Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term?

Background. It is postulated that some aspects of methotrexate toxicity may be related to its action as an anti-folate. Folic acid (FA) is often given as an adjunct to methotrexate therapy, but there is no conclusive proof th at it decreases the toxicity of methotrexate and there is a theoretical ris k that it may decrease the efficacy of methotrexate. Objectives. To look at the effect of stopping FA supplementation in UK rheu matoid arthritis (RA) patients established on methotrexate <20 mg weekly an d FA 5 mg daily, to report all toxicity (including absolute changes in haem atological and liver enzyme indices) and to report changes in the efficacy of methotrexate. Methods. In a prospective, randomized, double-blind, placebo-controlled stu dy, 75 patients who were established on methotrexate <20 mg weekly and FA 5 mg daily were asked to stop their FA and were randomized to one of two gro ups: placebo or FA 5 mg daily. Patients were evaluated for treatment toxici ty and efficacy before entry and then at intervals of 3 months for 1 yr. Results. Overall, 25 (33%) patients concluded the study early, eight (21%) in the group remaining on FA and 17 (46%) in the placebo group (P = 0.02). Two patients in the placebo group discontinued because of neutropenia. At 9 months there was an increased incidence of nausea in the placebo group (45 vs 7%, P = 0.001). The placebo group had significantly lower disease activ ity on a few of the variables measured, but these were probably not of clin ical significance. Conclusions. It is important to continue FA supplementation over the long t erm in patients on methotrexate and FA in order to prevent them discontinui ng treatment because of mouth ulcers or nausea and vomiting. Our data sugge st that FA supplementation is also helpful in preventing neutropenia, with very little loss of efficacy of methotrexate.