Rheumatology

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.

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. 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.

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.

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 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.

Abstract Cardiovascular disease (CVD) is a major cause of morbidity and premature mortality in people with rheumatoid arthritis (RA). Whether multidimensional cardiometabolic, inflammatory, renal, behavioral, and psychosocial factors define distinct cardiovascular risk phenotypes in RA remains unclear. This study aimed to identify data-driven phenotypes and evaluate their associations with prevalent CVD. We analyzed 3,252 adults aged over 20 years with self-reported RA from the 2005-2018 National Health and Nutrition Examination Survey (NHANES). Unsupervised partitioning around medoids (PAM) clustering using Gower distance identified distinct data-driven cardiovascular-risk profiles. Cluster validity was assessed using silhouette analysis and internal train test validation. Survey-weighted binary logistic regression evaluated associations between phenotype membership and prevalent CVD. Six clinically interpretable data-driven phenotypes were identified with varying CVD prevalence: Severe Metabolic Diabetic (40.3%), Aging Diabetic Hypertensive (34.9%), Non-Diabetic Intermediate (20.2%), Mild Metabolic (14.8%), Cardiometabolic (10.4%), and Smoking-Predominant (19.4%). Compared with the Cardiometabolic phenotype, the Severe Metabolic Diabetic phenotype exhibited the highest odds of prevalent CVD (aOR 4.11, 95%CI:2.56-6.59), followed by the Aging Diabetic-Hypertensive phenotype (aOR 3.38, 95%CI:2.22-5.15). Higher odds of prevalent CVD were also observed in the Smoking-Predominant (aOR 1.99, 95% CI: 1.26-3.13) and Non-Diabetic Intermediate (aOR 1.77, 95% CI: 1.10-2.84) phenotypes. The six-cluster solution demonstrated moderate separation and strong internal correspondence across training and testing sets, while the phenotype-informed model showed moderate discrimination for prevalent CVD (AUC = 0.72). Among adults with rheumatoid arthritis (RA), distinct data-driven phenotypes were identified based on combined patterns of metabolic, inflammatory, renal, behavioral, and psychosocial factors, with differing burdens of prevalent cardiovascular disease (CVD). Phenotype-based approaches may provide a comprehensive framework for characterizing multidimensional cardiovascular risk in RA.

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.

Systemic sclerosis (SSc) is a rare, heterogeneous autoimmune disease characterized by immune dysregulation, vasculopathy and fibrosis. While typically sporadic, SSc can in a minority of cases show familial clustering. Whole exome sequencing (WES), performed on six families with two affected members each, identified a total of 253 genes with rare, disease co-segregating variants predicted to affect protein function. Of these, we prioritized PRKD2, one of only three genes identified in two families. PRKD2 encodes Protein kinase D2: an intracellular serine-threonine kinase that amplifies T cell receptor (TCR) signaling. Both familial SSc-associated PRKD2 missense variants increased kinase activation, exerting overlapping, activating effects on TCR signaling in heterozygous knock-in Jurkat cells. A pan-PRKD inhibitor suppressed T cell activation in peripheral blood mononuclear cells from both familial SSc cases and controls. The enrichment of PRKD2 rare variants in a sporadic SSc cohort provides further support for its relevance to SSc pathogenesis. Together, these findings identify PRKD2 rare variants as potential genetic contributors to SSc, and PRKD2-mediated TCR signaling as a candidate disease-relevant and potentially targetable pathway.

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.

Objective: The principal diagnostic test for rheumatoid arthritis (RA) relies on the detection of anti-cyclic citrullinated peptide (CCP) antibodies. The CCP test exhibits moderate sensitivity and specificity but does not adequately detect a high proportion of cases or effectively distinguish RA from related conditions such as systemic lupus erythematosus (SLE). To discover improved diagnostic biomarkers for RA, we performed a comprehensive proteomic analysis of antibody-bound antigens present in RA, SLE, and healthy control (HC) sera and identified proteins associated with transforming growth factor-beta-1 (TGF-beta-1) signaling and assessed the sensitivity and specificity of antibodies against these antigens in comparison to CCP. Methods: Total antibodies were immunoprecipitated from pooled sera of HC individuals (n=3) and patients with clinically diagnosed RA (n=3) or SLE (n=3). Antibody-bound antigens were identified using multidimensional protein identification technology (MudPIT) shotgun proteomics. Candidate antigens associated with TGF-beta-1 signaling were selected for evaluation, and corresponding serum autoantibodies were assessed for their ability to classify RA using a POC lateral-flow immunochromatographic format. Results: Proteins present in antibody immunoprecipitations included TGF-beta-1-induced protein (TGFBI), thrombospondin 1 (TSP1), serum amyloid A1 (SAA), and fibronectin (FN). POC assays using these candidates, as well as TGF-beta-1 itself, as capture antigens were used to detect corresponding serum autoantibodies in 107 subjects with clinically diagnosed RA, 42 subjects with other rheumatic diseases (non-RA), and 121 HC subjects. Receiver operating characteristic curves were constructed using RA and HC groups to assess diagnostic performance, and optimal cutpoints identified using the Youden Index (maximizing the sum of sensitivity and specificity). CCP test results were determined using previously established thresholds. Using an analysis et of 169 subjects in the HC and RA groups who had values for TGFBI, SAA, and CCP, TGFBI autoantibodies achieved a sensitivity of 82%, specificity of 98.8%, positive likelihood ratio (PLR) of 65.6, and NLR of 0.2. SAA autoantibodies achieved a sensitivity of 92.1%, specificity of 85%, PLR of 6.1, and NLR of 0.1. Both outperformed CCP (sensitivity of 68.5%, specificity of 95%, PLR of 13.7, and NLR of 0.3). Using an analysis set of 120 subjects in the RA and non-RA groups who had values for TGFBI, SAA, and CCP, TGFBI and SAA autoantibodies exhibited sensitivities and specificities of 82 and 92.1% and 74.2 and 45.2%, respectively, compared to 68.5 and 74.2% for CCP. Autoantibodies to TGF-beta-1, TSP1, and FN exhibited only modest diagnostic performance. Conclusion: RA sera contain autoantibodies targeting multiple proteins associated with the TGF-beta-1 signaling pathway that is implicated in inflammatory processes in RA. Among the candidates tested, TGFBI and SAA autoantibodies exhibited the highest diagnostic performance in a POC lateral-flow format, supporting their potential utility as biomarkers for RA diagnosis. These findings also support further investigation of the TGF-beta-1 signaling pathway as a potential therapeutic target in RA.

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.

Objectives To evaluate whether access to a certified large language model (LLM)-based clinical decision support system improves physician diagnostic performance in rheumatology compared with conventional diagnostic resources alone. Methods In this multicentre, open-label, randomised controlled trial, 82 physicians from seven hospitals in two countries were randomised 1:1 to conventional diagnostic resources plus Prof. Valmed or conventional resources alone. Participants assessed three rheumatology vignettes before and after assistance. The primary outcome was top-1 diagnostic accuracy. Secondary outcomes included top-3 accuracy, diagnostic reasoning, confidence, case-processing time and perceived support quality. Results Top-1 accuracy increased from 22.2% to 33.3% in the intervention group and from 23.3% to 35.0% in the control group, with no between-group difference in improvement (adjusted OR 0.99, 95% CI 0.45 to 2.19; p=0.979). Differences in top-3 accuracy, diagnostic reasoning and confidence were also not significant. Assisted case-processing time was substantially shorter with LLM support (94 vs 206 s; adjusted mean difference -112 s, 95% CI -141 to -83; p<0.001). Information timeliness and perceived diagnostic support quality were rated significantly higher in the intervention group. Exploratory analyses showed persistent overconfidence and substantial AI over-reliance. Conclusions Certified LLM-based diagnostic support did not improve diagnostic accuracy compared with conventional resources, but substantially reduced case-processing time and improved perceived support quality. These findings suggest potential workflow benefits while highlighting overconfidence and over-reliance as important safety considerations.

Objective: The Brief-cope questionnaire explore coping behavior. However, the underlying factor structure remains a subject of ongoing debate. Exploratory factor analyses (EFA) conducted across different populations have identified factor solutions ranging from two to fourteen factors. As of yet, the underlying factor structure of the Brief-cope has not been investigated in patients with seropositive rheumatoid arthritis (RA). Therefore, the aim of this study was to explore the underlying factor structure of the Brief-cope in a German population of seropositive RA. Methods: 216 outpatients with seropositive RA completed the Brief-cope. An EFA with principal axis factoring and Promax rotation was conducted. Results: EFA indicated a five-factor solution. The five-factor solution explained 51.95% of variance. The identified factors were: (1) problem-focused coping (Cronbach's = .851), (2) emotion-focused coping ( = .754), (3) maladaptive coping ( = .747), (4) religious coping ( = .851), and (5) substance-use coping ( = .869). Conclusion: A five-factor solution provided the most appropriate representation of the underlying factor structure of the Brief-cope in patients with seropositive RA. This factor structure may serve as a suitable basis for future analyses of Brief-cope data in comparable RA populations.

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.

BACKGROUND Primary sclerosing cholangitis (PSC) is characterized by multifocal biliary strictures on MRI/MRCP. However,we have observed that young PSC patients often displayed a marked intrahepatic bile duct visibility,sometimes with gallbladder enlargement, before developing biliary strictures. This study aimed to evaluatewhether this imaging pattern was associated with subsequent diagnosis of PSC. PATIENTS AND METHODS This retrospective two-center study included patients younger than 21 years who had a baseline liverMRI/MRCP, without biliary strictures. The endpoint was a definite diagnosis of large duct PSC during follow-up. The association of baseline imaging findings with the endpoint was evaluated by multivariable logisticregression, Cox models, and Kaplan-Meier analyses. RESULTS Ninety-four patients were included: 54% were women, the mean age was 16.7 years, and 23% had IBD. Overa mean follow-up of 7.75 years, 21 patients were subsequently diagnosed with large duct PSC after a mediantime of 5.60 years. Marked intrahepatic bile duct visibility and gallbladder enlargement displayed goodperformance to predict the subsequent diagnosis of PSC (AUC, 0.77 and 0.69, respectively). The presence ofboth signs displayed a specificity of 1.00. In multivariable analyses, marked intrahepatic bile duct visibility andgallbladder enlargement were independently associated with subsequent PSC diagnosis (OR 17.00 (95% CI,3.10-93.24; p = 0.001) and 16.08 (95% CI, 2.29-113.02; p = 0.005) respectively) and shorter time to diagnosis(HR 9.42 (95% CI, 2.50-35.59; p < 0.001) and 7.59 (95% CI, 2.03-28.41; p = 0.003) respectively). Survivalanalyses confirmed the association between these two imaging signs and the subsequent PSC diagnosis (HR7.78 (95% CI, 2.62-23.16; p < 0.001) and 3.85 (95% CI, 1.64-9.08; p < 0.001) respectively). CONCLUSIONS In young patients without biliary strictures, marked intrahepatic bile duct visibility and gallbladder enlargementon MRI/MRCP were strongly associated with subsequent diagnosis of large duct PSC.

Objective: Rotator cuff tears involving the supraspinatus tendon are a common cause of shoulder pain. Ultrasound (US) is accessible, dynamic, and lower cost than MRI, but diagnostic performance may vary by tear severity, operator expertise. This systematic review and meta-analysis compared the US with MRI for supraspinatus tear detection. Methods: MEDLINE, Embase, Scopus, and CINAHL Plus were searched for studies published from January 2015 to June 2026. Study quality was assessed using QUADAS-2. Diagnostic outcomes included sensitivity, specificity, accuracy, PPV, NPV. Meta-analyses were performed separately for any, partial-thickness, and full-thickness tears when complete 2 x 2 data were available. Results: 23 studies comprising 1,452 participants were included. US demonstrated stronger and more consistent performance for full-thickness than partial-thickness tears. Mean sensitivity, specificity, and accuracy were 88.5%, 95.2%, and 93.4%, respectively, for full-thickness tears, compared with 71.5%, 91.5%, and 79.2% for partial-thickness tears. HSROC analysis showed pooled sensitivity and specificity of 96% and 76% for any tear, 94% and 80% for partial-thickness tears, and 96% and 98% for full-thickness tears. Agreement measures also generally favored full-thickness tears. Operator expertise, study quality varied, and only one study evaluated a handheld ultrasound system. Conclusion: Ultrasound demonstrates strong diagnostic performance for supraspinatus tears, particularly full-thickness tears, while partial-thickness tears remain more challenging. Given the high observed sensitivity, well-performed US may serve as a practical first-line modality to rule out full-thickness tears, with MRI remaining complementary for equivocal partial-thickness tears, associated pathology, and preoperative assessment.

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.

Fc{gamma}RIIa, encoded by FCGR2A, is a widely expressed Fc receptor implicated in autoimmunity and infectious disease susceptibility. To fine-map the rheumatoid arthritis (RA) association at the complex FCGR locus, we combined gene-specific resequencing, genetic association studies in UK and Spanish European cohorts, functional genomics, structural biology, biophysical analyses, and cellular assays. We identified a common European FCGR2A haplotype (2A.3), defined by Q27W, H131H, and the RA-associated SNP rs12746613, which showed the strongest association with RA. Multi-omics analyses demonstrated that 2A.3 is associated with reduced expression of the soluble FCGR2A splice variant and lower circulating soluble Fc{gamma}RIIa levels. Functional studies revealed altered IgG interactions and delayed Fc{gamma}RIIa signal transduction associated with Q27W, while structural analyses found no evidence for stable ectodomain dimerisation. Together, these findings identify 2A.3 as an important functional contributor to RA susceptibility and provide mechanistic insight into how FCGR2A variation may influence immune regulation and disease risk in Europeans.

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.