Histopathological Evaluation of Pouch Neoplasia in IBD and Familial Adenomatous Polyposis.

BACKGROUND: IPAA is often required for patients with ulcerative colitis or familial adenomatous polyposis after colectomy. This procedure reduces but does not completely eliminate the risk of neoplasia. OBJECTIVE: This study focuses on the histopathology of neoplasia in the ileal pouch, rectal cuff, and anal transition zone. DATA SOURCES: We performed a MEDLINE search for English-language studies published between 1981 and 2022 using the PubMed search engine. The terms "ileal pouch-anal anastomosis," "pouchitis," "pouch dysplasia," "pouch lymphoma," "pouch squamous cell carcinoma," "pouch adenocarcinoma," "pouch neoplasia," "dysplasia of rectal cuff," and "colitis-associated dysplasia" were used. STUDY SELECTION: Human studies of neoplasia occurring in the pouch and para-pouch were selected, and the full text was reviewed. Comparisons were made within and across studies, with key concepts selected for inclusion in this article. CONCLUSIONS: Neoplasia in the pouch is a rare complication in patients with IPAA. Annual endoscopic surveillance is recommended for familial adenomatous polyposis patients and ulcerative colitis patients with a history of prior dysplasia or carcinoma. In familial adenomatous polyposis, dysplastic polyps of the pouch are visible and readily amenable to endoscopic removal; however, glandular dysplasia in the setting of ulcerative colitis may be invisible on endoscopy. Therefore, random biopsies and adequate tissue sampling of the pouch and rectal cuff are recommended in this setting. The histological diagnosis of IBD-associated dysplasia can be challenging and should be confirmed by at least 1 expert GI pathologist. See video from the symposium.

Histologic Activity in an Endoscopically Normal-Appearing Pouch Predicts Future Risk of Pouchitis in Patients With Ulcerative Colitis.

INTRODUCTION: The impact of histologic inflammation on subsequent risk of acute pouchitis in patients with ulcerative colitis (UC) has not been robustly examined. METHODS: We examined the association between histologic inflammation in endoscopically normal-appearing ileal pouches in patients with UC with subsequent risk of antibiotic-responsive acute pouchitis. RESULTS: Among 163 study patients, 53% had histologic inflammation in an endoscopically normal-appearing ileal pouch. Histologic inflammation in the pouch was associated with an increased risk of pouchitis (24.1% vs 6.8%, adjusted odds ratio 4.41, 95% confidence interval 1.48-13.20). DISCUSSION: Histologic inflammation in an endoscopically normal pouch was associated with an increased risk of acute pouchitis.

The Reliability and Accuracy of Endoscopic Items and Scores Used in the Assessment of the Ileoanal Pouch and Cuff.

BACKGROUND AND AIMS: Currently used endoscopic items for the assessment of pouchitis and cuffitis have deficiencies in reliability and validation. We assessed the reliability and accuracy of new endoscopic items for pouchitis and of the Ulcerative Colitis Endoscopic Index of Severity [UCEIS] for cuffitis. METHODS: Three new endoscopic items were assessed and included in the Monash pouchitis endoscopic subscore: bleeding [absent/contact/spontaneous]; erosions [absent/<10/≥10]; and ulceration [absent/<10%/≥10%]. Three raters evaluated 44 pouchoscopy videos in duplicates, in random order. Intra- and inter-rater reliability of all endoscopic items and UCEIS were assessed. Clinical and histological pouchitis disease activity index [PDAI] subscores were also assessed and faecal calprotectin was measured. RESULTS: All three Monash endoscopic items had substantial intra-rater reliability with intraclass correlation coefficients [ICCs] >0.61 [95% CI >0.61], compared with only ulcers from the currently used PDAI endoscopic subscore, but inter-rater reliability was only substantial for ulceration and no better than those of the currently used endoscopic items. The Monash endoscopic subscore had a strong positive correlation with the reference standard global endoscopic lesion severity r = 0.80 [95% CI 0.80-0.80] and the reference standard PDAI endoscopic subscore r = 0.70 [95% CI 0.67-0.73], which was higher than the correlation observed for the currently used PDAI endoscopic subscore. The UCEIS had substantial intra-rater reliability, but only fair inter-rater reliability and poor diagnostic performance for cuffitis. CONCLUSIONS: The Monash endoscopic items, and endoscopic subscore they generate, have enhanced overall performance compared with the currently used PDAI items and subscore. Further validation and responsiveness to change in disease state are indicated.

Disease Activity Indices for Pouchitis: A Systematic Review.

BACKGROUND: Several indices exist to measure pouchitis disease activity; however, none are fully validated. As an initial step toward creating a validated instrument, we identified pouchitis disease activity indices, examined their operating properties, and assessed their value as outcome measures in clinical trials. METHODS: Electronic databases were searched to identify randomized controlled trials including indices that evaluated clinical, endoscopic, or histologic pouchitis disease activity. A second search identified studies that assessed the operating properties of pouchitis indices. RESULTS: Eighteen randomized controlled trials utilizing 4 composite pouchitis disease activity indices were identified. The Pouchitis Disease Activity Index (PDAI) was most commonly used (12 of 18; 66.7%) to define both trial eligibility (8 of 12; 66.7%), and outcome measures (12 of 12; 100%). In a separate search, 21 studies evaluated the operating properties of 3 pouchitis indices; 90.5% (19 of 21) evaluated validity, of which 42.1% (8 of 19) evaluated the construct validity of the PDAI. Criterion validity (73.7%; 14 of 19) was evaluated through correlation of the PDAI with fecal calprotectin (FCP; r = 0.188 to 0.71), fecal lactoferrin (r = 0.570 to 0.582), and C-reactive protein (CRP; r = 0.584). Two studies assessed correlation of the modified PDAI (mPDAI) with FCP (r = 0.476 and r = 0.565, respectively). Fair to moderate inter-rater reliability of the PDAI (k = 0.440) and mPDAI (k = 0.389) was reported in a single study. Responsiveness of the PDAI pre-antibiotic and postantibiotic treatment was partially evaluated in a single study of 12 patients. CONCLUSIONS: Development and validation of a specific pouchitis disease activity index is needed given that existing instruments are not valid, reliable, or responsive.

Meta-Analysis of IBD Gut Samples Gene Expression Identifies Specific Markers of Ileal and Colonic Diseases.

BACKGROUND: Inflammatory bowel diseases (IBDs) are characterized by chronic inflammation and tissue damages in limited segments of the digestive tract. Pathogenesis in the tissue and mucosal inflammation probably differs according to disease location. Our aim was to further analyze transcriptomic profiles in different locations of IBD, differentiating ulcerative colitis (UC), colonic Crohn's disease (CD), ileal CD, and pouchitis, with respect to normal colonic and ileal mucosa. We thus performed a meta-analysis focusing on specific transcriptomic signatures of ileal and colonic diseases. METHODS: We identified 5 cohorts with available transcriptomic data in ileal or colonic samples from active IBD and non-IBD control samples. The meta-analysis was performed on 1047 samples. In each cohort separately, we compared gene expression in CD ileitis and normal ileum; in CD colitis, UC, and normal colon; and finally in pouchitis and normal ileum. RESULTS: We identified specific markers of ileal (FOLH1, CA2) and colonic (REG3A) inflammation and showed that, with disease, some cells from the ileum start to express colonic markers. We confirmed by immunohistochemistry that these markers were specifically present in ileal or colonic diseases. We highlighted that, overall, colonic CD resembles UC and is distinct from ileal CD, which is in turn closer to pouchitis. CONCLUSIONS: We demonstrated that ileal and colonic diseases exhibit specific signatures, independent of their initial clinical classification. This supports molecular, rather than clinical, disease stratification, and may be used to design drugs specifically targeting ileal or colonic diseases.

We perform a meta-analysis of publicly available inflammatory bowel disease transcriptomes and identify FOLH1, REG3A, and CA2 as specific markers of ileal and colonic diseases. We demonstrate that Crohn's colitis resembles ulcerative colitis, while Crohn's ileitis resembles pouchitis.

Perianal Fistula After Ileoanal Pouch in Patients With Ulcerative Colitis: A Review of 475 Patients Operated on at a Major IBD Center.

BACKGROUND: Ileoanal pouch anastomosis is the surgical treatment of choice for patients with intractable ulcerative colitis. Perianal disease is a feature that is often present in Crohn's disease and infrequently in ulcerative colitis. OBJECTIVE: The aim of this study is to identify the incidence and factors associated with the development of postoperative perianal fistula in patients undergoing ileoanal pouch anastomosis for ulcerative colitis. DESIGN: A prospectively collected database at the time of surgery with subsequent follow-up was utilized. SETTING: The study was conducted at a high-volume single institution. PATIENTS: We studied a series of 475 consecutive patients with preoperative diagnosis of ulcerative colitis who underwent ileoanal pouch anastomosis. MAIN OUTCOME MEASURES: The incidence of postoperative perianal fistula and the factors correlating with its development were primary outcome measures of the study. RESULTS: The overall number of patients developing perianal fistulas was 44 of 475 (9%). Eleven patients with perianal fistula (25%) required return to ileostomy, of which 7 had pouch excision. Patients who developed a postoperative perianal fistula had a younger age at the onset of disease, had a lower age at index surgery, and were more likely to be subsequently classified as indeterminate colitis or Crohn's disease. Patients developing perianal fistulas were also more likely to develop partial dehiscence or stricture of the ileoanal anastomosis. LIMITATIONS: This study spans nearly 40 years during which the surgical procedure evolved. CONCLUSIONS: Young age at the onset of disease, lower age at surgery, and postoperative diagnosis of Crohn's disease and indeterminate colitis were the factors correlating with perianal fistulas. Delayed healing of the ileoanal anastomosis with partial separation and/or stricture also correlated with the onset of perianal fistulas. The severity of rectal inflammation at the time of surgery or the presence of stapled versus handsewn anastomosis did not correlate with the development of perianal fistulas. See Video Abstract at http://links.lww.com/DCR/B705. FSTULA PERIANAL POSTERIOR A RESERVORIO ILEOANAL EN PACIENTES CON COLITIS ULCERATIVA UNA REVISIN DE PACIENTES OPERADOS EN UN CENTRO PRINCIPAL DE EII: ANTECEDENTES:El reservorio ileoanal es el tratamiento quirúrgico de elección para los pacientes con colitis ulcerativa intratable. La enfermedad perianal es una característica que a menudo está presente en la enfermedad de Crohn y con poca frecuencia en la colitis ulcerativa.OBJETIVO:El objetivo del estudio es identificar la incidencia y los factores asociados con el desarrollo de fístula perianal posoperatoria en pacientes sometidos a reservorio ileoanal por colitis ulcerativa.DISEÑO:Base de datos recopilada prospectivamente en el momento de la cirugía con seguimiento subsecuente.ENTORNO CLÍNICO:El estudio se llevó a cabo en una única institución de gran volumen.PACIENTES:Estudiamos una serie de 475 pacientes consecutivos con diagnóstico preoperatorio de colitis ulcerativa a los que se les realizó reservorio ileoanal.PRINCIPALES MEDIDAS DE VALORACIÓN:La incidencia de fístula perianal posoperatoria y los factores que se correlacionan con su desarrollo fueron las principales medidas de resultado del estudio.RESULTADOS:El número total de pacientes que desarrollaron fístulas perianales fue 44 de 475 (9%). Once pacientes con fístula perianal (25%) requirieron volver a la ileostomía, de los cuales 7 tuvieron resección del reservorio. Los pacientes que desarrollaron fístula perianal posoperatoria tenían edad más temprana al inicio de la enfermedad, menor edad en el momento de la cirugía inicial y tenían más probabilidades de ser clasificados posteriormente como colitis indeterminada o enfermedad de Crohn. Los pacientes que desarrollaron fístulas perianales también fueron más propensos a desarrollar dehiscencia parcial o estenosis de la anastomosis ileoanal.LIMITACIONES:Este estudio abarca casi 40 años durante los cuales ha evolucionado el procedimiento quirúrgico.CONCLUSIONES:Edad temprana al inicio de la enfermedad, menor edad al momento de la cirugía, diagnóstico postoperatorio de enfermedad de Crohn y colitis indeterminada fueron los factores que se correlacionaron con las fístulas perianales. El retraso en la cicatrización de la anastomosis ileoanal con separación parcial y/o estenosis también se correlacionó con la aparición de fístulas perianales. La gravedad de la inflamación rectal en el momento de la cirugía o la presencia de anastomosis con grapas versus anastomosis manual no se correlacionó con el desarrollo de fístulas perianales. Consulte Video Resumen en http://links.lww.com/DCR/B705.

Appendiceal inflammation in colectomy is independently correlated with early pouchitis following ileal pouch anal anastomosis in ulcerative colitis and indeterminate colitis.

BACKGROUND: Appendiceal inflammation in colectomy is one of the histologic predictors of pouchitis in ulcerative colitis (UC) following ileal pouch anal anastomosis (IPAA). Fecal calprotectin level has been shown to increase 2 months prior to the onset of pouchitis. We evaluated whether inflammation and calprotectin expression in appendiceal specimens correlate with early-onset pouchitis in UC and indeterminate colitis (IC). MATERIALS AND METHODS: IPAA (2000-2018) cases with appendix blocks available in colectomy specimens were identified (n = 93, 90 UC, 3 IC). Histologic features thought to predict pouchitis were evaluated. The degree of appendiceal inflammation was scored. Calprotectin immunostain was performed on the appendix blocks and the extent of mucosal staining was quantified. Electronic medical records were reviewed for demographics, smoking history, clinical pouchitis, time of onset of pouchitis, and clinical and endoscopic components of the Pouchitis Disease Activity Index (PDAI) score. Follow-up pouch biopsies were reviewed and scored to generate histologic PDAI score, when available. RESULTS: Among the patients with clinical pouchitis (n = 73), moderate to severe appendiceal inflammation independently correlated with earlier pouchitis compared to no/mild inflammation (median time to pouchitis 12.0 vs. 23.8, log rank p = 0.016). Calprotectin staining correlated with inflammatory scores of the appendix (Spearman's rho, r = 0.630, p < 0.001) but not with early pouchitis (p > 0.05). CONCLUSIONS: The presence of moderate to severe appendiceal inflammation at the time of colectomy was associated with a shorter time to pouchitis following IPAA. Calprotectin immunostain may be used to demonstrate the presence of inflammation in the appendix but its role in predicting early pouchitis remains limited.

Pyloric gland metaplasia: Potential histologic predictor of severe pouch disease including Crohn's disease of the pouch in ulcerative colitis.

Crohn's disease of the pouch (CDP) is seen in a subset of ulcerative colitis (UC) patients following ileal pouch-anal anastomosis (IPAA). Histologic or clinical predictors of CDP are unknown. UC patients with subsequent CDP diagnosis were identified. The rationales for the diagnosis, the interval from the initial signs of CDP to the diagnosis, family history and smoking history were reviewed. Archived pathology materials were reviewed for the presence of pyloric gland metaplasia (PGM) and compared with those from UC with similar severity of pouchitis with CDP (matched UC controls), random UC controls, and ileocolectomies from primary CD patients. CDP diagnosis was made in 26 (18.1%) of 144 patients; all of them met commonly used diagnostic criteria for CDP. The diagnosis was rendered on average 15 months after the initial CD-like signs. PGM was found in 58% of CDP, more common than random UC controls but no different from primary CD and matched UC controls. PGM preceded first signs of CD in a subset. Patients with a family history of CD were more likely to develop CDP than those without a family history of any type of inflammatory bowel disease. Smoking status did not affect the likelihood of developing CDP. Finding PGM in proctocolectomy, ileostomy and follow-up biopsies in UC patients post IPAA may warrant close follow up for the potential development of pouchitis. Some of these patients, especially those with family history of CD, may further progress and develop severe disease meeting the clinical diagnostic criteria for CDP.

Single-Cell Transcriptional Survey of Ileal-Anal Pouch Immune Cells From Ulcerative Colitis Patients.

BACKGROUND & AIMS: Restorative proctocolectomy with ileal pouch-anal anastomosis is a surgical procedure in patients with ulcerative colitis refractory to medical therapies. Pouchitis, the most common complication, is inflammation of the pouch of unknown etiology. To define how the intestinal immune system is distinctly organized during pouchitis, we analyzed tissues from patients with and without pouchitis and from patients with ulcerative colitis using single-cell RNA sequencing (scRNA-seq). METHODS: We examined pouch lamina propria CD45+ hematopoietic cells from intestinal tissues of ulcerative colitis patients with (n = 15) and without an ileal pouch-anal anastomosis (n = 11). Further in silico meta-analysis was performed to generate transcriptional interaction networks and identify biomarkers for patients with inflamed pouches. RESULTS: In addition to tissue-specific signatures, we identified a population of IL1B/LYZ+ myeloid cells and FOXP3/BATF+ T cells that distinguish inflamed tissues, which we further validated in other scRNA-seq datasets from patients with inflammatory bowel disease (IBD). Cell-type-specific transcriptional markers obtained from scRNA-seq was used to infer representation from bulk RNA sequencing datasets, which further implicated myeloid cells expressing IL1B and S100A8/A9 calprotectin as interacting with stromal cells, and Bacteroidales and Clostridiales bacterial taxa. We found that nonresponsiveness to anti-integrin biologic therapies in patients with ulcerative colitis was associated with the signature of IL1B+/LYZ+ myeloid cells in a subset of patients. CONCLUSIONS: Features of intestinal inflammation during pouchitis and ulcerative colitis are similar, which may have clinical implications for the management of pouchitis. scRNA-seq enables meta-analysis of multiple studies, which may facilitate the identification of biomarkers to personalize therapy for patients with IBD. The processed single cell count tables are provided in Gene Expression Omnibus; GSE162335. Raw sequence data are not public and are protected by controlled-access for patient privacy.

Determinants of Pouch-Related Symptoms, a Common Outcome of Patients With Adenomatous Polyposis Undergoing Ileoanal Pouch Surgery.

INTRODUCTION: Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is performed in patients with adenomatous polyposis syndromes (APSs). Data regarding pouch outcomes in APS are scarce. The purposes of this study were to determine the prevalence of pouch-related symptoms in patients with APS and to identify the contributing factors. METHODS: This is a prospective cohort study. Demographic, surgical, and clinical data were collected. Endoscopy was performed, and biopsies from the terminal ileum, pouch, and cuff were obtained in all patients and reviewed by a dedicated pathologist. RESULTS: Fifty-one patients with APS after IPAA were followed. Twenty patients (39.2%) had pouch-related symptoms. Single-stage IPAA had better outcomes than 2-stage IPAA: fewer daily bowel movements (42.9% vs 13.8% with ≤5 daily bowel movement, P = 0.02), more solid consistency (52.4% vs 6.9%, P < 0.001), and less abdominal pain (19% vs 48.3%, P = 0.034). Younger age at IPAA (<20) was also associated with better outcomes: fewer daily bowel movement (58.3% vs 17.9% with ≤5 daily bowel movement, P = 0.011), less watery consistency (8.3% vs 53.8%, P = 0.005), and abdominal pain (8.3% vs 43.6%, P = 0.037). Eighteen patients (35.3%) had endoscopic signs of inflammation, and 22 patients (43.1%) had histologic signs of pouchitis. However, no correlation was found between symptoms and endoscopic or histologic findings. The median pouchitis disease activity index was low (2, interquartile range 1-4) and did not correlate with clinical symptoms. DISCUSSION: Pouch-related symptoms are common in patients with APS after IPAA. One-stage IPAA and younger age at surgery are associated with better clinical outcomes. However, symptoms do not correlate well with endoscopic or histologic findings or with pouchitis disease activity index and might be attributed to a functional pouch disorder.

Prolyl Hydroxylase Inhibition Mitigates Pouchitis.

BACKGROUND: Pouchitis is the most common long-term complication after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) or familial adenomatous polyposis (FAP), which can eventually progress to pouch failure, necessitating permanent stoma construction. Hypoxia-inducible transcription factor prolyl hydroxylase-containing enzymes (PHD1, PHD2, and PHD3) are molecular oxygen sensors that control adaptive gene expression through hypoxia-inducible factor (HIF). Emerging evidence supports PHDs as being therapeutic targets in intestinal inflammation. However, pharmacological inhibition of PHDs has not been validated as a treatment strategy in pouchitis. METHODS: PHD1-3 mRNA and protein expression were analyzed in mucosal pouch and prepouch ileal patient biopsies. After establishment of a preclinical IPAA model in rats, the impact of the pan-PHD small-molecule inhibitor dimethyloxalylglycine (DMOG) on dextran sulfate sodium (DSS)-induced pouchitis was studied. Clinical and molecular parameters were investigated. RESULTS: PHD1, but not PHD2 or PHD3, was overexpressed in pouchitis in biopsies of patients with IPAA for UC but not FAP. In addition, PHD1 expression correlated with disease activity. DMOG treatment profoundly mitigated DSS-induced pouchitis in a rodent IPAA model. Mechanistically, DMOG restored intestinal epithelial barrier function by induction of tight junction proteins zona occludens-1 and claudin-1 and alleviation of intestinal epithelial cell apoptosis, thus attenuating pouch inflammation. CONCLUSIONS: Together, these results establish a strong therapeutic rationale for targeting PHD1 with small-molecule inhibitors in pouchitis after IPAA for UC.

Current Practices in Ileal Pouch Surveillance for Patients With Ulcerative Colitis: A Multinational, Retrospective Cohort Study.

BACKGROUND AND AIMS: There are no universally accepted guidelines regarding surveillance of ulcerative colitis [UC] patients after restorative proctocolectomy and ileal pouch-anal anastomosis [IPAA]. There also exists a lack of validated quality assurance standards for performing pouchoscopy. To better understand IPAA surveillance practices in the face of this clinical equipoise, we carried out a retrospective cohort study at five inflammatory bowel disease [IBD] referral centres. METHODS: Records of patients who underwent IPAA for UC or IBD unclassified [IBDU] were reviewed, and patients with <1-year follow-up after restoration of intestinal continuity were excluded. Criteria for determining the risk of pouch dysplasia formation were collected as well as the use of pouchoscopy, biopsies, and completeness of reports. RESULTS: We included 272 patients. Median duration of pouch follow-up was 10.5 [3.3-23.6] years; 95/272 [35%] had never undergone pouchoscopy for any indication; 191/272 [70%] had never undergone pouchoscopy with surveillance as the specific indication; and 3/26 [12%] high-risk patients had never undergone pouchoscopy. Two cases of adenocarcinoma were identified, occurring in the rectal cuff of low-risk patients. Patients under the care of surgeons appeared more likely to undergo surveillance, but rates of incomplete reporting were higher among surgeons [78%] than gastroenterologists [54%, p = 0.002]. CONCLUSIONS: We observed wide variation in surveillance of UC/IBDU-IPAA patients. In addition, the rate of neoplasia formation among 'low-risk' patients was higher than may have been expected. We therefore concur with previous recommendations that pouchoscopy be performed at 1 year postoperatively, to refine risk-stratification based on clinical factors alone. Reports should document findings in all regions of the pouch and biopsies should be taken.

Increase in Processing Factors Is Involved in Skewed MicroRNA Expression in Patients with Ulcerative Colitis Who Develop Small Intestine Inflammation after Pouch Surgery.

Background: A large-scale increase in microRNA (miRNA) expression was observed in patients with ulcerative colitis who underwent pouch surgery and developed inflammation of the pouch (pouchitis). In this study, we assessed miRNA expression in these patients and investigated how regulation of its expression changes in the setting of pouchitis. Methods: Autologous samples that included mucosal biopsies, peripheral blood cells, and plasma were collected from the patients. Candidate primary and mature miRNA expressions were analyzed by quantitative polymerase chain reaction. A human intestinal epithelial cell line was used to test DICER activity, and the expression of key miRNA processing factors was analyzed by Western blot. miRNA-424 and its potential target serotonin reuptake transporter (SERT) expressions were examined by quantitative reverse transcription polymerase chain reaction and Western blot in human pouch tissues and in a human intestinal epithelial cell line stimulated with inflammatory cytokines TNF-α, IL-1ß, and INF-γ. Results: Candidate miRNA expression and protein expression of DICER-1, EXPORTIN-5, and AGO-2 were increased in association with pouch inflammation. Similarly, inflammatory cytokines increased protein expression of DICER-1, EXPORTIN-5, and AGO-2 and DICER activity in the epithelial cell line. The miRNA-424 expression increased whereas SERT expression decreased in the patients' mucosa. Similarly, incubation of the epithelial cell line with inflammatory cytokines resulted in increased miRNA-424 and decreased SERT mRNA and protein expression. Conclusions: The miRNA expression and processing are augmented in the inflamed intestinal mucosa of patients with pouchitis. These alterations are accompanied by increased expression of proteins involved in miRNA processing, suggesting that pouch inflammation contributes to miRNA processing and expression.

Colonic Histological Criteria Predict Development of Pouchitis after Ileal Pouch: Anal Anastomosis for Patients with Ulcerative Colitis.

BACKGROUND/AIMS: Pouchitis is one of the main complications after ileal pouch-anal anastomosis in patients with ulcerative colitis. The aim of this study was to determine whether the use of colonic histological criteria can predict the development of pouchitis. METHODOLOGY: We retrospectively reviewed 147 patients' clinical data and performed a histological evaluation of the resected total colon using Tanaka's criteria, which comprise the following 6 factors: ulceration (H1), crypt abscesses (H2), degree of mononuclear cell infiltration (MNCI) (H3), segmental distribution of MNCI (H4), eosinophil infiltration (H5), and extent of disease of resected colon (H6). RESULTS: The development of pouchitis and chronic pouchitis within 3 years after restoration of gastrointestinal continuity was recognized in 52 (35.4%) and 26 (17.7%) of the 147 patients, respectively. Using various combinations of each score, the H3 + H4 - H5 scores of patients with pouchitis or chronic pouchitis were significantly higher than those of patients without. A H3 + H4 - H5 score of >0.4 was a statistically significant risk factor for the development of both pouchitis and chronic pouchitis. CONCLUSIONS: The combination of the degree of MNCI, segmental distribution of MNCI, and eosinophil infiltration from histological criteria has utility in predicting the future development of pouchitis, especially chronic pouchitis.

Vedolizumab in the treatment of chronic, antibiotic-dependent or refractory pouchitis.

BACKGROUND: The most common complication after ileal pouch anal anastomosis in up to 50% of patients is an acute pouchitis. The majority of patients respond to antibiotic treatment. However, 10%-15% develops chronic antibiotic-dependent or refractory pouchitis which is usually hard to treat. AIM: To evaluate the effectiveness of vedolizumab in patients with chronic pouchitis. METHODS: Patients with chronic antibiotic-dependent or refractory pouchitis were treated with vedolizumab (300 mg at week 0, 2, 6 and 10) in 10 IBD centres and retrospectively registered. Data were recorded until week 14 of vedolizumab treatment. In total 20 patients (12 male, median age 43 years) were included for analysis. The effectiveness was measured using the Oresland Score (OS) at week 2, 6, 10 and 14 and the pouch disease activity index (PDAI) at week 0 and 14. RESULTS: The mean OS declined from 6.8 (range 2-12) to 3.4 (range 0-11). Concordantly, the mean PDAI after 14 weeks of treatment dropped from 10 (range 5-18) to 3 (range 0-10). Only three patients reported moderate side effects. No serious side effects were recorded. In addition, symptomatic co-medication such as loperamide and tincture of opium could be terminated in 8 out of 12 patients as well as antibiotic treatment could be stopped in 17 out of 19 patients. CONCLUSION: Our data indicate that vedolizumab could be an option in the treatment of patients with chronic, antibiotic-dependent or refractory pouchitis.

Intestinal Barrier Disruption in Ileal Pouchitis After Ileal Pouch-Anal Anastomosis in a Rat Model.

BACKGROUND: Pouchitis occurs in approximately 50% of patients with ulcerative colitis after ileal pouch-anal anastomosis (IPAA) but the pathogenesis remains unclear. We used a rat model of dextran sulfate sodium (DSS)-induced ileal pouchitis to examine whether intestinal barrier disruption plays a role in the development and progression of the disease. METHODS: Rats were randomly divided into DSS (underwent IPAA and administered 5% DSS orally), IPAA (underwent IPAA), and Sham groups (underwent switch abdominal surgery). In the DSS group, levofloxacin intervention and nonintervention subgroups were used to determine the influence of antibiotics on intestinal barrier dysfunction. Hematochezia and fecal scores were recorded. Ileum and pouch specimens were obtained for histological assessment. Immunohistochemistry was performed for myeloperoxidase and occludin protein expression. Levels of interleukin-1ß (IL-1ß), IL-6, IL-10, and tumor necrosis factor α mRNA were detected by real-time PCR. Plasma D-lactate concentrations were determined with colorimetry. RESULTS: Only rats in the DSS group experienced hematochezia, and their fecal and histological scores significantly increased (P < 0.01). Compared with the IPAA and Sham groups, levels of myeloperoxidase, IL-1ß, IL-6, tumor necrosis factor α, and plasma D-lactate significantly increased, whereas occludin and IL-10 reduced in the DSS group (P < 0.01). The levofloxacin subgroup showed increased occludin expression and more balanced inflammatory cytokine levels than the nonintervention subgroup. All differences showed linear correlations. CONCLUSIONS: The intestinal barrier was disrupted in this rat model of pouchitis. Increased proinflammatory and decreased anti-inflammatory factors aggravated the intestinal barrier damage. Antibiotics may ameliorate this process.

Intraepithelial lymphocytosis is a frequent finding in biopsies from ileal pouch-anal anastomoses.

Following restorative proctocolectomy with an ileal pouch-anal anastomosis, the small bowel mucosa undergoes several specific histologic adaptions, which may be unrelated to the underlying disease or symptoms of pouchitis. An increase in intraepithelial lymphocytes (IELs) has not been described as part of this spectrum. Mucosal biopsies of the ileal pouch and afferent limb of 230 patients (mean age: 45.7y [18.3-74.7], gender [female/male]: 117/113) with a functioning ileal pouch-anal anastomosis (mean time since ileostomy closure: 10.8months) and associated clinically annotated outcome data were assessed for IELs/100 enterocytes. Forty-two patients (18.3%) showed an increase in IELs (≥20 IELs/100 enterocytes [range 20-39]), in pouch and/or afferent limb biopsies. Intraepithelial lymphocytosis was more commonly observed in afferent limb compared to pouch biopsies (18.8% vs 8.3%; P = .42) and in familial adenomatous polyposis compared to ulcerative colitis patients (16% vs 8%; P = 0.36), but neither difference reached statistical significance. No cases with increased IELs displayed severe villous blunting. Increased IELs were not significantly associated with age, sex, ethnicity, smoking history, time since ileostomy, use of antibiotics, biologic agents, anti-diarrheal agents or probiotics, C-reactive protein levels or differential white cell count. None of the 42 patients with increased IELs had positive celiac serology (anti-human tissue transglutaminase IgA [ELISA] with corresponding total serum IgA). Intraepithelial lymphocytosis in pouch biopsies may represent a subclinical response to an altered bacterial microenvironment. Pathologists should be aware that intraepithelial lymphocytosis is part of the spectrum of changes in pouch biopsies, and only rarely is due to celiac disease.

Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.

Inflammatory bowel diseases are characterised by inflammation that compromises the integrity of the epithelial barrier. The intestinal epithelium is not only a static barrier but has evolved complex mechanisms to control and regulate bacterial interactions with the mucosal surface. Apical tight junction proteins are critical in the maintenance of epithelial barrier function and control of paracellular permeability. The characterisation of alterations in tight junction proteins as key players in epithelial barrier function in inflammatory bowel diseases is rapidly enhancing our understanding of critical mechanisms in disease pathogenesis as well as novel therapeutic opportunities. Here we give an overview of recent literature focusing on the role of tight junction proteins, in particular claudins, in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.