The Lancet Rheumatology

BackgroundJuvenile idiopathic arthritis (JIA) shows recognised sex differences, but their impact on treatment and early outcomes remains uncertain. This study assesses sex-specific patterns in onset, phenotype, treatment timing, and short- and medium-term outcomes in JIA. MethodsData were drawn from the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort of 1,789 children presenting with a new episode of arthritis. Demographics, subtype distribution, clinical features, and 6- and 12-month outcomes were stratified by sex. Cox, Kaplan-Meier, and linear regression models assessed associations between sex and treatment initiation and 12-month outcomes. ResultsThe cohort was predominantly female (64.3%), with a median age at symptom onset of 6.8 years. Girls were younger than boys at onset (6.1 vs 7.8 years, p<0.0001) and diagnosis (7.0 vs 9.1 years, p<0.0001) and demonstrated a distinct bimodal age distribution. Diagnostic delay was short and comparable (median 4.4 months, p=0.8932). At diagnosis, girls had slightly higher active joint counts (p=0.0080, while inflammatory markers were similar except in psoriatic JIA, where females had higher ESR and CRP. After adjustment, sex was not associated with time to methotrexate (HR 0.89, 95% CI 0.74-1.06) or biologic initiation (HR 0.91, 95% CI 0.72-1.16). Outcomes at 6- and 12-month were largely comparable, with only ESR showing a modest male-favoured improvement at 12 months (p=0.0480). ConclusionsSex shaped age at onset and subtype distribution but did not independently influence treatment timing or early outcomes, underscoring the value of sex-aware analyses while confirming broadly comparable short-term trajectories in JIA. Evidence before this studyRecent evidence on sex effects in JIA is genuinely mixed: several cohorts have reported that girls, despite more severe onset, show greater resolution of objective inflammation, while a newer, large network analysis found females had poorer outcomes across composite disease activity and pain, pointing to potential inequities or phenotype-driven differences. In parallel, boys, especially in enthesitis-related arthritis (ERA), often exhibit more persistent activity and risk of damage. Overall, the picture is controversial: sex appears to shape biology, trajectory, and patient-reported burden in different ways across subtypes and settings, reinforcing the need for sex-stratified analyses, careful adjustment for confounders, and precision approaches that integrate biomarkers, subtype, and social context in JIA care. Added value of this studyThe study establishes that, although sex is closely linked to JIA subtype distribution and baseline clinical features, it does not independently determine the timing of methotrexate or biologic initiation within a UK inception cohort. By analysing one of Europes largest prospective multicentre datasets, it provides strong evidence that treatment decisions appear to be guided by disease characteristics rather than demographic bias. Within the context of the UK National Health Service (NHS), where universal access to paediatric rheumatology care is a core principle, this study provides important epidemiological evidence on sex and equity in JIA. Although clear sex differences were observed in age at onset, subtype distribution, and certain diagnostic features, these did not translate into disparities in treatment timing or medium-term disease burden. The absence of sex-based differences in 6 and 12-month outcomes, despite variation in baseline presentation, suggests that the NHS model of coordinated, guideline-driven care may help buffer against inequities that might otherwise emerge in systems with variable access. These findings reinforce the value of population-based cohorts in evaluating equity within healthcare delivery and highlight that, in this setting, sex does not appear to drive differential treatment or short-term clinical trajectories. Implications of all the available evidence.This study underscores sex as an important biological variable in JIA. Although treatment initiation was equitable and disease-driven, baseline phenotype differences and isolated effects on 12-month outcomes highlight how sex interacts with JIA subtype and initial disease burden. Prior work shows that females often present earlier with higher inflammatory burden, while males are more frequently affected by ERA, a subtype linked to treatment resistance and poorer long-term outcomes. Yet published findings remain inconsistent, with some cohorts reporting better resolution of inflammation in females and others suggesting poorer outcomes. Our findings suggest that coordinated and guideline-driven care may minimise sex-related disparities in JIA, even when underlying biological or phenotypic differences exist. The comparable medium-term trajectories observed across sexes support equitable paediatric rheumatology care in the UK and highlight the need to continue monitoring for structural or access-related inequities beyond clinical measures.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes joint destruction along with extra-articular morbidity and early mortality. Abatacept (CTLA-4 Ig), a blocker of lymphocyte co-stimulation, has become a well-accepted biologic treatment with proven efficacy in established-RA and for preventing disease onset in predisposed individuals. To investigate the immunologic implications of abatacept treatment, we conducted a prospective, open-label trial with multi-omic single-cell analyses of lymphocytes and BCR repertoire profiling at predefined intervals. Treatment-induced low-disease activity correlated with coordinated depletion of circulating peripheral helper cells (Tph), late-activated naive cells (late-aNAV), and of CD27-IgD- (Double negative, DN) Zeb2+CD11c+ T-box transcription factor 21 (Tbet+) DN2 unconventional memory B cells, implicated in the tertiary lymphoid structures responsible for the propagation of pathologic autoimmune responses and joint destruction. Among B-cell subsets, DN2 had the greatest representation of molecular machinery for antigen-uptake, processing, and presentation. Among memory B-cell subsets, DN2 had the lowest representation of somatically generated N-glycosylation sites and somatic hypermutation. Yet abatacept induced DN2 cells to express elevated CXCR4 levels, which normalized upon drug withdrawal, suggesting that abatacept treatment may cause these cells to traffic out of pathologic synovial infiltrates. In conclusion, we have documented that abatacept affects the circulating immune cellular drivers of disease activity, Tph, late-aNAV and DN2. Therapeutic depletion of these pathologic lymphocyte subsets is associated with clinical benefits that can persist after therapy cessation. Hence, levels of these subsets may serve as surrogates for the overall burden of disease and potential response to abatacept therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/26348386v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@b44131org.highwire.dtl.DTLVardef@241f4eorg.highwire.dtl.DTLVardef@18361f6org.highwire.dtl.DTLVardef@9470b7_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryMulti-omics analyses showed costimulatory blockade depletes trafficking DN2 B cells and Tph cells that correlates with rheumatoid disease response.

ObjectivesRheumatoid arthritis (RA) exhibits clinical and biological heterogeneity, with synovial tissue stratified into histological pathotypes: lympho-myeloid, diffuse-myeloid, and pauci-immune fibroid. Although GWAS have uncovered RA risk loci, how genetic risk relates to synovial immunopathology remains unclear. To better understand how genetic predisposition may shape divergent early disease mechanisms, we characterised the expression patterns of GWAS-identified RA susceptibility genes and related rheumatic diseases across the synovial pathotypes. MethodsRNA-sequencing data from synovium of 87 treatment-naive, early RA patients from the Pathobiology of Early Arthritis Cohort. Differential gene expression between pathotypes and pathway enrichment analyses were performed using susceptibility genes for RA, osteoarthritis (OA), ankylosing spondylitis, psoriatic arthritis and systemic lupus erythematosus. ResultsRA susceptibility gene expression in synovial tissue separated patients by pathotype and correlated with markers of disease activity. RA susceptibility genes were significantly enriched among genes upregulated in lympho-myeloid synovium and linked to lymphocyte activation and differentiation pathways. In contrast, OA susceptibility genes were upregulated in diffuse-myeloid and fibroid synovium. Both patterns were most pronounced in ACPA-positive and directionally consistent in ACPA-negative patients. ConclusionRA genetic susceptibility is not evenly distributed across synovial pathotypes but is strongly biased toward the lympho-myeloid pathotype, indicating that current GWAS signals preferentially capture immune-driven disease mechanisms. Enrichment of OA susceptibility genes in diffuse-myeloid and fibroid pathotypes, even among ACPA-positive patients, suggests shared biological features between auto-immune and non-inflammatory degenerative joint diseases in certain RA subtypes. Synovial pathotype stratification is therefore essential for interpreting genetic risk and understanding disease heterogeneity. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABS- Rheumatoid arthritis (RA) is clinically and biologically heterogeneous, and its affected synovial tissue can be stratified into distinct immunohistological pathotypes. - GWAS have identified numerous genetic risk loci for RA and related rheumatic and inflammatory diseases. - It remains poorly understood how RA genetic risk relates to synovial tissue heterogeneity. What this study adds- GWAS-identified RA susceptibility genes show strong, pathotype-specific expression in synovial tissue, with marked enrichment in the lympho-myeloid pathotype. - OA susceptibility genes are primarily upregulated in diffuse-myeloid and pauci-immune fibroid RA synovium, indicating shared fibroblast- and remodelling-related pathways. - These gene expression patterns are most pronounced in ACPA-positive RA but remain directionally consistent in ACPA-negative RA. How this study might affect research, practice or policy- Synovial pathotype stratification should be incorporated into genetic studies of RA. - Pathotype-aware genetic studies may improve patient stratification and guide development of more targeted therapeutic strategies.

BackgroundDespite advances in therapy, optimal management of juvenile idiopathic arthritis (JIA) remains challenging. The ability to predict disease progression in JIA can improve personalized treatment decisions, but few reliable clinical predictors have been identified. We developed machine learning approaches to predict disease trajectories in children with JIA. MethodsUsing data from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry (years 2015-2024), we developed machine learning models to predict attainment of inactive disease in children with non-systemic JIA. We applied Dynamic Bayesian Networks (DBN) to model temporal dependencies and causal relationships, and Convolutional Neural Networks (CNN) to capture complex non-linear patterns. Model input included demographic factors, longitudinal clinical factors, and medication use in the preceding 12 months. FindingsA total of 8,093 participants were included. When tested on an independent test cohort, both DBN (AUC:0.76; precision:0.73; recall:0.83; F1-score:0.78; accuracy:0.71) and CNN (AUC:0.76; precision:0.71; recall:0.63; F1-score:0.67; accuracy:0.70) models achieved comparable performance in predicting inactive disease. Disease activity levels in the preceding 12 months, presence of enthesitis and uveitis were the strongest predictors. Causal relationships captured in the DBN model revealed suboptimal care patterns, likely shaped by insurance constraints and a predominantly reactive approach to JIA management. InterpretationOur study demonstrates that machine learning approaches can predict disease trajectories in JIA with good discriminative performance. Unlike prior studies that predict outcomes at single timepoints, our models are the first to predict inactive disease longitudinally. However, suboptimal care patterns in retrospective data limit models capacity to learn treatment-outcome relationships, underscoring critical opportunities to improve JIA care and the need for prospective comparative studies to better inform prediction models. FundingPatient-Centered Outcomes Research Institute (PCORI) Award (ME-2022C2-25573-IC). RESEARCH IN CONTEXT Evidence before this studyNumerous studies have sought to identify clinical predictors of JIA progression and outcomes. However, few reliable predictors have emerged and existing prediction models demonstrate limited performance. As a result, our ability to personalize treatment decisions based on individual risk of severe disease course remains limited. Added value of this studyWe developed novel machine learning models that predict individualized disease trajectories in children with polyarticular and oligoarticular JIA using data from their preceding 12-month clinical course. These models demonstrated strong discriminative performance and outperformed previously published machine learning approaches in JIA. Unlike prior studies limited to single time-point predictions, our models are the first to predict inactive disease longitudinally, enabling a patient-specific projection of disease progression over time. Importantly, our findings also bright to light patterns of suboptimal care, likely driven by insurance constraints and a reactive treatment paradigm, underscoring critical opportunities to improve JIA management. Implications of all the available evidenceOur models have the potential to support clinical decision-making by enabling early identification of children with JIA at risk for unfavorable disease trajectories. In addition, the suboptimal care patterns and systems-level barriers identified through our analyses highlight priority areas for quality improvement initiatives and policy interventions to reduce gaps in JIA care delivery.

Individuals who have serum elevations of anti-cyclic citrullinated protein (anti-CCP) antibodies are at risk for developing rheumatoid arthritis (RA), yet immunologic factors that lead to a transition from pre- to clinical RA remain unclear. Here, we used materials from anti-CCP antibody-positive individuals enrolled in a clinical trial that evaluated the efficacy of hydroxychloroquine to prevent clinical RA, and performed multi-modal single-cell profiling (transcriptome, surface proteins, T/B-cell receptor sequencing, and chromatin accessibility) on samples obtained at baseline and at RA onset in those who developed clinical RA (Converters) or follow-up point in matched Nonconverters. At both baseline and follow-up, Converters had expansions of peripheral helper T (Tph) cells and CD8+ T cells expressing GZMK and GZMB, along with elevated potentially autoreactive T-cell receptors in CD4+ T cells compared to Nonconverters. Induction of age-associated B cell signatures was observed in B cells of Converters prior to RA onset. Epigenetic profiling further identified chromatin accessibility changes in Converters over time, particularly within myeloid and NK cells. Lastly, predictive modeling using baseline immune features, including Tph cells, GZMK+XCL1+ CD8+, and GZMB+CD57+ CD8+ T cells, together with clinical features such as anti-CCP3 levels, RF-positivity, and HLA shared epitope status, stratified RA risk and predicted time to onset. These findings define immune endotypes in pre-RA that could serve as targets for future preventive interventions and be used to stratify the risk of developing clinical RA in anti-CCP antibody-positive individuals.

Rheumatoid arthritis is a prototypical autoimmune disease, characterised by prolonged systemic autoimmunity prior to organ-specific tissue inflammation. To achieve the contemporary goal of autoimmune disease prevention, a nuanced understanding of the transition from systemic autoimmunity to tissue-specific inflammation is critical. Here, we sought to identify immune signatures associated with the transition to subclinical joint inflammation detected by multi-joint ultrasound in anti-citrullinated protein antibodies (ACPA+)-positive individuals who imminently progress to RA. To achieve this, we performed single-cell transcriptomic and proteomic profiling on prospectively collected blood samples from high-risk ACPA+ imminent progressors, who were further stratified by the presence or absence of ultrasound (US)-detectable subclinical synovitis and compared them with ACPA+ non-progressors. We found type-1 interferon (IFN-I) activation in circulating CD14+ classical monocyte and GZMK+ CD8+ T cells preceding subclinical joint inflammation in ultrasound-negative (USneg) future progressors. In contrast, US-positive (USpos) future progressors exhibited a phenotypic shift in CD14+ classical monocytes towards IL1B+ expression and clonal expansion of GZMB+ cytotoxic CD8+ T cells at the onset of subclinical synovitis. Plasma proteomics also revealed a shift from Toll-like receptor-associated innate pathways in USneg future progressors toward effector and tissue-remodeling signatures in USpos future progressors. These findings suggest IFN-I-driven immune priming in specific immune subsets precedes the onset of subclinical joint inflammation, whereas tissue-directed inflammatory and cytotoxic programmes emerge at the onset of joint inflammation when clinical RA is imminent.

ObjectivesResearch of refractory disease in juvenile idiopathic arthritis (JIA) is limited, and a potential genetic contribution has yet to be investigated. This study aimed to explore the presence of rare monogenic disease gene coding variants in a refractory JIA population. MethodsCases were included with a record of inefficacy for methotrexate and [&ge;]1 biologic drug or exposure to methotrexate and [&ge;]2 biologic drugs for any reason. Whole exome sequencing data were analysed using VarSeq. rarity and pathogenicity filters were applied. Variants within an OMIM curated paediatric monogenic gene list, arthritis OMIM gene list, primary immunodeficiency gene panel (PanelApp) or gene reported for JIA drug response or toxicity (ClinPGX) were retained. ACMG classification excluded benign or likely benign variants. ResultsIn total, 83 individuals were included. Twelve variants were previously reported in other paediatric onset diseases with similar phenotypes to JIA. Seventeen variants were detected in twelve genes with an arthritis OMIM phenotype. Seventeen variants were detected within fourteen genes that were reported on the primary immunodeficiency panel (PanelApp) and were previously reported in a publication. A total of 39 variants were detected in genes from a JIA drug response or toxicity gene list (ClinPGX). ConclusionsThis study evidences that 66 individuals with refractory JIA carry rare variants associated with paediatric diseases, JIA susceptibility loci or drug response and toxicity. These variants could contribute to refractory disease, mimics of JIA/complicated phenotypes or effect treatment response. Longitudinal data are needed to confirm these findings.

Background: immune dysregulation underlies cardiovascular risk excess in systemic autoimmune diseases, such as rheumatoid arthritis (RA) and Sjogren disease (SjD). However, exact mediators are unknown. Regulatory autoantibodies targeting G protein coupled receptors, including CXCR3, have emerged as modulators of immune and vascular homeostasis, but their role in autoimmunity remains ill defined. Our aim was to evaluate antiCXCR3 levels in systemic autoimmunity and their potential value as biomarkers. Methods: antiCXCR3 IgG serum levels were quantified in early RA (n=84), clinically suspect arthralgia (n=12), and controls (n=65). Established RA (n=103) and SjD (n=44) were recruited for validation. Atherosclerosis was assessed by carotid ultrasound. Cytokines were measured by multiplex immunoassays. Cardiometabolic related proteins were evaluated using high-throughput targeted proteomics. Publicly available datasets were used for validation. Results: antiCXCR3 antibodies were significantly reduced in early RA and arthralgia compared with controls, independently of disease activity, autoantibodies, or systemic inflammation. This finding was confirmed in validation cohorts. AntiCXCR3 were negatively associated with good therapeutic outcomes upon csDMARD at 6 and 12 months. Lower anti-CXCR3 levels were independently associated with atherosclerosis occurrence and extent across conditions. Incorporating antiCXCR3 into mSCORE improved risk stratification. AntiCXCR3 were related to proteomic signatures linked to immune activation and to apoptosis, chemotaxis, and cell adhesion in an atherosclerosis dependent manner. Transcriptomic analyses indicated compartment specific CXCR3 dysregulation. Conclusion: reduced antiCXCR3 antibodies represent a shared hallmark bridging systemic autoimmunity and atherosclerosis burden, shaping our understanding on the regulatory role of antibodies at the vascular immune interface. Clinical translation of anti-CXCR3 antibodies hold promise to improve risk stratification.

Systemic autoimmune rheumatic diseases (SARDs) are a heterogeneous group of autoimmune conditions characterized by immune system dysregulation leading to chronic inflammation and tissue damage. The overlapping clinical manifestations make differential diagnosis challenging, highlighting the need for novel biomarkers to facilitate early diagnosis, stratification, and personalized treatment. Five SARDs including idiopathic inflammatory myopathies (n=210), rheumatoid arthritis (n=84), systemic sclerosis (n=100), Sjogren disease (n=99), and systemic lupus erythematosus (n=99), as well as healthy controls (n=400) and controls with acute infectious diseases (n=218) were selected for plasma protein profiling using Olink Explore 1536. Proteins with known association to SARDs as well as novel associations were identified through differential abundance analysis and machine learning. This explorative cross-sectional study demonstrates the importance of a pan-disease approach to biomarker identification within and between the five SARDs. NPX boxplots from this study are available open-access through the Human Protein Atlas, facilitating further plasma-proteome research on autoimmune diseases.

ObjectiveIdentifying risk factors enables stratification of patients susceptibility to inflammatory arthritis immune-related adverse events (IA-irAE). This retrospective study examines whether preexisting osteoarthritis (OA) increases the likelihood of de novo IA in patients treated with immune checkpoint inhibitors (ICIs). MethodsThe prevalence of OA among ICI-treated patients who developed IA-irAE, those who developed other types of irAEs but not IA (non-IA irAE), and those who did not develop any irAEs (non-irAE) were compared. Electronic medical records were reviewed to extract demographic, clinical and laboratory data. Group comparisons and logistic regression analyses were performed. Results181 de novo IA-irAE patients, 140 non-IA irAE patients and 170 non-irAE patients were included. The prevalence of OA was significantly higher in the IA-irAE group (69%) than the non-IA irAE group (48%) and the non-irAE group (48%) (both p < 0.001). The IA-irAE group demonstrated a higher frequency of multisite OA, with predominant hand involvement (62%) than the non-IA irAE with OA group (13%) and the non-irAE with OA group (13%) (both p < 0.001). A family history of autoimmune disease (AID) (OR 2.03, 95% CI 1.02-4.05), preexisting OA (OR 2.88, 95% CI 1.85-4.52) and melanoma (OR 2.63, 95% CI 1.56-4.47) were identified as risk factors for the development of IA-irAE. ConclusionsOA was more prevalent among ICI-treated patients developing IA-irAE than those who did not. Hand OA was the most common OA pattern in IA-irAE patients. Preexisting OA, melanoma and a family history of AID were risk factors for IA-irAE.

ObjectivesPatients with Systemic lupus erythematosus (SLE) who carry a high genetic burden often experience more severe disease. To understand the molecular consequences of polygenic risk, we analyzed single-cell gene expression profiles in SLE patients stratified by genetic risk. MethodsSingle-cell RNA sequencing (scRNA-seq) was performed on fresh peripheral blood mononuclear cells (PBMCs) from 16 female SLE patients, stratified by a weighted polygenic risk score (PRS), and 6 healthy controls (HCs). All patients were in low disease activity (LLDAS) and treated with antimalarials only. We assessed differential gene expression, interferon (IFN) signatures, transcription factor (TF) activity, and pathway enrichment across groups. ResultsPatients with High-PRS had significantly elevated IFN scores compared to HCs (p<0.001), whereas no significant difference was observed between Low-PRS patients and HCs (p>0.05) This pattern held across multiple immune cell types, including T cells, NK cells, and monocytes. Notable genes with increased expression in High-PRS patients included ISG15 and USP18 in plasmacytoid dendritic cells (pDCs), and IFI27 and RSAD2 in monocytes. IFN-related pathways were enriched in pDCs and monocytes in High-PRS patients, and only in monocytes in Low-PRS patients. TF analysis identified IRF7 and BATF3 as key candidate regulators in High-PRS of both cell types. ConclusionsHigh polygenic risk in SLE is associated with persistent activation of IFN signaling pathways, indicating that antimalarial treatment alone is insufficient to fully suppress IFN activity, even during remission or low disease activity.

Patients with myasthenia gravis (MG) may produce autoantibodies neutralizing type I interferons (AAN-I-IFN), which have been shown to underlie severe viral diseases, including critical COVID-19 pneumonia, in patients without MG. We studied an international cohort of 85 unvaccinated SARS-CoV-2-infected MG patients with no antiviral treatment. Hypoxemic pneumonia occurred in 48 of these patients, including 22 (45.8%) with AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in 14 (29.2%) patients. Six (16.2%) of the remaining 37 patients had AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in three patients. The risk of hypoxemic pneumonia was greater in MG patients with AAN-I-IFN neutralizing 10 ng/mL of both IFN-2 and IFN-{omega} (odds ratio and 95% confidence interval (OR [95% CI]): 12.7 [2.1-78.9], p=0. 0010) or IFN-2 at any dose (4.7 [1.5-15.0], p=0.0054) than in those without such autoantibodies. The risk of AAN-I-IFN production was much higher in MG patients than in the general population (28.9 [10.8-77.7], p=4.9x10-27). Fourteen patients had thymoma, which increased the risk of AAN-I-IFN (64% versus 27%, (OR [95% CI]: 5.6 [1.6-19.4], p=0.0050) and hypoxemic pneumonia (9.2 [1.9-44.2]; p=0.0019). Thymoma is, thus, associated with a higher risk of producing AAN-I-IFN, and these autoantibodies are associated with a higher risk of developing life-threatening COVID-19 pneumonia in patients with MG.

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease characterized by metabolic dysregulation, including altered lipid metabolism. While polyunsaturated fatty acids have been studied, the plasma levels, endogenous synthesis, and relevance of monounsaturated fatty acids (MUFAs) in RA remain unclear. This study examined plasma MUFA levels in RA and their associations with disease activity, adiposity, and intake. MethodsIn this cross-sectional study, 59 individuals with rheumatoid arthritis (RA) and 33 non-RA controls frequency-matched on age, sex, and BMI were recruited between 2017 and 2022. Clinical assessments included disease activity (DAS28), body composition, and metabolic parameters. Dietary intake was assessed using a 4-day food journal, and plasma fatty acids were quantified by gas chromatography in 82 participants with available samples. The stearoyl-CoA desaturase-1 (SCD-1) index was used as a proxy for endogenous MUFA synthesis. Associations between MUFAs and clinical variables were evaluated using univariate and multivariable regression (p<0.05). ResultsRA participants had higher waist-to-hip ratio, fat mass, fasting triglycerides, and lower physical activity than controls. Plasma palmitoleic and oleic acids and the SCD-1 index were higher in RA, whereas linoleic and arachidonic acids were lower. Saturated and omega-3 fatty acids were similar. Higher oleic and gondoic acids were independently associated with greater disease activity; oleic acid was linked to central adiposity, and palmitoleic acid was higher in women, suggesting sex- and adiposity-specific regulation. ConclusionsHigher plasma MUFAs in RA are associated with disease activity, adiposity, and sex, highlighting altered MUFA metabolism as a feature of RA and a potential target for metabolic intervention. Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSRheumatoid arthritis (RA) involves systemic inflammation and altered lipid metabolism. While polyunsaturated fatty acids have been studied extensively, the plasma levels, endogenous synthesis, and clinical relevance of monounsaturated fatty acids (MUFAs) in RA remain unclear. What this study addsPatients with RA have higher plasma MUFAs, including oleic and palmitoleic acids, and an elevated SCD-1 index, a marker of endogenous MUFA synthesis. Higher MUFAs are associated with disease activity, central adiposity, and sex-specific patterns, independent of dietary intake. How this study might affect research, practice or policyPlasma MUFAs could serve as potential biomarkers of RA disease activity and metabolic dysregulation. These findings suggest that altered MUFA metabolism contributes to inflammatory pathways, highlighting a potential target for future research, nutritional interventions, or therapeutic strategies.

Objectives: Juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM) are systemic autoimmune rheumatic diseases (RMDs) with childhood-onset associated with increased risk of damage accumulation and cardiovascular disease (CVD) over the life course. Methods: Damage associated with JSLE and JDM has been assessed using validated outcome measures in a longitudinal single-centre cohort study with long-term follow-up, involving data collected both retrospectively and prospectively. Descriptive statistics, sensitivity and regression analyses have been used to evaluate predictors of damage and CVD-risk. Results: We assessed comparatively a JSLE cohort (n=76), with a mean age of 24.3 +/- 4.2 years and a JDM cohort (n=79) with a mean 20.1 +/-5.0 years (p<0.001), with matched duration of follow-up (10.0 +/- 4.2 vs. 11.0 +/- 5.1, respectively, p=0.68). Traditional CVD-risk factors, including hypertension (p=0.02), dyslipidaemia (p=0.0005), and higher total cholesterol (p=0.01) and LDL-cholesterol (p=0.02) levels at the last assessment were higher in JSLE vs. JDM. Over the disease course, 39 (51.3%) AYA with JSLE vs. 47 (59.4%) AYA with JDM accumulated damage (p=0.307), which was independently predicted by the body mass index in both cohorts (p=0.038 and p=0.026, respectively). The PDAY score was the only tool able to stratify AYA based on CVD-risk (median = 5 (4-13) points in JSLE vs. 0 (0-3) points in JDM, p=0.0001), as all the adult CVD-risk scores were very low in both cohorts. Conclusions: This is the first comparative evaluation of JSLE vs. JDM in adulthood, which highlighted increased damage burden and CVD-risk in JSLE that warrants further investigation.

ObjectivesPatients with osteoarthritis (OA) affecting multiple joints have poorer health outcomes than those without, yet most research examines isolated joints, leaving a gap in multi-joint disease. This study aimed to describe radiographically defined hip (rHOA) and knee OA (rKOA) within UK Biobank (UKB), exploring interrelationships across joints, and associations with joint pain, obesity, race and deprivation. MethodsAutomated machine learning was applied to left and right hip and knee dual-energy X-ray absorptiometry scans. Radiographic OA (rOA) was defined as custom grades [&ge;]2. Joint pain was assessed through self-reported questionnaires. Descriptive statistics summarised the population characteristics. Logistic regression models examined bilateral and cross-joint associations, as well as associations with joint pain. Adjustments were made for age, sex, race, height, weight and deprivation. Other models examined the associations between body size and OA. ResultsAmong 59,475 individuals (mean age 65 years; 52.8% female), rHOA prevalence was 4,098 (6.9%)) and 4,841 (8.1%) for the right and left joints, respectively. The corresponding estimates for rKOA were 3,750 (6.3%) and 4,220 (7.1%). Overall, increasing grades of rOA and number of joints affected were more strongly associated with joint pain. Regarding joint-interrelationships, bilateral associations were stronger at the knee, whereas cross-joint associations (hip-knee) were weaker. Associations with BMI and height differed between the hip and knee. ConclusionsRadiographic hip and knee OA exhibit distinct patterns of interrelationship, associations with symptoms and risk factors, suggesting heterogeneity in disease process and the need for joint-specific treatment. Key MessagesO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LIOsteoarthritis (OA) commonly affects the hip and knee and is associated with pain and disability, with recognised risk factors such as age, obesity and deprivation. C_LIO_LIIncreasing interest in multi-joint OA challenges the traditional concept of lower-limb OA as a monoarthritis, but most research examines joints in isolation. C_LIO_LIGenetic evidence suggests that hip and knee OA may differ in underlying mechanisms, yet population-scale comparisons are limited. C_LI What this study adds?O_LIAmong 59,574 individuals, this study identifies that radiographic OA captures structurally and clinically relevant disease with increasing severity and greater number of joints affected, positively associated with chronic joint pain. C_LIO_LIRadiographic hip and knee OA demonstrated strong bilateral but weaker cross-joint associations, indicating preferential within-joint symmetry. C_LIO_LIRisk factors differed by anatomical site with BMI and weight strongly associated with knee OA and weakly associated with hip OA. Height showed the opposite associations. C_LI How this study might affect research, practice or policy?O_LIThese findings support that hip and knee OA may partially represent different disease processes rather than a single condition. C_LIO_LIClinical practice should consider cumulative joint involvement and joint-specific risk factors. C_LIO_LIFuture research should consider the development of more targeted treatment to prevent multi-joint progression. C_LI

ImportanceCardiovascular disease (CVD) is a major cause of morbidity/mortality in juvenile-onset systemic lupus erythematosus (JSLE), yet no reliable tools exist to stratify CVD-risk. ObjectiveTo identify serum biomarkers associated with atherosclerosis progression and response to atorvastatin. Design/SettingWe used data/samples from a sub-cohort of the APPLE trial (2009) which investigated atorvastatin vs. placebo to reduce atherosclerosis progression in JSLE, measured by change in carotid intima-media thickness (CIMT), and conducted a baseline autoantibody diagnostic-accuracy biomarker study. Participants/ExposureAPPLE trial participants (randomized 1:1 to atorvastatin vs. placebo) with matched baseline serum samples and stratified based on 36-month CIMT progression were included in the analysis. Main Outcomes and MeasuresBaseline serum autoantibodies were profiled using a functional proteomic platform (Sengenics, N=94). Empirical Bayes moderated t-test and Receiver Operating Characteristic (ROC) based logistic regression were applied to identify autoantibody signatures predictive of high vs. low atherosclerosis progression. ResultsNinety-four children and young people with JSLE (age mean [SD] =15.3 [2.4] years; 73 [78%] female, 8 [8.5%] Asian, 23 [24.5%] Black, 43 [45.7%] White, and 20 [21.3%] Other) were evaluated. Autoantibody levels against six novel autoantigens (STK24, RAD23B, HDAC4, STAT4, SEPTIN9, NFIA) classified high vs. low CIMT progression in the placebo arm (combined AUC 0.87, 95% CI -0.75 to 0.96). In the atorvastatin arm, autoantibodies to eight autoantigens (ABI1, ATP5B, CSNK2A2, NRIP3, PRKAR1A, PDK4, BATF, NUDT2), distinguished the statin responders vs. non-responders (combined AUC 0.96, 95% CI -0.88 to 1). An additional 27-autoantibody signature predicted response/partial response to atorvastatin (AUC 0.88, 95% CI - 0.76 to 0.97). Protein-protein interaction analysis identified endothelial disruption and lipid infiltration as key atherosclerosis mechanisms in atorvastatin non-responders. Combining the autoantibody prediction models with disease parameters and a metabolic signature did not increase model performance in either placebo (AUC 0.81, 95% CI - 0.68 to 0.94 vs. 0.87, 95% CI -0.75 to 0.96) or sttin arms (AUC 0.84, 95% CI -0.73 to 0.95 vs. 0.88, 95% CI -0.76 to 0.97). Conclusions and RelevanceThis study identified novel autoantibody signatures for atherosclerosis progression and statin response in JSLE, with potential utility for precision medicine approaches for CVD-risk management. Key PointsO_ST_ABSQuestionC_ST_ABSCan functional proteomic analyses identify autoantibody signatures predictive of atherosclerosis progression and response to statin treatment in children and young people with juvenile-onset systemic lupus erythematosus? FindingsUsing baseline samples from the APPLE trial (1:1 RCT of atorvastatin vs placebo), we identified novel autoantibody profiles that accurately distinguished individuals with high versus low carotid intima-media thickness progression over three years in both placebo (AUC 0.87, 95% CI-0.75 to 0.96) and atorvastatin groups (AUC 0.96, 95% CI-0.88 to 1). MeaningAutoantibody signatures show strong potential for early risk stratification and for identifying those most likely to benefit from statin therapy.

Multiple sclerosis (MS) therapies primarily rely on lymphocyte depletion or trafficking blockade, carrying risks of systemic immunosuppression; however, such treatments have limited efficacy in secondary progressive multiple sclerosis (SPMS). Thus, drugs that target stage-specific inflammation without broad immunosuppression are an unmet clinical need. In this double-blind, placebo-controlled phase II trial, 30 patients with relapsing MS received weekly oral OCH or placebo for 24 weeks. In the pre-specified SPMS subgroup (n=12), OCH achieved complete relapse prevention (p=0.0003), prolonged relapse-free survival (p=0.0079), no new lesions (0/6), with no evidence of disease activity (NEDA-3) in 5/6 patients. In comparison, for the placebo-treated group, 5/6 patients suffered relapses, 2/6 patients developed new lesions, and no placebo-treated SPMS achieved NEDA-3. Invariant natural killer T (iNKT) cells, a regulatory lymphocyte population that is numerically and functionally impaired in MS, are a potential target for MS therapy. Glycolipid OCH is a selective iNKT cell stimulator, skewing the cytokine environment towards Th2. OCH treatment resulted in increased IL-4-producing Th cells in patient peripheral blood while decreasing pathogenic GM-CSF-producing Th cells. Parallel studies in mouse models of MS (EAE) corroborated this mechanism and further revealed that OCH activated gut iNKT cells. Disease amelioration by OCH depended on IL-4 and its efficacy was further enhanced by depletion of B cells. These data revealed the gut-brain axis mediation of progressive-stage pathology distinct from relapsing-remitting MS. Findings from this bidirectional translational study uncover mechanistic differences between SPMS and other types of MS and highlight divergent roles for B cells and Th cells. Furthermore, OCH exerts its therapeutic benefit via targeting mechanisms that are distinct from currently available drugs; exploiting iNKT cell regulatory potential to reprogram pathogenic T helper responses without lymphocyte depletion. The unique yet effective nature of OCH treatment positions it as an attractive future oral therapy for SPMS. One Sentence SummaryThe iNKT cell activating ligand OCH suppresses disease activity selectively in secondary progressive MS in a phase II clinical trial, revealing stage-specific IL-4-mediated immune cell interactions in MS pathology.

Red blood cell (RBC) alloimmunization is a clinically significant complication in transfused patients whose immunological determinants remain incompletely understood. Type I interferon (IFN-I) signaling drives RBC alloimmunization in murine models, and systemic lupus erythematosus (SLE) is characterized by constitutive IFN-I hyperactivation alongside elevated alloimmunization rates. We analyzed three publicly available SLE RNA-seq cohorts (GSE72509, GSE112087, GSE122459; whole blood and PBMC; total n = 150 SLE) in a pre-specified discovery-replication-validation design. A 14-gene IFN-I signature score was computed per sample; differential expression, gene set enrichment analysis, and Spearman correlation were performed independently per cohort. IFN-I scores were significantly elevated in SLE versus healthy controls in all three cohorts (p < 0.01 each). IFN-high SLE patients showed 665 differentially expressed genes, with enrichment of alloimmunization-associated and plasmablast differentiation gene sets confirmed by GSEA. The alloimmunization signature score correlated significantly with IFN-I score across all three independent cohorts ({rho} = +0.77, +0.51, +0.60; all FDR q < 0.05); Tfh differentiation showed no association in any cohort. To our knowledge, this represents the first human transcriptomic evidence that IFN-I pathway activity in SLE is coupled to alloimmunization-associated immune programs in vivo. These findings identify IFN-I score as a candidate biomarker of alloimmunization susceptibility in SLE and provide translational rationale for prospective studies incorporating transfusion outcome data.

Rheumatoid arthritis (RA) is a heritable and common autoimmune condition. To date, most genetic associations were derived from individuals with either European or East Asian ancestries. Here, we applied a multimodal automated phenotyping strategy to define RA and performed a genome-wide association study (GWAS) of RA in the Million Veteran Program (MVP), including underrepresented African American (AFR) and Admixed American (AMR) populations. Meta-analyses with previous RA cohorts identified 152 autosomal genome-wide significant loci, of which 31 were novel. Inclusion of multi-ancestry data dramatically improved fine-mapping resolution. Functional characterization of these loci using single-cell transcriptomic and chromatin data suggested new RA genes such as CHD7 and CD247. We identified underappreciated functional roles of fine-grained immune cell states other than T cells, such as B cell and myeloid cell states. We observed that multi-ancestry polygenic risk scores using our data demonstrated better predictive ability, especially for AFR and AMR populations.

Inflammatory bowel disease (IBD) frequently co-occurs with immune-mediated and metabolic disorders, but whether these associations reflect shared genetics or causal effects remains unclear. We performed two-sample Mendelian randomization (MR) using large-scale genome-wide association study (GWAS) summary statistics to investigate potential causal effects of immune-mediated diseases and lifestyle traits on IBD, Crohns disease (CD), and ulcerative colitis (UC). SNP-based heritability and genetic correlations were estimated to contextualize findings. Following false discovery rate correction, genetically predicted psoriasis was positively associated with IBD (OR 1.15), CD (OR 1.23), and UC (OR 1.10), with the strongest effect observed for CD. Genetically predicted type 2 diabetes mellitus (T2DM) showed a modest inverse association with UC (OR 0.88). No lifestyle-related traits remained significant after correction. Sensitivity analyses indicated heterogeneity across instruments and evidence of directional pleiotropy in selected models, whereas no pleiotropy was detected for the T2DM-UC association. These findings support a role of psoriasis-related immune pathways in IBD susceptibility and suggest a potential inverse association between genetic liability to T2DM and UC.