Folic or Follnic Acid Supplementation Reduces the Liver Toxicity of Methotrexate
Methotrexate is an effective treatment for rheumatoid arthritis (RA), but its toxicity can lead to discontinuation of the drug in 30% of patients within the first year of treatment. Methotrexate is a folate antagonist and supplementation of MTX-treated patients with folate or folinic acid is believed to reduce MTX-associated toxicities. However, prior studies that attempted to address this question employed small numbers of patients and treated with less than standard doses of MTX.
Van Ede et al (Arthritis Rheum. 44:1515-1524, 2001) performed a multicenter study of 434 patients to determine the effect of folate replacement on MTX-associated toxicities. Patients who were nave to MTX were begun on MTX 7.5 mg/wk and were randomized to folate 1 mg/day OR folinic acid 2.5 mg/wk OR placebo. MTX was to be increased by 2.5 mg every 6 weeks (up to a maximum of 25 mg/wk) if patients failed to meet pre-defined response criteria. Folate dosages were doubled if the MTX dose was increased to 15 mg/wk or higher. Toxicities were monitored by self-report and by a standard toxicity form.
Results: Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, and only 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained almost entirely by a decreased incidence of elevated liver enzyme (ALT) in the folate supplementation groups. No significant differences in the frequencies of other toxicities were observed between the groups. Alcohol intake did not influence the rate of liver enzyme elevation in any of the three groups. Equivalent improvements in disease activity were observed among the three groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/wk) than in the folic and folinic acid groups (18.0 and 16.4 mg/wk, respectively).
Conclusion: Folate supplementation clearly reduced the incidence of liver enzyme elevation (ALT, specifically). Consequently, MTX was discontinued less frequently in the folate supplemented groups. Folate replacement had no effect on other toxicities. Slightly higher doses of MTX were prescribed in the folate supplementation groups to achieve similar levels of improvement in disease activity.
Editorial comment: This is an important study, the preliminary results of which were presented at the American College of Rheumatology meetings. It is encouraging to see the full report in published form. This is a well-designed study with large numbers of patients that clearly shows that folate supplementation reduces liver enzyme elevation. Since this is a frequent reason for discontinuing MTX, folate supplementation should now be encouraged as standard-of-care with MTX treatment. It was surprising that mucosal and GI side effects were not reduced with folate supplementation. The fact that folate supplemented patients “required” higher doses of MTX to achieve the same clinical responses as placebo treated patients suggests that folate supplementation may reduce the efficacy of MTX. However, one flaw in this study is that increases in MTX were not mandated in the protocol but rather suggested. This may have introduced some bias although the authors point out that failure to increase the MTX dosage despite insufficient clinical response occurred at similar rates in all three groups.