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.
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.
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.
We read with great interest the recent article by Laurent et al.1 which confirmed the potential role of innate lymphoid cells-2 (ILC2) in the establishment of fibrosis in human systemic sclerosis. It provided a novel idea that transforming growth factor-β (TGFβ) downregulates KLRG1 expression on ILC2 and contributes to its low interleukin 10 (IL10) production capacity, finally resulting in skin fibrosis. However, we feel confused when reading some parts of the article.
From the design of the overall experiment, we can clearly understand that the authors first determined the importance of ILC2 in fibrotic tissues, and then sought out the reason: the low IL10 production caused by TGF-β stimulation. Finally, they conducted relevent cell and animal experiments and draw the final conclusion. However, from the conclusion of the article, it is the reduction of IL10 that leads to the progression of fibrosis? It makes us confused because ILC2 is not the main cell producing IL10. As we all known, IL10 is a cytokine of multi-cell origin and almost all immune cells can synthesize IL102. Meanwhile, despite its relative increase in fibrotic tissues, the numberof Innate lymphoid cells is very rare3. With the diversification of IL10 sources, is the low IL10 production capacity of ILC2 the main cause of fibrosis?
In summary, we respect the original insight and contributions of the authors, and believe an in-depth study of the role of IL10 may be a new research direction.
We read with great interest the recent article by Laurent et al.1 which confirmed the potential role of innate lymphoid cells-2 (ILC2) in the establishment of fibrosis in human systemic sclerosis. It provided a novel idea that transforming growth factor-β (TGFβ) downregulates KLRG1 expression on ILC2 and contributes to its low interleukin 10 (IL10) production capacity, finally resulting in skin fibrosis. However, we feel confused when reading some parts of the article.
From the design of the overall experiment, we can clearly understand that the authors first determined the importance of ILC2 in fibrotic tissues, and then sought out the reason: the low IL10 production caused by TGF-β stimulation. Finally, they conducted relevent cell and animal experiments and draw the final conclusion. However, from the conclusion of the article, it is the reduction of IL10 that leads to the progression of fibrosis? It makes us confused because ILC2 is not the main cell producing IL10. As we all known, IL10 is a cytokine of multi-cell origin and almost all immune cells can synthesize IL102. Meanwhile, despite its relative increase in fibrotic tissues, the numberof Innate lymphoid cells is very rare3. With the diversification of IL10 sources, is the low IL10 production capacity of ILC2 the main cause of fibrosis?
In summary, we respect the original insight and contributions of the authors, and believe an in-depth study of the role of IL10 may be a new research direction.
References
1. Laurent P, Allard B, Manicki P, et al. TGFβ promotes low IL10-producing ILC2 with profibrotic ability involved in skin fibrosis in systemic sclerosis. Ann Rheum Dis 2021.
2. Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010;10:170-81.
3. Constantinides MG, McDonald BD, Verhoef PA, Bendelac A. A committed precursor to innate lymphoid cells. Nature 2014;508:397-401.
With great interest, we read the paper by Perez-Garcia et al for reporting the impaired fertility of 628 male patients with inflammatory arthritis (IA) from multiple hospitals in the Netherlands.1 Based on the result, the authors suggested that treatment strategies should be appropriately re-concerned for male IA patients who want to have children. Although the author has stated the limitations of the research, some details need to be addressed clearly.
Firstly, Disease duration may be an interfering factor of fertility.2 In this research, men diagnosed ≤40 years had a longer disease duration than men diagnosed ≥41 years, with a higher rate of low sperm quality and a lower number of children. Besides, smoking and drinking history were not included in the demographic characteristics of patients, since those factors may have great effects on male fertility.3 Then, the age of the partners of the participants were not taken into calculation which may have a great effect on the number of children of the male IA patients, and the willingness of the partners to have children as well. 4 5 The effects of disease and drugs on the results were not distinguished in the study, and both of them may have effects on the fertility.6
Secondly, all data were collected from a questionnaire survey, including the patient’s partner time to pregnancy, female fertility evaluation, and the patient’s sperm quality, which may cause subjective bias. We noticed that out of 628 patients, onl...
With great interest, we read the paper by Perez-Garcia et al for reporting the impaired fertility of 628 male patients with inflammatory arthritis (IA) from multiple hospitals in the Netherlands.1 Based on the result, the authors suggested that treatment strategies should be appropriately re-concerned for male IA patients who want to have children. Although the author has stated the limitations of the research, some details need to be addressed clearly.
Firstly, Disease duration may be an interfering factor of fertility.2 In this research, men diagnosed ≤40 years had a longer disease duration than men diagnosed ≥41 years, with a higher rate of low sperm quality and a lower number of children. Besides, smoking and drinking history were not included in the demographic characteristics of patients, since those factors may have great effects on male fertility.3 Then, the age of the partners of the participants were not taken into calculation which may have a great effect on the number of children of the male IA patients, and the willingness of the partners to have children as well. 4 5 The effects of disease and drugs on the results were not distinguished in the study, and both of them may have effects on the fertility.6
Secondly, all data were collected from a questionnaire survey, including the patient’s partner time to pregnancy, female fertility evaluation, and the patient’s sperm quality, which may cause subjective bias. We noticed that out of 628 patients, only 87 men reported the fertility evaluation outcome, which reduced the representation of the data to the overall sample of the study.
Thirdly, no negative control group was set in the study. There was no direct comparison between participants and the general population of the same age group, but only with men who were older than 40 years in the similar literature. In the results part, the mean total number of children per man for all participants was very close to the number of the men who were older than 40 years in the Netherlands, and whether it was significantly different was not mentioned. It seems to be uncertain that whether IA contributed to the impaired fertility of male patients.
We do believe that the male fertility situation of IA patients needs for great attention. But we suggest that the author should clearly addressed the confounders we talked about above. We also suggest that some objective examinations could be tested such as the patient's reproductive function, including semen analysis, hormonal investigation, microbiologic assessment, and scrotal ultrasound, rather than obtaining the information through questionnaire surveys.7 Moreover, we hope to read more comprehensive studies in which negative control groups were set into analysis in the coming future by the authors.
REFERENCES
1 Perez-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 Aug 9: annrheumdis-2021-220709. doi: 10.1136/annrheumdis-2021-220709.
2 Ursin K, Lydersen S, Skomsvoll JF, et al. Factors Associated With Time to Pregnancy in Women With Axial Spondyloarthritis: A Registry-Based Multicenter Study. Arthritis Care Res (Hoboken). 2021 Aug;73(8):1201-1209. doi: 10.1002/acr.24233.
3 Sansone A, Di Dato C, de Angelis C, Menafra D, Pozza C, Pivonello R, Isidori A, Gianfrilli D. Smoke, alcohol and drug addiction and male fertility. Reprod Biol Endocrinol. 2018 Jan 15;16(1):3. doi: 10.1186/s12958-018-0320-7.
4 Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril. 2001 Feb;75(2):237-48. doi: 10.1016/s0015-0282(00)01679-4.
5 Dolhain RJ. Rheumatoid arthritis and pregnancy; not only for rheumatologists interested in female health issues. Ann Rheum Dis. 2010 Feb;69(2):317-8. doi: 10.1136/ard.2009.120741.
6 Brouwer J, Hazes JM, Laven JS, et al. Fertility in women with rheumatoid arthritis: influence of disease activity and medication. Ann Rheum Dis. 2015 Oct;74(10):1836-41. doi: 10.1136/annrheumdis-2014-205383.
7 Jungwirth A, Giwercman A, Tournaye H, Diemer T, Kopa Z, Dohle G, Krausz C; European Association of Urology Working Group on Male Infertility. European Association of Urology guidelines on Male Infertility: the 2012 update. Eur Urol. 2012 Aug;62(2):324-32. doi: 10.1016/j.eururo.2012.04.048.
Thank you for pointing out that the conclusion was not clear. The authors would like to modify it to 'The interim analysis revealed that up to 66% of patients receiving APR reached REM/LDA, as measured by cDAPSA at 8 months.'
We thank Dr. Yudong Liu for commenting on our manuscript and on many of the same issues we raised 1. There are, however, some comments that require clarification and a response. It is true that anti-phospholipid antibodies (APLA) of various specificities and immunoglobulin isotypes have been reported in COVID-19 2. However, despite a historical connection of APLA with coagulopathies and anti-phospholipid syndrome (APS), to date there is no convincing evidence that APLA have this in vivo pathogenic effect in COVID-19. In our patients, despite the presence of APLA (e.g., IgG anti-cardiolipin), there was no link to thrombotic events, a finding echoed by other referenced studies 3 and recently reviewed 2,4. The recent publication by Chang et al 5 is mentioned but it is important to appreciate that their results were compared to “normal” controls and no clinical features (coagulopathy or APS) were reported, precluding any inferences to autoimmune diseases; it is a standalone description of COVID-19 findings. Like the Chang manuscript, we also reported an extensive array of autoantibodies in COVID-19, but when we used sera from contemporaneous non-COVID patients of similar disease severity as comparator controls, we did not find significant differences in the autoantibody repertoire between the COVID positive and negative cohorts 6. Many individuals displayed “certain autoimmune features” but that cannot be taken to be equivalent to autoimmune disease. Indeed, COVID-19 patients...
We thank Dr. Yudong Liu for commenting on our manuscript and on many of the same issues we raised 1. There are, however, some comments that require clarification and a response. It is true that anti-phospholipid antibodies (APLA) of various specificities and immunoglobulin isotypes have been reported in COVID-19 2. However, despite a historical connection of APLA with coagulopathies and anti-phospholipid syndrome (APS), to date there is no convincing evidence that APLA have this in vivo pathogenic effect in COVID-19. In our patients, despite the presence of APLA (e.g., IgG anti-cardiolipin), there was no link to thrombotic events, a finding echoed by other referenced studies 3 and recently reviewed 2,4. The recent publication by Chang et al 5 is mentioned but it is important to appreciate that their results were compared to “normal” controls and no clinical features (coagulopathy or APS) were reported, precluding any inferences to autoimmune diseases; it is a standalone description of COVID-19 findings. Like the Chang manuscript, we also reported an extensive array of autoantibodies in COVID-19, but when we used sera from contemporaneous non-COVID patients of similar disease severity as comparator controls, we did not find significant differences in the autoantibody repertoire between the COVID positive and negative cohorts 6. Many individuals displayed “certain autoimmune features” but that cannot be taken to be equivalent to autoimmune disease. Indeed, COVID-19 patients have developed Guillain Barré (not a COVID-specific condition) and there are anecdotal reports of other autoimmune diseases, but it is very important to realize that temporarily is not the same as causality 2.
Last, it is opined that our study “failed to detect aβ2-GP1 in patients with COVID-19, but other studies reported the existence of these aPLs”. However, this comment does not seem to appreciate that we used an assay that detected antibodies to domain 1 of β2-glycoprotein1 (β2-GP1) which is known to have higher specificity for and more clearly linked to the pathogenesis of APS than antibodies to other β2-GP1 domains 7. As we clarified in our manuscript, these findings are consistent with those of with Borghi et al 3 who detected antibodies to 2GP1 domains 2 and 4 but found no association with thrombotic events in COVID19 in 122 severe COVID-19 patients, once again challenging the notion that anti-2GP1 has any pathogenic role in COVID-19 2.
As to the dynamic and temporal/chronological sequence of autoantibody and APLA appearance, we clearly stated that “clinical data and serum samples were collected longitudinally at days 0, 1, 3, 5, 7 and 10; after day 10 or ICU discharge.” Our data (Table 2) and discussion on APLA 1 and other autoantibodies 6 showed that in some patients autoantibodies were present on admission to intensive care (IC) while in others they appeared during the stay in IC and in some the autoantibodies fell to within normal/reference range while in IC. Hence, the chronological autoantibody responses are quite heterogenous. We concur that important studies are still required, especially the assessment of whether autoimmunity evolves to autoimmune diseases in COVID-19 or following vaccination, as well as in long -COVID and multi-inflammatory syndrome.
References
1 Trahtemberg U, Rottapel R, Dos Santos CC, Slutsky AS, Baker A, Fritzler MJ. Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients. Ann Rheum Dis 2021; 80 (9):1236-1240. doi: 10.1136/annrheumdis-2021-220206.
2 Meroni PL, Borghi MO. Antiphospholipid antibodies and COVID-19 thrombotic vasculopathy: one swallow does not make a summer. Ann Rheum Dis 2021; 80(9):1105-1107. doi: 10.1136/annrheumdis-2021-220520.
3 Borghi MO, Beltagy A, Garrafa E, Curreli D, Cecchini G, Bodio C et al. Anti-Phospholipid Antibodies in COVID-19 Are Different From Those Detectable in the Anti-Phospholipid Syndrome. Front Immunol 2020; 11:584241-doi: 10.3389/fimmu.2020.584241.
4 Knight JS, Caricchio R, Casanova JL, Combes AJ, Diamond B, Fox SE et al. The intersection of COVID-19 and autoimmunity. J Clin Invest 2021; Oct 28. Online ahead of print:e154886-doi: 10.1172/JCI154886.
5 Chang SE, Feng A, Meng W, Apostolidis SA, Mack E, Artandi M et al. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun 2021; 12:5417-25509. doi: 10.1038/s41467-021-25509-3.
6 Trahtemberg U, Fritzler MJ, On behalf of the COVID-19 chapter of the "Longitudinal Biomarkers in Lung Injury" study groupCollaborators. COVID-19-associated autoimmunity as a feature of acute respiratory failure. Intensive Care Med 2021; 47(7):801-804. doi: 10.1007/s00134-021-06408-z.
7 Chighizola CB, Pregnolato F, Andreoli L, Bodio C, Cesana L, Comerio C et al. Beyond thrombosis: Anti-beta2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome. J Autoimmun 2018; 90:76-83.
I read with great interest the article by Trahtemberg et al.[1] on the clinical relevance of antiphospholipid antibodies (aPLs), in particular anticardiolipin antibodies (aCLs), in critically-ill COVID-19 positive and negative patients. Severe COVID-19 is associated with a hypercoagulable state. Early studies identified the presence of aPLs in critically-ill COVID-19 patients[2], which has attracted considerable attention as the presence of aPLs is one of the mechanisms leading to coagulopathy. Substantial efforts then tried to associate the thrombotic events seen in COVID-19 to aPLs status. The results seem negative, but a number of different types of autoantibodies were identified [3]. Chang et al. recently reported that autoantibodies were present in approximately half of the hospitalized COVID-19 patients, but in less than 15% of healthy controls [4]. In addition to aCLs and anti-beta 2 glycoprotein 1 antibodies (aβ2-GP1), they also identified autoantibodies targeting autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes as well as targeting interferons/interleukins and other cytokines[4]. These findings suggest that COVID-19, in particular patients with severe/critical conditions, displayed certain autoimmune features.
In the well-designed study by Trahtemberg et al., the authors expanded the cohort by including COVID-19 negative patients who were admitted to intensive care unit (ICU) with ac...
I read with great interest the article by Trahtemberg et al.[1] on the clinical relevance of antiphospholipid antibodies (aPLs), in particular anticardiolipin antibodies (aCLs), in critically-ill COVID-19 positive and negative patients. Severe COVID-19 is associated with a hypercoagulable state. Early studies identified the presence of aPLs in critically-ill COVID-19 patients[2], which has attracted considerable attention as the presence of aPLs is one of the mechanisms leading to coagulopathy. Substantial efforts then tried to associate the thrombotic events seen in COVID-19 to aPLs status. The results seem negative, but a number of different types of autoantibodies were identified [3]. Chang et al. recently reported that autoantibodies were present in approximately half of the hospitalized COVID-19 patients, but in less than 15% of healthy controls [4]. In addition to aCLs and anti-beta 2 glycoprotein 1 antibodies (aβ2-GP1), they also identified autoantibodies targeting autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes as well as targeting interferons/interleukins and other cytokines[4]. These findings suggest that COVID-19, in particular patients with severe/critical conditions, displayed certain autoimmune features.
In the well-designed study by Trahtemberg et al., the authors expanded the cohort by including COVID-19 negative patients who were admitted to intensive care unit (ICU) with acute respiratory failure. They found that aCLs were present in 59% severe COVID-19 patients, but were also detected in 35% contemporaneous non-COVID-19 patients. They also identified the presence of a broad range of non-antiphospholipid syndrome (APS) autoantibodies as well as anti-cytokine autoantibodies. Specifically, over 50% patients were positive for anti-nuclear antibodies (ANA), and 38% patients were positive for anti-cytokine autoantibodies [1]. These findings thus confirmed and extended previous observations that the autoimmune feature may be not restricted to severe COVID-19, but may be a common feature of severe respiratory diseases.
aPLs can be induced in a number of virus infections, but ANA and other autoantibodies are normally absent [5]. However, a broad range of autoantibodies, in particular ANA, are present in severe COVID-19, rendering the severe COVID-19 more resemble of a systemic autoimmune disease. In fact, by detailed characterization of B cell responses through high-dimensional flow cytometry, Woodruff et al. have found that the immunological landscape associated with effector B cell mobilization in COVID-19 is highly similar to the one observed in patients with active autoimmune processes, and in particular with active systemic lupus erythematosus (SLE)[6]. Instead of predicting thrombotic events, the autoimmune features may be associated with disease severity. Trahtemberg et al.[1] found that the presence of aCLs was associated with more severe disease independent of COVID-19 status, which is consistent with the findings by Woodruff et al., who have found that disease severity and poor clinical outcomes of COVID-19 are closely correlated with intense activation of the extrafollicular B cell pathway that leads to the generation of autoreactive antibody-secreting cell (ASCs) responses [6]. Multiple tissues/organs damage due to widespread and overwhelming inflammation (i.e. cytokine storm) during severe COVID-19 may result in excessive generation and accumulation of autoantigens [7], which could boost production of autoantibodies that had previously existed at very low levels in the body.
Although Trahtemberg et al.’s work provide critical insights that transient breakage of immune tolerance and the generation of autoantibodies may be a common phenomenon in severe viral infections, a number of questions need to be answered in furture studies. For example, the presence of autoantibodies in COVID-19 displayed substantial heterogeneity in terms of types and titers. For example, Trahtemberg et al. [1] failed to detect aβ2-GP1 in patients with COVID-19, but other studies reported the existence of these aPLs [2, 4, 8, 9]. Xiao et al. showed that the levels of aPLs rapidly decreased after hitting the peak [9]. It seems that the emergence of autoantibodies is due to a sporadic loss of self-tolerance. It thus remains unknown when aPLs first emerged and the chronological order of the emergence of different aPLs. It also remains unclear whether ANAs and other autoantibodies (i.e. anti-cytokine antibodies) follow the similar pattern. The timing of sample collection seems an important factor. Second, COVID-19 and some autoimmune disorders (i.e. SLE or APS) share some clinical and laboratory similarities. It has been reported that some patients develop autoimmune diseases, such as Guillain-Barre syndrome or SLE, after COVID-19 infection [10]. It is thus unclear whether or not COVID-19 infection accelerates the pathological process in these predisposed subjects, or just a coincidence. Third, it remains to be determined whether or not vaccinated subjects develop autoantibodies after being infected by SARS-CoV-2, especially in those who have severe COVID-19.
References
1. Trahtemberg U, Rottapel R, Dos Santos CC, Slutsky AS, Baker A, Fritzler MJ. Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients. Ann Rheum Dis. 2021 Sep; 80(9):1236-1240.
2. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 23; 382(17):e38.
3. Vojdani A, Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol. 2020 Aug; 217:108480.
4. Chang SE, Feng A, Meng W, Apostolidis SA, Mack E, Artandi M, et al. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun. 2021 Sep 14; 12(1):5417.
5. Mendoza-Pinto C, Garcia-Carrasco M, Cervera R. Role of Infectious Diseases in the Antiphospholipid Syndrome (Including Its Catastrophic Variant). Curr Rheumatol Rep. 2018 Aug 20; 20(10):62.
6. Woodruff MC, Ramonell RP, Nguyen DC, Cashman KS, Saini AS, Haddad NS, et al. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat Immunol. 2020 Dec; 21(12):1506-1516.
7. Wilson JG, Simpson LJ, Ferreira AM, Rustagi A, Roque J, Asuni A, et al. Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI Insight. 2020 Sep 3; 5(17).
8. Borghi MO, Beltagy A, Garrafa E, Curreli D, Cecchini G, Bodio C, et al. Anti-Phospholipid Antibodies in COVID-19 Are Different From Those Detectable in the Anti-Phospholipid Syndrome. Front Immunol. 2020; 11:584241.
9. Xiao M, Zhang Y, Zhang S, Qin X, Xia P, Cao W, et al. Antiphospholipid Antibodies in Critically Ill Patients With COVID-19. Arthritis Rheumatol. 2020 Dec; 72(12):1998-2004.
10. Liu Y, Sawalha AH, Lu Q. COVID-19 and autoimmune diseases. Curr Opin Rheumatol. 2021 Mar 1; 33(2):155-162.
Monti et. al. reported a decrease in Fast Track Clinic (FTC) assessments for Giant Cell Arteritis (GCA) during the COVID-19 pandemic and an increase in irreversible visual loss; other groups have found increased incidence of GCA during the COVID-19 pandemic.1,2,3 We created an FTC in 2017 to rapidly evaluate and treat patients with possible GCA using vascular ultrasound and also noticed an increase in permanent vision loss. We conducted a medical records review study during two time periods of patients referred to the FTC with concern for GCA to evaluate how many had permanent visual loss.4 The “COVID-19 period” was defined as 3/1/2020-8/31/2020 the “pre-COVID-19 period was 3/1/2019-8/31/2019. Patients received an ultrasound for GCA performed by a specially trained vascular sonographer. A positive ultrasound for GCA had either halo sign with compression in the temporal arteries and branches or increased intima-media thickness (IMT) in the large vessels. Patients were referred for temporal artery biopsy (TAB) at the discretion of the rheumatologist.
25 patients were referred to the FTC during both the COVID-19 period and pre-COVID-19 period and nine diagnosed with GCA in each group. 52% of patients experienced symptoms for less than two weeks prior to presenting to medical care during the COVID-19 period, 48% pre-COVID-19. The median number of days from the time first seen in the medical system until referral to the FTC was 7 days during COVID-19 compared to 8.5 day...
Monti et. al. reported a decrease in Fast Track Clinic (FTC) assessments for Giant Cell Arteritis (GCA) during the COVID-19 pandemic and an increase in irreversible visual loss; other groups have found increased incidence of GCA during the COVID-19 pandemic.1,2,3 We created an FTC in 2017 to rapidly evaluate and treat patients with possible GCA using vascular ultrasound and also noticed an increase in permanent vision loss. We conducted a medical records review study during two time periods of patients referred to the FTC with concern for GCA to evaluate how many had permanent visual loss.4 The “COVID-19 period” was defined as 3/1/2020-8/31/2020 the “pre-COVID-19 period was 3/1/2019-8/31/2019. Patients received an ultrasound for GCA performed by a specially trained vascular sonographer. A positive ultrasound for GCA had either halo sign with compression in the temporal arteries and branches or increased intima-media thickness (IMT) in the large vessels. Patients were referred for temporal artery biopsy (TAB) at the discretion of the rheumatologist.
25 patients were referred to the FTC during both the COVID-19 period and pre-COVID-19 period and nine diagnosed with GCA in each group. 52% of patients experienced symptoms for less than two weeks prior to presenting to medical care during the COVID-19 period, 48% pre-COVID-19. The median number of days from the time first seen in the medical system until referral to the FTC was 7 days during COVID-19 compared to 8.5 days pre-COVID-19. The median number of days from referral until ultrasound was completed was 1 day during COVID-19 and 2 days pre-COVID-19, and the median number of days on prednisone prior to ultrasound for GCA was 1 during COVID-19 and 2 pre-COVID-19. During the COVID-19 period, 7 patients received TAB compared to 13 patients pre-COVID-19. Median days to temporal artery biopsy was increased in during COVID-19 group at 21 days compared to 7 in the pre-COVID-19 group. All TABs were negative.
During the COVID-19 period, seven patients had a positive ultrasound for GCA, and two patients were diagnosed based on clinical history. During the pre-COVID-19 period five patients had positive ultrasound findings for GCA, and four patients were diagnosed based on clinical history.
Permanent vision loss due to GCA during the COVID-19 period occurred in four patients, and none in the pre-COVID-19 period. Vision loss improved somewhat but did not resolve entirely with treatment in 3 patients (one with bilateral anterior ischemic optic neuropathy (AION), one with unilateral AION and one with bilateral optic nerve edema), and 1 patient experienced permanent vision loss without any improvement due to unilateral retinal ischemia.
We found no change in referral rates during the COVID-19 pandemic but found alarming rates of permanent vision loss compared to historical controls. One notable difference between the two groups was the time from FTC activation to TAB, which was prolonged during the COVID-19 period; it seems unlikely to have contributed to negative outcomes as all TABs were negative and vision impairment occurred prior to FTC activation. This may indicate that complications arose as a result of either delayed presentation or delayed FTC activation, but this is not supported by our analysis. Patients in both groups were referred to the FTC quickly, and underwent workup within 1-2 days. Despite similarities, outcomes were worse during the COVID-19 period. Further research is necessary to elucidate the etiology of the increase in permanent vision loss in patients with GCA during the COVID-19 pandemic.
References
1. Monti, S. et al. Impact of delayed diagnoses at the time of COVID-19: increased rate of preventable bilateral blindness in giant cell arteritis. Ann. Rheum. Dis. 79, 1658–1659 (2020).
2. Lecler, A., Villeneuve, D., Vignal, C. & Sené, T. Increased rather than decreased incidence of giant-cell arteritis during the COVID-19 pandemic. Ann. Rheum. Dis. 80, e89–e89 (2021).
3. Luther, R. et al. Increased number of cases of giant cell arteritis and higher rates of ophthalmic involvement during the era of COVID-19. Rheumatol. Adv. Pract. 4, rkaa067 (2020).
4. Harris, P. A. et al. Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inform. 42, 377–381 (2009).
We thank Professors Lee and Song for their interest in our genome-wide association study (GWAS) of chronic widespread musculoskeletal pain (CWP)[1]. Their correspondence has raised several methodological concerns. First, CWP is a prominent feature of fibromyalgia. Clinically, it’s impossible to diagnose fibromyalgia without having CWP[2]. Therefore, the relevance of our findings to fibromyalgia cannot be ignored although we were careful not to conflate the two traits and did not claim genetic association with fibromyalgia. Second, the authors raise the relationship of the traits with age and sex; we adjusted for these covariates in the discovery GWAS and replication study. The important issue of body mass index (BMI) was much debated in our experimental design meetings. We elected not to adjust for BMI in the study for the following reasons:- (i) adjustment for heritable covariates (such as BMI) are not recommended in GWAS as this can lead to collider bias[3, 4] (ii) we wanted to explore the shared heritability of BMI and CWP using genetic correlation, (iii) adjustment for BMI would have affected genetic correlation and partial genetic correlation estimates reported in the paper and (vi) while so few variants have been described to date using GWAS for CWP, we were keen not to reduce the variance in the phenotype even if that led us to identify variants pleiotropic for BMI and CWP. Third, we have selected our controls for GWAS carefully by excluding important diagnostic con...
We thank Professors Lee and Song for their interest in our genome-wide association study (GWAS) of chronic widespread musculoskeletal pain (CWP)[1]. Their correspondence has raised several methodological concerns. First, CWP is a prominent feature of fibromyalgia. Clinically, it’s impossible to diagnose fibromyalgia without having CWP[2]. Therefore, the relevance of our findings to fibromyalgia cannot be ignored although we were careful not to conflate the two traits and did not claim genetic association with fibromyalgia. Second, the authors raise the relationship of the traits with age and sex; we adjusted for these covariates in the discovery GWAS and replication study. The important issue of body mass index (BMI) was much debated in our experimental design meetings. We elected not to adjust for BMI in the study for the following reasons:- (i) adjustment for heritable covariates (such as BMI) are not recommended in GWAS as this can lead to collider bias[3, 4] (ii) we wanted to explore the shared heritability of BMI and CWP using genetic correlation, (iii) adjustment for BMI would have affected genetic correlation and partial genetic correlation estimates reported in the paper and (vi) while so few variants have been described to date using GWAS for CWP, we were keen not to reduce the variance in the phenotype even if that led us to identify variants pleiotropic for BMI and CWP. Third, we have selected our controls for GWAS carefully by excluding important diagnostic confounders[5] and performed sensitivity GWAS analyses excluding non-musculoskeletal pain participants from the control group. It was not possible to exclude such diagnostic confounders from the replication cohorts. Finally, we observed no heterogeneity when we performed both sample size- and inverse variance weighted- meta-analyses. Thus, the meta-analysis findings may be considered valid for the full spectrum of CWP.
References
1. Rahman MS, Winsvold BS, Chavez Chavez SO, Borte S, Tsepilov YA, Sharapov SZ, et al. Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain. Annals of the Rheumatic Diseases. 2021:annrheumdis-2020-219624.
2. Häuser W, Sarzi-Puttini P, Fitzcharles MA. Fibromyalgia syndrome: under-, over- and misdiagnosis. Clin Exp Rheumatol. 2019 Jan-Feb; 37 Suppl 116(1):90-97.
3. Aschard H, Vilhjálmsson BJ, Joshi AD, Price AL, Kraft P. Adjusting for heritable covariates can bias effect estimates in genome-wide association studies. Am J Hum Genet. 2015 Feb 5; 96(2):329-339.
4. Vansteelandt S, Goetgeluk S, Lutz S, Waldman I, Lyon H, Schadt EE, et al. On the adjustment for covariates in genetic association analysis: a novel, simple principle to infer direct causal effects. Genetic epidemiology. 2009; 33(5):394-405.
5. Häuser W, Perrot S, Sommer C, Shir Y, Fitzcharles MA. Diagnostic confounders of chronic widespread pain: not always fibromyalgia. Pain Rep. 2017; 2(3).
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...
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...
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.
We read with great interest the recent article by Laurent et al.1 which confirmed the potential role of innate lymphoid cells-2 (ILC2) in the establishment of fibrosis in human systemic sclerosis. It provided a novel idea that transforming growth factor-β (TGFβ) downregulates KLRG1 expression on ILC2 and contributes to its low interleukin 10 (IL10) production capacity, finally resulting in skin fibrosis. However, we feel confused when reading some parts of the article.
...Show MoreFrom the design of the overall experiment, we can clearly understand that the authors first determined the importance of ILC2 in fibrotic tissues, and then sought out the reason: the low IL10 production caused by TGF-β stimulation. Finally, they conducted relevent cell and animal experiments and draw the final conclusion. However, from the conclusion of the article, it is the reduction of IL10 that leads to the progression of fibrosis? It makes us confused because ILC2 is not the main cell producing IL10. As we all known, IL10 is a cytokine of multi-cell origin and almost all immune cells can synthesize IL102. Meanwhile, despite its relative increase in fibrotic tissues, the numberof Innate lymphoid cells is very rare3. With the diversification of IL10 sources, is the low IL10 production capacity of ILC2 the main cause of fibrosis?
In summary, we respect the original insight and contributions of the authors, and believe an in-depth study of the role of IL10 may be a new research direction.
With great interest, we read the paper by Perez-Garcia et al for reporting the impaired fertility of 628 male patients with inflammatory arthritis (IA) from multiple hospitals in the Netherlands.1 Based on the result, the authors suggested that treatment strategies should be appropriately re-concerned for male IA patients who want to have children. Although the author has stated the limitations of the research, some details need to be addressed clearly.
Show MoreFirstly, Disease duration may be an interfering factor of fertility.2 In this research, men diagnosed ≤40 years had a longer disease duration than men diagnosed ≥41 years, with a higher rate of low sperm quality and a lower number of children. Besides, smoking and drinking history were not included in the demographic characteristics of patients, since those factors may have great effects on male fertility.3 Then, the age of the partners of the participants were not taken into calculation which may have a great effect on the number of children of the male IA patients, and the willingness of the partners to have children as well. 4 5 The effects of disease and drugs on the results were not distinguished in the study, and both of them may have effects on the fertility.6
Secondly, all data were collected from a questionnaire survey, including the patient’s partner time to pregnancy, female fertility evaluation, and the patient’s sperm quality, which may cause subjective bias. We noticed that out of 628 patients, onl...
Thank you for pointing out that the conclusion was not clear. The authors would like to modify it to 'The interim analysis revealed that up to 66% of patients receiving APR reached REM/LDA, as measured by cDAPSA at 8 months.'
We thank Dr. Yudong Liu for commenting on our manuscript and on many of the same issues we raised 1. There are, however, some comments that require clarification and a response. It is true that anti-phospholipid antibodies (APLA) of various specificities and immunoglobulin isotypes have been reported in COVID-19 2. However, despite a historical connection of APLA with coagulopathies and anti-phospholipid syndrome (APS), to date there is no convincing evidence that APLA have this in vivo pathogenic effect in COVID-19. In our patients, despite the presence of APLA (e.g., IgG anti-cardiolipin), there was no link to thrombotic events, a finding echoed by other referenced studies 3 and recently reviewed 2,4. The recent publication by Chang et al 5 is mentioned but it is important to appreciate that their results were compared to “normal” controls and no clinical features (coagulopathy or APS) were reported, precluding any inferences to autoimmune diseases; it is a standalone description of COVID-19 findings. Like the Chang manuscript, we also reported an extensive array of autoantibodies in COVID-19, but when we used sera from contemporaneous non-COVID patients of similar disease severity as comparator controls, we did not find significant differences in the autoantibody repertoire between the COVID positive and negative cohorts 6. Many individuals displayed “certain autoimmune features” but that cannot be taken to be equivalent to autoimmune disease. Indeed, COVID-19 patients...
Show MoreDear Editor,
I read with great interest the article by Trahtemberg et al.[1] on the clinical relevance of antiphospholipid antibodies (aPLs), in particular anticardiolipin antibodies (aCLs), in critically-ill COVID-19 positive and negative patients. Severe COVID-19 is associated with a hypercoagulable state. Early studies identified the presence of aPLs in critically-ill COVID-19 patients[2], which has attracted considerable attention as the presence of aPLs is one of the mechanisms leading to coagulopathy. Substantial efforts then tried to associate the thrombotic events seen in COVID-19 to aPLs status. The results seem negative, but a number of different types of autoantibodies were identified [3]. Chang et al. recently reported that autoantibodies were present in approximately half of the hospitalized COVID-19 patients, but in less than 15% of healthy controls [4]. In addition to aCLs and anti-beta 2 glycoprotein 1 antibodies (aβ2-GP1), they also identified autoantibodies targeting autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes as well as targeting interferons/interleukins and other cytokines[4]. These findings suggest that COVID-19, in particular patients with severe/critical conditions, displayed certain autoimmune features.
In the well-designed study by Trahtemberg et al., the authors expanded the cohort by including COVID-19 negative patients who were admitted to intensive care unit (ICU) with ac...
Show MoreMonti et. al. reported a decrease in Fast Track Clinic (FTC) assessments for Giant Cell Arteritis (GCA) during the COVID-19 pandemic and an increase in irreversible visual loss; other groups have found increased incidence of GCA during the COVID-19 pandemic.1,2,3 We created an FTC in 2017 to rapidly evaluate and treat patients with possible GCA using vascular ultrasound and also noticed an increase in permanent vision loss. We conducted a medical records review study during two time periods of patients referred to the FTC with concern for GCA to evaluate how many had permanent visual loss.4 The “COVID-19 period” was defined as 3/1/2020-8/31/2020 the “pre-COVID-19 period was 3/1/2019-8/31/2019. Patients received an ultrasound for GCA performed by a specially trained vascular sonographer. A positive ultrasound for GCA had either halo sign with compression in the temporal arteries and branches or increased intima-media thickness (IMT) in the large vessels. Patients were referred for temporal artery biopsy (TAB) at the discretion of the rheumatologist.
25 patients were referred to the FTC during both the COVID-19 period and pre-COVID-19 period and nine diagnosed with GCA in each group. 52% of patients experienced symptoms for less than two weeks prior to presenting to medical care during the COVID-19 period, 48% pre-COVID-19. The median number of days from the time first seen in the medical system until referral to the FTC was 7 days during COVID-19 compared to 8.5 day...
Show MoreWe thank Professors Lee and Song for their interest in our genome-wide association study (GWAS) of chronic widespread musculoskeletal pain (CWP)[1]. Their correspondence has raised several methodological concerns. First, CWP is a prominent feature of fibromyalgia. Clinically, it’s impossible to diagnose fibromyalgia without having CWP[2]. Therefore, the relevance of our findings to fibromyalgia cannot be ignored although we were careful not to conflate the two traits and did not claim genetic association with fibromyalgia. Second, the authors raise the relationship of the traits with age and sex; we adjusted for these covariates in the discovery GWAS and replication study. The important issue of body mass index (BMI) was much debated in our experimental design meetings. We elected not to adjust for BMI in the study for the following reasons:- (i) adjustment for heritable covariates (such as BMI) are not recommended in GWAS as this can lead to collider bias[3, 4] (ii) we wanted to explore the shared heritability of BMI and CWP using genetic correlation, (iii) adjustment for BMI would have affected genetic correlation and partial genetic correlation estimates reported in the paper and (vi) while so few variants have been described to date using GWAS for CWP, we were keen not to reduce the variance in the phenotype even if that led us to identify variants pleiotropic for BMI and CWP. Third, we have selected our controls for GWAS carefully by excluding important diagnostic con...
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