Background Methotrexate (MTX) treatment in rheumatoid arthritis (RA) can be hindered by side effects, including transaminase elevations. These might be a surrogate marker for liver disease. Folic acid (FA) supplementation reduces the incidence of toxicity while not compromising efficacy, thereby allowing more patients to continue treatment. Dutch rheumatologists prescribed 1 mg daily, and since 2004 5 mg (twice) weekly, due to changing reimbursement. No evidence is available that directly compares these doses with regards to liver enzyme elevations.

Purpose This non-inferiority comparative study compared the occurrence of transaminase elevations in RA patients on MTX, supplementing folic acid on either a (twice) weekly or daily basis.

Materials and methods All patients participating in the Nijmegen early RA inception cohort, initiating MTX and FA from January 1, 2000 with available charts and follow-up transaminase values were included in this study. Patients were split into two cohorts based on folic acid administration (daily vs (twice) weekly). The primary end point was the proportion of patients with abnormal liver enzyme findings in each group, measured in time to event. ‘Persistent abnormal liver enzyme values’ were defined as serum values of AST and/or ALT of either >3x more than the upper limit (UL), or >2x but <3x more than the UL, occurring on at least 2 of 4 consecutive evaluations Secondary outcome parameters included gastro-intestinal (GI) intolerance, MTX dose and DAS28. Data were analysed using Cox proportional hazard analysis for the specified end points. Sensitivity analysis was performed for alternate event definitions.

Results 133 (38%) patients had twice-weekly folic acid supplementation, 61 (18%) weekly and 153 (44%) daily folic acid supplementation. When corrected for location and ESR, an HR of 1.20 (0.46-3.10) was found for the association between folic acid dose and liver enzyme events. This remained non-significant in sensitivity analysis. For GI complaints, an HR of 4.22 (1.19-14.98) was found corrected for location, DMARD use, and disease duration.

Conclusions Changing to a weekly regimen makes no difference to the occurrence of liver enzyme elevations, but abolishes the preventive effect of folic acid with regards to GI intolerance. Combining this information with a comparatively low cost difference, daily folic acid supplementation should be preferred above weekly supplementation.