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.

Importance: Avacopan is a small-molecule C5aR1 antagonist used as adjunctive treatment for granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Evidence of real-world clinical effectiveness and safety is limited. Objective: Compare effectiveness and describe safety outcomes of avacopan plus SoC versus SoC alone. Design: Retrospective U.S. cohort study with prevalent new-user design emulating sequential nested trials with up to 12-month follow-up. Index dates: first avacopan prescription (avacopan arm); first rituximab or cyclophosphamide claim (SoC arm) during trial window. Setting: Optum Market Clarity administrative claims (October 2015 - June 2025). Participants: Adults receiving rituximab or cyclophosphamide after newly diagnosed or relapsing GPA/MPA. Comparative effectiveness cohort: patients meeting baseline eligibility. Safety cohort: adults with an avacopan prescription, regardless of other eligibility. Interventions: Avacopan plus SoC vs SoC alone. Main Outcomes and Measures: Relapse, prednisone-equivalent daily dose (PEDD) [≤]7.5 mg, and serious hepatic event hospitalization were prespecified, whereas cumulative oral glucocorticoid exposure was analyzed post-hoc. A strict hepatic-event screen required [1] acute/subacute hepatic failure, central hemorrhagic liver necrosis, or toxic liver disease and [2] [≥]1 code indicative of severe acute liver injury on the same claim; a relaxed hepatic-event screen required either criterion. Standardized mortality ratio and censoring weights accounted for baseline covariates and informative censoring. Treatment effects in the avacopan-treated population were estimated. Results: The effectiveness analysis included 183 avacopan and 4096 SoC index dates. The safety cohort had 828 avacopan users. There were 38 events of relapse in the avacopan arm and 956 in the SoC arm (weighted hazard ratio [95% CI]: 0.81 [0.59, 1.13]). PEDD [≤]7.5 mg was numerically more common with avacopan plus SoC at most timepoints. Cumulative glucocorticoid exposure was lower with avacopan plus SoC; between-arm differences exceeded 500 mg from months 5 through 12. No avacopan-exposed patients met the strict hepatic event screen definition. Relaxed hepatic event screen events occurred in 2 (1.1%), 5 (0.6%), and 10 (0.5%) patients in the avacopan effectiveness, avacopan safety, and SoC cohorts, respectively. Conclusions and Relevance: Early evidence from claims data suggests avacopan plus SoC may reduce relapse risk and enable faster glucocorticoid tapering vs SoC alone. Serious hepatic events appear rare.

Background: Psoriatic arthritis (PsA) is an inflammatory condition involving joints, tendon-bone entheses and synovium that can develop in individuals with psoriasis. Early, accurate clinical diagnosis remains difficult. Extracellular vesicles (EVs) carry proteins and miRNAs that Methods: PubMed and Embase were searched from inception through May 21st, 2026, and human studies examining EV-associated protein or miRNA biomarkers in PsA and related psoriatic or inflammatory diseases were included, with risk of bias assessed using a modified Newcastle-Ottawa Scale and diagnostic accuracy summarized using HSROC/BRMA models when data were sufficient. Results: Seven studies met the inclusion criteria, including 119 individuals with PsA (weighted mean age: 49.8 years; 43.7% female), 205 individuals with non-PsA psoriasis (weighted mean age: 46.4 years; female %: NA), 55 controls (weighted mean age: 44.5 years; 38.2% female), and 50 individuals with other inflammatory joint disorders (weighted mean age: 58.0 years; 58.0% female). EV-associated protein markers demonstrated heterogeneous findings related to immune, vascular, inflammatory, and osteoimmunological signaling. Only 4.2% (4/95) of miRNAs were consistently identified across studies comparing PsA with non-PsA psoriasis, with lower overlap (1.5%, 1/67) in studies comparing PsA with controls. ROC meta-analysis suggested preliminary diagnostic potential, particularly for distinguishing PsA from non-PsA psoriasis, although evidence was constrained by small study numbers. Conclusions: EV-associated proteins and miRNAs are potential biomarker candidates for PsA, reflecting inflammatory, vascular, and osteoimmunological processes underlying disease pathophysiology. However, current evidence remains preliminary and limited by small cohorts, methodological heterogeneity, and inconsistent reporting across studies.

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: The efficacy and safety of avacopan in ANCA-associated vasculitis (AAV) has been established in randomized trials of of avacopan as a glucocorticoid (GC) sparing therapy. However, real world evidence (RWE) has an important role in confirming effectiveness and evaluating safety in more generalizable settings. This study aimed to synthesize RWE on the effectiveness and safety of avacopan in adults with AAV. Methods: A systematic literature review and meta analysis of non interventional real world studies was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Eligible studies included adults with AAV treated with avacopan in routine clinical practice. Pooled estimates of effectiveness and safety outcomes were calculated using random effects meta-analyses. Primary outcomes included remission at 6 and 12 months and sustained remission at 12 months. Secondary outcomes included relapse, GC use and dosing, hepatotoxicity, infections, and treatment discontinuation. Exploratory outcomes included changes in estimated glomerular filtration rate (eGFR) and dialysis related endpoints. Results: A total of 71 studies were included and contributed to quantitative analyses. Pooled remission for patients on avacopan was 87% (95% CI: 75%-94%) at 6 months and 93% (95% CI: 86%-97%) at 12 months, and sustained remission was 86% (95% CI: 74%-93%) at 12 months. Relapse at 12 months was low (7%; 95% CI: 4%-11%). GC use was 36% at both 6 and 12 months. Improvements in eGFR were observed at 6 months (18 mL/min/1.73 m2) and 12 months (18 mL/min/1.73 m2), and dialysis liberation was 66% in a limited subset. Among avacopan patients, 11% experienced any hepatotoxicity, including 7% with serious (defined as directly reported or requiring hospitalization) hepatotoxicity, while 7% experienced serious (defined as directly reported or requiring hospitalization) infection. Conclusions: In real world clinical practice, avacopan is associated with high remission rates, low relapse rates, and a consistent GC sparing effect, with effectiveness comparable to standard of care regimens. Findings support its clinical use with appropriate safety monitoring; however, the observed heterogeneity in hepatotoxicity and the limited comparative effectiveness evidence highlight areas requiring further investigation.

Background: Avacopan, an oral complement C5a receptor inhibitor, has been shown to help patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) achieve and sustain remission with reduced glucocorticoid exposure and associated toxicity. As of January 20, 2026, estimated global post-marketing exposure exceeded 25,000 patient-years. Hepatic adverse events (AEs), predominantly liver enzyme elevations observed during clinical development, remain an important post approval safety risk. Since approval, vanishing bile duct syndrome (VBDS), a rare but serious complication of drug induced liver injury (DILI) has been reported with avacopan use. This analysis evaluated Amgen's global safety database data to characterize hepatic adverse event reports associated with avacopan, including VBDS. Methods: We conducted a retrospective descriptive analysis of hepatic AEs recorded in the Amgen global safety database. Results: As of 20 January 2026, serious hepatic AEs were reported at approximately 31 events/1,000 patient-years. The majority of hepatic events comprised laboratory abnormalities that resolved following avacopan discontinuation. Thirty-one VBDS cases were reported and, of those, 27 originated from Japan. Fatal VBDS cases were reported predominantly from Japan and occurred in patients >65 years. Conclusions: Hepatotoxicity remains an important avacopan-specific safety risk. Post-marketing data indicate that most hepatic events are reversible laboratory abnormalities; however, serious liver injury and VBDS, including fatal outcomes, have been reported, predominantly from Japan. No new safety risks have emerged from the ongoing Japanese post-marketing study. Further investigation is warranted to understand potential mechanisms underlying the disproportionate occurrence of serious VBDS events in Japanese patients and inform optimized risk-mitigation strategies.

Objective: The onset of juvenile idiopathic arthritis (JIA) in the early years ([≤]5 years) may negatively impact movement skill (encompassing related concepts of gross motor skills, fundamental movement skills, and functional ability) development. Few studies have explored the perceptions and needs of parents and physiotherapists towards children's difficulty with these movement skills, essential to identify potential areas for added support. The objective of this study is to understand the perceptions of physiotherapists and parents towards movement skills of children with JIA. Methods: Seventeen parents and 24 physiotherapists completed an online questionnaire consisting of multiple choice and open-ended questions about the movement skills of young children with JIA. Demographic and multiple choice questions were quantitively analysed using descriptive statistics. Open-ended responses were analyzed using qualitative conventional content analysis. Results: About half (47%) of parents perceived their children to have movement difficulties, and 75% of physiotherapists described the movement skills of children with JIA as worse than other children of the same age. Our qualitative analysis revealed three general themes including: functional task difficulties; clinical variability in movement skills; and psychosocial components of movement skill difficulties. Conclusion: This study provides an analysis of perceptions of physiotherapists and parents towards the movement skills of young children with JIA. A significant proportion of parents and physiotherapists identify movement difficulties among children with JIA that impact daily life. Future interventions co-designed with both parents and care providers targeting movement skills are needed.

Psoriatic disease (PsD) is associated with metabolic dysfunction-associated steatotic liver disease (MASLD), but the hepatic effects of biologic therapies are unclear. We evaluated paired liver MRI and multi-modal immunoprofiling in PsD patients initiating new systemic therapy. COLIPSO is a prospective cohort of adults with moderate-to-severe psoriasis or psoriatic arthritis (PsA) starting a new conventional synthetic or biologic disease-modifying antirheumatic drug (DMARD). Liver MRI was performed at baseline and ~6 months. A subset of participants with PsA underwent peripheral blood flow cytometry and single-cell RNA sequencing (scRNAseq). Primary outcomes were within-subject change in quantitative MRI measures of liver disease activity and fat content (iron-corrected T1 [cT1] and proton density fat fraction [PDFF]). Bayesian models were used. Thirty-five participants (mean age 50 +/- 13 years; 61% male) were followed for ~29 weeks. Baseline disease activity was moderate (mean DAPSA 29) and 40% had MASLD. IL 17 inhibitors (IL-17i) improved PDFF (-1.58 +/- 1.61%) and cT1(-43.6 +/- 52.7ms), whereas TNFi showed little change. Compared with csDMARD, IL 17i improved PDFF (probability of direction [pd] 89%) and cT1 (pd 93%), which was not seen with TNFi. Flow cytometry (n=17) linked baseline gamma delta T-cell and ThGM-CSF T-cell abundance with cT1 and PDFF. scRNAseq highlighted baseline transcriptomic signatures in MAIT cells associated with cT1 and PDFF. Naive T-cell RNA signatures at baseline were associated with MRI improvements. In PsD, only IL-17i were associated with improved liver disease in addition to improving clinical PsD outcomes. T-cell subtypes bridging innate and adaptive immunity were associated with liver disease features.

Background: Anti-synthetase syndrome (ASyS) is a subgroup of idiopathic inflammatory myopathies that is increasingly recognized as a distinct entity with features of myositis, interstitial lung disease, inflammatory arthritis, and Raynaud phenomenon. Co-reactivity with anti-Ro-52, an antibody directed against the Ro-52 E3 ubiquitin ligase, has been shown to be associated with progressive interstitial lung disease within this patient population. However, less is known regarding the association of anti-Ro-52 positivity with cardiovascular outcomes. Methods: A sub-cohort of patients with anti-synthetase antibodies at a large single institution center was retrospectively analyzed to define presence of anti-Ro-52 positivity (defined as anti-Ro-52 titer greater than or equal to 11 utilizing the line immunoblot platform, Euroline Autoimmune Inflammatory Myopathies, EuroImmun Diagnostics, Lubeck, Germany). Patients who did not meet 2017 ACR/EULAR classification criteria for idiopathic inflammatory myopathies were excluded from the final analysis. Cardiovascular outcomes ascertained via retrospective chart review included atrial fibrillation, left bundle branch block, right bundle branch block, pulmonary hypertension (confirmed via right heart catheterization), heart failure with reduced ejection fraction (HFrEF, defined as ejection fraction less than or equal to 40 percent), acute coronary syndrome (based on clinical diagnosis and angiography if available), and myocarditis (based on clinician diagnosis and either cardiac MRI or troponin elevation). When a pre-specified cardiac outcome was identified, the date of onset was recorded. Differences in proportions were analyzed via Chi-squared and Fishers exact tests, and time-to-event analyses were performed via Cox Proportional Hazards Models, incorporating a false discovery rate correction for multiple outcomes. All analyses were performed using SAS v9.4. Results: 88 patients were included in the final analysis, of whom 69 (78.4 percent) were categorized as anti-Ro-52 positive. Patients with anti-Ro-52 positivity had a higher maximum recorded serum creatine kinase (median 1297 vs 395 units per liter, p = 0.042). No significant associations between anti-Ro-52 positivity and the pre-defined cardiovascular outcomes were found over median follow up time of 12.5 years. Conclusions: In a large, single-center cohort of patients with ASyS, anti-Ro-52 positivity was not associated with an increased burden of negative cardiovascular outcomes, including the onset of pulmonary hypertension. Future studies may seek to further elucidate the mechanisms underlying the pleiotropic effects of anti-Ro-52 antibodies on the cardiopulmonary system.

Background Pain frequently persists in rheumatoid arthritis (RA), despite effective control of inflammation. The mechanisms driving this residual pain remain poorly characterised in individual patients. Methods In 172 patients with established RA and clinically relevant pain (mean NRS 6.5/10) and 80 pain free controls, we combined indicators of inflammatory disease (CRP, joint counts, power Doppler ultrasound), centrally mediated pain (Widespread Pain Index, painDETECT), psychological distress (PHQ ADS) and quantitative sensory testing (QST). Latent profile analysis was applied without predefined thresholds. Results Four phenotypes were identified: a peripheral, low-inflammation/low-central phenotype (38%); a predominantly inflammatory phenotype (7%); and moderate (43%) and severe (12%) centrally mediated phenotypes. Centrally mediated phenotypes reported the highest pain (NRS 8.2), worst disease impact and lowest employment. DAS28 CRP was similar in both the inflammatory and severe centrally mediated phenotypes but for different reasons, swollen joints and CRP versus tender joints , and did not distinguish them. Conditioned pain modulation was impaired relative to controls (p<0.001) and most reduced in the severe centrally mediated phenotype. Psychological distress was the strongest independent predictor of pain severity (model R squared=0.33), whereas inflammatory markers were not. Principal components analysis identified swollen joint count (loading 0.63) and the tender swollen joint difference (loading 0.60) as accessible clinical markers of the inflammatory and centrally mediated phenotypes respectively. Conclusions A data driven approach identified four mechanism-based pain phenotypes in RA. This framework moves pain assessment beyond inflammation alone and provides a basis for testing analgesic strategies to target the predominant pain mechanism in individual patients.

Background Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which can lead to progressive disability and damage to multiple organs. Obesity is associated with higher disease activity in RA and inadequate long-term outcomes, so better understanding of mechanisms linking adiposity to immune dysregulation might help to refine optimal treatments. Monocytes are important contributors to immune activation in RA through antigen presentation and costimulatory signaling. We hypothesized that adiposity enhances monocyte costimulatory programming in RA, thereby promoting adaptive immune activation. Methods Single-cell RNA sequencing was performed using the 10x Genomics Flex platform on purified circulating monocytes from 31 donors (16 RA participants fulfilling 2010 ACR/EULAR classification criteria and 15 non-RA controls) generating transcriptomic profiles for approximately 135,599 monocytes. Donor-level pathway enrichment scores were calculated for predefined immune activation pathways including antigen processing and presentation, interferon signaling, and regulation of T-cell costimulation. Analyses were performed at the donor level to avoid cell-level pseudoreplication. Associations with disease status and body mass index were evaluated using factorial linear models and Spearman correlation analyses. Results Single-cell transcriptomic profiling identified classical, intermediate-like, non-classical, and interferon-responsive monocyte populations. RA was associated with enrichment of antigen processing and presentation programs in circulating monocytes (p=0.0106), indicating a primed antigen-presenting state. In contrast, regulation of T-cell costimulation pathway enrichment did not differ by RA status alone. However, within RA participants, higher BMI was associated with increased enrichment of monocyte T-cell costimulatory pathways (Spearman {rho}=0.56, p=0.0248), unlike in non-RA controls. Gene-level analyses demonstrated strong baseline expression of CD86, while ICOSLG and TNFSF4 transcripts were expressed at low levels overall, consistent with inducible costimulatory signaling programs. Conclusions These findings support a model in which metabolic dysregulation amplifies monocyte-mediated immune activation and may contribute to worsened disease outcomes in RA.

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.

DREAM is a randomised, superiority, parallel-group, placebo-controlled, participant, clinician, and assessor blinded trial with an adaptive group sequential design that allows early stopping for efficacy or futility. The purpose is to investigate whether taking 60 mg of duloxetine daily for 12 weeks in addition to guideline-recommended advice, compared with placebo in addition to guideline-recommended advice, can reduce leg pain intensity in individuals with chronic sciatica. The primary outcome is leg pain intensity measured on a 0-10 numerical pain rating scale. It will be analysed using a repeated-measures linear mixed model. This statistical analysis plan pre-specifies the methods of analysis to be used in the interim analysis and the final analysis for the outcomes and key variables collected in the trial. It includes planned sensitivity analyses for the final analysis, including covariate adjustments and subgroup analyses, as well as the health economics analysis plan.

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.

Hematopoietic stem and progenitor cells (HSPCs) sustain the production of hundreds of billions of new cells per day to maintain our blood and immune system. In this process, HSPCs regulate the hematopoietic output by sensing and integrating diverse physiological cues. Thus, HSPCs express many receptors traditionally studied for their functions in the immune system, and this allows HSPCs to directly detect microbial compounds, endogenous danger signals, cytokines, and other inflammatory mediators. However, how the expression levels of such receptors on HSPCs change under chronic inflammation and how such changes alter HSPC functions and immune cell production remains unexplored. Working in a murine model of rheumatoid arthritis, we demonstrate the induction of microbial sensors TLR2 and CD14, orphan inflammatory receptor TREM1, and checkpoint receptor PD-L1 on HSPCs and particularly the myeloid progenitor cells in the arthritis-afflicted mice. Furthermore, we demonstrate that the stimulation of HSPCs through these receptors in culture can significantly alter the dynamics of cell expansion and differentiation, with distinct responses from HSPCs of arthritis-afflicted versus healthy control mice. We hypothesize that the induction and stimulation of HSPCs through these immune receptors under chronic inflammation may impact the output and functional properties of their immune cell progeny, positing HSPCs as central players in the pathogenic inflammatory responses of rheumatoid arthritis and potentially other chronic inflammatory diseases. HIGHLIGHTSO_LIHematopoietic progenitor cells in murine models of rheumatoid arthritis show an upregulation of immune receptors TREM1, PD-L1, TLR2, and CD14. C_LIO_LIStimulation of murine hematopoietic stem and progenitor cells through these receptors in culture alters the dynamics of their expansion and differentiation. C_LIO_LIIn such cultures, hematopoietic stem and progenitor cells from mice afflicted with rheumatoid arthritis show altered responses to stimulation as compared to healthy controls. C_LI