Abstract

Background & Aims: Crohn’s disease almost inevitably recurs after ileocolonic resection, and effective prophylactic therapy has not been identified. We investigated the efficacy and safety of ornidazole, a nitroimidazole antibiotic, for the prevention of clinical recurrence of Crohn’s disease after curative ileocolonic resection in a placebo-controlled double-blind clinical trial. Methods: Eighty patients were randomized to ornidazole 1 g/day or placebo started within 1 week of resection and continued for 1 year. The primary end point was the proportion of patients with clinical recurrence at 1 year. Secondary end points were endoscopic recurrence at 3 months and 12 months after resection. Results: Two patients in the ornidazole group withdrew consent and were not dosed. Ornidazole significantly reduced the clinical recurrence rate at 1 year from 15 of 40 (37.5%) patients in the placebo group to 3 of 38 (7.9%) patients in the ornidazole group (Fisher exact test, 8.03; P = .0046; odds ratio, 0.14; 95% confidence interval, 0.037–0.546). Ornidazole reduced endoscopic recurrence at 12 months from 26 of 33 (79%) in the placebo group to 15 of 28 (53.6%) in the ornidazole group (χ2, 4.37; P = .037; odds ratio, 0.31; 95% confidence interval, 0.10–0.94). Endoscopic recurrence at 3 and 12 months predicted clinical recurrence. Significantly more patients in the ornidazole group dropped out from the study because of side effects (P = .041). Conclusions: Ornidazole 1 g/day is effective for the prevention of recurrence of Crohn’s disease after ileocolonic resection. Background & Aims: Crohn’s disease almost inevitably recurs after ileocolonic resection, and effective prophylactic therapy has not been identified. We investigated the efficacy and safety of ornidazole, a nitroimidazole antibiotic, for the prevention of clinical recurrence of Crohn’s disease after curative ileocolonic resection in a placebo-controlled double-blind clinical trial. Methods: Eighty patients were randomized to ornidazole 1 g/day or placebo started within 1 week of resection and continued for 1 year. The primary end point was the proportion of patients with clinical recurrence at 1 year. Secondary end points were endoscopic recurrence at 3 months and 12 months after resection. Results: Two patients in the ornidazole group withdrew consent and were not dosed. Ornidazole significantly reduced the clinical recurrence rate at 1 year from 15 of 40 (37.5%) patients in the placebo group to 3 of 38 (7.9%) patients in the ornidazole group (Fisher exact test, 8.03; P = .0046; odds ratio, 0.14; 95% confidence interval, 0.037–0.546). Ornidazole reduced endoscopic recurrence at 12 months from 26 of 33 (79%) in the placebo group to 15 of 28 (53.6%) in the ornidazole group (χ2, 4.37; P = .037; odds ratio, 0.31; 95% confidence interval, 0.10–0.94). Endoscopic recurrence at 3 and 12 months predicted clinical recurrence. Significantly more patients in the ornidazole group dropped out from the study because of side effects (P = .041). Conclusions: Ornidazole 1 g/day is effective for the prevention of recurrence of Crohn’s disease after ileocolonic resection. Most patients with ileal or ileocolonic Crohn’s disease will undergo resection of the diseased bowel because of complications including stenosis, abscess, or fistula or because of intractable disease.1Becker J.M. Surgical therapy for ulcerative colitis and Crohn’s disease.Gastroenterol Clin North Am. 1999; 28: 371-390Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar New lesions, however, recur early after ileocolonic resection2D’Haens G.R. Geboes K. Peeters M. Baert F. Penninckx F. Rutgeerts P. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal excluded ileum.Gastroenterology. 1998; 114: 262-267Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar in the neoterminal ileum, and this recurrence will lead to recurrence of symptoms and eventually to new complications and reoperation.3Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn’s disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar Early recurrent lesions can readily be visualized by ileocolonoscopy, and in a previous study we showed that metronidazole, a nitroimidazole antibiotic especially active against anaerobes at a dose of 20 mg/kg body weight for 3 months, is effective to prevent early endoscopic recurrence of Crohn’s disease.4Rutgeerts P. Hiele M. Geboes K. Peeters M. Penninckx F. Aerts R. Kerremans R. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection.Gastroenterology. 1995; 108: 1617-1621Abstract Full Text PDF PubMed Scopus (706) Google Scholar Long-term use of high-dose metronidazole was associated with bothersome adverse effects. In this study, we investigated the efficacy and safety of nitroimidazole antibiotics to prevent clinical recurrence of Crohn’s disease. We used ornidazole, which is thought to be associated with fewer side effects than metronidazole. The drug was given for 1 year. This randomized double-blind placebo-controlled trial was conducted at the inflammatory bowel disease centers of the University Hospital and 1 large teaching hospital. The protocol was approved by the clinical trials ethics committee of both hospitals, and all patients gave written informed consent. Only patients with ileal involvement with or without right colonic disease were included in the study. All patients were included within 1 week of resection of all macroscopically involved bowel with anastomosis of noninvolved ileum to normal colon (ileocolonic anastomosis). All anastomoses were end to end and were hand-sewn. Exclusion criteria were pure fibrostenotic disease without biologic inflammation, strictureplasties, 2-step resections with temporary ileostoma, or allergy to nitroimidazole antibiotics. The patients received either ornidazole (Tiberal; Roche, Basel, Switzerland) 500 mg twice daily or an identical placebo daily for 54 weeks. Therapy was started as soon as normal feeding was resumed after surgery: in 90% of patients within 1 week and in all patients within 2 weeks of surgery. All other Crohn’s disease–related drugs were discontinued at the time of surgery except for glucocorticosteroids. Steroids were tapered after inclusion and were stopped within 1 month of inclusion. The primary end point of the study was the proportion of patients with clinical recurrence at 54 weeks after surgery. Clinical recurrence was defined as the occurrence of symptoms, including diarrhea, abdominal pain, and decreased well-being, regarded by experienced clinicians as a relapse of Crohn’s disease symptoms. The Crohn’s Disease Activity Index at that time needed to be >250. An increase from baseline was not calculated because the baseline Crohn’s Disease Activity Index could not be reliably determined so early after surgery. Clinical recurrence was also diagnosed if reoperation was necessary or if other Crohn’s disease–related therapy was necessary. The proportions of patients with clinical recurrence were also determined at 24 and 36 months, although the patients were dosed only during the first 12 months. The secondary end points were the proportion of patients with endoscopic recurrence at 3 and 12 months. Total ileocolonoscopy was performed at 3 and 12 months after surgery. A previously developed endoscopic recurrence score3Rutgeerts P. Geboes K. Vantrappen G. Beyls J. Kerremans R. Hiele M. Predictability of the postoperative course of Crohn’s disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar was used: I0: no lesionsI1: ≤5 aphthous lesionsI2: >5 aphthous lesions with normal mucosa between the lesions or skip areas of larger lesions or lesions confined to the ileocolonic anastomosisI3: diffuse aphthous ileitis with diffusely inflamed mucosaI4: diffuse inflammation with already larger ulcers, nodules, and/or narrowing Endoscopic recurrence was defined as a score of I2 or higher. Biopsy samples of the neoterminal ileum were taken and assessed blindly by 2 pathologists (G.D.H. and K.G.). Histological recurrence was diagnosed when each of the following abnormalities was present2D’Haens G.R. Geboes K. Peeters M. Baert F. Penninckx F. Rutgeerts P. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal excluded ileum.Gastroenterology. 1998; 114: 262-267Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar: disturbed villus architecture, epithelial cell alterations at the lateral side of the villi, and an inflammatory cell infiltrate including neutrophilic and eosinophilic polymorphs and mononuclear cells. A barium meal radiograph follow-through was also performed 1 year after surgery. The relationship between endoscopic recurrence and clinical recurrence and between radiological recurrence and clinical recurrence was investigated. Baseline characteristics were analyzed with descriptive analysis. The normality of the characteristics was tested with the Shapiro–Wilk test. If data were normally distributed, the mean ± SD is given. If not normally distributed, the median with interquartile range is given. We estimated, on the basis of prior recurrence-prevention studies,4Rutgeerts P. Hiele M. Geboes K. Peeters M. Penninckx F. Aerts R. Kerremans R. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection.Gastroenterology. 1995; 108: 1617-1621Abstract Full Text PDF PubMed Scopus (706) Google Scholar, 5McLeod R.S. Wolff B.G. Steinhart A.H. Carryer P.W. O’Rourke K. Andrews D.F. Blair J.E. Cangemi J.R. Cohen Z. Cullen J.B. Chaytor R.G. Greenberg G.R. Jaffer N.M. Jeejeebhoy K.N. MacCarty R.L. Ready R.L. Weiland L.H. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease.Gastroenterology. 1995; 109: 404-413Abstract Full Text PDF PubMed Scopus (245) Google Scholar, 6Brignola C. Cottone M. Pera A. Ardizzone S. Scribano M.L. De Franchis R. D’Arienzo A. D’Albasio G. Pennestri D. Mesalamine in the prevention of endoscopic recurrence after intestinal resection for Crohn’s disease.Gastroenterology. 1995; 108: 345-349Abstract Full Text PDF PubMed Scopus (193) Google Scholar, 7Lochs H. Mayer M. Fleig W. Mortensen P.B. Bauer P. Genser D. Petritsch W. Raithel M. Hoffmann R. Gross V. Plauth M. Staun M. Nesje L.B. Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine European Cooperative Crohn’s Disease Study VI.Gastroenterology. 2000; 118: 264-273Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 8Hanauer S.B. Korelitz B.I. Rutgeerts P. Peppercorn M.A. Thisted R.A. Cohen R.D. Present D.H. Post-operative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine or placebo a 2-year trial.Gastroenterology. 2004; 127: 723-729Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar that 30% of the patients in the placebo group would have clinical recurrence at 1 year. Randomization of 80 patients would give the study a 1-sided power of 80% to detect an absolute difference of 25% in the primary outcome parameter between study groups. Intention-to-treat analysis was performed that included all patients who started the medication. Chi-square or Fisher exact tests, when appropriate, were used to evaluate the effect of drug therapy on clinical recurrence and on endoscopic recurrence as a surrogate marker. Although therapy was given for only 1 year, all patients were followed up for 3 years, and exploratory analysis was performed at 2 and 3 years after resection. Logistic regression analysis was performed to control for the effect of baseline characteristics on 1-year outcome (SPSS 12.0; SPSS Inc., Chicago, IL). The α level was predefined at 5%. Eighty patients were included in the study: 40 in the ornidazole group and 40 in the placebo arm. Two patients, both in the ornidazole arm, withdrew informed consent and did not take any drugs. They were excluded from analysis. In contrast, all patients who dropped out during the study were included in the intention-to-treat analysis. The baseline characteristics of the 2 groups are summarized in Table 1. There was a significantly longer duration of disease in the ornidazole group than in the placebo group.Table 1Baseline Characteristics in the Ornidazole Compared With the Placebo GroupVariableOrnidazole group (n = 38)Placebo group (n = 40)P valueAge (y)NS Median (IQR)35 (26–44)30.5 (24–41.25) Range18–7018–68Female/Male (%)22/16 (57.9%/42.1%)20/20 (50.0%/50.0%)NSAge at onset (y)NS Median (IQR)23.5 (19–28)26 (22–35.25)Age at resection (y)NS Median (IQR)35 (26–43.75)32.5 (24.75–41.25)Duration of disease until resection (y).049 Median (IQR)7 (4–11.75)3 (0.5–7.25)Extent of resection (cm)NS Median (IQR)25 (19.25–35)25.5 (20–40)Behavior of diseaseNS Inflammatory (%)4 (10.5%)5 (12.5%) Stenosing (%)16 (42.1%)14 (35.0%) Penetrating (%)18 (47.4%)21 (52.5%)Number of resections (%)NS 126 (68.4%)31 (77.5%) 29 (23.7%)7 (17.5%) 32 (5.3%)2 (5.0%) >31 (2.6%)0Section margins with inflammation (%)15 (39.5%)8 (20.0%)NSSmoking Past (%)17 (44.7%)22 (55.0%)NS Present (%)17 (44.7%)19 (47.5%)NSImmunosuppression (%)7 (18.4%)9 (22.5%)NSSteroids (%)20 (52.3%)14 (35.0%)NSNS, not significant; IQR, interquartile range. Open table in a new tab NS, not significant; IQR, interquartile range. At 54 weeks, 3 of 38 patients (7.9%) had clinical recurrence in the ornidazole group, as compared with 15 of 40 (37.5%) in the placebo group (Fisher exact test, 8.03; P = .0046; odds ratio [OR], 0.14; 95% confidence interval [CI], 0.037–0.546). This gives a difference in proportions of 29.6% (95% CI, 11.5%–39.4%) The same analysis was performed at 2 and 3 years, although the patients received therapy for only 1 year. At 2 years, 11 of 37 patients (29.7%) in the ornidazole group (1 patient had died from melanoma) had clinical recurrence, compared with 18 of 40 (45%) in the placebo group (P = .17; difference of 15.3%; 95% CI, −6.4% to 34.8%). At 3 years, 17 of 37 (45.9%) patients had clinical recurrence in the ornidazole group, compared with 19 of 40 (47.5%) in the placebo group (P = .53; difference, 1.6%; 95% CI, −20% to 23.2%) . Baseline characteristics and treatment were entered into a logistic regression model. Only previous immunosuppression before inclusion (OR, 5.21; 95% CI, 1.06–25.6; P = .042) and treatment regimen (OR, 0.13; 95% CI, 0.023–0.683; P = .016) were associated with significantly different rates of clinical recurrence at 12 months after surgery (Table 2).Table 2Logistic Regression Analysis of Baseline Characteristics and Postoperative Therapy Influencing Clinical Recurrence at 1 YearVariableP valueOR95% CISex.460.05530.115–2.675Age.791.0400.781–1.387Age at onset.701.0270.896–1.177Age at resection.720.9480.706–1.274Extent of disease.780.9950.958–1.033Disease behavior.960.9750.336–2.832Number of resections.202.2920.652–8.065Section margins with inflammation.761.2760.271–5.997Previous smoking.138.4190.546–129.748Current smoking.320.2490.016–3.941Immunosuppression.0425.2161.063–25.608Glucocorticosteroids.970.9710.238–3.953Ornidazole.0160.1260.023–0.683 Open table in a new tab Ileocolonoscopy with biopsy was performed at 3 and 12 months after inclusion in the study. At 3 months, 66 patients underwent ileocolonoscopy. Twelve patients either refused the examination or had dropped out from the study. At 3 months, 11 of 32 (34.4%) patients treated with ornidazole had endoscopic recurrence, defined as a score of I2 or more, compared with 20 of 34 (58.8%) in the placebo group (P = .047; OR, 0.37; 95% CI, 0.13–0.99; difference in proportion, 24.4%; 95% CI, 4%–45.7%). At 12 months, 61 patients underwent ileocolonoscopy: 15 of 28 (53.6%) had endoscopic recurrence in the ornidazole group, compared with 26 (78.8%) of 33 in the placebo group (P = .037; OR, 0.31; 95% CI, 0.10–0.94; difference, 25.2%; 95% CI, 1.6%–45%). Recurrence was confirmed by histological examination in all patients with a score of I2 or more. Overall, 3 of 35 (9%) patients who had no endoscopic recurrence at 3 months developed symptomatic recurrence at 12 months, vs. 13 of 34 (38%) patients with endoscopic recurrence at 3 months (P = .004). At 12 months, none of the 20 (0%) patients without endoscopic recurrence in both groups of patients had symptomatic recurrence, whereas 18 of 41 (43.9%) patients with endoscopic recurrence also had symptomatic relapse (P = .0002). At 1 year, 56 patients underwent barium follow-through radiograph studies. Twelve of 28 patients (42.9%; 95% CI, 26%–61%) in the ornidazole group had radiological recurrence, as compared with 21 of 28 patients (75%; 95% CI, 56%–61%) in the placebo group (P = .014; difference, 32.1%; 95% CI, 6.4%–53%). Three patients without radiological recurrence had a score of at least I2 at ileocolonoscopy. More patients discontinued therapy because of side effects in the ornidazole group (12/38) than in the placebo group (5/40; P = .041). Significantly more side effects occurred in the ornidazole group (26/38 patients) than in the placebo group (12/40 patients; P = .0007). The reasons for withdrawal are summarized in Table 3, and adverse events are listed in Table 4. The paresthesias and polyneuropathy associated with ornidazole disappeared completely over 1–6 months after discontinuation.Table 3Dropouts in the Study Groups During the 12-Month Treatment PeriodOrnidazole (n = 12)Placebo (n = 5)Disturbed liver tests (n = 1)GI intolerance (n = 2)Metallic taste, nausea, vomiting (n = 5)Disease activity (n = 1)Paresthesias (n = 1)Non-Hodgkin lymphoma (n = 1)Polyneuropathy (n = 2)Pregnancy (n = 1)Disease activity (n = 1)Compliance (n = 2)GI, gastrointestinal. Open table in a new tab Table 4Side Effects During the 12-Month Treatment PeriodOrnidazole (n = 26)Placebo (n = 12)Disturbed liver tests (n = 5)Disturbed liver tests (n = 2)Paresthesias (n = 5)GI intolerance (n = 3)Polyneuropathy (n = 3)Fatigue (n = 4)Myopathy (n = 1)Flush (n = 1)GI intolerance (n = 4)Arthralgias (n = 1)Pruritus (n = 1)NHL (n = 1)Metallic taste (n = 3)Pregnancy (n = 1)Headache (n = 1)Psychosis (n = 1)Alcohol intolerance (n = 1)Acute arthritis (n = 1)Compliance (n = 2)GI, gastrointestinal; NH, non-Hodgkin lymphoma. Open table in a new tab GI, gastrointestinal. GI, gastrointestinal; NH, non-Hodgkin lymphoma. We found ornidazole to be an effective prophylactic therapy after surgery for Crohn’s disease. This nitroimidazole antibiotic prevented both bowel lesions as visualized at ileocolonoscopy and, most importantly, clinical recurrence at 1 year after surgery in this cohort of patients. The proportion of patients with clinical relapse at 1 year decreased from 37.5% in the placebo group to 7.9% in the ornidazole group. The only other clinical parameter predicting clinical recurrence was the discontinuation of immunosuppressants. Irrespective of the treatment during the trial year, patients who stopped the immunosuppression at the time of operation had an approximately 5 times increased chance of having a clinical recurrence at 1 year compared with patients who were not taking these drugs at the time of operation. One explanation might be that these patients had the worst disease severity before surgery. Various therapies have been explored for prophylaxis of Crohn’s disease recurrence, including sulfasalazine and mesalamine formulation, topically acting glucocorticosteroids, and immunosuppression. Also, probiotics and fish oils are under study for this indication. Of 3 placebo-controlled9Bergman L. Krause U Postoperative treatment with corticosteroids and salazosulphapyridine (Salazopyrin).Scand J Gastroenterol. 1976; 11: 651-656PubMed Google Scholar, 10Wenckert A. Kristensen M. Eklund A.E. Barany F. Jarnum S. Worning H. Folkenborg O. Holtz A. Bonnevie O. Rijs P. The long term prophylactic effect of salazosulphapyridine (Salazopyrin) in primary resected patients with Crohn’s disease.Scand J Gastroenterol. 1978; 13: 161-167Crossref PubMed Scopus (103) Google Scholar, 11Ewe K. Herfarth H.C. Malchow W.H. Jesdinsky H.J. Postoperative recurrence of Crohn’s disease in relation to radicality of operation and sulfasalazine prophylaxis a multicenter trial.Digestion. 1989; 42: 224-232Crossref PubMed Scopus (152) Google Scholar trials investigating sulfasalazine for prophylaxis, only the study of Ewe et al.11Ewe K. Herfarth H.C. Malchow W.H. Jesdinsky H.J. Postoperative recurrence of Crohn’s disease in relation to radicality of operation and sulfasalazine prophylaxis a multicenter trial.Digestion. 1989; 42: 224-232Crossref PubMed Scopus (152) Google Scholar showed a significant but modest reduction of surgical and radiological recurrence at 1 year. Studies exploring the prophylactic effect of mesalamine have faced problems of heterogenous trial design. Dosing regimens, the interval between surgery and the start of treatment, and the duration of follow-up have been highly variable. Of 4 placebo-controlled studies,5McLeod R.S. Wolff B.G. Steinhart A.H. Carryer P.W. O’Rourke K. Andrews D.F. Blair J.E. Cangemi J.R. Cohen Z. Cullen J.B. Chaytor R.G. Greenberg G.R. Jaffer N.M. Jeejeebhoy K.N. MacCarty R.L. Ready R.L. Weiland L.H. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease.Gastroenterology. 1995; 109: 404-413Abstract Full Text PDF PubMed Scopus (245) Google Scholar, 6Brignola C. Cottone M. Pera A. Ardizzone S. Scribano M.L. De Franchis R. D’Arienzo A. D’Albasio G. Pennestri D. Mesalamine in the prevention of endoscopic recurrence after intestinal resection for Crohn’s disease.Gastroenterology. 1995; 108: 345-349Abstract Full Text PDF PubMed Scopus (193) Google Scholar, 7Lochs H. Mayer M. Fleig W. Mortensen P.B. Bauer P. Genser D. Petritsch W. Raithel M. Hoffmann R. Gross V. Plauth M. Staun M. Nesje L.B. Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine European Cooperative Crohn’s Disease Study VI.Gastroenterology. 2000; 118: 264-273Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 12Sutherland L.R. Martin F. Bailey R.J. Fedorak R.N. Poleski M. Dallaire C. Rossman R. Saibil F. Lariviere L. A randomized, placebo-controlled, double-blind trial of mesalamine in the maintenance of remission of Crohn’s Disease The Canadian Mesalamine for Remission of Crohn’s Disease Study Group.Gastroenterology. 1997; 112: 1069-1077Abstract Full Text PDF PubMed Scopus (168) Google Scholar only the McLeod study5McLeod R.S. Wolff B.G. Steinhart A.H. Carryer P.W. O’Rourke K. Andrews D.F. Blair J.E. Cangemi J.R. Cohen Z. Cullen J.B. Chaytor R.G. Greenberg G.R. Jaffer N.M. Jeejeebhoy K.N. MacCarty R.L. Ready R.L. Weiland L.H. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease.Gastroenterology. 1995; 109: 404-413Abstract Full Text PDF PubMed Scopus (245) Google Scholar showed a significant decrease of the clinical recurrence rate at 72 months (41% for placebo; 31% for mesalamine; P = .031 by 1-tailed test). The Lochs study,7Lochs H. Mayer M. Fleig W. Mortensen P.B. Bauer P. Genser D. Petritsch W. Raithel M. Hoffmann R. Gross V. Plauth M. Staun M. Nesje L.B. Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine European Cooperative Crohn’s Disease Study VI.Gastroenterology. 2000; 118: 264-273Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar although negative overall, suggested in an exploratory analysis in the subgroup of patients with ileal disease only that mesalamine might be mildly effective. Overall, therefore, placebo-controlled trials of mesalamine for prophylaxis of recurrence of Crohn’s disease should be considered negative. A multicenter double-blind placebo-controlled European trial included 129 patients to be randomized to budesonide 6 mg/day or placebo within 2 weeks from surgery.13Hellers G. Cortot A. Jewell D. Leijonmarck C.E. Lofberg R. Malchow H. Nilsson L.G. Pallone F. Pena S. Persson T. Prantera C. Rutgeerts P. Oral budesonide for prevention of postsurgical recurrence in Crohn’s disease.Gastroenterology. 1999; 116: 294-300Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Most patients were operated on for fibrostenotic disease. Endoscopic and clinical recurrence rates were not different between groups at 3 and 12 months. A subanalysis showed a significant reduction in endoscopic lesions with budesonide (12 months: 32% vs. 65% for placebo; P < .05) in patients operated on for inflammatory luminal disease, but not in patients with fibrostenosis as the indication for surgery. Surprisingly, there are few data on the use of azathioprine/6-mercaptopurine (6-MP) in the postoperative setting. Only 1 multicenter placebo-controlled trial was performed: it compared 6-MP 50 mg with mesalamine 3 g/day.8Hanauer S.B. Korelitz B.I. Rutgeerts P. Peppercorn M.A. Thisted R.A. Cohen R.D. Present D.H. Post-operative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine or placebo a 2-year trial.Gastroenterology. 2004; 127: 723-729Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar The trial enrolled 131 patients in 5 centers, and they were randomized to 1 of the 3 groups in a double-blind, double-dummy design. Patients were assessed for clinical, radiological, and endoscopic radiologic recurrence at regular intervals throughout 24 months. Dropout rates were considerable in the course of the trial but were evenly distributed over the 3 groups. Clinical recurrence rates by life-table analysis at 24 months were 50% for 6-MP, 58% for mesalamine, and 77% for placebo. Endoscopic recurrence rates were 43%, 63%, and 64%, respectively. 6-MP was more effective than placebo (P < .05) at preventing clinical and endoscopic recurrence over 2 years. The benefit of 6-MP was lower than anticipated (21% risk reduction vs. placebo for endoscopic recurrence). The question was raised whether the dose of 6-MP chosen was too low to achieve a more pronounced effect. Ardizzone et al.14Ardizzone S. Maconi G. Sampietro G.M. Russo A. Radice E. Colombo E. Imbesi V. Molteni M. Danelli P.G. Taschieri A.M. Bianchi Porro G. Azathioprine and mesalamine for prevention of relapse after conservative surgery for Crohn’s disease.Gastroenterology. 2004; 127: 730-740Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar reported on an open comparative trial of azathioprine (2 mg · kg−1 · day−1) and mesalamine (3 g/day) for 24 months for prevention of relapse in 142 patients after conservative surgery for Crohn’s disease. On a per-protocol analysis, 17 patients (34%) receiving azathioprine and 28 (46%) receiving mesalamine experienced relapse; the difference was not significant. Therefore, although it is clear that mesalamine lacks efficacy for prophylaxis, the data are not convincing for 6-MP. More placebo-controlled studies of recurrence prevention with immunosuppressives are necessary to establish the role of azathioprine/6-MP in the prevention of postoperative recurrence of Crohn’s disease. The rationale for using antibiotics for the prevention of recurrence after ileal resection is that after removal of the ileocecal valve, the neoterminal ileum is exposed to high amounts of colonic bacteria, and it is well recognized that the flora plays an important role in the pathogenesis of Crohn’s disease and in all experimental animal models of inflammatory bowel disease. In a previous study, we showed that metronidazole with the same mode of action as ornidazole is effective to prevent severe endoscopic recurrence of Crohn’s disease lesions in the neoterminal ileum after resection.4Rutgeerts P. Hiele M. Geboes K. Peeters M. Penninckx F. Aerts R. Kerremans R. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection.Gastroenterology. 1995; 108: 1617-1621Abstract Full Text PDF PubMed Scopus (706) Google Scholar This surrogate measurement has not extensively been validated as an end point with clinical relevance for the study of postoperative Crohn’s disease evaluation. In a substudy15McLeod R.S. Wolff B.G. Steinhart A.H. Carryer P.W. O’Rourke K. Andrews D.F. Blair J.E. Cangemi J.R. Cohen Z. Cullen J.B. Chaytor R.G. Greenberg G.R. Jaffer N.M. Jeejeebhoy K.N. MacCarty R.L. Ready R.L. Weiland L.H. Risk and significance of endoscopic/radiological evidence of recurrent Crohn’s disease.Gastroenterology. 1997; 113: 1823-1827Abstract Full Text PDF PubMed Scopus (85) Google Scholar of the McLeod recurrence prevention trial with mesalamine, evidence of endoscopic/radiological recurrent ileal disease was found in 27.5% of patients at 1 year, 60.8% at 2 years, and 77.3% at 3 years in the placebo-treated group. Patients with severe endoscopic/radiological disease were more likely to be or to become symptomatic than those with minimal disease. The endoscopic radiologic recurrence rate in that study was lower than that reported in earlier studies. This might be due to the lower sensitivity of radiology to pick up early lesions. In the present study, we showed that endoscopic recurrence was predictive of clinical recurrence in both the placebo and active treatment groups and that ornidazole prevented both endoscopic and clinical recurrence. Ornidazole was chosen instead of metronidazole because it was claimed to have a better safety profile. In this study, considerable toxicity still occurred, but the incidence of severe side effects was lower than with metronidazole.4Rutgeerts P. Hiele M. Geboes K. Peeters M. Penninckx F. Aerts R. Kerremans R. Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection.Gastroenterology. 1995; 108: 1617-1621Abstract Full Text PDF PubMed Scopus (706) Google Scholar There are few published data on the use of ornidazole in Crohn’s disease. Triantafillidis et al.16Triantafillidis J.K. Nicolakis D. Emmanoullidis A. Antoniou A. Papatheodorou K. Cheracakis P. Ornidazole in the treatment of active Crohn’s disease short-term results.Ital J Gastroenterol. 1996; 28: 10-14PubMed Google Scholar reported on an open study with treatment of 25 patients with active Crohn’s disease with ornidazole 1 g/day: 18 patients achieved remission by 4 weeks. The short-term toxicity was low. The same authors17Triantafillidis J.K. Antoniou A. Emmanoulidis A. Nicolakis D. Barbatzas C. Cheracakis P. Ornidazole in the prevention of recurrence of Crohn’s disease.Ital J Gastroenterol Hepatol. 1998; 30: 446-447PubMed Google Scholar reported that ornidazole was effective in 19 patients for relapse prevention. Five of these patients were treated after surgical resection. Finally, the authors also reported on a patient who took at least 500 mg of ornidazole per day for 10 years without toxicity and had successful maintenance of remission.18Triantafillidis J.K. Nicolakis D. Antoniou A. Hereti I. Absence of toxicity of ornidazole after a 10-yr continuous daily use for Crohn’s disease.Am J Gastroenterol. 2001; 96: 254-255Crossref PubMed Google Scholar In this study, we found ornidazole to be effective to prevent tissue and clinical recurrence of Crohn’s disease only as long as the drug was administered. After cessation of the drug at 1 year, no significant difference between the treated patients and patients who had not received ornidazole was observed upon long-term follow-up. Our logistic regression suggests that patients who are receiving azathioprine/6-MP before surgery should be continued on this drug after surgery. Although this suggestion is based on an exploratory analysis in only a small subset of patients, this observation might be of importance in the planning of future postoperative prevention trials. This study also underscores the usefulness of early postoperative ileocolonoscopy to predict clinical recurrence of Crohn’s disease. All patients who had clinical recurrence at 1, 2, and 3 years of follow-up had clear-cut endoscopic recurrence of Crohn’s disease at 12 months after surgery irrespective of therapy. Although more validation is required, our study suggests that endoscopic recurrence is a good surrogate marker to be used as end point in clinical trials of Crohn’s disease prophylaxis after curative resection. In summary, this study shows that ornidazole is effective to prevent postoperative recurrence of Crohn’s disease. Therefore, we propose, on the basis of the present results, use of nitroimidazole antibiotics for postsurgical prophylaxis of Crohn’s disease. The chronic use of a lower dose of ornidazole, e.g., 500 mg/day, might be better tolerated long-term, but it is not clear whether such a dose will be effective for prophylaxis.