404 e-Letters

  • Response to Dr. Yudong Liu

    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...

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  • Correspondence on “Rheumatoid arthritis, systemic lupus erythematosus and primary Sjogren's syndrome shared megakaryocyte expansion in peripheral blood” by Wang, Y. et al

    With great interest, we read the article by Wang Y et al., which suggested that Megakaryocytes (MKs) expansion might contribute to the pathogenesis of Rheumatoid Arthritis (RA)1. MKs are large, polyploid cells that originate from hematopoietic stem cells (HSC) and give rise to platelets. However, the authors fall short in recognizing the role of MK-derived platelets in RA.
    Wang Y et al. identified increased MKs in peripheral blood of RA using single-cell RNA sequencing and flow cytometry approaches. They provide clues that MKs act as specific endogenous antigen-presenting cells (APCs), triggering the initial autoimmune T cell for RA pathogenesis1. Of note, novel evidence suggests that MKs derived from bone marrow (BM), lung2 and liver3, instead serve as immunomodulatory or secretory cells4. The generation of platelets is the primary function of MKs.
    Indeed, many characteristics and roles of platelets inherit from MKs. For example, once activated, platelets present antigens via MHC class I molecules (MHC-I) derived from parent MKs5; in this way, the immunogenic information can be conveyed to platelets. Similarly, platelets can also act as an essential immune effector in RA6. An array of platelet surface receptors is responsible for activation, adhesion, and thrombus formation via initiating a complex network of signaling pathways in the presence of ligands. In addition, it is well known that ligands for platelet receptors such as collagen, fibrinogen, serotonin,...

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  • Correspondence on “No efficacy of anti-IL-23 therapy for axial spondyloarthritis in randomised controlled trials but in post-hoc analyses of psoriatic arthritis-related ‘physician-reported spondylitis’?”.

    We read with interest the Viewpoint article by Braun and Landewé regarding post-hoc analysis of back pain in trials of IL-23 inhibitor therapy in patients with peripheral psoriatic arthritis (PsA) [1]. Indeed, we share their concerns regarding study design, the use of outcome measures developed for axial spondyloarthritis (axSpA) and, most importantly, the attribution of the diagnostic label “physician-reported spondylitis” in these patients. In addition to the issues eloquently outlined in the article, it is important to be aware that the pre-test probability of inflammatory disease being directly responsible for back pain is likely much lower in patients with PsA who are older, and therefore more likely to have mechanical or non-specific back pain, than people presenting with axSpA. In other words, even before doing any test, a middle-aged person with PsA, as represented in most phase III PsA clinical trials, is more likely to have non-inflammatory than inflammatory back pain. These “causes” of back pain do of course co-exist and are not easily distinguished by clinical or imaging assessments. For example, disc and degenerative spinal disease can lead to apparent inflammatory features, such as bone marrow oedema on magnetic resonance imaging [2, 3] that are likely a secondary response to altered biomechanical stresses rather than primary inflammatory disease and therefore unlikely to be responsive to biologic therapies. Furthermore, imaging data on the prevalence and na...

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  • Response from authors

    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.'

  • 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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