Severe Pouchitis Research Articles

Can preoperative CT/MR enterography preclude the development of Crohn's disease-like pouch complications in ulcerative colitis patients undergoing J pouch surgery?

We aimed to determine whether ulcerative colitis patients with preoperative negative computed tomography or magnetic resonance enterography (CTE/MRE) were less likely to develop Crohn's disease-like pouch complications (CDLPC) and establish risk factors and predictors for developing CDLPC. This was a single centre retrospective analysis of patients with ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBDU) who underwent total proctocolectomy with ileal J-pouch between January 2010 and December 2020. The study group comprised patients with negative preoperative CTE/MRE and the control group included patients operated without preoperative CTE/MRE. A total of 131 patients were divided into the negative CTE/MRE study group (76 [58%] patients) and control group (55 [42%] patients). There were no significant differences in incidence rates (21% vs. 23.6%, p = 0.83), time to developing CDLPC from ileostomy closure (22.3 vs. 23.8 months; p = 0.81), pouchitis rates (23.6% vs. 27.2%; p = 0.68), or pouch failure rates (5.2 vs. 7.2; p = 0.71). Multivariate Cox regression analysis showed backwash ileitis (HR 4.1; p = 0.03, CI: 1.1-15.1), severe pouchitis (HR 3.4; p = 0.039, CI: 1.0-10.9), and history of perianal disease (HR 3.4; p = 0.017, CI: 1.4-39.6) were independent predictors for CDLPC. Negative findings on MRE/CTE prior to J-pouch surgery in ulcerative colitis should be interpreted with caution as it is does not reliably exclude or predict development of CDLPC. These patients should be preoperatively counselled concerning the possibility of developing CDLPC regardless of lack of positive findings on preoperative CTE/MRE. Patients with backwash ileitis with a previous history of perianal disease should be informed of the potentially increased risk of developing such complications.

Vedolizumab for the Treatment of Chronic Pouchitis

BackgroundApproximately half the patients with ulcerative colitis who undergo restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) will subsequently have pouchitis, and among those patients, one fifth will have chronic pouchitis.MethodsWe conducted a phase 4, double-blind, randomized trial to evaluate vedolizumab in adult patients in whom chronic pouchitis had developed after undergoing IPAA for ulcerative colitis. Patients were assigned (in a 1:1 ratio) to receive vedolizumab intravenously at a dose of 300 mg or placebo on day 1 and at weeks 2, 6, 14, 22, and 30. All the patients received concomitant ciprofloxacin from weeks 1 to 4. The primary end point was modified Pouchitis Disease Activity Index (mPDAI)–defined remission (an mPDAI score of ≤4 and a reduction from baseline of ≥2 points in the mPDAI total score; scores range from 0 to 12, with higher scores indicating more severe pouchitis) at week 14. The mPDAI is based on clinical symptoms and endoscopic findings. Other efficacy end points included mPDAI-defined remission at week 34, mPDAI-defined response (a reduction from baseline of ≥2 points in the mPDAI score) at weeks 14 and 34, and PDAI-defined remission (a PDAI score of ≤6 and a reduction from baseline of ≥3 points; scores range from 0 to 18, with higher scores indicating more severe pouchitis) at weeks 14 and 34. The PDAI is based on clinical symptoms, endoscopic findings, and histologic findings.ResultsAmong the 102 patients who underwent randomization, the incidence of mPDAI-defined remission at week 14 was 31% (16 of 51 patients) with vedolizumab and 10% (5 of 51 patients) with placebo (difference, 21 percentage points; 95% confidence interval [CI], 5 to 38; P=0.01). Differences in favor of vedolizumab over placebo were also seen with respect to mPDAI-defined remission at week 34 (difference, 17 percentage points; 95% CI, 0 to 35), mPDAI-defined response at week 14 (difference, 30 percentage points; 95% CI, 8 to 48) and at week 34 (difference, 22 percentage points; 95% CI, 2 to 40), and PDAI-defined remission at week 14 (difference, 25 percentage points; 95% CI, 8 to 41) and at week 34 (difference, 19 percentage points; 95% CI, 2 to 37). Serious adverse events occurred in 3 of 51 patients (6%) in the vedolizumab group and in 4 of 51 patients (8%) in the placebo group.ConclusionsTreatment with vedolizumab was more effective than placebo in inducing remission in patients who had chronic pouchitis after undergoing IPAA for ulcerative colitis. (Funded by Takeda; EARNEST ClinicalTrials.gov number, NCT02790138; EudraCT number, 2015-003472-78.)

P584 Efficacy, safety, and tolerability of AMT-101, a gut selective oral IL-10 fusion, in the Phase 2 FILLMORE trial of patients with chronic pouchitis

Abstract Background Chronic pouchitis can occur in up to half of patients within 10 years of ileal pouch-anal anastomosis (IPAA) after proctocolectomy for ulcerative colitis (UC). There is a large unmet need for medical treatments. Methods This was a phase 2, randomized double-blind, parallel-group, 2 active-arm trial of the combined phase 2/3 trial in adults (18-75 years) with a prior history of UC with proctocolectomy and subsequent IPAA, who presented with chronic or recurrent pouchitis. The trial was conducted in US, Canada, and Western Europe. Approximately 20 patients were planned to be randomized 1:1 to either 3 mg or 10 mg AMT-101 doses administered once daily, orally, for 12 weeks. The key efficacy endpoints were: 1) the proportion of patients with symptomatic improvement, as measured by stool frequency response, and 2) the proportion of patients with histologic healing, as measured by Geboes scores. Histology and endoscopy were centrally read. Results 22 patients were randomized to receive AMT-101 3 mg (n=10) or 10 mg (n=12). The mean (SD) baseline absolute stool frequency was 13.4 (4.5). Overall, 36.4% (8/22) of patients achieved stool frequency response, defined as either a reduction of ≥ 3 stools and a ≥ 30% reduction in number of stools from baseline, or a return to post-IPAA number of stools or lower, at Week 12. 40% (4/10) and 33% (4/12) of patients dosed with 3 mg or 10 mg, respectively, achieved stool frequency response at Week 12. Rapidity of stool frequency response was demonstrated as early as Week 2 in both arms and was substantially maintained through Week 12. Patients had a median (IQR) baseline Geboes score of 5.1 (3.2 to 5.2), representing severe pouchitis with ulceration and tissue destruction. Across both arms, 22.7% (5/22) [20.0% (3 mg) and 25.0% (10 mg)] of patients met the histologic healing response of Geboes score ≤ 3.1, an objective assessment of disease improvement. Endoscopic assessments (SES-CD, ≥50% reduction) were also performed, with modest improvements [10% (3 mg) and 8.3% (10 mg)] at Week 12. There was no systemic AMT-101 PK (by design) nor anti-drug antibodies detected. Translational analysis revealed IL-10 biological responses in both arms. In tissue, IHC results showed increases in anti-inflammatory FOXP3+ (Tregs) and CD163+ (M2-macrophages) cells in the lamina propria. Treatment emergent adverse events were mostly mild to moderate, with only one treatment-unrelated serious adverse event. Conclusion AMT-101 3 mg and 10 mg both appeared to be safe and generally well tolerated. PK and translational data confirmed AMT-101’s gut-restricted profile over the 12-week treatment with tissue-level PD effects and no systemic exposure. The AMT-101 3 mg dose is advancing into a Phase 3 trial for chronic pouchitis.

A Case Report of Severe Pouchitis after Total Colectomy for Ulcerative Colitis Successfully Treated with Leukapheresis

A Case Report of Severe Pouchitis after Total Colectomy for Ulcerative Colitis Successfully Treated with Leukapheresis

Laparoscopic Proctocolectomy for Ulcerative Colitis and Crohn’s Disease of the Large Intestine: Short-Term and Long-Term Outcomes of 53 Cases

One- or two-stage restorative total colectomy is recognized as surgery of choice when treating ulcerative colitis and Crohn’s disease of the large intestine. The possible advantages of laparoscopic approach are still being discussed. The objective of the research was to evaluate postoperative quality of life, short-term and long-term functional outcomes of 53 cases of laparoscopically assisted proctocolectomy for ulcerative colitis and Crohn’s disease of the large intestine in order to improve further application of laparoscopic approach. Materials and methods. Primary restorative proctocolectomy with transanal mucosectomy and the ileal pouch-anal anastomosis was performed in 5 patients with ulcerative colitis; total colectomy with low anterior resection of the rectum and double stapling ileal pouch-rectal anastomosis was performed in 8 patients; total proctocolectomy (with abdominoperineal resection of the rectum, terminal ileostomy) was performed in 3 patients with Crohn’s disease and multiple perianal fistulas; total colectomy, low anterior resection of the rectum, and terminal ileostomy (the first stage of surgical treatment) was performed in 37 patients; the second stage restorative surgery (J-pouch construction and the pouch-anal/low rectal anastomosing) was performed in 17 patients. The restorative procedure was followed by temporary diverting ileostomy in all patients.Results. The conversion to laparotomy was required in 3 (5.7%) cases. In one case during the second stage restorative surgery the urine bladder wall was damaged, and sutured laparoscopically. There was no postoperative mortality. The major complications of the early postoperative period included pelvic abscesses (4 patients), pouch-anal anastomosis leakage (1 patient), postoperative ileus (3 patients), and ileal pouch-perineal fistula (1patient). Stool frequency was about 6 times in a 24 hour period (4-11 times) 12 months after ileostomy closure. Pouchitis was observed in 4 patients. Pouch failure occurred in 1 patient due to severe pouchitis and anal incontinence.Conclusions. Laparoscopic proctocolectomy with extracorporeal ileal pouch construction, transanal mucosectomy, and pouch-anal anastomosis are considered as surgery of choice for ulcerative colitis. The pouch-rectal anastomosing is feasible for Crohn’s disease in individual cases. Total laparoscopic proctocolectomy with intracorporeal ileal pouch construction may be the next step in clinical trials.

Endoscopic needle knife fistulotomy technique for ileal pouch-to-pouch fistula

A 19-year-old woman with refractory pan-ulcerative colitis, diagnosed in 2004, underwent a total proctocolectomy in 2006, followed by a two-stage ileoanal pull-through procedure. Severe pouchitis led to a two-stage J-pouch reconstruction in 2012. In June 2014, magnetic resonance enterography showed a pre-sacral abscess, which was drained percutaneously.

Large bowel mucosal neoplasia in the original specimen may increase the risk of ileal pouch neoplasia in patients following restorative proctocolectomy for ulcerative colitis

PurposeRestorative proctocolectomy is a current gold standard procedure for patients who require a colectomy for ulcerative colitis. The incidence of ileal pouch neoplasia is low. The aims of this study were to assess the prevalence of neoplasia in ileal pouch and investigate the risk factors for ileal pouch neoplasia.MethodsA total of 276 patients who underwent restorative proctocolectomy for ulcerative colitis between 1984 and 2009 were analyzed. Results of histological examinations of both original specimen and biopsies from the J-pouch taken during routine pouch endoscopy were evaluated. Patients’ records were analyzed for ulcerative colitis duration, the time from pouch creation to pouch neoplasia, presence of pouchitis, as well as the concurrent primary sclerosing cholangitis.ResultsAnalyzing the original specimen of large bowel, fifty-six lesions of low-grade dysplasia, twenty-five high-grade dysplasia, and five adenocarcinoma were revealed. All patients with dysplasia (n = 8) or adenocarcinoma (n = 1) of the J-pouch were positive for dysplasia in the original specimen. Duration of ulcerative colitis before surgery and duration time following restorative proctocolectomy were found as risk factors for J-pouch neoplasia with a significant difference (p = 0.01 and p = 0.0003, respectively). Patients with pouch neoplasia developed significantly more severe pouchitis (p = 0.00001).ConclusionsNeoplasia of the J-pouch is rare. Patients with neoplasia in the original specimen are more susceptible to develop neoplasia in the J-pouch. Precise follow-up in patients with neoplasia lesions in the original specimen should be recommended. Moreover, in patients with risk factors, the exact surveillance pouch endoscopy should be recommended.

Update on the pathogenesis and management of pouchitis.

Pouchitis is an inflammatory complication after restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA). IPAA is the surgical treatment of choice in patients with ulcerative colitis (UC) who require colectomy. Initial episodes of acute pouchitis generally respond to antibiotics but significant numbers of cases eventually become dependent on or refractory to antibiotics. Management of chronic antibiotic refractory pouchitis is challenging and can ultimately lead to pouch failure. The etiopathogenesis is unknown though recent studies have implicated bacterial dysbiosis of the pouch microbiota, NOD2 polymorphism, and Clostridium difficile infection in the development of severe pouchitis. Early identification of risk factors can help in tailoring therapy and reducing cases of chronic pouchitis.

Commentary: the effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis – authors' reply

In the study by Persborn et al., UC patients with pou-chitis entering remission following 4 weeks of combina-tion antibiotic therapy were treated with Ecologic 825for 8 weeks. They demonstrated that probiotics mayrestore mucosal barrier function and that bacterialdiversity correlates with barrier function. However, theprobiotic supplement did not influence the compositionof the mucosal pouch microbiota and, in the absence ofa control or placebo group, these findings may representconsequences of mucosal healing following induction ofremission with antibiotics.Larger studies are needed to assess whether, and bywhat mechanisms, probiotics affect epithelial barrierfunction in the maintenance of pouchitis and other typesof IBD and whether this mechanism of action is linkedto prevention of relapse. However, this study raisesimportant issues regarding the use of probiotics in thetreatment of IBD. It is essential to consider whether theprobiotic is intended to affect a particular immunothera-peutic target, or to alter the mucosal or the luminal com-position of the microbiota. It is also important toconsider the phase of disease in which probiotic therapymay be most efficacious, perhaps depending on theintended therapeutic target.ACKNOWLEDGEMENTDeclaration of personal interests: Dr Landy has receivedresearch funding from the Broad foundation as anemployee of Imperial College London. Dr Hart has beena speaker for and is on the adivsory board for MSD,Shire and Abbott. Dr Hart is an employee of North WestLondon Hospitals Trust.Declaration of funding interests: None.REFERENCES

Commentary: the effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis

Epithelial barrier function is likely to be critical in the initiation and persistence of intestinal inflammation. Impaired barrier function is present in Crohn’s, ulcerative colitis (UC) and pouchitis during active disease and remission. Strategies targeting restitution of barrier function are required for the treatment of inflammatory bowel diseases (IBD). Persborn et al. report the effects of the probiotic mixture Ecologic 825 on barrier function during maintenance treatment of pouchitis. Evidence for probiotics in the treatment, prevention and maintenance of remission of pouchitis is established. However, their mechanisms of action are as yet unknown. Probiotics increase bacterial diversity and alter innate and adaptive immune responses. In vitro and in animal models probiotics alter epithelial barrier function and the expression and distribution of epithelial tight junctions. In the study by Persborn et al., UC patients with pouchitis entering remission following 4 weeks of combination antibiotic therapy were treated with Ecologic 825 for 8 weeks. They demonstrated that probiotics may restore mucosal barrier function and that bacterial diversity correlates with barrier function. However, the probiotic supplement did not influence the composition of the mucosal pouch microbiota and, in the absence of a control or placebo group, these findings may represent consequences of mucosal healing following induction of remission with antibiotics. Larger studies are needed to assess whether, and by what mechanisms, probiotics affect epithelial barrier function in the maintenance of pouchitis and other types of IBD and whether this mechanism of action is linked to prevention of relapse. However, this study raises important issues regarding the use of probiotics in the treatment of IBD. It is essential to consider whether the probiotic is intended to affect a particular immunotherapeutic target, or to alter the mucosal or the luminal composition of the microbiota. It is also important to consider the phase of disease in which probiotic therapy may be most efficacious, perhaps depending on the intended therapeutic target.

The effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis

A total of 10-15% of patients with an ileoanal pouch develop severe pouchitis necessitating long-term use of antibiotics or pouch excision. Probiotics reduce the risk of recurrence of pouchitis, but mechanisms behind these effects are not fully understood. To examine mucosal barrier function in pouchitis, before and after probiotic supplementation and to assess composition of mucosal pouch microbiota. Sixteen patients with severe pouchitis underwent endoscopy with biopsies of the pouch on three occasions: during active pouchitis; clinical remission by 4 weeks of antibiotics; after 8 weeks of subsequent probiotic supplementation (Ecologic 825, Winclove, Amsterdam, the Netherlands). Thirteen individuals with a healthy ileoanal pouch were sampled once as controls. Ussing chambers were used to assess transmucosal passage of Escherichia coli K12, permeability to horseradish peroxidase (HRP) and ⁵¹Cr-EDTA. Composition and diversity of the microbiota was analysed using Human Intestinal Tract Chip. Pouchitis Disease Activity Index (PDAI) was significantly improved after antibiotic and probiotic supplementation. Escherichia coli K12 passage during active pouchitis [3.7 (3.4-8.5); median (IQR)] was significantly higher than in controls [1.7 (1.0-2.4); P < 0.01], did not change after antibiotic treatment [5.0 (3.3-7.1); P = ns], but was significantly reduced after subsequent probiotic supplementation [2.2 (1.7-3.3); P < 0.05]. No significant effects of antibiotics or probiotics were observed on composition of mucosal pouch microbiota; however, E. coli passage correlated with bacterial diversity (r = -0.40; P = 0.018). Microbial groups belonging to Bacteroidetes and Clostridium clusters IX, XI and XIVa were associated with healthy pouches. Probiotics restored the mucosal barrier to E. coli and HRP in patients with pouchitis, a feasible factor in prevention of recurrence during maintenance treatment. Restored barrier function did not translate into significant changes in mucosal microbiota composition, but bacterial diversity correlated with barrier function.

The Role of Genetics in the Surgical Management of Inflammatory Bowel Disease

The relatively recent discoveries of >100 genes potentially involved with the etiology of inflammatory bowel disease (IBD) have stimulated intense research. The study of the pathophysiologic consequences of defects in these genes and the potential for a more careful classification of IBD patients based on genotype are two evolving benefits of this newfound knowledge. However, the use of such genetic information in the clinical care of IBD patients, especially in the surgical field, has lagged. There are many unresolved surgical issues in IBD management that hold hope for improvement through the use of genetic information in the individual patient. This includes, for example, identifying Crohn's disease patients at increased risk for recurrence after surgery to institute earlier prophylactic measures or maximize the use of bowel length preserving procedures. In the case of ulcerative colitis, genetics may help in preoperative patient selection by predicting which patients might suffer from severe pouchitis or pouch-threatening complications, such as fistuli or strictures. Similarly, the imperfect ability of colonoscopy to identify colitic patients who develop cancer may be solved by genetic markers that would predict malignant degeneration and so allow more effective prophylactic surgery.

Genetic Risk Profiling and Gene Signature Modeling to Predict Risk of Complications After IPAA

Severe pouchitis and Crohn's disease-like complications are 2 adverse postoperative complications that confound the success of the IPAA in patients with ulcerative colitis. To date, approximately 83 single nucleotide polymorphisms within 55 genes have been associated with IBD. The aim of this study was to identify single-nucleotide polymorphisms that correlate with complications after IPAA that could be utilized in a gene signature fashion to predict postoperative complications and aid in preoperative surgical decision making. One hundred forty-two IPAA patients were retrospectively classified as "asymptomatic" (n = 104, defined as no Crohn's disease-like complications or severe pouchitis for at least 2 years after IPAA) and compared with a "severe pouchitis" group (n = 12, ≥ 4 episodes pouchitis per year for 2 years including the need for long-term therapy to maintain remission) and a "Crohn's disease-like" group (n = 26, presence of fistulae, pouch inlet stricture, proximal small-bowel disease, or pouch granulomata, occurring at least 6 months after surgery). Genotyping for 83 single-nucleotide polymorphisms previously associated with Crohn's disease and/or ulcerative colitis was performed on a customized Illumina genotyping platform. The top 2 single-nucleotide polymorphisms statistically identified as being independently associated with each of Crohn's disease-like and severe pouchitis were used in a multivariate logistic regression model. These single-nucleotide polymorphisms were then used to create probability equations to predict overall chance of a positive or negative outcome for that complication. The top 2 single-nucleotide polymorphisms for Crohn's disease-like complications were in the 10q21 locus and the gene for PTGER4 (p = 0.006 and 0.007), whereas for severe pouchitis it was NOD2 and TNFSF15 (p = 0.003 and 0.011). Probability equations suggested that the risk of these 2 complications greatly increased with increasing number of risk alleles, going as high as 92% for severe pouchitis and 65% for Crohn's disease-like complications. In this IPAA patient cohort, mutations in the 10q21 locus and the PTGER4 gene were associated with Crohn's disease-like complications, whereas mutations in NOD2 and TNFSF15 correlated with severe pouchitis. Preoperative genetic analysis and use of such gene signatures hold promise for improved preoperative surgical patient selection to minimize these IPAA complications.

Inulin supplementation in rat model of pouchitis.

Available data indicates potential effectiveness of prebiotic therapy in alleviating inflammation and prolonging the remission in inflammatory bowel disease. Documented successes of such therapies were the basis for this study. So far, there is no data related to the effectiveness of inulin application in symptomatic or severe pouchitis in humans or in animal model. The aim of the study was to determine the effect of inulin supplementation on the expression of intestinal inflammation and feeding efficiency in rats with induced pouchitis. Twenty-four Wistar rats were operated. After induction of pouchitis animals were randomly divided into control and supplementation groups receiving, respectively, semi-synthetic diet with or without inulin (in a lower (LD) or higher (HD) dose: 2.5 % or 5 % of total dietary content of mass) for a period of 6 weeks. Selected nutritional parameters were assessed throughout the study. Histopathological and immunohistochemical analysis of pouch mucosa specimens was also performed. The energy intake, weight gain, feeding efficiency, quality of stools were comparable in all studied groups. The intensity of inflammation (Moskovitz scale) and adaptive changes (Laumonier scale) did not differ between compared groups. The tissue expression of pro- and anti-inflammatory interleukins (IL-1α, IL-6, IL-10 and IL-12) was not different either. Inulin supplementation does not improve the quality of stools or the expression of intestinal inflammation in rats with induced pouchitis. It has no impact on the intensity of pouch adaptation or on feeding efficiency.

Are Inflammatory Bowel Disease Patients at an Increased Risk for Early Atherosclerosis? A Meta-Analysis

BODY: Background: Several studies have demonstrated that patients with inflammatory bowel diseases (IBD) have a high prevalence of Vitamin D deficiency. In addition, it has been postulated that low Vitamin D status is associated with more severe disease activity. There are limited data on the vitamin D status in ulcerative colitis patients after ileal pouch-anal anastomosis (IPAA). The purpose of this study was to assess the prevalence of vitamin D deficiency and insufficiency in patients after IPAA and to determine if there is an association between the severity of pouchitis and vitamin D status. Methods: We conducted a retrospective chart review of ulcerative colitis patients followed in the Center for Digestive Disorders at the Boston Medical Center who underwent an IPAA for ulcerative colitis (UC) between January 1, 2010 and November 15, 2010 and who had 25-hydroxyvitamin D [25(OH)D] levels obtained as part of their routine care. Demographic and clinical variables including patient age, gender, and race were obtained. 25(OH) D levels 30 ng/ml (p=0.822). 18.2% of vitamin D deficient patients had severe pouchitis compared with 25.0% of patients with normal 25(OH) D levels. Conclusion: Nearly all ulcerative colitis patients after IPAA are vitamin D deficient or insufficient. However, vitamin D status did not correlate with the severity of pouchitis. Future studies are needed to determine if vitamin D supplementation improves clinical outcomes after IPAA.

Infliximab and/or Azathioprine in the Treatment of Crohn's Disease-Like Complications After IPAA

Ileal pouch-anal anastomosis continues to be confounded by Crohn's disease-like complications after surgery. Such patients experience significant morbidity and often require either pouch excision or diversion. This study evaluated the effectiveness in our hands of infliximab and/or azathioprine/6-mercaptopurine in treating this patient population. We conducted a retrospective chart review of all patients who underwent IPAA who experienced Crohn's disease-like complications (pouch fistulas, stricturing small-bowel disease, or pouchitis unresponsive to antibiotics) after ileostomy closure. Patients were segregated according to treatment (azathioprine/6-mercaptopurine only, infliximab only, or both azathioprine/6-mercaptopurine and infliximab) and evaluated for clinical response defined by significant symptomatic improvement and avoidance of stoma. Of 382 IPAAs, 32 (8.4%) patients developed Crohn's disease-like complications a mean of 17 months after stoma closure. Of these, 22 were treated with azathioprine/6-mercaptopurine and/or infliximab with one lost to follow-up. Overall mean follow-up was 97 ± 11.8 months. Failure rate (requiring stomas) was highest in the fistula group treated with infliximab and azathioprine/6-mercaptopurine (6/13, 46%). Patients with stricturing disease (6) or severe pouchitis (2) were all effectively treated with azathioprine/6-mercaptopurine (5/6) or infliximab (1 patient allergic to azathioprine/6-mercaptopurine) and none of these patients required stomas. In the group not receiving stomas, bowel frequency improved from 8.3 ± 1 to 5.7 ± 0.5 per day (P < .05). Fistulizing disease after IPAA has the highest failure/stoma rate (46%) despite treatment with infliximab and/or azathioprine/6-mercaptopurine. IPAA patients with stricturing disease and/or antibiotic resistant pouchitis were successfully treated without stomas and all had resolution of symptoms, which suggests that fistulous disease after IPAA should be treated with infliximab, but stricturing disease and antibiotic resistant pouchitis may be effectively treated with azathioprine/6-mercaptopurine only. Such a protocol will potentially minimize the risks associated with infliximab in this difficult group of patients.

NOD2/CARD15 Mutations Correlate With Severe Pouchitis After Ileal Pouch-Anal Anastomosis

Pouchitis and Crohn's-like complications can plague patients after IPAA. NOD2 is an intracellular sensor for bacterial cell wall peptidoglycan. NOD2 mutations compromise host response to enteric bacteria and are increased in Crohn's disease. We hypothesize that IPAA patients with complications (Crohn's disease-like/pouchitis) have a higher rate of NOD2 mutations compared with asymptomatic IPAA patients. Patients were retrospectively subclassified into the following groups: 1) IPAA with Crohn's-like complications (n = 28, perianal fistula, pouch inlet stricture/upstream small-bowel disease, or biopsies showing granulomata) occurring at least 6 months after ileostomy closure; 2) IPAA with mild pouchitis (n = 33, ≤3 episodes/y for 2 consecutive years); 3) IPAA with severe pouchitis (n = 9, ≥4 episodes/y for 2 consecutive years or need for continuous antibiotics); 4) IPAA without complications or pouchitis (n = 37); 5) patients with Crohn's disease with colitis undergoing total proctocolectomy/ileostomy (n = 11); and 6) healthy controls (n = 269). The 3 NOD2 single-nucleotide polymorphism mutations (rs2066844, rs2066845, and rs2066847) previously identified as associated with Crohn's disease were genotyped using polymerase chain reaction. Groups were compared by use of χ with Yates continuity correction. NOD2 mutations were found in 8.5% of healthy controls. NOD2 mutations were significantly higher in the severe pouchitis group (67%) compared with both asymptomatic IPAA (5.4%, P < .001) and IPAA with Crohn's disease-like complications (14.3%, P = .008) groups. 1) Asymptomatic IPAA patients have a low incidence of NOD2 mutations not significantly different from patients with mild pouchitis or healthy controls. 2) Patients with severe pouchitis had the highest incidence of NOD2 mutations, suggesting that this group may have a compromised host defense mechanism to enteric bacteria. 3) Patients with Crohn's-like complications after IPAA have a significantly lower incidence of NOD2 mutations than patients with severe pouchitis, suggesting a different genetic makeup in these 2 patient groups. Preoperative assessment of NOD2 in the equivocal IPAA candidate may predict severe pouchitis and might assist in preoperative surgical decision making.

Successful treatment for pouchitis with rebamipide refractory to a combination of metronidazole (MNZ) and ciprofloxacin (CFX).

A 35-year-old male who had undergone proctocolectomy and ileo-anal pouch surgery (IPAA) because of ulcerative colitis presented with worsening diarrhea and hematochezia. Pouchitis was diagnosed, and he was prescribed with metronidazole (MNZ) and a betamethasone enema. However, his condition did not remarkably improve despite these strategies. Endoscopy revealed ulceration and inflammation in the ileal pouch together with contact bleeding and mucous discharge. He underwent granulocytapheresis (G-CAP) and was prescribed anal 5-aminosalicylic acid (5-ASA) and oral prednisolone. Oral azathioprine (AZA) and a combination of MNZ and ciprofloxacin (CFX) did not result in any improvement. He was then treated with rebamipide enemas twice daily for 8weeks without additional drug therapy. Two weeks thereafter, stool frequency started to decrease, fecal hemoglobin became negative, and his symptoms gradually improved. Endoscopic findings after the rebamipide therapy showed that the ulcers in the ileal pouch had mostly healed without obvious inflammation and bleeding. Rebamipide was thus maintained throughout the therapeutic period and for 13months of follow-up. Rebamipide effectively treated severe pouchitis that was refractory to intensive conventional medication including antibiotics and corticosteroids.

Ileo-anal j-pouch cancer: an unusual case in an unusual location

Restorative proctocolectomy with ileal pouchanal anastomosis (IPAA) is the surgical treatment of choice for complicated ulcerative colitis. Development of ileal pouch-related cancer is a rare event and usually occurs in association with backwash ileitis or chronic pouchitis. We report a case of adenocarcinoma at the inlet of an ileal pouch in a 68-year-old Caucasian male, 14 years after restorative proctocolectomy for ulcerative colitis in the absence of severe chronic pouchitis or backwash ileitis. The operative technique is described, with a review of the literature on ileal pouch cancer.

Clostridium Difficile-Associated Pouchitis

Pouchitis is the most common long-term sequela of ileal pouch-anal anastomosis (IPAA) following total proctocolectomy. No single pathogen is identified as being solely responsible for the pathogenesis of the disease. Here we describe a case of Clostridium difficile-associated pouchitis that was successfully treated with ciprofloxacin and tinidazole. Diagnosis and management of a patient with medically refractory pouchitis associated with Clostridium difficile infection is described. A 63-year-old male with underlying ulcerative colitis and IPAA presented with increased stool frequency and seepage for 2 months, which partially responded to oral metronidazole. While on the antibiotic therapy, pouch endoscopy was performed and showed severe pouchitis. Assays for Clostridium difficile toxins in stool specimens were positive. He was treated with a 4-week course of ciprofloxacin 500 mg BID and tinidazole 500 mg TID. His symptoms resolved within several days from the initiation of therapy. A repeat pouch endoscopy at week 5 showed a complete resolution of mucosal inflammation of the pouch, while tests for Clostridium difficile toxins became negative. Clostridium difficile-associated pouchitis is rare. However, Clostridium difficile infection should be excluded in patients with chronic refractory pouchitis.