390 e-Letters

  • The autoimmune feature of severe COVID-19

    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...

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  • How to improve Treg immune response in GCA? Comment on the paper of Adriawan et al.

    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...

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  • Response to 'Impact of delayed diagnoses at the time of COVID-19: increased rate of preventable bilateral blindness in giant cell arteritis' by Monti et. al.

    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...

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  • Response to ‘Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain’ by Lee and Song

    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...

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

    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...

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  • Correspondence to ”Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression”

    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...

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  • Creatinine Clearance

    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

    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...

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  • Response to: ‘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.' by Huang et al.

    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...

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  • Rapid response to: Correspondence to: “Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study” by “Deodhar et al.” by James Cheng-Chung Wei et al.

    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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