Prevention of Postoperative Recurrence in Crohn's Disease
Authors: Jonathan P. Terdiman
Journal: Clinical Gastroenterology and Hepatology (2007)

A 29-year old man with Crohn's disease undergoes an ileocolic resection to treat an intra-abdominal abscess. The patient was diagnosed the year before with ileal Crohn's disease and was treated with mesalamine and budesonide. Several months before the operation the patient developed progressive symptoms of right lower-quadrant pain and fevers. A computerized tomography scan of the abdomen and pelvis showed marked wall thickening of the distal ileum and a 4-cm fluid collection in the right pelvis along with adjacent mesenteric fat stranding. The pelvic abscess was surrounded by several loops of bowel and therefore was not drainable through a percutaneous approach. The patient was treated with antibiotics, but his symptoms persisted and the abscess did not decrease in size on a repeat computerized tomography scan. The patient underwent a laparoscopic ileocolic resection. The pelvic inflammatory mass along with all of the diseased distal 45 cm of terminal ileum and the normal-appearing cecum were resected, and a stapled side-to-side anastomosis was created. The surgical specimen was notable for deep fissuring ulcerations and creeping fat, and on microscopy there was moderately severe acute and chronic inflammation with poorly formed granuloma. The proximal and distal margins of the surgical specimen were free of disease on both gross and microscopic inspection. The patient has an uneventful postoperative recovery and was discharged home 5 days after the surgery. He is otherwise in excellent health and he does not use tobacco. How should recurrent Crohn's disease be prevented in this patient? The natural history of Crohn's disease remains one of inexorable progression of bowel injury culminating in the need for intestinal resection in upwards of 80% of patients during their lifetime. Surgical rates have remained high over the past few decades despite more widespread use of immune modulators, such as azathioprine. Newer biological agents, such as the anti–tumor necrosis factor (TNF)-α antibodies, infliximab or adulimumab, may alter the natural history of the disease through their ability to induce mucosal healing in the majority of treated patients, and short-term studies have shown that use of these agents results in fewer operations. However, the impact of these drugs on the need for intestinal resections over the long term has not yet been documented. Unfortunately, operative resection of the diseased bowel in Crohn's disease is not curative, even when all of the visible disease has been removed. Disease recurrence is extremely common, if not inevitable. Recurrences typically occur at the surgical anastomosis and involve the neoterminal ileum in patients with prior ileal disease. Recurrence can be defined as endoscopic or clinical, with a subset of the latter being complicated recurrences that require reoperation. Endoscopic recurrences are defined by the presence of visible inflammation and ulceration, and are thought to be coincidental or precede clinical recurrence in all cases. The reoccurrence of symptoms after an operation without endoscopic or radiographic evidence of disease may be attributable to many conditions other than recurrent Crohn's disease, such as irritable bowel syndrome, infection, bacterial overgrowth, partial bowel obstruction from adhesive disease, fat malabsorption, or bile salt wasting–induced diarrhea. Endoscopic recurrence rates within 1 year of resection vary, but in many studies approach or exceed 60% (Figure 1). Between one half and three fourths of endoscopic recurrences are severe, defined as the presence of diffuse aphthous ileitis with diffusely inflamed mucosa or the presence of diffuse inflammation with larger ulcers, nodules, or narrowing. Patients with severe endoscopic recurrence have the worst prognosis, with high rates of clinical recurrence (Table 1). Among all Crohn's patients undergoing intestinal resection, clinical recurrence occurs in 10%–30% of patients within 1 year, and increase steadily so that by 20 years after resection 75%–80% of patients have a symptomatic recurrence. The rates of recurrence requiring reoperation also steadily increase with time, and approach or exceed 50% within 20 years of the initial surgery in most series.Table 1Relationship of Endoscopic Recurrence Score at 1 Year and Clinical Recurrence at 5 Years After Intestinal ResectionScoreEndoscopic findings at 1 yearRates of clinical recurrence at 5 years0No lesions5%–10%1<5 aphthous lesions5%–10%2>5 aphthous lesions with normal mucosa between the lesions, or skip areas of larger lesions, or lesions confined within 1 cm of anastomosis20%–40%3Diffuse aphthous ileitis with diffusely inflamed mucosa50%–70%4Diffuse inflammation with larger ulcers, nodules, or narrowing90%–100% Open table in a new tab Although in Crohn's disease postoperative recurrence is extremely common, a minority of patients will have a prolonged remission after intestinal resection. Assessing the risk for recurrence based on patient-specific factors may permit a more rational use of prophylactic medications. Potential risk factors for recurrence can be grouped as patient-related, disease-related, or factors related to the operation itself. Patient-related factors include patient age, sex, and smoking status. Disease-related factors include age at disease onset, duration of disease before the operation, anatomic site of the disease, extent and severity of disease, history of a prior resection, and the disease phenotype at the time of surgery (ie, perforating, fibro stenotic, or inflammatory disease). Surgical factors include presence or absence of gross or microscopic margins free of disease, anastomotic technique, need for blood transfusions, and occurrence of perioperative complications. Among the patient-related factors, only tobacco use has been found consistently to increase the risk of postoperative recurrence independently, with many studies finding at least a 2-fold increased risk. Further, the risk increases with the number of cigarettes smoked per day. Importantly, patients who quit smoking have a marked decreased risk of disease recurrence, with up to a 70% reduction in the need for reoperation being reported. With respect to disease-related factors, it has been suggested that the intensity of inflammation before the initial operation may predict rapid recurrence. Indeed, several studies have found higher rates of postoperative recurrence among patients with a shorter duration of disease before the initial operation, or in those with a greater extent of disease leading to a greater length of resected bowel at the initial operation, or in those with perforating disease, or in those who have required a prior resection, but these findings have not been reaffirmed consistently. With respect to anatomic site of involvement, again no clear differences appear comparing patients with isolated small-bowel disease, ileocolonic disease, or pure colonic disease who undergo intestinal resection and reanastomosis. As with disease-related factors, no surgical factors are associated clearly with risk of postoperative disease recurrence. What is most important is that no study has found a difference in recurrence rates between patients undergoing a radical resection vs those undergoing a minimal resection. There is no benefit to assessing microscopic margins or to ensuring an adequate proximal and distal margin of grossly uninvolved bowel. The type of anastomosis also does not appear to be important, with a recent, multicenter, randomized, controlled trial showing no difference in disease recurrence rates whether or not a stapled or hand-sewn technique is used, although many surgeons today favor creating a wide lumen, side-to-side, stapled anastomosis. Recurrence rates are far lower in patients who undergo resection with diversion of the fecal stream via an ostomy. This is especially true among patients with Crohn's colitis who undergo colectomy with creation of an end ileostomy. In these patients, postoperative recurrence rates are only in the range of 20%–30% over 10 years. It makes sense to try to modify preoperative risk factors as much as possible, but most of the risk factors for recurrence are not modifiable. The major exception to this is tobacco use. All patients should be encouraged strongly to stop smoking after intestinal resection for Crohn's disease. In patients who quit smoking, the risk of recurrence can be expected to decrease by at least 50%. Many studies have suggested that the severity of inflammation preoperatively is a risk factor for recurrence, but whether or not aggressive treatment of inflammation before the surgery will lead to a reduction in recurrence rates postoperatively has never been studied. Enthusiasm for postoperative drug prophylaxis is tempered by the limited efficacy, costs, and risk of the available agents, and the lack of early recurrence in a subset of patients. Importantly, no data show that long-term adverse outcomes, such as the need for additional hospitalizations or surgeries, are averted by using drugs to prevent recurrence compared with a strategy of diagnostic vigilance with early treatment of endoscopic or symptomatic recurrence. Prophylactic therapy to reduce postoperative recurrence rates in Crohn's disease has been widely, but not universally, recommended, using one of several agents. The data supporting prophylactic therapy are mixed regarding efficacy. There are no data directly addressing the timing of the initiation of therapy, nor the required duration. Expert opinion has suggested that therapy should be initiated as soon as the patient is eating again after the operation and that the treatment continue for at least 1–2 years in the absence of a clinical recurrence. The results of studies are mixed regarding the ability of mesalamine to reduce the frequency and severity of postoperative recurrence. In the largest randomized placebo-controlled trial, 4 grams of mesalamine per day was no better than placebo at preventing clinical recurrence, although there was a 17% reduction in the rate of clinical recurrence among a subset of patients with isolated small-bowel disease. A meta-analysis that included the prior study, as well as 5 others, found that mesalamine did reduce rates of endoscopic recurrence by 18% and clinical recurrence by 15%. Further, in a recent placebo-controlled trial published after the meta-analysis was performed, 3 grams of mesalamine per day reduced the rate of clinical recurrence by 19% at 24 months, but the results did not reach statistical significance, nor was any benefit seen regarding rates of endoscopic recurrence. The optimal dose of mesalamine for prophylaxis has not been defined. A recent randomized controlled trial found no substantial benefit, however, of 4 grams of mesalamine per day as compared with 2.4 g/day. Taken all together, these result suggest a modest benefit, at best, of mesalamine therapy in doses greater than 2 g/day taken over a 1- to 2-year period, with an expected reduction in the rates of clinical recurrence in the range of 10%–20% Two nitroimidazole antibiotics have been studied: metronidazole and ornidazole. Metronidazole (20 mg/kg/day) given for 3 months postoperatively reduced rates of severe endoscopic and clinical recurrence at 1 year among patients who could tolerate the therapy, but the benefits were not sustained over long-term follow-up evaluation. Ornidazole (1 g/day), when given for 1 year postoperatively, reduced rates of endoscopic recurrence by 25% and clinical recurrence by 30% compared with placebo. Neither antibiotic is very well tolerated at these doses, blunting the enthusiasm for using these agents as first-line, long-term, prophylactic therapy. Lower doses of nitroimidazole antibiotics, however, may be effective and better tolerated. A recent study found a low rate of very severe endoscopic recurrence (22%) at 1 year after resection, with only 3 months of metronidazole at the low dose of 250 mg 3 times per day. The use of other drugs that may be better tolerated than the nitroimidazole antibiotics, such as ciprofloxacin or rifaximin, has not been evaluated in controlled studies. Azathioprine and 6-mercaptopurine (6-MP) are effective in the maintenance of drug-induced clinical remission in Crohn's disease. Unfortunately, the data supporting their use for postoperative prophylaxis are not robust. Even the most optimistic reading of the data suggests that the reduction of recurrence rates associated with the use of azathioprine or 6-MP is unlikely to be much in excess of 20%–25%. The best available data come from 1 of 2 controlled trials published in 2004. In the first, 6-MP at a dose of 50 mg/day did reduce endoscopic, severe endoscopic, and clinical recurrence by 21%, 26%, and 27%, respectively, over 24 months of treatment and follow-up evaluation. This study, however, has been widely criticized because the dose of 6-MP used was relatively low, the rate of subject withdrawal from the study was very high, and the rate of clinical recurrence was greater than the rate of endoscopic recurrence. In the second study, which was open-label, no statistically significant benefit was seen comparing azathioprine (2 mg/kg/day) with mesalamine (3 g/day) with respect to clinical or surgical relapse again over a 2-year treatment and follow-up period. Nevertheless, the study findings did suggest a possible beneficial effect of azathioprine. Among patients who were adherent to the protocol, there was an almost 50% reduction in the rate of surgical relapse (19% vs 10%) with the use of azathioprine. Also, among patients with a history of a prior intestinal resection the rate of clinical relapse was reduced from 36% to 13% when using azathioprine compared with mesalamine. Two additional recent studies that have been presented, but not published, also suggested that azathioprine or 6-MP are effective in preventing postoperative recurrence. In the first study, all patients received 3 months of metronidazole and also were randomized to receive either azathioprine (∼2 mg/kg/day) or placebo for 12 months. The risk of advanced endoscopic recurrence was lowered from 69% to 44% with azathioprine, and, in addition, 22% of the azathioprine patients were without any evidence of endoscopic recurrence compared with only 3% of the placebo patients. The second study was a retrospective analysis of a large cohort of Crohn's patients who had undergone an initial intestinal resection. The use of azathioprine or 6-MP resulted in a 25% reduction in the need for a second operation (49% to 24%) over a 10-year follow-up period. After adjusting for other factors that might influence the need for recurrence, sustained use of an immune modulator resulted in a 3-fold reduction in risk of requiring another operation. No data are available about the use of methotrexate in the prevention of postoperative recurrence. Corticosteroids, including budesonide, are ineffective in the prevention of postoperative recurrence. Despite the well-documented ability of the anti–TNF-α agents, infliximab, adulimumab and certolizumab pegol, to heal mucosa, maintain a medically induced remission, and even reduce rates of hospitalizations and need for operations, no data have been generated as to whether or not these agents can prevent postoperative recurrence. Similarly, the ability of the anti-α 4 integrin, natalizumab, to prevent postoperative recurrence has not been studied. Interleukin-10 therapy was ineffective in the prevention of postoperative recurrence. Although a recent, very small, controlled trial suggested a possible benefit in children placed on a polymeric diet after resection, there are really no convincing data that exist to support the use of dietary therapy or supplements, such as omega-3 fatty acids, in the prevention of postoperative recurrence. In addition, all controlled trials to date have failed to show any role for probiotics in the prevention of postoperative recurrence, although many available strains and probiotic mixtures have not been studied. Seminal work by Rutgeerts et al showed that endoscopic recurrence precedes and predicts clinical recurrence, and this group developed a scoring system to rate the severity of endoscopic findings (Table 1). In the original study, patients with no or very mild lesions (score of 0 or 1) at follow-up endoscopy 1 year after resection had a low risk of endoscopic progression or clinical recurrence, with clinical recurrence rates remaining less than 10% over 5–10 years of follow-up evaluation. However, patients with advanced lesions (score of 3 or 4) seen at follow-up endoscopy had a poor prognosis with further endoscopic progression and clinical recurrence occurring in upwards of 90% over time. Although the particulars of this scoring system have not been validated independently, one possible management strategy would be to defer all postoperative medical prophylaxis until a postoperative colonoscopy is performed 6–12 months after the intestinal resection. Medical therapy would be started in patients with moderate or advanced endoscopic recurrence, but would be withheld in patients with no or very mild recurrence. Because progression of endoscopic lesions does occur, repeat ileocolonoscopy might be performed in another 6–12 months to decide once again if medical therapy should be started, or to determine whether or not the therapy that has been started is effective and should be continued, or whether it should be stopped or changed. Although this management strategy based on endoscopic findings seems rational, it has not been studied. Also, no data exist on the use of radiologic studies, such as computerized tomography enterography, or other technologies such as capsule endoscopy, as a surrogate for conventional ileocolonoscopy in this setting. The latter methodologies would need to be used in circumstances in which the anastomosis is beyond the reach of the colonoscope. If capsule endoscopy is to be undertaken in this setting, caution must be exercised because of the increased risk of capsule retention. Although most patients with Crohn's disease who undergo intestinal resection will recur, some will not, and in those who do, the timing and intensity of the recurrence varies. The use of clinical features, such as disease phenotype, location, and severity, is not sufficient to predict postoperative recurrence in the individual patient. It would be desirable to have additional patient-specific data that could predict recurrence with high accuracy to better guide the use of medical prophylaxis. Markers that would detect recurrence in the preclinical phase, even before the occurrence of endoscopically visible lesions, also would be valuable. Unfortunately, no such markers exist. Acute phase reactants, such as the C-reactive protein, are used in clinical practice to help detect active disease, but their usefulness has not been studied in the postoperative setting. Recently, a number of stool-based tests, such as the fecal calprotectin, have been proposed to detect subtle disease activity, but their usefulness, especially in the postoperative setting, also is uncertain. The use of serologic markers, such as antibody profiles, to predict recurrence remains uninvestigated. A recent report found that carrying a Nod2/CARD15 variant does confer a 3-fold increased risk of postoperative recurrence, but this finding needs to be confirmed. The abilities of all of the medications studied so far to prevent postoperative recurrence are modest at best. There is an urgent need to find more effective medications, or medicine combinations. For example, the combination of a low-dose antibiotic and an immune modulator may be superior to either drug alone. Another obvious choice to prevent postoperative recurrence would be one of the biological drugs, such as infliximab or adulimumab, and there is currently a study underway examining the ability of infliximab to prevent postoperative recurrence. If proven to be effective, the optimal use of the anti–TNF-α agents in the postoperative setting needs to be defined. For example, these drugs might be started in the majority of postoperative patients, or started immediately only in those patients with very high risk clinical features, or reserved for patients with documented severe endoscopic recurrence regardless of prior medical therapy, or started only in those patients who have failed 6-MP or azathioprine. It also is unclear to what extent the medicines used by a patient before surgery should influence the choice of medications after the operation. It makes sense that the failure of a medicine to control the disease preoperatively would be associated with a failure of the drug to prevent recurrence postoperatively. There is definite uncertainty regarding the best postoperative therapy for patients already on anti–TNF-α drugs before their operations. In addition to determining which medicines, or combinations of medicines, are optimal in the prevention of postoperative recurrence, uncertainty remains with respect to the appropriate time to intervene, and the duration of the intervention. Because endoscopic recurrence precedes and predicts clinical recurrence in almost every case, it might be rational to withhold therapy until an endoscopic recurrence has been detected. There is currently a multicenter study underway in Europe to examine the difference in clinical outcomes using this management strategy compared with immediate postoperative use of prophylactic medicines. The only comprehensive guideline regarding the prevention of postoperative recurrence in Crohn's disease was published by the European Crohn's and Colitis Organization in 2006. The European Crohn's and Colitis Organization guidelines recommend that all patients be encouraged to stop smoking after surgery for Crohn's disease. Prophylactic treatment is recommended after small intestinal resection, with the drug of choice being mesalamine greater than 2 g/day. Nitroimidazole antibiotics can be used as an alternative. Azathioprine or 6-MP should be considered as first-line therapy in high-risk patients. High risk was defined as smoking, colonic disease location, or extent of disease greater than 100 cm. Perforating disease was not believed to be an important risk factor. The start of prophylaxis is recommended within 2 weeks of surgery and the duration of prophylaxis should be at least 2 years. In asymptomatic patients, if colonoscopy is performed and mild lesions are found, no change in therapy is recommended. Severe lesions are associated with a high risk of clinical recurrence, and starting therapy with azathioprine may be considered in this circumstance. This patient must continue to refrain from tobacco use. He should be started on 6-MP or azathioprine, with a target dose of approximately 1.5 mg/kg/per day or 2.5 mg/kg/per day, respectively (Figure 2). After 6 months he should undergo ileocolonoscopy. If no or minimal lesions are found, the medication should be continued and a repeat ileocolonoscopy should be performed a year later for the same purpose. If moderate to severe lesions are found at either colonoscopy (diffuse aphthous ileitis with diffusely inflamed mucosa or worse), regardless of symptoms, the patient should be started on an anti–TNF-α drug, either infliximab or adulimumab, to be given at regularly scheduled intervals. Controversy exists as to whether or not the immune modulator should be stopped if infliximab or adulimumab are started. At any point after the operation, recurrent symptoms should trigger a comprehensive evaluation to determine if the cause is recurrent Crohn's disease, or another problem, and the treatment plan should be modified accordingly.