, which causes fewer comorbidities. Hence, we think that it would be more appropriate if the control group could be non-TNF biologics users. We believe that the active comparator design with same indication would be better to ensure baseline comparability.

    1. Smeele, H.T.W., et al., Tumour necrosis factor inhibitor use during pregnancy is associated with increased birth weight of rheumatoid arthritis patients’ offspring. Annals of the Rheumatic Diseases, 2022: p. annrheumdis-2022-222679.
    2. Vargas-Terrones, M., T....

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  • Are chronic glucocorticoids truly safe in older patients with rheumatoid arthritis?

    Dear Editor,
    We read with great interest the article by Boers and colleagues [1]. The GLORIA trial is one-of-a-kind study and certainly represents a milestone for rheumatoid arthritis (RA) treatment in seniors. The overall message conveyed by the investigators is that glucocorticoids (GCs) at a dose of 5 mg/day is somehow safe and effective (at least for 2-years) in older patients with RA. However, we have some concerns regarding the latter claim and several questions for the authors.
    First, mean time on study drug was 19 months and only 60% completed the study. The authors stated that “the high rates of events in both groups over the observation period make it unlikely that the risk estimate would be substantially different in a more complete data set”. We somehow disagree. Fracture risk in glucocorticoid induced osteoporosis (GIOP) strictly depends on the treatment duration [2]. In addition, fracture risk remains elevated even after 1 year from GCs withdrawal [3], with possible long-term effects that were not captured by the GLORIA trial.
    Second, “over 2 years, spine bone density decreased by about 1% in prednisolone, but increased by 3% in placebo patients”. We frankly think that this difference might be relevant to many patients. BMD increases (in similar magnitude of the placebo group of the GLORIA trial) have been associated with significantly lower incidence of fracture in both clinical trials and observational studies [4,5]. Remarkably, a 2% perce...

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  • Correspondence on “Risk of cardiovascular events in patients having had acute calcium pyrophosphate crystal arthritis” by Tedeschi et al.

    We read with interest the study by Dr. Tedeschi and colleagues [1] which reported that patients with at least one episode of acute Calcium pyrophosphate (CPP) crystal arthritis had increased the risk of short (0-2 year) and long-term (2-10 year) non-fatal CV events compared with those without evidence of this acute crystalline arthritis. However, acute CPP crystal arthritis did not confer increased risk for all-cause mortality. This study focuses on an episode of acute calcium pyrophosphate (CPP) crystal arthritis as a significant clinical variable and is a valuable addition to the literature. However, some issues have not been addressed by the authors.
    First, epidemiologists agree that several clinical risk factors are associated with cardiovascular outcome, including acute cerebrovascular insufficiency, hyperparathyroidism, and phenotypes of CPP disease [2,3]. However, the authors did not exclude people with these risk factors, and an evaluation of these risk factors was not presented. The confounding effect of these variables may have contributed to the significant effect in causing cardiovascular disease.
    Second, it reported that longer disease duration of CPP crystal arthritis have also been considered to carry an elevated risk for cardiovascular disease [4]. Previous studies have clearly demonstrated that chronic CPP crystal arthritis did confer increased risk for myocardial infarction, acute coronary syndrome, and stroke[5]. However, the duration of CPP...

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  • Correspondence on “Peroxisome proliferator activated receptor-γ agonist pioglitazone improves vascular and metabolic dysfunction in systemic lupus erythematosus” by Hasni et al.

    We have read with great interest the results of the cross-over randomized controlled trial (RCT) by Hasni et al. assessing the effect of pioglitazone on arterial stiffness indices and cardio-metabolic risk parameters in subjects with systemic lupus erythematosus (SLE).1 Renal involvement is of utmost importance for the prognosis of SLE, with a significant proportion of affected patients developing lupus nephritis within the first years after diagnosis.2

    As demonstrated in the supplementary material of the article by Hasni et al.,1 treatment with pioglitazone resulted in a significant increase in blood urea nitrogen (BUN) (p = 0.005) and serum creatinine levels (p = 0.03), although the result seems to be of no clinical significance. It would be really interesting to know if the researchers also assessed the effect of pioglitazone on albuminuria levels in the enrolled participants. Among patients with diabetes mellitus thiazolidinediones have been shown to produce a significant reduction in urinary albumin to creatinine ratio (UACR), even among those with normo-albuminuria at baseline.3 Albuminuria should be taken into account, since it represents an additional prognostic marker for cardiovascular disease development, besides the established, traditional, cardiovascular risk factors.4 In addition, albuminuria is significantly associated with arterial stiffness indices, even in the general population setting, posing a potential causal link.5

    Therefore, if avai...

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  • 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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