Morgan and colleagues [1] clearly showed that supplementation with folic acid improved methotrexate tolerance in patients with rheumatoid arthritis. However, I find the conclusion that the folate supplement did not alter the efficacy of methotrexate somewhat difficult to accept on the basis of the data presented.

The data summarized in Table 2 of their report show that after 6 months of treatment, joint swelling and tenderness was either unchanged or worse in 39 and 35 patients, respectively, in the placebo group; 33 and 63 patients, respectively, in the low-dose folic acid group; and 13 and 43 patients, respectively, in the high-dose folic acid group. After 12 months of treatment, swelling or tenderness was unchanged or worse in 16 and 31 patients, respectively, in the placebo group; 9 and 43 patients, respectively, in the low-dose folic acid group; and 17 and 23 patients, respectively, in the high-dose folic acid group. I fail to see how one can evaluate efficacy from such data, given the large type II error entailed by the statistical analysis.

Toxicity seems to have been observed in only some patients who were not receiving folate. Was this toxicity predicted by folate status based on erythrocyte folate levels, dietary folate levels, multilobed neutrophil counts, and so forth? Several studies have shown that toxicity from folic acid antagonists is accentuated in patients who are folate deficient, and that even a folic acid antagonist that is usually inactive in humans (trimethoprim) may cause megaloblastic anemia in folate-deficient patients. It would be of interest if the toxicity observed in the control group was more common in patients whose folate status was worse, given that one might reserve folate supplements for these patients and thus not be required to determine whether efficacy is affected by such supplementation.