The Lancet Rheumatology

ObjectivesTo assess whether baseline ESR-CRP difference (D score) is associated with discontinuation due to loss of efficacy during Janus kinase inhibitor therapy after biologic failure in rheumatoid arthritis. MethodsSingle-centre retrospective cohort of 24 patients with rheumatoid arthritis who initiated a Janus kinase inhibitor after inadequate response to at least one biologic DMARD. D score was ESR (mm/h) minus CRP (mg/L). The primary outcome was discontinuation due to loss of efficacy; other discontinuations were censored. Kaplan-Meier curves and Cox models were used. ResultsSeven patients discontinued due to loss of efficacy. After dichotomisation at the median D score (20.3; n = 12 per group), 1-year LOE-free persistence was 90.9% in the high D group and 43.2% in the low D group (log-rank p = 0.004). The hazard ratio per 10-unit increase was 0.47 (95% CI 0.29 to 0.76; p = 0.002) and 0.41 after age adjustment (0.22 to 0.74; p = 0.003). ConclusionsBaseline D score was associated with lower risk of discontinuation due to loss of efficacy. Larger studies are needed. Key messagesO_LILoss-of-efficacy discontinuation tended to cluster in patients with low ESR and low CRP at baseline. C_LIO_LIHigher baseline D score was associated with fewer loss-of-efficacy discontinuations during JAK inhibitor therapy. C_LIO_LID score from ESR and CRP may complement post-biologic treatment decisions, pending external validation. C_LI

IntroductionPain is often persistent in patients with inflammatory arthritis (IA). There is limited research on pain mechanisms in early IA. We used detailed assessments to characterise pain types longitudinally. MethodsThis prospective observational study investigated the relative contribution of peripheral versus centrally mediated pain in newly diagnosed IA patients with pain scores [&ge;]3, followed over two years. Assessments included: disease activity (Disease Activity Score-28, musculoskeletal ultrasound); quality of life (Musculoskeletal Health questionnaire); mental health status (Patient Health Questionnaire Anxiety, Depression Scale) and pain characteristics (Fibromyalgia criteria, painDETECT, Static and Dynamic Quantitative Sensory Testing). Mixed-effects regression models examined longitudinal associations. ResultsAmong 66 participants (all baseline pain NRS [&ge;]3), pain decreased significantly in the first six months, with smaller, non-significant reductions thereafter. At 24 months, 49% still reported pain (NRS [&ge;]3) and 25% showed no pain improvement. Those with pain had higher baseline and longitudinal scores for centrally mediated pain (fibromyalgia severity, painDETECT) and psychological distress, despite similar baseline inflammation and similar reductions over time. Both baseline and longitudinal inflammation was not associated with subsequent pain (b -0.05, 95% CI -0.67 to 0.56), whereas higher centrally mediated pain markers predicted less pain reduction (b 1.41, 95% CI 0.83-1.99, p<0.001). ConclusionIn our early IA cohort, despite reductions in inflammation half of patients reported persistent pain, primarily driven by centrally mediated mechanisms. Early identification and treatment of this group may improve long-term outcomes. Key messages- This is the first longitudinal study assessing relative contributions of inflammation and centrally mediated pain features in early IA. - Despite reductions in inflammation half of patients reported persistent pain, primarily driven by centrally mediated mechanisms. - Early assessment and treatment of non-inflammatory pain mechanisms may improve long-term pain outcomes.

ObjectiveTo evaluate the criterion-related and discriminant validity, test-retest reliability and minimal detectable difference of The Index of ME Symptoms (TIMES) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) MethodsPeople with ME/CFS in the UK completed the TIMES online (n=1055). Rasch-transformed interval data and parametric statistics were used: Pearson correlations (with the ME severity scale); analysis of variance; intra-class correlations (ICC) and standard error of measurement of ICC measured criterion-related and discriminant validity, test-retest reliability and minimal detectable difference respectively. ResultsHighly significant (P<0.001) moderate (r=0.400-0.528) correlations were seen between the TIMES scales and severity of ME/CFS except the gastro-intestinal and immune systems scales (r= 0.315 and 0.302 P<0.001 respectively). Discriminant validity was demonstrated with significant differences in TIMES scores between all five levels of ME severity, except between levels 4 and 5 in some cases, which were underpowered due to the small group numbers. Test-retest reliability was excellent (ICC>0.7, p<0.001) except the cranial nerves and immune system scales which were good (ICC = 0.681 and 0.669, p<0.001) and minimal detectable difference was excellent (3.95-17.45%). ConclusionsThe Index of ME Symptoms (TIMES) scales are valid, reliable, sensitive assessments of symptoms in ME/CFS. They are freely available for use.

ObjectivesWhether febuxostat is associated with an increased cardiovascular risk compared to allopurinol in patients with gout remains controversial, with major randomized trials reporting conflicting results. This study aims to perform a comprehensive meta-analysis using reconstructed individual participant data (IPD) to evaluate the time-varying cardiovascular and mortality risk of febuxostat versus allopurinol in gout. MethodsWe conducted a one-stage individual participant data meta-analysis. PubMed, Embase, and Cochrane Library were searched up to November 2025 for randomized controlled trials and propensity score-matched observational studies reporting Kaplan-Meier curves for cardiovascular risk or all-cause mortality. Individual patient data were reconstructed from published curves. Time-varying hazard ratios (HRs) were estimated using a mixed-effects Cox model with treatment-by-time interaction across pre-specified intervals (0-12, 12-24, 24-48, >48 months). ResultsFour studies (n=19,090) were included. Analysis revealed significant time-varying effects. For cardiovascular risk, HRs were 0.89 (95% CI 0.79 to 0.99) at 0-12 months, 0.58 (0.50 to 0.68) at 12-24 months, 0.86 (0.74 to 0.99) at 24-48 months, and 1.09 (0.81 to 1.46) after >48 months. For all-cause mortality, HRs were 0.70 (0.62 to 0.79), 0.39 (0.33 to 0.45), 0.75 (0.65 to 0.86), and 1.02 (0.77 to 1.34) across the same intervals, respectively. ConclusionThe cardiovascular and mortality risk of febuxostat relative to allopurinol is time-dependent, showing a significant early reduction that attenuates over time. These findings advocate for a time-aware approach to clinical management and monitoring.

ObjectiveTo develop and psychometrically evaluate an assessment of symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) MethodsAn initial symptom list was devised from the relevant literature with the patient and clinician advisory groups. An online survey with 85 symptom items in eight domains was completed by people with ME/CFS. Each item had two response structures (assessing symptom frequency and severity on five-point scales). Rasch analysis assessed each domain for unidimensionality, targeting, internal reliability, item fit and local dependency. ResultsSurvey data (n=721) indicated various item anomalies and inter-item dependencies, leading to item re-formatting or removal. The frequency and severity-based responses broadly replicated each other, and a four-point response format appeared more appropriate than a five-point response format. Following Rasch-based scale amendments, a revised version with a single four-point response format was re-administered to test the modifications. Validation data (n=354) showed the modified scale had an improved response structure and functionality across all domains, satisfying Rasch model assumptions. Additionally, domain-level super-items allowed for a summated total score along with sub-scales summarising neurological and autonomic symptoms, again satisfying Rasch model assumptions. ConclusionsThe Index of ME Symptoms (TIMES) and its associated sub-scales and domain scales are stable, valid assessments of symptoms in ME/CFS.

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.

Managing chronic diseases with unpredictable care demand creates significant operational challenges for healthcare systems. Mapping long-term care trajectories is crucial for improving resource allocation, anticipating service needs, and designing efficient care pathways. We used a data-driven approach to map six-year care trajectories for 962 newly diagnosed multiple sclerosis patients, identify utilization clusters, and determine predictors of high utilization. We analyzed Event logs of remote, outpatient, emergency, and inpatient contacts from one year pre- to five years post-diagnosis using K-means clustering to identify utilization clusters, logistic regression to identify predictors of high utilization, and process mining to model variation between care trajectories. We identified two distinctive utilization clusters: a high-utilization cluster (14.1 % of patients) with persistently elevated annual encounter volumes across all care settings and low-utilization cluster (85.9 % of patients) with lower and declining use. Median service costs were {euro}18,736 vs. {euro}6,052 in high- and low-utilization clusters, respectively. Two or more early relapses were the strongest predictor of high utilization (OR = 6.33, 95 % CI 3.49-11.50, p < 0.001), with number of planned early remote and outpatient care contacts being also associated with future service utilization (OR = 1.07, 95 % CI 1.04-1.10, p < 0.001). High-utilization trajectories were approximately three times longer (82.4 vs 25.9 events) and more variable (3.1 vs 2.4 unique events per patient). These utilization clusters and their distinct trajectories provide a pragmatic segmentation of multiple sclerosis patients to support early identification of high-utilization subgroups and more robust capacity planning in specialist care. HighlightsO_LIWe tracked the care trajectories of 962 people with relapsing-remitting multiple sclerosis using a Finnish population-based specialist-care datalake covering both inpatient and outpatient neurology services. C_LIO_LIPatients fell into two distinct utilization clusters: a high-utilization cluster with frequent contacts across all care settings and a low-utilization cluster with lower and declining use. C_LIO_LITwo or more early relapses, and the number of early outpatient and remote contacts were strong predictors of a patients long-term affiliation in the high-utilization cluster. C_LIO_LISegmented care trajectories showed that high-utilization patients followed longer, more varied, and acute-oriented care patterns and had much higher service encounter costs. C_LIO_LIThese findings can help clinicians and managers identify potential high-utilization patients early, target resources more effectively, and plan for future healthcare demand. C_LI

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.

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.

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.

Predictors of Health-Related Quality of Life in Indonesian Women with Systemic Lupus Erythematosus: A Cross-Sectional Within-Cohort Analysis ObjectiveThis study aims to determine the effects of sleep quality along with age, marital status, socioeconomic status, depression, anxiety, disease activity, pain scale, and dose of corticosteroids on quality of life in women with SLE. MethodsVariables were assessed in 75 women with SLE using the Pittsburgh Sleep Quality Index (PSQI), Lupus Quality of Life (Lupus QoL), Depression, Anxiety, and Stress Scale-21 (DASS-21), and Mexican SLE Disease Activity Index (MEX-SLEDAI). Bivariate and multivariate analyses were performed to determine contributors to quality of life. ResultsOf 75 subjects, 35 (46.7%) patients had poor sleep quality. The mean QoL score for patients is 84.27. Poor sleepers had impaired QoL in physical health (p = 0.003), emotional health (p = 0.007), pain (p = 0.003), and planning (p = 0.006), with fatigue (p < 0.0001) as the most significantly impaired. Younger age (Mean {+/-} SD = 81.1 {+/-} 12.67; p = 0.014) and anxiety or depression (Mean {+/-} SD = 56.66 {+/-} 8.17; p = 0.006) were significantly associated with lower quality-of-life scores. The linear regression results showed an R-squared of 0.361, with anxiety ({beta} = 21.402), sleep quality ({beta} = 8.392), and age ({beta} = 5.526) as the most significant variables. Marital status, socioeconomic status, disease activity, pain scale, and corticosteroid dose did not correlate with QoL. ConclusionPoor sleep quality, anxiety, and younger age were significant independent predictors of lower QoL in women with SLE, explaining 36.1% of the variance. These findings suggest that psychosocial and sleep interventions are crucial for improving well-being in this population, potentially more so than focusing solely on disease activity. Summary Box: Key MessagesO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LISystemic Lupus Erythematosus (SLE) significantly diminishes health-related quality of life (HRQoL), particularly in Asian populations where severe organ involvement is more prevalent. C_LIO_LISleep disturbances affect a large majority of SLE patients globally (approximately 62%) and are closely linked to psychological distress and fatigue. C_LIO_LITraditional management focuses heavily on controlling systemic disease activity and organ damage, yet these clinical markers often correlate poorly with patient-reported well-being3. C_LI What does this study add?O_LIIn this cohort of Indonesian women with SLE, nearly half (46.7%) reported poor sleep quality. C_LIO_LIMultivariate analysis identified anxiety/depression ({beta} = -21.402), poor sleep quality ({beta} = - 8.392), and younger age ({beta} = 5.526) as the most significant independent predictors of lower HRQoL, collectively explaining 36.1% of the variance. C_LIO_LIFatigue was identified as the HRQoL domain most severely impaired by poor sleep quality. C_LIO_LINotably, in patients with predominantly low disease activity, markers like the MEX-SLEDAI and corticosteroid dose did not significantly impact HRQoL, highlighting a "disconnect" between clinical control and patient-perceived health. C_LI How might this study affect clinical practice?O_LIThe findings advocate for a shift in the SLE management paradigm from purely inflammatory control toward a multidisciplinary approach that includes routine screening for sleep quality and psychological health. C_LIO_LIClinicians should prioritize interventions such as Cognitive-Behavioral Therapy for Insomnia (CBT-I) and anxiety management, especially for younger patients who may experience greater disruption to life milestones. C_LI

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.

BackgroundAn adverse female sex-bias exists across many autoimmune disorders, yet its underlying mechanisms, particularly the role of sex hormones, remains poorly understood. Furthermore, the physiological influence of sex hormones in regulating T cell function remains undefined. We examined for the critical role of estrogen and progesterone, in regulating CD4+ T cell responses, specifically with respect to inflammation and their bone erosion potential in RA. MethodsInflammatory markers, circulating antibodies, sex hormone receptors, ER and PR levels were investigated in both RA patients and controls. Further, RA CD4+ T cells were stimulated in varying concentrations of estradiol and progesterone and assessed for modulation in cytokines, transcription factors, RANKL, and FasL expression. Subsequent ex-vivo studies were performed to examine the role of sex hormones in modulating T cell responses. ResultsRA patients displayed systemic inflammation and high circulating antibodies, with significantly higher expression in synovial fluid. Higher expression of ER and PR was evinced on RA CD4+ T cells. Upon hormone stimulation, two cohorts of patients namely responders and non-responders were observed with respect to modulation in cytokines, transcription factors, RANKL, and FasL expression. Our ex-vivo Th1 and Th17 cells demonstrated that sex hormones play a physiological role in modulating inflammation and have bone erosion potential. ConclusionOur findings demonstrate the pivotal significance of sex hormones in modulating TCR responses, thereby regulating inflammation and bone erosion in RA pathology. Further dissection of TCR signaling pathways with respect to sex hormone stimulation may provide promising targets for therapeutic implications. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/25342530v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@b74525org.highwire.dtl.DTLVardef@1cc01aorg.highwire.dtl.DTLVardef@1881e4forg.highwire.dtl.DTLVardef@17de2a8_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundAlthough ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) are very similar regarding pathophysiology and clinical treatments, especially NSTEMI comprises a much more heterogenic group of patients and underlying diseases. We therefore aimed to assess the treatments and outcomes of both entities in a large contemporary cohort. MethodsPatients with STEMI and NSTEMI between 01/2010 to 12/2018 were identified from the largest German Health Insurance (AOK, {approx}26 million members). Patient demographics, their hospital course, adherence to guideline-directed drug therapy and overall survival were assessed. ResultsIn total 544,529 patients (mean age 74, IQR 62-82), one third of whom had a STEMI. Chronic kidney disease, peripheral arterial disease, and heart failure were more common in patients with NSTEMI. Patients with STEMI were more likely to get coronary angiograms and percutaneous coronary interventions. Although STEMI more frequently led to cardiogenic shock, the rate of serious cardiac events was lower. Mortality was higher for STEMI only within the first 30 days, whereas long-term survival rates were better. The combination of statins, angiotensin converting enzyme inhibitors /angiotensin receptor blockers, beta blockers, and oral anticoagulants or antiplatelet agents was associated with higher overall survival in patients with STEMI (hazard ratio [HR] 0.20; 95% confidence interval [95%CI] 0.18 - 0.24; p<0.001) or NSTEMI (HR 0.30; 95%CI 0.28 - 0.33; p<0.001). Nevertheless, the prescription rates decreased over time, particular in patients with NSTEMI. ConclusionClear differences between STEMI and NSTEMI were observed regarding short-and long-term survival. Guideline-recommended therapy improved long-term survival, but decreased during the follow-up period.

ObjectivesTo investigate genetic architecture and identify novel risk loci shared between juvenile idiopathic arthritis (JIA) and other human leukocyte antigen (HLA)-associated autoimmune diseases (AIDs) by leveraging genome-wide association studies (GWAS) data. MethodsWe analyzed GWAS summary statistics from over two million participants (123,997 cases and 1,843,249 controls) of European ancestry across multiple AIDs including JIA, autoimmune thyroid disease (AITD), celiac disease, inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis (Ps), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and type 1 diabetes (T1D). The conjunctional false discovery rate (conjFDR) method was employed to identify shared genetic loci, followed by functional annotation and pathway analysis. ResultsWe identified 46 novel loci shared between JIA and various AIDs: 17 with AITD, 16 with RA, 13 with IBD, five each with MS and Ps, four with SLE, and seven with T1D. Notable shared risk genes included BACH2, UBASH3A, IRF4, IL12A-AS1, ETS1, PSMD14, FOXK1, NEK6, SP140, TNIP1, VAV3, CYP20A1, DNMT3A, LAX1, CASC15, ZC3H12C, KALRN, TBC1D1, PIK3CB, ANXA6, and HIF1A. Functional annotation revealed 170 nonsynonymous exonic variants and 478 potentially deleterious variants (CADD score > 12.37). Gene Ontology analysis consistently highlighted enrichment of T cell-related processes and immune system regulation pathways. ConclusionThis study expands the understanding of genetic architecture in JIA by identifying novel risk loci shared with other AIDs. The extensive genetic overlap and shared biological pathways, particularly in T cell-mediated immunity, suggest common pathogenic mechanisms and potential therapeutic targets across multiple autoimmune conditions.

BackgroundGout is the among the most prevalent arthritides worldwide and is associated with high morbidity, cardiovascular risk, and substantial healthcare burden. Despite effective urate-lowering therapies (ULT), many patients remain undertreated, particularly those with severe or complex disease. Nurse-led gout management has improved outcomes in primary care, but data in multimorbid tertiary center populations are lacking. ObjectiveTo evaluate the effectiveness of a supervised nurse-led gout clinic in achieving and maintaining serum urate (UA) targets in a tertiary hospital cohort. MethodsIn this observational study at University Hospital Bern (May 2023-Jan 2026), 69 patients with confirmed gout were enrolled. Patients were assigned to UA targets of <300 {micro}mol/L (Group 1: severe gout) or <360 {micro}mol/L (Group 2: non-severe gout). An advanced Practice Nurse (APN) provided education, a rheumatologist provided pharmacological management per 2020 ACR guidelines. UA levels, flare frequency, prophylaxis, and treatment adjustments were monitored, with follow-up at six and twelve months. ResultsGroup 1 required higher allopurinol doses than Group 2 (p<0.01). UA targets were achieved in 82% of Group 1 regimens and 68% of Group 2. Flare rates and prophylaxis use were comparable. At six and twelve months, 62-67% of Group 1 and 83-88% of Group 2 maintained UA targets. Failures were often due to external treatment modifications. No major ULT-related adverse events were observed. ConclusionSupervised nurse-led gout management effectively achieves UA targets in this "difficult-to-manage" cohort. Maintaining UA targets may benefit from shorter follow-up intervals and enhanced education for patients and healthcare providers.

BackgroundHaploinsufficiency of A20 (HA20) is an immune dysregulation disorder caused by loss-of-function TNFAIP3 mutations. This international multicenter study aimed to delineate its clinical spectrum, genetic basis, and natural history. MethodsA cross-sectional, retrospective analysis was conducted in HA20 patients with pathogenic or likely pathogenic TNFAIP3 variants. Clinical, laboratory and treatment data were assessed. Clustering analysis was applied to evaluate clinical features and disease phenotypes. Patients were stratified by age (< 16 years vs [&ge;] 16 years), country of origin (China vs U.S.), and gender. ResultsA total of 185 patients from 41 clinics across 7 countries were included (median onset 3.3 years). Common clinical features were mucocutaneous involvement (80.5%), recurrent fever (63.3%), gastrointestinal symptoms (58.6%), cytopenias (56.6%), arthritis/arthralgia (46.7%), and recurrent infections (35.5%). Compared with adults and patients from the U.S. cohort, intestinal ulcers were significantly more frequent in children and patients from the Chinese cohort (P = 0.002 and P < 0.0001, respectively), whereas uveitis was less common in these groups (P = 0.001 and P < 0.0001, respectively). Hierarchical clustering of clinical disease phenotypes based on Pearson distance identified two major clusters, an autoinflammation-predominant phenotype and an autoimmune-predominant phenotype. The autoinflammation-predominant phenotype was more common in children and patients from the Chinese cohort (P = 0.033 and P = 0.003, respectively). A total of 89 pathogenic TNFAIP3 mutations were identified, including 46 novel variants. Large deletions were associated with neurologic disease and developmental delay (P = 0.0054 and P = 0.0245, respectively); however, there were no clear association between disruptions of specific functional A20 domains and onset age or phenotype. Therapeutically, TNF and IL-1 inhibitors were effective in most patients, with thalidomide and JAK inhibitors used in refractory cases; 51.5% had achieved minimal disease activity at the most recent follow-up. ConclusionsHA20 is a common dominantly inherited immune dysregulation disorder with phenotypic heterogeneity and potential age-dependent evolution. This large international cohort highlights diagnostic and therapeutic strategies to advance evaluation and management of HA20.

BackgroundSymptom diaries are widely used in acute respiratory infection trials to capture patient-reported symptom severity and recovery. Longer questionnaires may provide a more complete clinical picture but can increase participant burden and reduce adherence. Evidence directly comparing long and short formats within the same trial is limited. ObjectiveTo compare adherence, symptom trajectories, agreement between recovery measures, and predictive performance for recovery-related outcomes between a short and long symptom diary in an outpatient SARS-CoV-2 trial MethodsThis secondary analysis of the CanTreatCOVID trial compared a 9-item Abbreviated Diary and a 34-item FLU-PRO Plus Diary over 14 days in non-hospitalized participants with confirmed SARS-CoV-2 infection. Outcomes included diary initiation, completion, completion rate, compliance, symptom trajectories, agreement between recovery outcomes, and predictive performance. Analyses used logistic regression, generalized estimating equations, survival models, and predictive modelling. ResultsOf 712 participants, 638 used the Abbreviated Diary and 74 the FLU-PRO Plus Diary. Baseline characteristics were similar between groups. Diary type was not significantly associated with diary initiation or full 14-day compliance, whereas treatment assignment was associated with higher adherence (p < 0.0001). Completion rates were slightly higher in the Abbreviated group (68.1% vs. 64.4%), but differences were not statistically significant. Agreement between "feeling recovered" and "return to usual health" was strong to excellent ({kappa} = 0.8371-0.8859), while agreement with "return to usual activities" was moderate ({kappa} = 0.5273-0.6583). Predictive models performed well for both diaries (AUCs 0.87-0.94), with only marginal gains from including the extended FLU-PRO Plus items. ConclusionIn this outpatient SARS-CoV-2 trial, abbreviated and extended symptom diaries produced comparable adherence, symptom trajectories, and predictive performance. Future research should extend follow-up beyond 14 days to capture longer-term patterns and test diary performance in more diverse and digitally underserved populations.

BackgroundChronic cardiovascular diseases (CVD) care quality remains suboptimal, globally. This study evaluated the feasibility and preliminary effect of a multicomponent, collaborative quality improvement (C-QIP) strategy among patients with CVD attending outpatient clinics in India. Methods and FindingsWe conducted a pragmatic feasibility randomized controlled trial in patients with ischemic heart disease, ischemic stroke or heart failure across public and private hospitals in India. Participants were individually randomized to C-QIP strategy (electronic decision support system, eDSS for providers, task-sharing with non-physician health workers, patient education, and SMS text reminders, and audit-feedback) or usual care. The primary outcomes were implementation measures: feasibility, fidelity, adoption, and acceptability from providers and patients perspectives. Secondary outcomes included prescription of guideline-directed medical therapy (GDMT), adherence to prescribed therapy, processes of care, and CVD risk factors. Of 410 participants enrolled (intervention arm=206 and usual care arm=204), mean age was 57.5 years, and 73.0% were male. Prior history of coronary heart disease was 74.6%, ischemic stroke: 18.5%, and heart failure: 18.0%. At trial end (mean follow-up 18 months), implementation outcomes were strong: retention at end-of-study was 192/206 (93.2%) in C-QIP and 187/204 (91.7%) in usual care arm; fidelity of the intervention remained high, e.g., 187/198 (94.4%) patients received lifestyle advice at end-of-study. Clinician adoption of eDSS prompts was high, and acceptance of DSS prompts varied by type of prompts, and both patients and providers reported high acceptability at trial end. GDMT use improved significantly in C-QIP vs usual care arm at end-of-study: in patients with ischemic heart disease use of antiplatelet + statin + ACEi/ARB + beta-blocker was 58.3% vs 32.4%, RR=1.45 (95%CI: 1.18-1.78); and among patients with ischemic stroke use of antiplatelet + statin + ACEi/ARB or diuretic was 76.7% vs 31.8%, RR=2.41 (95%CI: 1.52-3.81). GDMT among patients with heart failure were not different between groups (e.g., ACEi/ARB /ARNI + beta-blocker + MRA, 48.9% vs 48.6%, RR=1.26, 95%CI: 0.82-1.94). Patient adherence to prescribed therapy improved in C-QIP vs usual care arm: medications 90.9% vs 82.3%, RR 1.08 (1.04-1.12); diet plan 91.9% vs 82.3%, RR 1.07 (1.02-1.13); and physical activity 91.4% vs 70.4%, RR=1.23 (95%CI: 1.16-1.30). Processes of care improved significantly in C-QIP vs usual care arm, including more structured reminders (e.g., call after missed appointment 70.7% vs 4.4%, p<0.001) and longer clinician contact time (median 10 vs 7 minutes, p<0.001). CVD risk factors showed small, non-significant trends (e.g., modest diastolic BP reduction) for between-group differences in blood pressure, lipids and glycemia. ConclusionsThe C-QIP trial demonstrated that a multicomponent strategy is feasible, acceptable, and improved processes of chronic CVD care in India. Future large, confirmatory hybrid trials are needed to establish whether such quality improvement strategies can reduce cardiovascular morbidity and mortality. Trial RegistrationClinicaltrials.gov number: NCT05196659 Clinical Trials Registry India: CTRI/2022/04/041847

Background and AimFibromyalgia is an idiopathic chronic widespread pain syndrome affecting 2-4% of the general population globally. Besides widespread fibromyalgia pain, morning stiffness, associated neurologic as well as sleep problems are also reported. Disease is more prevalent in females of middle-age group with low socioeconomic status, thus deteriorating overall productivity and psychosocial health. There is no permanent cure of the disease. This study aimed to explore, validate and assess the effect of four weeks of supervised yogic intervention on pain status, quality of life, sleep, cortical excitability, flexibility and range of motion in fibromyalgia patients, as compared to standard therapy. MethodCase-control study, interventional study and assessor-blined randomized controlled trial, conducted in 120 fibromyalgia patients (60 yoga group: 60 waitlisted controls) and 60 age-matched healthy controls. Pain was assessed subjectively, using questionnaires and objectively, using quantitative sensory testing and ELISA. Sleep and quality of life were assessed using common and disease specific decsiptors. Flexibility and range of motion was assessed using sit and reach box, lateral goniometry and modified Schobers test. Transcranial magnetic stimulation on M1 was used to assess corticomotor excitability of participants. Study parameters were assessed at baseline and after four weeks of the intervention. ResultsA significantly poor sleep, flexibility and quality of life was reported in the fibromyalgia patients due to excruciating pain (VAS = 6.92{+/-}0.12); corticomotor function was also abnormal in the patients, which were restored after four weeks of yogic intervention. On subjective and objective assessment of pain, we found significant relief and improvement in pain status in the yoga group as compared to the waitlisted controls. Fibromyalgia impact, sleep, quality of life and flexibility were also found solely better in fibromyalgia patients undergoing yogic interventions. Cortical parameters, specifically RMT, MEPs and MEP recruitment curves showed a significant improvement in yoga group as compared to waitlisted controls. ConclusionFour weeks of regular and supervised yogic intervention may ameliorate pain, improve flexibility and range of motion and changes cortical plasticity in the Indian cohort of fibromyalgia patients, as compared to standard therapy. Yoga-based interventions can also improve overall quality of life and sleep impairmentsby reducing catastrophization and fibromyalgia impact.