The majority of us will routinely recommend the use of folic acid to minimize side effects of methotrexate. The optimal dose and timing of folic acid supplementation remains unclear. Some prefer daily therapy and others weekly or twice weekly dosing. Many clinicians recommend holding folic acid on the day of methotrexate due to a theoretical risk that it may impact the efficacy of methotrexate. When patients have ongoing side effects from methotrexate, many of us recommend increasing the dose of folic acid.
As part of the 3E recommendations in 2009, there was a systematic review of the use of folic acid with MTX (Visser, ARD, 2009). This included 9 studies of folic acid with MTX, and found folic acid supplementation reduces GI and liver toxicity of MTX. As a result, the experts recommended supplementing methotrexate with at least 5mg/week of folic acid.
This morning at EULAR, a group from India (Dhir et al) presented a double-blind RCT where they compared the effect of folic acid in 100 RA patients using doses of 10mg vs 30mg weekly on methotrexate toxicity and efficacy. Patients starting on MTX were randomized to receive folic acid 10mg (5mg tab x 2d; placebo x 4d) vs 30 mg (5mg daily) weekly, with no pill on the day of methotrexate administration. The co-primary endpoints included incidence of toxicity and change in disease activity at 24 weeks. The mean MTX doses at 24 weeks were fairly high at 22.8 (folic acid 10mg) and 21.4 (folic acid 30mg). Interestingly, there was no significant difference in side effects or clinical efficacy with the higher dose versus the lower dose of folic acid. If anything, the higher dose of folic acid had numerically more adverse effects.
Based on this data, we should probably continue to use previously recommended doses of folic acid (5-10mg) with methotrexate. Although there wasn’t a difference in side effects in MTX-naïve patients, I think it would be interesting to see if increasing the dose of folic acid is helpful in patients on low-dose folic acid who are having side effects with methotrexate. Clinically, when a patient is having difficulty tolerating MTX, prior to decreasing the MTX dose, I often increase the folic acid dose with variable success.
I don’t think that I will change this practice yet.
Dr. Jamal is a Clinical Associate Professor at the University of British Columbia and an active staff physician at Vancouver Coastal Health. Her interests include diagnosis and prognosis of early inflammatory arthritis, and timely assessment and access to care for patients with rheumatoid arthritis.View Full Bio