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

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.

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.

A population-based retrospective cohort study.

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.

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.

High-dose folic acid supplementation may be associated with an increased risk of MACE in RA patients taking MTX.