High-dose folic acid supplement is associated with increased cardiovascular risk in rheumatoid arthritis patients on methotrexate

Background: Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA), and folic acid is routinely co-prescribed to prevent folate deficiency. However, no consensus exists regarding the optimal dose and frequency of folic acid supplementation. Objectives: This study aimed to compare the incidence of major adverse cardiovascular events (MACE) in RA patients receiving high versus low doses of folic acid alongside MTX. Design: A population-based retrospective cohort study. Methods: RA patients using MTX without baseline MACE were recruited retrospectively from a citywide database in Hong Kong between 2006 and 2015 and followed until 2018. The primary outcome was the first occurrence of MACE. Cox regression analyses with time-varying covariates were used to assess the association between folic acid dosage and incident MACE, adjusting for demographics, traditional cardiovascular risk factors, markers of inflammation and anti-rheumatic drug use. Results: A total of 8405 RA patients on MTX were identified. Of these, 6854 (78.5%) were female and the mean age was 56.0 ± 13.5 years. Among the cohort, 2967 patients (35.3%) received ⩾5 mg of folic acid daily, while 5438 (64.7%) received 0–<5 mg. After a median follow-up of 9 years (interquartile range: 5 years), 504 patients (6.0%) developed MACE. Multivariable analyses showed that the use of folic acid ⩾5 mg daily was associated with a significantly higher risk of MACE (adjusted hazard ratios were 1.34 (95% confidence interval (CI) 1.09–1.64) in the erythrocyte sedimentation rate model and 1.39 (95% CI 1.14–1.71) in the C-reactive protein model) compared to lower doses. The association remained significant after inverse probability treatment weighting and machine-learning gradient boosted regression modelling. Conclusion: High-dose folic acid supplementation may be associated with an increased risk of MACE in RA patients taking MTX.