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Observational Study
. 2025 Apr 18;45(5):106.
doi: 10.1007/s00296-025-05838-y.

Methotrexate associates with ischemic cardiovascular risk reduction in males but not females: a transatlantic cardiovascular consortium for people with rheumatoid arthritis observational study

George A Karpouzas  1 , Sarah R Ormseth  2 , Piet Van Riel  3 , Elena Myasoedova  4 , Miguel A Gonzalez-Gay  5   6 , Alfonso Corrales  7 , Solbritt Rantapaa-Dahlqvist  8 , Petros Sfikakis  9 , Patrick Dessein  10 , Carol A Hitchon  11 , Virginia Pascual-Ramos  12 , Irazu Contreras Yanez  12 , Iris Jazmín Colunga-Pedraza  13 , Dionicio Angel Galarza-Delgado  13 , Jose Azpiri-Lopez  13 , Anne Grete Semb  14 , Durga Prasanna Misra  15 , George D Kitas  16 , Ellen M Hauge  17   18
Affiliations
Observational Study

Methotrexate associates with ischemic cardiovascular risk reduction in males but not females: a transatlantic cardiovascular consortium for people with rheumatoid arthritis observational study

George A Karpouzas et al. Rheumatol Int. .

Abstract

Objective: Patients with rheumatoid arthritis (RA) experience higher cardiovascular risk. Methotrexate may decrease this risk, although it is unclear whether males and females similarly benefit. We explored the influence of sex on the effect of methotrexate use on cardiovascular risk in RA.

Methods: An observational cohort of 4362 patients, 3223 (73.9%) females, without cardiovascular disease were included from an international cardiovascular consortium for RA. Outcomes were (a) major adverse cardiovascular events (MACE) including cardiovascular death, myocardial infarction, or stroke and (b) any ischemic cardiovascular events (iCVE) including MACE, angina, revascularization, transient ischemic attack, and peripheral arterial disease. The effects of sex, prevalent methotrexate use at enrollment visit and their interaction on MACE and iCVE were assessed with multivariable Cox regression models, reporting adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: There were 237 first MACE and 358 first iCVE. The sex by methotrexate interaction was significant for MACE (p = 0.005) and iCVE (p = 0.006), suggesting the effect of methotrexate use on cardiovascular risk differed among males and females. In males, methotrexate use associated with lower risk of MACE (HR 0.32, [95% CI 0.12-0.83]) and iCVE (HR 0.43 [95% CI 0.21-0.85]). In females, methotrexate use was not associated with MACE (p = 0.267) or iCVE (p = 0.407). In sensitivity analyses, models with inverse probability of treatment weighting and models additionally adjusting for inflammation yielded similar results.

Conclusion: Methotrexate use associated with cardiovascular benefit in males but not females with RA and the effect was independent of inflammation.

Keywords: Cardiovascular disease; Methotrexate; Rheumatoid arthritis; Sex.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by the institutional review boards of all participating centers and performed in accordance with the 1964 Declaration of Helsinki and its later amendments. These included the Mayo Clinic and Olmsted Medical Center Institutional Review Boards, CMO Arnhem Nijmegen, Dudley Local Research Ethics Committee, Office of the Oslo University Hospital’s Privacy and Data Protection Officer, Ethics Committee at the University Hospital of Umeå, John F Wolfe MD. Human Subjects Committee at Harbor-UCLA (project number of 13564-01, approval date 8/26/2009), Laiko Hospital Institutional Review Board (Athens, Greece), Human Research Ethics Committee (Medical) from the University of the Witwatersrand in Johannesburg, South Africa, University of Manitoba Health Research Ethics Board and the Manitoba Health Information Privacy Committee, Ethics Committee of Cantabria for Hospital Universitario de Valdecilla in Santander (Spain), Comites de Ética e Investigación del Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, and Arthritis Center Twente Institutional Review Board. Consent to participate: Informed consent was obtained from participants. Conflict of interest: The authors have no conflict of interest to declare that are relevant to the content of this article.

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