390 e-Letters

  • ‘Correspondence on “Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated with inactivated SARS-CoV-2 vaccine: a randomized clinical trial” by “Araujo CSR et al”‘.

    We read with great interest the recent article written by Araujo CSR et al entitled “Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated with inactivated SARS-CoV-2 vaccine: a randomized clinical trial” published in the Annals of Rheumatic Diseases on February 22, 2022 [1]. The major impact of this trial was the reinforcement of the immunogenic effect of a 2-week methotrexate discontinuation after each dose of the Sinovac-CoronaVac vaccine against SARS-CoV-2 compared to methotrexate continuation in patients with rheumatoid arthritis (seroconversion rates: 78.4% vs 54.5%, p-0.019 and geometric mean antibody titers: 34.2 (25.2–46.4) vs 16.8 (11.9–23.6), p=0.003, respectively).

    Previous experience with other non-COVID-19 vaccines, like the influenza or pneumococcal vaccines, has indicated that discontinuation of immunosuppresants improves the immunogenicity of a given vaccine [2,3]. Based on this knowledge, we had proposed that it would be beneficial for patients with autoimmune rheumatic diseases to get vaccinated against SARS-CoV-2 preferably when the underlying rheumatic disease is in remission and after temporal withdrawal of anti-metabolites within 10 days before and after each vaccine dose along with similar modifications in anti-cytokine drugs and corticosteroid dosages >10mg/ day (prednisone equivalent) [4]. In fact, applying that in a comparative study it was shown that the magnitude of antibody responses to mRNA-based S...

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  • Correspondence on "Characteristics associated with poor COVID-19 outcomes in individuals with systemic lupus erythematosus: data from the COVID-19 Global Rheumatology Alliance"

    Ugarte-Gil, et al (1) recently published a study reporting several characteristics associated with severe COVID-19 outcomes in people with systemic lupus erythematosus(SLE). Demographic factors, comorbidities, active or untreated SLE, and patients treated with glucocorticoids were the most noticeable features. Even though several covariates had been taken into consideration to minimize the impacts of these confounders, we presume vaccination could play a crucial role in the COVID-19 outcomes.
    Previous studies had pointed out the protective effect that vaccination could provide against poor outcomes in the general population (2). In spite of a lack of evidence on the efficacy of COVID-19 vaccines in patients with SLE, achieving adequate sero-protection after receiving COVID-19 vaccine could be expected according to the expert opinion based on the knowledge on the use of other vaccines in this specific group of patients (3). A review article published by Wei Tang, et al (4) showed that commonly used immunosuppressants inclusive of glucocorticoids, methotrexate, mycophenolate mofetil/mycophenolic acid and rituximab might impede vaccine responses, causing less sufficient immune responses after getting COVID-19 vaccines in SLE patients. Hence, we suggest a subgroup analysis according to whether being vaccinated or not to have better data interpretation and to clarify the possible factors that may lead to critical consequences in SLE patients infected with COVID-19.

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  • Correspondence on “Multilevel factors predict medication adherence in rheumatoid arthritis: a 6-month cohort study” by Balsa et al.

    We read with great interest the recent publication by Balsa et al.,[1] which reported that patient–physician agreement on the treatment, the type of treatment prescribed (favoring second-line conventional disease-modifying rheumatic drugs and biological disease-modifying rheumatic drugs/targeted synthetic disease-modifying rheumatic drugs), and the patient feeling privileged by the medication received are effective predictors of medication adherence in patients with rheumatoid arthritis (RA). In contrast, sociodemographic or clinical factors were not associated with medication adherence. This study focuses on medication adherence 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 studies assessing a relation at one moment in time are called cross-sectional studies.[2] If the follow-up time is considered, the study is longitudinal, and it is either a cohort or a case-control study. A cohort or a case-control study must be applied to variables that can be reasonably assumed stable over time. However, this study was a six-month multicentre observational longitudinal prospective study, and medication adherence is related to psychological, communicational, and logistic factors measured at the same time. Therefore, this study is better labeled a cross-sectional study, since psychological, communicational, and logistic factors cannot be assumed to be...

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  • Standard cardiovascular risk scales for people with gout?

    Dear editor,
    I read with interest the recently published new EULAR recommendations for managing the cardiovascular risk in patients with inflammatory rheumatic diseases [1]. They were long-awaited, and opportunely the targeted diseases are now broader, as previous ones focused primarily on chronic inflammatory arthritis [2].

    With rising numbers worldwide, gout is a major cardiovascular risk factor directly linked to all forms of atherosclerotic diseases. By having gout, there is a 40% increased chance of dying from the coronary disease [3]. So, focused management to reduce these serious complications is necessary, and establishing an individual patient's risk is essential. Surprisingly, the experts rely on risk prediction using standard risk assessment tools, claiming the absence of validation studies. I should partially disagree at this point. Certainly, no longitudinal studies have evaluated the predicted rates of cardiovascular events in gout to date. However, our group studied the discriminative value of SCORE and Framingham tools in detecting patients with carotid plaques, a high-risk indicator [4]. A moderate discriminative capacity was unveiled, with areas under the curve of 0.711 for SCORE and 0.683 for Framingham [5]. Specificity was quite good, but the tools lacked enough sensitivity. Moreover, Gamala and colleagues incorporated gout into the modified Dutch SCORE as an inflammatory risk factor [6]. It led to a 28.3% upgrade to the high-risk stag...

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  • Calcinosis and obinutuzumab

    We thank the author for this comment and his interest in our report. We agree that obinutuzumab has shown efficacy in a phase 2 trial in rituximab-naïve SLE patients. In our report, three of four patients did not respond to rituximab prior to receiving obinutuzumab. In our CREST syndrome patient (case 4), the combined obinutuzumab/chemotherapy led to a remission of her chronic lymphatic leukemia; leukocyte counts dropped from >200/nl to normal values. During this therapy, cutaneous calcinosis located on the distal upper extremities gradually regressed until its disappearance in clinical examination. We thank the author for pointing out that due to multiple comedications the disappearance of calcinosis cannot be solely traced back to obinutuzumab. However, we are not aware of cases in which calcinosis resolved due to chemotherapy so that we think obinutuzumab might have been at least partially responsible for this improvement. Further studies are needed to corroborate the effect of obinutuzumab on cutaneous manifestations in systemic sclerosis.

  • Correspondence on “Blocking GM-CSF Receptor α with mavrilimumab reduces infiltrating cells, pro-inflammatory markers, and neoangiogenesis in ex-vivo cultured arteries from patients with giant cell arteritis”

    We read with great interest the article by Corbera-Bellalta et al. entitled “Blocking GM-CSF Receptor α with mavrilimumab reduces infiltrating cells, pro-inflammatory markers, and neoangiogenesis in ex-vivo cultured arteries from patients with giant cell arteritis” (1). We believe that the study is of great importance because it demonstrates that blocking the GM-CSF pathway alleviates crucial pathological hallmarks of giant cell arteritis (GCA). These hallmarks include leukocyte infiltration, production of pro-inflammatory cytokines, tissue destructive matrix metalloproteinases (MMP’s), and neoangiogenesis. Additionally, the recently reported preliminary data of the first phase II clinical trial of mavrilimumab in combination with a 26-week glucocorticoid (GC) taper in GCA patients is very promising (2). The primary end point, being the difference in the time to first relapse between mavrilimumab treatment and placebo was achieved (p=0.0263). Moreover, the sustained remission rate at 26 weeks was higher in the mavrilimumab vs placebo group (83.2% vs 49.9%, respectively, p =0.0038).

    Recently, we reported on a distinct CD206+ macrophage subset that produces YKL-40 and MMP-9 in GCA affected vessels (3, 4). We proposed a pathogenic model in which these CD206+ macrophages play major roles in fueling leukocyte infiltration, vascular destruction, and neoangiogenesis. Furthermore, we showed that these CD206+/MMP-9+/YKL-40+ tissue destructive and proinflammatory macrophage...

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  • Response to ‘Correspondence on ‘Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis’ by Kai-di Wang’ by Cheng et al

    We thank Cheng et al1 for their interest in our paper ‘Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis’.2 Below we provide point-by-point replies to the comments.
    First, we would like to clarify the roles of digoxin and ouabain in this study. We performed three rounds of drug screening and found that only ouabain could robustly induce the expressions of anabolic marker genes, including COL2A1, aggrecan (ACAN) and cartilage oligomeric matrix protein (COMP).3,4 The fact that ouabain belongs to a family of cardenolides prompted us to determine whether other cardenolides also possess the similar anabolic effects in chondrocytes, which led to the isolation of digoxin as another cardenolide that could also induce the expressions of anabolic marker genes in chondrocytes. We appreciate the author’s statement that ouabain demonstrated better protection against OA in some assays mentioned in their correspondence. However, digoxin also showed significant protective effects against OA in multiple analyses performed, quite similar to ouabain. For instance, there is no difference in the osteophyte number between digoxin and ouabain treatment groups (Figure 2F and 2G). More importantly, digoxin is known to be the only safe inotropic drug for oral use that improves hemodynamics.5 This led us to hypothesize that records related to digoxin might be accessible in general practitioner based medical records databases. Indeed, we foun...

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  • CD4+ T cell transcriptomic characteristics regulated by lncRNA in patients with rheumatoid arthritis

    We read with great interest the article by Eunji et al.1, who reported changes in target expression in patients with rheumatoid arthritis (RA), possibly via meQTL-mediated DMR, thereby affecting CD4+ T cell differentiation. The mechanism merits further attention, as it may provide insight into the cause of autoimmune disease.
    As the authors stated, CD4+ T cells play an important role in the pathogenesis of RA. From February 2016 to October 2021, 2518 patients with RA in our hospital provided peripheral blood samples to test CD4+ T cell subsets by flow cytometry. Compared with 100 healthy controls (HCs), we observed altered CD4+ T cell numbers in RA patients. RA patients had a lower absolute number of regulatory T cells (Tregs) (P < 0.001) but a higher proportion of effector T cells, such as Th17 (P < 0.05) (Figure 1).
    Recent major advances have been made in our understanding of genomic and epigenetic changes in arthritis, particularly regarding aberrant DNA methylation, microRNA and noncoding RNA deregulation, and altered histone modifications, which alter the transcriptional activity of genes involved in autoimmune responses2. In addition to the findings of Eunji et al. that mutation-driven methylation altered CD4+ T cell expression to increase RA risk, lncRNAs also played a key role in regulating CD4+ T cell gene signatures. In our study, high-throughput sequencing data from CD4+ T cell subpopulations of 27 RA patients and 24 HCs were obtained from GSE1...

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  • Attenuated response to fourth dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series: Correspondence

    Dear Editor, we read the article entitle “Attenuated response to fourth dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series [1]” with a great interest. The efficacy of COVID-19 vaccine among specific groups of vaccine recipients with underlying disease is a current important clinical issue. For many groups of patients, including to those with autoimmune diseases, the low immune response to standard vaccination is observed. Extra-dose vaccination is proposed. For the fourth dose of COVID-19 vaccine, it is currently a new idea. Few reports are published. The clinical evidence is required for supporting whether the fourth dose of vaccine will be useful or not and whether there will be any risk of too much vaccination [2]. This report is one of an early publication on this issue. A previous publication is on kidney transplant case. As expected, the high immune response after the fourth dose of vaccine is observed [3]. However, as also seen in the present report, there are various types of first, second and third dose vaccines that each subject in the series received and it might affect the final immune response after the fourth dose vaccine administration. Also, there is usually no confirmation to rule out a possible incidence of asymptomatic COVID-19 infection which might occur in the period between doses of COVID-19 vaccines. These important concerns should be addressed and control of those confounding factors is important if further clinical res...

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  • Calcinosis and Obinutuzumab

    Dear Editor,
    I want to congratulate Kvacskay et al. on an ingenious case series. While we have had evidence of the efficacy of obninutuzumab in lupus nephritis (2) in phase 2 trials and the RIM trial did show the efficacy of rituximab in anti-Jo1 positive myositis hence the expected responses with obinutuzumab, owing to its greater and more effective B cell depletion. The most interesting of the cases was case 4, where, according to the authors, obinutuzumab led to clearance of calcinosis in the patient. In a case series by Narváez et al.(4) only 50% of the patients with calcinosis in systemic sclerosis responded to rituximab (none of them had a complete response) in the systematic review, only one patient had a complete response to the treatment; overall among 19 patients, only 1 had complete response, so complete response with obinutuzumab is quite exciting as nothing sort of works for calcinosis.
    When the authors mean complete response, do they mean complete radiological response and clinical response?
    Also, the patient was given chlorambucil and bendamustine for her CLL, so the authors' attributing the response was solely due to obinutuzumab is doubtful.

    1. Kvacskay P, Merkt W, Günther J, et al. Obinutuzumab in connective tissue diseases after former rituximab-non-response: a case series. Annals of the Rheumatic Diseases. Published Online First: 13 January 2022. doi: 10.1136/annrheumdis-2021-221756
    2.Furie RA, Aroca G, Cascino MD, e...

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