Association between immune-associated disorders and adverse outcomes of ileal pouch-anal anastomosis.

OBJECTIVES: Autoimmune disorders (ADs) frequently coexist with inflammatory bowel disease. The aim of the study was to determine whether coexisting AD in patients with ileal pouches increases the risk for chronic antibiotic-refractory pouchitis (CARP) and other inflammatory conditions of the pouch. METHODS: A total of 622 patients seen in our Pouchitis Clinic were enrolled. We compared the prevalence of adverse outcomes of the pouch (including CARP, Crohn's disease of the pouch, and pouch failure) in patients with or without concurrent AD and assessed the factors for these adverse outcomes. RESULTS: There were seven pouch disease categories: normal (N=60), irritable pouch syndrome (N=112), active pouchitis (N=131), CARP (N=67), Crohn's disease (N=131), cuffitis (N=83), surgical complications (N=36), and anismus (N=2). The prevalence of AD in these pouch disease categories was 4.5%, 12.5%, 9.2%, 13.4%, 10.7%, 3.8%, 1.5%, and 0%, respectively. The presence of at least one AD at time of pouch surgery was shown to be associated with a twofold increase in the risk for CARP (hazard ratio=2.29; 95% CI: 1.52, 3.46; P<0.001) and for pouch-associated hospitalization (hazard ratio=2.39; 95% CI: 1.59, 3.58; P<0.001). The presence of AD was not associated with increased risk for irritable pouch syndrome, active pouchitis, Crohn's disease, cuffitis, surgical complications, or pouch failure. Patients with Crohn's disease of the pouch had a 2.42 times higher risk for pouch failure (P=0.042) than these without. Active smoking or a history of smoking was shown to be associated with an increased risk for pouch-associated hospitalization and pouch failure. CONCLUSIONS: AD appears to be associated with an increased risk for CARP, and the presence of the association between these AD and pouch disorders may stimulate further research on the link of these organ systems on an immunological basis.

Enterochromaffin cell hyperplasia in irritable pouch syndrome.

BACKGROUND: Irritable pouch syndrome (IPS) is a functional disease in patients with ileal pouch-anal anastomosis following colectomy for ulcerative colitis (UC). The pathophysiology of IPS is characterized by the presence of visceral hypersensitivity, similar to that seen in irritable bowel syndrome. However, the exact etiology and pathogenesis of IPS are not known. We hypothesized that serotonin-containing enteroendocrine cells or enterochromaffin (EC) cell hyperplasia and alterations in the mucosal immune cells may contribute to the patients' symptoms. The aim of the study was to assess EC cell hyperplasia and alterations in the mucosal immune cells in IPS. METHODS: The Pouchitis Disease Activity Index (PDAI) was used to quantify symptoms and mucosal inflammation in 36 patients with IPS and 25 patients with normal pouches. The histology and immunohistochemistry of pouch mucosal biopsies were assessed by a blinded gastrointestinal pathologist for intraepithelial lymphocytes (IEL), CD3+ T cells, CD25- (interleukin [IL]-2 receptor), tryptase- (mast cells), and serotonin-expressing cells. The numbers of IEL and immune-stained cells were compared between the two groups. RESULTS: Both groups were compatible demographically in terms of age, gender, duration of UC, stage, indication, and duration of the pouch surgery. There were no differences in the number of IEL, CD3+ T cells, CD25+ cells, and mast cells between the IPS and normal control groups. However, there were a significantly larger number of EC cells in the IPS group than that in the control group (54.8 +/- 24.9 vs 36.7 +/- 17.5 per 4 200x epithelial cells, P < 0.005). The number of EC cells appeared to be correlated with the symptom score (r = 0.276, P= 0.032). There were no significant correlations between the PDAI endoscopy and histology scores and the number of EC cells or between the PDAI scores and the number of IEL or other immune-stained cells. CONCLUSIONS: A greater number of EC cells were found in the IPS group than the normal pouch group, and the number of EC cells appeared to be correlated with the clinical symptoms of IPS. EC cell hyperplasia may be a contributing mechanism of visceral hypersensitivity and symptoms in IPS.

Clinical features and quality of life in patients with different phenotypes of Crohn's disease of the ileal pouch.

PURPOSE: Crohn's disease of the pouch can occur in patients with colectomy and ileal pouch-anal anastomosis performed for ulcerative colitis. The clinical features of inflammatory, fibrostenotic, and fistulizing Crohn's disease have not been characterized. METHODS: A total of 73 eligible patients with Crohn's disease of the pouch, who were seen in the Pouchitis Clinic, were enrolled: 25 with inflammatory Crohn's disease, 17 with fibrostenotic Crohn's disease, and 31 with fistulizing Crohn's disease. The clinical phenotypes of Crohn's disease were based on a combined assessment of clinical, endoscopic, radiographic, and histologic features. Clinical symptoms, endoscopic and histologic features, and health-related quality-of-life scores were assessed. RESULTS: Demographic and clinical features, including preoperative and postoperative parameters, were similar between the three phenotypes of Crohn's disease of the pouch. The use of nonsteroidal anti-inflammatory drugs, neuropsychiatric drugs, antidiarrheal agents, and Crohn's disease medicines was not different between the three groups. Predominant symptoms, as expected, were significantly different between the three phenotypes: diarrhea and/or pain in 92 percent of patients with inflammatory Crohn's disease, obstructive symptoms in 64.7 percent of patients with fibrostenotic Crohn's disease, and fistular drainage in 51.6 percent of those with fistulizing Crohn's disease (P < 0.0001). There was no statistical difference in quality-of-life scores between the three phenotypes, adjusted for disease activity. There was no significant correlation between quality-of-life and symptom scores in any of the three groups. Although not statistically significant, patients with fistulizing Crohn's disease (16.1 percent) tended to have an increased risk for pouch failure compared with inflammatory (8 percent) or fibrostenotic (5.9 percent) Crohn's disease. CONCLUSIONS: Predominant symptoms were different in clinical phenotypes of Crohn's disease. Each of the three phenotypes of Crohn's disease similarly affected quality-of-life. Fistulizing Crohn's disease may be associated with a higher risk for pouch failure.

Risk factors for diseases of ileal pouch-anal anastomosis after restorative proctocolectomy for ulcerative colitis.

BACKGROUND & AIMS: Although pouchitis is considered the most common adverse sequela of ileal pouch-anal anastomosis (IPAA), inflammatory and noninflammatory conditions other than pouchitis are increasingly being recognized. The risk factors for these non-pouchitis conditions, including Crohn's disease (CD) of the pouch, cuffitis, and irritable pouch syndrome (IPS), have not been studied. The aim of this study was to assess risk factors for inflammatory and noninflammatory diseases of IPAA in a tertiary care setting. METHODS: The study consisted of 240 consecutive patients who were classified as having healthy pouches (N = 49), pouchitis (N = 61), CD of the pouch (N = 39), cuffitis (N = 41), or IPS (N =50). Demographic and clinical features were assessed to determine risk factors for each of these conditions by using logistic regression analysis. RESULTS: Risk factors remaining in the final logistic regression models were for pouchitis: IPAA indication for dysplasia (odds ratio [OR], 3.89; 95% confidence interval [CI], 1.69-8.98), never having smoked (OR, 5.09; 95% CI, 1.01-25.69), no use of anti-anxiety agents (OR, 5.19; 95% CI, 1.45-18.59), or use of NSAIDs (OR, 3.24; 95% CI, 1.71-6.13); for CD of the pouch: a long duration of IPAA (OR, 1.20; 95% CI, 1.12-1.30) and current smoking (OR, 4.77; 95% CI, 1.39-16.25); for cuffitis: arthralgias (OR, 4.13; 95% CI, 1.91-8.94) and younger age (OR, 1.16; 95% CI, 1.01-1.33); and for IPS: use of antidepressants (OR, 4.17, 95% CI, 1.95-8.92) or anti-anxiety agents (OR, 3.21; 95% CI, 1.34-7.47). CONCLUSIONS: The majority of risk factors for the 4 inflammatory and noninflammatory conditions of IPAA are different, suggesting that each of these diseases has a different etiology and pathogenesis. The identification and modification of these risk factors might help patients and clinicians to make a preoperative decision for IPAA, reduce IPAA-related morbidity, and improve response to treatment.

Comprehensive evaluation of inflammatory and noninflammatory sequelae of ileal pouch-anal anastomoses.

BACKGROUND AND AIMS: Ileal pouch-anal anastomosis (IPAA) improves quality of life (QOL) for ulcerative colitis patients who require surgery. Crohn's disease (CD) of the pouch, pouchitis, cuffitis, and irritable pouch syndrome (IPS) have an adverse impact on physical and psychological well-being, which can compromise the gain in QOL after the surgery. Their clinical, endoscopic, and histologic features have not been fully characterized. The aim of this study was to compare demographic, clinical, endoscopic, and histologic features between CD of the pouch, pouchitis, cuffitis, IPS, and normal pouches. METHODS We enrolled 124 patients: normal pouches (N = 26), CD of the pouch (N = 23), pouchitis (N = 22), cuffitis (N = 21), and IPS (N = 32). Symptomatology, endoscopy, histology, and the Cleveland Global QOL and the Irritable Bowel Syndrome-QOL scores were compared among the groups. RESULTS: Univariate analysis of demographic and clinical data showed a possible association between NSAID use and pouchitis, extraintestinal manifestation and cuffitis, and antidepressant use and IPS. There were no differences in the Pouchitis Disease Activity Index symptom scores between the disease groups, with an exception of bleeding, which occurred almost exclusively in cuffitis. Endoscopy was useful in discriminating between CD of the pouch, pouchitis, cuffitis, and normal pouches or IPS. Patients with diseased IPAA had worse QOL scores. CONCLUSIONS: Symptoms largely overlapped among the disease groups of IPAA. Endoscopy is valuable for diagnosis. Inflammatory or noninflammatory sequelae of IPAA adversely affected patients' QOL.

In vivo colonoscopic optical coherence tomography for transmural inflammation in inflammatory bowel disease.

BACKGROUND & AIMS: Transmural inflammation, a distinguishing feature of Crohn's disease (CD), cannot be assessed by conventional colonoscopy with mucosal biopsy. Our previous ex vivo study of histology-correlated optical coherence tomography (OCT) imaging on colectomy specimens of CD and ulcerative colitis (UC) showed that disruption of the layered structure of colon wall on OCT is an accurate marker for transmural inflammation of CD. We performed an in vivo colonoscopic OCT in patients with a clinical diagnosis of CD or UC using the previously established, histology-correlated OCT imaging criterion. METHODS: OCT was performed in 40 patients with CD (309 images) and 30 patients with UC (292 images). Corresponding endoscopic features of mucosal inflammation were documented. Two gastroenterologists blinded to endoscopic and clinical data scored the OCT images independently to assess the feature of disrupted layered structure. RESULTS: Thirty-six CD patients (90.0%) had disrupted layered structure, whereas 5 UC patients (16.7%) had disrupted layered structure (P < .001). Using the clinical diagnosis of CD or UC as the gold standard, the disrupted layered structure on OCT indicative of transmural inflammation had a diagnostic sensitivity and specificity of 90.0% (95% CI: 78.0%, 96.5%) and 83.3% (95% CI: 67.3%, 93.3%) for CD, respectively. The kappa coefficient in the interpretation of OCT images was 0.80 (95% CI: 0.75, 0.86, P < .001). CONCLUSIONS: In vivo colonoscopic OCT is feasible and accurate to detect disrupted layered structure of the colon wall indicative of transmural inflammation, providing a valuable tool to distinguish CD from UC.

Ex vivo histology-correlated optical coherence tomography in the detection of transmural inflammation in Crohn's disease.

BACKGROUND AND AIMS: Distinguishing Crohn's disease (CD) from ulcerative colitis (UC) can be difficult. Transmural inflammation, a key feature of CD, cannot be assessed by conventional colonoscopy with biopsy. Optical coherence tomography (OCT) provides high-resolution, cross-sectional images of the gut wall and might become a new diagnostic tool. The aims of this study were to perform histology-correlated OCT on surgical specimens of CD and UC and to determine its diagnostic accuracy. METHODS: Colectomy specimens from patients with a preoperative diagnosis of CD (N = 24) or UC (N = 24) were studied with OCT in the operating room. OCT and histopathology were assessed blindly, and diagnostic accuracy of OCT was assessed. RESULTS: Eight preoperatively identified UC patients (33%) with transmural inflammation on postoperative histology were diagnosed with CD, and all 8 had a disrupted layered structure on OCT, a characteristic feature of transmural disease. Sixteen UC patients (67%) had superficial inflammation on histology; of them, 13 (81%) had an intact layered structure on OCT. All 24 preoperative CD patients had transmural inflammation on histology, and 23 (96%) had a disrupted layered structure on OCT. Of 585 histology-OCT image sets from the 48 patients, 152 sets (26%) had transmural inflammation on histology. The sensitivity and specificity for OCT to detect transmural disease were 86% and 91%, respectively. CONCLUSIONS: Transmural inflammation, as characterized by disruption of the layered structure of colon wall on OCT, is an accurate marker for the diagnosis of CD. Ex vivo OCT predicted transmural inflammation on postoperative histopathology.

Treatment of rectal cuff inflammation (cuffitis) in patients with ulcerative colitis following restorative proctocolectomy and ileal pouch-anal anastomosis.

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the treatment of choice in the majority of patients with ulcerative colitis (UC) who require surgery. To ease the construction of the IPAA and improve functional outcome by minimizing sphincter related stretch injury, a stapling technique is being commonly used in the pouch-anal anastomosis. Despite its advantages, the procedure normally leaves a 1-2 cm of anal transitional zone or rectal cuff, which is susceptible to recurrence of residual UC or cuffitis. Cuffitis can cause symptoms mimicking pouchitis. AIM: To conduct an open-labeled trial of topical mesalamine in patients with cuffitis. METHODS: We treated 14 consecutive patients with cuffitis by giving mesalamine suppositories 500 mg b.i.d. (mean 3.2 months, range 1-9 months). The Cuffitis Activity Index (adapted from the Pouchitis Disease Activity Index) scores and improvement in symptoms of bloody bowel movements and arthralgias were measured as primary and secondary outcomes. RESULTS: All patients had surgery for medically refractory UC. There were significant reductions in the total Cuffitis Activity Index scores after the therapy (11.93 +/- 3.17 vs 6.21 +/- 3.19, p < 0.001). Symptom (3.24 +/- 1.28 vs 1.79 +/- 1.31), endoscopy (3.14 +/- 1.29 vs 1.00 +/- 1.52), and histology (4.93 +/- 1.77 vs 3.57 +/- 1.39) scores each were significantly reduced (p < 0.05). Ninety-two percent of patients with bloody bowel movements and 70% of patients with arthralgias improved after the therapy. No systemic or topical adverse effects were reported. CONCLUSION: Topical mesalamine appears well tolerated and effective in treating patients with cuffitis, with improvement in symptom as well as endoscopic and histologic inflammation.

A cost-effectiveness analysis of diagnostic strategies for symptomatic patients with ileal pouch-anal anastomosis.

OBJECTIVE: Pouchitis is often diagnosed based on symptoms and empirically treated with antibiotics (treat-first strategy). However, symptom assessment alone is not reliable for diagnosis, and an initial evaluation with pouch endoscopy (test-first strategy) has been shown to be more accurate. Cost-effectiveness of these strategies has not been compared. The aim of this study was to compare cost-effectiveness of different clinical approaches for patients with symptoms suggestive of pouchitis. METHODS: Pouchitis was defined as pouchitis disease activity index scores > or =7. The frequency of pouchitis in symptomatic patients with ileal pouch was estimated to be 51%; the efficacy for initial therapy with metronidazole (MTZ) and ciprofloxacin (CIP) was 75% and 85%, respectively. Cost estimates were obtained from Medicare reimbursement data. RESULTS: Six competing strategies (MTZ trial, CIP trial, MTZ-then-CIP trial, CIP-then-MTZ trial, pouch endoscopy with biopsy, and pouch endoscopy without biopsy) were modeled in a decision tree. Costs per correct diagnosis with appropriate treatment were $194 for MTZ trial, $279 for CIP trial, $208 for MTZ-then-CIP trial, $261 for CIP-then-MTZ trial, $352 for pouch endoscopy with biopsy, and $243 for pouch endoscopy without biopsy. Of the two strategies with the lowest cost, the pouch endoscopy without biopsy strategy costs $50 more per patient than the MTZ trial strategy but results in an additional 15 days for early diagnosis and thus initiation of appropriate treatment (incremental cost-effectiveness ratio $3 per additional day gained). The results of base-case analysis were robust in sensitivity analyses. CONCLUSIONS: Although the MTZ-trial strategy had the lowest cost, the pouch endoscopy without biopsy strategy was most cost-effective. Therefore, based on its relatively low cost and the avoidance of both diagnostic delay and adverse effects associated with unnecessary antibiotics, pouch endoscopy without biopsy is the recommended strategy among those tested for the diagnosis of pouchitis.

Modified pouchitis disease activity index: a simplified approach to the diagnosis of pouchitis.

PURPOSE: Pouchitis is the most common complication of ileal pouch-anal anastomosis for ulcerative colitis. Our previous study suggested that symptoms alone are not reliable for the diagnosis of pouchitis. The most commonly used diagnostic instrument is the 18-point pouchitis disease activity index consisting of three principal component scores: symptom, endoscopy, and histology. Despite its popularity, the pouchitis disease activity index has mainly been a research tool because of costs of endoscopy (especially with histology), complexity in calculation, and time delay in determining histology scores. It is not known whether pouch endoscopy without biopsy can reliably diagnose pouchitis in symptomatic patients. The aim of the present study was to determine whether omitting histologic evaluation from the pouchitis disease activity index significantly affects the sensitivity and specificity of diagnostic criteria for pouchitis. METHODS: Ulcerative colitis patients with an ileal pouch-anal anastomosis and symptoms suggestive of pouchitis were evaluated. Patients with chronic refractory pouchitis and Crohn's disease were excluded. Patients with pouchitis disease activity index scores of seven or more were diagnosed as having pouchitis. Different diagnostic criteria were compared on the basis of the pouchitis disease activity index component scores. Nonparametric receiver-operating-characteristic curves were used to measure proposed pouchitis scores' diagnostic accuracy compared with diagnosis from the pouchitis disease activity index. The receiver-operating-characteristic area under the curve measured how much these diagnostic strategies differed from each other. RESULTS: Fifty-eight consecutive symptomatic patients were enrolled; 32 (55 percent) patients were diagnosed with pouchitis. With the use of the pouchitis disease activity index as a criterion standard, the use of only symptom and endoscopy scores (modified pouchitis disease activity index) produced an area under the curve of 0.995. Establishing a cut-point of five or more for diseased patients resulted in a sensitivity equal to 97 percent and specificity equal to 100 percent. CONCLUSIONS: Diagnosis based on the modified pouchitis disease activity index offers similar sensitivity and specificity when compared with the pouchitis disease activity index for patients with acute or acute relapsing pouchitis. Omission of endoscopic biopsy and histology from the standard pouchitis disease activity index would simplify pouchitis diagnostic criteria, reduce the cost of diagnosis, and avoid delay associated with determining histology score, while providing equivalent sensitivity and specificity.