Can folate supplementation reduce the incidence of methotrexate toxicity?




Arthritis Rheum

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Consumer Data: Folic Acid
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Methotrexate is an antimetabolite, or drug that opposes or replaces a metabolite while being structurally very similar to that metabolite. It is used in the treatment different types of tumors, in psoriasis and in rheumatoid arthritis in adults. This drug is a powerful agent and the precautions are taken seriously. It is typically only used in cases that are life threatening or for which other treatments have not been successful.
Part of the concern over methotrexate is in regard to the toxicity associated with its use. Among other side effects, methotrexate has the potential to be both acutely and chronically toxic for the functioning of the liver. Reducing this serious side effect could allow patients to maintain their drug therapy for a longer period of time. In looking at complementary therapies that might reduce this toxicity, a study was conducted using folate supplementation.
This study was a 48-week, randomized, double-blind, placebo-controlled trial involving 434 patients with rheumatoid arthritis. Patients were randomized to receive 7.5 mg/week of methotrexate in combination with either placebo, 1 mg/day of folic acid or 2.5 mg/week of folinic acid. Depending upon response the dose of methotrexate could be increased up to 25 mg/week. When the methotrexate dose reached 15 mg/day the folate doses were doubled. Discontinuation of methotrexate due to adverse events was the primary end point with secondary end points including the methotrexate dosage and parameters of methotrexate efficacy and toxicity. 38 percent of the placebo group had to discontinue methotrexate due to toxicity related effects. The discontinuation rate in the folic acid group was 17% and 12% in the folinic acid group.
The difference in these rates was likely due to a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. The various measures of disease activity improvement were equal among all groups. At the end of the study the mean methotrexate dosages were as follows; 14.5 mg/week in the placebo group, 18 mg/week in the folic acid group and 16.4 mg/week in the folinic acid group. The authors concluded that the "folate supplementation regimens reduced the incidence of elevated liver enzyme levels during [methotrexate] therapy, and as a consequence, [methotrexate] was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of [methotrexate] were prescribed to obtain similar improvement in disease activity in the folate supplementation groups."1


1. van Ede AE. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. Jul 2001;44(7):1515-24.