470 e-Letters

  • A few quentions about prospective nature of the study and dropout rates, and pointing out discrepancies in some of the actual data

    Muhammed Abdulkerim Sahin, MD
    Research Assistant
    İstanbul University-Cerrahpaşa Faculty Of Medicine, İstanbul, TÜRKİYE
    ORCID: 0000-0001-8077-8549
    E-mail: md.abdulkerim@gmail.com

    Yusuf Yazici, MD
    Clinical Associate Professor of Medicine
    NYU Grossman School of Medicine, New York, NY
    ORCID: 0000-0002-7605-5759
    E-mail: yusuf.yazici@nyulangone.org

    We have read with interest the paper by De Miguel E et al., " Subclinical giant cell arteritis increases the risk of relapse in polymyalgia rheumatica" (1). We had a few questions about the prospective nature of the cohort. The authors state that "Demographic, clinical and laboratory baseline data were collected prospectively.” and also that “Follow-up data regarding treatment and occurrence of relapses at months 3, 6, 12, 18 and 24 were retrieved retrospectively.” If this was a prospectively designed study cohort, patients would be continuously enrolled, and let's say 6 months into the start of the study, the initial patients who enrolled in the first weeks of the study would have their month 3 visits likely completed. Why wouldn't the follow up data for the initial patients coming for their month 3 visit, or any patient follow up data, be prospectively planned to be collected at that time, rather than retrospectively collected at a later date? Retrieving...

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  • Correspondence on ‘2023 ACR/EULAR antiphospholipid syndrome classification criteria’ by ‘Medha et al’.

    With regard to the article on ‘2023 ACR/EULAR antiphospholipid syndrome classification criteria’ by ‘Medha et al’, we believe that it contains substantial inadequacies in the obstetric domain, which weakens the application of this guideline in the antiphospholipid syndrome classification.
    Firstly, on the clinical criteria obstetric domain, the classification arbitrarily divides fetal death into two categories------pregnancy loss between 10 weeks 0 days and 15 weeks 6 days gestation (early fetal death), or between 16 weeks 0 days and 34 weeks 0 days gestation, which has no support from previous consensus to set 16 weeks as a cutoff point1,2. In addition, since the author bestow the same weigh on these two categories, makes the dividing line even more unnecessary. And on top of that, in terms of fetal death, the classification slights to take pregnancy loss beyond 34 weeks of gestation into account. In our dataset of the past 7 years, the incidence of pregnancy loss beyond 34 gestational weeks in all diagnosed obstetric antiphospholipid syndrome associated fetal loss cases is 4.3% (3/70). Also, it is in accordance with other datasets in which include fetal loss beyond 34 gestational weeks as bona fide OAPS patients3. Hence, this particular classification serves no purpose in increasing its specificity, while jeopardizing its sensitivity.
    Secondly, the preeclampsia with severe features column fails to include placental abruption4, heart failure5 and He...

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  • The unintended outcome of a comparison of biomarker-driven strategies for maintenance of remission in ANCA-associated vasculitis.

    I read the report by Zonozoi et al. with great interest (1). It is of particular importance to note that while the intent of this trial was to compare biomarker-driven strategies for maintenance of remission in ANCA-associated vasculitis, the design of the trial resulted in a much different outcome. Given the result that more than seven times as much rituximab was given to patients in the B-cell biomarker arm relative to the autoantibody biomarker arm, the practical and main result of this trial is a comparison of continuing or discontinuing rituximab after ~2 years of remission on rituximab. Since the MAINRITSAN3 trial has shown that discontinuing rituximab after ~2 years of remission has a large impact on relapse rates, a trial that effectively compares biomarkers would need to have similar amounts of rituximab in each arm in order to prevent the result from being dominated by excess or lack of rituximab (2). In concordance, the results of the current trial are nearly identical to those of MAINRITSAN3, with a 4% relapse rate in the heavily treated arms of both trials, and 21% and 26% relapse rate with little or no treatment, respectively. As it turns out, since doses of rituximab were 1000 mg in the current trial and 500 mg in MAINRITSAN3, the total dose of rituximab during the maintenance phase of the heavily treated arms were almost identical for both trials as well.

    In this study, only a minority of clinical relapses (no more than 6 of 20 patients with potent...

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  • Reservations on the use of a B cell repopulation strategy to maintain remission in ANCA vasculitis.

    We read the article “Maintenance of remission of ANCA vasculitis by rituximab based on B cell repopulation versus serological flare: a randomised trial” with interest as we believe that this may cause a paradigm shift in the way that these patients are managed. However, as Immunologists, we have some reservations with regards to the impact that these changes may have.

    The authors report administering much higher doses of rituximab to patients enrolled in the B cell arm of the study, compared to the ANCA arm (mean 3.6g vs 0.5g per person), and the decision to re-introduce rituximab was based on a very low cutoff of ≥10 cells/mm3 (=0.01 x109/L; local reference range >0.1 x109/L). As such, we would expect a much more pronounced immunosuppressive effect in those patients and, not surprisingly, a higher rate of serious infectious adverse events were reported in the B cell arm. More importantly, 2 patient deaths due to COVID-19 were noted in this group, while none in the ANCA arm.

    Several similar cases of persistent or fatal COVID-19 infection in patients treated with rituximab have been reported in the literature[1,2]. Severe infectious sequalae due to multiple other viruses have also been reported, including hepatitis B, VZV, CMV, enterovirus, adenovirus, JC virus, BK virus, HPV, HSV and others[3]. A similar pattern emerges in patients with absent B cells due to any other cause, which suggests a key role for peripheral B cells in their development[4].

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  • Methodological Evaluation of the CONSUL Trial: Unveiling Insights and Considerations in Golimumab Treatment for Axial Spondyloarthritis

    I am writing to submit a formal review and feedback on the article titled "Comparison of the Effect of Golimumab Monotherapy vs. Golimumab in Combination with NSAIDs on Radiographic Progression in Axial Spondyloarthritis: The CONSUL Trial"(1) authored by Proft et al. This communication aims to provide constructive insights into the methodology of the study.

    The utilization of a randomized controlled trial (RCT) design is a commendable strength of the research, facilitating a robust comparison between treatment groups. The inclusion of patients at high risk for progression is also noteworthy, enhancing the study's relevance to a population where intervention effects are of particular importance.

    However, a critical examination of the study's methodology reveals certain considerations that warrant attention. The absence of blinding for both patients and investigators introduces the potential for bias in reporting subjective outcomes. This lack of blinding(2), coupled with the uneven distribution of prior biologic Disease-Modifying Anti-Rheumatic Drug (bDMARD) use between groups at baseline, necessitates cautious interpretation of treatment effects.(3)

    Furthermore, the relatively modest sample size (n=109) poses limitations on the statistical power of the study, potentially affecting the generalizability of its findings. Acknowledging that results from this specific population may not universally extend to broader axial Spondyloarthrit...

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  • Correspondence on ‘Withdrawal of immunosuppressants and low-dose steroids in patients with stable IgG4-RD (WInS IgG4-RD): an investigator-initiated, multicentre, open-label, randomised controlled trial’ by Peng et al.

    We read with great interest the article by Peng et al [1]. Here, the authors demonstrate that immunosuppressive agents with or without low-dose steroids used during the maintenance phase decrease the rate of relapse. Consistent with the literature, serum IgG4 [2–5], total IgE levels [2] and eosinophil ratio [2,4,6] were found to be associated with relapse. We are interested to know if other factors reported in the literature, such as the number of organs involved [3,4,7] and the clinical phenotype according to latent class analysis (as described in Lanzillotta et al. [8]) are associated with an increased risk of relapse in this study.

    One point not highlighted in the study is that while approximately half of the patients in Group 1 (withdrawal of both steroid and immunosuppressives) experienced a relapse after 18 months, the other half did not. This finding raises important questions about determining the optimal length of treatment and timing of treatment withdrawal. Low-dose steroids or immunosuppressive agents are recommended for maintaining remission in IgG4-RD [9]. However, the duration of remission maintenance is unknown. We are interested to know which factors are associated with continued remission in steroid and immunosuppressive withdrawal group, which may guide future studies.

    1. Peng L, Nie Y, Zhou J, et al. Withdrawal of immunosuppressants and low-dose steroids in patients with stable IgG4-RD (WInS IgG4-RD): an investigator-initi...

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  • Response to HLA-B27, axial spondyloarthritis and survival by Zhixiu Li et al.

    The authors report that AS is associated with an increased mortality, more so among the females (1). Their observations further strengthen the recent understanding that women are not so lucky (2) after all, when they acquire AS. However, we would like to point out to a neglected point in the current report, an issue related to the proposed sex differences in the risk of death.
    The mean age of entry of AS patients into this work was 44 years. On the other hand, we know that AS usually starts well before age 30 and according to one study, at a median age of 25 for males and 28 for females (3). Thus, most of the patients in the current report had AS years before entering this study. Therefore, the current report really concerns the fate of AS patients after quite a number of years of disease duration. A previous study about mortality in AS had shown that males and females had a similar survival after disease onset for about a decade after which the decrease in male survival became apparent. On the other hand, it took 35 years from disease onset when the female survival began to decrease (4). It follows that the design of the current work does not allow us to assess the survival of AS from the time of disease onset.
    Finally, we surely agree with the authors that more work is needed to assess the proposed increased mortality among women with AS.

  • Concerns and Considerations on Rituximab Dosing Strategies in ANCA Vasculitis Maintenance

    Dear Editor,

    We read with great interest the study by Zonozi and colleagues, which presented the outcomes of a randomized trial comparing rituximab dosing strategies for maintaining remission in ANCA vasculitis [1]. The study proposed that rituximab dosed for B-cell repopulation results in fewer clinical relapses than when dosed for a rise in ANCA level. While acknowledging the valuable contribution of this study, we would like to express a few concerns related to methodology.

    First, the authors chose to evaluate B-cell repopulation by assessing CD20-positive B-cell levels in peripheral blood. This deviation from the conventional approach of assessing CD19-positive B-cell levels, as seen in prior studies [2,3], prompts inquiries about the reasoning behind selecting CD20 as a marker for repopulation. This is particularly important considering its role in the rituximab dosing strategy within the B-cell arm.

    Second, the study design suggests a dosage of 1gm in the B-cell arm for B-cell repopulation and 2gm, typically a remission induction dose in the ANCA arm, for serological flare. This differs from the usual practise of 500mg observed in MAINRITSAN2 and MAINRITSAN3 trials for maintenance of remission, and it would be beneficial to understand the reasoning behind this choice within the context of this study [2,3].

    Third, a study by Thiel and colleagues demonstrated a significantly prolonged duration of B-cell depletion following rituximab treatmen...

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  • Discrepancy in Patient and Control Numbers in the Article "Proteomic and Genomic Profiling of Plasma Exosomes from Patients with Ankylosing Spondylitis"

    Dear Editors of the Annals of the Rheumatic Diseases,

    I am writing to bring to your attention a discrepancy I have identified in Table 1 of the article titled "Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis" published in your esteemed journal. The error pertains to the numbers of patients and controls listed in the table, which do not align with the description provided in the "Patient and public involvement" section of the article's MATERIALS AND METHODS.

    This inconsistency has the potential to mislead readers and may impact their understanding and interpretation of the study's findings. After careful consideration and verification, it is evident that the data provided in Table 1 should accurately reflect the numbers described in the "Patient and public involvement" section. I respectfully recommend rectifying the table to ensure alignment with the stated patient and public involvement.

    I appreciate the opportunity provided by the Annals of the Rheumatic Diseases for open discourse, which serves to uphold the integrity and accuracy of scientific research. My intention is to contribute to the improvement of the published work, ensuring its accuracy and reliability. Addressing this discrepancy will further enhance the quality of the published work and provide readers with the precise and reliable information they seek.

    Thank you for your attention to this matter...

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  • Comment on: Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis

    Dear Editors:
    We read with interest the article by Moulin et al. entitled ‘Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis’.1 Alterations in tryptophan (Trp) metabolism have been documented in the context of rheumatoid arthritis (RA). The aim of this study was to ascertain whether these alterations contribute to the development of RA and can be regarded as potential therapeutic targets. Based on the authors' findings, both preclinical and clinical data suggest that modifications in Trp metabolism actively contribute to the pathogenesis of RA and may represent a novel therapeutic approach.
    Following a comprehensive analysis of the article, we have identified an error that requires further investigation and rectification. According to the data presented in Table 1, it is apparent that within the ESPOIR cohort, 45 individuals (77.5%) out of the 574 patients are identified as female. However, it is imperative to acknowledge that the accurate representation should indicate that a total of 445 individuals (77.5%) out of the 574 patients are indeed female.
    Nevertheless, we would like to express our gratitude to the authors for shedding light on the involvement of Trp metabolism alterations in the pathogenesis of RA and proposing it as a potential novel therapeutic avenue.

    1. Moulin D, Millard M, Taïeb M, et al. Counteracting tryptophan metabolism alterations as a new therapeutic s...

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