Protective effect of methotrexate against severe forms of COVID-19 in rheumatoid arthritis: A retrospective cohort study

Liñán-Ponce F.; Leiva-Goicochea J.; Gross-Melo F. · Reumatologia Clinica (2026) · DOI: 10.1016/j.reuma.2026.502160

Resumen

Introduction: The COVID-19 pandemic posed a unique challenge for patients with rheumatoid arthritis (RA) receiving immunomodulatory therapy. Methotrexate (MTX), a first-line agent for RA, has pleiotropic effects that may modulate both viral replication and the inflammatory response. This study aimed to determine whether MTX use is associated with a lower incidence of severe or critical COVID-19. Material and methods A retrospective cohort study was conducted among patients with a confirmed diagnosis of RA and a documented episode of COVID-19 between 2020 and 2023 at Hospital Víctor Lazarte Echegaray (Trujillo, Peru). Patients with additional autoimmune diseases, neoplasia, pregnancy, significant organ damage, or use of biologic therapy were excluded. Two groups were compared: 207 patients treated with MTX and 155 treated with other conventional disease-modifying antirheumatic drugs. Primary outcomes were severe/critical COVID-19 and 28-day mortality; secondary outcomes included oxygen supplementation, ICU admission, mechanical ventilation, and length of hospitalization. Results: MTX use was associated with a lower frequency of severe/critical COVID-19 (10.6 vs. 22.6%; RR 0.47; 95% CI 0.29-0.77; p = 0.003) and reduced 28-day mortality (1.4 vs. 5.2%; RR 0.27; 95% CI 0.07-0.98; p = 0.041). MTX-treated patients required less supplemental oxygen (16.9 vs. 35.5%; p = 0.001), fewer ICU admissions (4.8 vs. 12.9%) and mechanical ventilation (1.9 vs. 5.8%), and had a shorter median hospital stay (7 vs. 9 days; p = 0.002). Conclusions: Methotrexate use was associated with reduced disease severity, mortality, and hospitalization duration in RA patients with COVID-19. These findings support a potential protective effect of MTX and highlight the need for multicenter prospective studies to confirm its clinical benefit.