Morgan and colleagues [1] evaluated folate supplementation during methotrexate therapy for rheumatoid arthritis. It is encouraging to see evidence that such supplementation can reduce the severity of common side effects related to methotrexate therapy. Some questions remain, however, regarding the study design, the conclusions, and the recommendations.

First, patients in the high-dose arm of the study reportedly received 27.5 mg of folic acid per week (or approximately 5 mg/d as reported); however, previous interim reports of what I believe to be the same study stated that patients assigned to this arm received 50 mg weekly (10 mg/d for 5 days) [2, 3]. Why was the dose changed? Were problems associated with the original dose, and, if the dose was changed after initiation of the study, how did that affect the blinding?

Second, the mean methotrexate dose reported in Morgan and colleagues' study (between 8.5 and 9.5 mg/wk) is slightly lower than that reported in previous controlled efficacy studies (10.5 mg/wk) and much lower than that of the long-term cohort studies (12.5 to 14 mg/wk). This discrepancy raises the question of the effectiveness of this supplementation throughout the range of methotrexate doses (5 to 30 mg/wk) currently used by rheumatologists. Almost one third of the patients in each study arm showed no clinical improvement while receiving these methotrexate doses, and almost two thirds of the patients reported some side effects related to methotrexate. The patients receiving high-dose folic acid fared no better (in fact, they fared worse) in terms of the frequency of side effects than those receiving the lower dose (high-dose, 65%; low-dose, 48%). Thus, the data suggest that one should not adjust the folic acid dose through the range of folic acid used in the study to respond to side effects.

These points highlight some of the major differences between the study by Morgan and colleagues and our study [4], which showed the effectiveness of low-dose leucovorin. My colleagues and I studied the overall frequency and severity of side effects and adjustments of medication in response to side effects persisting for more than 3 weeks. We also evaluated the full range of weekly methotrexate doses (as high as 30 mg/wk) and used a mean weekly methotrexate dose of 12 to 13 mg, which is more consistent with doses used in long-term cohort studies.

Before we embrace folic acid therapy over leucovorin therapy because of its reduced cost (between $6.00 and $20.00 a month), the comparative efficacy of folic acid over leucovorin must be proven. From the standpoint of convenience, taking a half tablet or one tablet of leucovorin 24 hours after methotrexate administration seems acceptable compared with taking one or more folic acid tablets daily for 5 days beginning 48 hours after methotrexate administration.