Methotrexate for treatment of active treatment resistant Crohn's disease

Alfadhli AAF, McDonald JW, Feagan BG

Published Online:

January 21, 2009

Although corticosteroids are effective for treating Crohn's disease, approximately 20% of patients who respond become sick again when steroids are withdrawn and become steroid dependent. Furthermore, corticosteroids exhibit significant adverse effects. This review shows that methotrexate (25 mg/week) injected intramuscularly for 16 weeks among patients with active treatment resistant Crohn's disease may be an effective treatment. Although mild side effects are more common with high dose methotrexate therapy, no serious side effects have been observed. Lower doses of methotrexate (12.5 to 15 mg/week) taken orally are not effective treatment for Crohn's disease. There is also evidence that methotrexate reduces the need for steroid treatment. This reduction in steroid use could reduce steroid induced side effects for people with chronic Crohn's disease.

Abstract (click to read)

Background:

Although corticosteroids are effective for induction of remission of Crohn's disease, approximately 20% of patients who respond relapse when steroids are withdrawn and become steroid dependent (Binder 1985). Furthermore, corticosteroids exhibit significant adverse effects. The success of methotrexate as a treatment for rheumatoid arthritis led to its evaluation in patients with refractory Crohn's disease. Methotrexate has been studied for induction of remission of refractory Crohn's disease and has become the principal alternative to azathioprine/6MP therapy. The evidence for its effectiveness has not been subjected to a systematic review.

Objectives:

To conduct a systematic review of the evidence for effectiveness of methotrexate for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy.

Search strategy:

A computer-assisted search of MEDLINE and EMBASE for relevant studies published in English, French, Spanish, Italian and German between 1966 and July 2004. Manual searches of reference lists from potentially relevant papers were performed to identify additional studies. The Cochrane Controlled Trials Register and the IBD Review Group Specialized Trials Register were also searched.

Selection criteria:

Randomized controlled trials involving patients of age > 17 years with refractory Crohn's disease defined by conventional clinical, radiological and endoscopic criteria, which was categorized as being active (Crohn's disease activity index >150).

Data collection and analysis:

Outcome measures: The outcome measure was the rate of induction of remission and complete withdrawal from steroids in the treatment and control groups after > 16 weeks of treatment. A secondary outcome was induction of remission with reduction in steroid dose of at least 50%. Selection of trials: The results of the searches above were reviewed independently by two observers and relevant studies selected according to the predefined selection criteria. Any disagreement among reviewers was resolved by consensus. The same two reviewers assessed the methodological quality of each trial (details of randomization method, including whether intention-to-treat analysis was possible from the published data, number of patients lost to follow-up, and if a blinded outcome assessment was used). A standard data extraction form was used. Appropriateness of combining results: Trials were first reviewed to assess the clinical comparability of trial protocols and study populations.

Main results:

Five randomized trials were identified. The five studies differed with respect to participants, intervention, and outcomes to the extent that it was considered to be inappropriate to combine the data statistically. Three small studies which employed low doses of methotrexate orally showed no statistically significant difference between methotrexate and placebo/control medication treated patients. One small study which used a higher dose of intravenous/oral methotrexate showed no statistically significant difference between methotrexate and azathioprine. A larger study which employed a higher dose of methotrexate intramuscularly showed substantial benefit (number needed to treat, NNT=5). Adverse effects were more common with high dose intramuscular methotrexate therapy than with placebo.

Authors' conclusions:

There is evidence from a single large randomized trial on which to recommend the use of methotrexate 25 mg intramuscularly weekly for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Although adverse effects were more common than with placebo, they were not severe. There is no evidence on which to base a recommendation for use of lower dose oral methotrexate.

This record should be cited as:

Alfadhli AAF, McDonald JW, Feagan BG. Methotrexate for induction of remission in refractory Crohn's disease. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD003459. DOI: 10.1002/14651858.CD003459.pub2

Assessed as up to date:

July 22, 2004

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Primary Review Group:

Inflammatory Bowel Disease and Functional Bowel Disorders Group

Health topics:

Gastroenterology > Inflammatory bowel disease > Crohn's disease: induction of remission

Cochrane Summaries^beta

Independent high-quality evidence for health care decision making

Methotrexate for treatment of active treatment resistant Crohn's disease

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