Background/Purpose: Patients with rheumatoid arthritis (RA) experience higher cardiovascular risk compared to non-inflammatory disease controls. Methotrexate (MTX) may decrease cardiovascular risk in patients with RA. It is, however, unclear whether sex differentially impacts cardiovascular risk in MTX users and non-users and whether men and women derive equal benefit from methotrexate use. We here explored the influence of sex on cardiovascular risk in MTX nonusers and users. We further evaluated the effect of MTX treatment on cardiovascular risk in males and females with RA.

Methods: We evaluated 4362 patients and no cardiovascular disease prospectively included in an observational cohort [An International Cardiovascular Consortium for people with RA (ATACC-RA)]. Outcomes were (a) major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction or stroke and (b) any ischemic cardiovascular events (CVE) including MACE, stable angina, coronary revascularization, transient ischemic attack and peripheral arterial disease with or without revascularization. Missing data were imputed using multiple imputation with 10 repetitions. Multivariable Cox models stratified by center evaluated the impact of sex, baseline MTX use and their interaction on event risk after adjusting for age, hypertension, diabetes, family history, smoking, total cholesterol to high-density lipoprotein cholesterol ratio, disease duration, and activity score (DAS28 ESR). Two sensitivity analyses were conducted; The first used inverse probability of treatment weights to balance differences in MTX treated and untreated patients. The second included patients enrolled in the cohort on or after January 1, 2000, when MTX use became more prevalent.

Results: There were 237 first MACE and 358 total ischemic CVE during follow-up. Male sex associated with an 81% and 58% greater risk of MACE and any ischemic CVE respectively (Figure 1). Among MTX nonusers, incidence of MACE and any ischemic CVE was higher in males [17.6 (95% CI 14.4-21.3) and 24.5 (20.7-28.9) events/1000PY] compared to females [6.9 (5.7-8.4) and 11.4 (9.8-13.3) events/1000PY, all p for difference < 0.001]. In adjusted Cox models, male nonusers had a 2.09-fold and 74% higher risk of MACE and any ischemic CVE compared to female nonusers (both p< 0.001, Figures 1 and 2). In contrast, among users, incidence of MACE and any ischemic CVE was not different in males [4.2 (1.7-10.0) and 7.6 (4.0-14.6) events/1000PY] versus females [6.4 (4.4-9.2) and 9.4 (6.9-12.8) events/1000PY] and sex was not associated with event risk in MTX users. Among males, MTX use associated with a 66% and 55% lower risk of MACE and any ischemic CVE (p=0.026 and 0.024). In contrast, MTX use was not associated with MACE or any ischemic CVE in females [adjusted HR 1.33 (0.83-2.14) and 1.21 (0.81-1.79)]. Both sensitivity analyses yielded similar results.

Conclusion: RA males not using MTX exhibit higher risk of MACE and any ischemic CVE compared to female nonusers, while no differences were observed between male and female users. Baseline MTX use associated with lower risk of MACE and all ischemic CVE in males but not females.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/methotrexate-use-associates-with-ischemic-cardiovascular-risk-reduction-in-males-but-not-females-with-rheumatoid-arthritis/