Methotrexate associates with ischemic cardiovascular risk reduction in males but not females: a transatlantic cardiovascular consortium for people with rheumatoid arthritis observational study.
Karpouzas, George A Ormseth, Sarah R Van Riel, Piet Myasoedova, Elena Gonzalez-Gay, Miguel A Corrales, Alfonso Rantapaa-Dahlqvist, Solbritt Sfikakis, Petros Dessein, Patrick Hitchon, Carol A
Karpouzas, George A
Ormseth, Sarah R
Van Riel, Piet
Myasoedova, Elena
Gonzalez-Gay, Miguel A
Corrales, Alfonso
Rantapaa-Dahlqvist, Solbritt
Sfikakis, Petros
Dessein, Patrick
Hitchon, Carol A
Affiliation
Harbor-UCLA Medical Center; Radboud University Medical Centre; University of Cantabria; The Dudley Group NHS Foundation Trust et al
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Publication date
2025-04-18
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Abstract
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. 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). 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. Methotrexate use associated with cardiovascular benefit in males but not females with RA and the effect was independent of inflammation.
Citation
Karpouzas GA, Ormseth SR, Van Riel P, Myasoedova E, Gonzalez-Gay MA, Corrales A, Rantapaa-Dahlqvist S, Sfikakis P, Dessein P, Hitchon CA, Pascual-Ramos V, Yanez IC, Colunga-Pedraza IJ, Galarza-Delgado DA, Azpiri-Lopez J, Semb AG, Misra DP, Kitas GD, Hauge EM. Methotrexate associates with ischemic cardiovascular risk reduction in males but not females: a transatlantic cardiovascular consortium for people with rheumatoid arthritis observational study. Rheumatol Int. 2025 Apr 18;45(5):106. doi: 10.1007/s00296-025-05838-y.�