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for induction of remission of Crohn's disease, approximately 20% of patients who respond relapse when steroids are withdrawn and become steroid dependent.
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.
Dr Alfadhli and colleagues conducted a systematic review of the evidence for effectiveness of methotrexate for induction of remission with active Crohn's disease.
The researchers looked at active Crohn’s disease in the presence and absence of concomitant steroid therapy.
|3 small studies were identified that used low doses of methotrexate orally|
|The Cochrane Database of Systematic Reviews|
The research team conducted a computer-assisted search of MEDLINE and EMBASE for randomized controlled trials involving patients of age more than 17 years.
The team searched for relevant studies published in English, French, Spanish, Italian and German between 1966 and 2004.
Manual searches of reference lists from potentially relevant papers were performed to identify additional studies.
In addition, the researchers searched the Cochrane Controlled Trials Register as well as the Inflammatory Bowel Disease Review Group Specialized Trials Register.
The team defined refractory Crohn's disease by conventional clinical, radiological and endoscopic criteria, categorized as being active with a disease activity index more than 150.
The outcome measure was the rate of induction of remission and complete withdrawal from steroids in treatment and control groups after more than 16 weeks.
The investigators included a secondary outcome of induction of remission and reduction in steroid dose of at least 50%.
The results of the searches above were reviewed independently by two observers and relevant studies were selected according to the predefined selection criteria.
The team resolved any disagreement by consensus and used a standard data extraction form.
The same two researchers assessed the methodological quality of each trial by considering details of randomization method and whether intention-to-treat analysis was possible from the published data.
The quality of each trial was also assessed by the number of patients lost to follow-up, and whether a blinded outcome assessment was used.
In considering the appropriateness of combining results, the researchers first assessed trials according to the clinical comparability of trial protocols and study populations.
The investigators identified 5 randomized trials and these were considered inappropriate to combine because they differed with respect to participants, intervention, and outcomes.
The team found 3 small studies which employed low doses of methotrexate orally.
The pooled results of these 3 studies showed no statistically significant difference between methotrexate and placebo/control medication treated patients.
The investigators identified 1 small study which used a higher dose of intravenous/oral methotrexate that showed no statistically significant difference.
A larger study which employed a higher dose of methotrexate intramuscularly showed substantial benefit.
The researchers found adverse effects were more common with high dose intramuscular methotrexate therapy than with placebo.
Dr Alfadhli concludes, “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.”