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Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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.

Background & Aims: The effect of different treatment regimens on antibody responses to infliximab and their clinical significance was examined by using data from ACCENT I. Methods: Patients with Crohn's disease (n = 573) received 5 mg/kg infliximab (week 0) and then were randomly assigned to blinded infusions at weeks 2 and 6 and every 8 weeks until week 46 of placebo (group I), 5 mg/kg infliximab (group II), or 5 mg/kg infliximab at weeks 2 and 6, followed by 10 mg/kg thereafter (group III). At week 14 or later, patients losing response could cross over to episodic infliximab treatment increased by 5 mg/kg. Samples for antibody determination were collected before the first infusion and at weeks 14, 22, 54, 62, 72, and, if applicable, before and after crossover. Results: Through week 72, antibodies to infliximab were detected in 30%, 10%, and 7% of groups I, II, and III, respectively (P < 0.0001). Patients receiving immunomodulators had a lower incidence of antibodies compared with patients receiving infliximab alone (10% and 18%, respectively; P = 0.02). Antibodies were associated with a 12% absolute increase in infusion reactions but no increase in serious infusion reactions or serum sickness-like reactions. In the overall population, similar proportions of antibody-positive and antibody-negative patients achieved clinical response (64% and 62%, respectively; P = NS) or clinical remission (41% and 39%, respectively; P = NS) at week 54. Notably, 86% of patients responded to retreatment, and 63% were in clinical response at week 54; however, fewer antibody-positive group I patients attained clinical remission (31%) compared with those who were antibody negative (37%) or antibody inconclusive (54%) (P = NS). Conclusions: Reduced antibody formation and greater clinical benefit were observed with an induction regimen followed by maintenance treatment compared with a single dose followed by episodic retreatment in Crohn's disease patients treated with infliximab.

Background & Aims: The aim of this study was to perform a meta-analysis of the efficacy results from 3 placebo-controlled multicenter clinical trials of slow-release mesalamine (Pentasa) for the acute treatment of mild to moderate Crohn's disease. Methods: Three trials fulfilled the selection criteria (double-blind, placebo-controlled, randomized studies in adult patients treated with Pentasa 4 g/day for active Crohn's disease). The efficacy and safety was evaluated in these trials by using the Crohn's Disease Activity Index (CDAI) as the primary efficacy variable. The study duration was 16 weeks in all 3 trials. The total numbers of patients were 304 in the Pentasa 4-g/day treatment groups and 311 in the placebo groups. A meta-analysis was performed based on the study reports. Results: For the intent-to-treat patients in the Pentasa groups, the overall mean reduction of the CDAI from baseline to the final visit was -63 points. The corresponding CDAI change in the placebo groups was -45 points; the net difference was -18 points. Compared with placebo, the 4-g/day dose of Pentasa was associated with a statistically significant overall improvement in the CDAI from baseline to the final visit (P = 0.04). When the meta-analysis was restricted to protocol correct patients, the effect of Pentasa became more pronounced (overall mean reduction of -83 CDAI points; P = 0.02, compared with placebo). Contrary to the consistent effects with Pentasa, the trial-specific reductions of the CDAI with placebo differed significantly between the trials. Conclusions: The meta-analysis of 3 large, double-blind, randomized studies in the treatment of active Crohn's disease confirms that Pentasa 4 g/day is superior to placebo in reducing the CDAI but the clinical significance of the magnitude of this difference is not clear.

Background & aims: This analysis of Crohn's disease patients treated with infliximab in ACCENT I compared episodic and scheduled treatment strategies under conditions that simulate clinical practice. Methods: After 5 mg/kg infliximab at week 0, 573 patients were randomized to infusions at weeks 2 and 6 and every 8 weeks until week 46 of placebo (episodic), infliximab 5 mg/kg at weeks 2 and 6 followed by 5 mg/kg (5 mg/kg scheduled) every 8 weeks, or infliximab 5 mg/kg at weeks 2 and 6 followed by 10 mg/kg (10 mg/kg scheduled) every 8 weeks. At or after week 14, treatment could be given with a dose of infliximab 5 mg/kg higher upon loss of response. Results: The efficacy of scheduled infliximab therapy was better than episodic treatment. Crohn's Disease Activity Index (CDAI) scores were consistently significantly better in the 10 mg/kg scheduled maintenance group from weeks 10 to 54, and response and remission rates (combined scheduled) were significantly higher from weeks 10 to 30. A greater proportion of patients achieved complete mucosal healing at week 54 (P = 0.041). A lower proportion developed antibodies to infliximab in the scheduled groups than in the episodic group (9% [5 mg/kg], 6% [10 mg/kg], 28% [episodic], respectively). Scheduled strategy patients had fewer Crohn's disease-related hospitalizations (P = 0.014) and surgeries (P = 0.01) than episodic strategy patients. Conclusions: The scheduled infliximab groups, particularly the 10 mg/kg group, had better CDAI and Inflammatory Bowel Disease Questionnaire (IBDQ) responses than those in the episodic group. Both scheduled groups had fewer hospitalizations, higher rates of mucosal healing, and fewer developed antibodies than those in the episodic group, with no increase in side effects.

This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice Committee. The paper was approved by the Committee on May 18, 2003, and by the AGA Governing Board on July 25, 2003.

Background & Aims: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. Methods: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of @?150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. Results: At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. Conclusions: A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported. GASTROENTEROLOGY 1999;117:527-535

Background & Aims: Inhibition of tumor necrosis factor is a proposed mechanism for the anti-inflammatory properties of thalidomide. We performed an open-label trial of thalidomide in refractory Crohn's disease. Methods: Twenty-two patients with refractory Crohn's disease (Crohn's Disease Activity Index [CDAI] > 200 and/or draining perianal disease) initiated therapy with thalidomide, 200 mg at bedtime (18 patients), or 300 mg at bedtime (4 patients). CDAI and goal interval scores (GIS) were assessed at weeks 0, 4, and 12. Clinical response for patients with luminal disease was defined as reduction in CDAI score of >150 points and for fistula patients was 2 scores of >=1+ in 3 parameters of the GIS. Clinical remission was defined as a total CDAI < 150 (luminal patients) or >=2+ for all parameters of the GIS (fistula patients). Results: Nine patients with luminal disease and 13 with fistulas (16 male, 6 female) were enrolled. The median CDAI score at entry was 371 (95-468). Sixteen patients completed 4 weeks of treatment (12 clinical responses, 4 clinical remissions). All 14 patients completing 12 weeks met criteria for clinical response. Nine achieved clinical remission (3 luminal, 6 fistula patients). The median CDAI score was 175 (30-468; P < 0.001 vs. baseline). Conclusions: Thalidomide is efficacious in some patients with refractory Crohn's disease. GASTROENTEROLOGY 1999;117:1271-1277

Background & Aims: Infliximab, an anti-tumor necrosis factor monoclonal antibody, rapidly reduces signs and symptoms of active Crohn's disease. The aim of this study was to determine whether repeated infusions of infliximab would effectively and safely maintain the remitting benefit. Methods: The efficacy, safety, pharmacokinetics, and immunogenicity of 4 repeated treatments with 10 mg/kg infliximab given every 8 weeks were compared with the effects of placebo in a randomized, double-blind, placebo-controlled, parallel group trial. Seventy-three patients with active Crohn's disease who had not adequately responded to conventional therapies and then had demonstrated a clinical response (>=70-point decrease in the Crohn's Disease Activity Index) to an initial infusion of infliximab (or placebo) were studied. Results: Retreatment with infliximab maintained the clinical benefit through the retreatment period and 8 weeks after the last infusion in nearly all patients retreated with infliximab. Median values for Crohn's Disease Activity Index, inflammatory bowel disease questionnaire (a quality of life measurement), and serum C-reactive protein concentration were maintained at remission levels with infliximab retreatment, but not with placebo retreatment. Retreatment with infliximab every 8 weeks maintained serum infliximab concentration and was well tolerated with a low incidence of immunogenicity. One case of lymphoma and 1 case of suspected lupus were reported; the complete long-term safety profile of infliximab requires additional clinical investigation. Conclusions: Long-term treatment with infliximab showed efficacy and tolerability in managing symptoms of patients with active Crohn's disease not responding to conventional treatments. GASTROENTEROLOGY 1999;117:761-769

Background & Aims: Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohn's disease and to explore the effects of dose and schedule on platelet count and Crohn's disease activity. Methods: A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohn's disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 @mg . kg^-^1 . wk^-^1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. Results: Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 @mg . kg^-^1 . wk^-^1 as 2 or 5 weekly doses and 16 @mg . kg^-^1 . week^-^1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 @mg . kg^-^1 . wk^-^1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. Conclusions: Short-term treatment with rhIL-11 is well tolerated in patients with active Crohn's disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohn's disease at 16 @mg . kg^-^1 . wk^-^1 given in 2 equal doses. GASTROENTEROLOGY 1999;117:58-64

Background & Aims: Budesonide is a highly potent topical glucocorticosteroid that is characterized by low systemic availability as a result of high first-pass hepatic metabolism. The aim of this study was to evaluate the efficacy and safety of three doses of an enema preparation of budesonide in patients with active distal ulcerative colitis/proctitis. Methods: In a double-blind multicenter trial, 233 patients were randomized to receive either a placebo enema or budesonide enema at a dose of 0.5 mg/100 mL, 2.0 mg/100 mL, or 8.0 mg/100 mL. The primary efficacy variables were an improvement of sigmoidoscopic inflammation grade, total histopathology score, and remission rates. Effects on cortisol concentrations were also assessed. Results: After 6 weeks of treatment, there was significant improvement in sigmoidoscopy and histopathology scores in the budesonide 2.0-mg and 8.0-mg dose groups compared with placebo. Remission was achieved in 19% of patients in the 2.0-mg budesonide group (P @? 0.050) and 27% of patients in the 8.0-mg budesonide group (P @? 0.001) compared with 4% in the placebo group. More than 90% of all budesonide patients had a normal adrenocorticotropin (ACTH)-stimulated cortisol response at the last visit. The budesonide enemas were well tolerated. Conclusions: Budesonide enema is both effective and safe for the treatment of active distal ulcerative colitis/proctitis. A dose of 2.0 mg/100 mL budesonide is the lowest effective dose. GASTROENTEROLOGY 1998;115:525-532

Background & Aims: Two European genome-wide screens for inflammatory bowel disease have identified two significant regions of linkage on chromosomes 16 (IBD1) and 12 (IBD2) and two regions with suggestive levels of significance (chromosomes 3p and 7q). The aim of this study was to determine if there was evidence for linkage to these regions in non-Jewish and Ashkenazi Jewish families multiplex for Crohn's disease from the United States. Methods: One hundred forty-eight affected relative pairs, 34% Ashkenazim, were genotyped with 10-14 highly polymorphic markers overlying each candidate region. Nonparametric multipoint and two-point linkage analyses were performed. Results: Significant evidence for replication of linkage was found only for the chromosome 16 locus, IBD1, maximal at D16S769 (nonparametric linkage score [NPL], 2.49; P = 0.007). Analysis by ethnicity showed stronger evidence for Ashkenazim (D16S769; NPL = 2.52; P = 0.007) than for non-Jewish white populations (D16S401; NPL = 1.40; P = 0.082). There was no significant evidence for replication on chromosome 12 (IBD2). Minimal evidence for extension of linkage evidence was observed for the chromosomes 3p and 7q regions. Conclusions: American families, particularly Ashkenazim, have significant evidence for the Crohn's disease susceptibility locus, IBD1, on chromosome 16, but not for IBD2 on chromosome 12. GASTROENTEROLOGY 1998;115:1056-1061