52 e-Letters

published between 2019 and 2022

  • 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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  • Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis

    We read with great interest the recent study by Kai-di Wang and colleagues1, published in the Annals of Rheumatic Disease, which showed LRP4 was isolated as a novel target of digoxin, and deletion of LRP4 abolished digoxin’s regulations of chondrocytes. We appreciate this meaningful research very much, and we believe that this study has significant guiding for providing new insights into the understanding of digoxin’s chondroprotective action and underlying mechanisms, but also present new evidence for repurposing digoxin for osteoarthritis (OA). However, we have some questions to discuss with the authors except for the limitations the authors mentioned in the study.
    As all we know, the authors used two cardenolides to conduct the experiments, ouabain and digoxin. We can know that ouabain and digoxin can both enhance chondrogenesis and stimulate chondrocyte anabolism from the result of Figure 1. More importantly, we found that the relative staining level in ouabain treated groups was much higher compared with that in digoxin group (Figure 1B). Moreover, the mRNA expressions of transcriptional levels of chondrogenic marker genes, such as COL2A1, Comp, ACAN, SOX5, SOX6, and SOX92-4 were also much higher compared with that in digoxin group (Figure 1C). The similar situation was showed in Figure 1D-G, which may indicate ouabain better enhance chondrogenesis and stimulate chondrocyte anabolism than that of digoxin. In addition, we may also speculate ouabain bette...

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  • Correspondence on ‘Impaired fertility in men diagnosed with inflammatory arthritis: results of a large multicentre study (iFAME-Fertility)’ by Perez-Garcia et al.

    We read with deep interest the article by Perez-Garcia LF et al1, which was aimed at investigating the impact of inflammatory arthritis (IA) on male fertility outcomes, fertility rate, family planning, childlessness and fertility problems. The authors concluded that IA could impair male fertility. We really appreciate the work done by the authors. However, there are some worthwhile issues that need to be explored.
    Firstly, although the patients were divided into three groups by age, it was not analyzed in detail whether there were differences in sample size between each disease (Spondyloarthritis (SpA) and rheumatoid arthritis (RA) etc.) in the group. Since older patients usually had longer disease course and even more serious disease, it might introduce bias to the study results. Therefore, the average onset age of each group should be consistent. Additionally, since the actual mean total number of children per man in all patients was 1.69, almost the same as the estimated number 1.7, it could hardly draw the conclusion that diagnosed with IA could impair fertility in men. Moreover, why was the mean total number of children per man in patients over 40 (1.88) higher than the estimated number and the actual number (1.79)? Was longer IA disease course associated with higher mean total number of children per man?
    Secondly, the authors mentioned that the men still having future fertility intentions were excluded in the study. As stated by the authors, the peak of r...

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  • Correspondence on “Short-term dose and duration-dependent glucocorticoid risk for cardiovascular events in glucocorticoid-naïve patients with rheumatoid arthritis” by Ocon et al.

    We read with great interest the article by Ocon et al.,1 which reported that daily doses of ≥5 mg of prednisone-equivalents, elevated cumulative dose and extended duration of use of glucocorticoid (GC) over the preceding six-month and one-year intervals are associated with an increased risk for incident cardiovascular event (CVE) in steroid-naïve patients with rheumatoid arthritis (RA). Additionally, they also noted that no association with risk for CVE was found with daily prednisone of ≤4 mg or shorter cumulative doses and durations. This study is a valuable addition to the literature. However, some issues have not been addressed by the authors.
    First, metabolic syndrome and its components could mediate and may be causal in the association between CVE in RA and use of GC in the dose ranges and duration of use, which may offset the significance level.2 3 Additionally, a mediation analysis could have been used to address this mediation effect. Although metabolic syndrome and its severity can be identified and controlled, the likelihood of future metabolic syndrome complications cannot be assessed in most cases. However, the baseline metabolic syndrome data of the two groups were not available in this study. It is important to consider the context of metabolic syndrome when evaluating CVE for glucocorticoid-naïve patients with RA who initiate ‘low-dose’ GC over short-term intervals of use.
    Second, a family history of cardiovascular disease is a strong risk facto...

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  • Cyclophosphamide in parenchymal CNS involvement due to Behcet disease.

    Dear Editor,
    The authors did not clarify if there is a role of cyclophosphamide in neurobehcet disease and if there is a recommended stratification for choosing immunosuppressive agents according to the severity of neurological manifestations.

    Thank you.

  • Correspondence on “Joint inflammation tends to recur in the same joints during the rheumatoid arthritis disease course” by Heckert et al

    With great interest, we read the recently published article by Heckert et al regarding the tendency of recurrence of joint inflammation in patients with rheumatoid arthritis (RA) based on the sub-analysis of the BeSt study 1. In this study, the authors found that joint swelling in RA patients tended to recur in the same joints over time (OR 2.37, 95% CI 2.30 to 2.43, p<0.001). We congratulate the teams for their great work. Meanwhile, the important and interesting findings prompt us to think about the possible underlying mechanisms, which was just simply explained in the discussion. The authors pointed out that previous exposure to inflammatory triggers might mount a local alert state in the joint, promoting site-specific recurrence of inflammation. 2 We agree to their hypothesis, and would like to comment on the possible mechanisms in more depth from the aspect of Resident memory T cells (TRM) to the clinical findings.
    TRM cells have been recognized as a group of sentinels maintained in diverse anatomic compartments which resident in the tissue niche for a long-term in both human and mouse models. TRM requires distinct signals for the maintenance and survival in specific tissues. 3 4 It has been found that TRM is associated with the onset, progression and relapse of autoimmune diseases, such as psoriasis, spondylarthritis and lupus. 5-7 Recently, TRM which residents in the synovium was proved to be essential for the flare of arthritis in the animal model of recur...

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  • Vaccinations and rheumatoid arthritis: no problem?

    Dear Editor,
    We read the article [1] that was published online in ARD on 22 October 2021 with great interest. Many thanks and respect to the authors of this study. To the best of our knowledge, this is the first large retrospective cohort study to have addressed this problem. Vaccination of patients with rheumatoid arthritis (RA) and other musculoskeletal disorders (MSDs) is one of the most important issues for rheumatologists. We have also studied this problem. Our paper has been included in the references. [2] Arthritis after vaccination has been debated for a long time, [3,4] and the main question is "Consequence or coincidence?". [5] There are already several reports of RA flares after SARS-CoV-2 vaccination, [6–8] and some reports of flares in other MSDs. [9] In Korea, five unusual cases of polyarthralgia and myalgia syndrome were reported in patients after vaccination. [10] However, all these studies are case reports or case series. The cohort study in The BMJ [1] will be one of the major studies drawing up national recommendations for vaccination of patients with RA. Therefore, it is necessary to carefully examine any points that may lead to incorrect conclusions.
    It seems to us that the conclusion, "there is no increased risk of possible flare following two doses of COVID-19 vaccination" is unambiguous and insufficiently substantiated. Perhaps such a conclusion can be drawn correctly only for strong flares (requiring hospitalisation)...

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