1. In patients with surgically induced remission of CD, the AGA suggests early pharmacological prophylaxis over endoscopy-guided pharmacological treatment. Conditional recommendation, very low quality of evidence.
Comments: Patients, particularly those at lower risk of recurrence, who place a higher value on avoiding the small risks of adverse events from pharmacological prophylaxis and a lower value on the potential risk of early disease recurrence may reasonably select endoscopy-guided pharmacological treatment over prophylaxis.
It should be emphasized that there was significant uncertainty in estimating the relative effectiveness of early pharmacological prophylaxis (started within 8 weeks of surgery) over endoscopy-guided treatment, in which patients would be started on therapy only if there was evidence of endoscopic recurrence on colonoscopy performed 6 to 12 months after surgical resection. A single clinical trial of 63 postoperative patients with CD failed to show that early pharmacological prophylaxis with azathioprine compared with endoscopy-guided therapy resulted in nonsignificant reductions in clinical (relative risk [RR], 0.83; 95% confidence interval [CI], 0.46–1.50) or endoscopic recurrence (RR, 0.91; 95% CI, 0.59–1.42). Because there is clinical equipoise as to which strategy is superior, the decision of one approach over the other must be individualized and take into consideration the risk of postoperative recurrence and the patient’s values and preferences. Although there is no validated clinical score that predicts recurrence, there are clinical features such as prior bowel resection, penetrating disease, and cigarette smoking that have been associated with higher risk of recurrence. Based on these clinical risk factors, the technical review panel synthesized 2 illustrative risk groups with corresponding rates of clinical and endoscopic recurrence at 18 months in the absence of any intervention in postsurgical patients with CD (Table 4Table 4). The panel favored early pharmacological prophylaxis over endoscopy-guided management because it is likely that the majority of patients who have undergone surgical resection in clinical practice may have one or more risk factors, conferring an increased risk of disease recurrence, as was observed in published clinical studies used to derive these estimates. In those with a lower risk of recurrence, the potential risk of adverse events from medical therapy may outweigh the potential benefits. Patients who share similar characteristics as those in the lower-risk illustrative group may reasonably choose endoscopy-guided pharmacological treatment.
2. In patients with surgically induced remission of CD, the AGA suggests using anti-TNF therapy and/or thiopurines over other agents. Conditional recommendation, moderate quality of evidence.
Comments: Patients at lower risk for disease recurrence or who place a higher value on avoiding the small risk of adverse events of thiopurines and/or anti-TNF treatment and a lower value on a modestly increased risk of disease recurrence may reasonably choose nitroimidazole antibiotics (for 3–12 months).
Table 4 Illustrative Risk Groups for Recurrence of CD After Surgical Resection in the Absence of Any Intervention
|Illustrative risk groups
||Typical patient characteristics corresponding to risk category
||Illustrative risk of clinical recurrence (>18 mo after surgery)
||Illustrative risk of endoscopic recurrence (>18 mo after surgery)
||Older patient (older than 50 y)
First surgery for a short segment of fibrostenotic disease (<10 to 20 cm)
Disease duration >10 y
||Younger patient (younger than 30 y)
≥2 prior surgeries for penetrating disease, with or without perianal disease
The selection of anti–tumor necrosis factor (TNF) therapy and/or thiopurines as first-line agents for early pharmacological prophylaxis is based on moderate quality of evidence. Based on clinical trials, anti-TNF therapy compared with placebo resulted in 49% and 76% relative reductions in clinical and endoscopic recurrence at 18 months, respectively. Similarly, postoperative prophylaxis with thiopurines resulted in 65% and 60% relative decreases in clinical and endoscopic recurrence, respectively. There was also moderate-quality evidence showing that antibiotics reduced the risk of endoscopic and clinical recurrence by approximately 50%.
Because the cumulative dosing of nitroimidazoles may lead to peripheral neuropathy, their use is usually limited to 3 to 12 months, and disease usually recurs within a couple of years after antibiotics are stopped. Moreover, antibiotics are probably inferior to anti-TNF agents by a large extent (moderate-quality evidence) and may be modestly inferior to thiopurines (low-quality evidence) in reducing disease recurrence. For these reasons, the panel designated antibiotics as second-line alternatives for patients who are concerned about the adverse effects of anti-TNF and thiopurine therapy and who have lower risk of recurrence. If the decision is to treat with antibiotics in the postoperative setting, nitroimidazole antibiotics (eg, metronidazole) should be used because they are the only class that has been adequately studied. There is low-quality evidence favoring anti-TNF agents over thiopurines for reducing disease recurrence, with possibly a large effect size. The choice between anti-TNF and thiopurine monotherapy for preventing disease recurrence should include assessment of the patient’s risk of disease recurrence and risk-benefit considerations in the context of patients’ values and preferences. Although no direct evidence was available on the use of the combination of anti-TNF agents and thiopurines for reducing disease recurrence in the postoperative setting, indirect evidence from luminal CD supports its use as a potentially efficacious strategy in patients at highest risk.5x 5Terdiman, J.P., Gruss, C.B., Heidelbaugh, J.J...., and AGA Institute Clinical Practice and Quality Management Committee. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti–TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn's disease. Gastroenterology. 2013; 145: 1459–1463
Abstract | Full Text | Full Text PDF | PubMed | Scopus (49) See all References 5
3. In patients with surgically induced remission of CD, the AGA suggests against using mesalamine (or other 5-aminosalicylates), budesonide, or probiotics. Conditional recommendation, low quality of evidence and very low quality of evidence.
The guideline panel conditionally recommended against the use of mesalamine (or other 5-aminosalicylates [5-ASAs]) because of the overall low quality of evidence to support its effectiveness in reducing postoperative recurrence. Although there was low-quality evidence to suggest that it reduced clinical recurrence compared with placebo (RR, 0.59; 95% CI: 0.43–0.82), the evidence favoring its use to prevent endoscopic recurrence was even less compelling due to imprecision, inconsistency, and strongly suspected publication bias. Additionally, indirect evidence from patients with inflammatory luminal CD also supports the lack of benefit of 5-ASAs for inducing or maintaining remission.6x 6Ford, A.C., Kane, S.V., Khan, K.J. et al. Efficacy of 5-aminosalicylates in Crohn's disease: systematic review and meta-analysis. Am J Gastroenterol. 2011; 106: 617–629
Crossref | PubMed | Scopus (102)See all References , 7x 7Lim, W.C. and Hanauer, S. Aminosalicylates for induction of remission or response in Crohn's disease. Cochrane Database Syst Rev. 2010; : CD008870
PubMed See all References There was substantial uncertainty regarding the effectiveness of budesonide and probiotics in the postoperative setting due to very low quality of evidence. The main risk of using 5-ASA, budesonide, and probiotics is disease recurrence by foregoing more effective therapies.
4. In patients with surgically induced remission of CD receiving pharmacological prophylaxis, the AGA suggests postoperative endoscopic monitoring at 6 to 12 months after surgical resection over no monitoring. Conditional recommendation, moderate quality of evidence.
Moderate-quality evidence from the Postoperative Crohn’s Endoscopic Recurrence (POCER) randomized clinical trial suggested that endoscopic monitoring (with algorithmic treatment step-up in case of endoscopic recurrence) was superior to standard of care (continuing pharmacological strategy adopted in the early postoperative period) in reducing clinical (RR, 0.82; 95% CI, 0.56–1.18) and endoscopic recurrence (RR, 0.73; 95% CI, 0.56–0.95).1x 1Regueiro, 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
Abstract | Full Text | Full Text PDF | PubMedSee all References , 8x 8De 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
Abstract | Full Text | Full Text PDF | PubMed | Scopus (69) See all References In this study, 83% of subjects were categorized as high risk for recurrence and received either azathioprine or adalimumab following surgery, and all subjects received metronidazole for 3 months postoperatively. Thus, even patients who were already on postoperative prophylaxis benefited from endoscopic monitoring with colonoscopy at 6 to 12 months. However, in making this recommendation conditional, the guideline panel acknowledged that patients who are already on long-term prophylactic therapy may reasonably choose to forego the inconvenience and small risks of colonoscopy. Moreover, if pharmacological therapy is unlikely to be escalated in the presence of asymptomatic endoscopic recurrence, because of either patient preference or clinician judgement, then the risks and costs of endoscopic monitoring likely outweigh the benefits. There is insufficient clinical evidence to inform how often endoscopic monitoring should be performed following the initial postoperative colonoscopy.
5. In patients with surgically induced remission of CD not receiving pharmacological prophylaxis, the AGA recommends postoperative endoscopic monitoring at 6 to 12 months after surgical resection over no monitoring. Strong recommendation, moderate quality of evidence.
There are no clinical trials comparing endoscopic monitoring with the standard of care in patients with surgically induced remission of CD who are not on any prophylactic therapy. As previously mentioned, patients enrolled in the POCER trial received some form of early pharmacological prophylaxis; all patients received metronidazole, and the vast majority also received a thiopurine or adalimumab.8x 8De 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
Abstract | Full Text | Full Text PDF | PubMed | Scopus (69) See all References 8 However, this trial provides indirect evidence for the relative effectiveness of endoscopic monitoring (with algorithmic treatment step-up in case of endoscopic recurrence) in patients not receiving any early pharmacological prophylaxis. In fact, these data very likely underestimate the potential benefits of endoscopic monitoring in patients who are not on any pharmacological therapy. The AGA issued a strong recommendation because of the high likelihood of benefit from detection of endoscopic recurrence by colonoscopy, the risk of which is as high as 90% within 1 year of surgery in those not receiving any prophylaxis. This monitoring may prompt the initiation of medical therapy if endoscopic recurrence is detected. Although no studies on patients’ values and preferences were available to inform this recommendation, the patient representative on the panel expressed that many patients who are not on any pharmacological prophylaxis may prefer to know if there is endoscopic recurrence, because it may prompt initiation of medical therapy.
6. In patients with surgically induced remission of CD with asymptomatic endoscopic recurrence, the AGA suggests initiating or optimizing anti-TNF and/or thiopurine therapy over continued monitoring alone. Conditional recommendation, moderate quality of evidence.
Comments: Patients who place a higher value on avoiding the small risk of adverse events of thiopurines or anti-TNF treatment and a lower value on the increased risk of clinical recurrence following asymptomatic endoscopic recurrence may reasonably choose continued endoscopic monitoring.
In the POCER trial, initiation or escalation of therapy with thiopurines or azathioprine was part of the treatment strategy triggered by the detection of endoscopic recurrence at 6 months.8x 8De 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
Abstract | Full Text | Full Text PDF | PubMed | Scopus (69) See all References 8 This therapeutic approach was associated with lower clinical and endoscopic recurrence. There was sparse direct evidence to inform the comparative effectiveness of various pharmacological agents for patients with asymptomatic endoscopic recurrence in the postoperative setting. The preference for an aggressive approach with anti-TNF agents and thiopurines either as monotherapy or combination therapy is based on indirect evidence from the AGA clinical guideline on the role of anti-TNF and immunomodulators in the maintenance of remission in patients with inflammatory luminal CD.5x 5Terdiman, J.P., Gruss, C.B., Heidelbaugh, J.J...., and AGA Institute Clinical Practice and Quality Management Committee. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti–TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn's disease. Gastroenterology. 2013; 145: 1459–1463
Abstract | Full Text | Full Text PDF | PubMed | Scopus (49) See all References 5 Thiopurine monotherapy, with its slower onset of action and potentially lower efficacy, may be more appropriate for those with less severe endoscopic recurrence (ie, Rutgeerts’ score of i2). Patients who are apprehensive about the adverse effects of therapy and less concerned about the risk of clinical recurrence may choose to forego therapy and continue endoscopic monitoring. This approach may be reasonable, especially for patients with less severe endoscopic recurrence (ie, Rutgeerts’ score of i2). Patients considering continued endoscopic monitoring should also take into account the inconvenience and small risks associated with serial colonoscopy while weighing the conceivable risk of ongoing mucosal injury. For those who choose continued endoscopic monitoring, it may be valuable to have a discussion about what end points may be used to help guide a decision to initiate pharmacological therapy. Patients who have endoscopic recurrence while already on a thiopurine should have step-up therapy with the addition of an anti-TNF agent either as monotherapy or combination therapy.