Crohn disease often recurs after surgical resection. Despite extensive research in the prevention of postoperative Crohn disease, optimal management strategies have yet to be defined. Risk of disease recurrence needs to be carefully balanced against potential risks associated with treatment. Patients with low risk of postoperative recurrence may not require medication, whereas those at moderate risk may benefit from antibiotics or immunomodulators. Those at highest risk of recurrence may benefit from biologic therapy for maintenance of surgical remission. Postoperative colonoscopy within 1 year of resective surgery is important for identification of disease recurrence and modification of medications.
Crohn disease is a chronic relapsing inflammatory disease of the gastrointestinal tract with a myriad of systemic manifestations. The cause is unknown, but immunologic, genetic, and environmental factors are thought to be involved. Pathologically, it is characterized by noncaseating granuloma and transmural inflammation, which can affect the gut from the mouth to the anus. The most commonly affected sites of Crohn disease involvement in the gastrointestinal tract are the ileum and ascending colon. Thus, the most common surgery for Crohn disease is resection of the distal ileum and cecum.
It is estimated that 75% of patients with Crohn disease will eventually undergo surgery. Indications for surgery include failure of medical management or complications of Crohn disease, such as perforation, obstruction, fistula formation, toxic megacolon, or malignancy. In recent years, “bowel-conserving” surgery has been advocated for Crohn disease, in which only the grossly involved bowel is removed. This surgical strategy is based on radical surgery not being curative and on major advances in more effective medical therapies.
Approximately 30% of patients who have undergone bowel resection for Crohn disease will require another operation for recurrence within 5 years. Moreover, optimal medical management of patients with Crohn disease after surgery is still controversial. In this article, the authors evaluate the literature on postoperative medications for Crohn disease and provide management recommendations.
Natural history
It is estimated that approximately 30% of patients who require surgery for Crohn disease will experience symptomatic recurrence within 3 years, and as high as 60%, within 10 years. Relapse rates in the placebo group of randomized double-blind trials provide a reasonable guide of natural history of Crohn disease after surgery. In a meta-analysis, Renna and colleagues found that the pooled estimate of 1-year relapse rates in the placebo groups was 10% to 38%. A logistic regression analysis of the factors associated with postoperative recurrence revealed that study duration was the only significant factor.
Endoscopic recurrence is more common than symptomatic relapse, approaching 90% one year after surgery. Endoscopic findings that indicate recurrence include small aphthous ulcers, deep linear ulcers, mucosal inflammation, fistulae, and strictures. These varying degrees of endoscopic disease activity may be seen within 3 months of surgery in more than 70% of patients. The most common site of recurrence is the surgical anastomosis, especially the proximal side of the anastomosis. The cause for recurrence at this location is thought to be related to luminal contents, specifically intestinal flora. Endoscopic recurrence precedes clinical recurrence, and the severity of endoscopic findings predicts the risk of clinical recurrence.
Risk factors for clinical recurrence
Various clinical variables, disease patterns, and surgical techniques have been studied to determine factors associated with recurrence and disease severity.
Active cigarette smoking has consistently been shown to be an independent risk factor for recurrence with relative risk ranges from 1.4 to 4.3. The need for immunosuppressive drugs is associated with smoking in a dose-dependent fashion, and the adverse effect of smoking is more strongly associated with early recurrence in women than in men. Several studies have found that the disease pattern that is seen at the initial surgery influences postoperative course. Crohn disease can be divided into 2 subtypes, perforating and nonperforating. Patients with the perforating type require surgery for fistula, abscess, or free perforation, whereas for the nonperforating type, the indications include obstruction, failure of medical treatment, hemorrhage, or toxic megacolon. In the multivariate analysis, surgery for the perforating indication was an independent predictor of early recurrence. In addition, recurrences requiring additional surgery occurred twice as fast in the perforating type as in the nonperforating type. Patients tend to recur with a similar disease pattern and require repeat surgery for similar indications.
The anatomic site that is affected by Crohn disease is another disease-specific variable that determines recurrence rates. Involvement of the small bowel was associated with an increased risk of recurrence requiring another surgery.
Surgical techniques of anastomosis have also been studied. In several studies, side-to-side stapled ileocolic anastomosis was associated with a lower risk of recurrence than hand-sewn anastomosis. In one large case-control study, ileocolic anastomosis that was made in a side-to-side stapled fashion was associated with 24% recurrence rate, which was significantly lower than the 57% recurrence rate in the group with conventional end-to-end hand-sewn anastomosis. Additional studies have confirmed these results, and they have found that side-to-side anastomosis after ileocolic resection was associated with lower recurrence rates than end-to-end anastomosis.
Endoscopic recurrence has been established as one of the greatest objective predictors of clinical recurrence. An endoscopic recurrence score developed by Rutgeerts and colleagues is the most widely accepted scoring system for measuring postoperative recurrence ( Table 1 , Fig. 1 ). It stratifies the endoscopic finding into 5 categories, reflecting a spectrum of disease severity. At 1 year, those with endoscopic findings of the i0 or i1 subtype had a 10% risk of clinical recurrence at 10 years; those with the i2 subtype had a 20% risk, at 10 years; and those with the i3 or i4 subtype had a 50% risk, as early as within 5 years, with many of them requiring surgery.
| Endoscopic Score | Definition |
|---|---|
| i0 | No lesions |
| i1 | ≤5 aphthous lesions |
| i2 | >5 aphthous lesions with normal mucosa between the lesions, or skip areas of larger lesions, or lesions confined to the ileocolic anastomosis |
| i3 | Diffuse aphthous ileitis with diffusely inflamed mucosa |
| i4 | Diffuse inflammation with already larger ulcers, nodules, and/or narrowing |
Risk factors for clinical recurrence
Various clinical variables, disease patterns, and surgical techniques have been studied to determine factors associated with recurrence and disease severity.
Active cigarette smoking has consistently been shown to be an independent risk factor for recurrence with relative risk ranges from 1.4 to 4.3. The need for immunosuppressive drugs is associated with smoking in a dose-dependent fashion, and the adverse effect of smoking is more strongly associated with early recurrence in women than in men. Several studies have found that the disease pattern that is seen at the initial surgery influences postoperative course. Crohn disease can be divided into 2 subtypes, perforating and nonperforating. Patients with the perforating type require surgery for fistula, abscess, or free perforation, whereas for the nonperforating type, the indications include obstruction, failure of medical treatment, hemorrhage, or toxic megacolon. In the multivariate analysis, surgery for the perforating indication was an independent predictor of early recurrence. In addition, recurrences requiring additional surgery occurred twice as fast in the perforating type as in the nonperforating type. Patients tend to recur with a similar disease pattern and require repeat surgery for similar indications.
The anatomic site that is affected by Crohn disease is another disease-specific variable that determines recurrence rates. Involvement of the small bowel was associated with an increased risk of recurrence requiring another surgery.
Surgical techniques of anastomosis have also been studied. In several studies, side-to-side stapled ileocolic anastomosis was associated with a lower risk of recurrence than hand-sewn anastomosis. In one large case-control study, ileocolic anastomosis that was made in a side-to-side stapled fashion was associated with 24% recurrence rate, which was significantly lower than the 57% recurrence rate in the group with conventional end-to-end hand-sewn anastomosis. Additional studies have confirmed these results, and they have found that side-to-side anastomosis after ileocolic resection was associated with lower recurrence rates than end-to-end anastomosis.
Endoscopic recurrence has been established as one of the greatest objective predictors of clinical recurrence. An endoscopic recurrence score developed by Rutgeerts and colleagues is the most widely accepted scoring system for measuring postoperative recurrence ( Table 1 , Fig. 1 ). It stratifies the endoscopic finding into 5 categories, reflecting a spectrum of disease severity. At 1 year, those with endoscopic findings of the i0 or i1 subtype had a 10% risk of clinical recurrence at 10 years; those with the i2 subtype had a 20% risk, at 10 years; and those with the i3 or i4 subtype had a 50% risk, as early as within 5 years, with many of them requiring surgery.
| Endoscopic Score | Definition |
|---|---|
| i0 | No lesions |
| i1 | ≤5 aphthous lesions |
| i2 | >5 aphthous lesions with normal mucosa between the lesions, or skip areas of larger lesions, or lesions confined to the ileocolic anastomosis |
| i3 | Diffuse aphthous ileitis with diffusely inflamed mucosa |
| i4 | Diffuse inflammation with already larger ulcers, nodules, and/or narrowing |
Surveillance strategy
Scheduled postoperative assessment for recurrence, to allow for early detection and intervention, is important. There are a range of clinical, laboratory-based, radiological, and endoscopic evaluation parameters that have been assessed. The Crohn disease activity index (CDAI) is a clinical research score that is used to define clinical activity and response to medical therapy. Although the most widely applied activity score in research studies and publications, the CDAI may not accurately predict postoperative Crohn disease recurrence.
Currently, colonoscopy seems to be the best modality for evaluation of mucosal Crohn disease recurrence at the ileocolic anastomosis and neoterminal ileum. Proactive evaluation for endoscopic recurrence often detects mucosal inflammatory changes that precede clinical recurrence. Effective treatment of endoscopically recurrent Crohn disease in the postoperative setting is an area of great research interest. Early treatment of mucosally evident inflammation may prove effective in altering the natural course of disease, with prevention of clinical recurrence and of need for future surgery. It is currently not known whether prophylactic treatment immediately after surgery is more effective than treatment that is based on subsequent endoscopic findings.
Medical treatment trials for postoperative Crohn disease
In the following sections, the authors review the data from prospective randomized trials on postoperative prevention of Crohn disease.
5-Aminosalicylic Acid Medications
5-Aminosalicylic acid (5-ASA) medications have been most extensively studied in postoperative treatment of Crohn disease. Despite several randomized trials evaluating the efficacy of 5-ASAs in the prevention of postoperative recurrence, the benefit of these agents has not been uniformly established. This is probably due to the heterogeneity of trial designs and the drug preparations and doses that are administered in the studies.
Early randomized trials on the use of sulfasalazine (salazosulfapyridine) did not show benefit of its use in the postoperative setting. In the largest study of 5-ASAs in the postoperative setting by Lochs and colleagues, patients either received 5-ASA (mesalamine 4 g/d) or placebo over 18 months after initial surgery for Crohn disease. The clinical recurrence rates were lower in the 5-ASA–treated group than in the control group (24.5% vs 31.4%; P = .10), but they did not reach statistical significance. In another randomized trial, 5-ASA (mesalamine 2.4 g/d) did reduce symptomatic recurrence rates at 24 months of follow-up (18% vs 41% among those receiving mesalamine vs placebo; P = .006). Regarding endoscopic recurrence, Florent and colleagues found that mesalazine (1 g, 3 times a day) did not significantly reduce endoscopic recurrence rates at 12 weeks (50% vs 63%; P = .16).
Ewe and colleagues found that sulfasalazine (3 g/d) significantly reduced clinical recurrence rates at 1 year (16% vs 28%; P <.01), and this effect was sustained at 2 years of follow-up. In another large multicenter randomized trial, Brignola and colleagues found that 12 months of mesalazine (3 g/d) was associated with lower rates of endoscopic recurrence and severity score. However, clinical recurrence rates were similar in the 2 groups. In another study, 5-ASA (mesalamine 3 g/d) was found to significantly reduce symptomatic recurrence rates (31% vs 41%; P = .031)and endoscopic and radiological recurrence rates. In this study, 5-ASA was generally safe, with only 1 case of serious side effects (pancreatitis).
Recently, a double-blind, randomized, multicenter trial was performed to evaluate efficacy of different doses of mesalazine in preventing postoperative endoscopic and clinical recurrence. Two hundred six patients, who had undergone surgery for terminal ileum involvement, were randomized to receive 4.0 g/d or 2.4 g/d of mesalazine, 2 weeks after surgery. At 12 months after surgery, endoscopic recurrence was more frequent in the 2.4 g/d group than in the 4.0 g/d group, but clinical recurrence rates were similar in the 2 groups.
A meta-analysis of available trials suggests that 5-ASA reduces overall postoperative recurrence rates by only 13%. Therefore, the current evidence indicates that the 5-ASAs are generally safe for postoperative Crohn disease prophylaxis, but they may only slightly reduce clinical and endoscopic recurrence.
Nitroimidazole Antibiotics
Rutgeerts and colleagues studied the efficacy of metronidazole after ileocecal resection for Crohn disease, in a placebo-controlled randomized fashion. Metronidazole (20 mg/kg/d) was started within 1 week of surgery and was administered for 3 months. Endoscopic recurrence rates and severity at 3 months were evaluated. The metronidazole group had lower incidence of early endoscopic recurrence of Crohn disease in the neoterminal ileum, compared with placebo group (75% vs 52%; P = .09). Compared with the placebo group, metronidazole significantly reduced the clinical recurrence rates at 1 year (4% vs 25%). However, patients in the metronidazole arm experienced more frequent side effects (23.3% vs 6.7%). In another study using ornidazole (1 g/d), the same group found significantly lower clinical recurrence rates in the treatment group, compared with the placebo group, at 12 months (7.9% vs 37.5%; P = .0046). Ornidazole also significantly reduced endoscopic recurrence rates at 12 months (53.6% vs 79%; P = .037), and endoscopic findings at 3 and 12 months predicted clinical course. In terms of side effects, however, the ornidazole group was associated with a higher rate of discontinuation of therapy, compared with the placebo group (31.6% vs 12.5%). Unlike the 5-ASAs, the nitroimidazole antibiotics may have a role in preventing postoperative Crohn disease recurrence, but long-term tolerance of these agents is limited.
Budesonide
In 2 large randomized trials, oral budesonide was found to be ineffective in reducing recurrence rates. In both studies, the frequency of clinical recurrences was similar in the budesonide group and the placebo group at 3 and 12 months. Ewe and colleagues found that the endoscopic and clinical recurrence rates after 1 year were not significantly different in the treatment group, compared with the placebo group. Hellers and colleagues found that the endoscopic recurrence rates did not differ between the groups at 3 and 12 months. However, they found significantly lower endoscopic recurrence rates in the subgroup of patients who underwent surgery for inflammatory Crohn disease, but not in the subgroup whose surgical indication was a fibrostenotic stricture. Overall, data are lacking in support of budesonide use for prevention of Crohn disease in the postoperative setting.
6-Mercaptopurine/Azathioprine
Immunomodulators, such as 6-mercaptopurine (6MP) and azathioprine (AZA) are commonly used to maintain medically induced remission in Crohn disease. In a randomized open-label study, AZA (2 mg/kg/d) was compared with mesalamine (3 g/d) as a secondary preventive treatment after bowel resection for Crohn disease. The clinical relapse rates were similar in the 2 groups at 24 months. In a subgroup analysis, patients with a prior history of bowel resections benefited more from AZA than from mesalamine in the prevention of clinical relapse, with an odds ratio of 4.83. However, significantly more patients receiving AZA experienced side effects than those receiving mesalamine (22% vs 8%). In another study, Hanauer and colleagues randomized 131 patients after bowel resection and ileocolic anastomosis to placebo, mesalamine (3 g/d), or 6MP (50 mg/d). They found that clinical recurrence at 2 years was 50% in the 6MP group, 58% in mesalamine group, and 77% in the placebo group. However, this study also demonstrated the limitation of 6MP as a prophylactic therapy; only 69% of patients were able to complete the treatment course and were evaluable at the end of the study, because of the significant side effects of 6MP. These 2 studies show that immunomodulators are more effective than mesalamine in the prevention of postoperative recurrence, albeit with a higher side-effect profile.
A regimen that combined an immunosuppressive drug with an antibiotic was studied in a double-blind randomized trial. Eighty-one patients were given metronidazole (250 mg, 3 times a day) for 3 months. The patients were then randomized to receive either AZA (100 mg/d for body weight<60 kg or 150 mg/d for body weight>60 kg) or placebo for 12 months. The endoscopic recurrence rates were significantly lower at 12 months in the group which was given AZA and metronidazole, compared with the metronidazole-alone group (69% vs 44%; P = .048).
Biologic Therapy
The use of infliximab in Crohn disease has been a major therapeutic advance and is effective for fistulizing disease and for the induction and maintenance of remission in patients with moderately to severely active Crohn disease. In a double-blind placebo-controlled trial to assess efficacy of infliximab in the postoperative setting, infliximab significantly reduced recurrence rates after ileocolic resection. In this study, patients who underwent surgery for Crohn disease were randomized to either infliximab (5 mg/kg administered as a standard 3-dose induction, with a maintenance dose every 8 weeks) or placebo for 1 year. Infliximab or placebo was started within 4 weeks of surgery. Corticosteroids and antibiotics were discontinued within 12 weeks of surgery. AZA, 6MP, or 5-ASA products were continued as long as the patients were maintained on stable doses for at least 12 weeks before starting the study. The study found that 9.1% in the infliximab group developed endoscopic recurrence, compared with 84.6% in the placebo group ( P = .0006). Furthermore, the infliximab patients had a lower risk of endoscopic, histologic, and clinical recurrence at 1 year. Further study is needed to confirm the results from this small study and determine the length of infliximab treatment that is required beyond 1 year.
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