Crohn's disease is a chronic inflammatory disease of the intestines that frequently occurs in the lower part of the small intestine, called the ileum. However, Crohn’s disease can affect any part of the digestive tract, from the mouth to the anus. The most common symptoms are abdominal pain and diarrhea. Prevention of clinical relapse (resumption of symptoms of active disease) in patients in remission is an important objective in the management of Crohn’s disease. Methotrexate is a drug that suppresses the body's natural immune responses and may suppress inflammation associated with Crohn’s disease. The purpose of this systematic review was to examine the effectiveness and side effects of methotrexate used to maintain remission in Crohn's patients.
This review identified five studies that included a total of 333 participants. Two studies compared methotrexate (administered by pill or intramuscular injection) to a placebo (a sugar pill or a saline injection). One of these two studies also compared methotrexate to 6-mercaptopurine (an immunosuppressive drug). One small study compared methotrexate to both 6-mercaptopurine and 5-aminosalicylic acid (an anti-inflammatory drug). Two studies compared combination therapy with methotrexate and infliximab (a biological drug that is a tumour necrosis factor-alpha antagonist) to infliximab used by itself. One high quality study (76 patients) shows that methotrexate (15 mg/week) injected intramuscularly (i.e. into muscles located in the arm or thigh) for 40 weeks is superior to placebo for preventing relapse (return of disease symptoms) among patients whose disease became inactive while taking higher doses of intramuscular methotrexate (25 mg/week). Side effects occurred in a small number of patients. These side effects are usually mild in nature and include nausea and vomiting, cold symptoms, abdominal pain, headache, joint pain and fatigue. One small study (22 patients) found no difference in continued remission between low dose methotrexate (12.5 mg/week) taken orally and placebo and suggests that low dose oral methotrexate is not an effective treatment for inactive Crohn's disease. However this result is uncertain due to the small number of patients assessed in the study. Large-scale studies of methotrexate given orally at higher doses for maintenance of remission in Crohn’s disease may provide stronger evidence for the use of methotrexate in this manner. A pooled analysis of two studies (50 patients) found no difference in continued remission between oral methotrexate (12.5 to 15 mg/week) and 6-mercaptopurine (1 mg/kg/day). No firm conclusions can be drawn as these results are uncertain due to poor study quality and small numbers of patients. A small study (13 patients) found no difference in continued remission between methotrexate and 5-aminosalicylic acid. No conclusions can be drawn from this study as the results are very uncertain due to poor study quality and small numbers of patients. A pooled analysis of two studies (145 patients) found no difference in continued remission between combination therapy and infliximab. Combination therapy with methotrexate and infliximab does not appear to be any more effective for maintenance of remission than infliximab used by itself. This result is uncertain because one study was of poor quality (the other was high quality) and small numbers of patients.
Moderate quality evidence indicates that intramuscular methotrexate at a dose of 15 mg/week is superior to placebo for maintenance of remission in Crohn's disease. Intramuscular methotrexate appears to be safe. Low dose oral methotrexate (12.5 to 15 mg/week) does not appear to be effective for maintenance of remission in Crohn's disease. Combination therapy (methotrexate and infliximab) does not appear to be any more effective for maintenance of remission than infliximab monotherapy. The results for efficacy outcomes between methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Large-scale studies of methotrexate given orally at higher doses for maintenance of remission in Crohn’s disease may provide stronger evidence for the use of methotrexate in this manner.
Safe and effective long-term treatments that reduce the need for corticosteroids are needed for Crohn's disease. Although purine antimetabolites are moderately effective for maintenance of remission patients often relapse despite treatment with these agents. Methotrexate may provide a safe and effective alternative to more expensive maintenance treatment with TNF-α antagonists. This review is an update of a previously published Cochrane review.
To conduct a systematic review of randomized trials examining the efficacy and safety of methotrexate for maintenance of remission in Crohn's disease.
The Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED, EMBASE, and the Cochrane IBD/FBD Group Specialized Trials Register were searched from inception to June 9, 2014. Study references and review papers were also searched for additional trials.
Randomised controlled trials (RCTs) that compared methotrexate to placebo or any other active intervention for maintenance of remission in Crohn's disease were eligible for inclusion.
Two authors independently reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome measure was the proportion of patients maintaining clinical remission as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). We calculated the pooled risk ratio (RR) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria.
Five studies (n = 333 patients) were included in the review. Three studies were judged to be at low risk of bias. Two studies were judged to be at high risk of bias due to blinding. Intramuscular methotrexate was superior to placebo for maintenance of remission at 40 weeks follow-up. Sixty-five per cent of patients in the intramuscular methotrexate group maintained remission compared to 39% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 76 patients).The number needed to treat to prevent one relapse was four. A GRADE analysis indicated that the overall quality of evidence supporting this outcome was moderate due to sparse data (40 events). There was no statistically significant difference in maintenance of remission at 36 weeks follow-up between oral methotrexate (12.5 mg/week) and placebo. Ninety per cent of patients in the oral methotrexate group maintained remission compared to 67% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 22 patients). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to very sparse data (17 events). A pooled analysis of two small studies (n = 50) showed no statistically significant difference in continued remission between oral methotrexate (12.5 mg to 15 mg/week) and 6-mercaptopurine (1 mg/kg/day) for maintenance of remission. Seventy-seven per cent of methotrexate patients maintained remission compared to 57% of 6-mercaptopurine patients (RR 1.36, 95% CI 0.92 to 2.00). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was very low due to high risk of bias in one study (no blinding) and very sparse data (33 events). One small (13 patients) poor quality study found no difference in continued remission between methotrexate and 5-aminosalicylic acid (RR 2.62, 95% CI 0.23 to 29.79). A pooled analysis of two studies (n = 145) including one high quality trial (n = 126) found no statistically significant difference in maintenance of remission at 36 to 48 weeks between combination therapy (methotrexate and infliximab) and infliximab monotherapy. Fifty-four percent of patients in the combination therapy group maintained remission compared to 53% of monotherapy patients (RR 1.02, 95% CI 0.76 to 1.38, P = 0.95). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to high risk of bias in one study (no blinding) and sparse data (78 events). Adverse events were generally mild in nature and resolved upon discontinuation or with folic acid supplementation. Common adverse events included nausea and vomiting, symptoms of a cold, abdominal pain, headache, joint pain or arthralgia, and fatigue.