Methotrexate for induction of remission in refractory Crohn's disease
ABSTRACT 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corticosteroids are effective for induction of remission of Crohn's disease, many patients relapse when steroids are withdrawn or become steroid dependent.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 a previously published Cochrane review.
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.
We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized register from inception to June 27, 2012 for relevant studies. Conference proceedings and reference lists were also searched to identify additional studies.
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.
The primary outcome was failure to failure to enter remission and withdrawal 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.
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 it was considered to be inappropriate to pool the data for meta-analysis. Three small studies which employed low doses of 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.
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 infiximab 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.
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ABSTRACT: To assess the efficacy and safety of mycophenolate mofetil (MMF) prospectively in inflammatory bowel disease (IBD) patients intolerant or refractory to conventional medical therapy. Crohn's disease (CD) or ulcerative colitis/IBD unclassified (UC/IBDU) patients intolerant or refractory to conventional medical therapy received MMF (500-2000 mg bid). Clinical response was assessed by the Harvey Bradshaw index (HBI) or colitis activity index (CAI) after 2, 6 and 12 mo of therapy, as were steroid usage and adverse effects. Fourteen patients (9 CD/5 UC/IBDU; 8M/6F; mean age 50.4 years, range 28-67 years) were treated and prospectively assessed for their response to oral MMF. Of the 11 patients who were not in remission on commencing MMF, 7/11 (63.6%) achieved remission by 8 wk. All 3 patients in remission on commencing MMF maintained their remission. Ten patients were still on MMF at 6 mo with 9/14 (64.3%) in remission, while of 12 patients followed for 12 mo, 8 were in remission without dose escalation (66.7%). Three patients were withdrawn from the MMF due to drug intolerance. There were no serious adverse events attributed due to the medication. MMF demonstrated efficacy in the management of difficult IBD. MMF appeared safe, well tolerated and efficacious for both short and long-term therapy, without the need for dose escalation. Further evaluation of MMF comparing it to conventional immunosuppressants is required.World Journal of Gastroenterology 05/2009; 15(13):1594-9. · 2.43 Impact Factor
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ABSTRACT: New medical therapies have improved outlook in inflammatory bowel disease but published impact on surgical rates has been modest suggesting that many patients are still not attaining remission. To review remission rates with current medical treatments for inflammatory bowel disease. We searched MEDLINE (source PUBMED, 1966 to January, 2011). Induction and maintenance of remission was observed in 20% (range, 9-29.5%) and 53% (range, 36.8-59.6%) of ulcerative colitis (UC) patients treated with oral 5-ASA derivatives. Induction of remission was noted in 52% (range, 48-58%) of Crohn's disease (CD) patients and 54% of UC patients treated with steroids in population-based cohorts. Maintenance of remission was reported in 71% (range, 56-95%) of CD patients on azathioprine over a 6-month to 2-year period and in 60% (range, 41.7-82.4%) in UC at 1 year or longer. Induction and maintenance of remission was noted in 39% (range, 19.3-66.7%) and 70% (range, 39-90%) of CD patients on methotrexate over a 40-week period. Induction of remission was reported in 32% (range, 25-48%), 26% (range, 18-36%) and 20% (range, 19-23%) of CD patients on infliximab, adalimumab or certolizumab pegol, respectively. The corresponding figures were 45% (range, 39-59%), 43% (range, 40-47%) and 47.9% at weeks 20-30 among initial responders. Induction of remission was observed in 33% (range, 27.5-38.8%) and 18.5% of UC patients on infliximab or adalimumab, respectively. Maintenance of remission was noted in 33% (range, 25.6-36.9%) of UC patients on infliximab at week 30. Approximately one-fifth of CD and UC patients treated with biologicals require intestinal resection after 2-5 years in referral-centre studies. In the era of biologics, the proportion of patients with inflammatory bowel disease not entering remission remains high.Alimentary Pharmacology & Therapeutics 02/2011; 33(8):870-9. DOI:10.1111/j.1365-2036.2011.04599.x · 4.55 Impact Factor
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ABSTRACT: Crohn's disease is a disorder of unknown etiology and complicated pathogenesis. A substantial amount of evidence has accumulated recently and has been applied to clinical practice. The present guidelines were developed based on recent evidence and the formal consensus of experts relevant to this disease. Here we provide an overview of these guidelines, as follows. Target disease: Crohn's disease Users: Clinical practitioners in internal medicine, surgery, gastroenterology, and general practice Purpose: To provide appropriate clinical indicators to practitioners Scope of clinical indicators: Concept of Crohn's disease, epidemiology, classifications, diagnosis, treatment, follow up, and special situations Intervention: Diagnosis (interview, physical examination, clinical laboratory tests, imaging, and pathology) and treatment (lifestyle guidance, drug therapy, nutritional therapy, surgery, etc.) Outcome assessment: Attenuation of symptoms, induction and maintenance of remission, imaging findings, quality of life (QOL), prevention of complications and harm of therapy Methods for developing these guidelines: Described in the text Basis of recommendations: Integration of evidence level and consensus of experts Cost-benefit analysis: Not implemented Evaluation of effectiveness: Yet to be confirmed Status of guidelines: Updated version of the first Guidelines published in 2010 Publication sources: Printed publication available and electronic information in preparation Patient information: Not available Date of publication: October 2011 These guidelines were intended primarily to be used by practitioners in Japan, and the goal of these guidelines is to improve the outcomes of patients with Crohn's disease.Journal of Gastroenterology 10/2012; 48(1). DOI:10.1007/s00535-012-0673-1 · 4.02 Impact Factor