Statistics from Altmetric.com
About half of patients with ileal Crohn's disease have a clinical relapse within five years of a first resection; half will need a second operation by 10 years. The proposal that recurrence can be prevented is clearly untenable as there are no data whatsoever to indicate that any currently available measure can reduce to zero the postoperative relapse rate. However, I will take a less literal interpretation of the motion and review the evidence against the suggestion that the postoperative rate of symptomatic, as opposed to endoscopic, recurrence of ileal Crohn's1 can be reduced by therapeutic interventions.
There is strong retrospective data that stopping smoking halves the symptomatic recurrence rate up to 10 years after surgery.2,3 Furthermore, although not specifically relating to the postoperative course, a recent prospective trial has confirmed that stopping smoking improves the natural history of Crohn's.4
A meta-analysis5 covering four trials6–9 suggested that long term aminosalicylates slightly reduced the risk of symptomatic relapse after surgery (risk reduction 13%, making the number of patients needing to be treated (NNT) to prevent one recurrence 8). However, a more recent placebo controlled European study10 showed no advantage for Pentasa (4 g/day) except in patients with localised ileal disease in whom the clinical relapse rate at 18 months was 22% on Pentasa and 40% on placebo. Furthermore, reassessment of the data analysed in Cammá's meta-analysis5 after inclusion of the European results,10 and exclusion of Caprilli's trial,6 which was not blinded or placebo controlled, decreased the risk reduction to only 8% (NNT 12%).11 This NNT is probably too high to support use of aminosalicylates for postoperative prophylaxis except in the minority of patients with exclusively ileal disease.
Oral metronidazole (400 mg three times daily for three months only) delayed symptomatic as well as endoscopic recurrence one year after surgery but the clinical advantage over placebo was lost beyond that period.12 Furthermore, the side effects of metronidazole make it an unattractive agent for widespread or long term use. Preliminary data suggest a beneficial effect for a better tolerated nitroimidazole, ornidazole (1 g/day for a year), on endoscopic recurrence but information on clinical relapse is not yet available.13
Controlled ileal release budesonide (6 mg/day) halved the postoperative endoscopic recurrence rate at one year for inflammatory but not fibrostenotic Crohn's, but clinical relapses were as common as in placebo treated patients.14
In a preliminary study, low dose 6-mercaptopurine (50 mg/day) was better than placebo and aminosalicylates in preventing symptomatic, endoscopic, and radiological recurrence after surgery.15 However, the placebo relapse rate was 70% at two years, and a recurrence rate of 53% for patients given 6-mercaptopurine scarcely represents a ringing endorsement of this treatment, particularly in view of its potential side effects. Thiopurines need further evaluation, at full dose, for postoperative prophylaxis.
Interleukin 10 was no better than placebo in preventing postoperative endoscopic or clinical relapse at one year in a recent study16 but trials of other biological therapies, including infliximab, antibiotics and probiotics, a liquid formula diet, and other immunomodulatory approaches such as fish oil17 would be of interest. Such studies should be stratified for operation type and phenotypic and even genotypic risk factors, and include longer follow up than hitherto.18
Apart from stopping smoking, no therapeutic measure can be unreservedly recommended for routine prophylaxis after ileal resection for Crohn's. Although colonoscopy at, say, six months after surgery might be used to select patients, according to the severity of endoscopic recurrence,1 for specific therapies, the validity of this approach needs confirmation in further clinical trials.
Having been instructed by the editor to be deliberately negative about existing data, I shall end by stating what I actually do. Smokers are urged to stop. A discussion with the immediately postoperative patient about the available pharmacological evidence is often concluded by patients with uncomplicated disease indicating their enthusiasm to be off all tablets after months or years of such treatment. Patients with exclusively ileal disease are advised however to use Pentasa (4 g/day).10 Those with aggressive, perforating, or extensive disease, or a second or later resection, are advised to take (and in many instances of course continue on) a thiopurine in full dose, despite the lack of data to support this approach. Sadly, I am unable to reassure patients that any drug will substantially reduce their chances of symptomatic recurrence after ileal surgery.
Clinical recurrence of Crohn's disease after surgery is the consequence of early and evolutive recurrent lesions in the bowel.
True prophylactic therapy prevents the development of these early “new” lesions.
The most promising prophylactic therapies are early postoperative antibiotic therapy and immunosuppression.
The optimal postoperative strategy involves endoscopic or radiologic studies of the bowel to identify those patients that have developed early recurrent lesions.
Recurrence of Crohn's disease after ileal resection cannot yet be prevented.
Stopping smoking may decrease recurrence rate but prospective studies are lacking.
Aminosalicylates reduce the risk of clinical recurrence after resection of exclusively small bowel disease, but their prophylactic efficacy in most patients with Crohn's is marginal.
Nitroimidazole antibiotics, budesonide, and 6-mercaptopurine have been shown to reduce postoperative endoscopic recurrence rates, but none has yet been shown to have sufficient effect on the clinical relapse rate to be recommended routinely for long term prophylaxis.
There is a need for further trials of immunomodulatory agents, antibiotics, and probiotics for postoperative prophylaxis of Crohn's disease.