- Email: [email protected]
Endoscopic evaluation of postoperative recurrence in the patient with Crohn’s disease
Endoscopic Evaluation of Postoperative Recurrence in the Patient with Crohn’s Disease Jean-Paul Achkar, MD Recurrence of Crohn’s disease following surgical resection is a significant problem with reported symptomatic recurrence rates as high as 55% at 5 years and 76% at 15 years. The underlying pathophysiology of recurrent disease and the reason for its localization to the neo-terminal ileum are not well understood. Endoscopic visualization of the anastomosis and the neo-terminal ileum can provide important information about recurrence of Crohn’s disease following surgical resection. Endoscopic recurrences have been found as soon as 2 months following surgery and recurrence rates as high as 72% to 93% have been reported in the first year after surgery. Studies have shown that there is a progression of endoscopic lesions, from scattered aphthous ulcers to large ulcers and strictures over time, and that this progression is predictive of the subsequent clinical course. Patients with more advanced endoscopic lesion are more likely to develop early recurrence of symptoms and subsequent complications of the disease. Tech Gastrointest Endosc 6:165-168 © 2004 Elsevier Inc. All rights reserved.
P
Pathophysiology of Postoperative Recurrence
Center for Inflammatory Bowel Disease, Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to: Dr. Jean-Paul Achkar, Cleveland Clinic Foundation, Department of Gastroenterology, Desk A30, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: [email protected]
It has long been known that a diverting ileostomy can lead to improvement of symptoms in patients with active Crohn’s colitis.11-13 In addition, recurrence rates after surgical resection are higher for patients undergoing anastomotic procedures than those for patients requiring end ileostomies.14-16 In a long-term follow-up of a single surgeon’s practice of resections for colonic Crohn’s disease, postoperative recurrence developed in 15% of patients who underwent proctocolectomy with end ileostomy compared with 71% of those who underwent subtotal colectomy with ileorectal anastomosis.14 There is also evidence that the preoperative site of disease impacts on risk of recurrence in patients undergoing resection with ileostomy. Ho and coworkers evaluated outcomes in 182 Crohn’s disease patients with end ileostomies.15 Using Kaplan–Meier life-table analysis, the authors demonstrated that surgical recurrence rates were significantly higher in patients who underwent ileostomy for ileocolonic disease (42% at 10 years) than those for patients with isolated colonic disease (15% at 10 years); P ⬍ 0.01. These studies suggest that fecal stream and bowel continuity play an important etiologic role in the postoperative recurrence of Crohn’s disease. Further support for this theory comes from studies that demonstrate that histological changes and mucosal lesions begin to appear rapidly after exposure to intestinal contents once continuity is restored after an initial diverting ileostomy procedure.17,18 For example, in a study from Belgium, five patients who had undergone surgical resection with a diverting ileostomy proximal to an ileocolonic anastomosis were studied.17 These patients
revalence rates for Crohn’s disease in population-based cohorts in North America range between 26 and 199 cases per 100,000 persons.1 Up to 57% of Crohn’s disease patients in these cohorts will require at least one surgical resection at some point in their disease course.1 However, such surgery is usually only a temporizing intervention because of the high rate of recurrent disease.2,3 Therefore, postoperative recurrence poses a significant problem in the management of patients with Crohn’s disease. The frequency of postoperative recurrence depends on definitions used.2,3 Recurrence is typically first detected on endoscopic or radiologic studies and has been noted as early as three months postoperatively (endoscopic recurrence). Some studies have suggested endoscopic recurrence rates as high as 72 to 93% in the first year after surgery.4-6 Recurrence of symptoms has been reported to be as high as 55% at 5 years and 76% at 15 years (clinical recurrence).7 The need for further surgical resection (surgical recurrence), which can be considered the most severe form of recurrence, is fortunately much less, with approximately one third of patients requiring further surgical intervention within 10 years of their initial surgery.7-10
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166 had no histological or endoscopic evidence of anastomotic disease 6 months after surgery compared with an endoscopic recurrence rate of 71% at 6 months among 75 patients who underwent surgical resection without a diverting ileostomy proximal to an ileocolonic anastomosis. Six months after takedown of the diverting ileostomy, all five patients developed histological and endoscopic evidence of recurrent disease. These authors subsequently studied three patients with a diverting ileostomy proximal to an ileocolonic anastomosis whose ileal effluents were infused daily into the distal limb of the ileostomy and found that within eight days, histological and immunologic evidence of recurrence could be detected.18 Specific toxins or antigens that cause this association between fecal stream and postoperative disease recurrence have not been identified but possible factors include intestinal bacteria and dietary components.16,19 The potential pathogenic role of bacteria in the postoperative setting is suggested by a study that demonstrated heavy colonization by a colonic-like bacterial flora in the neo-terminal ileum following ileocolonic resection.20 In addition, antibiotics and probiotics have both been shown to reduce the risk of postoperative disease recurrence.21-23 Smoking has also been shown to increase the risk of postoperative recurrence.24-27 In one study, the need for repeat surgery 5 and 10 years after the first intervention was found to be significantly lower in nonsmokers (20% and 41%) compared with smokers (36% and 70%).24 The odds ratio for postoperative recurrence in women who smoked was higher than that for men (4.2 versus 1.5). Similarly, Cottone and coworkers found that smoking was an independent risk factor for clinical, surgical and endoscopic Crohn’s disease recurrence (odds ratio, 2.2; 95% confidence interval, 1.2-3.8).25 Another study demonstrated that patients who quit smoking were less likely to have undergone re-operation for recurrent disease (relative incidence rate 0.27, 95% confidence interval, 0.15-0.47).27
Role of Endoscopy in Assessing Postoperative Recurrence It has been well recognized that recurrence of Crohn’s disease most commonly develops in the ileal segment immediately proximal to the ileocolonic anastomosis, referred to as the neo-terminal ileum.4-6 Studies have shown that, after resection of ileal disease, recurrence typically develops proximal to the anastomosis while resection for ileocolonic disease is associated with recurrence on both sides of the anastomosis.3 Therefore, endoscopic visualization of the anastomosis and the neo-terminal ileum can provide important information about endoscopic recurrence of Crohn’s disease following surgical resection. The remainder of this review will focus on the role of endoscopy in assessment of postoperative recurrence. There is a temporal spectrum of disease recurrence following surgery in Crohn’s disease. The earliest detectable changes are seen on a histological level followed subsequently by endoscopic changes and later by clinical symp-
J-P. Achkar toms. A recent study evaluated three patients with a diverting ileostomy proximal to an ileocolonic anastomosis who were asked to infuse their ileal effluents daily into the distal limb of their ileostomy.18 These patients were examined endoscopically with collection of six biopsy specimens at the ileal side and two biopsy specimens at the colonic side of the anastomosis. All biopsies were entirely normal at baseline. However, within eight days of daily infusion of the ileal effluent, there was histological evidence of mucosal inflammation in the neo-terminal ileum. Immunologic evidence of inflammation was also seen as demonstrated by increased epithelial HLA-DR expression, and expression of the KP-1 antigen associated with activation by mononuclear cells. In addition, marked up regulation of intercellular adhesion molecule-1, and lymphocyte function-associated antigen-1 was observed reflecting epithelial and transendothelial lymphocyte recruitment. Endoscopic recurrences have been found as soon as 2 months following surgery28 and recurrence rates as high as 72% to 93% have been reported in the first year after surgery.4-6 A more recent study, however, suggested lower recurrence rates of 28% at 1 year and 77% at 3 years.29 It is important to note that the majority of patients with endoscopic recurrence at 1 year are asymptomatic. In these endoscopic studies, anywhere from 42% to 80% of patients with evidence for endoscopic recurrence at 1 year had no symptoms of recurrent disease.4-6 However, over time, the risk of clinical recurrence progressively increases. In one study that followed 42 patients with ileocolonic Crohn’s who underwent resection, the endoscopic recurrence rate was 93% at one year postoperatively compared with a clinical recurrence rate of 37% at one year.5 By 3 years postoperatively, the endoscopic recurrence rate remained high at 100% while clinical recurrence had increased to 86%. Interestingly, there is a progression of endoscopic lesions, from scattered aphthous ulcers to large ulcers and strictures over time, and this progression is predictive of the subsequent clinical course. Rutgeerts and coworkers evaluated 114 patients who were at various time intervals following surgical resection with ileocolic anastomosis for Crohn’s disease.4 The incidence of endoscopic recurrence at the level of the anastomosis was 72% in patients examined within one year of surgery, 79% in patients examined one to three years after surgery, and 77% in patients examined more than three years after surgery. Although the incidence of recurrence was stable over time, there was a progression of endoscopic changes from mild lesions early on to more advanced lesions as time progressed (Table 1). Excluding nonspecific changes of hyperemia and friability, the earliest evidence of recurrence consisted of aphthous ulceration in the neo-terminal ileum, a finding seen in 76% of patients with recurrence within one year of resection. In contrast, one to three years after surgery, more advanced lesions such as nodules and large ulcers were the most common endoscopic findings and 3 years after surgery, rigid stenosis of the anastomosis was frequently found (Table 1). Similarly, Olaison and coworkers found that, among 30 patients who underwent more than one colonoscopy after surgical resection for Crohn’s, 73% progressed to a more severe stage of endoscopic changes between the first and last endoscopies.5 The most common changes found at colonos-
Evaluation of recurrence of Crohn’s disease
167
Table 1 Spectrum of Endoscopic Changes Over Time Following Surgical Resection* Endoscopic Findings
<1 Year after Surgery
1-3 Years after Surgery
>3 Years after Surgery
76% 24% 0
32% 53% 15%
5% 49% 46%
Aphthous ulcers Nodules & large ulcers Rigid anastomotic stenosis *From Ref. 4.
copies performed at 3 months and 1 year following surgery were aphthous or small ulcers. In contrast, larger ulcers and fibrous strictures were commonly found at colonoscopies performed 3 years following surgery.5 Based on such findings, Rutgeerts and coworkers developed an endoscopic scoring system for postoperative neoterminal ileal lesions and they found that these endoscopic scores correlated with the subsequent risk of development of clinical symptoms.6 The scoring system consists of the parameters shown in Table 2. These authors prospectively followed 89 patients who were undergoing ileal resection and partial colectomy with ileocolonic anastomosis.6 All patients underwent colonoscopies with scoring based on the above system within the first year after surgery and also at least at 3 years and 6 years after surgery. Of several potential risk factors evaluated, the endoscopic score was most strongly correlated with risk of clinical recurrence at one year following surgery. In addition the severity of endoscopic recurrence correlated with subsequent risk of clinical recurrence. Patients with endoscopic scores of i,0 or i,1 were unlikely to develop symptoms or complications of recurrent disease during subsequent follow-up. In contrast, patients with endoscopic scores of i,3 or i,4 developed early recurrence of symptoms and subsequent complications over the follow-up period. Among patients with i,4 lesions at one year postoperatively, all developed symptomatic recurrence within a subsequent four year follow-up period including inflammatory masses in 48% and perforation in 2 patients. A subsequent prospective study found similar results using a more simple scoring scale that included endoscopic or radiographic changes.29 In this study, changes were classified as either minimal (aphthous ulcers on endoscopy or granularity on radiologically) or severe (stricture, deep ulcers, cobblestoning, or fistulization). Patients with minimal endoscopic or radiographic changes were less likely to develop symptoms on subsequent follow-up compared with patients Table 2 Rutgeerts Endoscopic Scoring System for Postoperative Ileal Findings* Score i,0 i,1 i,2
i,3 i,4 *From Ref. 6.
Endoscopic Findings No lesions < 5 aphthous ulcers > 5 aphthous ulcers with normal intervening mucosa OR skip areas of larger lesions OR lesion confined to the anastomosis Diffuse aphthous ileitis with diffusely inflamed mucosa Diffuse inflammation with larger ulcers, nodules, and/or narrowing
with severe endoscopic or radiographic changes with symptomatic recurrence rates of 42% versus 72% respectively (P ⫽ 0.0437). Of note, almost 50% of patients were symptomatic at the time of their endoscopic recurrence.
Conclusion and Future Directions In summary, endoscopic visualization of the neo-terminal ileum and ileocolonic anastomosis can help in assessing recurrence of disease following surgical resection in patients with Crohn’s disease. However, the exact role of endoscopy in the clinical management of such patients needs to be further defined. Clinicians are routinely faced with the problem of not being able to predict which patients will develop clinical recurrence and/or how soon such recurrences will develop following surgery. This, along with limited studies evaluating medical therapies other than mesalamine to prevent postoperative recurrence,3 leads to uncertainty in making treatment recommendations in the postoperative setting. Further prospective endoscopic and medical therapy studies are needed to help guide clinicians and patients in making such decisions. However, in the interim, the studies by Rutgeerts and coworkers6 and McLeod and coworkers29 would suggest that colonoscopy performed one to three years after surgery in asymptomatic patients may help guide recommendations for initiation of medical therapy following surgery. Specifically, asymptomatic patients with advanced endoscopic changes could be considered for initiation of medical therapy in hopes of preventing or minimizing what appears to be a high subsequent clinical relapse risk. Alternatively, in patients who develop symptoms suggestive of recurrence before such elective evaluation, endoscopy can then be used to objectively confirm the recurrence of Crohn’s disease. Other means of assessing endoscopic or radiographic recurrence will also need to be studied in the future. For example, a recent study compared virtual colonoscopy to conventional colonoscopy in evaluating postoperative recurrence in Crohn’s.30 The results of this study demonstrated that virtual colonoscopy was not sensitive for detecting early lesions such as erosions and ulcers but was relatively accurate for detecting stricturing lesions at the anastomosis.30 Similarly, with growing experience in the use of capsule endoscopy in the diagnosis and management of patients with inflammatory bowel disease,31,32 the role of this test following surgical resection in Crohn’s disease should be evaluated as a potentially less invasive means of assessing endoscopic recurrence.
References 1. Loftus EV Jr., Schoenfeld P, Sandborn WJ: The epidemiology and natural history of Crohn’s disease in population-based patient cohorts
J-P. Achkar
168
2. 3. 4.
5.
6.
7. 8. 9.
10. 11.
12. 13.
14.
15. 16.
17.
18.
from North America: A systematic review. Aliment Pharmacol Ther 16:51-60, 2002 D’Haens G, Rutgeerts P: Postoperative recurrence of Crohn’s disease: Pathophysiology and prevention. Inflamm Bowel Dis 5:295-303, 1999 Achkar JP, Hanauer SB: Medical therapy to reduce postoperative Crohn’s disease recurrence. Am J Gastroenterol 95:1139-1146, 2000 Rutgeerts P, Geboes K, Vantrappen G, et al: Natural history of recurrent Crohn’s disease at the ileocolonic anastomosis after curative surgery. Gut 25:665-672, 1984 Olaison G, Smedh K, Sjodahl R: Natural course of Crohn’s disease after ileocolonic resection-endoscopically visualized ileal ulcers preceding symptoms. Gut 33:331-335, 1992 Rutgeerts P, Geboes K, Vantrappen G, et al: Predictability of the postoperative course of Crohn’s disease. Gastroenterology 99:956-963, 1990 Borley NR, Mortensen NJ, Jewell DP: Preventing postoperative recurrence of Crohn’s disease. Br J Surg 84:1493-1502, 1997 Sachar DB: The problem of postoperative recurrence of Crohn’s disease. Med Clin North Am 74:183-188, 1990 Lock MR, Farmer RG, Fazio VW, et al: Recurrence and reoperation for Crohn’s disease: The role of disease location in prognosis. N Engl J Med 304:1586-1588, 1981 Michelassi F, Balestracci T, Chappell R, et al: Primary and recurrent Crohn’s: Experience with 1379 patients. Ann Surg 214:230-240, 1991 Oberhelman HA, Kohatsu S, Taylor KD, et al: Diverting ileostomy in the surgical management of Crohn’s disease of the colon. Am J Surg 115:231-239, 1968 Zelas P, Jagelman DG: Loop ileostomy in the management of Crohn’s colitis in the debilitated patient. Ann Surg 191:164-168, 1980 Harper PH, Truelove SC, Lee ECG, et al: Split ileostomy and ileocolostomy for Crohn’s disease of the colon and ulcerative colitis. Gut 24: 106-113, 1983 Goligher JC: The long-term results of excisional surgery for primary and recurrent Crohn’s disease of the large intestine. Dis Colon Rectum 28:51-55, 1985 Ho I, Greenstein AJ, Bodian CA, et al: Recurrence of Crohn’s disease in end ileostomies. Inflamm Bowel Dis 1:173-178, 1995 Janowitz HD, Croen EC, Sachar DB: The role of the fecal stream in Crohn’s disease: An historical and analytic review. Inflamm Bowel Dis 4:29-39, 1998 Rutgeerts P, Goboes K, Peeters M, et al: Effect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet 338:771-774, 1991 D’Haens GR, Geboes K, Peeters M, et al: Early lesions of recurrent
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Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 114:262-267, 1998 Sartor RB: Postoperative recurrence of Crohn’s disease: The enemy is within the fecal stream [editorial]. Gastroenterology 114:398-407, 1998 Neut C, Bulois P, Desreumaux P, et al: Changes in the bacterial flora of the neoterminal ileum after ileocolonic resection for Crohn’s disease. Am J Gastroenterol 97:939-946, 2002 Rutgeerts P, Hiele M, Geboes K, et al: Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 108:1617-1621, 1995 Rutgeerts P, Van Assche G, D’Haens G, et al: Ornidazol for prophylaxis of postoperative Crohn’s disease: Final results of a double blind placebo controlled trial. Gastroenterology 122:A80, 2002(abstr) Campieri M, Rizzello F, Venturi A, et al: Combination of antibiotic and probiotic treatment is efficacious in prophylaxis of post-operative recurrence of Crohn’s disease: A randomized controlled study vs. mesalamine. Gastroenterology 118:A781, 2000(abstr) Sutherland LR, Ramcharan S, Bryant H, et al: Effect of cigarette smoking on recurrence of Crohn’s disease. Gastroenterology 98:1123-1128, 1990 Cottone M, Rosselli M, Orlando A, et al: Smoking habits and recurrence in Crohn’s disease. Gastroenterology 106:643-648, 1994 Yamamoto T, Allan RN, Keighley MRB: Smoking is a predictive factor for outcome after colectomy in patients with Crohn’s colitis. Br J Surg 86:1069-1070, 1999 Ryan WR, Allan RN, Yamamoto T, et al: Crohn’s disease patients who quit smoking have a reduced risk of reoperation for recurrence. Am J Surg 187:219-225, 2004 Tytgat GNJ, Mulder CJJ, Brummelkamp WH: Endoscopic lesions in Crohn’s disease early after ileocecal resection. Endoscopy 20:260-262, 1988 McLeod RS, Wolff BG, Steinhart H, et al: Risk and significance of endoscopic/radiologic evidence of recurrent Crohn’s disease. Gastroenterology 113:1823-1827, 1997 Biancone L, Fiori R, Tosti C, et al: Virtual colonoscopy compared with conventional colonoscopy for stricturing postoperative recurrence in Crohn’s disease. Inflamm Bowel Dis 9:343-350, 2003 Lo SK: Capsule endoscopy in the diagnosis and management of inflammatory bowel disease. Gastrointest Endoscopy Clin N Am 14:179-193, 2004 Kornbluth A, Legnani P, Lewis BS: Video capsule endoscopy in inflammatory bowel disease. Past, present, and future. Inflamm Bowel Dis 10:278-285, 2004
P
Pathophysiology of Postoperative Recurrence
Center for Inflammatory Bowel Disease, Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to: Dr. Jean-Paul Achkar, Cleveland Clinic Foundation, Department of Gastroenterology, Desk A30, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: [email protected]
It has long been known that a diverting ileostomy can lead to improvement of symptoms in patients with active Crohn’s colitis.11-13 In addition, recurrence rates after surgical resection are higher for patients undergoing anastomotic procedures than those for patients requiring end ileostomies.14-16 In a long-term follow-up of a single surgeon’s practice of resections for colonic Crohn’s disease, postoperative recurrence developed in 15% of patients who underwent proctocolectomy with end ileostomy compared with 71% of those who underwent subtotal colectomy with ileorectal anastomosis.14 There is also evidence that the preoperative site of disease impacts on risk of recurrence in patients undergoing resection with ileostomy. Ho and coworkers evaluated outcomes in 182 Crohn’s disease patients with end ileostomies.15 Using Kaplan–Meier life-table analysis, the authors demonstrated that surgical recurrence rates were significantly higher in patients who underwent ileostomy for ileocolonic disease (42% at 10 years) than those for patients with isolated colonic disease (15% at 10 years); P ⬍ 0.01. These studies suggest that fecal stream and bowel continuity play an important etiologic role in the postoperative recurrence of Crohn’s disease. Further support for this theory comes from studies that demonstrate that histological changes and mucosal lesions begin to appear rapidly after exposure to intestinal contents once continuity is restored after an initial diverting ileostomy procedure.17,18 For example, in a study from Belgium, five patients who had undergone surgical resection with a diverting ileostomy proximal to an ileocolonic anastomosis were studied.17 These patients
revalence rates for Crohn’s disease in population-based cohorts in North America range between 26 and 199 cases per 100,000 persons.1 Up to 57% of Crohn’s disease patients in these cohorts will require at least one surgical resection at some point in their disease course.1 However, such surgery is usually only a temporizing intervention because of the high rate of recurrent disease.2,3 Therefore, postoperative recurrence poses a significant problem in the management of patients with Crohn’s disease. The frequency of postoperative recurrence depends on definitions used.2,3 Recurrence is typically first detected on endoscopic or radiologic studies and has been noted as early as three months postoperatively (endoscopic recurrence). Some studies have suggested endoscopic recurrence rates as high as 72 to 93% in the first year after surgery.4-6 Recurrence of symptoms has been reported to be as high as 55% at 5 years and 76% at 15 years (clinical recurrence).7 The need for further surgical resection (surgical recurrence), which can be considered the most severe form of recurrence, is fortunately much less, with approximately one third of patients requiring further surgical intervention within 10 years of their initial surgery.7-10
1096-2883/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.tgie.2004.09.007
165
166 had no histological or endoscopic evidence of anastomotic disease 6 months after surgery compared with an endoscopic recurrence rate of 71% at 6 months among 75 patients who underwent surgical resection without a diverting ileostomy proximal to an ileocolonic anastomosis. Six months after takedown of the diverting ileostomy, all five patients developed histological and endoscopic evidence of recurrent disease. These authors subsequently studied three patients with a diverting ileostomy proximal to an ileocolonic anastomosis whose ileal effluents were infused daily into the distal limb of the ileostomy and found that within eight days, histological and immunologic evidence of recurrence could be detected.18 Specific toxins or antigens that cause this association between fecal stream and postoperative disease recurrence have not been identified but possible factors include intestinal bacteria and dietary components.16,19 The potential pathogenic role of bacteria in the postoperative setting is suggested by a study that demonstrated heavy colonization by a colonic-like bacterial flora in the neo-terminal ileum following ileocolonic resection.20 In addition, antibiotics and probiotics have both been shown to reduce the risk of postoperative disease recurrence.21-23 Smoking has also been shown to increase the risk of postoperative recurrence.24-27 In one study, the need for repeat surgery 5 and 10 years after the first intervention was found to be significantly lower in nonsmokers (20% and 41%) compared with smokers (36% and 70%).24 The odds ratio for postoperative recurrence in women who smoked was higher than that for men (4.2 versus 1.5). Similarly, Cottone and coworkers found that smoking was an independent risk factor for clinical, surgical and endoscopic Crohn’s disease recurrence (odds ratio, 2.2; 95% confidence interval, 1.2-3.8).25 Another study demonstrated that patients who quit smoking were less likely to have undergone re-operation for recurrent disease (relative incidence rate 0.27, 95% confidence interval, 0.15-0.47).27
Role of Endoscopy in Assessing Postoperative Recurrence It has been well recognized that recurrence of Crohn’s disease most commonly develops in the ileal segment immediately proximal to the ileocolonic anastomosis, referred to as the neo-terminal ileum.4-6 Studies have shown that, after resection of ileal disease, recurrence typically develops proximal to the anastomosis while resection for ileocolonic disease is associated with recurrence on both sides of the anastomosis.3 Therefore, endoscopic visualization of the anastomosis and the neo-terminal ileum can provide important information about endoscopic recurrence of Crohn’s disease following surgical resection. The remainder of this review will focus on the role of endoscopy in assessment of postoperative recurrence. There is a temporal spectrum of disease recurrence following surgery in Crohn’s disease. The earliest detectable changes are seen on a histological level followed subsequently by endoscopic changes and later by clinical symp-
J-P. Achkar toms. A recent study evaluated three patients with a diverting ileostomy proximal to an ileocolonic anastomosis who were asked to infuse their ileal effluents daily into the distal limb of their ileostomy.18 These patients were examined endoscopically with collection of six biopsy specimens at the ileal side and two biopsy specimens at the colonic side of the anastomosis. All biopsies were entirely normal at baseline. However, within eight days of daily infusion of the ileal effluent, there was histological evidence of mucosal inflammation in the neo-terminal ileum. Immunologic evidence of inflammation was also seen as demonstrated by increased epithelial HLA-DR expression, and expression of the KP-1 antigen associated with activation by mononuclear cells. In addition, marked up regulation of intercellular adhesion molecule-1, and lymphocyte function-associated antigen-1 was observed reflecting epithelial and transendothelial lymphocyte recruitment. Endoscopic recurrences have been found as soon as 2 months following surgery28 and recurrence rates as high as 72% to 93% have been reported in the first year after surgery.4-6 A more recent study, however, suggested lower recurrence rates of 28% at 1 year and 77% at 3 years.29 It is important to note that the majority of patients with endoscopic recurrence at 1 year are asymptomatic. In these endoscopic studies, anywhere from 42% to 80% of patients with evidence for endoscopic recurrence at 1 year had no symptoms of recurrent disease.4-6 However, over time, the risk of clinical recurrence progressively increases. In one study that followed 42 patients with ileocolonic Crohn’s who underwent resection, the endoscopic recurrence rate was 93% at one year postoperatively compared with a clinical recurrence rate of 37% at one year.5 By 3 years postoperatively, the endoscopic recurrence rate remained high at 100% while clinical recurrence had increased to 86%. Interestingly, there is a progression of endoscopic lesions, from scattered aphthous ulcers to large ulcers and strictures over time, and this progression is predictive of the subsequent clinical course. Rutgeerts and coworkers evaluated 114 patients who were at various time intervals following surgical resection with ileocolic anastomosis for Crohn’s disease.4 The incidence of endoscopic recurrence at the level of the anastomosis was 72% in patients examined within one year of surgery, 79% in patients examined one to three years after surgery, and 77% in patients examined more than three years after surgery. Although the incidence of recurrence was stable over time, there was a progression of endoscopic changes from mild lesions early on to more advanced lesions as time progressed (Table 1). Excluding nonspecific changes of hyperemia and friability, the earliest evidence of recurrence consisted of aphthous ulceration in the neo-terminal ileum, a finding seen in 76% of patients with recurrence within one year of resection. In contrast, one to three years after surgery, more advanced lesions such as nodules and large ulcers were the most common endoscopic findings and 3 years after surgery, rigid stenosis of the anastomosis was frequently found (Table 1). Similarly, Olaison and coworkers found that, among 30 patients who underwent more than one colonoscopy after surgical resection for Crohn’s, 73% progressed to a more severe stage of endoscopic changes between the first and last endoscopies.5 The most common changes found at colonos-
Evaluation of recurrence of Crohn’s disease
167
Table 1 Spectrum of Endoscopic Changes Over Time Following Surgical Resection* Endoscopic Findings
<1 Year after Surgery
1-3 Years after Surgery
>3 Years after Surgery
76% 24% 0
32% 53% 15%
5% 49% 46%
Aphthous ulcers Nodules & large ulcers Rigid anastomotic stenosis *From Ref. 4.
copies performed at 3 months and 1 year following surgery were aphthous or small ulcers. In contrast, larger ulcers and fibrous strictures were commonly found at colonoscopies performed 3 years following surgery.5 Based on such findings, Rutgeerts and coworkers developed an endoscopic scoring system for postoperative neoterminal ileal lesions and they found that these endoscopic scores correlated with the subsequent risk of development of clinical symptoms.6 The scoring system consists of the parameters shown in Table 2. These authors prospectively followed 89 patients who were undergoing ileal resection and partial colectomy with ileocolonic anastomosis.6 All patients underwent colonoscopies with scoring based on the above system within the first year after surgery and also at least at 3 years and 6 years after surgery. Of several potential risk factors evaluated, the endoscopic score was most strongly correlated with risk of clinical recurrence at one year following surgery. In addition the severity of endoscopic recurrence correlated with subsequent risk of clinical recurrence. Patients with endoscopic scores of i,0 or i,1 were unlikely to develop symptoms or complications of recurrent disease during subsequent follow-up. In contrast, patients with endoscopic scores of i,3 or i,4 developed early recurrence of symptoms and subsequent complications over the follow-up period. Among patients with i,4 lesions at one year postoperatively, all developed symptomatic recurrence within a subsequent four year follow-up period including inflammatory masses in 48% and perforation in 2 patients. A subsequent prospective study found similar results using a more simple scoring scale that included endoscopic or radiographic changes.29 In this study, changes were classified as either minimal (aphthous ulcers on endoscopy or granularity on radiologically) or severe (stricture, deep ulcers, cobblestoning, or fistulization). Patients with minimal endoscopic or radiographic changes were less likely to develop symptoms on subsequent follow-up compared with patients Table 2 Rutgeerts Endoscopic Scoring System for Postoperative Ileal Findings* Score i,0 i,1 i,2
i,3 i,4 *From Ref. 6.
Endoscopic Findings No lesions < 5 aphthous ulcers > 5 aphthous ulcers with normal intervening mucosa OR skip areas of larger lesions OR lesion confined to the anastomosis Diffuse aphthous ileitis with diffusely inflamed mucosa Diffuse inflammation with larger ulcers, nodules, and/or narrowing
with severe endoscopic or radiographic changes with symptomatic recurrence rates of 42% versus 72% respectively (P ⫽ 0.0437). Of note, almost 50% of patients were symptomatic at the time of their endoscopic recurrence.
Conclusion and Future Directions In summary, endoscopic visualization of the neo-terminal ileum and ileocolonic anastomosis can help in assessing recurrence of disease following surgical resection in patients with Crohn’s disease. However, the exact role of endoscopy in the clinical management of such patients needs to be further defined. Clinicians are routinely faced with the problem of not being able to predict which patients will develop clinical recurrence and/or how soon such recurrences will develop following surgery. This, along with limited studies evaluating medical therapies other than mesalamine to prevent postoperative recurrence,3 leads to uncertainty in making treatment recommendations in the postoperative setting. Further prospective endoscopic and medical therapy studies are needed to help guide clinicians and patients in making such decisions. However, in the interim, the studies by Rutgeerts and coworkers6 and McLeod and coworkers29 would suggest that colonoscopy performed one to three years after surgery in asymptomatic patients may help guide recommendations for initiation of medical therapy following surgery. Specifically, asymptomatic patients with advanced endoscopic changes could be considered for initiation of medical therapy in hopes of preventing or minimizing what appears to be a high subsequent clinical relapse risk. Alternatively, in patients who develop symptoms suggestive of recurrence before such elective evaluation, endoscopy can then be used to objectively confirm the recurrence of Crohn’s disease. Other means of assessing endoscopic or radiographic recurrence will also need to be studied in the future. For example, a recent study compared virtual colonoscopy to conventional colonoscopy in evaluating postoperative recurrence in Crohn’s.30 The results of this study demonstrated that virtual colonoscopy was not sensitive for detecting early lesions such as erosions and ulcers but was relatively accurate for detecting stricturing lesions at the anastomosis.30 Similarly, with growing experience in the use of capsule endoscopy in the diagnosis and management of patients with inflammatory bowel disease,31,32 the role of this test following surgical resection in Crohn’s disease should be evaluated as a potentially less invasive means of assessing endoscopic recurrence.
References 1. Loftus EV Jr., Schoenfeld P, Sandborn WJ: The epidemiology and natural history of Crohn’s disease in population-based patient cohorts
J-P. Achkar
168
2. 3. 4.
5.
6.
7. 8. 9.
10. 11.
12. 13.
14.
15. 16.
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