421 e-Letters

  • Correspondence on Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis" by Kerschbaumer et al

    I am writing a correspondence on the article "Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis" by Kerschbaumer et al 1. The authors' systematic approach to comparing the treatment effects of pharmaceutical compounds in rheumatoid arthritis clinical trials with placebo and active treatment controls is commendable. The results of the study, showing significantly higher responses in active comparator trials compared to placebo controlled trials, provide valuable insights into the influence of control groups in RCTs. However, I have a few critical points to raise regarding the study's methodology and conclusions. Firstly, the matching of active treatment arms to comparable regimens, populations, background therapy, and outcome reporting was based solely on the nature of the control group, which is not an ideal approach. This method of matching could have led to unequal comparison groups and biased results 2. In order to ensure that the comparison between active treatment and control groups is fair and accurate, a more comprehensive and systematic approach to matching should have been employed. Secondly, the conclusion that placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials may be an overgeneralization. The authors did not consider other potential confounding factors that could explain the difference...

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    We read the article “2022 American College of Rheumatology/EULAR Classification Criteria for Giant Cell Arteritis" by Ponte et al. with great interest (1). There was a long-standing need for revision of classification criteria for giant cell arteritis (GCA) due to the insufficient sensitivity of the ACR 1990 criteria in recent studies (2). This could be explained by enrolment of patients with different clinical phenotypes to the cohorts depending on the improvement in the imaging methods in addition to clinician’s assessment over the years. Especially, implementation of cross-sectional imaging including FDG – PET improved the diagnosis of GCA and facilitated the recognition of disease patterns without cranial manifestations. Patients with isolated extra-cranial involvement were reported to have a diagnostic delay up to 5 months compared to classical GCA patients and late recognition of large vessel involvement could cause permanent organ damage (3). Thoracic aorta dilatation / aneurysm has been reported in 15% and large artery stenosis in 30% in patients with proven aortic inflammation (4). The ACR 1990 Criteria were not sufficient to identify this subgroup and patients who participate in clinical trials evaluating the efficacy of further treatment options. The new criteria were expected to fill this gap.

    We implemented new criteria to our single reference center cohort with long-term follow-up consisted of 89 patients with a median follow-up time of 4 years T...

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  • Correspondence on Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis

    We are submitting a correspondence in regards to the paper "Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis" by Lotte van Ouwerkerk et al.1 published in Ann Rheum Dis. 2022 Dec 16. The study is an important contribution to the field as it aimed to investigate the effectiveness of glucocorticoids (GC) as a bridging therapy for rheumatoid arthritis (RA) patients. The study combined data from 7 clinical trial arms that included GC bridging schedule in the initial treatment of RA, to investigate whether patients with RA can discontinue GC after GC 'bridging' and to identify factors that may affect this. The study has several strengths, such as the use of individual patient data meta-analysis which allows for a more comprehensive and detailed analysis. Additionally, the study's aim to investigate the effectiveness of GC as a bridging therapy is admirable, as it addresses an important question in the field of RA treatment2 3. However, the study also has some limitations that must be taken into account when interpreting the results. Firstly, the sample size of 1653 patients may not be representative of the general population of RA patients. This could limit the generalizability of the study's findings and may not fully capture the diversity of RA patients. Additionally, the study's short-term follow-up period of 18 months may not be enough...

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  • What can we learn from MS-IP regarding anti-OJ antibodies?

    Although, several novel autoantibodies in idiopathic inflammatory myopathies (IIM) have been described, a serological gap persists which poses a diagnostic challenge. In this context, we read with interest the article by Vulsteke et al. [1]. The untargeted protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) identified a novel autoantibody to cytoplasmic cysteinyl-tRNA-synthetase (CARS1, anti-Ly). In addition, rare ASA, such as anti-OJ, anti-Zo and anti-KS, and common ASA could also be identified by IP-MS. Consequently, Vulsteke et al. [1] concluded that IP-MS is a promising method for discovery detection of autoantibodies, especially autoantibodies that target complex autoantigens.
    We agree that IP-MS represents a powerful discovery tool for novel autoantibodies. However, the gained knowledge is most valuable for more conventional in-vitro diagnostic platforms. Although the IP-MS method holds promise, due to the lack of standardization it is unlikely that it will be applicable for IVD solutions soon. Established alternative methods include ELISA [2], line immunoassay (LIA) and a recently developed particle-based multi-analyte technology (PMAT) that has been evaluated for the detection of MSA [3-5].
    Due to the antigen complexity, anti-OJ are among the most difficult MSA to detect [6, 7]. According to an international survey, despite concern about its accuracy, LIA is commonly used for the detection of MSA inc...

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  • Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomized controlled ORAL surveillance trial: Comment on the Article by Curtis et al.

    I read the paper by Curtis et al. with great interest [1]. A new analysis using this paper’s data has yielded important results that should be presented here.
    The authors state that (1) in patients with rheumatoid arthritis (RA) aged ≥50 years with ≥1 additional cardiovascular risk factor, the risk of adjudicated malignancies excluding non-melanoma skin cancer (NMSC), lung cancer and NMSC was higher with tofacitinib versus tumor necrosis factor inhibitor (TNFi); (2) lung cancer was the most frequently reported malignancy in tofacitinib-treated patients; and (3) history of atherosclerotic cardiovascular disease (ASCVD) or increasing risk scores were associated with higher malignancy incidence rates (IRs) across treatment.
    Atherosclerosis can be caused by various factors, such as smoking, high cholesterol, hypertension, hyperglycemia, diabetes, and genetic factors [2]. However, atherosclerosis can also develop due to infection [3]. These infections include Helicobacter pylori (H. pylori), pneumonia, periodontal disease, and viruses such as cytomegalovirus, human immunodeficiency virus (HIV), herpes simplex virus, Epstein-Barr virus (EBV), human papilloma viruses (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and recently, severe acute respiratory syndrome coronavirus-2 [3, 4].
    Some infections that cause atherosclerosis are thought to contribute to cancer in humans. The fractions of different types of cancer, and of all cancers worldwide and in dif...

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  • Correspondence on “ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update” by Ramiro et al.

    The recent Spondyloarthritis international Society-European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations provided a comprehensive update on the management of axial spondyloarthritis (axSpA). (1) The 15 recommendations were agreed upon with two relevant updates and two newly formulated. Recommendation 9 was updated based on systematic literature review from 2016 up to January 1st, 2022, to include targeted synthetic DMARDs (tsDMARDs, ie, Janus kinase inhibitors (JAKi)) for patients with persistently high disease activity despite conventional treatments, where current practice is to start therapy with biological DMARDs (bDMARDs), tumour necrosis factor inhibitors (TNFi) or interleukin-17 inhibitors (IL-17i). (1, 2) The new therapeutic option is appreciated by physicians and patients as previously bDMARDs were the only option in patients with persistently high disease activity despite conventional treatments and the current practice was to start with TNFi therapy. (3) At the time of formulation of the recommendation data from only four phase 2/3 randomized controlled trials (RCT) in radiographic axSpA were available (N = 779). (2) Since the recommendation was published upadacitinib was approved by European Medicines Agency (EMA) for non-radiographic axSpA based on the data from a phase 3 SELECT-AXIS 2 trial. (1, 4) Additionally due to the safety signals seen with tofacitinib in rheumatoid arthritis (RA), until additional data becomes available a note...

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  • Is there adequate evidence for the adoption of multipliers for cardiovascular risk estimation in rheumatic autoimmune diseases?

    We read with interest the article by Conrad et al. [1] that advocated modification of cardiovascular risk (CVR) scores to incorporate risk multipliers for each rheumatic and musculoskeletal disease (RMD). The proposed multipliers were based on hazard ratios for incident cardiovascular diseases in a nationwide study of electronic medical records in the UK [2]. This proposal contradicts recent recommendations in the 2022 EULAR recommendations for CVR management in patients with RMDs [3]. Based on a review of the evidence, including data of elevated CVR in other nationwide studies, and appraisal by experts, these recommendations did not support use of CVR multipliers in RMDs [3]. It is therefore important to examine several issues raised by this proposal.
    First, the objective of study from which the multipliers were derived [1] was not to assess the added predictive validity of CVR score modifiers, but rather to examine the incidence of cardiovascular disease in patients with autoimmune diseases. Confidence in the validity of the multipliers is not high, considering that data on blood pressure were missing in one-third of patients, while data on cholesterol and smoking were missing in two-thirds and almost one-half, respectively [2]. Also, whether these risk estimates apply in countries with baseline CVRs different from the UK is unclear [3].
    Second, the suggested multipliers were based on risk estimates of a wide range of cardiac or vascular diseases, including p...

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  • Correspondence on “Occupational inhalable agents constitute major risk factors for rheumatoid arthritis, particularly in the context of genetic predisposition and smoking” by Tang et al.

    We read with interest the publication by Tang and coauthors on occupational risks for rheumatoid arthritis (RA) (1), which builds on previous valuable observations from the Swedish EIRA cohort.

    Their findings can be further strengthened when contextualized with other studies of occupation and RA from the U.S. and the U.K., in which higher prevalences of inhalational risk exposure are found. Results from U.S. population-based surveys, with a combined sample of nearly 5000 ever-employed males, showed that work in silica-exposing jobs exclusive of mining was associated with greater than three-fold odds of RA in both of the two regions studied (Appalachia and the Southwest Mountain States).(2,3) Because such non-mining silica exposure was common (28% and 18%, respectively), the population attributable fraction (PAF) within these groups was considerable: 27% (95% CI 23%, 30%) and 17% (95% CI 13%, 20%), respectively.

    Results from a U.K. study show additional effects of inhalational exposures (with silica being the most common) on RA seropositivity, antibody titer, and age of onset. (4) A study of 726 men with RA from Cornwall demonstrated that inhalational exposures were strongly associated with having seropositive RA, with higher RF antibody titers and earlier age of onset compared to unexposed patients. In that study, 75% of subjects had inhalational exposures lasting more than one year, and the estimated PAF for being strongly RF positive RA was 24.2%.

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  • Comments on the article: “Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy"

    To the Editor
    I recently have read with great interest the article written by Dr. Feist et al. entitled “Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study” published in Annals of the Rheumatic Diseases (1). In this randomized double-blinded clinical study, the effect of a monoclonal antibody against a proinflammatory cytokine, interleukin-6, was compared to placebo. The study showed beneficial effects of Olokizumab in patients with rheumatoid arthritis on their clinical manifestations and their self-reported outcomes. This study provides strong evidence regarding the use of this monoclonal antibody for treatment of adult patients with moderate to severe active rheumatoid arthritis not responding to tumor necrosis factor inhibitors; however, there are several issues that worth mentioning.
    In this study, adult patients with active disease status who received methotrexate for at least 12 weeks prior to the initial screening of the study were enrolled. Based on the inclusion criteria of the study, the eligible participants were those individuals with moderate to severe rheumatoid arthritis who had not an adequate response to methotrexate alone and therefore, they were in need for disease-modifying antirheumatic drugs and they should had received and f...

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  • Correspondence on "Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis" by Solomon et al.

    We have read with interest the results of the study conducted by Solomon and colleagues, showing that addition of tumor necrosis factor inhibitor (TNFi) versus sulfasalazine and hydroxychloroquine on methotrexate regimen among individuals with rheumatoid arthritis (RA) did not result in a significantly greater reduction in arterial inflammation, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta.1 A closer look at participants' baseline characteristics revealed that a significant proportion of recruited patients (45.2%) had concomitant arterial hypertension.1 Renin-angiotensin system (RAS) blockers have been shown to exert at some extent anti-inflammatory effects,2 partially explaining the relatively low TBR among patients with established atherosclerotic cardiovascular disease, treated with angiotensin converting enzyme inhibitors.3 Similarly, in subjects with a recent acute coronary syndrome, treatment with an angiotensin-II receptor blocker resulted in a significant reduction in TBR over a 6 month period of treatment.4 Therefore, we strongly believe that a subgroup analysis of the primary endpoint according to baseline use of RAS blockers would provide useful additional insights into the interesting research hypothesis formulated by Solomon and colleagues.

    1. Solomon DH, Giles JT, Liao KP, et al. Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arth...

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