Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. A controlled double blind study of azathioprine in the management of Crohn's disease. Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. A controlled trial of azathioprine in Crohn's disease. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn's disease. Methotrexate in chronic active Crohn's disease: a double-blind, randomized, Israeli multicenter trial. A randomized, double-blind trial of Lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn's disease. A multicenter, randomized, double-blind trial of everolimus versus azathioprine and placebo to maintain steroid-induced remission in patients with moderate-to-severe active Crohn's disease.
To test the effectiveness of 6-mercaptopurine (6-MP) in the treatment of Crohn's disease, we entered 83 chronically ill patients into a two-year double-blind study comparing 6-MP with placebo. Crossover data showed that improvement occurred in 26 of 39 courses of 6-MP (67%) as compared with three of 39 courses of placebo (8%) (P less than 0.001). Non-crossover data likewise confirmed the superiority of 6-MP. The drug was more effective than placebo in closing fistulas (31 vs 6%) and in permitting discontinuation or reduction of steroid dosage (75 vs. 36%) (P less than 0.001). The onset of response to 6-MP was often delayed, with 32% of patients taking longer than three months to respond, and 19% taking longer than four months. Adverse side effects to 6-MP occurred in 10% of patients and were uniformly reversible. We conclude that 6-MP is an effective and useful agent in the management of Crohn's disease. While immunosuppressive agents are used widely in the management of Crohn's disease, their efficacy has not been well established in randomised controlled trials. This study was designed to examine whether azathioprine increases remission rate when used in conjunction with a diminishing dose regimen of prednisolone over a period of 12 weeks. It further examined whether azathioprine offers any therapeutic advantage over placebo in the maintenance of remission in Crohn's disease over a period of 15 months. Sixty three patients with active Crohn's disease were treated with a 12 weeks diminishing dose of prednisolone and at the same time entered into a randomised, double blind 15 month trial of either azathioprine (2.5 mg/kg) or placebo. Remission rates between the two groups were compared at 12 weeks and at 15 months. There was no significant difference in the proportion of patients who had achieved and maintained remission by week 12 but at 15 months there was a highly significant difference in the proportion of patients in remission (42% receiving azathioprine v 7% receiving placebo), p = 0.001. Using life tables this beneficial effect was reflected as the difference in the median number of days on the trial (p = 0.02). There were significantly greater decreases over the trial period in the median erythrocyte sedimentation rate, C reactive protein, and leucocyte count in the azathioprine group. There were no cases of severe bone marrow suppression or clinical pancreatitis. In conclusion, azathioprine offers a therapeutic advantage over placebo in the maintenance of remission in Crohn's disease. No therapy has been shown to reliably prevent the evolution of postoperative recurrence of Crohn's disease. The aim of the current trial was to compare 6-mercaptopurine (6-MP) and mesalamine with placebo for the prevention of clinical, endoscopic, and radiographic recurrence of Crohn's disease after resection and ileocolic anastomosis.
                Five centers randomized 131 patients to receive 6-MP (50 mg), mesalamine (3 g), or placebo daily in a double-blind, double-dummy trial. Patients had clinical assessments at 7 weeks and then every 3 months; colonoscopy at 6, 12, and 24 months; and small bowel series at 12 and 24 months. End points were clinical, endoscopic, and radiographic recurrence rates at 24 months.
                Clinical recurrence rates (intent to treat) by life-table analysis at 24 months were 50% (95% confidence interval [CI], 34%-68%), 58% (95% CI, 41%-75%), and 77% (95% CI, 61%-91%) in patients receiving 6-MP, mesalamine, and placebo, respectively. Endoscopic recurrence rates were 43% (95% CI, 28%-63%), 63% (95% CI, 47%-79%), and 64% (95% CI, 46%-81%), and radiographic recurrence rates were 33% (95% CI, 19%-54%), 46% (95% CI, 29%-66%), and 49% (95% CI, 30%-72%), respectively. 6-MP was more effective than placebo ( P < 0.05) at preventing clinical and endoscopic recurrence over 2 years. Patient withdrawals resulted in 69% of the study population evaluable for the clinical recurrence end point.
                6-MP, 50 mg daily, was more effective than placebo at preventing postoperative recurrence of Crohn's disease and should be considered as a maintenance therapy after ileocolic resection. To determine the efficacy of azathioprine in the treatment of Crohn's disease, a 26-week double-blind trial was performed. 20 patients with Crohn's disease, requiring at least 10 mg of prednisone/day over the 3 months prior to entering the study were randomized into placebo (10 patients) and major criterion of success in the trial. There were 7 relapses in the placebo group (5 patients) and 2 relapses in the azathioprine group (2 patients). Complications including fistulae were not affected by the medications. The mean reduction in steriod dosage in the azathioprine group at the end of the trial (-15.5 mg) was greater than in the placebo group (-6.1 mg). These results suggest that azathioprine may permit reduction or discontinuation of steroids without the worsening of symptoms in some patients who appear to require steroids for control of their symptoms. The clinical features of this "AZA-responsive subgroup" remain to be defined. Clinical experience suggests that 6-mercaptopurine (6-MP) is effective therapy for children with active steroid-dependent Crohn's disease (CD). We report the results of a prospective, placebo-controlled, multicenter trial evaluating the combination of 6-MP and prednisone as therapy for children with newly diagnosed moderate-to-severe CD.
                Fifty-five children (age, 13+/-2 years) were randomized to treatment with 6-MP (1.5 mg x kg(-1) x day(-1)) or placebo within 8 weeks of initial diagnosis. Both groups also received prednisone (40 mg/day). Prednisone dosage adjustments were based on a defined schedule determined by the change in a subject's disease activity score, and steroid administration was discontinued as remission was achieved. Study treatment with 6-MP or placebo continued for 18 months.
                Groups were comparable for age, sex, and site and activity of disease. In the 6-MP group, the duration of steroid use was shorter (P<0.001) and the cumulative steroid dose lower at 6, 12, and 18 months (P<0.01). Although remission was induced in 89% of both groups, only 9% of the remitters in the 6-MP group relapsed compared with 47% of controls (P = 0.007). Growth was comparable in both groups. No clinically significant adverse events occurred, although mild leukopenia and increases in aminotransferase activity were noted in the 6-MP group.
                Addition of 6-MP to a regimen of corticosteroids significantly lessens the need for prednisone and improves maintenance of remission. 6-MP should be part of the initial treatment regimen for children with newly diagnosed moderate-to-severe CD. 51 patients with Crohn's disease who were in good health while taking azathiprine, 2 mg/kg body-weight/day, for at least six months were allocated either to a group in which azathioprine was continued or to one in which a control tablet was substituted. The trial lasted one year unless relapse recurred earlier. The cumulative probability of relapse was nil at six months and 5% (+/-5 S.D.) at a year among those on azathioprine, compared with 25% (+/-9 S.D.) at six months and 41% (+/-11 S.D.) at a year among those in the control group (P less than 0.01). 1 patient in whom azathioprine was continued died of pancytopenia in the fourth month of the trial. Azathioprine is potentially toxic but appears to reduce the relapse-rate in Crohn's disease. At present only one large controlled study has indicated that parenteral methotrexate may be effective in chronic active Crohn's disease (CD).
                To evaluate the effectiveness of oral methotrexate in chronic steroid-dependent CD.
                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.
                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 clinically indicated.
                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.
                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. Probiotics are widely used by patients with Crohn's disease (CD) in an attempt to improve their health, but few controlled studies have been done to evaluate the efficacy of these therapies. We conducted a randomized, placebo-controlled trial of the probiotic Lactobacillus rhamnosus strain GG (LGG) to see if the addition of LGG to standard therapy prolonged remission in children with CD. Concomitant medications allowed in the study included aminosalicylates, 6-mercaptopurine, azathioprine, and low-dose alternate day corticosteroids. Seventy-five children (age range, 5-21 yr) with CD in remission were randomized to either LGG (n=39) or placebo (n=36) and followed for up to 2 years. The median time to relapse was 9.8 months in the LGG group and 11.0 months in the placebo group (P=0.24); 31% (12/39) of patients in the LGG group developed a relapse compared with 6/36 (17%) of the placebo group (P=0.18). The LGG was well tolerated, with a side effect profile comparable with placebo. This study suggests that LGG does not prolong time to relapse in children with CD when given as an adjunct to standard therapy. A prospective study was undertaken to compare the efficacy of everolimus versus azathioprine or placebo in maintaining steroid-induced remission in active Crohn's disease (CD) and assess the safety and pharmacokinetics of everolimus.
                This was a randomized, double-blind, placebo-controlled, proof-of-concept study in adults with moderate-to-severe active CD. The patients received oral steroids for a rapid induction of remission plus everolimus 6 mg/day, azathioprine 2.5 mg/kg/day, or placebo as maintenance treatment. The main outcome measure was the treatment success, defined as a steroid-free remission by the end of month 3 and maintained until study cutoff without the use of prohibited efficacy treatments.
                Following an interim analysis, the study was terminated before enrollment was completed due to the lack of efficacy. The full intent-to-treat population comprised 138 patients. Only 96 patients who entered the study > or =7 months prior to data cutoff were included in the primary efficacy population. The treatment success was achieved in 13 of 38 everolimus patients, 22 of 36 azathioprine patients, and 8 of 22 placebo patients. Using the Kaplan-Meier estimates at month 7, the incidence of treatment success was 22.0% with everolimus group (95% confidence interval [CI] 6.7-37.3%, P= 0.610 vs placebo), 38.3% with azathioprine group (95% CI 20.6-55.9%, P= 0.500 vs placebo), and 28.8% with placebo group (95% CI 7.7-49.9%). The type and incidence of adverse events in the everolimus cohort were similar to those reported in the approved transplantation indications.
                The safety and tolerability of everolimus (6 mg/day) in patients with active CD were comparable to azathioprine. At this dose, everolimus is not more efficacious in achieving a steroid-free remission in active CD than the comparators.
Azathioprine and 6-mercaptopurine are more effective than placebo for maintenance of remission in Crohn's disease. Higher response rates were obtained with azathioprine than 6-mercaptopurine. However, the one study evaluating 6-mercaptopurine used a relatively low dose of the drug. Future studies should look at the effect of higher doses of 6-mercaptopurine. There is weak evidence for a steroid sparing effect with azathioprine treatment.