Hold the Anti-TNF Therapy After Surgery — Why the Rush?

A surgical resection for a patient with Crohn’s disease is a major milestone in the natural history of their condition. It is without a doubt that patients who require surgery will make avoiding further surgery a priority and accordingly many patients will consider any possible preventive measure. I explain to patients that surgery is usually required for one of two reasons. The first is that our best attempts to control the immune dysfunction of Crohn’s disease have not been effective enough to deal with the persistent damage to their bowel, making surgery a necessity. The second possibility is that there has been such an excessive amount of damage to the bowel over time that the involved segment must be removed as medical therapy cannot reverse that damage. We have traditionally put patients into a high-or low-recurrence risk category in part based on trying to understand whether their requirement for surgery was reason one or two. Patients with ongoing immune dysfunction would be at a high risk of recurrence, whereas those with no ongoing immune dysfunction would be at low risk.

AGA has recently presented reasonable patient characteristics that appropriately select a patient who is at high risk of recurrence: young (less than 30 years old), smoker and two or more prior surgeries for penetrating disease, irrespective of perianal disease.1 Such high-risk patients likely have ongoing immune dysfunction, which will quickly cause further damage to their bowel, leading to symptom recurrence and ultimately another resection if this process is not effectively interrupted. Therefore, these patients require the most effective form of therapy we can offer. Anti-TNF therapy has been our gold standard to date when effective control of Crohn’s disease is needed. As a result, in high-risk patients who have so much to lose if not treated appropriately, we consider starting an anti-TNF agent immediately in the postoperative setting. However, following surgery, we may not always be able to identify those patients with ongoing immune dysfunction and the resulting potential for further intestinal damage. It is entirely possible that some patients who are deemed high risk no longer have this ongoing derangement of their immune system and, therefore, don’t need any attempt to control it. In such patients, starting an anti-TNF agent postoperatively would not provide a benefit that would outweigh the risk and cost of this treatment.

Knowing the natural history of postoperative recurrence has helped me to develop an approach, in my practice, which deals with this complicated situation by selecting those most likely to benefit from anti-TNF therapy. Approximately one quarter of patients who have their first resection will require another one within five years.1 An early manifestation of progression of recurrent Crohn’s disease is the appearance of endoscopic evidence of inflammation in the neoterminal ileum (defined using the Rutgeerts classification2), which can occur in up to 90 percent of patients one year after their resection.1 When a patient has severe endoscopic recurrence, one can be confident that the disease process will progress, leading eventually to both symptomatic recurrence and potential further surgery. Accordingly, the clinical question that requires answering is ‘can we wait for development of severe endoscopic recurrence and thus potentially avoid ‘over treating’ patients who would not have required an anti-TNF agent and thereby spare them the potential toxicity and cost associated with this medication?’ Furthermore, ‘can we avoid compromising the treatment of such patients and keep their risk of both symptomatic and surgical recurrence at the same rate, as if they were started on their medication immediately after their surgery?’

In [certain] patients, starting an anti-TNF agent postoperatively would not provide a benefit that would outweigh the risk and cost of this treatment.

These questions have not yet been addressed; however, two studies give me confidence that this ‘wait-and-see’ approach is appropriate for most patients, most of the time. The Postoperative Crohn’s Endoscopic Recurrence (POCER) study did specifically evaluate the strategy to tailor postoperative therapy based on early endoscopy evidence of recurrence compared to empiric treatment which included in high-risk patients azathioprine or adalimumab (if intolerant to azathioprine) to standard of care monitoring.3 At 18 months, those patients who had a colonoscopy early to assess recurrence were less likely to have endoscopic recurrence compared to those who were offered treatment based on their risk factors but did not have early endoscopic assessment. This study also provided valuable insight into the role of fecal calprotectin in monitoring postoperative recurrence.4 The likelihood of significant endoscopic recurrence if the fecal calprotectin was less than 100 μg/g was low. Therefore, in my patients whom I am particularly worried about recurrence, I consider measuring fecal calprotectin early (three months postoperative), and every three months after their first colonoscopy, which I perform six-to-nine months after resection. The second study compared early azathioprine treatment in the postoperative setting with the initiation of azathioprine only when severe endoscopic recurrence was found. This was a small study (63 patients in total), but the rates of both clinical and endoscopic recurrence two years after surgery did not differ and approximately 50 percent of patients in the endoscopic assessment group were able to avoid treatment.5 However, due to the small sample size, the limited power of this study does not make it possible to be certain that there is no meaningful difference between the two groups. In contrast, a third study (the PREVENT trial), which treated all high-risk patients with infliximab immediately after their resection, did not reach its primary endpoint (clinical recurrence), but did demonstrate prevention of endoscopic recurrence.6

The obvious piece of the puzzle we are missing is a randomized controlled trial in high-risk Crohn’s disease patients comparing anti-TNF therapy immediately after surgery to initiation of therapy after endoscopic recurrence. The difference in both efficacy and safety would be key endpoints to assess. My suspicion is that this trial is not likely to happen anytime soon, so our decisions will remain somewhat uncertain. However, I do feel confident that early endoscopic assessment followed by frequent fecal calprotectin in postoperative Crohn’s disease patients is the optimal way to decide who requires anti-TNF therapy and equally important who does not require treatment.

Miguel Regueiro, MD, provides a different view on when to start anti-TNF therapy.

Dr. Bressler has advised for and received research support from Takeda, Janssen and AbbVie.

1. Regueiro, M., Velayos, F., Greer, J.B. et al, American Gastroenterological Association technical review on the management of Crohn’s disease after surgical resection. Gastroenterology. 2017;152:277-295.
2. Rutgeerts, P., Geboes, K., Vantrappen, G. et al, Predicability of the postoperative course of Crohn’s disease. Gastroenterology. 1990;99:956-963.
3. De Cruz, P., Kamm, M.A., Hamilton, A.L. et al, Crohn’s disease management after intestinal resection: a randomized trial. Lancet. 2015;385:1406-1417.
4. Wright, E.K., Kamm, M.A., De Cruz, P. et al, Measurement of fecal calprotectin improves monitoring and detection of recurrence of Crohn’s disease after surgery. Gastroenterology. 2015;148:938-947.
5. Ferrante, M., Papamichael, K., Duricova, D. et al,Systematic versus endoscopy-driven treatment with azathioprine to prevent postoperative ileal Crohn’s disease recurrence. J Crohns Colitis. 2015;9:617-624.
6. Regueiro, M., Feagan, B.G., Zhou, B. et al, Infliximab reduces endoscopic, but not clinical recurrence of Crohn’s disease after ileocolic resection. Gastroenterology. 2016;150:1568-1578.

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