title: Methotrexate for induction of remission in refractory Crohn's disease.
abstract: BACKGROUND
  Although corticosteroids are effective for induction of remission of Crohn's disease, many patients relapse when steroids are withdrawn or become steroid dependent.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 or 6-mercaptopurine therapy. This systematic review is an update of previously published Cochrane reviews.
  
  
  OBJECTIVE
  The primary objective was to assess the efficacy and safety of methotrexate for induction of remission in patients with active Crohn's disease in the presence or absence of concomitant steroid therapy.
  
  
  METHODS
  We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized register from inception to June 9, 2014 for relevant studies. Conference proceedings and reference lists were also searched to identify additional studies.
  
  
  METHODS
  Randomized controlled trials of methotrexate compared to placebo or an active comparator for treatment of active refractory Crohn's disease in adult patients (> 17 years) were considered for inclusion.
  
  
  METHODS
  The primary outcome was failure to enter remission and withdraw from steroids. Secondary outcomes included adverse events, withdrawal due to adverse events, serious adverse events and quality of life. We calculated the relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis. The Cochrane risk of bias tool was used to assess the methodological quality of included studies. The GRADE approach was used to assess the overall quality of evidence supporting the primary outcome.
  
  
  RESULTS
  Seven studies (495 patients) were included. Four studies were rated as low risk of bias. Three studies were rated as high risk of bias due to open label or single-blind designs. The seven studies differed with respect to participants, intervention, and outcomes to the extent that meta-analysis was considered to be inappropriate. GRADE analyses indicated that the quality of evidence was very low to low for most outcomes due to sparse data and inadequate blinding. Three small studies which employed low dose oral methotrexate showed no statistically significant difference in failure to induce remission between methotrexate and placebo or between methotrexate and 6-mercaptopurine. For the study using 15 mg/week of oral methotrexate 33% (5/15) of methotrexate patients failed to enter remission compared to 11% (2/18) of placebo patients (RR 3.00, 95% CI 0.68 to 13.31). For the study using 12.5 mg/week of oral methotrexate 81% (21/26) of methotrexate patients failed to enter remission compared to 77% (20/26) of placebo patients (RR 1.05, 95% CI 0.79 to 1.39). This study also had an active comparator arm, 81% (21/26) of methotrexate patients failed to enter remission compared to 59% (19/32) of 6-mercaptopurine patients (RR 1.36, 95% CI 0.97 to 1.92). For the active comparator study using 15 mg/week oral methotrexate, 20% (3/15) of methotrexate patients failed to enter remission compared to 6% of 6-mercaptopurine patients (RR 3.20, 95% CI 0.37 to 27.49). This study also had a 5-ASA arm and found that methotrexate patients were significantly more likely to enter remission than 5-ASA patients. Twenty per cent (3/15) of methotrexate patients failed to enter remission compared to 86% (6/7) of 5-ASA patients (RR 0.23, 95% CI 0.08 to 0.67). One small study which used a higher dose of intravenous or oral methotrexate (25 mg/week) showed no statistically significant difference between methotrexate and azathioprine. Forty-four per cent (12/27) of methotrexate patients failed to enter remission compared to 37% of azathioprine patients (RR 1.20, 95% CI 0.63 to 2.29). Two studies found no statistically significant difference in failure to enter remission between the combination of infliximab and methotrexate and infliximab monotherapy. One small study utilized intravenous methotrexate (20 mg/week) for 5 weeks and then switched to oral (20 mg/week). Forty-five per cent (5/11) of patients in the combination group failed to enter remission compared to 62% of infliximab patients (RR 0.73, 95% CI 0.31 to 1.69). The other study assessing combination therapy utilized subcutaneous methotrexate (maximum dose 25 mg/week). Twenty-four per cent (15/63) of patients in the combination group failed to enter remission compared to 22% (14/63) of infliximab patients (RR 1.07, 95% CI 0.57 to 2.03). A large placebo-controlled study which employed a high dose of methotrexate intramuscularly showed a statistically significant benefit relative to placebo. Sixty-one per cent of methotrexate patients failed to enter remission compared to 81% of placebo patients (RR 0.75, 95% CI 0.61 to 0.93; number needed to treat, NNT=5). Withdrawals due to adverse events were significantly more common in methotrexate patients than placebo in this study. Seventeen per cent of methotrexate patients withdrew due to adverse events compared to 2% of placebo patients (RR 8.00, 95% CI 1.09 to 58.51). The incidence of adverse events was significantly more common in methotrexate patients (63%, 17/27) than azathioprine patients (26%, 7/27) in one small study (RR 2.42, 95% CI 1.21 to 4.89). No other statistically significant differences in adverse events, withdrawals due to adverse events or serious adverse events were reported in any of the other placebo-controlled or active comparator studies. Common adverse events included nausea and vomiting, abdominal pain, diarrhea, skin rash and headache.
  
  
  CONCLUSIONS
  There is evidence from a single large randomized trial which suggests that intramuscular methotrexate (25 mg/week) provides a benefit for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Lower dose oral methotrexate does not appear to provide any significant benefit relative to placebo or active comparator. However, these trials were small and further studies of oral methotrexate may be justified. Comparative studies of methotrexate to drugs such as azathioprine or 6-mercaptopurine would require the randomization of large numbers of patients. The addition of methotrexate to infliximab therapy does not appear to provide any additional benefit over infliximab monotherapy. However these studies were relatively small and further research is needed to determine the role of methotrexate when used in conjunction with infliximab or other biological therapies.
authors.affiliation: Robarts Clinical Trials, Robarts Research Institute, P.O. Box 5015, 100 Perth Drive, London, ON, Canada, N6A 5K8.
authors.forename: John W D
authors.initials: JW
authors.lastname: McDonald
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: David J
authors.initials: DJ
authors.lastname: Tsoulis
authors.forename: John K
authors.initials: JK
authors.lastname: MacDonald
authors.forename: Brian G
authors.initials: BG
authors.lastname: Feagan
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001379:Azathioprine / Q000627:therapeutic use; D003424:Crohn Disease / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D060828:Induction Chemotherapy / Q000379:methods*; D000069285:Infliximab; D015122:Mercaptopurine / Q000627:therapeutic use; D008727:Methotrexate / Q000627:therapeutic use*; D011241:Prednisone / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D013256:Steroids / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D013256:Steroids; D000069285:Infliximab; D015122:Mercaptopurine; D001379:Azathioprine; D011241:Prednisone; D008727:Methotrexate
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