The Lancet Rheumatology

BackgroundHydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin. MethodsNew user cohort studies were conducted including 16 severe adverse events (SAEs). Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days. Self-controlled case series (SCCS) were conducted to further establish safety in wider populations. Separately, SAEs associated with hydroxychloroquine-azithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UK, and USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (CalHRs) according to drug use. Estimates were pooled where I2<40%. ResultsOverall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included. No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22-3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02-1.45]) ConclusionsShort-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19. Trial registration numberRegistered with EU PAS; Reference number EUPAS34497 (http://www.encepp.eu/encepp/viewResource.htm?id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine. Funding sourcesThis research received partial support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and Senior Research Fellowship (DPA), US National Institutes of Health, Janssen Research & Development, IQVIA, and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI16C0992]. Personal funding included Versus Arthritis [21605] (JL), MRC-DTP [MR/K501256/1] (JL), MRC and FAME (APU). The European Health Data & Evidence Network has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968. The JU receives support from the European Unions Horizon 2020 research and innovation programme and EFPIA. No funders had a direct role in this study. The views and opinions expressed are those of the authors and do not necessarily reflect those of the Clinician Scientist Award programme, NIHR, NHS or the Department of Health, England.

CONTEXT AND OBJECTIVEWe propose to systematically review the available evidence to evaluate if patients with immune mediated inflammatory diseases under pharmacological treatment with immunosuppressants, immunobiologics, Disease-Modifying Anti-Rheumatic Drugs (DMARD) or targeted synthetic DMARDs have better or worse outcomes when infected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This study is a protocol for our rapid living systematic review. METHODS: Protocol for a rapid living systematic review methodology following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidance. To conduct the rapid systematic review, we will employ abbreviated systematic review methods, including: not performing independent screens of abstracts and not searching grey literature. As this will be a living review, it will be continuously updated.

IntroductionShared decision-making (SDM) is a process whereby patients are supported to reach decisions about their healthcare in collaboration with healthcare professionals. International policy and clinical guidelines highlight the ethical imperative of SDM and recommend SDM for many healthcare decisions and contexts. However, despite decades of SDM research, the impact of implementing SDM interventions within health care remains uncertain. High-quality health technology assessment (HTA) requires an understanding of how interventions to facilitate the adoption and implementation of SDM (e.g., through the use of patient decision aids, decision coaching, question prompt lists, training and feedback, or service changes) impact clinical and health service outcomes. Yet, synthesis of the existing literature is hindered by substantial heterogeneity in the evaluation of interventions to facilitate SDM. A core outcome set (COS) is an agreed standardised set of outcomes that should be measured and reported in all effectiveness studies. There is a COS for SDM in the context of rheumatology (rheuCOS-SDM), designed for use in research studies (e.g., clinical trials or observational studies) evaluating the impact of SDM interventions on clinical outcomes for patients. It is unclear, however, whether the outcome domains identified within a rheumatology context are relevant, comprehensive, or comprehensible when applied to a variety of SDM interventions tailored to and interacting with a range of patient populations, healthcare settings and contexts. The aim of this study is to develop a generic COS for evaluating the impact of SDM interventions on various outcomes. Outcomes for consideration may include assessments of the behaviours and experiences of patients, important others (e.g., carers or relatives) and health professionals, the dynamics within patient-professional interactions, health outcomes for individuals and for the wider population, and the cost-effectiveness of care. The broad scope of the COS will ensure its applicability and utility within diverse healthcare contexts and enable the synthesis of evidence to draw clear conclusions about the impact of SDM interventions, to influence healthcare policy. We define this new, comprehensive COS as the COS-SDM. Methods and AnalysisThrough engagement with key interest holders (including patients and members of the public, clinicians and academics), we agreed on the scope of the COS and to adhere to the Core Outcome Measures in Effectiveness Trials (COMET) handbook and Core Outcome Set-STAndards for Development (COS-STAD) guidelines. This will involve production of a long (comprehensive) list of candidate outcome domains (using evidence synthesis, a COS developed in the context of Rheumatology, and qualitative interviews with interest holders internationally), prioritisation of a short (refined) list of core outcome domains (utilising a sequential two-round international online Delphi), and reaching consensus on the final outcome set (through international meetings, applying modified nominal group techniques and predefined criteria for agreement). Ethics and DisseminationResearch ethics approval has been granted in the UK (University of Bristol Faculty Ethics Committee, ref: 7741; University of Exeter Faculty Ethics Committee, ref: 8207624). The final COS will be disseminated by presentation at international conferences and publication in a peer-reviewed journal. Further dissemination is planned through our patient/public advisory group, professional networks, and executive group channels, to publicise the COS to patient groups, funders, journal editors, international regulatory bodies and HTA boards. RegistrationThis project has been registered in the COMET database (www.comet-initiative.org/Studies/Details/3586).

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.

OBJECTIVESTo investigate the incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases receiving targeted biologic and synthetic disease modifying anti-rheumatic drugs (tDMARDs) and to explore the possible effect of these treatments in the clinical expression of COVID-19. METHODSA cross-sectional study comprising of a telephone survey and electronic health records review was performed including all adult and paediatric patients with rheumatic diseases treated with tDMARDs in a large rheumatology tertiary centre in Barcelona, Spain. Demographics, disease activity, COVID-19 related symptoms and contact history data were obtained from the start of the 2020 pandemic. Cumulative incidence of confirmed cases (SARS-CoV-2 positive PCR test) was compared to the population estimates for the same city districts from a governmental COVID-19 health database. Suspected cases were defined following WHO criteria and compared to those without compatible symptoms. RESULTS959 patients with rheumatic diseases treated with tDMARDs were included. We identified 11 confirmed SARS-CoV-2 positive cases in the adult cohort and no confirmed positive cases in the paediatric cohort. All patients had a successful recovery and only one patient required admission in the intensive care unit. When using the same classification criteria (only COVID-19 positive cases with pneumonia), COVID-19 incidence rates of the rheumatic patient cohort were very similar to that of the general population [(0.48% (95% CI 0.09 to 8.65%)] and [0.58% (95% CI 5.62 to 5.99%)], respectively. We found significant differences in tDMARDs proportions between the suspected and non-suspected cases (p=0.002). CONCLUSIONAdult and paediatric patients with rheumatic diseases on tDMARDs do not seem to present a higher risk of COVID-19 or a more severe disease outcome when compared to general population. Our exploratory analysis suggests that the proportion of COVID-19 suspected cases differs between tDMARDs.

ObjectivesOptimization of biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA) may be feasible in those who have maintained remission for at least six months. However, this approach carries the risk of disease flare, underscoring the need for reliable predictors to guide clinical decisions. MethodsThe OPTIBIO trial (EudraCT 2012-004482-40) was a phase IV, randomized, open-label, non-inferiority study conducted in five hospitals in Spain. RA patients in sustained remission on stable bDMARD therapy were randomized 1:1 to standard care or dose reduction. The primary outcome was to compare to proportion of joint flare at 12 months by a non-inferiority analysis analyzed by the intention-to-treat principle and identify predictors for flare and sustained remission. Results195 patients were randomized: 99 to the control group and 96 to the optimization group. Thirty-nine flares occurred (optimization: 22.7%, control: 17.2%), with a risk difference of -5.5% (95% CI: -16.8% to 5.7%; P = 0.33). Two predictive models were developed: one for flares (AUC: 0.84) including 3v-DAS28-CRP, VAS pain, erosions, systolic blood pressure, and hemoglobin, and another for sustained remission (AUC: 0.77) including 3v-DAS28-CRP, age, and rheumatoid factor. Adding molecular biomarkers improved AUCs to 0.91 and 0.88, respectively. No significant differences in adverse events were observed. ConclusionbDMARD dose optimization was non-inferior to standard therapy on the flare rate but demonstrated similar safety. Predictive models for remission and flares were developed, which may help select patients to ensure safe implementation of this strategy, highlighting the need for personalized treatment. Key messagesO_LIbDMARD dose optimization was non-inferior to standard therapy on the flare C_LIO_LIClinical models classified patients in terms of disease severity C_LIO_LIIncorporation of molecular markers to clinical models improved their prediction power C_LI

BackgroundThe recent outbreak of COVID-19 has raised concerns in the rheumatology community about the management of immunosuppressive patients diagnosed with inflammatory rheumatic diseases. It is not clear whether the use of biologic agents may suppose a risk or protection against SARS-CoV2 infection however, it has been suggested that severe respiratory forms of COVID-19 occur as result of exacerbated inflammation status and cytokine production. This prompted the use of IL-6 (tocilizumab and sarilumab) and IL-1 inhibitors (anakinra) in severe COVID-19 disease and more recently JAK1/2 inhibitor (baricitinib). Therefore, patients with rheumatic diseases provide a great opportunity to learn about the use of biological agents as protective drugs against SARS-CoV2. ObjectivesTo estimate COVID-19 infection rate in patients treated with biologic agents for rheumatic inflammatory diseases, determine the influence of biologic agents treatment as a risk or protective factor and studying the prognosis of rheumatic patients receiving biologic agents compared to general population in a third level Hospital setting in Leon, Spain. MethodsWe performed a retrospective observational study including patients seen at Rheumatology department who received biological therapy for rheumatic diseases between December 1st 2019 and June 1st 2020 and analysed COVID-19 infection rate. All patients being attended at the rheumatology outpatient clinic with diagnosis of inflammatory rheumatic disease receiving treatment with biologic agents were included. Main variable was the hospital admission related to COVID-19. The covariates were age, sex, comorbidities, biologic agent and need for hospitalization. We performed a multivariate logistic regression model to assess risk factors of hospital admission. ResultsThere was a total of 3711 patients with COVID-19 requiring hospitalization. 30 patients out of a total of 820 patients (3.6%) receiving biological therapy had contracted COVID-19 and four required hospital care. Crude incidence rate of COVID-19 requiring hospital care among the general population was 2.75%, and it was 0.48% among the group with underlying rheumatic diseases. A total of 423 patients died, 2 of which received treatment with biologic agents. Patients who tested positive for COVID-19 were older (female: median age 61.8 IQR 46.5-75; male: median age 68 IQR 48.5-72) than those who were negative for COVID-19 (female: median age 58.4 IQR 48-69; male: median age 55.9 IQR 46-66) and more likely to have cardiovascular disease (27 % vs 10%, OR 3. 41 (CI 1.47 - 7.94), p 0.004), be active smokers (13% vs 5%, OR 3.14 (CI 1.04-9.47), p 0.04) and receiving treatment with IL-12/23 inhibitors (6.7% vs 1.4%, OR 5.06 (CI 1.07-23.91) and rituximab (13% vs 2%, 2.66 (CI 1.03-7.27), p 0.04) and were less likely to be receiving treatment with IL-6 inhibitors (0% vs 14%, CI (0.006-0.97, p <0.05). When exploring the effect of the rest of the therapies between groups (affected patients vs unaffected), we found no significant differences in bsDMARD proportions. IL-1 inhibitors, IL6 inhibitors, JAK inhibitors and belimumab treated patients showed the lowest incidence of COVID-19 among adult rheumatic patients. We found no differences in sex or rheumatological disease between patients who tested positive for COVID-19 and patients who tested negative were found. ConclusionsOur findings suggest that use of biological therapy does not associate with severe manifestations of COVID-19, and it is likely to have a protective effect against them when compared to the general population.

IntroductionCost and drug toxicity often deter prolonged therapeutic use of anti-TNF agents in ankylosing spondylitis (AS). A planned study was completed to endorse our clinic-based observation of long-term relief following short-term administration of an anti-TNF agent. Methods50 consenting patients with symptomatic active chronic AS under rheumatology care in a community clinic were enrolled; naive for anti-TNF. 40 mg standard biosimilar Adalimumab (Bs-ADA, Exemptia) was injected subcutaneously every fortnight for six injections (10 weeks). Patients were monitored at several predetermined time points. Improvement was assessed with standard indices (Assessment Spondyloarthritis International Society/ASAS and Bath). An intention to treat analysis was performed: significant p <0{middle dot}05 ResultsPatients showed early and substantial significant improvement in pain, NSAID requirement, function, and in several indices (ASAS 20 & 40, ASAS partial remission, BASDAI, BASFI, ASDAS) which persisted after stopping injections. 84% and 52 % of patients respectively showed ASAS 20 improvement at weeks 12 and 48: corresponding to ASAS partial remission at 34% and 24%. Over 50% of patients maintained prolonged improvement and provided proof of concept (defined apriori). Serum Interleukin-6 assay showed a sharp reduction at 24 weeks. None developed TB or serious drug toxicity. 11 patients withdrew (mostly inadequate response). The absence of control was a limitation. ConclusionA ten-week administration of biosimilar adalimumab in difficult-to-treat AS showed early substantial improvement which often persisted for 24 weeks. This unconventional strategy was socioeconomically appealing. It merits further validation and acceptance, especially in resource strained settings.

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

ObjectivesTo evaluate and compare the individual therapeutic efficacy of NICE-recommended physical activity (PA) and pharmacological interventions on pain amongst adults with rheumatoid arthritis (RA). MethodsA systematic-review and meta-analysis of studies published between March 1988 and April 2025 was conducted across seven databases; AMED, MEDLINE, CINAHL Plus, SPORTDiscus, EMBASE, Google Scholar, Web of Science, and reference lists. Included were monotherapeutic randomised controlled trials (RCTs) of DMARDs, NSAIDS, analgesics, aerobic and/or resistance training for managing pain perceptions; measured as change in pre-and-post-intervention scores using the visual analogue scale (VAS). Participants were aged [&ge;]18 years whose condition met American College of Rheumatology (ACR; 1987/2010) RA-criteria. Pooled meta-analyses results were presented as mean differences (MDs) and 95% confidence-intervals (95% CIs). Risk of bias (ROB) and certainty of evidence were assessed with the ROB 2 tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. ResultsSearches identified 3286 articles. 25 trials were selected for inclusion (6468 participants); 14 RCTs of 11 aerobic-and/or-resistance-training programs (n=916), three yoga regimes, an individual joint-protection programme, a trial of Rocabado exercises, and 11 RCTs of 21 DMARD/NSAID monotherapies (n=5552); baricitinib, celecoxib, filgotinib, hydroxychloroquine, ketoprofen, leflunomide(n=2), methotrexate, naproxen (n=2), sarilumab, sulphasalazine, tofacitinib, and upadacitinib. Weighted mean differences in pain perceptions for behavioural and pharmacological interventions were -2.47mm (95% CI: -3.14 - -1.81, p<0.00001) and -11.20mm (95% CI: -11.35 - -11.05, p<0.00001) respectively. ConclusionDespite inconsistent control of medication histories and PA-prescription, adherence to behavioural and pharmacological interventions can successfully alleviate pain. First-line management using DMARDs or NSAIDs appears to be more effective than yoga, Rocabado exercises, or aerobic and/or resistance training alone. Systematic review registration numberCRD420251069339 Key MessagesO_LIBoth pharmacological and physical activity interventions can successfully reduce pain perceptions amongst patients with RA. C_LIO_LIIndependent use of DMARDs or NSAIDs appears to alleviate pain more than aerobic and/or resistance-training. C_LI

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

BackgroundTwo years into the global vaccination program, important questions about the association between COVID-19 vaccines and autoimmune diseases have arisen. A growing number of reports have documented associations between COVID-19 vaccination and autoimmunity, suggesting, for example, a causal link between vaccination and new-onset and/or relapsing autoimmune disorders such as type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Graves disease, and Hashimotos thyroiditis. These autoimmune phenomena have occurred with various COVID-19 vaccines and research is required to elucidate the underlying mechanisms and causal directions, for example, whether persons with no history of autoimmune disorders may experience them upon vaccination or persons with autoimmune disorders may experience exacerbation or new adverse events post-vaccination. Methods and analysisSpecific objectives of this scoping review will address the following questions: Can COVID-19 vaccination trigger and/or exacerbate autoimmune disorders? Are persons with autoimmune disorders at higher risk of experiencing additional autoimmune disorders? What are the mechanisms connecting autoimmune disorders with COVID-19 vaccination? Can COVID-19 vaccination interact with immunosuppressive therapy in persons with autoimmune disorders? Does the risk of autoimmune disorders following COVID-19 vaccination differ by vaccine type, age, gender, or other still unidentified characteristics (e.g., SES)? What is the consensus of care concerning COVID-19 vaccination in persons with autoimmune disorders and what evidence informs it? Our review will follow Arksey and OMalleys (2005) framework, enhanced by Levac et al.s team-based approach (2010), and adhering to the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. To capture the broadest range of perspectives on the phenomenon of interest, data will be synthesized through numerical summaries describing general characteristics of included studies and thematic analysis. Subgroup analysis of primary outcomes will be performed to compare findings according to 1) the previous existence of autoimmune disorder, 2) the presence of relevant co-morbidities, 3) vaccine type; and other relevant factors that we may encounter as the research proceeds. SignificanceCOVID-19 has triggered the largest vaccination campaign in history, targeting literally the global human community. Drug safety is a crucial aspect of any medical intervention, critical to a proper assessment of the balance of risks and benefits. Our investigation should yield information useful to improve medical and public health practice in multiple ways, including assisting in clinical decision-making, policy development, and ethical medical practice.

BackgroundHydroxychloroquine has been shown to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, but early clinical studies found no benefit treating patients with coronavirus disease 2019 (COVID-19). We set out to evaluate the effectiveness of hydroxychloroquine for prevention, as opposed to treatment, of COVID-19 mortality. MethodsWe pre-specified and conducted an observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, representing 40% of the general population in England. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use prior to the COVID-19 outbreak in England and risk of COVID-19 mortality among people with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Model adjustment was informed by a directed acyclic graph. ResultsOf 194,637 patients with RA or SLE, 30,569 (15.7%) received [&ge;] 2 prescriptions of hydroxychloroquine in the six months prior to 1 March 2020. Between 1 March 2020 and 13 July 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0.23% (95% CI 0.18-0.29) among users and 0.22% (95% CI 0.20-0.25) among non-users; an absolute difference of 0.008% (95% CI -0.051-0.066). After accounting for age, sex, ethnicity, use of other immunuosuppressives, and geographic region, no association with COVID-19 mortality was observed (HR 1.03, 95% CI 0.80-1.33). We found no evidence of interactions with age or other immunosuppressives. Quantitative bias analyses indicated observed associations were robust to missing information regarding additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality. ConclusionWe found no evidence of a difference in COVID-19 mortality among patients who received hydroxychloroquine for treatment of rheumatological disease prior to the COVID-19 outbreak in England. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPublished trials and observational studies to date have shown no evidence of benefit of hydroxychloroquine as a treatment for hospitalised patients who already have COVID-19. A separate question remains: whether routine ongoing use of hydroxychloroquine in people without COVID-19 protects against new infections or severe outcomes. We searched MEDLINE/PubMed for pharmacoepidemiological studies evaluating hydroxychloroquine for prevention of severe COVID-19 outcomes. The keywords "hydroxychloroquine AND (COVID OR coronavirus OR SARS-CoV-2) AND (prophyl* OR prevent*) AND (rate OR hazard OR odds OR risk)" were used and results were filtered to articles from the last year with abstracts available. 109 papers were identified for screening; none investigated pre-exposure prophylactic use of hydroxychloroquine for prevention of severe COVID-19 outcomes. Clinical trials of prophylactic use of hydroxychloroquine are ongoing; however, the largest trial does not expect to meet recruitment targets due to "...unjustified extrapolation and exaggerated safety concerns together with intense politicisation and negative publicity." In the absence of reported clinical trials, evidence can be generated from real-world data to support the need for randomised clinical trials. Added value of this studyIn this cohort study representing 40% of the population of England, we investigated whether routine use of hydroxychloroquine prior to the COVID-19 outbreak prevented COVID-19 mortality. Using robust pharmacoepidemiological methods, we found no evidence to support a substantial benefit of hydroxychloroquine in preventing COVID-19 mortality. At the same time, we have shown no significant harm, and this generates the equipoise to justify continuing randomised trials. We have demonstrated in this study that it is feasible to address specific hypotheses about medicines in a rapid and transparent manner to inform interim clinical decision making and support the need for large-scale, randomised trial data. Implications of all the available evidenceThis is the first study to investigate the ongoing routine use of hydroxychloroquine and risk of COVID-19 mortality in a general population. While we found no evidence of any protective benefit, due to the observational nature of the study, residual confounding remains a possibility. Completion of trials for prevention of severe outcomes is warranted, but prior to the completion of these, we found no evidence to support the use of hydroxychloroquine for prevention of COVID-19 mortality.

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.

ObjectivesRheumatoid arthritis (RA) is associated with elevated risk of cardiovascular (CV) events that has been attributed to inflammation although this is not well supported by randomised controlled trial (RCT) data. This RCT evaluated the effect of adalimumab upon endothelial function and arterial stiffness in ACPA-positive RA. MethodsSixty subjects with active ACPA-positive RA stratified as Early (<12 months n=30) or Established (>12 months n=30) were enrolled and randomised 1:1 within each group to receive 40 mg adalimumab or placebo. They were assessed by DAS28-CRP, Reactive Hyperaemic Index (RHI) and Carotid-Femoral Pulse Wave Velocity (CF-PWV) twice prior to treatment and then at 1, 4, 12 and 24 weeks with one final open-label at 36 weeks. Secondary analysis evaluated the effects of disease duration, Shared Epitope (SE) and smoking status. ResultsThere were significant treatment effects upon DAS28-CRP at weeks 1, 4 and 12 in Early RA with transient effects upon RHI at week 1 in Established RA and CF-PWV in Early RA at week 4. Area-under-the-curve analysis found positive treatment effects in subjects expressing one SE (DAS28-CRP p 0.031, CF-PWV p 0.034) and in non-smokers (DAS28-CRP p 0.096, CF-PWV p 0.033). ConclusionsThis RCT appeared to show positive treatment effects upon CV risk. However, the effect of adalimumab upon RHI may be type 1 statistical error and the effect upon CF-PWV more likely represents physiologic pain-driven mechanisms rather than structural effects. This study highlights the challenges, the limitations, strengths of and opportunities for CV biomarker research in this complex field.

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

BackgroundTo characterize disease course and remission in a longitudinal observational study of newly diagnosed, initially treatment naive patients with seropositive rheumatoid arthritis (RA). MethodsPatients with early untreated seropositive RA were recruited from 28 UK centres. Multiple clinical and laboratory measures were collected every 3 months for up to 18 months. Disease activity was measured using DAS28-CRP and SDAI. Logistic regression models examined clinical predictors of 6-month remission and latent class mixed models characterized disease course. ResultsWe enrolled 275 patients of whom 267 met full eligibility and provided baseline data. According to SDAI definition, 24.3% attained 6-month remission. Lower baseline HAQ and SDAI predicted 6-month remission (p=0.002 and 0.021). Alcohol intake and baseline prescribing of methotrexate with a second DMARD (versus monotherapy without glucocorticoids) were also predictive. Three distinct SDAI trajectory subpopulations emerged; corresponding to an Inadequate Responder group (6.5%), and Higher and Lower Baseline Activity Responder groups (22.4% and 71.1%). Baseline HAQ and SF-36 MCS only distinguished these groups. Additionally a number of baseline clinical predictors correlated with disease activity severity within subpopulations. Beneficial effects of alcohol intake were found across subpopulations. ConclusionsThree distinct disease trajectory subpopulations were identified. Differential effects of functional and mental well-being, alcohol consumption and baseline RA medication prescribing on disease activity severity were found across subpopulations. Heterogeneity across trajectories cannot be fully explained by baseline clinical predictors. Biological markers collected early in disease course (within 6 months) may help patient management and to better target existing and novel therapies.

Subjects in medical research have predominantly been male (1). Women experience 50-75% more adverse drug responses (2) resulting in withdrawn medications (3). While sex differences in metabolism, disease and treatment response are increasingly recognised, sex-informed medicine is lagging. In 2016, USAs National Institutes of Health (NIH) formulated the Sex as a Biological Variable policy (4), stating that grant recipients must consider sex in experimental design, planning, analysis and reporting of their findings. Australian data is lacking on the inclusion of both males and females as well as appropriate analysis of sex differences. We analysed the 219 Medical Journal of Australia (MJA) research articles over 2019-2023 (Box 1). We tallied when; i) both males and females were included in the study, ii) sex differences were reported and/or considered, and iii) the analysis was appropriate to support sex-related claims. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/24310791v1_figB1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@157d654org.highwire.dtl.DTLVardef@1b832d2org.highwire.dtl.DTLVardef@108b50org.highwire.dtl.DTLVardef@2a3a73_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOBox 1.C_FLOATNO Analysis of Original Research Articles in the Medical Journal of Australia in the last five years (2019-2023). Of 219 Original Research Articles, 146 included both male and female participants. 37 of those also considered sex as a biological variable. C_FIG We found that articles published in MJA are including males and females, however testing of sex differences is uncommon and appropriate statistical analysis is lacking. We hope that this article will bring attention to this fundamental issue and improve future efforts to investigate sex differences.

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.

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