OBJECTIVE: Our objective was to assess the incidence of major adverse cardiovascular events (MACEs) in patients with rheumatoid arthritis (RA) treated with JAK inhibitors (JAKi), tumor necrosis factor inhibitors (TNFi), or biologic disease-modifying antirheumatic drugs with other modes of action (bDMARD-OMA) in a multicountry, real-world population. METHODS: Patients with RA from 15 registries in the JAK-pot collaboration were included. MACE incidence was analyzed using two approaches: a within-registry analysis aggregating country-specific estimates from registers with >25 incident MACEs through meta-analysis and an individual-level data combined analysis. We used adjusted linear mixed Poisson regression to obtain incidence rate ratios (IRRs) of MACEs between treatment groups, accounting for multiple treatment courses. RESULTS: The study included 73,008 treatment courses (16,417 JAKi, 35,373 TNFi, and 21,218 bDMARD-OMA) and 828 incident MACEs among 51,233 patients. Median follow-up time was 1.3 years, with most of the follow-up concentrated in the first two years of treatment. Incidence rates were 7.0, 7.6, and 11.8 per 1,000 person-years for JAKi, TNFi, and bDMARD-OMA, respectively. Compared to TNFi, JAKi (within-registry adjusted IRR 0.89, 95% confidence interval [CI] 0.63-1.25) had similar incidence rates of MACEs and bDMARD-OMA had higher rates (within-registry adjusted IRR 1.35, 95% CI 1.10-1.66). Combined analysis showed similar results. CONCLUSION: Observational data from the JAK-pot collaboration show no evidence of an increase in cardiovascular events during the first two years of use with JAKi compared to TNFi in the general RA population.

BioReg Vienna Austria

Centre for Epidemiology Versus Arthritis Division of Musculoskeletal and Dermatological Sciences School of Biological Sciences Faculty of Biology Medicine and Health The University of Manchester Manchester Academic Health Science Centre Manchester United Kingdom

Centre Hospitalier de l'Université de Montréal Institut de Recherche en Rhumatologie Montréal Québec Canada

Clinical Epidemiology Division Department of Medicine Solna Karolinska Institutet Stockholm Sweden

Department of Precision and Regenerative Medicine and Ionian Area Rheumatology Unit University of Bari Bari Italy

Department of Rheumatology Geneva University Hospital and Geneva Center for Inflammation Research University of Geneva Geneva Switzerland

Department of Rheumatology Geneva University Hospital Geneva Switzerland

Department of Rheumatology University Medical Centre Ljubljana and Faculty of Medicine University of Ljubljana Ljubljana Slovenia

Departments of Medicine and Rheumatology Helsinki University Hospital The National Register of Biological Medicines Helsinki Finland

Deutsches Rheuma Forschungszentrum Programme Area Epidemiology and Charité Universitätsmedizin Berlin Germany

Deutsches Rheuma Forschungszentrum Programme Area Epidemiology Berlin Germany

Diakonhjemmet Hospital Center for Treatment of Rheumatic and Musculoskeletal Diseases Oslo Norway

Institute of Rheumatology Prague Czech Republic

National Institute for Health and Care Research Manchester Biomedical Research Centre Manchester University NHS Trust Manchester United Kingdom

NOVA Medical School Universidade Nova de Lisaboa and Reuma pt Sociedade Portuguesa de Reumatologia Lisbon Portugal

NOVA Medical School Universidade Nova de Lisaboa Lisbon Portugal

Research Unit Spanish Society of Rheumatology Madrid Spain

Rheumatology and Clinical Immunology University Hospital of Heraklion Crete Greece

University of Medicine Center of Rheumatic Diseases Bucharest Romania

University of Montpellier and Physiology and Experimental Medicine of the Heart and Muscles Montpellier France

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Hansildaar R, Vedder D, Baniaamam M, et al. Cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout. Lancet Rheumatol 2021;3(1):e58–e70. PubMed PMC

Aviña‐Zubieta JA, Choi HK, Sadatsafavi M, et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta‐analysis of observational studies. Arthritis Rheum 2008;59(12):1690–1697. PubMed

Lauper K, Gabay C. Cardiovascular risk in patients with rheumatoid arthritis. Semin Immunopathol 2017;39(4):447–459. PubMed

England BR, Thiele GM, Anderson DR, et al. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ 2018;361:k1036. PubMed PMC

Low ASL, Symmons DPM, Lunt M, et al; British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR‐RA) and the BSRBR Control Centre Consortium. Relationship between exposure to tumour necrosis factor inhibitor therapy and incidence and severity of myocardial infarction in patients with rheumatoid arthritis. Ann Rheum Dis 2017;76(4):654–660. PubMed PMC

Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic review and meta‐analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol 2011;108(9):1362–1370. PubMed PMC

Ytterberg SR, Bhatt DL, Mikuls TR, et al; ORAL Surveillance Investigators. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 2022;386(4):316–326. PubMed

Xeljanz (tofacitinib): initial clinical trial results of increased risk of major adverse cardiovascular events and malignancies (excluding NMSC) with use of tofacitinib relative to TNF— alpha inhibitors. European Medicine Agency; 2021. Accessed June 17, 2024. https://www.ema.europa.eu/en/documents/dhpc/direct‐healthcare‐professional‐communication‐dhpc‐xeljanz‐tofacitinib‐initial‐clinical‐trial‐results‐increased‐risk‐major‐adverse‐cardiovascular‐events‐and‐malignancies‐excluding‐nmsc‐use‐tofacitinib_en.pdf

Initial safety trial results find increased risk of serious heart‐related problems and cancer with arthritis and ulcerative colitis medicine Xeljanz, Xeljanz XR (tofacitinib). US Food and Drug Administration FDA; 2021. Accessed June 17, 2024. https://www.fda.gov/drugs/drug‐safety‐and‐availability/initial‐safety‐trial‐results‐find‐increased‐risk‐serious‐heart‐related‐problems‐and‐cancer‐arthritis

Bower H, Frisell T, di Giuseppe D, et al. Comparative cardiovascular safety with janus kinase inhibitors and biological disease‐modifying antirheumatic drugs as used in clinical practice: an observational cohort study from Sweden in patients with rheumatoid arthritis. RMD Open 2023;9(4):e003630. PubMed PMC

Popa CD, Opdam MAA, den Broeder N, et al. Therapy with JAK inhibitors or bDMARDs and the risk of cardiovascular events in the Dutch rheumatoid arthritis population. Rheumatology 2023;63(8):2142–2146. PubMed

Meissner Y, Schäfer M, Albrecht K, et al. Risk of major adverse cardiovascular events in patients with rheumatoid arthritis treated with conventional synthetic, biologic and targeted synthetic disease‐modifying antirheumatic drugs: observational data from the German RABBIT register. RMD Open 2023;9(4):e003489. PubMed PMC

Aymon R, Mongin D, Bergstra SA, et al. Evaluation of discontinuation for adverse events of JAK inhibitors and bDMARDs in an international collaboration of rheumatoid arthritis registers (the ‘JAK‐pot’ study). Ann Rheum Dis 2024;83(4):421–428. PubMed PMC

Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease‐modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2023;82(1):3–18. PubMed

Lauper K, Iudici M, Mongin D, et al. Effectiveness of TNF‐inhibitors, abatacept, IL6‐inhibitors and JAK‐inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the ‘JAK‐pot’ collaboration. Ann Rheum Dis 2022;81(10):1358–1366. PubMed PMC

Pombo‐Suarez M, Sanchez‐Piedra C, Gómez‐Reino J, et al. After JAK inhibitor failure: to cycle or to switch, that is the question – data from the JAK‐pot collaboration of registries. Ann Rheum Dis 2023;82(2):175–181. PubMed

England BR, Sayles H, Mikuls TR, et al. Validation of the Rheumatic Disease Comorbidity Index. Arthritis Care Res (Hoboken) 2015;67(6):865–872. PubMed

von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008;61(4):344–349. PubMed

R Core Team . R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2023. Accessed October 10, 2023. https://www.R-project.org/

van Buuren S, Groothuis‐Oudshoorn K. mice: multivariate imputation by chained equations in R. J Stat Softw 2011;45(3):1–67.

Batko B, Stajszczyk M, Świerkot J, et al. Prevalence and clinical characteristics of rheumatoid arthritis in Poland: a nationwide study. Arch Med Sci 2019;15(1):134–140. PubMed PMC

Putrik P, Ramiro S, Keszei AP, et al. Lower education and living in countries with lower wealth are associated with higher disease activity in rheumatoid arthritis: results from the multinational COMORA study. Ann Rheum Dis 2016;75(3):540–546. PubMed

Putrik P, Ramiro S, Moltó A, et al. Individual‐level and country‐level socioeconomic determinants of disease outcomes in SpA: multinational, cross‐sectional study (ASAS‐COMOSPA). Ann Rheum Dis 2019;78(4):486–493. PubMed

Arts EEA, Popa CD, Den Broeder AA, et al. Prediction of cardiovascular risk in rheumatoid arthritis: performance of original and adapted SCORE algorithms. Ann Rheum Dis 2016;75(4):674–680. PubMed

Hoisnard L, Vegas LP, Dray‐Spira R, et al. Risk of major adverse cardiovascular and venous thromboembolism events in patients with rheumatoid arthritis exposed to JAK inhibitors versus adalimumab: a nationwide cohort study. Ann Rheum Dis 2023;82(2):182–188. PubMed

Khosrow‐Khavar F, Kim SC, Lee H, et al. Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in Routine care patients with Rheumatoid Arthritis (STAR‐RA) study. Ann Rheum Dis 2022;81(6):798–804. PubMed PMC

Min HK, Kim H, Jeong HJ, et al. Risk of cancer, cardiovascular disease, thromboembolism, and mortality in patients with rheumatoid arthritis receiving Janus kinase inhibitors: a real‐world retrospective observational study using Korean health insurance data. Epidemiol Health 2023;45:e2023045. PubMed PMC

Crowson CS, Rollefstad S, Kitas GD, et al; A Trans‐Atlantic Cardiovascular Risk Consortium for Rheumatoid Arthritis (ATACC‐RA). Correction: challenges of developing a cardiovascular risk calculator for patients with rheumatoid arthritis. PLoS One 2017;12(4):e0175605. PubMed PMC