RMD Open

Objectives To assess the effects of 24 weeks active treatment with baricitinib, a JAK1/2 inhibitor, in adult idiopathic inflammatory myopathy (IIM). Methods Patients with active dermatomyositis (DM) or polymyositis (PM) were enrolled into a 1:1 randomized treatment delayed-start design clinical trial (NCT04208464). Participants received 24 weeks baricitinib plus 12 weeks follow-up (Immediate-start), or 12 weeks standard of care plus 24 weeks baricitinib (Delayed-start). The primary outcome was clinical response after 24 weeks active treatment, defined as minimal improvement (Total Improvement Score >20 [TIS20]). Secondary outcomes included: TIS40 (moderate), TIS60 (major) response, between-arm comparison, time to achieve response, change in clinical outcome measures. steroid-sparing and cumulative adverse events. Results 14/15 (93%) randomized participants (mean age 43.2 years [11.6 SD]; 13 DM, 2 PM; 11 female) completed the study (baseline to 36 weeks) and all achieved TIS20 at 24 weeks post-active treatment (95% exact CI 0.68-1.00). 9/15 (60%) achieved TIS40 response and 2/15 (13%) TIS60 response. At 12 weeks post-randomization, 11/15 (73%) patients achieved at least TIS20 (95%CI 0.45-0.92), including all Immediate-start arm patients and four Delayed-start arm patients. At the same time point, evidence of a difference was noted for patient global, extramuscular, CDASI skin activity, pain, fatigue and SF-36 mental/physical health scores. Two hospitalisation serious adverse events were documented, neither related to study drug. Conclusions Treatment of IIM with baricitinib resulted in improved clinical outcome after 24 weeks. Significant improvement after 12 weeks treatment was also evident. No significant safety concerns were raised. A randomized placebo-controlled trial is needed to confirm the efficacy in patients with IIM.

Background The phase 3 ADVOCATE trial evaluated the efficacy and safety of avacopan in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Concerns raised regarding the 2019 primary endpoint adjudication process prompted a blinded, independent readjudication of all participants' primary outcomes, the results of which are described here. Methods Patients with GPA or MPA were randomized 1:1 to receive oral avacopan 30 mg twice daily or oral prednisone on a scheduled taper, each in combination with rituximab- or cyclophosphamide-based standard of care. In 2026, the Duke Clinical Research Institute Clinical Events Classification group conducted an independent, blinded committee re-adjudicated the Birmingham Vasculitis Activity Score (BVAS), relapse, and remission from weeks 26 through 52 using procedures aligned with the original adjudication charter. The primary endpoints were remission at week 26 and sustained remission at week 52. As per the original analysis plan, noninferiority and superiority were declared if the lower bounds of the 95% confidence interval (CI) for the difference in the primary outcome rates between avacopan and a prednisone taper were greater than -20.0 and 0.0 percentage points, respectively. Results Among 330 participants in the intent-to-treat population, remission at week 26 was achieved by 68.1% (113/166) and 67.1% (110/164) of participants in the avacopan and prednisone taper groups, respectively, in the 2026 readjudication (adjusted difference: 2.2%; 95% CI, -7.5, 11.9), compared with 72.3% (120/166) and 70.1% (115/164) in the 2019 primary outcome adjudication (adjusted difference: 3.4%; 95% CI, -6.0, 12.8). Sustained remission at week 52 was achieved by 61.4% (102/166) and 52.4% (86/164) of participants, respectively, in the 2026 readjudication (adjusted difference: 9.8%; 95% CI, -0.3, 19.9), compared with 65.7% (109/166) and 54.9% (90/164) in the 2019 readjudication (adjusted difference: 12.5%; 95% CI, 2.6, 22.3). Concordance between the 2019 and 2026 adjudications was 95.2% for remission and 93.6% for sustained remission. Conclusion The re-analysis of ADVOCATE based on the 2026 readjudication further supports the efficacy of avacopan for GPA/MPA. Non-inferiority of avacopan versus a prednisone taper was confirmed at weeks 26 and 52 despite a median 81% reduction in glucocorticoid exposure observed in the avacopan versus prednisone taper groups. While a consistent numerical difference favoring avacopan at week 52 was observed in the 2019 and 2026 analyses, this difference did not reach statistical superiority.

Background. Tocilizumab (TCZ), a monoclonal antibody directed against the interleukin-6 receptor, is used in rheumatoid arthritis (RA) after inadequate response or secondary loss of response to conventional synthetic and biological disease-modifying antirheumatic drugs (DMARDs). Real-world data from North African cohorts remain scarce. We assessed the effectiveness and safety of TCZ in routine care and explored baseline factors associated with 6-month outcomes. Methods. We conducted a retrospective, single-centre cohort study of 44 consecutive patients with RA treated with TCZ between April 2019 and January 2024 in the Department of Rheumatology, Moulay Ismail Hospital, Meknes, Morocco. Demographic, clinical, laboratory, treatment and follow-up data were extracted from medical records using a standardised electronic form. The primary effectiveness outcome was the European Alliance of Associations for Rheumatology (EULAR) response at 6 months; DAS28-ESR remission was defined as DAS28-ESR below 2.6. Safety outcomes comprised infections, neutropenia, liver-enzyme abnormalities and lipid abnormalities. Longitudinal changes were compared with the Wilcoxon signed-rank test, and associations between baseline variables dichotomised at their median and 6-month outcomes were examined with chi-square tests, in SPSS version 29. Results. The cohort comprised 33 women (75.0%), with a median age of 57 years (range 32-82) and a mean RA duration of 12.97+/-9.1 years. Patients had received a mean of 2.5+/-1.8 previous conventional DMARDs, and 41 (93.2%) had received at least one previous biological agent, including two or more tumour necrosis factor (TNF) inhibitors in 36 (81.8%). At 6 months, outcome data were available for 34 patients: 23 (67.6%) achieved a good EULAR response, 6 (17.6%) a moderate response and 5 (14.7%) no response; 12 (35.3%) were in DAS28-ESR remission. Mean DAS28-ESR fell from 5.10+/-1.18 at baseline to 2.74+/-1.38 at 6 months and 2.45+/-1.33 at 12 months, and the mean prednisone-equivalent dose fell from 8.3+/-7.1 to 5 mg/day. Twenty-two infectious episodes were recorded, including one serious infection (purulent pleurisy) requiring hospitalisation; 5 patients (11.4%) had a temporary interruption and 1 (2.3%) a permanent discontinuation for hepatic cytolysis. A neutrophil count below 1,500/mm3 occurred in 13 patients (29.5%), with no count below 1,000/mm3, while mean neutrophils declined from 6.3+/-3.0 to 2.6+/-1.2 G/L at 12 months. Mean LDL cholesterol rose from 1.18 to 1.49 g/L and HDL cholesterol from 0.58 to 0.82 g/L. Rheumatoid-factor positivity was the only baseline variable associated with the EULAR response category (p=0.007); a baseline tender joint count above six was associated with a lower remission rate (23.5%, p=0.007), as was, borderline, a pain visual analogue scale above 65 mm (31.2%, p=0.05). Conclusions. In this heavily pretreated real-world RA cohort, TCZ was associated with a substantial and sustained reduction in disease activity and a manageable safety profile consistent with its known signals. A high baseline articular and pain burden was associated with a lower probability of remission. The small sample, incomplete 6-month follow-up, retrospective design and absence of adjusted effect estimates limit interpretation, and the reported associations should be regarded as hypothesis-generating.

Objectives. Before-and-after transcriptomics in rheumatic disease often yields no reproducible treatment signal, though disease-state stratification is robust. We asked whether exposure and response-prediction labels fall below the detection floor of the designs defining them, while matched disease-state labels do not. Methods. Eight public datasets were analysed (paired juvenile dermatomyositis n = 10; RA before/after methotrexate, n = 28 pairs; lupus nephritis n = 10; controlled exposures; a single-cell dose series). Response labels in current use (one benchmark trajectory, five published signatures) were audited in every analysable source cohort, using effect sizes (dz) against each design's exact minimum detectable effect. Results. Disease-state labels were detectable: the interferon signature declined in 10/10 juvenile dermatomyositis patients (p = 0.002; 59.5% of score variance). No exposure label cleared its design floor in any clinical cohort; a drug-matched methotrexate prior was nominally significant in juvenile dermatomyositis yet did not clear its floor (dz = -0.80; CI spanning it). Exposure became detectable only where prior-context and intensity were jointly favourable (multi-day target tissue dz = 1.24, q = 0.018; well-level pseudobulk dz = +3.70, floor 1.80). Audited response labels failed in 14 of 15 cohorts (93%; descriptive binomial 95% CI 68-100): eleven below their floors, three sign-reversed; the largest training cohort pooled to zero (dz = +0.07; I2 = 69%). Effect size ordered reported AUCs monotonically. Conclusion. Under conventional treatment intensities, exposure and response-prediction labels are either undetectable below the design floor or detected with a sign that does not replicate; disease-state labels are detectable. Part of the negative literature reflects a design floor.

Background: Chronic lowgrade inflammation in long standing rheumatoid arthritis (RA) contributes not only to joint damage but also to metabolic dysregulation, endothelial dysfunction, and elevated cardiovascular (CV) risk. Although combination disease modifying anti rheumatic drugs (DMARDs) remain the mainstay of therapy, their long term efficacy in controlling systemic inflammation and preventing metabolic complications appears limited. Phytochemicals such as resveratrol, a polyphenolic compound widely used in traditional and complementary medicine, possess anti inflammatory and immunomodulatory properties. Objectives: To investigate whether resveratrol can complement the immunomodulatory effects of combination DMARDs in long duration RA patients by modulating inflammatory cytokines and the JNK-IRS-Akt insulin signaling axis. Methods: This study enrolled early and late rheumatoid arthritis patients to assess disease activity, vascular markers, and ex vivo PBMC responses. PBMCs were isolated for cytotoxicity testing and resveratrol treatment, followed by ELISA and Western blot analysis. Statistical comparisons evaluated immunomodulatory effects and alterations in inflammatory signaling. Results: Longitudinal follow up of RA patients showed significant first year improvement in disease activity and atherosclerotic markers, correlated with MTX dose. An early versus late RA comparison revealed elevated cytokines and enhanced JNK mediated stress signaling in longstanding disease. Resveratrol maintained PBMC viability, reduced LPS induced TNF&alpha and adipokine levels, and downregulated pJNK and GSK&beta, indicating targeted anti inflammatory modulation independent of Akt activation. Conclusion: Chronic RA showed persistent inflammatory and metabolic dysregulation driven by JNK-NF&kappaB activation. Resveratrol reduced cytokines, corrected adipokine imbalance, and selectively inhibited JNK, suggesting adjunct therapeutic value alongside DMARDs for improving immunometabolic disturbances in long-standing RA.

Background. Small fibre pathology has been proposed as a peripheral substrate for a subset of patients with fibromyalgia. A 2019 meta-analysis of 8 studies (222 patients) reported a pooled prevalence of 49% with moderate heterogeneity, and concluded that this supported a distinct fibromyalgia phenotype. The evidence base has since expanded substantially. Methods. We systematically searched PubMed for original human studies reporting the proportion of adults with fibromyalgia showing abnormal small fibre findings on an objective structural or functional test (skin biopsy with intraepidermal nerve fibre density, corneal confocal microscopy, sudomotor testing, microneurography, or laser-evoked potentials). Proportions were pooled with a random-effects model on the logit scale (REML). We pre-specified subgroup analyses by diagnostic method and assessment site, meta-regression on publication year and sample size, leave-one-out sensitivity analysis, and risk-of-bias appraisal with the JBI prevalence checklist. Where cohorts overlapped, the most complete report was retained. Search and initial screening were AI-assisted; eligibility, extraction and appraisal were performed independently by two reviewers with consensus. Results. Of 83 records, 34 studies met eligibility and 21 (1,268 patients) provided extractable proportions. Applying a uniform rule of abnormality at any assessed site, the pooled prevalence was 46.5% (95% CI 34.3-59.1), with I2=92.7% and a 95% prediction interval of 8.6% to 89.0%. Individual estimates ranged from 0% to 85.2%. Contrary to our pre-specified hypothesis, diagnostic method did not explain heterogeneity (QM p=0.89, R2=0). Assessment site was the dominant moderator: using each study's site-specific data, distal-leg assessment yielded 30.5% (22.4-40.1; 15 studies) and proximal-thigh assessment 73.9% (53.5-87.4; 4 studies). Three studies assessed both sites in the same patients and all three found more abnormality proximally (31.6% vs 46.2%; 12.3% vs 85.2%; 9.7% vs 83.9%). Publication year (p=0.50) and sample size (p=0.24) were not associated with prevalence. Leave-one-out estimates remained between 44.4% and 49.6%. Conclusions. More than tripling the evidence base did not stabilise the pooled prevalence estimate and more than doubled heterogeneity (I2 68% to 93%). The prediction interval now spans almost the entire possible range, and the method difference reported in 2019 is no longer detectable. Studies do not share a common definition of abnormality, and several do not report one at all. A pooled prevalence figure for small fibre pathology in fibromyalgia is therefore not currently interpretable; a standardised case definition is a prerequisite for meaningful synthesis. The anatomical site of assessment, not the technique, emerges as the dominant source of variation and should be treated as a primary moderator in future work.

Background The ADVOCATE trial evaluated treatment with avacopan for granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Concerns regarding the 2019 primary outcome adjudication procedures in nine participants prompted readjudication in 2026 of primary outcomes for all participants. Methods Patients with GPA/MPA were randomized 1:1 to prednisone taper or avacopan 30 mg twice daily; participants received treatment with cyclophosphamide or rituximab. An independent, blinded committee readjudicated the primary outcomes of remission at week 26 and sustained remission at week 52. Noninferiority and superiority were established if lower bounds of the 95% confidence interval (CI) for difference in rates were greater than -20.0 and 0.0 percentage points, respectively. Secondary outcomes included glucocorticoid exposure and toxicity, kidney parameters, health-related quality of life, and safety. Results Among 330 participants, remission at week 26 was achieved by 68.1% and 67.1% in the avacopan and prednisone groups, respectively, in the 2026 readjudication (adjusted difference: 2.2%; 95% CI, -7.5, 11.9), compared with 72.3% and 70.1% in the 2019 adjudication (adjusted difference: 3.4%; 95% CI, -6.0, 12.8). Sustained remission at week 52 was achieved by 61.4% and 52.4%, respectively, in the 2026 readjudication (adjusted difference: 9.8%; 95% CI, -0.3, 19.9), compared with 65.7% and 54.9% in the 2019 adjudication (adjusted difference: 12.5%; 95% CI, 2.6, 22.3). Secondary endpoints favored the avacopan group. Conclusions Treatment of GPA/MPA with avacopan in combination with rituximab or cyclophosphamide, when compared with a prednisone taper, resulted in similarly high rates of remission and sustained remission, but reductions in glucocorticoid exposure and toxicity.

Background Disease flares in dermatomyositis (DM) are unpredictable and often detected weeks to months after their onset. Interferon (IFN)-related gene signatures are implicated in DM, but their value for longitudinal flare prediction remains unclear. We hypothesized that longitudinal transcriptomic profiling using minimally invasive blood microsampling would detect IFN gene signatures preceding and during DM disease flares. Methods In this feasibility study, patients were included if they had inactive or minimally active disease and at least one of the following criteria: recent diagnosis within 2 years, a documented flare in the prior year, or ongoing tapering of immunosuppressive therapy. Patients self-assessed their disease activity weekly for 6 months using the International Myositis Assessment and Clinical Study group (IMACS) patient global assessment (PtGA; numerical rating scale, range 0-10). Disease flares, defined as a PtGA increase >2 for 2 consecutive weeks, triggered an in-person visit for confirmation by a physician. During the follow-up period, patients also self-collected weekly blood microsamples (125uL) that were shipped by courier to the study center. From those weekly blood microsamples, RNA sequencing was performed on 54 samples collected across 9 timepoints using an Illumina platform. Bioinformatic analyses included alignment, quality assessment, and gene-level quantification to evaluate differential gene expression and RNA processing changes during DM flares. Results Six DM patients were included in this study (2 anti-MDA5, 2 anti-Mi2, 1 anti-NXP2, 1 no myositis-specific antibodies). All were female with ages at study entry ranging from 46 to 72 years. Three of the six patients experienced a flare during their 6-month follow-up. The mean (SD) RNA integrity score for the weekly blood microsamples collected was 7,61 (0,64). IFN scores were significantly higher in flare-associated samples than in no flare samples (linear mixed-effects model with individual patient as a random intercept, P = 5.13 x 10E-4). Gene set enrichment analysis of hallmark gene sets identified enrichment of IFN-related gene sets in pre-flare and flare samples with IFN Alpha Response and IFN Gamma Response showing the highest positive normalized enrichment scores. Conclusion This study demonstrates the technical feasibility of combining home-based longitudinal blood microsampling with transcriptomic profiling in dermatomyositis. IFN gene score were higher in flare-associated than in no-flare samples, supporting further investigation of IFN-related signatures as candidate biomarkers for longitudinal disease monitoring.

Introduction: Across major phases of the COVID-19 pandemic (March 2020-April 2023), we compared the burden of severe COVID-19 among individuals with systemic autoimmune rheumatic diseases (SARDs) versus immunocompetent individuals with and without comorbidities. Methods: This population-based cohort study used administrative datasets to estimate crude and age- and sex-standardized SARS-CoV-2 and severe COVID-19 incidences among adults >18 years with SARDs, chronic comorbidities, or no comorbidities. Relative to the latter, we used Cox models to derive adjusted hazard ratios (aHRs) for infection, hospitalization, and intensive care unit admission or death (ICU/death) during the pre-vaccination (March-December 2020), vaccination pre-Omicron (December 2020-December 2021), and Omicron (December 2021-April 2023) periods. Results: We included 81,434 adults with SARDs, and 2,020,356 with comorbidities versus 3,144,700 without comorbidities. Despite similar adjusted infection rates, the SARDS cohort had higher risks of hospitalization and ICU/death during the pre-vaccination period (aHRs: 3.4, 95%CI:2.8-4.1; and 4.0, 95%CI:2.8-5.7, respectively), persisting through the Omicron period (aHRs: 4.5, 95%CI:4.0-4.9; and 4.4, 95%CI:3.6-5.4, respectively). Among SARDS, rheumatoid arthritis, psoriatic arthritis and systemic lupus erythematosus contributed highest burden, with comparable hospitalization and mortality rates among younger rheumatoid arthritis versus healthy older adults. Highly immunosuppressive rituximab- or mycophenolate-treated patients had highest hospitalization and ICU/death risks, particularly during the Omicron period (aHRs: 11.9, 95%CI:9.9-14.3; and 17.6, 95%CI:13.0-23.9, respectively). Conclusion: Individuals with SARDs, especially receiving highly immunosuppressive therapies, experienced elevated COVID-19 burden and severe outcome risks throughout the pandemic, warranting their prioritized consideration during future public health emergencies.

Objectives. Observational studies report large, conflicting associations between common drugs and hip or knee replacement. We tested them in the serious adverse event (SAE) tables of randomized trials on ClinicalTrials.gov. Methods. We included randomized drug trials with at least 500 participants. A language model classified arms from summaries without outcome counts (masked by instruction only). We pooled osteoarthritis-related SAEs by drug class as Mantel-Haenszel risk ratios (RRs). Because the plan followed a preliminary analysis of 72 trials, we report estimates rather than tests, checked by positive and negative controls and calibration. Results. The 881 placebo- or usual-care-controlled trials included 1.75 million participants and 9,408 osteoarthritis-related SAEs. The tables reproduced CANTOS's own canakinumab effect (RR 0.57, 95% CI 0.39 to 0.82), the anti-nerve growth factor excess (2.31, 1.82 to 2.92) and two of three modest effects specified before extraction: gallbladder disease with glucagon-like peptide-1 receptor agonists (GLP-1RAs; 1.36, 1.22 to 1.51) and ketoacidosis with sodium-glucose cotransporter-2 (SGLT2) inhibitors (1.96, 1.48 to 2.60). In the same trials, osteoarthritis-related SAEs did not differ detectably with GLP-1RAs (0.97, 0.86 to 1.10; calibrated 0.87, 0.54 to 1.41) or SGLT2 inhibitors (0.96, 0.82 to 1.12; calibrated 0.86, 0.53 to 1.40). Other proposed drugs gave imprecise estimates. Post hoc, 8 of 21 published observational estimates differed from randomized ones, in both directions (3 to 6 after calibration). Conclusions. Over about two years, GLP-1RAs and SGLT2 inhibitors had no detectable effect on osteoarthritis-related SAEs in trials that detected their known effects. Slow or modest structural effects remain possible.

Objective: To assess the accuracy of codes and algorithms used to identify selected connective tissue diseases (CTDs) in electronic health records (EHRs) and administrative databases. Methods: We searched MEDLINE, Embase, and CENTRAL databases for studies that validated case definitions in EHRs against a reference standard, including rheumatologist-confirmed diagnosis or clinical classification criteria. Title/abstract screening, full-text review, data extraction, and quality appraisal were independently performed in duplicate. Findings were synthesised narratively and through a bivariate random-effects meta-analysis of sensitivity and specificity. Results: A total of 38 studies were included. Systemic lupus erythematosus (SLE) was the most frequently studied disease, followed by systemic sclerosis (SSc). Across diseases, progressively restrictive algorithms generally improved positive predictive value (PPV), although the optimal strategy varied by disease. In SLE, multiple diagnostic codes provided the most favorable overall performance, whereas adding clinical data provided limited incremental benefit. In SSc, disease-specific clinical features, particularly Raynaud's phenomenon, improved case identification, while specialist or inpatient-based algorithms performed better for polymyositis/dermatomyositis, although evidence was limited. For SLE, meta-analysis yielded pooled sensitivity of 0.90 (95% Cis 0.70-0.97), specificity of 0.83 (95% CIs 0.54-0.95), and PPV of 0.75 (95% CIs 0.59-0.86). Evidence for Sjogren's Disease was limited to one study, and no studies evaluated MCTD/UCTD. Conclusions: Optimal EHR case-identification strategies vary by disease and should be tailored to disease-specific clinical and diagnostic characteristics rather than algorithm complexity alone. Future research should develop and externally validate robust, standardised algorithms in representative populations, using rigorous validation methods, and assess the added value of longitudinal EHR data, biomarkers, and computational phenotyping approaches.

Objectives: Patients with pediatric acute-onset neuropsychiatric syndrome (PANS) frequently report pain and fatigue. While some patients experience resolution of pain and fatigue following improvement in psychiatric symptoms, others develop persistent symptoms resembling fibromyalgia. Understanding these trajectories is critical for early identification and intervention in patients at risk for chronic pain or fatigue. In this study we characterize fibromyalgia symptoms in PANS and identify predictors of symptom progression following a PANS flare. Design: Prospective observational cohort study. Setting: Stanford University Immune Behavioral Health (IBH) Clinic in Menlo Park, California, USA. Participants: 204 consecutive patients with PANS evaluated by the IBH Clinic. The average (SD) age at first neuropsychiatric deterioration was 8.2 (3.3) years. Main outcome measures: We prospectively collected data on pain, fatigue, and other fibromyalgia symptoms using the 2016 American College of Rheumatology (ACR) Fibromyalgia Survey Questionnaire (FSQ), which includes the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS). For the reference standard, clinician-documented diagnoses of pain syndromes were ascertained through a retrospective review of participants' electronic medical records. We report the prevalence of these symptoms in PANS patients and controls and evaluate factors associated with time to meeting ACR fibromyalgia criteria threshold scores following clinic presentation using a Cox proportional hazards model. Results: Among 204 patients with PANS (110 boys [54%]), eighty-five (42%) met ACR fibromyalgia criteria threshold scores at least once during follow-up (95% CI at 10 years follow-up time: 60.5 [46.7-74.5]). Twenty-eight of these 85 patients (13.7% of total cohort) progressed to meet full ACR fibromyalgia criteria (95% CI at 10 years follow-up time: 24.1 [15.6-36.2]). Compared with controls, patients with PANS reported substantially elevated rates of pain, daytime fatigue, waking unrefreshed, and cognitive symptoms (brain fog). Higher scores on the WPI and SSS at presentation were associated with a higher hazard of subsequently meeting ACR fibromyalgia criteria threshold scores. Conclusions: Fibromyalgia symptoms were common in this PANS cohort, with a notable subset developing symptoms meeting full ACR fibromyalgia criteria. These findings suggest that pain and fatigue may represent post-inflammatory sequelae of PANS and may overlap mechanistically with other post-infectious conditions. Recognizing these symptom patterns may inform clinical management, development of outcome measures, and future clinical trials in these patients, as well as support investigation into shared neuroimmune mechanisms underlying post-infectious pain and fatigue syndromes.

Objectives Juvenile idiopathic arthritis (JIA) is a collection of childhood onset rheumatic conditions that more frequently occur in females in most subtypes. Sex influences disease biology, treatment trajectories, and patient outcomes, however, no study to date has investigated the interaction of sex with autosomal genetic risk to JIA. Methods Genotype data from 3748 JIA cases (2551 female, 1197 male) and 9196 controls (5136 female, 4060 male) were analysed using a sex-stratified genome-wide association analysis. Systemic JIA was excluded. HLA imputation and fine-mapping were performed using SNP2HLA. Sex-specific effects were assessed using an omnibus sex-interaction test for multi-allelic amino acid positions. A subtype specific analysis was repeated in rheumatoid factor (RF) negative polyarthritis and oligoarthritis (1862 female, 718 male). Results A sex-combined analysis identified genome-wide significant (P<5x10-8) loci across the HLA region and nine loci outside the HLA region, including a novel association at rs231977 (NUPR1). Markers within the HLA region were significantly sex-dimorphic (P<5x10-8) and nine loci outside of the HLA region were suggestive for sex dimorphism (P<5x10-6), including SPRY2. HLA fine-mapping identified lysine at position 70 of HLA-B conferring greater male JIA risk, and tyrosine at position 10 of HLA-DRB1 conferring greater female JIA risk. Subtype specific analysis strengthened the association of tyrosine at position 10 of DRB1 in females. Conclusions This study provides the first evidence that autosomal genetic risk factors contribute to JIA risk in a sex-dimorphic manner, mirroring known clinical observations, and highlighting the importance of incorporating sex-stratified methods in future JIA studies.

Neutralizing antibodies are a correlate of protection (CoP) of SARS-CoV-2 vaccine efficacy. However, data informing CoPs often explicitly exclude people on immunosuppressive therapies who are at an increased risk of symptomatic and severe COVID-19, delayed viral clearance, and death. Investigating the relationship between antibodies and protection for people on immunosuppressive therapies could provide insights into mechanisms of protection. We performed a systematic search to identify studies reporting SARS-CoV-2 binding antibody levels after mRNA vaccination in people with hematological malignancies, neurological disorders, rheumatic diseases, and mixed immune-mediated inflammatory disorders (IMIDs) on immunosuppressive therapies including B-cell depletion, JAK inhibitors, and S1P inhibitors, as well as healthy controls. Binding antibody levels varied between cohorts receiving different immunosuppressive treatments. Compared to healthy controls the lowest antibody levels were observed in subjects treated with B-cell depletion (54.5-fold reduction, 95% CI: 34.5-86.2) and S1P inhibitors (24.8-fold reduction, 95% CI: 13.2-46.7). To assess the association between antibody level and protection, we used data from a previous study of COVID-19 vaccine effectiveness in people with the same underlying conditions. We linked vaccine effectiveness estimates with the predicted antibody level in people on immunosuppressive therapies (using antibody data including this meta-analysis of binding antibody levels). Predicted neutralizing antibody levels were correlated with vaccine effectiveness both for infection and hospitalization (p<0.0001 and p<0.0001, respectively). However, we found that for any given antibody level, people who are immunosuppressed had lower protection against infection and hospitalization than a healthy population.

Objective: Autoantibodies are central for pathology of rheumatoid arthritis (RA) and diabetes mellitus (DM) carrying high predictive and diagnostic value. Here, we explore the frequency and functional potential of DM-related antibodies (DMab) in RA. Methods: DMab targeting glutamic acid decarboxylase (GAD65ab), tyrosine phosphatase-like islet antigen 2 (IA2ab) and zinc transporter 8 (ZnT8ab) were measured in 326 DM-free RA patients (260 females, 66 males), using specific ELISAs. The DMab profile was analysed in relation to 30 clinical and serological variables. ZnT8+ cells were detailed by a public single-cell transcriptome in RA synovial tissue. Results: DMab production was more frequent in females, dominated by ZnT8ab (86%), followed by GAD65ab (26.4%) and IA2ab (7.0%). DMab-positive patients, and specifically ZnT8ab-positive women, had higher levels of insulin and HOMA-IR index and lower serum IL-6, IFN{gamma}, and IL-9. Multivariable logistic regression estimating ZnT8ab, IA2ab, GAD65ab production revealed that BDNF, insulin and DAS28 were positive predictors of ZnT8ab. Increasing ZnT8ab levels were inversely related to RAab in the mixed interaction model. CD14+ cell transcriptome identified association between an activated secretory cell type and increasing ZnT8ab levels. Additionally, ZnT8ab levels were in direct proportion with ZnT8 production in RA CD4+ T cells. Single-cell transcriptome of RA synovial tissue revealed ZnT8+ cells among the lubricin producing lining layer fibroblasts programmed for invasive behaviour. Conclusion: This study reveals frequent production of ZnT8ab in non-diabetic RA patients and identifies their antigenic target expressed in lining synovial fibroblasts of RA joints.

Background. Giant cell arteritis (GCA) is the commonest systemic vasculitis and a medical emergency. High-dose glucocorticoids are started on suspicion, before confirmation, and cause substantial dose-dependent harm in the many patients who prove not to have GCA. Diagnostic confirmation by temporal artery biopsy or ultrasound remains imperfect. The performance of both approaches is influenced by the clinical context and, for ultrasound, operator expertise, creating the potential for both unnecessary treatment and delayed or missed diagnosis. A laboratory-based, multi-analyte proteomic blood test may help, but its intended use and performance requirements are undefined. Objective. To develop, by structured expert consensus, a Target Product Profile (TPP) for a laboratory-based, multi-analyte proteomic blood test to aid the diagnosis of cranial GCA in secondary care, used alongside clinical assessment, imaging and/or biopsy, with the primary objective of reducing unnecessary glucocorticoid exposure without increasing missed cases, from a UK health-system perspective. Methods and analysis. A multidisciplinary committee of approximately 15 to 30 members, including patient and public representatives, will follow a three-phase process: a scoping phase that confirms the intended use and the prioritised list of characteristics; a drafting phase that specifies minimum (acceptable) and preferred (desirable) values across the TPP domains, using outcome-based methods where feasible; and a consensus-building phase using an up-to-three-round modified Delphi (75% consensus threshold) with interim consensus meetings and a 28-day public consultation. Reporting follows ACCORD and CREDES.

Background and objectivesMyasthenia gravis associated with antibodies against muscle-specific kinase (MuSK-MG) is a well-characterized IgG4-autoimmune disease, however, the mechanisms driving IgG4 predominance remain poorly understood. This study investigated whether promoter DNA methylation of cytokine genes involved in IgG4 class switching is associated with this immune response. MethodsPeripheral blood mononuclear cells were isolated from MuSK-MG patients (n=36), acetylcholine receptor myasthenia gravis (AChR-MG) patients as disease controls (n=7), and sex-matched healthy controls (n=12). Promoter DNA methylation of IL4, IL10, and IL13 was assessed by methylation-sensitive high-resolution melting and relative cytokine mRNA expression by qPCR. Associations with clinical variables, and antibody levels were subsequently evaluated. ResultsMuSK-MG patients showed lower median IL13 promoter methylation compared with healthy controls (p = 0.004). Median IL4 promoter methylation was also reduced in MuSK-MG compared with healthy controls (p < 0.001) and AChR-MG disease controls (p < 0.001), whereas no differences were observed for IL10 promoter methylation. Relative mRNA expression of IL4 (p = 0.0005), IL10 (p = 0.0462), and IL13 (p = 0.0002) was increased in MuSK-MG compared with AChR-MG. Compared with healthy controls, only IL4 expression remained significantly increased (p < 0.0001). Promoter methylation was inversely correlated with relative mRNA expression for IL4 (p < 0.0001), while IL13 showed a similar but non-significant trend (p = 0.054), no association was observed for IL10. Multivariable analysis demonstrated that treatment at sampling was independently associated with lower IL10 and IL13 promoter methylation, whereas no associations were observed with age, sex, disease phase, or disease duration. Promoter methylation did not correlate with total serum IgG4 or anti-MuSK IgG4 levels. DiscussionMuSK-MG is associated with selective hypomethylation of IL4 and IL13 promoters accompanied by increased cytokine gene expression, while IL10 promoter methylation remains unchanged. The association between treatment and IL10 and IL13 promoter methylation suggests that immunosuppressive therapy may influence epigenetic regulation in MuSK-MG. Together, these findings support a role for epigenetic dysregulation of Th2-associated cytokines in the immunological environment associated with IgG4 subclass switch. To our knowledge, this is the first study investigating IL4, IL10, and IL13 promoter DNA methylation in MuSK-MG.

Sensory neuropeptides, particularly Substance P (SP) and -calcitonin gene-related peptide (CGRP), are implicated in osteoarthritis (OA) pathogenesis. This study elucidates their specific roles in spontaneous, age-related OA. Male and female mice deficient in SP (Tac1-/-), CGRP (CGRP-/-), or both (DKO) were evaluated at 6, 12, and 18 months of age. Assessments included histological OARSI scoring for articular cartilage matrix structure, Luminex arrays for systemic serum cytokines, and flow cytometry for local synovial immune cell profiling. Wild type (WT) mice developed early-stage, age-related cartilage degradation, predominantly in the lateral compartment. Conversely, all neuropeptide-deficient strains exhibited significant structural protection against this process. Systemically, SP deficiency distinctly altered cytokine profiles (e.g., decreased IL-23, increased IP-10), whereas CGRP deficiency caused minimal systemic shifts, highlighting a disconnect between circulating markers and local joint preservation. Locally, flow cytometry revealed profound, sexually dimorphic, and age-dependent neuroimmune alterations. In young males, neuropeptide deficiency significantly reduced synovial macrophage counts to levels comparable to those of aged WT mice. Furthermore, male CGRP-/- mice exhibited an age-related accumulation of CD8+ cytotoxic T cells. In contrast to males, young WT females demonstrated higher baseline CD8+ T cell counts that declined with age, whereas these subpopulations remained persistently low in KO mice. SP and CGRP act as critical modulators of age-related cartilage degradation. Their absence provides robust structural protection mediated through highly localized, sexually dimorphic neuroimmune pathways. These findings emphasize the necessity of targeting the local joint microenvironment for future personalized, sex-specific OA therapies.

Objective: Tissue-specific biomarkers that are reliable and associated with clinical manifestations of idiopathic inflammatory myopathy (IIM) are lacking. The blood circulation in individuals serves as a central conduit, allowing communication between tissues and facilitating clearance and recycling of tissue-derived proteins. Thus we applied a dual antibody-based proximity extension assay to profile the plasma proteome in subtypes of patients with IIM. Methods: Plasma samples from 201 patients diagnosed with IIM at Karolinska University Hospital were analyzed using Olink. Clinical manifestations, disease activity measurements, and laboratory results were collected. First, we evaluated differential protein abundance across IIM subtypes. Then we calculated tissue scores for each disease subtype using tissue gene expression databases. Finally, interferon (IFN) and complement pathway scores were calculated. Results: Plasma from patients with dermatomyositis was enriched for IFN signaling and skin associated proteins, anti-synthetase syndrome (ASyS) for lung associated proteins, immune-mediated necrotizing myopathy (IMNM) for muscle associated proteins, and inclusion body myositis for T cell response proteins. Patients with IMNM showed the highest tissue score for skeletal muscles, and ASyS for lung tissue score. Skeletal muscle scores correlated strongly with muscle disease activity visual analog scale scores, creatinine kinase levels, and muscle weakness score. Patients with interstitial lung disease along with and those with anti-Jo1 autoantibodies showed differential enrichment of surfactant proteins and IFN pathway activation. Conclusions: Circulatory proteome is a promising tool to capture distinct tissue-specific responses that correlate with disease activity and tissue injury in patients with IIM.

Background: Smartphone enabled remote patient monitoring has the potential to complement conventional follow-up in inflammatory arthritis. We previously presented the finger fold index (FFI) derived from hand photographs as ratio of automated detected proximal interphalangeal (PIP) joint diameter and surface of dorsal finger folds as a digital biomarker for clinical joint swelling and disease activity in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Objective: To evaluate the feasibility, image quality, patient engagement, and clinical utility of both HCP- and patient-collected hand photographs integrated into a national rheumatology registry, and to assess the performance of the FFI as an image-derived digital biomarker for clinical joint swelling of the proximal interphalangeal joints in a real-world arthritis cohort. Methods: In this longitudinal multicenter study, a photo function with written instructions were integrated into the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry and their mySCQM mobile application, respectively. Patients with RA or PsA contributed longitudinal smartphone photographs together with patient-reported outcomes (PROs) via the mySCQM mobile application while health care professionals (HCPs) acquired images during routine visits. After manual quality assessment, images were processed using an automated computer vision pipeline to derive the FFI, a digital biomarker based on dorsal finger-fold morphology. Image quality was evaluated for both HCP- and participant-collected photographs, and patient engagement was assessed. Associations between FFI, clinical proximal interphalangeal (PIP) joint swelling, RADAI-5, DAS28-CRP and longitudinal changes were assessed. A generalized linear mixed model was used to estimate the association between FFI and joint swelling while accounting for repeated measures and within-subject correlations. Results: Between 2023 and 2025, 374 RA and PsA patients were included. HCPs captured 977 hand images while 174 patients collected 1228 hand images via the mySCQM app. Patients demonstrated sustained engagement after instruction, contributing a mean of seven images during data collection. Following quality control, 1729 hand images comprising 4048 PIP joints were included for analysis. Image quality was comparable between patient-acquired and HCP-acquired photographs; 78.3% of the patient-acquired vs. 73.5% of the HCP-acquired hand images were suitable to run the ML-model. 23.1% of the cropped joints had to be removed after the running of the FFI algorithm due to false diameter or finger fold detection e.g. due to wrong hand positioning. In images taken by HCPs, mean FFI and DAS28-CRP were weakly but significantly correlated (Spearmans {rho} = 0.164; 95% CI [0.004 to 0.317]; p = 0.039). Conversely, RADAI-5 scores did not correlate with the mean FFI in RA patients (r = 0.007, p = 0.932, 95% CI [-0.169-0.183]). At follow-up visits, clinical swelling resolved in 40 joints, of which in 68.0% the direction of the delta FFI was concordant with the clinical change. In contrast, 13 joints developed incident clinical swelling, of which 87.5% had a direction of the delta FFI that was concordant with the clinical change. However, the GLMM showed no significant associations between swelling and joint location or time-varying FFI, and no evidence of interaction between FFI and PIP joint. Conclusion: Integration of patient self-imaging into a remote monitoring application for inflammatory arthritis is feasible and achieves image quality comparable to clinician acquired photographs. The FFI derived from collected images shows association with clinical joint swelling and disease activity scores, but not PROs. In a substantial proportion of images, the FFI algorithm could not be applied because of insufficient image quality. More standardized image acquisition and further refinement of the FFI algorithm are warranted.