While corticosteroids are often used to induce remission of Crohn's disease, the many side effects of these agents make them problematic for maintenance therapy. Alternatives to corticosteroids include mercaptopurine and azathioprine, but these agents are generally not as effective in controlling the disease. Methotrexate induces remission of active Crohn's disease but its effectiveness for maintenance therapy is unknown. Feagan and colleagues evaluated the effectiveness of methotrexate in patients whose Crohn's disease was in remission.
The double-blind, placebo-controlled study included 76 patients with chronically active Crohn's disease that had been induced into remission after 16 to 24 weeks of methotrexate injections, at 25 mg weekly. Remission was defined as no need for prednisone or a score of 150 or less on the Crohn's disease activity index. This index uses eight clinical features, such as the number of liquid or very soft stools, the severity of abdominal pain, the presence or absence of an abdominal mass or extraintestinal manifestations. With this index, scores can range from zero to 600. A score of 150 or less indicates inactive disease, and a score higher than 450 indicates critical illness.
Patients were randomly assigned to receive intramuscular injections of methotrexate, at 15 mg weekly, or placebo for 40 weeks. The Crohn's disease activity index was used to assess efficacy of therapy. A 100-point increase from the baseline score or the need for prednisone, mercaptopurine or azathioprine was considered to signify relapse of the disease. Patients were evaluated every four weeks, and dosage adjustments were made as needed because of abnormal values on hepatic or hematologic tests.
After 40 weeks of follow-up, 26 (65 percent) of the 40 patients in the methotrexate group remained in remission, compared with 14 (39 percent) of the 36 patients in the placebo group. This translated to a 26.1 percent absolute reduction in the risk of relapse with methotrexate maintenance therapy.
Patients in the methotrexate group had fewer relapses than did those in the placebo group. Eleven patients (28 percent) in the methotrexate group required steroid therapy because of relapse compared with 21 patients (58 percent) in the placebo group. Of the 36 patients who had a relapse, 22 were treated with 25 mg of methotrexate weekly, usually in addition to prednisone. In 12 (55 percent) of these 22 patients, prednisone was subsequently discontinued, and these 12 were in remission at week 40 of the study.
None of the patients in the methotrexate group had a severe adverse event. Two patients in the placebo group had an adverse event. Nausea and vomiting occurred in 16 patients who received methotrexate and in nine patients who received placebo. Only one patient discontinued methotrexate therapy because of nausea and vomiting. The overall incidence of recorded adverse events was the same in both groups.
The authors conclude that methotrexate is safe and effective for maintaining remission in patients with Crohn's disease. Although adverse events were rare in this study, treatment with methotrexate requires monitoring for evidence of hematologic, hepatic and pulmonary toxicity. Because of the risk of teratogenicity, methotrexate should not be used in women of childbearing age.