Rheumatology

ObjectiveThis systematic review aimed to assess the diagnostic accuracy of algorithms used to identify rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) in electronic health records (EHRs). MethodsWe searched MEDLINE, Embase, and CENTRAL databases and included studies that validated case definitions against a reference standard such as rheumatologist-confirmed diagnosis or ACR/EULAR classification criteria. Title/abstract screening, full-text review, data extraction and quality assessment were all completed in duplicate. Results were synthesised narratively and using a bivariate random-effects meta-analysis of sensitivity and specificity. ResultsA total of 35 studies were included. Algorithms varied widely in complexity, ranging from single ICD codes to combinations including disease-modifying antirheumatic drugs (DMARDs), hospitalisation records, and specialist diagnosis. Algorithms combining ICD codes with DMARD prescriptions (pooled sensitivity= 0.79 95% CI 0.61-0.90, specificity= 0.96 95% CI 0.72-1.00, PPV= 0.78 95% CI 0.63-0.88) or requiring an ICD code assigned by a rheumatologist (pooled sensitivity= 0.91 95% CI 0.70-0.98, specificity= 0.94 95% CI 0.49-1.00, PPV= 0.70 95% CI 0.64-0.75) showed the highest accuracy, with balanced sensitivity, specificity, and positive predictive value (PPV). Less restrictive algorithms demonstrated high sensitivity but lower PPV. Substantial heterogeneity was observed across studies, likely due to differences in algorithm structure, data sources, and validation methods. Despite this variability, we used conceptually coherent categories to allow for meaningful synthesis, prioritising clinical interpretability. ConclusionsThese findings support the use of more specific algorithms when diagnostic certainty is essential and highlight the need for further validation of high-performing algorithms across diverse healthcare systems. Significance and Innovations{blacksquare} This is the first comprehensive systematic review to evaluate and synthesize the accuracy of algorithms used to identify rheumatoid arthritis and juvenile idiopathic arthritis in electronic health records (EHRs), addressing a growing need as real-world data become increasingly central in rheumatology research. {blacksquare}The findings provide critical guidance for researchers and clinicians on the strengths and limitations of commonly used case definitions, helping improve validity of studies using administrative or EHR data. {blacksquare}By categorizing algorithms based on their components and reference standards, this review offers a practical framework for selecting the most appropriate algorithm depending on the study purpose and data source. {blacksquare}The review highlight gaps in validation efforts and emphasizes the need to validate high-performing algorithms across diverse healthcare settings and evolving coding systems, ensuring accurate disease identification in current and future research.

BackgroundInterleukin-6 (IL-6) is a cytokine that plays a key role in systemic hyperinflammation and may mediate the relationship between acute COVID-19 and severe long-term outcomes such as Long COVID or death. IL-6 modulating drugs may reduce patients risk of severe post-COVID-19 outcomes. MethodsWe conducted an emulated target trial in a retrospective cohort of patients with moderate-to-severe rheumatoid arthritis who were prescribed IL-6 receptor antagonists (sarilumab or tocilizumab, pooled treatment) or other biologic agents (anakinra or baricitinib, pooled comparator) in 2022. We compared the 12-month cumulative incidence of mortality and Long COVID (diagnosed and probable) between groups using Super Learner and targeted maximum likelihood estimation, adjusting for covariates of interest. ResultsIn our cohort of 3,553 patients, we found that prescription of IL-6 receptor antagonists was associated with a lower 12-month cumulative mortality (adjusted relative risk (aRR) 0.40, 95% CI 0.27, 0.59), diagnosed Long COVID aRR 0.42, 95% CI 0.23, 0.78), and probable Long COVID (aRR 0.71, 95% CI 0.61, 0.83), compared to prescription of other biologic agents, among rheumatoid arthritis patients. ConclusionsIL-6 receptor antagonists may prevent the incidence of severe post-COVID-19 outcomes, such as Long COVID or mortality. This supports the hypothesis that IL-6 may be a mechanistic biomarker of COVID-19 sequelae and that acute COVID-19 severity may mediate this relationship.

ObjectiveDespite significant improvements in diagnosis delay and treatment strategies, the burden of Systemic Lupus Erythematosus (SLE) remains high. The objective of the study was to assess the association between diagnosis delay, disease activity and burden on daily life (BoDL) in a large sample of European patients with SLE. MethodsIn May 2020, Lupus Europe, the European umbrella patient association for SLE, conducted a multilingual anonymous online cross-sectional study to individuals with a self-reported physicians diagnosis of SLE living in Europe. The BoDL score was computed using 1 to 5 Likert scales on 5 domains (mobility, anxiety/depression, self-care, daily activities and pain/discomfort) and the sum was rescaled on a 0 (minimum Burden on daily life) to 100 (maximum BoDL) scale. Comparisons between independent groups were made using the Mann-Whitney test for continuous outcomes and the Chi-2 test (or Fishers exact test) for quantitative data. ResultsData of 4,150 SLE patients from 35 European countries were analysed. Those with a diagnosis of SLE within 2 years of first symptoms had significantly lower mean BoDL scores than those diagnosed after 5 years (33.6 versus 44.0, p<0.001). The BoDL score was better in SLE patients feeling that their lupus had been under control during the last 3 months versus the others (34.0% versus 47.6%, p<0.001). ConclusionThis large international study highlights the association between diagnosis delay and self-perceived disease activity with the burden of the disease on the daily life of people living with SLE. Healthcare pathways, which may accelerate diagnosis and optimize therapeutic management, are necessary to improve patients outcomes in SLE.

ObjectivesTo evaluate the safety, tolerability, pharmacokinetics (PK), biomarker response, and efficacy of E6742 in a phase 1/2 study in patients with systemic lupus erythematosus (SLE). MethodsTwo sequential cohorts of SLE patients were enrolled and randomized to 12 weeks of twice-daily treatment with E6742 (100 or 200 mg; n = 8 or 9) or placebo (n = 9). ResultsThe proportion of patients with any treatment-emergent adverse events (TEAEs) was 58.8% in the E6742 group (37.5% for 100 mg; 77.8% for 200 mg) and 66.7% in the placebo group. No Common Terminology Criteria for Adverse Events [&ge;] Grade 3 TEAEs occurred. PK parameter levels were similar between SLE patients and healthy adults in previous phase 1 studies. The interferon gene signature (IGS) and levels of proinflammatory cytokines (interleukin-1{beta}, interleukin-6, tumor necrosis factor-) after ex-vivo challenge with a Toll-like receptor 7/8 agonist were immediately decreased by E6742 treatment. Dose-dependent improvements in the British Isles Lupus Assessment Group-based Composite Lupus Assessment response were observed at Week 12 in the E6742 (37.5% for 100 mg; 57.1% for 200 mg) and placebo (33.3%) groups. E6742 also had therapeutic effects on other symptoms, including skin inflammation, arthritis, and levels of anti-double-stranded DNA antibodies and complements. ConclusionsE6742 had a favorable safety profile and was well tolerated, with marked IGS responses and sufficient efficacy signals in patients with SLE. These results provide the first clinical evidence to support E6742 in the treatment of SLE, and support larger, longer-term clinical trials. Trial registration numberNCT05278663. KEY MESSAGESWhat is already known on this topic O_LIBecause of the limited efficacy and safety concerns of current drug therapies, unmet medical needs remain for many patients with systemic lupus erythematosus (SLE), necessitating new, more efficacious drugs. C_LIO_LIThere is strong evidence for the relationship between Toll-like receptor (TLR)7/8 and SLE pathophysiology, and two phase 1 clinical studies of E6742, a small molecular selective dual antagonist of TLR7/8, in healthy adults showed good tolerance without safety issues. C_LI What this study adds O_LIE6742 was well tolerated in this phase 1/2 clinical trial of patients with SLE, demonstrating a favorable safety profile and providing a markedly improved interferon gene signature and sufficient efficacy signals. C_LI How this study might affect research, practice or policy O_LIThis study provides the first clinical evidence to suggest that E6742, as a first-in-class TLR7/8 inhibitor, may be beneficial for SLE. C_LIO_LIThe study outcomes also support larger, longer-term clinical trials of E6742. C_LI

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.

ObjectiveTo determine whether SLE patients with inflammatory joint symptoms and ultrasound-synovitis achieve better clinical responses to glucocorticoid compared to patients with normal scans. Secondary objectives included identification of clinical features predicting ultrasound-synovitis. MethodsA longitudinal muticentre study of SLE patients with physician-diagnosed inflammatory joint pain was undertaken. Clinical assessments, patient-reported outcomes, and bilateral hands and wrist ultrasound were collected at 0-, 2- and 6-weeks after intramuscular methylprednisolone 120mg. The primary outcome (determined via internal pilot analysis) was EMS-VAS at 2-weeks, adjusted for the baseline value, comparing patients with positive (GS[&ge;]2 and/or PD[&ge;]1) and negative ultrasound. Post-hoc analyses adjusting for fibromyalgia were performed. ResultsOf 133 patients recruited, 78/133 had positive ultrasound, but only 68% of these had [&ge;]1 swollen joint. Of 66/133 patients with [&ge;]1 swollen joint, 20% had negative ultrasound. Positive ultrasound was associated with joint swelling, symmetrical small joint distribution and serology. In full analysis set (n=133) there was no difference in baseline-adjusted EMS-VAS at week 2 (-7.7mm 95% CI - 19.0mm, 3.5mm, p=0.178). After excluding 32 fibromyalgia patients, response was significantly better in patients with positive ultrasound at baseline (baseline-adjusted EMS-VAS at 2-weeks - 12.1 mm, 95% CI -22.2mm, -0.1mm, p=0.049). This difference was greater when adjusted for treatment (-12.8mm (95% CI -22mm, -3mm), p=0.007). BILAG and SLEDAI responses were higher in ultrasound-positive patients. ConclusionsIn SLE patients without fibromyalgia, those with positive ultrasound had a better clinical response to therapy. Imaging-detected synovitis should be used to select SLE patients for therapy and enrich clinical trials.

ObjectiveTo develop an automatic gout register to improve gout management. MethodsWe analysed the electronic health records (EHR) of all patients >18 years old from a tertiary academic hospital (2013-2022) based on six criteria: International Classification of Diseases 10 (ICD-10) gout diagnosis, urate-lowering therapy (ULT) prescription, uric acid crystal in joint aspiration and gout-related terms in problem lists, clinical or imaging reports. We assessed the positive and negative predictive value (PPV and NPV) of the query by chart reviews. ResultsOf 2,110,902 out- and inpatients, 10,289 had at least one criterion for gout. The combination of joint aspiration OR diagnostic in the problem list OR [&ge;] 2 other criteria created a register of 5,138 patients, with a PPV of 92.4% (95%CI: 88.5 to 95.0), and an NPV of 94.3% (95%CI: 91.9 to 96.0). PPV and NPV were similar amongst outpatients and inpatients. Incidence was 2.9 per 1000 person-year and dropped by 30% from the COVID-19 pandemic onward. Patients with gout were on average 71.2 years old (SD 14.9), mainly male (76.5%), overweight (69.5%) and polymorbid (mean number of comorbidities of 3, IQR 1-5). More than half (57.4%) had received a urate lowering treatment, 6.7% had a gout that led to a hospitalisation or [&ge;]2 flares within a year, and 32.9% received a rheumatology consultation. ConclusionAn automatic EHR-based gout register is feasible, valid and could be used to evaluate and improve gout management. Interestingly, the register uncovered a marked underdiagnosis or underreporting of gout since the COVID-19 pandemic. Key messagesWhat is already known on this topic? - Gout is the most prevalent inflammatory arthritis, but it remains undertreated despite affordable and effective treatment options. - Quantifying this undertreatment and detecting its causes and risk factors to pilot quality improvement initiative requires an extensive register of gout patients. What this study adds? - This is the first automatic EHR-based gout register, allowing frequent, inexpensive, and sustainable updates. - The automated queries show high positive and negative predictive values to identify gout patients. How this study might affect research, practice or policy? - This register can facilitate the assessment of the adequacy of gout management and the monitoring of quality indicators following improvement projects, or change in policies - It provides an easy platform for cohort studies or adaptive trials - Its methodology is reproducible, facilitating the establishment of gout or other disease registers within different EHR systems

ObjectivesAnti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE). Recently, an association of these autoantibodies with severe COVID-19 was reported in the general population. We assessed whether having pre-existing anti-IFN autoantibodies was associated with COVID-19 infection in SLE patients. MethodsPatients with SLE who developed COVID-19 between April 1st to October 1st, 2020 were studied. Biobanked pre-COVID-19 plasma from these SLE subjects and healthy controls were tested for anti-IFN IgG autoantibodies by ELISA. The ability of plasma anti-IFN autoantibodies to block signal transducer and activator of transcription 1 (STAT1) phosphorylation by recombinant human IFN in vitro was assessed by flow cytometry. ResultsTen SLE subjects with COVID-19 were identified. A 40% of these subjects had stable autoantibodies against IFN for up to three years preceding COVID-19 diagnosis. A 50% of the subjects with these autoantibodies neutralized IFN induced STAT1 phosphorylation.None of the other SLE samples blocked IFN signaling. ConclusionsWe noted an increased prevalence of pre-existing anti-IFN autoantibodies in SLE patients with COVID-19 compared to the reported prevalence in lupus patients and the general population with severe COVID-19. Autoantibodies against IFN in SLE patients may be pathogenic and patients with them maybe at-risk of developing COVID-19. Key MessagesO_ST_ABSWhat is already known about this subject?C_ST_ABS- Anti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE) and have recently been associated with severe COVID-19 in the general population. What does this study add?- SLE subjects with COVID-19 had an increased prevalence of pre-existing anti-IFN autoantibodies compared to the reported prevalence in lupus patients and the general population with severe COVID-19. - Plasma from 50% of subjects with these autoantibodies were able to block in vitro activity of IFN. - SLE patients with pre-existing anti-IFN autoantibodies had more severe COVID-19 manifestations. How might this impact on clinical practice or future developments?- Anti-IFN autoantibodies may be pathogenic and could prove to be a helpful prognostic marker to predict which SLE patient may develop COVID-19 and inform preventive measures and management of this subset of patients.

ObjectiveThis meta-analysis evaluates the association between HLA-DRB1 alleles and rheumatoid arthritis (RA) susceptibility in Mediterranean populations, incorporating regional subgroup analyses, heterogeneity assessment, and evidence quality grading. MethodsA systematic search was conducted across 11 major databases and grey literature sources until December 31, 2023. Eligible studies reported HLA-DRB1 allele frequencies in RA patients and controls from Mediterranean countries. Pooled odds ratios were calculated using random-effects models. Heterogeneity was assessed using Cochranes Q, I{superscript 2}, prediction intervals, cumulative distribution function and meta-regression. Risk of bias was evaluated using the Risk of Bias in Non-randomized Studies--of Exposures (ROBINS-E) tool. Publication bias was examined using funnel-plots, the trim-and-fill method, and Ruckers-test. Sensitivity analyses excluded studies with very-high risk of bias and performed leave-one-out diagnostics. Post hoc statistical power analyses were performed for each allele comparison. Evidence certainty was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Registered in PROSPERO (CRD42025641117). ResultsForty-eight studies from 13 Mediterranean countries (6,536 RA cases, 10,211 controls) were included. HLA-DRB1*01, *04, *09, and *10 were associated with increased RA risk, with *04 showing the highest pooled effect size (OR = 2.412, 95%CI [2.204-2.641]). HLA-DRB1*03, *07, *08, *11, *12, *13, and *14 were protective, with *13 having the lowest odds ratio (OR = 0.580, 95%CI [0.527-0.638]). Subgroup analyses identified additional risk variants (*01:01, *04:01, *04:04, *04:05, *04:08, and *10:01) and one protective allele (*04:03). No significant regional differences were found between Southern Europe and the Middle East and North Africa. Heterogeneity ranged from moderate to high (I{superscript 2} = 37.9%- 61.1%). Most allele comparisons exhibited sufficient power, although some associations (*03, *08, *09, and *04:03) were unstable in sensitivity analyses. Overall certainty of evidence was rated low to very low. ConclusionsHLA-DRB1*04 and *10 were strongly associated with RA risk, while *13 and *07 were protective. Although HLA-DRB1*09 was significantly associated with RA, it was unstable and supported by very low quality evidence. Despite similar patterns across regions, heterogeneity and study limitations underscore the need for better-controlled, population-specific genetic studies.

BackgroundSulfasalazine induced cytopenia, nephrotoxicity, and hepatotoxicity is uncommon during long-term treatment. Some guidelines recommend three monthly monitoring blood-tests indefinitely while others recommend stopping monitoring after one year. To rationalise monitoring we developed and validated a prognostic model for clinically significant blood, liver, or kidney toxicity during established sulfasalazine treatment. DesignRetrospective cohort study. SettingUK primary-care. Data from Clinical Practice Research Datalink Gold and Aurum formed independent development and validation cohorts. ParticipantsAge [&ge;]18 years, new diagnosis of an inflammatory condition and sulfasalazine prescription. Study period01/01/2007 to 31/12/2019. OutcomeSulfasalazine discontinuation with abnormal monitoring blood-test result. Analysis: Patients were followed-up from six months after first primary-care prescription to the earliest of outcome, drug discontinuation, death, 5 years, or 31/12/2019.Penalised Cox regression was performed to develop the risk equation. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination. Results8,936 participants were included in the development cohort (473 events, 23,299 person-years) and 5,203 participants were included in the validation cohort (280 events, 12,867 person-years).Nine candidate predictors were included. The optimism adjusted R2D and Royston D statistic in the development data were 0.13 and 0.79 respectively. The calibration slope (95% confidence interval (CI)) and Royston D statistic (95% CI) in validation cohort was 1.19 (0.96-1.43) and 0.87 (0.67-1.07) respectively. ConclusionThis prognostic model for sulfasalazine toxicity utilises readily available data and should be used to risk-stratify blood-test monitoring during established sulfasalazine treatment.<colcnt=1> Evidence before this study?O_LIHepatic, haematological, and renal toxicity from sulfasalazine occurs uncommonly after the first-few months of treatment. Nevertheless, the manufacturers and some specialist societies e.g., the American College of Rheumatology recommend monitoring blood-tests at three monthly intervals during established treatment. Other guidelines e.g., from the British Society of Rheumatology recommend no monitoring after the first two years of treatment. C_LIO_LIIt is not known whether hepatic, haematological, and renal toxicities due to sulfasalazine can be predicted and monitoring be risk-stratified. C_LI Added value of this study?O_LIThis study developed a prognostic model that discriminated patients at varying risk of sulfasalazine toxicity during long-term treatment. It had excellent performance characteristics in an independent validation cohort. C_LIO_LIThe model performed well across age-groups, and in people with rheumatoid arthritis and other inflammatory conditions. C_LIO_LIAny cytopenia or liver enzyme elevation prior to start of follow-up, chronic kidney disease stage-3, diabetes, methotrexate prescription, leflunomide prescription, and age were strong predictors of sulfasalazine toxicity. C_LI Implications of all the available evidenceO_LIThis prognostic model utilises information that can be easily ascertained during clinical visits. It can be used to inform decisions on the interval between monitoring blood-tests. C_LIO_LIThe results of this study ought to be considered by national and international Rheumatology guideline writing groups to rationalise monitoring during long-term sulfasalazine treatment. C_LI

BackgroundRheumatoid Arthritis (RA) is a chronic rheumatological condition which causes inflammation of both the joint lining and extra-articular sites. It affects around 1% of the UK population and, if not properly treated, can lead joint damage, disability, and significant socioeconomic burden. The risk of long-term damage is reduced if treatment is started in an early disease stage with treatment in the first 3 months being associated with significantly improved clinical outcomes. However, treatment is often delayed due to long referral waits and challenges in identifying early RA in primary care. We plan to use large primary care datasets to develop and validate an RA risk prediction model for use in primary care, with the aim to provide an additional mechanism for early diagnosis and referral for treatment. MethodsWe identified candidate predictors from literature review, expert clinical opinion, and patient research partner input. Using coded primary care data held in Clinical Practice Research Datalink (CPRD) Aurum, we will use a time to event Cox proportional hazards model to develop a 1-year risk prediction model for RA. This will be validated first in CPRD GOLD and then independently in the Secure Anonymised Information Linkage dataset. We will also conduct a sensitivity analysis for the same model at 2-5-year risk, with a secondary outcome of RA and initiation of a disease modifying drug, and with the addition of laboratory test results as candidate predictors. DiscussionThe resulting risk prediction model may provide an additional mechanism to distinguish early RA in primary care and reduce treatment delays through earlier referral.

IntroductionCoronavirus disease 2019 (COVID-19) has infected over 22 million individuals worldwide. It remains unclear whether patients with COVID-19 and Rheumatoid Arthritis (RA) experience worse clinical outcomes compared to similar patients with COVID-19 without RA. AimThe aim of this study is to provide insights on how COVID-19 impacted patients with RA given the nature of the disease and medication used. MethodsRA cases were identified via International Classification of Diseases (ICD) codes and COVID-19 cases by laboratory results in the U.S. based TriNetX network. Patients with COVID-19 and RA were propensity-score matched based on demographics with patients with COVID-19 without RA at a 1:3 ratio. A hospitalized sub-population was defined by procedure codes. ResultsWe identified 1,014 COVID-19 patients with RA and 3,042 non-RA matches selected from 137,757 patients. The odds of hospitalization (non-RA:23%, RA:24.6%, OR:1.08, 95% CI: 0.88 to 1.33) or mortality (non-RA:5.4%, RA:6%, OR:0.93, 95% CI: 0.65 to 1.34) were not significantly different. The hospitalized sub-population included 249 patients with COVID-19 and RA and 745 non-RA matches selected from 21,435 patients. The risk of intensive care unit (ICU) admission (non-RA:18.8%, RA:18.1%, OR:0.94, 95% CI: 0.60 to 1.45), and inpatient mortality (non-RA:14.4%, RA:14.5%, OR:0.86, 95% CI: 0.53 to 1.40) were not significantly different. ConclusionWe didnt find evidence suggesting patients with COVID-19 and RA are more likely to have severe outcomes than patients with COVID-19 without RA. Key Messages- Patients with Rheumatoid Arthritis (RA) tend to be older, and often have co-morbidities which could put them at greater risk of severe COVID-19 outcomes. - This study is one of the largest studies of COVID-19 infected RA populations to date. We did not find increased risk of hospitalization, ICU admission, or mortality among RA patients vs. matched non-RA patients. - Patients previously exposed to anti-coagulants experienced higher risks of hospitalization and overall mortality. Extra attention is needed for treating such patients.

BackgroundC282Y genetic homozygosity is the main cause of the iron-overload disorder haemochromatosis. Musculoskeletal pain and arthropathy are common in haemochromatosis, but less is known about chondrocalcinosis (cartilage calcification) with the C282Y variant, especially in the community. We assessed knee chondrocalcinosis in iDXA (dual-energy X-ray absorptiometer) images from UK Biobank volunteers by HFE genotype. MethodsData were from 236 European genetic ancestry C282Y homozygotes and 236 age, sex, and BMI-matched controls with no C282Y alleles (48-80 years, mean 64.6, SD {+/-}7.6). 435 of 472 participants had relevant left and right knee iDXA imaging. Evidence of chondrocalcinosis was assessed by an experienced reporting radiographer blind to genotype to ensure unbiased and objective evaluation. Logistic regression models were age, sex and BMI matched. ResultsKnee chondrocalcinosis was present in 15.9% (14/88) of C282Y homozygous males and <5.9% (<5/84) of males without variants (OR=7.76, 95% CI: 1.71-35.25, p=0.008). 57.1% (8/14) of the male homozygotes with knee chondrocalcinosis reported knee pain during the previous three months, but <28.6% also had a haemochromatosis diagnosis. In females, 6.0% (8/134) of C282Y homozygotes had knee chondrocalcinosis, vs <3.9% (<5/129) without variants. However, the odds of chondrocalcinosis were not significantly higher in C282Y homozygotes (OR=1.98, 95% CI: 0.58-6.76, p=0.273), therefore a larger sample size may be required to detect a smaller effect in female homozygotes. ConclusionIn this community genotyped sample, male C282Y homozygotes had a markedly increased odds of knee chondrocalcinosis. Evaluation of serum ferritin levels to identify possible haemochromatosis may be justified in knee chondrocalcinosis management.

ObjectivesInvestigate the prevalence and mortality impact of interstitial lung abnormalities (ILA) in rheumatoid arthritis (RA) and non-RA comparators. MethodsWe analyzed associations between ILA, RA, and mortality in COPDGene, a multicenter prospective cohort study of current or former smokers, excluding known interstitial lung disease (ILD) or bronchiectasis. All participants had research chest high-resolution computed tomography (HRCT) reviewed by a sequential reading method to classify ILA as present, indeterminate, or absent as well as fibrotic or nonfibrotic ILA subtype. RA cases were identified by self-report RA and DMARD use; non-RA comparators had neither an RA diagnosis nor used DMARDs. We examined the association and mortality risk of RA and ILA using multivariable logistic regression and Cox regression. ResultsWe identified 83 RA cases and 8725 non-RA comparators with HRCT performed for research purposes. ILA prevalence was 16.9% in RA cases and 5.0% in non-RA comparators. After adjusting for potential confounders including genetics, smoking, and other lifestyle factors, ILA were more common among those with RA compared to non-RA (OR 4.76 95%CI 2.54 to 8.92). RA with ILA or indeterminate for ILA was associated with higher mortality compared to non-RA without ILA (HR 3.16, 95%CI 2.11 to 4.74) and RA cases without ILA (HR 3.02, 95%CI 1.36 to 6.75). ConclusionsRA was associated with ILA and this persisted after adjustment for smoking and genetic/lifestyle risk factors. RA with ILA in chronic heavy smokers had 3-fold increased mortality, emphasizing the importance of further screening and treatment strategies for subclinical ILD in RA. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIUp to a third of patients with rheumatoid arthritis (RA) may have evidence of subclinical interstitial lung abnormalities on computed tomography (CT) scans of the chest. C_LIO_LICigarette smoking and the MUC5B promoter variant are known risk factors for RA-associated interstitial lung disease. C_LI What this study addsO_LIWe found that 17% of RA patients had subclinical interstitial lung abnormalities. RA had 4-fold higher odds of interstitial lung abnormalities than non-RA comparators, adjusted for smoking, the MUC5B promoter variant, and other factors. C_LIO_LIParticipants with RA and no interstitial lung abnormalities were not at increased mortality risk while those with interstitial lung abnormalities or indeterminate for ILA had a three-fold increased risk of mortality compared to RA and non-RA patients without interstitial lung abnormalities. C_LI How this study might affect research, practice or policyO_LIThe presence of subclinical interstitial lung abnormalities confers significant mortality risk in RA and emphasizes the need to establish the clinical utility of screening, prevention, and treatment strategies targeting subclinical lung disease. C_LI

ObjectivesPatients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) are at increased long-term risk of cardiometabolic diseases. The prevalence of obesity in AAV has not been well documented. We aimed to characterise change in body weight following a diagnosis of active AAV and to determine the risk factors for this. MethodsWe examined data from a single-centre registry of patients with AAV, diagnosed between 2003 and 2023. We evaluated changes in body weight and BMI following diagnosis. Using linear regression, we identified factors contributing to an increase in BMI at six-months. Logistic regression was used to define predictors for obesity at six-months. ResultsTwo-hundred and fifteen patients with active AAV were included in the analysis. Patients experienced a mean gain in body weight of 5.2% in the first six-months; this was maintained for at least two-years. 64.1% of patients were overweight or obese at six-months. Weight gain was greater following first presentation of AAV compared to relapsing disease. Baseline factors associated with an increase in BMI at six-months included higher eGFR ({beta}=0.70 [0.36-1.03], P<0.001) and earlier year of presentation ({beta}=0.38 [0.08-0.69], P=0.008). Higher eGFR (aOR=1.36 (1.08-2.72), P<0.001) and baseline BMI (aOR=2.57 (1.81-3.64), P<0.001) were associated with an increased likelihood of obesity at six-months. ConclusionWeight gain is common following a diagnosis of active AAV. This is less pronounced than it was two-decades ago. Better kidney function and higher baseline BMI are associated with a greater risk of being obese at six-months. Management of AAV should include risk mitigation for developing an unhealthy high BMI. Key messagesO_LIWeight gain and an unhealthy high BMI are prevalent following diagnosis of active AAV. C_LIO_LIHigher baseline eGFR is associated with greater weight-gain in the first six-months following diagnosis. C_LIO_LIWeight gain is less pronounced following treatment of relapsing disease compared to initial presentation. C_LI

ObjectivesWe aimed to estimate how rheumatology healthcare use has changed since the COVID-19 pandemic and determine demographic characteristics associated with observed changes in healthcare use. MethodsUsing three primary and secondary care electronic health record datasets in England (with the approval of NHS England), Scotland, and Wales, we identified individuals with a diagnosis of rheumatoid arthritis (RA) before 01/04/2019. We determined the proportion of people with rheumatology hospital outpatient appointments each month (April 2019-December 2022 (Wales and Scotland), April 2019-November 2023 (England)) and quantified changes using interrupted time-series analysis. We used logistic regression to determine characteristics associated with having fewer appointments compared to 2019. ResultsWe identified 145,065, 3,813 and 13,637 individuals coded with RA in England, Scotland, and Wales, respectively. At the start of the COVID-19 pandemic the number of rheumatology outpatient appointments dropped sharply across all nations. In England and Scotland, the percentage of monthly appointments has continued to decline. In Wales, while there was a gradual recovery, rheumatology services have not returned to pre-pandemic levels. In contrast, the number of appointments for all other specialist outpatient appointments have recovered in all nations. Ethnic minorities, those living in more deprived areas and urban areas had fewer appointments after the start of the pandemic compared to 2019. ConclusionFor the first time, we compared healthcare use across three UK nations and found that rheumatology outpatient appointments had not recovered to pre-COVID-19 pandemic levels, particularly in Scotland and England. Certain patient groups had fewer appointments during the study period. Key messagesO_LIRheumatology outpatient appointments remain below pre-pandemic levels, particularly in England and Scotland, unlike other specialties. C_LIO_LIEthnic minorities, deprived communities, and urban residents had fewer rheumatology appointments post-pandemic than in 2019. Rheumatology services need data-driven strategies to provide better support, tailored to local community needs. C_LI

BackgroundRisk factors and screening strategies for rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have received limited evaluation in patients with early RA. We investigated RA-ILD prevalence, risk factors, and the performance of proposed RA-ILD screening methodologies in a multicenter, prospective study of patients with early RA. MethodsParticipants with early RA, defined as being within two years of RA diagnosis, were enrolled at five US sites and assessed with high-resolution computed tomography (HRCT) chest imaging, pulmonary function tests, and autoantibodies. RA-ILD presence was determined through independent HRCT review by thoracic radiologists. We investigated RA-ILD risk factors using multivariable logistic regression and reported the predictive performance of RA-ILD screening strategies (ANCHOR-RA, 2023 ACR/CHEST, Four Factor Score, and ESPOIR). ResultsAmong 172 participants (74% female, 82% seropositive, median RA duration 0.79 years, mean age 55.3 years), 19 (11%) had ILD on HRCT. Moderate/high RA disease activity by DAS28-ESR (OR 7.00 [1.95, 25.1]) and age [&ge;]60 years (OR 3.87 [1.33, 11.3]) were associated with RA-ILD. Sensitivity and specificity of screening strategies ranged from 0.32-0.95 and 0.32-0.81, respectively. The number of early RA patients needing screening to detect one ILD case ranged from 3.6 to 6.4. DiscussionIn this prospective, multicenter study, ILD prevalence in early RA was 11%. Disease activity and older age were strongly associated with ILD in early RA, and several proposed ILD screening strategies performed showed promise for enabling ILD screening in early RA. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSO_LISeveral risk factors for rheumatoid arthritis-associated interstitial lung disease have been identified. However, most prior studies have focused on patients with established RA. C_LIO_LISeveral approaches to RA-ILD screening have been proposed, including the recent 2023 ACR/CHEST guidelines. However, none have been specifically evaluated in patients with early RA. C_LI What this study addsO_LIIn a multicenter, prospective cohort of patients with early RA (diagnosed within 2 years of enrollment), moderate or high RA disease activity and older age were significantly associated with evidence of interstitial lung disease on high resolution CT chest imaging. C_LIO_LISeveral proposed RA-ILD screening criteria performed well in the early RA period. The simplest screening strategy included older age, male sex, and moderate/high RA disease activity and had a number needed to screen of 3.6 patients to detect one RA-ILD case. C_LI How this study might affect research, practice or policyO_LISimple screening strategies using demographic and clinical data may enable selection of early RA patients for RA-ILD screening. C_LI

ObjectiveAn increased risk of primary biliary cholangitis (PBC) has been reported in patients with systemic sclerosis (SSc). Our study aims to investigate the shared genetic susceptibility between the two disorders and to define candidate causal genes using cross-phenotype GWAS meta-analysis. MethodsWe performed cross-phenotype GWAS meta-analysis and colocalization analysis for SSc and PBC. We performed both genome-wide and locus-based analysis, including tissue and pathway enrichment analyses, fine-mapping, colocalization analyses with expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets, and phenome-wide association studies (PheWAS). Finally, we used an integrative approach to prioritize candidate causal genes from the novel loci. ResultsWe detected a strong genetic correlation between SSc and PBC (rg = 0.84, p = 1.7 x 10-6). In the cross-phenotype GWAS meta-analysis, we identified 44 non-HLA loci that reached genome-wide significance (p < 5 x 10-8). Evidence of shared causal variants between SSc and PBC was found for nine loci, five of which were novel. Integrating multiple sources of evidence, we prioritized CD40, ERAP1, PLD4, SPPL3, and CCDC113 as novel candidate causal genes. The CD40 risk locus colocalized with trans-pQTLs of multiple plasma proteins involved in B cell function. ConclusionOur study supports a strong shared genetic susceptibility between SSc and PBC. Through cross-phenotype analyses, we have prioritized several novel candidate causal genes and pathways for these disorders. Key messages What is already known on this topicO_LISystemic sclerosis (SSc) and primary biliary cholangitis (PBC) are autoimmune disorders that exhibit overlapping clinical and histological features. C_LIO_LIThe prevalence of PBC is higher in patients with SSc compared to the general population. C_LIO_LIMultiple susceptibility genomic loci have been identified for SSc and PBC through genome-wide association studies (GWAS). C_LI What this study addsO_LIThere is a strong genetic correlation between SSc and PBC, comparable in magnitude to the genetic correlation between SSc and systemic lupus erythematosus (SLE). This shared genetic susceptibility aligns with the observed increased relative risk of developing PBC and SLE in individuals with SSc. C_LIO_LIUsing cross-phenotype GWAS and colocalization analysis, we have discovered nine genomic loci that account for the shared genetic etiology. Five of the nine loci were novel. C_LIO_LIUsing an integrative approach, we have prioritized five novel candidate causal genes: CD40, ERAP1, PLD4, SPPL3 and CCDC113. C_LIO_LIThe CD40 risk allele for SSc and PBC is paradoxically associated with reduced CD40 levels. Causal inference analyses indicate that this reduction in CD40 levels, due to CD40 locus polymorphism, leads to an increase in various plasma proteins involved in B cell activation, including the CD40 ligand. C_LI How this study might affect research, practice or policyO_LIMechanistic studies are needed to confirm the candidate causal genes prioritized by our in silico analyses. C_LIO_LIOur study advocates for heightened awareness among rheumatologists regarding the possibility of concurrent PBC in patients with SSc. C_LI

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease affecting approximately 0.5-1.0% of the adult population and is a significant contributor of disability worldwide. While Phase III randomized controlled trials (RCTs) remain the gold standard for evaluating pharmacological treatments, they often fail to capture outcomes that reflect patients lived experiences, also referred to as functioning. The International Classification of Functioning, Disability and Health (ICF) Brief Core Set for RA offers a standardized, patient-centered framework for assessing functioning across relevant domains. ObjectiveTo examine the extent to which functioning-related outcomes in Phase III pharmacological RCTs for RA align with the ICF Brief Core Set for RA and to identify the most frequently represented functioning categories. MethodsA scoping review was conducted following PRISMA-ScR guidelines. Literature was searched in MEDLINE, EMBASE, and ClinicalTrials.gov from 2010 to 2025. Phase III RCTs evaluating pharmacological interventions in adult patients with RA were included. Functioning-related outcomes were extracted and mapped to ICF categories using standardized linking rules. ResultsOf 852 records screened, 91 met the inclusion criteria. Functioning was frequently assessed through patient-reported outcomes and composite clinical measures. The most commonly linked ICF categories included sensation of pain (b280) and mobility of joint functions (b710) from the body functions domain; walking (d450) and carrying out daily routine (d230) from the activities and participation domain; and structures of the shoulder (s720), upper (s730), and lower extremities (s740) from the body structures domain. However, none of the studies explicitly used the ICF framework. ConclusionFunctioning is implicitly assessed in RA pharmacological trials, yet the ICF framework remains underutilized. Explicit integration of the ICF Brief Core Set for RA into trial design could improve the standardization, comparability, and patient-centeredness of outcome measurement, ensuring that clinical research better reflects what matters most to individuals living with RA.

BackgroundObesity is associated with lower treatment response in patients with rheumatoid arthritis (RA). Among obese patients, abatacept was suggested as a preferable option to tumour necrosis factor alpha (TNF) inhibitors. Sex and gender differences in RA were described. ObjectivesTo assess the comparative effectiveness of etanercept, infliximab, and abatacept, compared to adalimumab, in patients with RA stratified by body mass index (BMI) and sex. MethodsObservational cohort study in the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry (1997-2019). RA patients were classified in BMI-based cohorts: obese, overweight, and normal weight. Each BMI cohort was studied overall and stratified by sex. The study outcome was remission within 12-months, defined as a disease activity score (DAS28) <2.6. Missingness was addressed using confounder-adjusted response rate with attrition correction (CARRAC). Logistic regression compared the effectiveness of etanercept, infliximab, and abatacept versus adalimumab. ResultsThe study included 443 obese, 829 overweight, and 1243 normal weight RA patients. Across the BMI cohorts, there were no significant differences in the odds of remission at [&le;]12-months for the study drugs compared to adalimumab. However, among females, an inverse effect for infliximab was found, whereby overweight patients had higher odds of remission, while obese patients had lower odds of remission, compared to the respective adalimumab users. ConclusionsDespite the previous hypothesis, treatment with abatacept showed similar odds of remission compared to adalimumab in all BMI cohorts. Conversely, compared to adalimumab, infliximab performed better in overweight female patients but worse in female patients with obesity. However, further validation is needed.