The Lancet Rheumatology

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

ObjectivesTo examine seasonal trends in the prescription of colchicine MethodsA retrospective cohort study using a population level dataset of all community prescriptions for colchicine dispensed in England between December 2014 and November 2019. ResultsSignificant seasonal variation exists in colchicine prescriptions (p<0.0001). Colchicine prescriptions were maximal in the summer months (June, July) in each of the years studied and lowest in the winter. Significant variation in colchicine prescriptions was observed between the summer and the winter(p<0.001), spring (p=0.0177) and autumn(p<0.001) months. ConclusionSeasonal trends in colchicine prescribing closely mirror previously observed seasonal trends in acute gout incidence providing further evidence that acute gout demonstrates seasonality and, in England, is more common in the summer.

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

Background. Polypharmacy is common in autoimmune rheumatic diseases (ARDs) and increases adverse drug events (ADEs), but comparative evidence across diseases is limited. We aimed to quantify ADE burden and identify medications associated with ADE risk across six ARDs, and to examine shared and disease specific patterns across diseases. Methods. We conducted a retrospective cohort study at a tertiary medical center (2010 to 2024). Adults with ankylosing spondylitis (AS), psoriatic arthritis (PsA), rheumatoid arthritis (RA), Sjogren's disease (SjD), systemic lupus erythematosus (SLE), or systemic sclerosis (SSc) were identified using diagnostic codes. ADEs were ascertained using validated case definitions. Medications were mapped to Anatomical Therapeutic Chemical classes; active exposure was defined within 30 days before the index date. Polypharmacy was defined as more than 5 concurrent medications (minor 5 to 10; major >10). Within each ARD, nested case control analyses matched on encounter type (1:4) were performed, and adjusted odds ratios (aORs) were estimated using conditional logistic regression. Findings. Among 10,578 patients, 3,154 (29.8%) experienced at least one ADE. ADE burden varied across diseases, with the highest prevalence observed in SSc (35.9%). Polypharmacy was common (57.3% minor, 39.4% major) and medication burden was consistently higher in ADE cases across encounter types (eg, SLE outpatient median 12 vs 6; inpatient 20 vs 10; emergency 17 vs 8). Across ARDs, the strongest associations with ADEs were observed for supportive and symptom directed therapies (acid suppressors, pain adjuncts, and sedative hypnotic/psychotropic medications), whereas conventional disease-modifying antirheumatic drugs (DMARDs) showed weaker associations. Disease-specific signatures included gastrointestinal agents in SSc (metoclopramide aOR 12.32), antibiotics and respiratory agents in AS (ciprofloxacin aOR 13.71, fluticasone aOR 8.88). Interpretation ADEs affect nearly one third of ARD patients and increase with medication burden. Risk concentrates in supportive and symptom directed therapies rather than DMARDs, with both shared and disease-specific patterns. Optimizing prescribing, particularly for pain management and corticosteroid use, can reduce medication-related harm.

ObjectiveTo assess the comparative efficacy and safety of approved biologic disease-modifying antirheumatic drugs (bDMARDs), biosimilars, and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) for patients with rheumatoid arthritis (RA) who had inadequate responses to methotrexate (MTX). Results53 eligible studies were identified and 44 studies were included in a network meta-analysis. Using Surface Under the Cumulative Ranking Curve (SUCRA), tofacitinib (10 mg bid) with MTX [Relative risk (RR) 95% confidence interval (CI) 4.65 (2.98-7.27)] and tofacitinib (10 mg bid) [RR (95%CI)1.96 (1.27-3.03)] were ranked highest among tsDMARDs for increasing remission rate at 24-26 weeks and 48-52 weeks, respectively. For bDMARDs, tocilizumab (8 mg/kg) with MTX was ranked with highest treatment effect for remission at both 24-26 and 48-52 weeks [RR (95%CI) 3.06 (2.27-4.12); RR (95%CI) 2.52 (1.94-3.28)]. For safety, baricitinib (4 mg) and tofacitinib (5 mg bid) with MTX likely showed an increased risk of HZ with statistical significance [for baricitinib, RR (95%CI) 3.52 (1.38-9.02) at 24-26 weeks, and RR (95%CI) 4.20 (1.22-14.48) at 48-52 weeks, and for tofacitinib, RR (95%CI) 5.38 (1.00-28.91) at 48-52 weeks]. No statistically significant safety concerns for serious infection, tuberculosis (TB), cancer, and cardiovascular (CV) events were identified. ConclusionsFor RA patients who failed MTX, bDMARDs, biosimilars, and tsDMARDs monotherapy and combination therapy with MTX provided better treatment outcomes than MTX monotherapy with modest safety concerns within 24-52 weeks. A scarcity of longer-term effects and post-market surveillance necessitates further analyses using long-term patient-level data to improve the medication profile. Rheumatology key messagesO_LIFor RA patients who failed MTX and other conventional DMARDs, different types of DMARDs are available. C_LIO_LIAt dose- and time point-specific levels, tofacitinib (10 mg bd) showed the highest probability to be the most effective in achieving remission at 24-26 weeks. C_LIO_LIAn increased risk of herpes zoster was found for baricitinib (4 mg) and tofacitinib (5 mg bid) with MTX. C_LI

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

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

ObjectivesTo investigate COVID-19 breakthrough infection after third mRNA vaccine dose among patients with RA by immunomodulator drug class, and we hypothesized that CD20 inhibitors (CD20i) would have higher risk for breakthrough COVID-19 vs. TNF inhibitors (TNFi). MethodsWe performed a retrospective cohort study investigating breakthrough COVID-19 among RA patients at Mass General Brigham in Boston, MA, USA. Patients were followed from the date of 3rd vaccine dose until breakthrough COVID-19, death, or end of follow-up (18/Jan/2023). Covariates included demographics, lifestyle, comorbidities, and prior COVID-19. We used Cox proportional hazards models to estimate breakthrough COVID-19 risk by immunomodulator drug class. We used propensity score (PS) overlap-weighting to compare users of CD20i vs. TNFi. ResultsWe analyzed 5781 patients with RA that received 3 mRNA vaccine doses (78.8% female, mean age 64.2 years). During mean follow-up of 12.8 months, 1173 (20.2%) had breakthrough COVID_19. Use of CD20i (adjusted HR 1.74, 95%CI 1.30-2.33) and glucocorticoid monotherapy (adjusted HR 1.47, 95%CI 1.09-1.98) were each associated with breakthrough COVID-19 compared to TNFi use. In the PS overlap-weighted analysis, CD20i users also had higher breakthrough COVID-19 risk than TNFi users (HR 1.62, 95%CI 1.02-2.56). A sensitivity analysis excluding patients with cancer or interstitial lung disease yielded similar findings. ConclusionsWe identified CD20i and glucocorticoid monotherapy as risk factors for breakthrough COVID-19 among patients with RA after a 3rd vaccine dose. This contemporary study highlights the real-world impact of blunted immune responses in these subgroups and the need for effective risk mitigation strategies. What is already known about this topicO_LIPatients with RA are at increased risk for COVID-19 breakthrough infection after two vaccine doses so a third dose is recommended to complete the initial series. C_LIO_LISome immunomodulator medications, particularly CD20 inhibitors, can impact vaccine immunogenicity and waning. C_LI What this study addsO_LICD20 inhibitor use was associated with increased risk of COVID-19 breakthrough infection in people with RA who received 3 vaccine doses compared to TNF inhibitor use. C_LIO_LIGlucocorticoid monotherapy was also associated with increased risk of COVID-19 breakthrough infection. C_LI How this study might affect research, practice or policyO_LIPatients with RA who are using CD20 inhibitors or glucocorticoid monotherapy should be prioritized for risk mitigation strategies after the initial vaccine series of 3 mRNA doses. C_LIO_LIThe impact of additional vaccine doses, timing of medication dosing, and other protective measures will need further study. C_LI

ObjectiveRheumatic disease patients on certain immunomodulators are at increased risk of impaired humoral response to SARS-CoV-2 vaccines. We aimed to identify factors associated with breakthrough infection among patients with rheumatic diseases. MethodsWe identified patients with rheumatic diseases being treated with immunomodulators in a large healthcare system who received at least two doses of either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) vaccines or one dose of the Johnson & Johnson-Janssen (J&J) vaccine. We followed patients until SARS-CoV-2 infection, death, or December 15, 2021, when the Omicron variant became dominant in our region. We estimated the association of baseline characteristics with the risk of breakthrough infection using multivariable Cox regression. ResultsWe analyzed 11,468 patients (75% female, mean age 60 years). Compared to antimalarial monotherapy, multiple immunomodulators were associated with higher risk of infection: anti-CD20 monoclonal antibodies (aHR 5.20, 95% CI: 2.85, 9.48), CTLA-4 Ig (aHR 3.52, 95% CI: 1.90, 6.51), mycophenolate (aHR 2.31, 95% CI: 1.25, 4.27), IL-6 inhibitors (aHR 2.15, 95% CI: 1.09, 4.24), JAK inhibitors (aHR 2.02, 95% CI: 1.01, 4.06), and TNF inhibitors (aHR 1.70, 95% CI: 1.09, 2.66). mRNA-1273 recipients had a lower risk of breakthrough infection compared to BNT162b2 recipients (aHR 0.66, 95% CI: 0.50, 0.86). There was no association of sex, body mass index, smoking status, race, or ethnicity with risk of breakthrough infection. ConclusionAmong patients with rheumatic diseases, multiple immunomodulators were associated with increased risk of breakthrough infection. These results highlight the need for additional mitigation strategies in this vulnerable population.

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.

ObjectiveVaccination decreases the risk of severe COVID-19 but its impact on post-acute sequelae of COVID-19 (PASC) is unclear among patients with systemic autoimmune rheumatic diseases (SARDs) who may have blunted vaccine immunogenicity and be vulnerable to PASC. MethodsWe prospectively enrolled SARD patients from a large healthcare system who survived acute infection to complete surveys. The symptom-free duration and the odds of PASC (any symptom lasting [&ge;] 28 or 90 days) were evaluated using restricted mean survival time and multivariable logistic regression, respectively, among those with and without breakthrough infection ([&ge;] 14 days after initial vaccine series). ResultsAmong 280 patients, the mean age was 53 years, 80% were female, and 82% were white. The most common SARDs were inflammatory arthritis (59%) and connective tissue disease (24%). Those with breakthrough infection had more upper respiratory symptoms, and those with non-breakthrough infection had more anosmia, dysgeusia, and joint pain. Compared to those with non-breakthrough COVID-19 infection (n=164), those with breakthrough infection (n=116) had significantly more symptom-free days over the follow-up period (+28.9 days, 95% CI: 8.83, 48.89; p=0.005) and lower odds of PASC at 28 and 90 days (aOR 0.49, 95% CI: 0.29, 0.83 and aOR 0.10, 95% CI: 0.04, 0.22, respectively). ConclusionVaccinated patients with SARDs were less likely to experience PASC compared to those not fully vaccinated. These findings support the benefits of vaccination for patients with SARDs and suggest that the immune response to acute infection is important in the pathogenesis of PASC in SARD patients. Key MessagesO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LIPost-acute sequelae of COVID-19 (PASC) affects 20-50% of COVID-19 survivors, though the impact of vaccination on the risk and severity of PASC is unclear, especially among those with systemic autoimmune rheumatic diseases (SARDs) who may have impaired responses to vaccines and be particularly vulnerable to PASC. C_LI What this study adds?O_LIIn this prospective cohort of SARD patients recovering from COVID-19, we found that those with breakthrough vs non-breakthrough infection had more symptom-free days over the follow-up period (adjusted difference +28.9 days, 95% CI: 8.38, 48.89; p=0.005) and a lower odds of PASC at 28 days (aOR 0.49, 95% CI: 0.29, 0.83) and at 90 days (aOR 0.10, 95% CI: 0.04, 0.22). C_LIO_LIPatient-reported pain and fatigue scores were lower, reflecting less severe pain and fatigue, in those with breakthrough infection compared to those with non-breakthrough infection. C_LI How this study might affect research, practice, or policy?O_LIThis study extends our understanding of the benefits of vaccination against COVID-19 in patients living with SARDs and reinforces the importance of vaccinating this vulnerable population. C_LIO_LIOur findings suggest that the initial immune response to acute SARS-CoV-2, as influenced by vaccination, affects PASC risk but this requires further study. C_LI

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.

ObjectiveThe Broccoli in Osteoarthritis (BRIO Study) was conducted to determine whether dietary sulforaphane (SFN), consumed as broccoli, improves pain and/or physical function in participants with knee osteoarthritis (OA). This was a proof of principle study to test the feasibility of the trial to optimise the design of an appropriately powered study. DesignTwo-centre, double-blind, two-arm parallel, randomised placebo-controlled, dietary intervention feasibility trial. Patients with radiographic knee osteoarthritis (Kellgren-Lawrence score 2-3), with pain of at least 4 on a scale of 0-10 were recruited. The intervention was a high glucoraphanin broccoli, (source of SFN), or a matched placebo (no SFN) soup. Pain and measures of physical function were measured at baseline, 6 and 12 weeks. ResultsThe mean WOMAC pain score (scale 0 - 20) was decreased by 4.2 (95% CI: 1.03,7.38) following intervention, Similar patterns of improvement were observed for other pain and function outcome measures. Study data, sample collections and intervention adherence were 100% compliant except where COVID restrictions applied. Acceptability for randomisation was 100% and acceptability for the intervention was 92%. There were three related adverse events, two of which were expected. ConclusionsHigh glucosinolate broccoli soup is a novel approach to managing OA that is widely accessible and can be used on a large scale. This study shows that it is an acceptable way of delivering dietary bioactives and has potential for therapeutic benefit. The primary outcome of pain improved in the intervention group compared to the placebo and the confidence interval encompassed the minimal clinically important difference. The data provide justification for proceeding to a large scale, appropriately powered intervention trial.

ImportanceCarriage of HLA-B*58:01 has been shown to have a strong association with the development of allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and drug reaction and eosinophilia and systemic symptoms (DRESS) in many populations globally; however, there is a critical need to determine if this is generalizable to varying populations including those in the United States (US). ObjectiveTo perform HLA class I and II association studies in a cohort of US patients diagnosed with allopurinol-induced SJS/TEN or DRESS compared to allopurinol tolerant and population controls. Design, Setting, and ParticipantsWe enrolled consenting individuals who had specialist adjudicated allopurinol-induced SJS/TEN or DRESS (collectively allopurinol-SCAR). HLA carriage in these cases was compared to allopurinol tolerant and population controls identified through Vanderbilt University Medical Center (VUMC) BioVU, a biobank which includes 94,489 individuals with imputed human leukocyte antigen (HLA) class I and II typing from genotyping array data. Main Outcomes and MeasuresWe performed HLA class I and II conditional logistic regression case-control analyses between allopurinol-SCAR cases and both population controls and allopurinol tolerant controls matched on age, sex, and self-identified race. We reported odds ratio (OR) and 95% confidence interval (CI) with Bonferroni corrected P (Pc) <.05. ResultsThe conditional logistic regression analyses included allopurinol-SCAR cases (n=16) and 10:1 matched allopurinol tolerant controls (n=160). We found two HLA class I alleles independently associated with increased risk of allopurinol-induced SCAR: HLA-B*58:01 (OR 28 [95% CI, 8.6 - 100.6]) and HLA-A*34:02 (OR 20.6 [95% CI, 3.3 - 131.1]). We did not identify any HLA class II alleles meeting the Pc level of significance. Conclusions and RelevanceWe found HLA-B*58:01 to be strongly associated with allopurinol-induced SCAR, generalizing findings from previous studies. Additionally, we found HLA-A*34:02 to be a second independent genetic risk factor for allopurinol-SCAR. These findings underscore the need to conduct specific population-based studies that both reproduce known and uncover novel HLA associations in order to reduce harm through contributions to screening, risk stratification, and diagnosis. KEY POINTSO_ST_ABSQuestionC_ST_ABSIs the association between HLA-B*58:01 and allopurinol-SCAR generalizable to admixed populations in the US or are additional HLA associations involved? FindingsIn this HLA association study with 16 patients of primarily self-identified Black race of adjudicated allopurinol-induced SJS/TEN or DRESS, we demonstrate a strong association with the established risk allele, HLA-B*58:01, and, for the first time, identified HLA-A*34:02 as an additional independent risk factor. MeaningHLA-B*58:01 is absent in more than one-third of our US cohort of allopurinol-SCAR cases suggesting that more comprehensive screening and diagnostic approaches are necessary to prevent additional cases in genetically heterogenous populations.

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.

Background. Tocilizumab (TCZ), a monoclonal antibody directed against the interleukin-6 receptor, is used in rheumatoid arthritis (RA) after inadequate response or secondary loss of response to conventional synthetic and biological disease-modifying antirheumatic drugs (DMARDs). Real-world data from North African cohorts remain scarce. We assessed the effectiveness and safety of TCZ in routine care and explored baseline factors associated with 6-month outcomes. Methods. We conducted a retrospective, single-centre cohort study of 44 consecutive patients with RA treated with TCZ between April 2019 and January 2024 in the Department of Rheumatology, Moulay Ismail Hospital, Meknes, Morocco. Demographic, clinical, laboratory, treatment and follow-up data were extracted from medical records using a standardised electronic form. The primary effectiveness outcome was the European Alliance of Associations for Rheumatology (EULAR) response at 6 months; DAS28-ESR remission was defined as DAS28-ESR below 2.6. Safety outcomes comprised infections, neutropenia, liver-enzyme abnormalities and lipid abnormalities. Longitudinal changes were compared with the Wilcoxon signed-rank test, and associations between baseline variables dichotomised at their median and 6-month outcomes were examined with chi-square tests, in SPSS version 29. Results. The cohort comprised 33 women (75.0%), with a median age of 57 years (range 32-82) and a mean RA duration of 12.97+/-9.1 years. Patients had received a mean of 2.5+/-1.8 previous conventional DMARDs, and 41 (93.2%) had received at least one previous biological agent, including two or more tumour necrosis factor (TNF) inhibitors in 36 (81.8%). At 6 months, outcome data were available for 34 patients: 23 (67.6%) achieved a good EULAR response, 6 (17.6%) a moderate response and 5 (14.7%) no response; 12 (35.3%) were in DAS28-ESR remission. Mean DAS28-ESR fell from 5.10+/-1.18 at baseline to 2.74+/-1.38 at 6 months and 2.45+/-1.33 at 12 months, and the mean prednisone-equivalent dose fell from 8.3+/-7.1 to 5 mg/day. Twenty-two infectious episodes were recorded, including one serious infection (purulent pleurisy) requiring hospitalisation; 5 patients (11.4%) had a temporary interruption and 1 (2.3%) a permanent discontinuation for hepatic cytolysis. A neutrophil count below 1,500/mm3 occurred in 13 patients (29.5%), with no count below 1,000/mm3, while mean neutrophils declined from 6.3+/-3.0 to 2.6+/-1.2 G/L at 12 months. Mean LDL cholesterol rose from 1.18 to 1.49 g/L and HDL cholesterol from 0.58 to 0.82 g/L. Rheumatoid-factor positivity was the only baseline variable associated with the EULAR response category (p=0.007); a baseline tender joint count above six was associated with a lower remission rate (23.5%, p=0.007), as was, borderline, a pain visual analogue scale above 65 mm (31.2%, p=0.05). Conclusions. In this heavily pretreated real-world RA cohort, TCZ was associated with a substantial and sustained reduction in disease activity and a manageable safety profile consistent with its known signals. A high baseline articular and pain burden was associated with a lower probability of remission. The small sample, incomplete 6-month follow-up, retrospective design and absence of adjusted effect estimates limit interpretation, and the reported associations should be regarded as hypothesis-generating.

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

ObjectivePatients with immunological diseases exhibit distinct comorbidity patterns, categorized into low comorbidity, polyautoimmunity, and polyinflammation clusters. This retrospective cohort study aimed to validate these profiles in rheumatoid arthritis (RA), examine their longitudinal trajectories, and assess their impact on treatment persistence. MethodsRA patients receiving targeted therapies, and their associated treatments, were identified from the French pharmacy dispensing database LRx. Comorbidity clusters were assigned using a multinomial regression model, and state sequence analysis with hierarchical clustering was used to define temporal trajectories. Cox regression models evaluated DMARD persistence across trajectories. ResultsAmong 15,189 RA patients (maximum follow-up: 10 years), initial comorbidity profiles included low comorbidity (61.9%), polyautoimmunity (24.7%), and polyinflammation (13.4%). Four trajectory patterns emerged: stable low comorbidity (50%), dominant polyautoimmune (31%), stable polyinflammatory (9%), and low comorbidity switching to polyinflammation (polyinflammation switchers, 10%). The prevalence of polyautoimmunity and polyinflammation increased with age by 2.5% and 3.8% per decade, respectively. Patients with stable polyinflammation had the lowest classical synthetic DMARD persistence (HR: 1.79 [1.33-2.42], reference: polyinflammation switchers). Stable low comorbidity patients had the highest biological and targeted synthetic DMARD persistence (polyinflammation switchers aHR: 1.32 [1.09-1.60], reference: stable low comorbidity). ConclusionComorbidity trajectories in RA influence DMARD persistence, reflecting distinct etiopathological subgroups with potential theranostic relevance.

ObjectivesIdentifying causal biomarkers of rheumatoid arthritis (RA) to improve treatment and monitor disease progression remains a critical but elusive goal. To search for putatively causal protein biomarkers of RA, we designed an integrative genomic strategy utilizing Mendelian randomization (MR), which allows for causal inference between an exposure and an outcome by incorporating genetic variants associated with an exposure (circulating protein level) and inferring its effect on the outcome (rheumatoid arthritis). MethodsWe utilized genetic variants associated with 71 cardiovascular disease-related proteins measured in nearly 7000 Framingham Heart Study participants in conjunction with variants associated with RA in a genome-wide association study (GWAS) from the UK Medical Research Council Integrative Epidemiology Unit (19,234 cases, 61,565 controls) to identify putatively causal proteins for RA. In addition, we applied MR to study circulating rheumatoid factor (RF) levels using GWAS of RF from the UK Biobank (n=30,565) as the outcome. ResultsWe identified the soluble receptor for advanced glycation end products (sRAGE), a critical inflammatory pathway protein, as putatively causal and protective for both RA (odds ratio per 1 standard deviation increment in inverse-rank normalized sRAGE level=0.482; 95% confidence interval 0.374-0.622; p=1.85x10-08) and RF levels ({beta} [change in RF level per sRAGE increment]=-1.280; SE=0.434; p=0.003). ConclusionsBy integrating GWAS of 71 cardiovascular disease-related proteins, RA, and RF, we identified sRAGE as a putatively causal protein protective for both RA ad RF levels. These results highlight the AGER/RAGE axis as a promising new target for RA treatment.

Objectives To evaluate whether access to a certified large language model (LLM)-based clinical decision support system improves physician diagnostic performance in rheumatology compared with conventional diagnostic resources alone. Methods In this multicentre, open-label, randomised controlled trial, 82 physicians from seven hospitals in two countries were randomised 1:1 to conventional diagnostic resources plus Prof. Valmed or conventional resources alone. Participants assessed three rheumatology vignettes before and after assistance. The primary outcome was top-1 diagnostic accuracy. Secondary outcomes included top-3 accuracy, diagnostic reasoning, confidence, case-processing time and perceived support quality. Results Top-1 accuracy increased from 22.2% to 33.3% in the intervention group and from 23.3% to 35.0% in the control group, with no between-group difference in improvement (adjusted OR 0.99, 95% CI 0.45 to 2.19; p=0.979). Differences in top-3 accuracy, diagnostic reasoning and confidence were also not significant. Assisted case-processing time was substantially shorter with LLM support (94 vs 206 s; adjusted mean difference -112 s, 95% CI -141 to -83; p<0.001). Information timeliness and perceived diagnostic support quality were rated significantly higher in the intervention group. Exploratory analyses showed persistent overconfidence and substantial AI over-reliance. Conclusions Certified LLM-based diagnostic support did not improve diagnostic accuracy compared with conventional resources, but substantially reduced case-processing time and improved perceived support quality. These findings suggest potential workflow benefits while highlighting overconfidence and over-reliance as important safety considerations.