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Therapy of Metronidazole With Azathioprine to Prevent Postoperative Recurrence of Crohn's Disease: A Controlled Randomized Trial

2008; Elsevier BV; Volume: 135; Issue: 4 Linguagem: Inglês

10.1053/j.gastro.2008.07.010

1528-0012

Geert R. D’Haens, Séverine Vermeire, Gert Van Assche, Maja Noman, Isolde Aerden, Gust Van Olmen, Paul Rutgeerts,

Autoimmune and Inflammatory Disorders

Background & Aims: More than 80% of Crohn's disease (CD) patients undergoing resection suffer recurrence of their disease. Therapy with aminosalicylates, antimetabolites, or antibiotics leads to a modest reduction in the incidence of recurrence. Goal: We sought to examine whether metronidazole for 3 months together with azathioprine (AZA) for 12 months is superior to metronidazole alone to reduce recurrence of postoperative CD in “high-risk” patients. Methods: CD patients undergoing curative ileocecal resection with ≥1 risk factor for recurrence received metronidazole (3 months) and AZA/placebo (12 months). The primary end point was the proportion of patients with significant endoscopic recurrence 3 and 12 months after surgery. Secondary end points included clinical recurrence, safety, and tolerability of treatment. Results: Eighty-one patients were randomized; 19 discontinued the study early. Significant endoscopic recurrence was observed in 14 of 32 (43.7%) patients in the AZA group and in 20 of 29 (69.0%) patients in the placebo group at 12 months postsurgery (P = .048). Intention-to-treat analysis revealed endoscopic recurrence in 22 of 40 (55%) in the AZA group and 32 of 41 (78%) in the placebo group at month 12 (P = .035). At month 12, 7 of 32 patients had no endoscopic lesions in the AZA group, versus 1 of 29 in the placebo group (P = .037). Conclusions: Despite the enhanced risk of recurrence, the overall incidence of significant recurrence was rather low, probably owing to the metronidazole treatment that all patients received. Concomitant AZA resulted in lower endoscopic recurrence rates and less severe recurrences 12 months postsurgery, predicting a more favorable clinical outcome. This combined treatment seems to be recommendable to all operated CD patients with an enhanced risk for recurrence. Background & Aims: More than 80% of Crohn's disease (CD) patients undergoing resection suffer recurrence of their disease. Therapy with aminosalicylates, antimetabolites, or antibiotics leads to a modest reduction in the incidence of recurrence. Goal: We sought to examine whether metronidazole for 3 months together with azathioprine (AZA) for 12 months is superior to metronidazole alone to reduce recurrence of postoperative CD in “high-risk” patients. Methods: CD patients undergoing curative ileocecal resection with ≥1 risk factor for recurrence received metronidazole (3 months) and AZA/placebo (12 months). The primary end point was the proportion of patients with significant endoscopic recurrence 3 and 12 months after surgery. Secondary end points included clinical recurrence, safety, and tolerability of treatment. Results: Eighty-one patients were randomized; 19 discontinued the study early. Significant endoscopic recurrence was observed in 14 of 32 (43.7%) patients in the AZA group and in 20 of 29 (69.0%) patients in the placebo group at 12 months postsurgery (P = .048). Intention-to-treat analysis revealed endoscopic recurrence in 22 of 40 (55%) in the AZA group and 32 of 41 (78%) in the placebo group at month 12 (P = .035). At month 12, 7 of 32 patients had no endoscopic lesions in the AZA group, versus 1 of 29 in the placebo group (P = .037). Conclusions: Despite the enhanced risk of recurrence, the overall incidence of significant recurrence was rather low, probably owing to the metronidazole treatment that all patients received. Concomitant AZA resulted in lower endoscopic recurrence rates and less severe recurrences 12 months postsurgery, predicting a more favorable clinical outcome. This combined treatment seems to be recommendable to all operated CD patients with an enhanced risk for recurrence. See Maser EA et al on page 1112 in CGH. See Maser EA et al on page 1112 in CGH. The majority of patients with ileocecal Crohn's disease (CD) who undergo surgical resection develop postoperative recurrence of the disease in the neoterminal ileum.1Kyle J. Prognosis after ileal resection for Crohn's disease.Br J Surg. 1971; 58: 735-737Crossref PubMed Scopus (34) Google Scholar, 2Greenstein A.J. Sachar D.B. Pasternack B.S. et al.Reoperation and recurrence in Crohn's colitis and ileocolitis.N Engl J Med. 1975; 293: 685-690Crossref PubMed Scopus (234) Google Scholar, 3Whelan G. Farmer R.G. Fazio V.W. et al.Recurrence after surgery in Crohn's disease.Gastroenterology. 1985; 88: 1826-1833PubMed Google Scholar Seventy-three percent of all operated patients have endoscopic signs of recurrent disease 1 year after surgery, and 85% have recurrence after 3 years.4Rutgeerts P. Geboes K. Vantrappen G. et al.Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar Moreover, the severity of the endoscopic lesions has been predictive of the further clinical course of the disease. None of the currently available medical therapies have influenced the incidence of postoperative recurrence to an important extent. Studies with mesalamine preparations have yielded conflicting results. The benefit of continuous treatment with rather high doses of these drugs was at most only modest.5Caprilli R. Gassull M.A. Escher J.C. et al.European evidence based consensus on the diagnosis and management of Crohn's disease: special situations.Gut. 2006; 55: i36-i58Crossref PubMed Scopus (406) Google Scholar An alternative treatment is the immunomodulator 6-mercaptopurine (6-MP), although the results are not all that convincing. Whereas in a prospective trial a fixed dose of 6-MP of 50 mg/d was significantly better in preventing endoscopic recurrence 1 and 2 years postoperatively6Hanauer S.B. Korelitz B.I. Rutgeerts P. et al.Postoperative 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 (418) Google Scholar in comparison with 3 g of a sustained-release formulation of mesalamine (Pentasa, Ferring, Denmark) or placebo, no difference between AZA and mesalamine was seen in prevention of clinical recurrence in another study.7Ardizzone S. Maconi G. Sampietro G.M. et al.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 (281) Google Scholar Furthermore, antibacterial agents directed against anaerobic bacteria (ornidazole and metronidazole) were shown to be effective in reducing the severity of endoscopic recurrence, but prolonged administration of these antibiotics caused significant toxicity, mainly neuropathy and gastrointestinal intolerance.8Rutgeerts P. Peeters M. Hiele M. et al.A placebo controlled trial of metronidazole for recurrence prevention of Crohn's disease after resection of the terminal ileum.Gastroenterology. 1995; 108: 1617-1621Abstract Full Text PDF PubMed Scopus (719) Google Scholar, 9Rutgeerts P. Van Assche G. Vermeire S. et al.Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, placebo- controlled trial.Gastroenterology. 2005; 128: 856-861Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar The role of intestinal bacteria as inducers of recurrent CD has recently received a lot of interest, because reinfusion experiments showed that signs of inflammation appear within 8 days after the contact between the ileal mucosa and the ileal fluid has been restored, except when this fluid has been sterilized.10D'Haens G. Geboes K. Peeters M. et al.Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum.Gastroenterology. 1998; 114: 262-267Abstract Full Text Full Text PDF PubMed Scopus (755) Google Scholar, 11Rutgeerts P. Geboes K. Peeters M. et al.Effect of fecal stream diversion on recurrence of Crohn's disease in the neoterminal ileum.Lancet. 1991; 338: 771-774Abstract PubMed Scopus (659) Google Scholar, 12Harper P.H. Lee E.C.G. Kettlewell M.G.W. et al.Role of fecal stream in the maintenance of Crohn's colitis.Gut. 1985; 26: 279-284Crossref PubMed Scopus (172) Google Scholar It was the goal of the present study to compare the theoretically most potent prevention strategy, a combination of the immunomodulator azathioprine (AZA) and a 3-month course of metronidazole, to the latter treatment alone in patients carrying an elevated risk of developing postoperative recurrence of CD. All consecutive patients undergoing curative ileal or ileocolonic resection with ileocolonic anastomosis for CD at 2 teaching hospitals (University Hospital Leuven and Imelda General Hospital, Bonheiden, Belgium) between August 1999 and September 2005 were invited to participate in the trial. A requirement for eligibility was the presence of ≥1 risk factor for the development of early/severe postoperative recurrence of their CD, based on the available literature: young age (<30 years); active smoking; corticosteroid use in the 3 months before surgery; surgery for the 2nd, 3rd, or 4th resection; and perforating disease, namely, abscess or fistula as an indication for surgery.13Greenstein A.J. Lachman P. Sachar D.B. et al.Perforating and non-perforating indications for repeated operations in Crohn's disease: evidence for two clinical forms.Gut. 1988; 29: 588-592Crossref PubMed Scopus (366) Google Scholar, 14Sutherland L.R. Ramcharan S. Bryant H. et al.Effect of cigarette smoking on recurrence of Crohn's disease.Gastroenterology. 1990; 98: 1123-1128Abstract Full Text PDF PubMed Scopus (336) Google Scholar, 15Sachar D.B. Wolfson D.M. Greenstein A.J. et al.Risk factors for postoperative recurrence of Crohn's disease.Gastroenterology. 1983; 85: 917-921PubMed Scopus (126) Google Scholar Patients had to be between 18 and 70 years old and had to understand and sign a written informed consent form. Women of childbearing age needed to have a negative pregnancy test and had to use adequate birth control measures during the whole study. Exclusion criteria included the presence of macroscopic evidence for CD proximally or distally to the site of resection or the presence of frank pancolitis or an ileorectal anastomosis (ileosigmoidal anastomosis was allowed). Patients with a stoma were also excluded, as well as those who were operated on for fibrostenosis only, without evidence of inflammatory activity on histology. Patients with former intolerance to metronidazole and/or AZA, who wished to become pregnant during the study, who had a low white blood cell count at inclusion (<4000), who had alcohol or drug abuse, or who had used AZA in the 2 months before surgery were also excluded, as well as patients with malignancies and/or ongoing infectious disease (hepatitis, tuberculosis, AIDS) with the exception of herpes simplex infection. Former use of biologicals was not permitted. The trial was approved by the medical ethical committee at the University of Leuven, Belgium. All patients received 3 months of metronidazole therapy at a dose of 250 mg 3 times per day. Patients who could not tolerate metronidazole were switched to ornidazole 500 mg twice per day orally. Half of the patients also received AZA; the other half received placebo. The dose of AZA was body weight dependent. Patients whose body weight was 60 kg received 3 tablets or 150 mg AZA. Hence, the number of tablets sometimes changed during the study. Randomization took place in the pharmacy of the Leuven University Hospitals within 2 weeks after surgery. The random allocation sequence was delivered by a randomization program written in Visual Basic version 6. In principle, patients started their medication as soon as they were able to resume oral intake. At the time of surgery, all concomitant anti-inflammatory medications were discontinued, except for glucocorticosteroids, which were gradually tapered over 6 weeks after surgery. Antibiotics were allowed during the study for concurrent infections, but not for CD. Topical therapy for perianal CD could be continued if necessary. Cholestyramine was allowed for the treatment of bile acid diarrhea. Patients were instructed to take their other drugs at least 1 hour after the intake of cholestyramine. Patients underwent clinical evaluation with physical examination and biochemical analysis at baseline and weeks 2, 6, 12, 20, 28, 36, 44, and 52 after randomization. Laboratory assessments included peripheral blood counts, C-reactive protein levels, alkaline phosphatase, bilirubin, serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, creatinine, and urea levels. At week 12 and 52, an ileocolonoscopy was performed with determination of Rutgeerts' score for ileal recurrence of CD by an endoscopist who was unaware of treatment assignment (Table 1).4Rutgeerts P. Geboes K. Vantrappen G. et al.Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar Adverse events and concomitant medication were recorded at every scheduled or unscheduled visit. Adverse events were recorded as mild, moderate, severe, or life threatening and the relationship with the study drugs was assessed as not related, possibly related, probably related, or definitely related. All events were followed to satisfactory resolution and/or stabilization. All actions taken were recorded in the files.Table 1Rutgeerts' Endoscopic Score for Recurrence of CD in the Neoterminal IleumScoreCriteria0No lesions1 5 Aphthoid ulcers with normal mucosa in between or skip areas of larger lesions or lesions confined to the ileocolonic anastomosis3Diffuse ileitis with larger ulcers but normal mucosa in between4Diffuse ileitis with large ulcers, nodules/narrowing without normal mucosa in between Open table in a new tab Elevations of liver function tests, regularly observed with metronidazole and also with AZA, were dealt with as follows: An elevation of transaminases up to 3 times the upper limit of normal and of alkaline phosphatase 2 times the upper limit of normal were allowed and did not lead to a change in therapy or discontinuation. More severe abnormalities led to discontinuation of therapy and study participation. Leukopenia, a common, dose-dependent side effect of AZA, was handled as follows: If the total white count was <3500, the dose of AZA/placebo was reduced to 1 tablet (50 mg) per day. If on 1 tablet per day the patient still had a white count 250), the severity of endoscopic recurrence, and the incidence of adverse events. Patients who developed symptoms suggestive of clinical recurrence were kept in the trial if possible until the final evaluation at month 12. If symptoms were too severe, however, patients were withdrawn from the trial and further treated according to the investigator's opinion. We estimated, on the basis of prior recurrence–prevention studies, that 50%–55% of the patients in the placebo group would have endoscopic recurrence at 1 year.4Rutgeerts P. Geboes K. Vantrappen G. et al.Predictability of the postoperative course of Crohn's disease.Gastroenterology. 1990; 99: 956-963Abstract PubMed Google Scholar, 8Rutgeerts P. Peeters M. Hiele M. et al.A placebo controlled trial of metronidazole for recurrence prevention of Crohn's disease after resection of the terminal ileum.Gastroenterology. 1995; 108: 1617-1621Abstract Full Text PDF PubMed Scopus (719) Google Scholar, 9Rutgeerts P. Van Assche G. Vermeire S. et al.Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, placebo- controlled trial.Gastroenterology. 2005; 128: 856-861Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar Assuming an efficacy of 65% of AZA, a β error of .10 and an α error of ≦.05 in a 2-sided test model, it was calculated that 80 patients were needed to be enrolled in the trial (40 placebo and 40 AZA) to detect differences in significant endoscopic recurrence among the groups. Fisher's exact test was used to evaluate the effect of drug therapy on endoscopic recurrence at 3 and 12 months. Confidence intervals for proportions were being calculated as proposed by Simon.16Simon R. Confidence intervals for reporting results of clinical trials.Ann Intern Med. 1986; 105: 429-435Crossref PubMed Scopus (340) Google Scholar Clinical recurrence rates were analyzed by life table analysis. Both intention-to-treat and per-protocol analyses were performed. The characteristics of the study populations in the AZA and placebo group were comparable (Table 2). Eighty-one patients agreed to participate in the study and were randomized (37 female/44 male [46%/54%]; mean age 40.2 ± 12.05 years). Five patients had used AZA before their surgery (3 in the AZA group, duration 6, 12, and 18 months and 2 in the placebo group, duration 6 and 36 months). Twenty-one patients were on corticosteroids at the time of surgery and 23 had already had an earlier ileocolonic resection, evenly distributed among both groups.Table 2Patient Characteristics and Risk Factors for Recurrence in the Study PopulationMetronidazole/AZAMetronidazole/PLACPn (female/male)40 (24/16)41 (20/21).37Mean age (range)38.8 (22–67)40.0 (21–69).971st/2nd/3rd surgery24/12/232/8/1.34Smoking Current1317.37 Former127 Never1517Age 250) occurred, 7 in the placebo group and 3 in the AZA group (P = .31 and .31 [Fisher's]). Four patients left the trial early because of severe clinical symptoms (3 placebo and 1 AZA patient). The other 6 patients (4 placebo and 2 AZA patients) continued the study until month 12 and underwent colonoscopy at week 52. Whereas all 6 had a recurrence stage i2 at week 12, the severity had changed to stage i4 in 3 patients, stage i3 in 2 patients, and remained unchanged at stage i2 in 1 patient. The adverse events that occurred during the trial are shown in Table 4. Metallic taste and epigastric discomfort were only seen in the first 3 months and hence probably induced by metronidazole. Pancreatitis did somewhat surprisingly not occur. Arthralgia was predominantly reported by patients who were using AZA, although 1 patient discontinued the trial because of arthralgia in the metronidazole/placebo group. Notably, elevation of liver function tests was predominantly seen in patients on metronidazole/placebo. Overall, the study therapy was well tolerated. In total, only 4 patients discontinued therapy because of subjective intolerance (3 in the first 12 weeks and 1 later on).Table 4Adverse Events Observed in >1 PatientMetronidazole/AZA weeks 0–12 (n = 40)Metronidazole/Placebo weeks 0–12 (n = 41)PMetronidazole/AZA weeks 12–52 (n = 35)M/Placebo weeks 12–52 (n = 38)PMetallic taste66NS00NSHeadache073.24100NSParesthesias03.24100NSEpigastric pain33NS00NSNausea21.61600NSArthralgia50.02621.616Angina20.24111NSSkin rash20.24100NSURT infection00NS20.241WBC 2.5 ULN03.24103.241M, metronidazole; SGPT, serum glutamate pyruvate transaminase; ULN, upper limit of normal; URT, upper respiratory tract infection; WBC, white blood cells. Open table in a new tab M, metronidazole; SGPT, serum glutamate pyruvate transaminase; ULN, upper limit of normal; URT, upper respiratory tract infection; WBC, white blood cells. This study demonstrates that patients with an elevated risk of developing postoperative recurrence of CD have a lower likelihood of severe recurrence when they receive treatment with a 3-month induction treatment of metronidazole in combination with AZA: Significant endoscopic recurrence was observed in 14 of 32 patients (43.7%) in the AZA group and in 20 of 29 (69.0%) patients in the placebo group at 12 months postsurgery (P = .048), with absence of inflammatory lesions at month 12 in 1 of 29 and in 7 of 32 patients, respectively (P = .037). The prevention of postoperative recurrence of CD remains a challenge to patients and physicians. The vast majority of patients indeed develop recurrence, but the time frame is difficult to predict and patients often remain free of symptoms for many years. The question when exactly patients should be offered medical treatment has several potential answers: immediately after surgery (based on the reinfusion experiments showing histologic inflammatory changes after 8 days10D'Haens G. Geboes K. Peeters M. et al.Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum.Gastroenterology. 1998; 114: 262-267Abstract Full Text Full Text PDF PubMed Scopus (755) Google Scholar), at the time significant endoscopic lesions are demonstrated, or at the time of symptomatic relapse. The last option is probably the least ideal because tissue damage (stenosis or perforation) at that point may already be irreversible and eventually may necessitate a new operative intervention. The second option (endoscopy-guided treatment) seems valuable as long as the lesions can still be healed without permanent tissue damage, a goal that can be reached with AZA in a certain proportion of patients, but definitely not in all.17D'Haens G. Geboes K. Ponette E. et al.Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease.Gastroenterology. 1997; 112: 1475-1481Abstract Full Text PDF PubMed Scopus (239) Google Scholar Therefore, a genuine “preventive” therapy that is initiated immediately after surgery may offer the best clinical outcome and potentially alter the natural history of the disease in the long term. Earlier trials with antibacterial agents directed against anaerobic bacteria (nitroimidazoles) have shown that even short-term treatment (3 months) offers a long-term benefit.8Rutgeerts P. Peeters M. Hiele M. et al.A placebo controlled trial of metronidazole for recurrence prevention of Crohn's disease after resection of the terminal ileum.Gastroenterology. 1995; 108: 1617-1621Abstract Full Text PDF PubMed Scopus (719) Google Scholar The European ECCO consensus on the diagnosis and management of CD supported the statement that nitroimidazole antibiotics, which also have immunosuppressive properties,18Grove D.I. Mahmoud A.A.F. Warren K.S. Suppression of cell-mediated immunity by metronidazole.Int Arch Allergy Appl Immunol. 1977; 54: 422-427Crossref PubMed Scopus (98) Google Scholar, 19Blair V. Ullman U. The influence of metronidazole and its two main metabolites on murine in vitro lymphocyte transformation.Eur J Clin Microbiol. 1983; 2: 568-570Crossref PubMed Scopus (19) Google Scholar, 20Arndt H. Palitzsch K. Grisham M. et al.Metronidazole inhibits leucocyte-endothelial cell adhesion in rat mesenteric venules.Gastroenterology. 1994; 106: 1271-1276PubMed Google Scholar are to be considered valuable agents in the setting of postoperative CD prevention. For this reason, a 3-month course of metronidazole was chosen as baseline therapy for the current clinical trial. As mentioned, Rutgeerts et al8Rutgeerts P. Peeters M. Hiele M. et al.A placebo controlled trial of metronidazole for recurrence prevention of Crohn's disease after resection of the terminal ileum.Gastroenterology. 1995; 108: 1617-1621Abstract Full Text PDF PubMed Scopus (719) Google Scholar performed a controlled trial with metronidazole 20 mg/kg per day or placebo started within a week after the resection for 12 weeks. At week 12, severe endoscopic recurrence was observed in 13% of metronidazole treated patients and in 43% of placebo-treated patients (P = .02). The effects of this intervention seemed to be prolonged with a reduction in clinical recurrence rates at 1, 2, and 3 years. Absence of endoscopic lesions was seen in 48% of the metronidazole treated patients, clearly more than the 29% lesion-free patients in the current study. Possible explanations for this difference are the higher doses of metronidazole that were administered (20 mg/kg per day vs 750 mg/d), or the lower propensity to develop recurrence in a cohort that included all patients irrespective of the risk profile. This may also explain the lower clinical relapse rates at 1 year (7% in the Rutgeerts study vs 18% of the patients in the placebo group of the current study). In addition, the quality of endoscopic imaging has improved significantly in the last decades, which could explain why subtle lesions are currently detected more easily. In a similar trial with ornidazole (Tiberal, Roche, Basel, Switzerland), a sibling molecule to metronidazole, which was expected to be better tolerated with prolonged use and that was given for a full year after surgery, the same group of investigators reported endoscopic recurrence (grade ≥i2) at 3 and 12 months in 59% and 79% of placebo-treated patients versus in 34% and 54% of the ornidazole-treated patients, respectively.9Rutgeerts P. Van Assche G. Vermeire S. et al.Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, double-blind, placebo- controlled trial.Gastroenterology. 2005; 128: 856-861Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar Because the current study did not have a real placebo group, a comparison can only be made with the ornidazole-treated patients. We found severe endoscopic recurrence in 44% of patients treated with 3 months of metronidazole plus 12 months of AZA and this seems to compare favorably with the 54% endoscopic recurrence rate in the ornidazole study. Furthermore, clinical recurrence was observed in 8% of the ornidazole-treated patients 1 year after surgery, similar to the 8% clinical recurrence rate in the patients receiving combination treatment in the current study. Of the patients receiving ornidazole for 12 months, 12 of 38 (32%) withdrew from the trial because of side effects versus 8 of 40 (20%) patients on metronidazole and AZA, suggesting that the latter treatment is at least as well tolerated. The central question we addressed is whether the addition of a thiopurine immunosuppressive agent, established for the treatment of active CD, would lead to a stronger reduction of recurrence than nitro-imidazole antibiotics alone. The effect of 6-MP as monotherapy was already studied in a North American–European prospective, double-blind, controlled trial.6Hanauer S.B. Korelitz B.I. Rutgeerts P. et al.Postoperative 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 (418) Google Scholar Patients were randomized to treatment with 50 mg 6-MP per day, 3 g mesalamine per day, or placebo. Treatment and follow-up lasted 2 years. Intent-to-treat analysis showed endoscopic relapse of grade ≥i2 in 43% and i3+i4 in 16% of the patients on 6-MP, compared with 64% and 42%, respectively, on placebo (P = .03 and .13) after 2 years. Despite these favorable results, as many as 50% of the 6-MP treated patients presented with clinical relapse by year 2. The data of this study are hardly comparable with other studies because of the high dropout rate (56%). It has been suggested that the results could have improved if the investigators had used higher doses of 6-MP, as recommended in clinical practice (1–1.5 mg/kg per day).21Sandborn W.J. Azathioprine: state of the art in inflammatory bowel disease.Scand J Gastroenterol Suppl. 1998; 225: 92-99Crossref PubMed Scopus (122) Google Scholar Given the fact that many patients in earlier recurrence trials may have received unnecessary treatment because of their low propensity toward recurrence, we decided only to include patients with an elevated risk based on literature data. Smoking as a risk factor has undoubtedly been studied most extensively, but other observational studies also suggest “perforating behavior” of the disease, >1 resection, young age, and steroid use at the time of surgery (a surrogate marker of more aggressive disease) as additional risk factors to be taken into account.13Greenstein A.J. Lachman P. Sachar D.B. et al.Perforating and non-perforating indications for repeated operations in Crohn's disease: evidence for two clinical forms.Gut. 1988; 29: 588-592Crossref PubMed Scopus (366) Google Scholar, 14Sutherland L.R. Ramcharan S. Bryant H. et al.Effect of cigarette smoking on recurrence of Crohn's disease.Gastroenterology. 1990; 98: 1123-1128Abstract Full Text PDF PubMed Scopus (336) Google Scholar, 15Sachar D.B. Wolfson D.M. Greenstein A.J. et al.Risk factors for postoperative recurrence of Crohn's disease.Gastroenterology. 1983; 85: 917-921PubMed Scopus (126) Google Scholar In the study by Hanauer et al,6Hanauer S.B. Korelitz B.I. Rutgeerts P. et al.Postoperative 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 (418) Google Scholar perforating disease type was a predictor of clinical recurrence. The benefit of 6-MP was also more pronounced in patients with perforating disease.6Hanauer S.B. Korelitz B.I. Rutgeerts P. et al.Postoperative 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 (418) Google Scholar In the current study, we were unable to identify any particular characteristic that created a higher risk than other factors that were studied. The presence of a higher number of risk factors was not associated with a higher relapse risk. The effects of smoking were not different in both groups and smokers did not have a worse disease course. Despite this “high–risk” population, the prevalence of clinical recurrence in this trial was rather low (8.5% in the AZA and 18% in the placebo group). In the European ECCDS-IV study, where 324 patients with Crohn's resections were randomized to placebo or mesalamine (Pentasa 4 g/d), the intent-to-treat analysis demonstrated that the cumulative clinical relapse rates after 18 months amounted to 24.5% ± 3.6% in the mesalamine group and 31.4% ± 3.7% in the placebo group (P = NS).22Lochs H. Mayer M. Fleig W.E. et al.Prophylaxis of postoperative relapse in Crohn's disease with mesalazine (Pentasa): European Cooperative Crohn's Disease Study VI.Gastroenterology. 2000; 118: 264-273Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar The low numbers in our trial could be attributed to the fact that all patients received 3 months of antibiotics. Furthermore, the addition of AZA to 3 months of metronidazole was more often protective against the development of new mucosal lesions. In fact, the likelihood of having a “normal mucosa” in the neoterminal ileum after 1 year of treatment was 21.9% for AZA versus 3.4% for placebo. The therapeutic regimen we used in this trial was overall well tolerated. In the first 12 weeks, only 1 patient withdrew because of subjective intolerance of the antibiotic, although 2 other patients were discontinued because of hepatotoxicity and arthralgia, both probably drug related. In the rest of the 12 months on treatment, patients on AZA seemed to tolerate their regimen quite well (only 3 discontinuations). Indeed, the majority of withdrawals were observed in the placebo group (9 vs 3 between weeks 12 and 52). What is the relevance of our findings for daily clinical practice? Given the tolerability of the regimen we studied and especially the complete resolution of all typical imidazole side effects in the weeks after the 3-month induction course, it may be recommendable to offer this treatment to all patients with an elevated risk for developing recurrence. It remains to be studied whether AZA alone (without metronidazole induction and in optimal doses) is equally beneficial. Our study did not investigate the effects of metronidazole alone in the prevention of postoperative recurrence of CD, but the benefits of this agent were demonstrated in earlier trials. The regimen we propose seems to be more potent than mesalamine therapy, often proposed as the standard of care in postoperative recurrence. However, mesalamine is rather expensive and patients need to swallow many tablets and this leads to limited compliance. Based on a meta-analysis including studies without placebo group, the rate of endoscopic recurrence with mesalamine therapy is reduced by only 18% (number needed to treat, 5.5).23Camma C. Viscido A. Lattella G. et al.Mesalamine in the prevention of clinical and endoscopic postoperative recurrence of Crohn's disease: a meta-analysis.Dig Liver Dis. 2002; 34: A86Abstract Full Text PDF PubMed Google Scholar The ECCO consensus statements even state in the mesalamine section that “no treatment” may be an option in certain patients.5Caprilli R. Gassull M.A. Escher J.C. et al.European evidence based consensus on the diagnosis and management of Crohn's disease: special situations.Gut. 2006; 55: i36-i58Crossref PubMed Scopus (406) Google Scholar Ideally, all patients with CD who have undergone an ileocecal resection should be stratified according to their risk profile. More work that also includes genetic and serologic markers is needed here. Low-risk patients can be left untreated but should undergo an ileocolonoscopy 6–12 months later to ascertain that the inflammation is not recurring aggressively. If so, immunomodulatory treatment is indicated. High-risk patients should always receive postoperative treatment with an immunomodulator. The addition of a 3-month course of metronidazole may add to the benefit. Further prospective trials to establish the validity of this approach are ongoing.