What therapy is optimal for preventing postoperative recurrence of Crohn’s disease?

Although there is a downward trend of patients with Crohn’s disease undergoing surgical management, surgery remains an important treatment option for Crohn’s disease. In fact, no guidelines or specific evidence base exists that directs the optimal timing of surgery for Crohn’s disease. It is the experience of the gastroenterologist that guides him or her on the timing to recommend surgery for patients with short segments of disease likely but not definitively fibrostenotic based on imaging or for the inflammatory or bleeding segment that has been unresponsive to two different biologic agents. Is it time for a third biologic, or will that delay the inevitable and place the patient at increased risk? In this era of multiple biologic therapies, well-timed surgeries continue to play important roles in the management of Crohn’s disease. However, it is critical to postoperatively intervene such that surgery is less likely to become a recurrent necessity.

The acceptance that optimal treatment includes mucosal healing as well as symptom control has led to routine endoscopic surveillance in persons for whom the anastomotic site is easily accessible via the endoscope. It is standard care that patients with a distal ileal, ileocecal, or even segmental colonic resection undergo colonoscopy within one year of surgery.1 Results from the POCER trial showed that undergoing endoscopy at six months, as well as guiding advancing care as needed, led to statistically better outcomes at 18 months than in patients whose gastroenterologist hypothesized as to the best postoperative preventive therapeutic approach.2 However, as seen in the POCER trial, when active disease was found at six months and patients were stepped up from metronidazole to a thiopurine or from a thiopurine to adalimumab or from adalimumab to combination therapy, active disease was still evident at 18 months in 49 and 65 percent of study patients, respectively.2 Statistically better outcomes were observed with colonoscopy performed at six months, but these are still disappointing outcomes if these are our best therapies. Hence, gastroenterologists are still making hypotheses as to what the best options for treatment are in a given patient, even when using endoscopy to provide some guidance on the possible need for more therapy.

Rutgeerts et al conducted two trials of nitroimidazole and showed that metronidazole taken for three months or ornidazole taken for 12 months could significantly reduce clinical recurrence and, in the ornidazole, study, endoscopic recurrence.1 For patients whose first resections are to treat fibrostenotic disease, I administer metronidazole 1 g/day, and I ask that these patients continue it as long as they can tolerate it. Although no study has proven that using nitroimidazole longer than 12 months is beneficial, if metronidazole is altering gut flora in a positive, preventive way, it makes sense that the benefits of the drug will dissipate once it is stopped.

The absence of evidence with regard to these therapies in the postoperative setting should not deter their use when either seems to be a valid option for patients with complex disease.

I have been surprised as to the sizeable cohort who tolerate metronidazole well — sometimes without problems for several years! For my patients who cannot tolerate metronidazole, I will prescribe a trial of 500 mg/day. If they are intolerant of any dose of metronidazole, I will use a thiopurine as preventive therapy. For patients with complicated disease — at least two resections — or penetrating disease (known preoperatively or discovered intraoperatively), I prescribe anti–tumor necrosis factor (TNF) therapy taken postoperatively.

It is worth noting that the PREVENT trial did not meet its primary end point of reducing clinical recurrence at one year, but the reduction observed in endoscopic recurrence at one year is enough evidence for me that infliximab may reduce the likelihood of disease recurrence.3 One randomized controlled study and several cohort studies evaluating adalimumab in the postoperative setting suggest that it is effective, and I use it in patients who prefer subcutaneous therapy. Some patients who have started on an anti-TNF for a short period preoperatively have been considered to have failed before surgery was deemed necessary. This should not deter the postoperative use of infliximab, because it may have simply been started too late in the disease course. However, true failures of anti-TNF have indeed occurred preoperatively, so the gastroenterologist must hypothesize as to the optimal postoperative preventive agent. Vedolizumab and ustekinumab are options now available. The absence of evidence with regard to these therapies in the postoperative setting should not deter their use when either seems to be a valid option for patients with complex disease.

If you have practiced long enough in the prebiologic era, you have a cadre of patients who had resections and spent many years not taking postoperative therapy who are in clinical remission. Unfortunately, no predictive biomarkers yet exist nor do we yet understand the specific clinical disease pattern likely to have a very long lag time between surgery and disease recurrence. In this era of biologics, it is likely that patients desiring surgery have more complex disease and oftentimes are presenting to us later in their disease course. Hence, the vast majority — if not all — of our patients will require postoperative preventive medical therapy. This scenario should not be confused with patients who undergo resection of a segment with a stricture, fistula, or both and have known active inflammatory disease in other segments still in situ. That patient’s postoperative therapy is active therapy — not preventive — and often requires creative strategies, especially if the patient presents for surgery after his or her Crohn’s disease failed to respond to one or more biologics.

Gastroenterologists have a small evidence base to guide postoperative therapy for Crohn’s disease. In general, gastroenterologists must adopt an approach based on good clinical judgment and be adaptable to the individual nuances of every case.

Key take away points

  • All patients who undergo intestinal resection for Crohn’s disease should receive postoperative disease preventive therapy.
  • Nitroimidazole has been shown to reduce clinical recurrence rates and treatment duration of one year also reduces one-year endoscopic recurrence rates. Metronidazole can be used in cases of relatively uncomplicated disease in patients who have undergone their first resection and tolerate these drugs.
  • Anti-TNF therapy should be used as postoperative preventive therapy, especially in patients undergoing repeated resection or in those who have penetrating disease.
  • No one-size-fits-all approach exists for postoperative preventive therapy in patients with Crohn’s disease. Thiopurines, vedolizumab, and ustekinumab may also be considered depending on an individual patient’s preoperative and postoperative clinical circumstances and history with other medications.

Dr. Bernstein is on the advisory boards of Abbvie Canada, Janssen Canada, Pfizer Canada, Shire Canada, Ferring Canada, Takeda Canada, Napo Pharmaceuticals and 4D Pharma. Dr. Bernstein has been hired as a consultant for Mylan and is on the speaker’s bureau for Abbvie Canada, Ferring Canada, Shire Canada and Janssen Canada. 

1. Rutgeerts, 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- 861.
2. De Cruz, P., Kamm, M.A., Hamilton, A.L. et al, Crohn’s disease management after intestinal resection: a randomised trial. Lancet. 2015;385:1406-1417.
3. Regueiro, M., Feagan, B.G., Zou, B. et al, Infliximab reduces endoscopic, but not clinical, recurrence of Crohn’s disease after ileocolonic resection. Gastroenterology. 2016;150:1568-1578.

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