Folic Acid Reduces Methotrexate Efficacy

By Anne Harding

NEW YORK (Reuters Health) Nov 08 - A new study provides additional evidence that folic acid can reduce the efficacy of methotrexate.
Methotrexate inhibits dihydrate folate reductase and thus reduces levels of folate in the body, Dr. Dinesh Khanna of the University of Cincinnati in Ohio noted in an interview with Reuters Health. This can lead to mouth sores and other side effects.
While nearly all US patients on methotrexate receive folic acid to prevent side effects, Dr. Khanna said, European physicians tend only to prescribe folic acid when such side effects actually occur.
"There has been a debate for a while in the medical field on whether folic acid can affect efficacy," he added.
To investigate, Dr. Khanna and his team pooled data from a US and a European study of rheumatoid arthritis patients receiving methotrexate as a comparator in randomized controlled trials of leflunomide. They analyzed primary outcome data at 52 weeks for a total of 668 patients, 225 of whom were taking folic acid and 443 of whom were not.
The researchers used a statistical technique called propensity scoring to adjust for the substantial baseline differences between the patients who were taking folic acid and those who were not.
Seventeen percent more patients in the group that did not receive folic acid met American College of Rheumatology (ACR) improvement criteria by week 52 of the study, while ACR 50% responses were 14% higher in the non-folic acid group and ACR 70% responses were 12% higher.
Twenty nine-percent of patients in the US study, most of whom were on folic acid, had elevated liver transaminase levels, compared with 62% of patients in the European study, most of whom were not taking folic acid.
The current findings are based on post-hoc analysis, and should be considered "hypothesis generating," the researchers write in the October issue of Arthritis & Rheumatism.
However, Dr. Khanna added, physicians should be aware that when their rheumatoid arthritis patients taking methotrexate are started on folic acid, they may have a flare-up of the disease. "This is something to keep in mind," he said. "These patients may require a higher dose of methotrexate."

Arthritis Rheum 2005;52:3030-3038.