Methotrexate For Maintenance Of Remission Research Articles

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.

Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial. To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis. The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included. Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included. Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes. Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported. Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).

European experience with methotrexate treatment in Crohn's disease: a multicenter retrospective analysis.

Methotrexate (MTX) has been utilized for the treatment of Crohn's disease (CD) for decades. Nevertheless, current data provide equivocal evidence on the efficacy of MTX in CD.The aims of this study were to describe the efficacy of MTX for maintenance of remission in CD and to identify the factors associated with the probability of steroid-free clinical remission in a multicenter European referral center cohort. This was a retrospective cohort analysis. Consecutive patients treated with MTX for CD were included from 11 referral centers. Patients receiving concomitant treatment with tumor necrosis factor inhibitors or thiopurines were excluded. The main outcome was steroid-free clinical remission; the secondary outcomes included the rate of complications leading to MTX discontinuation and duration of relapse-free survival in patients achieving the main outcome. Between July 1992 and January 2012, 118 patients were identified for inclusion. MTX administration route was oral for induction in 31.4% and for maintenance in 49.1% of the patients. Steroid-free remission was achieved in 44/118 (37.2%) patients and was maintained relapse free by 28/44 (63.6%) for a median of 12 (3.5-18.5) months. At least one adverse effect was reported by 28.9% of the patients. No clinical or demographic factors were associated with either likelihood of achieving a clinical response or duration of relapse-free survival. MTX treatment induced steroid-free clinical remission in over a third of CD patients and maintained it for a year in almost two-thirds of the responders. MTX should be considered a viable therapeutic option in CD patients refractory to other therapies.

Methotrexate for maintenance of remission in ulcerative colitis.

Methotrexate, a folate antagonist, is an immunosuppressant drug that is effective for treating several inflammatory disorders including Crohn's disease. Ulcerative colitis, a related chronic inflammatory bowel disease, can be challenging to treat. T his updated systematic review summarizes the current evidence on the use of methotrexate for induction maintenance of remission in ulcerative colitis. The objectives of this review were to assess the efficacy and safety of methotrexate for maintenance of remission in patients with ulcerative colitis. We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. Randomized controlled trials in which methotrexate was compared to placebo or an active comparator in patients with quiescent ulcerative were considered for inclusion. Two authors independently extracted data and assessed the risk of bias for each study. The primary outcome was the occurrence of clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included frequency and nature of adverse events, change of disease activity score and steroid-sparing effect. We calculated the risk ratio and corresponding 95% confidence interval for dichotomous outcomes. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. Three trials (165 patients) fulfilled the inclusion criteria. One study compared oral methotrexate (12.5 mg/week) to placebo, another compared oral methotrexate (15 mg/week) to 6-mercaptopurine (6-MP, 1.5 mg/kg/day) or 5-aminosalicylic acid (5-ASA, 3 g/day) and the other compared methotrexate (15 mg/week) in combination sulfasalazine (3 g/day) to sulfasalazine. The placebo-controlled study was rated as low risk of bias. The study comparing methotrexate to 6-MP and 5-ASA was rated as high risk of bias and the study assessing methotrexate and sulfasalazine was rated as unclear risk of bias for sequence generation, allocation concealment and blinding. The placebo-controlled study found no statistically significant differences in the proportion of patients who maintained remission. At nine months, 36% (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64, 95% CI 0.28 to 1.45). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (15 events). The study comparing combination therapy to sulfasalazine found no statistically significant difference in the proportion of patients who maintained remission. At 12 months, 100% (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of sulfasalazine patients (RR 1.32, 95% CI 0.94 to 0.86), A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to unknown risk of bias and very sparse data (23 events). There were no statistically significant differences in maintenance of remission rates between methotrexate and 6-MP or between methotrexate and 5-ASA. At 76 weeks, 14% (1/7) of methotrexate patients maintained remission compared to 64% (7/11) of 6-MP patients (RR 0.22, 95% CI 0.03 to 1.45) and 0% (0/2) of 5-ASA patients (RR 1.13, 95% CI 0.06 to 20.71). A GRADE analysis indicated that the overall quality of the evidence from this study was very low due to high risk of bias and very sparse data. Adverse events reported in these studies included transient leucopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia The results for efficacy and safety outcomes between methotrexate and placebo, methotrexate and sulfasalazine, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration of methotrexate would be effective in quiescent ulcerative colitis is unknown. At present there is no evidence supporting the use of methotrexate for maintenance of remission in ulcerative colitis. More studies are needed to determine the efficacy and safety of methotrexate maintenance therapy in patients with quiescent ulcerative colitis. Large scale methodologically rigorous randomized controlled trials are needed. These studies should investigate higher doses of methotrexate (e.g. 15 to 25 mg/week) and parenteral administration.

Methotrexate for maintenance of remission in Crohn's disease.

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. 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.

Methotrexate for maintenance of remission in chronic active Crohnʼs disease

According to current guidelines methotrexate (MTX) should be considered as a second-line immunomodulator in patients with chronic active Crohn's disease (CD) if purine analogs are not tolerated or there is a lack of efficacy. However, its therapeutic role remains controversial to the present day. Medical records of all eligible patients treated in the outpatient clinic of the Johann Wolfgang Goethe-University Hospital between December 2000 and January 2009 were reviewed. Sixty-three patients were identified. The mean duration of treatment was 100 weeks (range, 2-364 weeks) with a mean cumulative dose of MTX of 2130 mg (range, 40-9005 mg). In 50 (79%) patients started on MTX clinical remission could be achieved within 3 months of treatment. The cumulative probability of these patients to maintain remission was 95.3%, 89.5%, 70.6%, and 62.8% at 6 months, 1, 2, and 3 years of treatment, respectively. The respective figures of the meta-analysis were 94%, 86%, 75%, 53%, and 43. Drug-related side effects were reported in 50 patients (79%), leading to withdrawal of MTX in 21 cases (33%). Along with previous observations our data demonstrate the efficacy of MTX as a second-line immunomodulator in chronic active CD. However, its use is limited due to intolerable side effects in a large proportion of patients. The results should encourage further research in order to establish the definite significance of MTX in chronic active CD.

Inflammatory bowel disease.

The pathogenesis of inflammatory bowel disease (IBD) continues to be explored, with the emphasis on genetically determined host immune dysregulation as it applies to interactions with luminal bacteria. The role of endoscopic ultrasound in the evaluation of IBD continues to be studied. Recent advances in the evaluation of enterocutaneous fistulas have been made through the use of hydrogen peroxide to enhance definition of the fistula course and characteristics of the neighboring bowel, as evaluated by transabdominal ultrasound. Refinements have been made in the use and interpretation of the results of surveillance colonoscopy for detection of colorectal cancer and dysplasia in IBD, but a consistent approach still needs to be applied by individual practitioners. New data exist on the usefulness of methotrexate for maintenance of remission, while a lack of efficacy has been demonstrated for mesalamine in the prevention of postoperative recurrence. The role of anti-tumor necrosis factor (TNF) antibody therapy in the treatment of IBD continues to be investigated.

Methotrexate for Maintenance of Remission in Crohn's Disease

Methotrexate (25 mg intramuscularly once weekly, for 16 to 24 weeks) has been shown to induce remission in Crohn's disease. However, methotrexate's