Postoperative Crohn's Disease Maintenance
Other studies of note include Papay et al.'s retrospective analysis of 326 CD patients undergoing intestinal resection who were assessed for exposure to thiopurines. One hundred and sixty-one patients were identified that were treated with MP/AZA. No dosing information was reported in the study. Case notes were analysed for predictors of surgical recurrence and a smoking questionnaire was distributed. There was no assessment made of endoscopic or clinical recurrence rates as the authors felt that surgical re-operation remains the hardest endpoint for Crohn's disease recurrence. Surgical re-operation rate was significantly reduced at 26.8% in those receiving a thiopurine for over 36 months as compared to 42.4%, 55% and 53.9% in those receiving thiopurines for 3–35 months, <3 months those and without post-operative thiopurines respectively (P = 0.004). The data collected span two decades and thus one can expect the type of resection, surgical experience, thiopurine dosage and use of anti-TNF agents in addition to recall bias of smoking history all to limit meaningful conclusions.
A randomised trial by Reinisch et al. assessed medical intervention in a subgroup of post-operative patients with proven endoscopic recurrence, and thus is not considered with the above randomised trials. They describe a 12 month double-blinded, double-dummy trial in which 78 Crohn's disease patients with moderate–severe endoscopic recurrence (Rutgeerts' score >i2a) post-intestinal resection were randomised to mesalazine 4 g/day vs. AZA 2–2.5 mg/kg/day. The median time from intestinal resection to enrolment into the study was 13.5 months (range 6.3–26.1) for AZA and 12.5 months (range 5.8–19.8) for mesalazine, meaning that some patients would be 3.5 years post-surgery at study completion. There was no difference in treatment failure [defined as clinical recurrence CDAI > 200 or adverse drug reactions (ADR)] between the groups 22% (n = 9) vs. 10% (n = 4). However, all of the AZA treatment failures were secondary to drug reactions (including six pancreatitis) while all of the mesalazine failures were secondary to clinical recurrence. Interestingly, there was a significantly greater proportion of patients with reduction in Rutgeerts' score ≥1 point (63% vs. 34%) and a significant median change in Rutgeerts' score of − 1.5 vs. 0 for AZA vs. mesalazine intervention.
A prospective observational study by Domènech et al. consecutively recruited 56 patients treated with AZA 2–2.5 mg/kg after undergoing curative intestinal resection and anastomosis. Cumulative probability of endoscopic recurrence was 44%, 53%, 69% and 82%, at 1, 2, 3 and 5 years, respectively (Rutgeerts' score i > 1). Two patients experienced early clinical recurrence at 3 months and one patient was lost to follow-up. Of the postulated factors affecting recurrence (age, disease location, disease behaviour, smoking, time from diagnosis and type of resection) none were predictive of clinical or endoscopic relapse. Given the lack of a control arm however, it is impossible to discern the natural history of these patients' disease had they been exposed to conventional/placebo treatment.
A recent controlled trial, also from Domènech et al. assesses the benefit of randomising 50 patients to 3 months metronidazole or placebo added to AZA 2–2.5 mg/kg in the reduction in endoscopic recurrence (i2) at 6 months after ileocolic or ileorectal anastomosis for active disease. This reveals no benefit for 3 months metronidazole treatment (28% vs. 44%) with comparable rates of recurrence with other controlled data.
Non-RCT Studies of Note
Other studies of note include Papay et al.'s retrospective analysis of 326 CD patients undergoing intestinal resection who were assessed for exposure to thiopurines. One hundred and sixty-one patients were identified that were treated with MP/AZA. No dosing information was reported in the study. Case notes were analysed for predictors of surgical recurrence and a smoking questionnaire was distributed. There was no assessment made of endoscopic or clinical recurrence rates as the authors felt that surgical re-operation remains the hardest endpoint for Crohn's disease recurrence. Surgical re-operation rate was significantly reduced at 26.8% in those receiving a thiopurine for over 36 months as compared to 42.4%, 55% and 53.9% in those receiving thiopurines for 3–35 months, <3 months those and without post-operative thiopurines respectively (P = 0.004). The data collected span two decades and thus one can expect the type of resection, surgical experience, thiopurine dosage and use of anti-TNF agents in addition to recall bias of smoking history all to limit meaningful conclusions.
A randomised trial by Reinisch et al. assessed medical intervention in a subgroup of post-operative patients with proven endoscopic recurrence, and thus is not considered with the above randomised trials. They describe a 12 month double-blinded, double-dummy trial in which 78 Crohn's disease patients with moderate–severe endoscopic recurrence (Rutgeerts' score >i2a) post-intestinal resection were randomised to mesalazine 4 g/day vs. AZA 2–2.5 mg/kg/day. The median time from intestinal resection to enrolment into the study was 13.5 months (range 6.3–26.1) for AZA and 12.5 months (range 5.8–19.8) for mesalazine, meaning that some patients would be 3.5 years post-surgery at study completion. There was no difference in treatment failure [defined as clinical recurrence CDAI > 200 or adverse drug reactions (ADR)] between the groups 22% (n = 9) vs. 10% (n = 4). However, all of the AZA treatment failures were secondary to drug reactions (including six pancreatitis) while all of the mesalazine failures were secondary to clinical recurrence. Interestingly, there was a significantly greater proportion of patients with reduction in Rutgeerts' score ≥1 point (63% vs. 34%) and a significant median change in Rutgeerts' score of − 1.5 vs. 0 for AZA vs. mesalazine intervention.
A prospective observational study by Domènech et al. consecutively recruited 56 patients treated with AZA 2–2.5 mg/kg after undergoing curative intestinal resection and anastomosis. Cumulative probability of endoscopic recurrence was 44%, 53%, 69% and 82%, at 1, 2, 3 and 5 years, respectively (Rutgeerts' score i > 1). Two patients experienced early clinical recurrence at 3 months and one patient was lost to follow-up. Of the postulated factors affecting recurrence (age, disease location, disease behaviour, smoking, time from diagnosis and type of resection) none were predictive of clinical or endoscopic relapse. Given the lack of a control arm however, it is impossible to discern the natural history of these patients' disease had they been exposed to conventional/placebo treatment.
A recent controlled trial, also from Domènech et al. assesses the benefit of randomising 50 patients to 3 months metronidazole or placebo added to AZA 2–2.5 mg/kg in the reduction in endoscopic recurrence (i2) at 6 months after ileocolic or ileorectal anastomosis for active disease. This reveals no benefit for 3 months metronidazole treatment (28% vs. 44%) with comparable rates of recurrence with other controlled data.
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