Don’t Delay: Start Anti-TNF Therapy Shortly after Surgery

Most Crohn’s disease patients who undergo an intestinal resection will have postoperative recurrence. The most effective way to prevent recurrence is to initiate an anti-TNF within four weeks of surgery. It has been my practice that patients at high risk for postoperative Crohn’s disease recurrence initiate anti-TNF shortly after they are discharged from the hospital. It should be noted that in the tertiary IBD center in which I practice, I tend to see patients at higher risk, e.g. those with penetrating disease or who have had prior surgical resections. We know that more than two thirds of these patients will have postoperative Crohn’s disease recurrence and nearly 50 percent require another surgery. Postoperatively, I use the standard induction and maintenance schedule for the anti-TNF. Given that most of the data on postoperative Crohn’s disease has been with infliximab and adalimumab, these are the two medications I use most. Prior to initiating (or resuming) postoperative anti-TNF therapy, I wait for the surgeon to ‘clear’ the patient of any infection or wound complications. This outpatient clearance visit typically occurs approximately two weeks after the surgery.

If a patient had been on an anti-TNF prior to the surgery, I will usually resume the same anti-TNF after the surgery. In these patients, I do not give a re-induction course unless they had not received the anti-TNF for more than three months prior to surgery. The rational for resuming the same anti-TNF after surgery is based on the fact that I’m not convinced that these patients are primary failures of the anti-TNF, which would make me consider switching to another class of medication; rather, their disease course progressed to a complication that only surgery would fix. In the majority of patients, I treat with an anti-TNF, I will use a concomitant immunomodulator — i.e. azathioprine — presuming they are not intolerant. I do this primarily for prevention of immunogenicity. One year after surgery, if there is no disease recurrence, I will decrease and often stop the immunomodulator. With the advent of therapeutic drug monitoring, I have a number of postoperative anti-TNF patients on monotherapy without an immunomodulator. I will check levels of the anti-TNF and adjust accordingly. There is no good data to support this practice in the postoperative setting, but I have begun doing this on certain patients.

As I noted earlier, my perspective on the use of anti-TNF after surgery is biased by the fact that I practice in a tertiary referral center. My patients tend to be at higher risk for postoperative Crohn’s disease recurrence. This is evident from my initial publication of postoperative infliximab that included 24 patients from my center who mainly had penetrating disease and prior surgery.1 To this point, and to be fair and balanced in considering postoperative Crohn’s disease management, I think it is important to take into account risk factors that predict recurrence.

Factors associated with the highest risk for postoperative recurrence include smoking, penetrating or perforating disease and prior Crohn’s disease surgery. Why not consider a medication other than an anti-TNF for postoperative Crohn’s disease prevention? The available data suggest that probiotics, corticosteroids and 5-aminosalicylates are of little benefit in preventing post-operative recurrence. Antibiotics, specifically metronidazole and ornidazole, have been shown to be of some benefit in preventing postoperative recurrence, but most cannot tolerate these long-term. The benefit is lost when these medications are discontinued. Azathioprine and 6-Mercaptopurine are efficacious in maintaining remission in patients with moderate-to-severe Crohn’s disease. However, when used in the postoperative setting, approximately one-half of patients have recurrence and many patients are intolerant. Anti-TNFs have the best efficacy in preventing postoperative Crohn’s disease with several studies and meta-analyses favoring this approach.2 The recent AGA technical review and guidelines also support the use of anti-TNFs postoperatively, but the benefit must be weighed against risk and the patient’s personal preferences must be taken into account.3,4


Postoperative anti-TNFs are the most effective strategy for prevention of Crohn’s disease


I suggest the decision on treatment be based on the patient’s risk for postoperative recurrence. I consider patients at low-risk for recurrence as those who have had long-standing Crohn’s disease (more than 10 years), and whose indication for surgery is a short (less than 10 cm) fibro-stenotic stricture. Given the slow progression of disease in a limited segment of bowel, these patients are less likely to have aggressive postoperative recurrence, and I do not routinely place these patients on postoperative medications. I perform an ileocolonoscopy six months postoperatively and, if there is no endoscopic recurrence (i.e. i0 or i1), I do not start medication and repeat a colonoscopy one-to-three years later. If there is evidence of early endoscopic recurrence (Rutgeerts’ score i>2), I start an anti-TNF agent. A fecal calprotectin > 100 mg/ml at three months after surgery may be a reasonable method in which to assess for early postoperative recurrence.5 At present, this is not routinely part of my practice.

I consider patients at moderate risk for postoperative recurrence as those naïve to immunomodulators or biologics, with a relatively short duration of disease (less than 10 years) prior to surgery, who undergo resection for a long segment (greater than 10 cm) of small bowel inflammation. I perform an ileocolonoscopy six months postoperatively and, if there is evidence of endoscopic recurrence, I add an anti-TNF agent. After finding a high rate of recurrence in these patients, I am beginning to shift my practice to initiating anti-TNFs in this moderate-risk group as well.

For patients at high risk for recurrence, I initiate an anti-TNF agent within two-to-four weeks of surgery and, if i0 or i1 recurrence, I will continue. If there is endoscopic recurrence (≥i2) at six months, I check anti-TNF levels and optimize accordingly.

In sum, most of my patients who undergo an intestinal resection for Crohn’s disease are at high risk for recurrence and will receive an anti-TNF within four weeks of surgery. I still think that postoperative anti-TNFs are the most effective strategy for prevention of Crohn’s disease. Whether other biologic classes have the same efficacy remains to be seen.


Brian Bressler, MD, MS, FRCPC, provides a different view of this debate.


Dr. Regueiro has retainer agreements with AbbVie, Takeda, Amgen, Janssen, Pfizer and UCB.

References
1. Regueiro, M., Schraut, W., Baidoo, L. et al, Infliximab prevents Crohn’s disease recurrence after ileal resection. Gastroenterology. 2009;136:441-50.e1; quiz 716.
2. Singh, S., Garg, S.K., Pardi, D.S., Wang, Z., Murad, M.H., Loftus, E.V., Jr. Comparative efficacy of pharmacologic interventions in preventing relapse of Crohn’s disease after surgery: a systematic review and network meta-analysis. Gastroenterology. 2015;148:64-76.e2; quiz e14.
3. Regueiro, M., Velayos, F., Greer, J.B. et al, American Gastroenterological Association Technical Review in the Management of Crohn’s Disease After Surgical Resection. Gastroenterology. 2017;152:277-295.
4. Nguyen, G.C., Loftus, E.V. Jr, Hirano, I., Falck-Ytter, Y., Singh, S., Sultan, S. AGA Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on the Management of Crohn’s Disease After Surgical Resection. Gastroenterology. 2017;152:271-275.
5. 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(5):938-947.Figure. Postoperative Crohn’s disease algorithm.

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