A placebo-controlled, randomized, double-masked, variable dosage, clinical trial of azathioprine with and without methylprednisolone in multiple sclerosis. A controlled double blind study of azathioprine in the management of Crohn's disease. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. Long-term use of mesalamine (Rowasa) suppositories in remission maintenance of ulcerative proctitis. Comparison between high dose 5-aminosalicylic acid and 6-methylprednisolone in active Crohn's ileocolitis. A multicenter randomized double-blind study. German 5-ASA Study Group. Double-blind, placebo-controlled evaluation of 5-ASA suppositories in active distal proctitis and measurement of extent of spread using 99mTc-labeled 5-ASA suppositories. Is maintenance therapy always necessary for patients with ulcerative colitis in remission? [Azathioprine and 5-ASA in the prevention of postoperative recurrence of Crohn's disease]. Comparative efficacy of coated, oral 5-aminosalicylic acid (Claversal) and sulphasalazine for maintaining remission of ulcerative colitis. International Study Group.
Ninety-eight patients with multiple sclerosis (MS) in the chronic progression phase entered a 3-year clinical trial to determine if azathioprine (AZ) alone or with adrenal cortical steroids stabilizes the course of MS. In group AM, the patients took AZ throughout and methylprednisolone (MP) for the first 36 weeks. Group AP received AZ and placebo instead of MP. Group PP took placebos for both drugs. We adjusted the AZ to maintain the total white blood cell count within 3,000 to 4,000/mm3; we gave the MP in a fixed dose "pulse" and alternate-day regimen. The "intent-to-treat" groups had no statistically significant differences in the rates of progression among the 3 treatments. Subgroup analysis suggests that patients in the AM group who completed treatment exactly according to protocol did statistically significantly better than the placebo recipients using the sum of Standard Neurological Examination scores, slightly better using the quantitative neuro-performance tests, but no better using Mickey's Illness Severity Scores or Kurtzke's Disability Status Scale. Also, the AZ-treated groups had half the relapse rate of the placebo-treated group. Adverse reactions to AZ accounted for most withdrawals. Hematologic and hepatic abnormalities were significantly associated with AZ, but serious non-MS abnormalities were uncommon and were equally distributed among the 3 groups. Addition of MP to the AZ slightly improved the efficacy of the treatment, but also increased the adverse effects. The benefits of AZ with or without steroids did not outweigh the risks, and therefore we do not recommend this treatment for patients with chronic progressive MS. 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. To determine whether azathioprine can prevent relapse in ulcerative colitis.
                One year placebo controlled double blind trial of withdrawal or continuation of azathioprine.
                Outpatient clinics of five hospitals.
                79 patients with ulcerative colitis who had been taking azathioprine for six months or more. Patients in full remission for two months or more (67), and patients with chronic low grade or corticosteroid dependent disease (12) were randomised separately. 33 patients in remission received azathioprine and 34 placebo; five patients with chronic stable disease received azathioprine and seven placebo.
                Rate of relapse. Relapse was defined as worsening of symptoms or sigmoidoscopic appearance.
                For the remission group the one year rate of relapse was 36% (12/33) for patients continuing azathioprine and 59% (20/34) for those taking placebo (hazard rate ratio 0.5, 95% confidence interval 0.25 to 1.0). For the subgroup of 54 patients in long term remission (greater than six months before entry to trial) benefit was still evident, with a 31% (8/26) rate of relapse with azathioprine and 61% (17/28) with placebo (p less than 0.01). For the small group of patients with chronic stable colitis (six were corticosteroid dependent and six had low grade symptoms) no benefit was found from continued azathioprine therapy. Adverse events were minimal.
                Azathioprine maintenance treatment in ulcerative colitis is beneficial for at least two years if patients have achieved remission while taking the drug. Demonstration of the relapse preventing properties of azathioprine has implications for a large number of patients with troublesome ulcerative colitis, who may benefit from treatment with azathioprine. The purpose of this study was to evaluate the efficacy and safety of a single nightly 500-mg Rowasa (mesalamine) suppository as maintenance therapy for patients with ulcerative proctitis in remission.
                In this 24-month, multicenter, double-blind trial, 65 patients with ulcerative proctitis in clinical and endoscopic remission were randomized to receive either a single nightly 500-mg rectal mesalamine (Rowasa) suppository or matching placebo as sole therapy. Efficacy was assessed by time to relapse (defined as rectal bleeding or increase in stool frequency for > or =1 wk and active inflammation upon endoscopy).
                Mean time to relapse was 453.4 days for mesalamine-treated patients and 158.0 days for placebo-treated patients. Survival analysis demonstrated that time to relapse was significantly greater for mesalamine-treated patients than for placebo-treated patients (p < 0.001). In addition, at both 12 and 24 months, the proportion of placebo-treated patients (86% at 12 months and 89% at 24 months) who relapsed was significantly (p < or = 0.001) greater than mesalamine-treated patients (32% and 46%, respectively). No statistically significant differences occurred between treatment groups in the reporting of any particular adverse event or the number of patients reporting adverse events.
                The results demonstrate that mesalamine suppositories are efficacious, well tolerated, and safe for the long-term maintenance of remission of ulcerative proctitis. The value of 5-aminosalicylic acid (5-ASA) in Crohn's disease (CD) is still under discussion. In a previous study 2 g 5-ASA per day were inferior to a standard glucocorticoid treatment with 6-methylprednisolone (6-MPred) (Can J Gastroenterol 1990; 4: 446-51). In the present study we tested whether in active CD response rates to 4.5 g 5-ASA/day were not different from those to 6-MPred.
                Multicenter randomized double-blind double-dummy trial. 34 patients with active CD (CDAI > 150) were included. 17 patients were in the 5-ASA group (Salofalk, 4.5 g/day), 17 patients in the 6-MPred group (Urbason, initial dose 48 mg/day, weekly tapering). Duration of treatment was 8 weeks. Main outcome measure was remission of CD (CDAI < 150) and decrease of at least 60 points.
                Both groups were comparable with respect to demographic and clinical parameters. The median CDAI decrease in the 5-ASA group was 85, in the 6-MPred group 122 (p = 0.7437). The median AUC of the CDAI in the 5-ASA group was 1027, in the 6-MPred group 950 (p = 0.137). The median AUC of the CDAI per treatment day was 22.94 in the 5-ASA group, and 17.33 in the 6-MPred group (p = 0.0555). On an intention-to-treat basis remission rates after 8 weeks were 40.0% in the 5-ASA group and 56.3% in the 6-MPred group (p = 0.5867).
                Response rates to 5-ASA or 6-MPred were not significantly different although there was a trend towards a higher efficacy of 6-MPred. 5-ASA may be considered as alternative treatment in patients with activer CD who are intolerant to or refuse glucocorticoids. Patients with active distal proctitis received either 5-aminosalicylic (5-ASA) acid or identical placebo suppositories, 500 mg t.i.d. for 6 weeks. Activity at 3 and 6 wks was assessed using a Disease Activity Index (DAI), derived from four categories: number of daily evacuations more than usual, evacuations containing blood, sigmoidoscopy appearance, and physician's overall assessment. Each category was graded 0-3. There was thus 0-12 points scored ranging from complete remission to severe disease. A minimum score of 3 from two categories was necessary for study entry. Of 27 patients randomized, 14 received active medication and 13 placebo. Of the 14 patients, with initial mean DAI 7.1 +/- 1.8, 11 were in complete remission at 6 wks (78.6%). Whereas, there was no significant change in the placebo group, with initial mean DAI 7.1 +/- 1.8. An additional 6 patients with inflammatory bowel disease and 6 healthy volunteers were given 99mTc-labelled 5-aminosalicylic acid suppositories. The extent of spread was limited to the rectum, and the suppositories were retained for 3 hours. There was no absorbed radioactivity. 5-ASA suppositories are safe, well-tolerated, and effective treatment for active distal proctitis. The efficacy of sulphasalazine and mesalazine in preventing relapse in patients with ulcerative colitis is well known. It is less clear how long such maintenance should be continued, and if the duration of disease remission is a factor that affects the risk of recurrence.
                To determine whether the duration of disease remission affects the relapse rate, by comparing the efficacy of a delayed-release mesalazine (Asacol, Bracco S.p.A., Milan, Italy) against placebo in patients with ulcerative colitis with short- and long-duration of disease remission.
                112 patients (66 male, 46 female, mean age 35 years), with intermittent chronic ulcerative colitis in clinical, endoscopic and histological remission with sulphasalazine or mesalazine for at least 1 year, were included in the study. Assuming that a lower duration of remission might be associated with a higher relapse rate, the patients were stratified according to the length of their disease remission, prior to randomization into Group A (Asacol 26, placebo 35) in remission from 1 to 2 years, or Group B (Asacol 28, placebo 23) in remission for over 2 years, median 4 years. Patients were treated daily with oral Asacol 1.2 g vs. placebo, for a follow-up period of 1 year.
                We employed an intention-to-treat analysis. In Group A, whilst no difference was found between the two treatments after 6 months, mesalazine was significantly more effective than placebo in preventing relapse at 12 months [Asacol 6/26 (23%), placebo 17/35 (49%), P = 0.035, 95% Cl: 48-2.3%]. In contrast, in Group B no statistically significant difference was observed between the two treatments, either at 6 or 12 months [Asacol 5/28 (18%), placebo 6/23 (26%), P = 0.35, 95% Cl: 31-14%] of follow-up. Patients in group B were older, and had the disease and remission duration for longer, than those in Group A.
                Mesalazine prophylaxis is necessary for the prevention of relapse by patients with ulcerative colitis in remission for less than 2 years, but this study casts doubt over whether continuous maintenance treatment is necessary in patients with prolonged clinical, endoscopic and histological remission, who are at very low risk of relapse. Recurrence of Crohn's disease (CD) lesions in the neo-ileum after apparently curative resection frequently occurs after surgery. The most appropriate prophylactic treatment has not been clearly defined. This study evaluated the efficacy of 5-ASA and azathioprine in decreasing postoperative recurrence and analysed the presence of variables associated with recurrence. Thirty-nine patients (mean age 32.8 years, range 18-61) with a history of ileal or ileocecal surgical resection were studied. They received 5-ASA (3 mg/day) or azathioprine (50 mg/day) immediately after the operation and for 2 years thereafter. Patients were followed clinically (Crohn's disease activity index) and serologically every 3 months and by imaging methods every 6 months. The latter included colonoscopy with ileoscopy and if not available, small bowel barium or ultrasonographic study. Laboratory tests included ESR, C-reactive protein, white blood cell and platelet count, fibrinogen and albumin. The end-point evaluated included clinical recurrence (CR), serological recurrence (SR: alteration of at least three of the above-mentioned variables) and morphologic recurrence (MR: endoscopic recurrence > 1 according to Rutgeerts score or radiological or ultrasonographic recurrence). Eighteen patients received azathioprine and 21 received 5-ASA. Thirty-four patients were evaluated. The cumulative proportion of patients with recurrence was 29% (CR), 35% (SR) and 50% (MR). Statistical analysis did not show significant differences between the two groups. Twenty-seven patients completed the 2-year study (11 in the azathioprine group and 16 in the 5-ASA group). Crude relapse rates were 37% (CR), 44% (SR) and 69% (MR) in the 5-ASA group and 36% (CR), 45% (SR) and 64% (MR) in the azathioprine group. No statistically significant differences were observed between groups. No variables associated with recurrence were detected. In conclusion, treatment does not prevent a high percentage of postsurgical recurrence. 5-ASA (3 g/day) and azathioprine (50 mg/day) showed similar efficacy in the prevention of recurrence. The safety and efficacy of Claversal (coated, oral 5-aminosalicylic acid (5-ASA) 0.75 g/day) and sulphasalazine 1.5-2.0 g/day were compared for the maintenance treatment of ulcerative colitis in a 1-year double-blind trial. Three hundred and thirty-four patients, whose disease was controlled on a stable dose of sulphasalazine (1.5-2.0 g/day) for a 1-month pre-trial, entered the study. On entry, patients were assigned in a random manner to continue sulphasalazine or to switch to coated 5-ASA. One hundred and thirty-one patients in the coated 5-ASA group and 142 on sulphasalazine were analysed for efficacy. No significant difference was observed between treatments with respect to the cumulative rate of relapse. Over the 12 months, 30 (28%) of the coated 5-ASA patients versus 29 (23%) of those treated with sulphasalazine had an exacerbation of their disease (log rank test P = 0.7011). The incidence of drug-related adverse events and subsequent withdrawals was similar. The high incidence of side-effects usually associated with sulphasalazine was not observed, probably due to the fact that this population was tolerant of sulphasalazine pre-trial. Of the 37 patients who reported adverse events with previous sulphasalazine therapy, however, only two (8%) of the 24 experienced those events when randomized to coated 5-ASA while five (38%) of the 13 who continued on sulphasalazine reported those same events. Coated 5-ASA is a safe, effective therapy for maintaining ulcerative colitis in remission.
The pooled analyses suggest that 5-ASA preparations may be superior to placebo for the maintenance of surgically-induced remission in patients with CD. The results of the pooled analyses should be interpreted with caution because adequately powered studies demonstrated no difference and publication bias (failure to publish negative studies) may be an issue. The potential benefit provided by 5-ASA drugs is modest with a number needed to treat of approximately 16 to 19 patients to avoid one relapse which raises issues about the cost-effectiveness of this therapy. However, 5-ASA drugs are safe and well tolerated. The incidence of adverse events was not different in patients receiving 5-ASA compared with those receiving placebo. There is insufficient evidence to allow any conclusions on how 5-ASA preparations compare with azathioprine or 6-mercaptopurine.