Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial Long-term Methotrexate for Crohn's Disease: Safety and Efficacy in Clinical Practice Methotrexate in Crohn's disease: results of a randomized, double-blind, placebo-controlled trial. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. 6‐Mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid‐dependent inflammatory bowel disease Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn's disease: a randomised, investigator-blind study. Methotrexate in chronic active Crohn's disease: a double-blind, randomized, Israeli multicenter trial. Long-term results with azathioprine therapy in patients with corticosteroid-dependent Crohn's disease: open-label prospective study. Methotrexate in Crohn's disease: long-term efficacy and toxicity A randomized dose–response and pharmacokinetic study of methotrexate for refractory inflammatory Crohn’s disease and ulcerative colitis Bioavailability of oral vs. subcutaneous low‐dose methotrexate in patients with Crohn's disease Mucosal healing with methotrexate in Crohn’s disease: a prospective comparative study with azathioprine and infliximab Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease.
BACKGROUND We did a r and omised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn 's disease who respond to a single infusion of infliximab .  METHODS 573 patients with a score of at least 220 on the Crohn 's disease activity index ( CDAI ) received a 5 mg/kg intravenous infusion of infliximab at week 0 . After assessment of response at week 2 , patients were r and omly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 ( group I ) , repeat infusions of 5 mg/kg infliximab at the same timepoints ( group II ) , or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg ( group III ) . The prespecified co- primary endpoints were the proportion of patients who responded at week 2 and were in remission ( CDAI < 150 ) at week 30 and the time to loss of response up to week 54 in patients who responded . Analyses of the co- primary endpoints were by intention to treat . FINDINGS 335 ( 58 % ) patients responded to a single infusion of infliximab within 2 weeks . At week 30 , 23 of 110 ( 21 % ) group I patients were in remission , compared with 44 of 113 ( 39 % ) group II ( p=0.003 ) and 50 of 112 ( 45 % ) group III ( p=0.0002 ) patients . Thus , patients in groups II and III combined were more likely to sustain clinical remission than patients in group I ( odds ratio 2.7 , 95 % CI 1.6 - 4.6 ) . Throughout the 54-week trial , the median time to loss of response was 38 weeks ( IQR 15 to > 54 ) and more than 54 weeks ( 21 to > 54 ) for groups II and III , respectively , compared with 19 weeks ( 10 - 45 ) for group I ( p=0.002 and p=0.0002 , respectively ) .  Infliximab safety was consistent with that seen in other trials of infliximab in Crohn 's disease and rheumatoid arthritis . In particular , the incidence of serious infections was similar across treatment groups . INTERPRETATION Patients with Crohn 's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54 , to discontinue corticosteroids , and to maintain their response for a longer period of time , if infliximab treatment is maintained every 8 weeks Goals To assess the efficacy and safety profile of methotrexate ( MTX ) for the treatment of Crohn 's disease ( CD ) in clinical practice . Background MTX is widely used for some chronic immunologic diseases . Although some r and omized controlled trials suggest its efficacy in CD , this drug remains a second-line , underused , immunomodulator . Study Medical records of all patients treated with MTX for CD in our center ( n=44 ) were review ed . Clinical and epidemiologic parameters , including risk factors for hepatotoxicity , were registered . Results MTX was prescribed mainly for steroid-dependency ( n=22 ) and as concomitant treatment to infliximab ( n=18 ) . Mean duration of treatment was 22.9±19 months , with a mean cumulative dose of MTX of 1169±784 mg . Thirty-nine percent of patients developed drug-related side effects , hepatotoxicity being the most frequent [ 13 patients ( 30 % ) ] . However , only 5 patients ( 11 % ) had to discontinue MTX . In steroid-dependent CD patients  , disease remission and complete steroid withdrawal was achieved in 77 % of cases . Seven patients lost their initial response to MTX during follow-up , leading to a cumulative probability of remission of 39 % after 3 years of treatment . Conclusions MTX is well tolerated in most CD patients . Although a great proportion of steroid-dependent CD patients achieve disease remission and steroid withdrawal , there is a trend to a loss of efficacy with time . Larger , long-term studies are necessary to establish the role of MTX in the management of CD BACKGROUND / AIMS Immunosuppression with methotrexate may be useful in the treatment of Crohn 's disease . We tested the efficacy of methotrexate in refractory Crohn 's disease in a r and omized , controlled trial . METHODOLOGY R and omized , double-blind placebo-controlled trial of methotrexate in 33 patients with steroid-dependent Crohn 's disease , 33 % of whom had previously failed therapy with 6-mercaptopurine .  Patients were given placebo or oral methotrexate 15 mg/week , or adjusted up to 22.5 mg/week , for up to 1 year or until treatment failure . Outcome was assessed by reduction in prednisone dosage , Crohn 's Disease Activity Index , hospital admission , and laboratory parameters . RESULTS Four patients were dropped from the study for non-compliance and one because of intercurrent illness , and 28 patients could be evaluated . Fewer methotrexate-treated patients ( 6/13 or 46 % ) had flares of Crohn 's disease as compared to placebo-treated patients ( 12/15 or 80 % ) , but this did not achieve statistical significance ( p<0.1 ) . There was a non-significant trend toward an increased number of significant side effects in the methotrexate-treated patients ( 3/13 or 23 % ) as compared to the placebo-treated patients ( 0/15 or 0 % ) ( p<0.2 ) . Laboratory indices of inflammation did not differ between the two groups . CONCLUSIONS The  methotrexate-treated  group showed a trend toward fewer Crohn 's disease flares , balanced by an increased number of significant side effects BACKGROUND Treatment with infliximab , a chimeric monoclonal IgG1 antibody against tumor necrosis factor , can result in the formation of antibodies against infliximab . We evaluated the clinical significance of these antibodies in patients with Crohn 's disease . METHODS In a cohort of 125 consecutive patients with Crohn 's disease who were treated with infliximab infusions  , we evaluated the concentrations of infliximab and of antibodies against infliximab  , clinical data , side effects ( including infusion reactions ) , and the use of concomitant medications before and 4 , 8 , and 12 weeks after each infusion . RESULTS A mean of 3.9 infusions ( range , 1 to 17 ) per patient were administered over a mean period of 10 months . Antibodies against infliximab  were detected in 61 percent of patients . The presence of concentrations of 8.0 microg per milliliter or greater before an infusion predicted a shorter duration of response ( 35 days , as compared with 71 days among patients with concentrations of less than 8.0 microg per milliliter ; P<0.001 ) and a higher risk of infusion reactions ( relative risk , 2.40 ; 95 percent confidence interval , 1.65 to 3.66 ; P<0.001 ) .  Infliximab concentrations were significantly lower at four weeks among patients who had had an infusion reaction than among patients who had never had an infusion reaction ( median , 1.2 vs. 14.1 microg per milliliter ; P<0.001 ) . Patients who had infusion reactions had a median duration of clinical response of 38.5 days , as compared with 65 days among patients who did not have an infusion reaction ( P<0.001 ) . Concomitant immunosuppressive therapy was predictive of low titers of antibodies against infliximab  ( P<0.001 ) and high concentrations of  infliximab  four weeks after an infusion ( P<0.001 ) . CONCLUSIONS The development of antibodies against infliximab is associated with an increased risk of infusion reactions and a reduced duration of response to treatment . Concomitant immunosuppressive therapy reduces the magnitude of the immunogenic response BACKGROUND Although corticosteroids are highly effective in improving symptoms of Crohn 's disease , they may have substantial toxicity . In some patients , attempts to discontinue corticosteroids are unsuccessful . METHODS We conducted a double-blind , placebo-controlled multicenter study of weekly injections of methotrexate in patients who had chronically active Crohn 's disease despite a minimum of three months of prednisone therapy . Patients were r and omly assigned to treatment with intramuscular methotrexate ( 25 mg once weekly ) or placebo for 16 weeks . The patients also received prednisone ( 20 mg once a day ) , which was tapered over 10 weeks unless their condition worsened . The primary outcome measure was clinical remission at the end of the 16-week trial . Remission was defined by the discontinuation of prednisone and a score of < or = 150 points on the Crohn 's Disease Activity Index . RESULTS A total of 141 patients were r and omly assigned in a 2:1 ratio to  methotrexate ( 94 patients ) or placebo ( 47 patients ) . After 16 weeks , 37 patients ( 39.4 percent ) were in clinical remission in the methotrexate group , as compared with 9 patients ( 19.1 percent ) in the placebo group ( P = 0.025 ; relative risk , 1.95 ; 95 percent confidence interval , 1.09 to 3.48 ) . The patients in the methotrexate group received less  prednisone  overall than those in the placebo group ( P = 0.026 ) . The mean ( + /- SE ) score on the Crohn 's Disease Activity Index after 16 weeks of treatment was significantly lower in the methotrexate group ( 162 + /- 12 ) than in the placebo group ( 204 + /- 17 , P = 0.002 ) . The changes in quality -of-life scores and serum orosomucoid concentrations were similar . In the methotrexate group , 16 patients ( 17 percent ) withdrew from treatment because of adverse events ( including asymptomatic elevation of serum aminotransferase in 7 and nausea in 6 ) , as compared with 1 patient ( 2 percent ) in the placebo group . CONCLUSIONS In a group of patients with chronically active Crohn 's disease , methotrexate was more effective than placebo in improving symptoms and reducing requirements for prednisone Background As treatment of steroid‐dependent patients with inflammatory bowel disease ( IBD ) is controversial , we analysed the efficacy and tolerance of 6‐mercaptopurine ( 6‐MP ) and methotrexate ( MTX ) added to prednisone in increasing and maintaining the disease remission rate . Methods Seventy‐two steroid‐dependent IBD patients , 34 with ulcerative colitis ( UC ) and 38 with Crohn 's disease ( CD ) , receiving treatment with prednisone  were r and omly assigned in a 2:2:1 ratio to additionally receive , orally , over a period of 30 weeks 1.5 mg/kg/day of 6‐MP ( group A ) or 15 mg/week of MTX ( group B ) , or 3 g/day of 5‐aminosalicylic acid ( 5‐ASA ) ( group C ) . All patients who achieved remission were included in a maintaining remission study for 76 weeks . Remission was defined after stopping prednisone as a CD activity index of < 150 and normal serum orosomucoid concentration for CD patients and a Mayo Clinic score < 7 for UC patients . Results With regard to achieved remission , a significantly higher ( P < 0.05 ) rate existed for UC patients in group A ( 78.6 % ) than in group C ( 25 % ) , with no statistical differences in group B ( 58.3 % ) versus C. For CD patients , the rates were significantly higher ( P < 0.001 and 0.01 , respectively ) in groups A ( 93.7 % ) and B ( 80 % ) versus C ( 14 % ) . With regard to maintaining remission , UC patients in group A ( 63.6 % ) presented significantly higher rates ( P < 0.0015 and P < 0.001 , respectively ) versus 14.3 % in group B and none in group C. For CD patients , statistical differences ( P < 0.001 ) existed when comparing rates in groups A ( 53.3 % ) and B ( 66.6 % ) versus none in group C. Noticeable side effects appeared in 13.3 % of patients from group A and 11.5 % from group B. Conclusions These results suggest that 6‐MP or MTX added to prednisone could be effective in steroid sparing , as well as in achieving and maintaining remission in steroid‐dependent IBD patients . MTX was less effective in maintaining remission in UC patients BACKGROUND AND AIMS The efficacy of azathioprine in the treatment of chronic active Crohn 's disease is well established . However , this drug has a long onset of action . Methotrexate has also been shown to be effective in chronic active Crohn 's disease . The aim of this study was to evaluate the efficacy and safety of methotrexate in comparison with azathioprine , and to establish whether methotrexate has a shorter onset of action in this setting . METHODS Patients with chronic active Crohn 's disease were admitted to this investigator-blind study . Chronicity was defined as the need for steroid therapy of > or = 10 mg/day for at least 4 months during the preceding 12 months , with at least one attempt to discontinue treatment . The disease had to be clinical ly active at entry , with a Crohn 's Disease Activity Index of > or = 200 . Six patients treated with azathioprine and methotrexate , respectively , were found to have enterocutaneous and perianal fistulas . At entry , all patients received prednisolone ( 40 mg once a day ) which was tapered over a period of 12 weeks unless their clinical condition deteriorated . All patients were r and omised to receive i.v . methotrexate 25 mg/week , or oral azathioprine 2 mg/kg per day , for a 6-month follow-up period . After the first 3 months , methotrexate was switched to oral administration maintaining the same dose . The primary efficacy outcome considered was the proportion of patients entering first remission after 3 and 6 months of therapy . Clinical remission was defined as the lack of need for steroid treatment and a Crohn 's Disease Activity Index score of < or = 150 points at each scheduled visit . RESULTS In the 54 patients ( 26 F , 28 M , mean age 34 years , range 18 - 60 ) r and omly assigned to methotrexate ( n=27 ) or azathioprine ( n=27 ) , no statistically significant difference was found between the two treatment regimens with respect to remission rate after 3 ( methotrexate 44 % , azathioprine 33 % , p=0.28 , ( 95 % CI , 0.369 - 0.147 ) , and 6 months ( methotrexate 56 % , azathioprine 63 % , p=0.39 , 95 % CI , 0.187 - 0.335 ) , respectively . Six patients withdrew from therapy due to adverse events : 3/27 ( 11 % ) in methotrexate and 3/27 ( 11 % ) in azathioprine .  Drug-related adverse events ( asthenia , nausea and vomiting ) that did not require withdrawal from therapy were more frequent in the methotrexate group ( azathioprine : 2/27 ( 7 % ) ; methotrexate : 12/27 ( 44 % ) , p=0.00009 ) . The frequency of these adverse events was comparable during the intravenous or oral administration of the drug . CONCLUSIONS This study confirms that methotrexate is effective in inducing remission in patients with chronic active Crohn 's disease , therapeutic efficacy being comparable , but not faster , than that of azathioprine BACKGROUND At present only one large controlled study has indicated that parenteral methotrexate may be effective in chronic active Crohn 's disease ( CD ) . AIM To evaluate the effectiveness of oral methotrexate in chronic steroid-dependent CD . PATIENTS Patients with active CD , who have received steroids and /or immunosuppressives for at least 4 months during the preceding 12 months and with a current Harvey-Bradshaw index of > or = 7 were studied . METHODS Methotrexate ( 12.5 mg weekly ) or 6-mercaptopurine ( 50 mg daily ) , or placebo were given during the 9 months of the trial in addition to steroids and 5-aminosalicylic acid as clinical ly indicated . RESULTS Eighty-four patients were included ( methotrexate , 26 patients ; 6-mercaptopurine , 32 patients ; placebo , 26 patients ) . The proportion of patients entering first remission as well as the proportions of patients relapsing after first remission were not significantly different between the groups . The mean Harvey-Bradshaw index and the mean monthly steroid dose were also similar . However , when each patient was evaluated as his or her own control , the reduction in steroid dose , the general well being , and the reduction in abdominal pain were significantly better in the methotrexate treated patients . CONCLUSIONS Methotrexate at a weekly oral dose of 12.5 mg was found to be moderately better than 6-mercaptopurine and placebo in patients with chronic active CD BACKGROUND A substantial number of patients with Crohn 's disease ( CD ) become dependent on steroids after induction therapy . Treatment with azathioprine ( AZA ) may be beneficial in such patients . The present open-label study evaluated the long-term safety and efficacy of AZA in steroid-dependent CD patients . METHODS Adult patients with steroid-dependent CD were enrolled for AZA therapy over a 7-year period . The average dose of AZA was 2.0 - 3.0 mg/kg per day , adjusted according to clinical response and occurrence of adverse effects . Steroid therapy was tapered off according to a predefined schedule . Long-term outcome and adverse reactions were evaluated . RESULTS Sixty-nine patients were prospect ively included .  Steroid-free remission was achieved in 68 - 81 % of patients , partial response in 14.5 - 27.3 % and failure to respond to AZA in 4 - 15.9 % over the initial 48 months . However , the rate of wean from steroid therapy decreased to 53 - 60 % while the rate of failure increased from 6.7 % to 17.6 % after this period . A breakthrough of symptoms during continuous AZA therapy was common , particularly after 48 months on AZA . The mean leukocyte count at the end of 12 months of therapy was significantly lower in patients who achieved complete response on AZA than in the non-responders ( 5197 + /- 1250 cells/mm(3 ) vs 8340 + /- 1310 cells/mm(3 ) , respectively ; P < 0.01 ) . Azathioprine was relatively well-tolerated and the incidence of serious adverse effects was small . CONCLUSIONS Azathioprine was relatively safe and moderately effective for long-term maintenance of steroid-free clinical remission in corticosteroid-dependent CD patients . Patients were more successfully weaned from prednisone treatment , and clinical remission was more often maintained during the first 48 months of AZA therapy . A significant decrease in the white blood cell count at the end of 12 months on AZA was the single factor associated with weaning from steroid dependence OBJECTIVE : A 16-wk , placebo-controlled trial has recently shown weekly low-dose methotrexate to be an effective treatment for patients with chronically active Crohn 's disease . The long-term efficacy and safety of this antimetabolite drug , however , are not yet well established and are assessed in this study . METHODS : A total of 49 patients with Crohn 's disease who were treated with methotrexate for ≥6 months were studied . All patients had been chronically treated with steroids ; but at the time of initiation , only 27 were still on steroids . Of the 49 patients , 42 had previously taken azathioprine but were no longer on this drug because of intolerance or failure .  Clinical remission was defined as a Harvey-Bradshaw index of < 4 . RESULTS : In all , 41 patients achieved complete clinical remission and were maintained on methotrexate for a median of 18 months ( range , 7–59 months ) . In these patients the probabilities of relapse were 29 % , 41 % , and 48 % at 1 , 2 , and 3 yr , respectively . A higher rate of relapse was observed in women and in patients with ileocolitis . Adverse reactions were recorded in 24 patients , requiring discontinuation of methotrexate in five . A liver biopsy was performed in 11 patients ; a mild steatosis was found in five , a slight dilation of the sinusoids in one , a granulomatous hepatitis with a mild portal fibrosis in one , and a slight periportal fibrosis in one patient . CONCLUSIONS : This study suggests a long-term benefit of maintenance treatment with methotrexate in patients with chronically active Crohn 's disease , with side effects that are usually only moderate The optimum initial dose of methotrexate for steroid‐requiring inflammatory bowel disease is not known Background : Oral methotrexate and folic acid are partly absorbed by a common intestinal transporter Aliment Pharmacol Ther 2011 ; 33 : 714–721 BACKGROUND & AIMS Methotrexate and infliximab are effective therapies for Crohn 's disease ( CD ) . In the combination of maintenance methotrexate-infliximab trial , we evaluated the potential superiority of combination therapy over infliximab alone . METHODS In a 50-week , double-blind , placebo-controlled trial , we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy ( 15 - 40 mg/day ) within the preceding 6 weeks . Patients were assigned r and omly to groups given methotrexate at an initial weekly dose of 10 mg , escalating to 25 mg/week ( n = 63 ) , or placebo ( n = 63 ) . Both groups received infliximab ( 5 mg/kg of body weight ) at weeks 1 , 3 , 7 , and 14 , and every 8 weeks thereafter . Prednisone was tapered , beginning at week 1 , and discontinued no later than week 14 . The primary outcome was time to treatment failure , defined as a lack of prednisone-free remission ( CD Activity Index , < 150 ) at week 14 or failure to maintain remission through week 50 . RESULTS Patients ' baseline characteristics were similar between groups . By week 50 , the actuarial rate of treatment failure was 30.6 % in the combination therapy group compared with 29.8 % in the infliximab monotherapy group ( P = .63 ; hazard ratio , 1.16 ; 95 % confidence interval , 0.62 - 2.17 ) . Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein . No clinical ly meaningful differences were observed in secondary outcomes . Combination therapy was well tolerated . CONCLUSIONS The combination of infliximab and methotrexate , although safe , was no more effective than infliximab alone in patients with CD receiving treatment with prednisone . ClincialTrials.gov number , NCT00132899
BACKGROUND 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 up date of a previously published Cochrane review .
OBJECTIVES To conduct a systematic review of r and omized trials examining the efficacy and safety of methotrexate for maintenance of remission in Crohn 's disease .