The Lancet Rheumatology

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: Five biologics target sequential nodes of the type 2 (T2) inflammatory axis in severe asthma and have each been anecdotally linked to eosinophilic or paradoxical inflammatory adverse events. Whether these reflect a class effect or drug-specific signatures is untested. Methods: We performed a case-noncase disproportionality analysis of FAERS, 2022-2024. Asthma-indication reports naming tezepelumab, dupilumab, mepolizumab, benralizumab, or omalizumab as primary suspect were compared against the pooled other four (active-comparator design) across 7 pre-specified eosinophilic, vasculitic (including EGPA), cutaneous, and ocular outcomes. A signal was robust if the reporting odds ratio (ROR) 95% CI lower bound exceeded 1 and a Bayesian criterion was also met. Results: Among 50,360 reports (dupilumab n=29,652; mepolizumab n=8,846; omalizumab n=5,484; benralizumab n=4,372; tezepelumab n=2,006), benralizumab showed robust signals for EGPA (ROR 5.06), vasculitis (ROR 4.60), and peripheral eosinophilia (ROR 1.80). Mepolizumab showed a robust vasculitis signal (ROR 1.85); its similarly sized EGPA association narrowly missed the robustness criterion despite significance after correction for multiple testing. Dupilumab showed no EGPA/vasculitis excess but a robust ocular-inflammation signal (ROR 7.81). Tezepelumab and omalizumab showed no robust signal in any domain. EGPA/vasculitis onset occurred earlier after dupilumab (median 20-44 days) than anti-IL-5-axis agents (median 195-550 days; p[≤]0.012); mepolizumab's signal did not reproduce over the full 2015-2024 window (calendar-time confounding). Conclusion: FAERS active-comparator analysis reveals drug-specific, not class-uniform, adverse-event reporting patterns: anti-IL-5-axis agents disproportionately report EGPA/vasculitis, and dupilumab disproportionately reports ocular inflammation with markedly earlier onset. These hypothesis-generating signals cannot establish causality and require confirmation through case-level or comparative pharmacoepidemiological studies.

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.

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 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.

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.

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.

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 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.

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.

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.

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.

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.

While progress has been made in identifying the true risk-driving single nucleotide polymorphisms (SNPS) on juvenile idiopathic arthritis (JIA) risk haplotypes, the affected cells and target genes largely remain unknown. We used data from a previously published massively parallel reporter assay (MPRA) to query human data in the Database of Immune Cell eQTLs (DICE) and the Gene-Tissue Expression (GTEx) database to identify affected cells and target genes of MPRA-identified SNPs in immune cells and relevant tissues. SNPs identified on MPRA were associated with gene expression levels in a broad range of immune cells in the DICE database, including CD4+ and CD8+ T lymphocytes, monocytes, NK cells, and B cells. MPRA-identified SNPs showed strong associations with gene expression in GTEx whole blood, spleen, and/or EBV-stimulated lymphocytes. Our data show the efficacy of combining MPRA and using human cells/tissue expression data to elucidate complex mechanisms driving genetic risk for JIA.

Background VEXAS syndrome is a late onset autoinflammatory disease caused by somatic UBA1 mutations and characterized by heterogeneous systemic and hematologic manifestations. We aimed to describe all identified Belgian cases through a national multicenter cohort. Methods We conducted a retrospective study across four Belgian tertiary centers. Clinical, biological, genetic, therapeutic, and outcome data were collected using standardized anonymized case report forms. Analyses were descriptive. Results Twenty-one male patients were identified between January 2018 and May 2025. General symptoms such as Fatigue, weight loss and sweating occurred in 95% of cases. The most frequent manifestations were cutaneous (85.7%), hematologic (76.2%), articular (66.7%), thromboembolic (57.1%), chondritis (42.9%), ophthalmologic (38.1%), pulmonary (38.1%). Other manifestations also included vasculitis (61.9%). At diagnosis, 95% had anemia, macrocytic in 57%, and 28.6% had thrombocytopenia. Corticosteroids were the main first line therapy. Second line treatments included anti IL 6 agents (46.7%), JAK inhibitors (20%), and azacitidine (14.3%). Complete remission occurred in 50% of patients receiving anti IL 6 therapy and in 33% treated with either JAK inhibitors or azacitidine. Two patients underwent allogeneic stem cell transplantation, one died from infectious complications. Twenty six infectious episodes were recorded, including opportunistic infections. Six patients (28.6%) died during follow-up, four from infectious complications. Conclusion This first Belgian national cohort confirms the clinical heterogeneity of VEXAS syndrome and highlights substantial infectious morbidity and mortality. Access to targeted second-line therapies, particularly anti IL-6 agents and JAK inhibitors, remains challenging despite apparent clinical benefit.

Objective: To determine outcomes by referral route (any Advice and Guidance [A&G] versus elective referrals only) for patients with inflammatory bowel disease (IBD), Parkinson's disease, and systemic lupus erythematosus (SLE). Design: Population-based retrospective cohort study. Setting: Linked Clinical Practice Research Datalink (CPRD) Aurum primary care records, 2015-2022. Participants: Patients with incident diagnosis of IBD, Parkinson's disease, or SLE. Main Outcome Measures: Time from the earliest recorded A&G or elective referral to diagnosis, first recorded definitive treatment and first attended outpatient appointment. Secondary outcomes included counts of primary care consultations, prescriptions, referrals, and outpatient appointments. Propensity score weighted flexible parametric survival analyses accounted for differences between exposure groups. Results: Among 71,145 eligible patients, A&G was recorded for 1,137 (3.0%) with IBD, 971 (3.4%) with Parkinson's, and 243 (4.9%) patients with SLE. Compared with elective referral only, A&G was associated with slower time to diagnosis for IBD (adjusted median difference 15.9 weeks; hazard ratio 0.58, 95% confidence interval 0.52 to 0.66), Parkinson's disease (11.4 weeks; 0.57, 0.51 to 0.64), and SLE (6.3 weeks; 0.82, 0.73 to 0.91). However, A&G was not associated with a longer time to treatment or first attended outpatient appointment. An increase in primary care consultations following A&G was observed in patients later diagnosed with IBD and SLE. Conclusion: A&G was associated with a longer diagnostic interval than elective referral only. These findings do not establish that A&G caused diagnostic delay. A&G might be used at an earlier stage of more complex diagnostic pathways.

Objective. Triage of rheumatology outpatient referrals is a high-volume administrative task that consumes senior specialist time without advancing patient care. The human triage system is only moderately accurate and reproducible. We assessed whether contemporary large language models (LLMs) are able to perform well enough to support automating this task in practice. In addition, the effects of different prompting techniques on triage accuracy and cost was assessed to help identify to optimal approach. Methods. Twenty referral scenarios spanning the urgency spectrum, based on real referrals were created by a certified Australian rheumatologist. Four rheumatologists triaged all cases independently and blinded, to produce a consensus reference standard. Twenty-three LLMs each triaged every referral into one of five urgency categories, three times (1380 outputs per condition). The experiment was run with a simple prompt and repeated with a advanced prompt supplying explicit triage expectations and worked examples. Results. All 2760 attempts returned valid categories. Under the simple prompt, performance separated into distinct tiers, larger models were more accurate (Spearman rho=0.42; P=.047) and accuracy tracked cost. Advanced prompting minimised between-model variance in accuracy 5.3-fold (0.014 to 0.003; Levene P=.01), abolished the size-accuracy association (rho=-0.05; P=.83) and removed the accuracy-cost relationship. Leading models matched expert consensus on most cases, within or above the range reported for human triage. Under-triage errors persisted with some LLMs. Conclusion. Contemporary LLMs categorise rheumatology referral urgency as well or better than published human triage systems. Advanced LLM prompting methods substitute for the reasoning capability of larger models, suggesting that LLM performance on this task may not require the most expensive models. The tools to automate this administrative task appear to already exist. Strong candidate LLMs that might serve a production ready solution have been identified.

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.

Abstract Objective Our objective was to define the natural history of hyper IgE syndrome. Well, there have been a number of large cross-sectional studies. It has been difficult to provide anticipatory care for the growing adult population. Methods The USIDNET registry was used to identify patients with hyper IgE syndrome. We evaluated all patients regardless of genetic etiology. Complications were extracted as text from the problem list or ICD codes, and each complication was date stamped, which allowed us to estimate the age at which the complication arose. Results Many of the complications previously identified were seen in this cohort. The most feared complications were uncommon, however, developmental delay and psychosis affected nearly a fifth of the cohort which has not been previously reported. Conclusions As the number of adults with hyper IgE syndrome increases our awareness of late onset complications is important. Aspergillus and pneumatoceles were less common than seen in some other cohorts. However, the significant rate of psychosis will represent a significant challenge for clinicians.