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.
We read with great interest the recently published article by Adriawan et al 1 in which the authors confirmed that the regulatory T response is deficient in GCA, which is related, at least in part, to a defect in the glycolytic pathway that yields to, a decrease in the expression of GARP and CD25 and a decrease in calcium influx after T-cell receptor engagement.
Apart the fact that this study did not find a decrease in the percentage of circulating Treg, probably due to the small number of patients included compared to the other studies,2,3 these results confirm previous work in the field, including our own,3 and add new elements which provide a better understanding in the mechanistic pathways involved in this Treg dysfunction in GCA. The data from these 3 studies 1-3 suggest that interleukin-6, which is a major therapeutic target in GCA, plays a central role in the increase of FoxP3-exon 2 deficient (FoxP3∆2) Tregs, whose suppressive capacities are reduced, but which also induce an increase in IL-17 production because these cells produce more IL-17 than healthy Tregs and favour the Th17 polarization of effector CD4+ T cells.3
In their work, the authors also showed that tocilizumab, by blocking IL-6 signaling, restores the calcium influx of Tregs and thus their suppressive function.1 This result is in agreement with our recently reported data showing that tocilizumab restored the ability of Tregs to inhibit effector T cell proliferation and Th17 polarization...
We read with great interest the recently published article by Adriawan et al 1 in which the authors confirmed that the regulatory T response is deficient in GCA, which is related, at least in part, to a defect in the glycolytic pathway that yields to, a decrease in the expression of GARP and CD25 and a decrease in calcium influx after T-cell receptor engagement.
Apart the fact that this study did not find a decrease in the percentage of circulating Treg, probably due to the small number of patients included compared to the other studies,2,3 these results confirm previous work in the field, including our own,3 and add new elements which provide a better understanding in the mechanistic pathways involved in this Treg dysfunction in GCA. The data from these 3 studies 1-3 suggest that interleukin-6, which is a major therapeutic target in GCA, plays a central role in the increase of FoxP3-exon 2 deficient (FoxP3∆2) Tregs, whose suppressive capacities are reduced, but which also induce an increase in IL-17 production because these cells produce more IL-17 than healthy Tregs and favour the Th17 polarization of effector CD4+ T cells.3
In their work, the authors also showed that tocilizumab, by blocking IL-6 signaling, restores the calcium influx of Tregs and thus their suppressive function.1 This result is in agreement with our recently reported data showing that tocilizumab restored the ability of Tregs to inhibit effector T cell proliferation and Th17 polarization in vitro. However, our in vivo results temper these data. First, we found that this effect was less clear-cut in patients treated with tocilizumab and prednisone, since only the improvement in the ability of Treg to inhibit Th17 polarization was statistically significant after 3 months of treatment when the disease was in remission.3 Moreover, in the study we conducted,3,4 the percentage of Treg or FoxP3∆2 Tregs did not evolve differently between relapsers and non-relapsers after 6 months of follow-up (figure 1). Thus, we hypothesize that the blockade of the IL-6 effect is less complete in in vivo than in vitro experiments and/or that other signaling pathways are involved in the regulation of Treg biology.
As CD25 expression, which has suppressive functions, is decreased in FoxP3∆2 Tregs and induced by the effect of IL-2, it may be useful to investigate the value of combination therapies coupling IL-6 pathway blockade with tocilizumab and low-dose IL-2 administration in order to potentiate the Treg immune response, as it has been tried in other vasculitides.5
REFERENCES
1. Adriawan IR, Atschekzei F, Dittrich-Breiholz O, et al. Novel aspects of regulatory T cell dysfunction as a therapeutic target in giant cell arteritis. Annals of the rheumatic diseases 2021.
2. Miyabe C, Miyabe Y, Strle K, et al. An expanded population of pathogenic regulatory T cells in giant cell arteritis is abrogated by IL-6 blockade therapy. Annals of the rheumatic diseases 2017;76:898-905.
3. Samson M, Greigert H, Ciudad M, et al. Improvement of Treg immune response after treatment with tocilizumab in giant cell arteritis. Clinical & translational immunology 2021;10:e1332.
4. Samson M, Devilliers H, Ly KH, et al. Tocilizumab as an add-on therapy to glucocorticoids during the first 3months of treatment of Giant cell arteritis: A prospective study. European journal of internal medicine 2018;57:96-104.
5. Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. The New England journal of medicine 2011;365:2067-77.
Figure 1: variation of the percentages of Treg (CD4+CD25highFoxP3+) and Treg deficient in exon 2 of FoxP3 (FoxP3∆2 Treg) in patients treated with glucocorticoids (GC) and tocilizumab (8 mg/Kg/4 weeks IV for 4 infusions [week 0 to week 12]) for a new onset GCA depending on the occurrence of relapse from week 12 to week 26 of follow-up. NS: non-significant (comparison of the variation between both groups; Student t-tests).
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).
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.
Dear editor:
We read with great interest in the article by Maria Prendecki, which reported repeated SARS-CoV-2 vaccinations could induce humoral and T-cell responses in those patients who are immunosuppressed. The authors collected data from a total 161 patients with immune-mediated glomerulonephritis and vasculitis from 17 January 2021 and 9 March 2021, and conducted a cohort study. However, some conclusions and findings in this study need to be further clarified.
Firstly, in the sample collection and baseline data of the RESULTS section, we can see that a total of 114 patients have previously received rituximab treatment, 69 of which received Rituximab treatment in the past six months. However, in the statistical table 1, we see that there were only 99 patients who had previously treated with rituximab, and only 56 patients received rituximab treatment within six months. Is the difference in sample data between the two likely to affect the statistical results?
Secondly, the article focused on patients in the IS group only for matching age and vaccine type. Does the article ignore the past medical history or past medication history for matching?
Last but not least, there is a big difference in the interval between the first dose of vaccine and the second dose of the patient in the healthy group and the IS group, and the second dose of the healthy group can only choose the BNT vaccine. Will the above two likely to have interference factors in this...
Dear editor:
We read with great interest in the article by Maria Prendecki, which reported repeated SARS-CoV-2 vaccinations could induce humoral and T-cell responses in those patients who are immunosuppressed. The authors collected data from a total 161 patients with immune-mediated glomerulonephritis and vasculitis from 17 January 2021 and 9 March 2021, and conducted a cohort study. However, some conclusions and findings in this study need to be further clarified.
Firstly, in the sample collection and baseline data of the RESULTS section, we can see that a total of 114 patients have previously received rituximab treatment, 69 of which received Rituximab treatment in the past six months. However, in the statistical table 1, we see that there were only 99 patients who had previously treated with rituximab, and only 56 patients received rituximab treatment within six months. Is the difference in sample data between the two likely to affect the statistical results?
Secondly, the article focused on patients in the IS group only for matching age and vaccine type. Does the article ignore the past medical history or past medication history for matching?
Last but not least, there is a big difference in the interval between the first dose of vaccine and the second dose of the patient in the healthy group and the IS group, and the second dose of the healthy group can only choose the BNT vaccine. Will the above two likely to have interference factors in this research?
Finally, the definition of how the healthy participants were selected into this study does not seem to be very clear.
For the above reasons, we recommend that sample collection should be considered in this study. This will allow us to realize the immune response to the SARS-CoV-2 vaccination between the IS group and healthy volunteer group more thoroughly.
Which method was used for the estimation of creatinine clearance? If Cockcroft-Gault equation was used, was the Ideal Body Weight used for patients with normal BMI and the Adjusted Body Weight for obese patients?
Correspondence on “Native joint infections in Iceland 2003-2017: an increase in postarthroscopic infections” by Gunnlaugsdóttir et al
Similar to the periprosthetic joint infections, the diagnosis and treatment of native joint infections (NJIs) is also challenging. If not promptly recognized and adequately treated, NJIs can lead to devastating consequences, such as threatening septicemia and loss of joint function.1 The incidence of NJIs seems to be increasing but remains rare.2,3 Therefore, few studies investigated the epidemiology, clinical risk factors, and outcomes of NJIs, and a nationwide study would provide the best attainable level of evidence on this issue.2,3 With great interest, we read the article by Gunnlaugsdóttir and colleagues,4 in which they provide epidemiological, clinical, and prognostic analysis of patients with culture-proven NJI over a 15-year period. They found that the incidence of NJIs has remained stable in Iceland over the past 15 years, but the proportion of iatrogenic infections is high, especially seen a significant increase of iatrogenic infections following arthroscopic procedures. The authors should be applauded for their tremendous initiative and extensive efforts at illustrating the results. We compliment the authors for their comprehensive nationwide study, while there are a few points that we wish to raise.
First, as discussed by the authors, when compared with a previous nationwide study covering 1990–2002, there was no sig...
Correspondence on “Native joint infections in Iceland 2003-2017: an increase in postarthroscopic infections” by Gunnlaugsdóttir et al
Similar to the periprosthetic joint infections, the diagnosis and treatment of native joint infections (NJIs) is also challenging. If not promptly recognized and adequately treated, NJIs can lead to devastating consequences, such as threatening septicemia and loss of joint function.1 The incidence of NJIs seems to be increasing but remains rare.2,3 Therefore, few studies investigated the epidemiology, clinical risk factors, and outcomes of NJIs, and a nationwide study would provide the best attainable level of evidence on this issue.2,3 With great interest, we read the article by Gunnlaugsdóttir and colleagues,4 in which they provide epidemiological, clinical, and prognostic analysis of patients with culture-proven NJI over a 15-year period. They found that the incidence of NJIs has remained stable in Iceland over the past 15 years, but the proportion of iatrogenic infections is high, especially seen a significant increase of iatrogenic infections following arthroscopic procedures. The authors should be applauded for their tremendous initiative and extensive efforts at illustrating the results. We compliment the authors for their comprehensive nationwide study, while there are a few points that we wish to raise.
First, as discussed by the authors, when compared with a previous nationwide study covering 1990–2002, there was no significant change in the overall incidence of iatrogenic infections among adults, the number of infections is rising due to an increase in the number of arthroscopic procedures. However, in the previous nationwide study, there was a significant increasing trend in the annual volume of arthroscopic procedures during the 1990–2001 financial year, and since then the annals volume of arthroscopies became relatively stable (estimated by the number of arthroscopic procedures during 2010–2017 was 21342). Therefore, the markedly increased infections among adults following arthroscopic procedures may attribute to other risk factors. For instance, the increased iatrogenic infections may be associated with the hospital- or surgeon-related risk factors. Previous studies have demonstrated a volume-outcome relationship in arthroscopic rotator cuff repair, which suggested that higher surgical volume (i.e., annualized case volume or hospital volume) was associated with decreased surgical complications.5,6 For arthroscopy of the knee, a simulation study suggests that consultant-level skills are not reached until 170 procedures have been performed.7 Thus, we speculate the increased postarthroscopic infections might be associated with hospitals or surgeons with a low annual caseload, such as a hospital that adopted arthroscopy as new technology or a surgeon who was early in the learning curve.8
Second, the increased postarthroscopic infections may not only be associated with the increased number of procedures but also associated with the dramatically increased indications for arthroscopy. Over the past decades, with the rapid development of arthroscopic techniques, the application field of arthroscopy has been a breakthrough. The application of arthroscopy has extended to all major limb joints and several smaller joints, and as a minimally invasive therapeutic technology, arthroscopy is increasingly performed instead of traditional open surgeries.9 The authors have compared the frequency of arthroscopies with other Nordic countries and suggested that arthroscopic knee procedures are overused in Iceland. However, it would be more plausible if the authors analyzed the variation of the arthroscopic indications. Besides, during the dissemination of arthroscopic skills and technologies for new indications, the surgeons had to ascend the learning curve, which could also affect the incidence of NJIs.
Third, the authors adopted strict eligible criteria (culture-proven NJIs), in combination with the rather low incidence of NJIs, which led to limited power to assess the epidemiological, clinical, and prognostic characteristics of patients with NJIs. It has been well established that with a large enough sample size, a test has the power to detect any discrepancy from the null however small.10 For this reason, a statistically significant result may have limited practical implications, or we may have a statistically insignificant result, yet useful information could be obtained from the data. Therefore, the statistically significant results cannot be interpreted simply by themselves, instead, further investigation should be done to figure out whether there is practical or clinical significance.
References
1. Roerdink RL, Huijbregts HJTAM, van Lieshout AWT, et al. The difference between native septic arthritis and prosthetic joint infections: A review of literature. J Orthop Surg (Hong Kong) 2019;27(2):2309499019860468.
2. Geirsson AJ, Statkevicius S, Víkingsson A. Septic arthritis in Iceland 1990-2002: increasing incidence due to iatrogenic infections. Ann Rheum Dis 2008;67(5):638–43.
3. Kennedy N, Chambers ST, Nolan I, et al. Native Joint Septic Arthritis: Epidemiology, Clinical Features, and Microbiological Causes in a New Zealand Population. J Rheumatol 2015;42(12):2392–7.
4. Gunnlaugsdóttir SL, Erlendsdóttir H, Helgason KO, et al. Native joint infections in Iceland 2003-2017: an increase in postarthroscopic infections. Ann Rheum Dis 2021:annrheumdis-2021-220820.
5. Weinheimer KT, Smuin DM, Dhawan A. Patient Outcomes as a Function of Shoulder Surgeon Volume: A Systematic Review. Arthroscopy 2017;33(7):1273–1281.
6. Warner JJP, Higgins LD. Editorial Commentary: Volume and Outcome: 100 Years of Perspective on Value From E.A. Codman to M.E. Porter. Arthroscopy 2017;33(7):1282–1285.
7. Price AJ, Erturan G, Akhtar K, et al. Evidence-based surgical training in orthopaedics: how many arthroscopies of the knee are needed to achieve consultant level performance? Bone Joint J 2015;97-B(10):1309–15.
8. Simpson AH, Howie CR, Norrie J. Surgical trial design - learning curve and surgeon volume: Determining whether inferior results are due to the procedure itself, or delivery of the procedure by the surgeon. Bone Joint Res 2017;6(4):194–195.
9. Carr AJ, Price AJ, Glyn-Jones S, et al. Advances in arthroscopy-indications and therapeutic applications. Nat Rev Rheumatol 2015;11(2):77–85.
10. Mayo DG, Spanos A. Error statistics. In Philosophy of statistics. North-Holland, 2011:153–198.
We thank Huang and co-authors (1) for their correspondence on our work (2). We want to take the opportunity to clarify the raised issues.
The first issue raised was the question regarding the investigation of dose-dependent effects of treatments. For treatments in which dose-dependent effects are important, different doses have been studied and the relationship has been shown. This is the case with the use of glucocorticoids (GC). Using an Andersen-Gill model with inverse probability weights we found an adjusted Hazard ratio (HR) for herpes zoster (HZ) of 4.42 (2.50 to 7.83) for GC of more than 10 mg/day compared to no GC and 1.47 (1.17 to 1.85) for GCs of 5 to 10 mg/day. To answer the question about a possible effect of (different) duration of exposure on the outcome we would like to point out, that this information (exposure duration of disease-modifying anti-rheumatic drugs (DMARDs)) is naturally accommodated in the Andersen-Gill model which we used to calculate estimates.
Regarding the second issue raised, the analysis of other immunosuppressant treatments, we admit that we did not consider those treatments in our analyses due to the rare prescribing rates of these medications, except from leflunomide, especially in monotherapy. In particular, the proportion of patients with concomitant use of leflunomide with biologic DMARDs was approximately 10%, while concomitant use of cyclosporin with biologic DMARDs was below 1% and only 4 patients received mycophenol...
We thank Huang and co-authors (1) for their correspondence on our work (2). We want to take the opportunity to clarify the raised issues.
The first issue raised was the question regarding the investigation of dose-dependent effects of treatments. For treatments in which dose-dependent effects are important, different doses have been studied and the relationship has been shown. This is the case with the use of glucocorticoids (GC). Using an Andersen-Gill model with inverse probability weights we found an adjusted Hazard ratio (HR) for herpes zoster (HZ) of 4.42 (2.50 to 7.83) for GC of more than 10 mg/day compared to no GC and 1.47 (1.17 to 1.85) for GCs of 5 to 10 mg/day. To answer the question about a possible effect of (different) duration of exposure on the outcome we would like to point out, that this information (exposure duration of disease-modifying anti-rheumatic drugs (DMARDs)) is naturally accommodated in the Andersen-Gill model which we used to calculate estimates.
Regarding the second issue raised, the analysis of other immunosuppressant treatments, we admit that we did not consider those treatments in our analyses due to the rare prescribing rates of these medications, except from leflunomide, especially in monotherapy. In particular, the proportion of patients with concomitant use of leflunomide with biologic DMARDs was approximately 10%, while concomitant use of cyclosporin with biologic DMARDs was below 1% and only 4 patients received mycophenolate mofetil at baseline. Therefore, we restrained from further stratification due to the small sample sizes within some treatment groups. Other treatments are not collected regularly in the register therefore the use of CYP3A4 inhibitors/CYP2C19 could not be studied.
Information on HZ contact and previous HZ history was available only for a small proportion of patients. However, the use of an Andersen-Gill model enabled us to include recurrent events for this analysis by taking the complete follow-up time into account.
We had investigated all available information on comorbidities for this analysis. Their occurrence was equally distributed over the treatments. Therefore we only included information on relevant comorbidities (table 1).
1. Huang Y, Hsu W, Lin Y, Wei J. Correspondence on 'Risk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT register.' Ann Rheum Dis 2021.
2. Redeker I, Albrecht K, Kekow J, Burmester GR, Braun J, Schafer M, et al. Risk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT register. Ann Rheum Dis 2021.
We welcome the correspondence to our article, which reported results of a phase III study (NCT03502616), by James Cheng-Chung Wei and colleagues.1
Considering the primary endpoint, Assessment of SpondyloArthritis International Society (ASAS) 20 response rates at week 16, significant improvements vs placebo were evident with tofacitinib 5 mg two times per day (BID). The response rate with tofacitinib 5 mg BID did decline very slightly from week 12 to week 16, before continuing to improve through week 48 (figure 2A). A similar pattern was observed in some secondary endpoints (ASAS40 response rates [figure 2B]; change from baseline in Ankylosing Spondylitis Disease Activity Score [ΔASDAS; figure 3A] and high-sensitivity C-reactive protein [ΔhsCRP; figure 3B]; ASAS 5/6 response [supplemental figure 3B]; ASDAS low disease activity [ASDAS LDA; supplemental figure 4C]; and ASDAS inactive disease [supplemental figure 4D]), although for all other endpoints, improvements were steady or increased through week 16.
We believe that what may be perceived as a ‘dip’ in efficacy at week 16 was likely due to patient variability. Notably, this ‘dip’ was most pronounced for ASAS20 response rates, an endpoint which is often associated with variability, compared with the more conservative endpoints (ASAS40 response rates, ASAS5/6 and ASDAS LDA), for which the differences between week 12 and week 16 were numerically smaller than for ASAS20 response rates. Additionally, for hsCRP,...
We welcome the correspondence to our article, which reported results of a phase III study (NCT03502616), by James Cheng-Chung Wei and colleagues.1
Considering the primary endpoint, Assessment of SpondyloArthritis International Society (ASAS) 20 response rates at week 16, significant improvements vs placebo were evident with tofacitinib 5 mg two times per day (BID). The response rate with tofacitinib 5 mg BID did decline very slightly from week 12 to week 16, before continuing to improve through week 48 (figure 2A). A similar pattern was observed in some secondary endpoints (ASAS40 response rates [figure 2B]; change from baseline in Ankylosing Spondylitis Disease Activity Score [ΔASDAS; figure 3A] and high-sensitivity C-reactive protein [ΔhsCRP; figure 3B]; ASAS 5/6 response [supplemental figure 3B]; ASDAS low disease activity [ASDAS LDA; supplemental figure 4C]; and ASDAS inactive disease [supplemental figure 4D]), although for all other endpoints, improvements were steady or increased through week 16.
We believe that what may be perceived as a ‘dip’ in efficacy at week 16 was likely due to patient variability. Notably, this ‘dip’ was most pronounced for ASAS20 response rates, an endpoint which is often associated with variability, compared with the more conservative endpoints (ASAS40 response rates, ASAS5/6 and ASDAS LDA), for which the differences between week 12 and week 16 were numerically smaller than for ASAS20 response rates. Additionally, for hsCRP, there was a very small difference between week 12 and week 16, consistent with the natural variability observed in the measurements over time in this study. Furthermore, as ASDAS inactive disease is a very stringent outcome measure, which is challenging to achieve and maintain, some variability in the observed responses was to be expected. Of note, 15 patients had inactive disease at week 12, compared with nine patients at week 16. Finally, at week 16, all patients entered the open-label phase of the study, with those receiving placebo switching to tofacitinib 5 mg BID in a blinded manner until the final database release. It is not uncommon to see a perceived ‘dip’ in efficacy at the last visit of the blinded phase in a randomized study, ahead of the open-label extension phase. While the exact cause of this phenomenon is not known, it may be related to patients’ belief that they could have been receiving placebo when they are informed that the blinded phase is over and that they will be entering the open-label phase.
Patients in the study could indeed continue stable background non-steroidal anti-inflammatory drugs (NSAIDs), oral corticosteroids or conventional synthetic disease-modifying drugs (csDMARDs), methotrexate or sulfasalazine. As noted by Wei JC-C, et al., tofacitinib in combination with methotrexate has been shown to be efficacious and well-tolerated in previous phase II and phase III studies of patients with rheumatoid arthritis.2-4 However, methotrexate and systemic corticosteroids have not demonstrated efficacy in the axial skeleton.5 6 We therefore do not believe that methotrexate provides any additional benefits for axial symptoms in ankylosing spondylitis. Notably, in the current study, the proportion of patients using NSAIDs was balanced across treatment groups (both approximately 80%; Table 1), and while csDMARD use was not as balanced (22% of patients receiving tofacitinib 5 mg BID vs 32% of patients receiving placebo), we believe that this should not have had an effect on the results specific to signs and symptoms of axial disease. Furthermore, if there was an effect of csDMARDs, with the imbalance mentioned above, it would have gone against tofacitinib.
We agree with Wei JC-C, et al., that the ASAS Health Index (ASAS-HI) assesses the overall picture of a broad range of health aspects,7 and is therefore a reliable and comprehensive measure to include in clinical trial protocols.8 In the current study, we measured the Ankylosing Spondylitis Quality of Life score, a widely accepted measure,9 which was pre-specified in the clinical trial protocol and is used as standard in the regulatory setting (and is mandated by the Food and Drug Administration). As this study is complete and data collection has ended, we are unable to include the ASAS-HI at this stage, but we will be sensitive to survey fatigue in future clinical trials and continue to advocate for specific endpoints such as the ASAS-HI to be included.
We believe that we have addressed the queries and concerns of Wei JC-C, et al. as far as possible within the scope of this correspondence.
Acknowledgements
Medical writing support, under the guidance of the authors, was provided by
Kimberley Haines, MSc, CMC Connect, McCann Health Medical Communications, and was funded by Pfizer Inc, New York, NY, USA in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med 2015;163:461–464).
References
1. Wei JC-C, Ker A, Yang C-R, et al. Correspondence to “Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study” by “Deodhar et al.”. Ann Rheum Dis 2021. https://ard.bmj.com/content/80/8/1004.responses#correspondence-to-%E2%80....
2. Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken) 2011;63(8):1150–58. doi: 10.1002/acr.20494
3. Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet 2013;381(9865):451–60. doi: 10.1016/S0140-6736(12)61424-X
4. Kremer J, Li Z-G, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med 2013;159(4):253–61. doi: 10.7326/0003-4819-159-4-201308200-00006
5. Haibel H, Brandt HC, Song IH, et al. No efficacy of subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open-label trial. Ann Rheum Dis 2007;66(3):419–21. doi: 10.1136/ard.2006.054098
6. Haibel H, Fendler C, Listing J, et al. Efficacy of oral prednisolone in active ankylosing spondylitis: results of a double-blind, randomised, placebo-controlled short-term trial. Ann Rheum Dis 2014;73(1):243–46. doi: 10.1136/annrheumdis-2012-203055
7. Assessment of SpondyloArthritis International Society. Description of ASAS Health Index 2021 [Available from: https://www.asas-group.org/instruments/asas-health-index/#:~:text=The%20....
Accessed 24 August 2021.
8. Kiltz U, van der Heijde D, Boonen A, et al. Measurement properties of the ASAS Health Index: results of a global study in patients with axial and peripheral spondyloarthritis. Ann Rheum Dis 2018;77(9):1311–17. doi: 10.1136/annrheumdis-2017-212076
9. Doward LC, Spoorenberg A, Cook SA, et al. Development of the ASQoL: a quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis 2003;62(1):20–26.
Dear 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 MoreWe read with great interest the recently published article by Adriawan et al 1 in which the authors confirmed that the regulatory T response is deficient in GCA, which is related, at least in part, to a defect in the glycolytic pathway that yields to, a decrease in the expression of GARP and CD25 and a decrease in calcium influx after T-cell receptor engagement.
Show MoreApart the fact that this study did not find a decrease in the percentage of circulating Treg, probably due to the small number of patients included compared to the other studies,2,3 these results confirm previous work in the field, including our own,3 and add new elements which provide a better understanding in the mechanistic pathways involved in this Treg dysfunction in GCA. The data from these 3 studies 1-3 suggest that interleukin-6, which is a major therapeutic target in GCA, plays a central role in the increase of FoxP3-exon 2 deficient (FoxP3∆2) Tregs, whose suppressive capacities are reduced, but which also induce an increase in IL-17 production because these cells produce more IL-17 than healthy Tregs and favour the Th17 polarization of effector CD4+ T cells.3
In their work, the authors also showed that tocilizumab, by blocking IL-6 signaling, restores the calcium influx of Tregs and thus their suppressive function.1 This result is in agreement with our recently reported data showing that tocilizumab restored the ability of Tregs to inhibit effector T cell proliferation and Th17 polarization...
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...
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...
Show MoreWith 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...
Dear editor:
We read with great interest in the article by Maria Prendecki, which reported repeated SARS-CoV-2 vaccinations could induce humoral and T-cell responses in those patients who are immunosuppressed. The authors collected data from a total 161 patients with immune-mediated glomerulonephritis and vasculitis from 17 January 2021 and 9 March 2021, and conducted a cohort study. However, some conclusions and findings in this study need to be further clarified.
Firstly, in the sample collection and baseline data of the RESULTS section, we can see that a total of 114 patients have previously received rituximab treatment, 69 of which received Rituximab treatment in the past six months. However, in the statistical table 1, we see that there were only 99 patients who had previously treated with rituximab, and only 56 patients received rituximab treatment within six months. Is the difference in sample data between the two likely to affect the statistical results?
Show MoreSecondly, the article focused on patients in the IS group only for matching age and vaccine type. Does the article ignore the past medical history or past medication history for matching?
Last but not least, there is a big difference in the interval between the first dose of vaccine and the second dose of the patient in the healthy group and the IS group, and the second dose of the healthy group can only choose the BNT vaccine. Will the above two likely to have interference factors in this...
Which method was used for the estimation of creatinine clearance? If Cockcroft-Gault equation was used, was the Ideal Body Weight used for patients with normal BMI and the Adjusted Body Weight for obese patients?
Correspondence on “Native joint infections in Iceland 2003-2017: an increase in postarthroscopic infections” by Gunnlaugsdóttir et al
Show MoreSimilar to the periprosthetic joint infections, the diagnosis and treatment of native joint infections (NJIs) is also challenging. If not promptly recognized and adequately treated, NJIs can lead to devastating consequences, such as threatening septicemia and loss of joint function.1 The incidence of NJIs seems to be increasing but remains rare.2,3 Therefore, few studies investigated the epidemiology, clinical risk factors, and outcomes of NJIs, and a nationwide study would provide the best attainable level of evidence on this issue.2,3 With great interest, we read the article by Gunnlaugsdóttir and colleagues,4 in which they provide epidemiological, clinical, and prognostic analysis of patients with culture-proven NJI over a 15-year period. They found that the incidence of NJIs has remained stable in Iceland over the past 15 years, but the proportion of iatrogenic infections is high, especially seen a significant increase of iatrogenic infections following arthroscopic procedures. The authors should be applauded for their tremendous initiative and extensive efforts at illustrating the results. We compliment the authors for their comprehensive nationwide study, while there are a few points that we wish to raise.
First, as discussed by the authors, when compared with a previous nationwide study covering 1990–2002, there was no sig...
We thank Huang and co-authors (1) for their correspondence on our work (2). We want to take the opportunity to clarify the raised issues.
Show MoreThe first issue raised was the question regarding the investigation of dose-dependent effects of treatments. For treatments in which dose-dependent effects are important, different doses have been studied and the relationship has been shown. This is the case with the use of glucocorticoids (GC). Using an Andersen-Gill model with inverse probability weights we found an adjusted Hazard ratio (HR) for herpes zoster (HZ) of 4.42 (2.50 to 7.83) for GC of more than 10 mg/day compared to no GC and 1.47 (1.17 to 1.85) for GCs of 5 to 10 mg/day. To answer the question about a possible effect of (different) duration of exposure on the outcome we would like to point out, that this information (exposure duration of disease-modifying anti-rheumatic drugs (DMARDs)) is naturally accommodated in the Andersen-Gill model which we used to calculate estimates.
Regarding the second issue raised, the analysis of other immunosuppressant treatments, we admit that we did not consider those treatments in our analyses due to the rare prescribing rates of these medications, except from leflunomide, especially in monotherapy. In particular, the proportion of patients with concomitant use of leflunomide with biologic DMARDs was approximately 10%, while concomitant use of cyclosporin with biologic DMARDs was below 1% and only 4 patients received mycophenol...
We welcome the correspondence to our article, which reported results of a phase III study (NCT03502616), by James Cheng-Chung Wei and colleagues.1
Considering the primary endpoint, Assessment of SpondyloArthritis International Society (ASAS) 20 response rates at week 16, significant improvements vs placebo were evident with tofacitinib 5 mg two times per day (BID). The response rate with tofacitinib 5 mg BID did decline very slightly from week 12 to week 16, before continuing to improve through week 48 (figure 2A). A similar pattern was observed in some secondary endpoints (ASAS40 response rates [figure 2B]; change from baseline in Ankylosing Spondylitis Disease Activity Score [ΔASDAS; figure 3A] and high-sensitivity C-reactive protein [ΔhsCRP; figure 3B]; ASAS 5/6 response [supplemental figure 3B]; ASDAS low disease activity [ASDAS LDA; supplemental figure 4C]; and ASDAS inactive disease [supplemental figure 4D]), although for all other endpoints, improvements were steady or increased through week 16.
We believe that what may be perceived as a ‘dip’ in efficacy at week 16 was likely due to patient variability. Notably, this ‘dip’ was most pronounced for ASAS20 response rates, an endpoint which is often associated with variability, compared with the more conservative endpoints (ASAS40 response rates, ASAS5/6 and ASDAS LDA), for which the differences between week 12 and week 16 were numerically smaller than for ASAS20 response rates. Additionally, for hsCRP,...
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