Methotrexate improved symptoms and reduced the need for prednisone in chronic active Crohn disease
ACP J Club. 1995 July-Aug;123:9. doi:10.7326/ACPJC-1995-123-1-009
Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn's disease. N Engl J Med. 1995 Feb 2;332:292-7.
To evaluate the effectiveness of methotrexate in patients with chronic active Crohn disease.
Randomized, double-blind, placebo-controlled trial with 16-week follow-up.
7 university medical centers in North America.
141 patients (mean age 35 y, 55% men) with chronic active Crohn disease and duration of symptoms of ≥ 3 months despite daily doses of ≥ 12.5 mg of prednisone with at least 1 attempt to discontinue treatment. Exclusion criteria were long-term low-dose prednisone therapy, critical illness, hepatic disease, renal dysfunction, lung disease, systemic infection, pregnancy, cancer, high alcohol consumption, hypersensitivity to methotrexate, erythrocyte macrocytosis, body weight 40% greater than normal, diabetes mellitus, need for nonsteroidal anti-inflammatory drugs, or use of immunosuppressive drugs in the previous 3 months. No patients were lost to follow-up.
Patients were assigned to receive intramuscular methotrexate, 25 mg (n = 94), or placebo (n = 47) weekly for 16 weeks. Patients also received prednisone, 20 mg/d, which was tapered over 10 weeks unless their condition worsened.
Main outcome measures
The main outcomes were remission and the successful discontinuation of prednisone. Other outcomes were mean scores on the Crohn's Disease Activity Index and the Inflammatory Bowel Disease Questionnaire and the mean serum orosomucoid concentration.
After 16 weeks, 37 patients (39%) in the methotrexate group were in clinical remission compared with 9 patients (19%) in the placebo group (P = 0.016) (Table). The patients in the methotrexate group used less prednisone overall than those in the placebo group (P = 0.026). The average of the mean scores on the Crohn's Disease Activity Index after 16 weeks of treatment was lower in the methotrexate group than in the placebo group (162 vs 204, P = 0.002). The treatment group had improved quality-of-life scores and decreased serum orosomucoid concentrations. 16 patients (17%) withdrew from treatment because of adverse effects compared with 1 patient (2%) in the placebo group.
Methotrexate improved symptoms and reduced the need for prednisone in patients with chronic active Crohn disease.
Sources of funding: Medical Research Council of Canada; Crohn's and Colitis Foundation of America through donations from the David and Minnie Berk Foundation; Crohn's and Colitis Foundation of Canada.
For article reprint: Dr. B.G. Feagan, 6 of 12 University Hospital, 339 Windemere Road, London, Ontario N6A 5A5, Canada. FAX 519-663-3232.
Table. Methotrexate vs placebo in Crohn disease*
|Outcome at 16 wk||Intramuscular methotrexate||Placebo||RBI (95% CI)||NNT (CI)|
|Clinical remission||39%||19%||106% (13 to 295)||5 (3 to 19)|
*Abbreviations defined in Glossary; RBI, NNT, and CI calculated from data in article.
This well-designed trial by Feagan and colleagues showed that intramuscular methotrexate improved the short-term outcome of patients with Crohn disease and chronic steroid dependency managed at tertiary care centers.
Intramuscular methotrexate for Crohn disease was described in the report of an earlier open and uncontrolled trial (1). Weekly injection is less convenient than oral therapy and requires patient motivation and compliance. The study by Feagan and colleagues covers only 4 months of therapy. Crohn disease is a chronic disorder and is usually followed over years. As the author of an accompanying editorial (2) asked, would methotrexate show similar benefit over years of therapy?
Methotrexate has undeniable toxicity, including liver disease, hypersensitivity pneumonitis, bone marrow depression, teratogenicity, gastrointestinal toxicity, headaches, dizziness, fatigue, mood alterations, abortifacient properties, and induction of opportunistic infections. In this study, 17 patients receiving methotrexate withdrew because of toxicity. The most common problems were nausea and abnormal liver function test results.
Future trials are needed to answer important questions: Is oral therapy effective? Does methotrexate provide long-term benefit? What is the long-term toxicity of methotrexate in patients with Crohn disease? Is methotrexate therapy more beneficial for small-bowel or colonic Crohn disease, or is the site irrelevant?
Patients with Crohn disease who require methotrexate are managed best by clinicians familiar with methotrexate toxicity in centers currently doing trials.
Neil W. Randall, MD
Geisinger ClinicDanville, Pennsylvania, USA