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...
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 found that digoxin was the only cardenolides drug included in the data from The Health Improvement Network (THIN). Results indicated that digoxin use was associated with reduced risk of knee or hip OA-associated joint replacement among patients with atrial fibrillation. Therefore, we chose both ouabain and digoxin as the representatives of cardenolides in this study and emphasized the potential importance of digoxin in treating patients with OA in clinics.
Second, it would be ideal and probably more valuable to focus on digoxin use in OA patients without other diseases, including atrail fibrillation. Unfortunately, such information is unavailable in the available database, including The Health Improvement Network (THIN), this is because of the fact that digoxin is only used in patients with atrial fibrillation with or without OA.
Both ouabain and digoxin are FDA-approved drugs and their side effects have been well established. In addition, both ouabain and digoxin did not show detectable toxicity in our in vitro and in vivo assays (online supplemental figure 11). Having said that, we do appreciate the comments that combined use of digoxin and ouabain with lower dosages of drugs may exert synergistic protective effects against OA and may reduce their side effects, which worthwhile further investigations in future.
REFERENCES
1 Cheng YZ, Zhou LJ and Hai Y. Correspondence on ‘Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis’ by Kai-di Wang. Ann Rheum Dis 2022.
2 Wang KD, Ding X, Jiang N, et al. Digoxin targets low density lipoprotein
receptor-related protein 4 and protects against osteoarthritis. Ann Rheum Dis 2021
De1: annrheumdis-2021-221380.
3 Fu WY, Hettinghouse A, Chen Y., et al., 14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis. Ann Rheum Dis 2021;80(12): p. 1615-1627.
4 Liu, RH, Chen YH, Fu WY, et al., Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against inflammatory arthritis. Ann Rheum Dis 2019;78(11): p. 1524-1535.
5 Kjeldsen K, Nørgaard A, Gheorghiade M. Myocardial Na,K-ATPase: the molecular
basis for the hemodynamic effect of digoxin therapy in congestive heart failure.
Cardiovasc Res 2002;55:710–3.
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...
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 GSE118829, which contains naive CD4+ T, central memory CD4+ T, and effector memory CD4+ T cell gene signatures. Using the RobustRankAggreg algorithm, we found that 75 integrated differentially expressed (DE) lncRNAs and 2730 DE mRNAs were co-expressed in naive, central memory, and effector memory CD4+ T cells (Figure 2A–C). In the mRNA expression profile, 489 common DE genes were used in the subsequent studies described below (Figure 2D).
We obtained 748 paired DE mRNAs and lncRNAs with a Pearson correlation coefficient > 0.7 and P < 0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the upregulated lncRNA-related mRNAs (lrmRNAs) were enriched in the Th17 cell differentiation pathway. In addition, several genes were enriched in the Jak/STAT signaling pathway, which is involved in the pathogenesis of RA (Figure 2E)3. Downregulated lrmRNAs were associated mainly with Th1 and Th2 cell differentiation. In addition, these genes were enriched in histone demethylation, which suggested that lrmRNAs affect methylation (Figure 2F)3.
These findings revealed the different CD4+ T cell subsets in patients with RA and revealed the role of lncRNAs in regulating CD4+ T transcriptomic features, which might be an important aspect of the methylation regulatory mechanism.
Reference:
1. Ha E, Bang SY, Lim J, et al. Genetic variants shape rheumatoid arthritis-specific transcriptomic features in CD4(+) T cells through differential DNA methylation, explaining a substantial proportion of heritability. Annals of the rheumatic diseases 2021;80(7):876-83. doi: 10.1136/annrheumdis-2020-219152 [published Online First: 2021/01/14]
2. Wang Z, Chang C, Lu Q. Epigenetics of CD4+ T cells in autoimmune diseases. Current opinion in rheumatology 2017;29(4):361-68. doi: 10.1097/bor.0000000000000393 [published Online First: 2017/04/01]
3. Deviatkin AA, Vakulenko YA, Akhmadishina LV, et al. Emerging Concepts and Challenges in Rheumatoid Arthritis Gene Therapy. Biomedicines 2020;8(1) doi: 10.3390/biomedicines8010009 [published Online First: 2020/01/16]
Contributors
Study design and manuscript writing: RZ, SS and JQ. Data extraction, quality assessment, analysis and interpretation of data: RZ, SS and JQ. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. P-FH and X-FL had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding
This work was supported by the National Natural Science Foundation of China (No. 82001740).
Conflict of interest statement
The authors declare that there is no conflict of nterest.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the Second Hospital of Shanxi Medical University (2016 KY-007).
Patient consent
The data was anonymous and the requirement for informed consent was waived.
Figure 1. Comparison of peripheral CD4+ T subsets between healthy controls (n = 100) and RA patients (n = 2518). The absolute counts (Figure A–D) and proportions (Figure E–H) of Th1 (CD4+IFN-γ+), Th2 (CD4+IL-4+), Th17 (CD4+IL-17+), and Tregs (CD4+CD25+FOXP3+) were determined by flow cytometry combined with standard absolute counting beads. Data are presented as the mean ± SD and were compared using unpaired two-tailed t-tests.
Figure 2. Common specific genes and enrichment analysis of CD4+ T cells. (A–C) The volcano plot shows that DE lncRNAs and DE mRNAs in central memory CD4+ T cell (CH), effector memory CD4+ T cell (EH), and naïve CD4+ T cell (NH) . Blue and red represent downregulated and upregulated lncRNAs and mRNAs, respectively. DE lncRNAs and DE mRNAs were selected based on P < 0.05. (D) Heatmap of the 75 DE lncRNAs determined using the RobustRankAggreg method with an adjusted P < 0.05. (E and F) Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology enrichment analyses of biological processes associated with the commonly expressed lncRNA-related mRNAs, which included 250 upregulated and 121 downregulated genes.
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...
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 researches on the fourth dose of COVID-19 vaccine is planned.
Conflict of interest
Authors ask for waiving for any charge for this correspondence.
References
1. Teles M, Connolly CM, Frey S, Chiang TP, Alejo JJ, Boyarsky BJ, Shah AA, Albayda J, Christopher-Stine L, Werbel WA, Segev DL, Paik JJ. Attenuated response to fourth dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series. Ann Rheum Dis. 2022 Jan 17:annrheumdis-2021-221641. doi: 10.1136/annrheumdis-2021-221641. Online ahead of print.
2. Burki TK. Fourth dose of COVID-19 vaccines in Israel. Lancet Respir Med. 2022 Jan 11:S2213-2600(22)00010-8.
3. . Caillard S, Thaunat O, Benotmane I, Masset C, Blancho G. Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case SeriesAnn Intern Med. 2022 Jan 11:L21-0598. doi: 10.7326/L21-0598. Online ahead of print.Kamar N, Abravanel F, Marion O, Romieu-Mourez R, Couat C, Del Bello A, Izopet J. Assessment of 4 Doses of SARS-CoV-2 Messenger RNA-Based Vaccine in Recipients of a Solid Organ Transplant. JAMA Netw Open. 2021 Nov 1;4(11):e2136030.
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...
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, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Annals of the Rheumatic Diseases 2022;81:100-107.
3. Oddis CV, Reed AM, Aggarwal R, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013;65(2):314-324. doi:10.1002/art.37754
4. Narváez, Javier et al. “Effectiveness and safety of rituximab for the treatment of refractory systemic sclerosis associated calcinosis: A case series and systematic review of the literature.” Autoimmunity reviews vol. 18,3 (2019): 262-269. doi:10.1016/j.autrev.2018.10.006
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...
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 better protect against OA in a surgically induced model in vivo than that of digoxin, especially from Figure 2H and Figure 2I. However, the study emphasized the importance of digoxin instead of ouabain from the beginning to the end. Therefor we are wondering what the role of ouabain played in the whole experiment procedure compared to digoxin on earth.
On the other hand, Figure 4 demonstrated that digoxin use was associated with reduced risk of knee or hip OA-associated joint replacement among patients with atrial fibrillation. This is easy to understand. However, we want to know how many OA patients with atrial fibrillation in the world. What’s the percentage this kind of patients in the whole OA patients?
This is why we are more interest in digoxin used in OA patients without atrial fibrillation. Whether digoxin can have the same protection among OA patients without atrial fibrillation.What’s more, What’s the side effect when using digoxin to OA patients with normal heart function?
We would like to point out that since ouabain and digoxin can both enhance chondrogenesis and stimulate chondrocyte anabolism to protect against OA. We suppose whether we can use digoxin combined with ouabain at the same time to treat with OA patients. The most reason why this hypothesis we have is that we can perhaps reduce the side effect by using lower dose of digoxin, but do not affect the function of protecting against OA patients. And digoxin plus ouabain with different doses group can be planned to further experiments. Maybe we can find a better treatment to OA patients.
References
1 Wang KD, Ding X, Jiang N, et al. Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis. Ann Rheum Dis. 2021 De1: annrheumdis-2021-221380.
2. Nenna R, Turchetti A, Mastrogiorgio G, et al.COL2A1 Gene Mutations: Mechanisms of Spondyloepiphyseal Dysplasia Congenita. Appl Clin Genet. 2019;12:235-238.
3. Lin EA, Liu C-J. The role of ADAMTSs in arthritis. Protein Cell. 2010;1:33–47.
4. Liu C-ju, Zhang Y, Xu K, et al. Transcriptional activation of cartilage oligomeric matrix
protein by SOX9, SOX5, and SOX6 transcription factors and CBP/p300 coactivators.
Front Biosci.2007;12:3899–910.
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...
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 reproductive age in the Netherlands is 30-40 years old and the percentage of childless men ranges between 20% and 25%2. In this study result, however, fertility intentions of men diagnosed under 30 and 31–40 years were lower compared with men diagnosed over 40. Unfortunately, the authors did not explore the probable reasons regarding social-economic factors. Just as in China, the percent of younger voluntary childless population significantly decreased as well3.
Thirdly, if it was intended to investigate on male fertility, it was more plausible to detect sperm quality, sexual dysfunction and other direct factors that might affect fertility. Therefore, the manuscript title seems to be exaggerating the effect of IA disease on fertility. Actually, the manuscript mainly focused on younger IA patients’ desire to have children rather than their fertility.
We respect the significant contributions of the authors and look forward to the follow-up results of this study.
REFERENCES
1Perez-Garcia LF, Röder E, Goekoop RJ, et al. Impaired fertility in men diagnosed with inflammatory arthritis: results of a large multicentre study (iFAME-Fertility) . Ann Rheum Dis 2021;80:1545-52.
2CBvd S. More childless men, 2010. Available: https://www.cbs.nl/en-gb/news/2010/27/more-childless-men.
3Liu F, Li Z, Fertility rate, age structure and financial development. Audit Economy Research 2019;34:117-26.
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...
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 factor that is independently associated with CVE risk among glucocorticoid-naïve patients, which reflects the inherited and shared environmental predisposition to CVE.4 5 Traditional risk factors, such as high low-density lipoprotein cholesterol levels, type 2 diabetes, and hypertension have strong genetic determinants and cluster in families. Hence, one should expect a family history of cardiovascular disease to be a clinically meaningful risk factor. As the family history data between the two groups were not available from this study, there might be residual confounding bias because of unmeasured factors.
In conclusion, although we have some concerns about Ocon et al.,1 we applaud the authors for their commendable work and hope that this study will benefit readers. We look forward to further work on the important topic of glucocorticoid-naïve patients with RA management and hope that early preventive application for CVE will benefit in glucocorticoid-naïve patients with RA.
References:
1. Ocon AJ, Reed G, Pappas DA, et al. Short-term dose and duration-dependent glucocorticoid risk for cardiovascular events in glucocorticoid-naïve patients with rheumatoid arthritis. Ann Rheum Dis 2021;80:1522-9.
2. Wen J, Yang J, Shi Y, et al. Comparisons of different metabolic syndrome definitions and associations with coronary heart disease, stroke, and peripheral arterial disease in a rural Chinese population. PLoS One 2015;10:e0126832.
3. Jasiukaitienė V, Lukšienė D, Tamošiūnas A, et al. The impact of metabolic syndrome and lifestyle habits on the risk of the first event of cardiovascular disease: results from a cohort study in Lithuanian urban population. Medicina (Kaunas) 2020;56:18.
4. Moonesinghe R, Yang Q, Zhang Z, et al. Prevalence and cardiovascular health impact of family history of premature heart disease in the United States: analysis of the national health and nutrition examination survey, 2007–2014. J Am Heart Assoc 2019;8: e012364.
5. Mühlenbruch K, Menzel J, Dörr M, et al. Association of familial history of diabetes or myocardial infarction and stroke with risk of cardiovascular diseases in four German cohorts. Sci Rep 2020;10: 15373.
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.
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...
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 recurrent synovitis by adapting a T-cell-driven, joint specific model of antigen-induced arthritis. 8 In a subsequent study on human RA synovium, a subset of T cell was also found to display TRM markers, especially in the late-stage leukocyte-poor tissues. These synovial TRM cells exhibited a restricted T cell receptor repertoire. Moreover, it has been shown that CD8+ rather than CD4+ TRM plays a predominant role in recurrent joint-specific inflammation.
We therefore propose that the synovial TRM cells may be involved in or even play an essential role in the arthritis recurrence in the same joint in RA patients. The mechanism also suggests a new potential therapeutic approach for achieving sustained RA remission by targeting synovial TRM. This is worthy of further investigation.
Reference
1. Heckert SL, Bergstra SA, Matthijssen XME, et al. Joint inflammation tends to recur in the same joints during the rheumatoid arthritis disease course. Annals of the rheumatic diseases 2021 doi: 10.1136/annrheumdis-2021-220882 [published Online First: 2021/09/01]
2. Friščić J, Böttcher M, Reinwald C, et al. The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity 2021;54(5):1002-21.e10. doi: 10.1016/j.immuni.2021.03.003 [published Online First: 2021/03/25]
3. Clark RA. Resident memory T cells in human health and disease. Science translational medicine 2015;7(269):269rv1. doi: 10.1126/scitranslmed.3010641 [published Online First: 2015/01/09]
4. Szabo PA, Miron M, Farber DL. Location, location, location: Tissue resident memory T cells in mice and humans. Science immunology 2019;4(34) doi: 10.1126/sciimmunol.aas9673 [published Online First: 2019/04/07]
5. Boyman O, Hefti HP, Conrad C, et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. The Journal of experimental medicine 2004;199(5):731-6. doi: 10.1084/jem.20031482 [published Online First: 2004/02/26]
6. Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nature medicine 2012;18(7):1069-76. doi: 10.1038/nm.2817 [published Online First: 2012/07/10]
7. Winchester R, Wiesendanger M, Zhang HZ, et al. Immunologic characteristics of intrarenal T cells: trafficking of expanded CD8+ T cell β-chain clonotypes in progressive lupus nephritis. Arthritis and rheumatism 2012;64(5):1589-600. doi: 10.1002/art.33488 [published Online First: 2011/12/02]
8. Chang MH, Levescot A, Nelson-Maney N, et al. Arthritis flares mediated by tissue-resident memory T cells in the joint. Cell reports 2021;37(4):109902. doi: 10.1016/j.celrep.2021.109902 [published Online First: 2021/10/28]
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)...
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). The study was conducted using data from population-based electronic medical records of 5493 patients with RA. The “endpoints” were: “any specialist outpatient clinic (SOPC) consultation or hospitalization related to RA or reactive arthritis.” This “was considered a proxy of arthritis flare.” There can be several reasons for the absence of a mild flare of RA after vaccination.
First, the reluctance of patients to visit a doctor during a pandemic in cases of mild flares. Several patients were consulted online or “helped themselves.” Visits to doctors have significantly decreased (at least in Kazakhstan) because some hospitals have been redesigned into covid hospitals.
Second, some patients could consult in private clinics, which may not be included in the state system (SOPC). Our centre, Shymkent Medical Centre of Joint Diseases, is private. We described two cases of arthritis after vaccination, [2,8] which were not included in the government electronic registers. It is possible that many private clinics in Hong Kong are not included in the SOPC system.
Third, new arthritis-related prescription records cannot be an accurate indicator of the presence of mild flares. To assess mild flares, new arthritis-related prescription records (conventional synthetic/biological/target synthetic disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs [NSAIDs], or corticosteroids) were analysed. Most often, patients with RA know how to deal with mild flares by themselves. Most patients already had these medicines (96%). They may take only 2–3 tablets of NSAIDs or corticosteroids, and could refuse to visit the doctor for a new prescription, especially during quarantine. In addition, these medicines can reduce the number of RA flares, including post-vaccination flares.
The analysed study is quite necessary, timely, and will be cited several times in the future. We fully agree with the main “key message” of this study: “Individuals with RA should be encouraged to receive the vaccine against COVID-19.” But, it is necessary to conduct additional research concerning doctor-patient contact in this cohort to confirm or disprove our assumptions. This may be possible with the help of a questionnaire.
References
1 Li X, Tong X, Yeung WWY, et al. Two-dose COVID-19 vaccination and possible arthritis flare among patients with rheumatoid arthritis in Hong Kong. Ann Rheum Dis 2021;0:1–5. doi:10.1136/annrheumdis-2021-221571.
2 Baimukhamedov C. Arthritis of the left elbow joint after vaccination against SARS-CoV-2 infection. Int J Rheum Dis 2021;24:1218–20. https://doi.org/10.1111/1756-185X.14202.
3 Sibilia J, Maillefert JF. Vaccination and rheumatoid arthritis. Ann Rheum Dis 2002;61:575–6.
4 Agmon-Levin N, Paz Z, Israeli E et al. Vaccines and autoimmunity. Nat Rev Rheumatol 2009;5:648–52.
5 Schattner A. Consequence or coincidence? The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines. Vaccine 2005;23:3876–86.
6 Terracina KA, Tan FK. Flare of rheumatoid arthritis after COVID-19 vaccination. Lancet Rheumatol 2021;3:e469–70. https://doi.org/10.1016/S2665-9913(21)00108-9.
7 Magliulo D, Narayan S, Ue F et al. Adult-onset Still’s disease after mRNA COVID-19 vaccine. Lancet Rheumatol 2021;3:e680–2. https://doi.org/10.1016/S2665-9913(21)00219-8.
8 Baimukhamedov C, Makhmudov S, Botabekova A. Seropositive rheumatoid arthritis after vaccination against SARS-CoV-2 infection. Int J Rheum Dis 2021 September 29. doi: 10.1111/1756-185X.14220. Online ahead of print.
9 Obeid M, Fenwick C, Pantaleo G. Reactivation of IgA vasculitis after COVID-19 vaccination. Lancet Rheumatol 2021;3:e617. https://doi.org/10.1016/S2665-9913(21)00211-3.
10 Hyun Hakjun, Song JY, Seong H et al. Polyarthralgia and myalgia syndrome after ChAdOx1 nCOV-19 vaccination. J Korean Med Sci 2021 August 30;36:e245. https://doi.org/10.3346/jkms.2021.36.e245.
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.
Show MoreFirst, 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...
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.
Show MoreAs 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...
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...
Show MoreDear 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
Show More2.Furie RA, Aroca G, Cascino MD, e...
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.
Show MoreAs 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...
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.
Show MoreFirstly, 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...
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.
Show MoreFirst, 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...
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.
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.
Show MoreTRM 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...
Dear Editor,
Show MoreWe 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)...
Pages