Fibrostenotic Crohn's Disease Research Articles

Su1853 Identification of a Genetic Risk Variant in the WWOX Gene Associated With Recurrent Fibrostenotic Crohn's Disease

Su1853 Identification of a Genetic Risk Variant in the WWOX Gene Associated With Recurrent Fibrostenotic Crohn's Disease

Clinical Outcomes of Surgery Versus Endoscopic Balloon Dilation for Stricturing Crohn’s Disease

Endoscopic balloon dilation and surgery are commonly practiced in stricturing Crohn's disease. Nonetheless, there are still scant data directly comparing these 2 strategies. The aim of this study was to compare the short- and long-term outcomes of endoscopic balloon dilation versus surgical resection in symptomatic Crohn's strictures. This was a retrospective cohort study. The study was conducted at a single tertiary center. Seventy-nine patients were identified, 40 in the surgical group and 39 in the endoscopic balloon dilation group (mean age 42.8 ± 13.9 versus 38.5 ± 12.2 years). The outcomes of all patients referred for endoscopic balloon dilation were compared with patients referred to surgery because of stricturing disease between the years 2006 and 2013. The primary outcome was the need for reintervention (either endoscopic balloon dilation or surgery) for symptomatic Crohn's disease during follow-up. The proportion of patients who required any reintervention during follow-up was significantly lower in the surgical group versus the endoscopic balloon dilation group (OR = 5.62 (95% CI, 1.66-19.01); p = 0.005). The need for surgery/resurgery during follow-up was also significantly lower in the surgically treated group (OR = 3.53 (95% CI, 1.01-12.29); p = 0.047). Reintervention-free survival and surgery-free survival were both significantly shorter in the endoscopically treated group in a Kaplan-Mayer analysis. The rate of major complications was similar in the endoscopically and surgically treated groups (7.6% versus 7.5%; p = 0.7). The small cohort and the retrospective data collection were limitations of this study. In our cohort of patients with fibrostenotic Crohn's disease, a direct comparison showed reduced need for reinterventions with a similar rate of immediate major complications after surgery compared with endoscopic balloon dilation.

Increased IGF-IEc expression and mechano-growth factor production in intestinal muscle of fibrostenotic Crohn's disease and smooth muscle hypertrophy.

The igf1 gene is alternatively spliced as IGF-IEa and IGF-IEc variants in humans. In fibrostenotic Crohn's disease, the fibrogenic cytokine TGF-β1 induces IGF-IEa expression and IGF-I production in intestinal smooth muscle and results in muscle hyperplasia and collagen I production that contribute to stricture formation. Mechano-growth factor (MGF) derived from IGF-IEc induces skeletal and cardiac muscle hypertrophy following stress. We hypothesized that increased IGF-IEc expression and MGF production mediated smooth muscle hypertrophy also characteristic of fibrostenotic Crohn's disease. IGF-IEc transcripts and MGF protein were increased in muscle cells isolated from fibrostenotic intestine under regulation by endogenous TGF-β1. Erk5 and MEF2C were phosphorylated in vivo in fibrostenotic muscle; both were phosphorylated and colocalized to nucleus in response to synthetic MGF in vitro. Smooth muscle-specific protein expression of α-smooth muscle actin, γ-smooth muscle actin, and smoothelin was increased in affected intestine. Erk5 inhibition or MEF2C siRNA blocked smooth muscle-specific gene expression and hypertrophy induced by synthetic MGF. Conditioned media of cultured fibrostenotic muscle induced muscle hypertrophy that was inhibited by immunoneutralization of endogenous MGF or pro-IGF-IEc. The results indicate that TGF-β1-dependent IGF-IEc expression and MGF production in patients with fibrostenotic Crohn's disease regulates smooth muscle cell hypertrophy a critical factor that contributes to intestinal stricture formation.

390 Epigenetic and Post-Translational Modification of STAT3 Regulates Its Spatiotemporal Trafficking and Transcriptional Activity in Mesenchymal Cells of Crohn's Disease and Animal Models of Crohn's Disease

STAT3 activity is governed by phosphorylation and acetylation. Post-translational modifications determine localization to the nucleus for transcriptional activity, or to signaling endosomes for regulation of signaling pathways. We recently identified a pattern of high pSTAT3(S727) and low pSTAT3(Y705) levels due to autocrine IL-6 production in mesenchymal cells of strictures in fibrostenotic Crohn's disease. The opposite is seen in the normal intestine in the same patient. This pattern characterizes B2 from other Crohn's phenotypes. We recently showed that STAT3 regulates transcription of TGFβ1 and collagen I. TheAIM of this study is to determine the post-translational and epigenetic modifications that determine the subcellular trafficking and function of STAT3. METHODS: Subepithelial myofibroblasts (SEMF) and smooth muscle cells (SMC) were isolated from strictured intestine and normal intestine of patients with fibrostenotic Crohn's disease and from intestine of TNBS treated C57Bl/6J mice and RAG(-/-) mice following transfer of CD4+CD45RBhi T-cells both after 8 weeks. Isolated cells were used to prepare RNA and cell lysates. Histologic sections were also prepared for immunofluorescence. Cell lysates and immunofluorescent staining of primary cultured cells were used to determine STAT3 subcellular localization of phosphorylated Y705 and S727 and acetylated K685. RESULTS: In both animal models expression of TGF-β1 and Collagen I increased in mesenchymal cells after 8 weeks similar to Crohn's disease. Similar patterns of S727 and Y705 phosphorylation and K685 acetylation and subcellular localization were observed in SEMF and SMC in B2 Crohn's disease (Figure 1), TNBS colitis and T-cell transfer. Phospho S727 and Acetyl K685 were increased and phospho Y705 was decreased in strictures in mice. Phospho S727 and acetyl K685 were localized to the nucleus, phospho Y705 was localized to endosomes in humans (Figrue 2) and mice. The opposite pattern was seen in normal intestine and control mice. IL-6-induced STAT3 nuclear localization of phospho S727 and acetyl K685 was enhanced by inhibition of histone deacetylation with Trichostatin A (500nM) and blocked by the inhibition of acetylation with the p300/CBP acetylation inhibitor, C646 (2.5 μM). IL-6-induced Erk1/2 activation and mesenchymal cell proliferation was inhibited by transfection of a dominant negative STAT3(Y705F) mutant or by pharmacologic inhibition of STAT3 phosphorylation. CONCLUSIONS: Activity of STAT3 is regulated by post-transcriptional modification of phosphorylation state and by epigenetic modification of acetylation of lysine residues that determine its subcellular localization and activity. Distinct subcellular localization to nucleus or signaling endosome differentially regulate transcription of TGF-β1 and collagen IαI, and proliferation of mesenchymal cells, respectively.

Su1285 Glycoproteomic Profiling of Serum Markers of Fibrosis in Fibrostenotic Crohn's Disease -An Objective Measure of Intestinal Damage?

Introduction: Ulcerative colitis (UC), one of the two main types of chronic Inflammatory Bowel Disease (IBD), is a significant health problem that is characterized by symptomatic periods (flare-up) interspersed with asymptomatic periods (remission). Since there is no cure for UC, the therapeutic goal is to prevent flare-ups and promptly treat them when they occur. Identifying biological and psychological markers that predict flare-up would significantly improve the management of UC by optimizing treatment to prevent flare-up. The aim of this study was to objectively define biopsychomarkers that predict UC flare-up. Methods: 54 UC patients in remission were included in this prospective longitudinal study. UC patients had at least one documented flare-up within the past 12 months and were either taking no IBD medication or were on a stable dose of IBD medication for at least three months prior to enrollment. Baseline information collected included: markers of inflammation and UC disease activity (i.e., stool calprotectin, serum CRP, serum cytokines, UC disease activity index, sigmoidoscopy score, histological score), sigmoid mucosal microarray analysis for mRNA of genes of interest (i.e., 70 genes), markers of stress (i.e., fasting serum ACTH, 24h urinary cortisol, PSQ), quality of life measure (IBDQ), and psychological assessments (i.e., BDI, STAI, MAAS, PHCS). Flare-up was defined as Mayo UC-DAI >2 plus rectal bleeding score ≥2 and sigmoidoscopy score of ≥2. Results: Twenty seven out of 54 UC subjects (50%) flared over a 12-month period. None of the psychological assessments or markers of stress were significant predictors of UC flare-up. Nor were stool calprotectin or serum C-reactive protein (CRP), ACTH, TNFα, or IL10 predictive of flare-up. However, endoscopy score (grade 1), serum IL6, and serum IL8 were significantly different between UC patients with and without flare-up. Analysis of gene expression in mucosal biopsy found eight genes predictive of UC flare-up including inflammatory (IL23R, STAT3, HMGB1), stress (CRHR2), brain-gut axis (NPY), intestinal barrier (TJP1), as well as other (TP53, LRRK2) genes. Furthermore, expression of HMGB1, OCLN (intestinal barrier), and TP53 predicted whether flare-up occurred within 6 or 12 months. Conclusion: Our prospective study found that: (1) stool calprotectin, serum TNFα, ACTH, IL10, urine cortisol, histological score, and psychological measures at baseline did not predict UC flare-up; (2) high serum IL6, low serum IL8, and grade 1 endoscopy score (i.e., loss of vascular pattern) at baseline predicted UC flare-up during the following 12 months; and (3) a characteristic mucosal gene signature predicted early (i.e., within six months) and late (i.e., within 12 months) UC flare-up.

Sa1733 Tofacitinib Inhibits JAK1 and STAT3-Dependent Increases in Profibrotic TGF β1 and Collagen I αI in Muscle Cells From Patients With Montreal B2 Fibrostenotic Crohn's Disease

Sa1733 Tofacitinib Inhibits JAK1 and STAT3-Dependent Increases in Profibrotic TGF β1 and Collagen I αI in Muscle Cells From Patients With Montreal B2 Fibrostenotic Crohn's Disease

Circulating fibrocytes and Crohn's disease

Despite advances in medical therapy, there remains no effective preventive or non-surgical therapeutic option for fibrostenotic Crohn's disease (CD). Symptomatic recurrences are common, necessitating reintervention. Intestinal fibroblasts mediate stricture formation, but their exact source is unclear. Recent evidence indicates that circulating fibrocytes drive fibrosis through differentiation into fibroblasts and the production of extracellular matrix proteins. The aim of this review is to describe current understanding of the pathophysiology underlying fibrosis in CD, the cellular and molecular biology of fibrocytes and their role in CD. The electronic literature (January 1972 to December 2012) on 'circulating fibrocytes' and 'Crohn's fibrosis' was reviewed. Circulating fibrocytes appear universally involved in organ fibrosis. A complex array of cytokines, chemokines and growth factors regulate fibrocyte biology, and these are associated with fibrogenesis in CD. The cytokines transforming growth factor β1, connective tissue growth factor and interleukin 13, overexpressed in the strictured Crohn's intestine, promote fibrocyte generation and/or differentiation. Levels of circulating fibrocytes are raised in conditions marked by exaggerated fibrosis. These and other observations prompt a characterization of fibrocyte activity in CD with a view to investigating a pathogenic role.

Obliterative Portal Venopathy: A Rare Cause of Pre-sinusoidal Portal Hypertension

Introduction: Making an etiologic diagnosis in patients with noncirrhotic portal hypertension can often be a formidable challenge for clinicians. We describe a rare case of pre-sinusoidal intrahepatic portal hypertension. Case: A 54-year-old man presented with an upper GI bleed. He had a longstanding history of fibrostenotic Crohn's disease s/p surgical resections and therapy with various immunomodulating agents. He had a history of massive splenomegaly and thrombocytopenia (platelets ˜40,000), for which he'd been followed by a hematologist without a definitive diagnosis, despite numerous tests including a bone marrow biopsy. An EGD revealed large, grade four esophageal varices, for which he underwent several variceal band ligation sessions. Initial CT imaging demonstrated a non-cirrhotic liver with a 25-cm spleen, patent portal, hepatic and splenic veins, and no ascites. LFT's were normal, and an MRCP showed no evidence of PSC. Viral, autoimmune, and genetic etiologies of chronic liver disease were unrevealing. A transjugular liver biopsy revealed a borderline elevated hepatic venous pressure gradient of 8 mmHg. Histology showed moderate macrovesicular steatosis (30%) and a NAFLD activity score (NAS) of 3/8. In addition, there were prominent periportal shunt vessels with muscularization of small portal vein branches and nodular regenerative hyperplasia changes; all consistent with a diagnosis of “obliterative portal venopathy (OPV).” There was mild periportal fibrosis (2/4), but no cirrhosis. A full hypercoaguable work-up failed to reveal an underlying clotting disorder. A partial splenic artery embolization was performed to reduce the spleen volume, prevent recurrent portal hypertensive bleeding, and improve the patient's thrombocytopenia. Several weeks post-procedure, his platelet count rose to the 200,000 range, and there was complete resolution of varices on follow-up EGD. He has since developed evidence of some thrombosis in the splenic and portal veins, requiring anti-coagulation. Discussion: OPV has also been termed “hepatoportal sclerosis,” “noncirrhotic intrahepatic portal hypertension,” and “idiopathic presinusoidal portal hypertension,” a rare etiology of portal hypertension diagnosed by the astute pathologist, based on specific histologic features. There is usually minimal-to-moderate portal fibrosis, but no cirrhosis and a patent splenoportal venous axis. The mechanism of disease pathogenesis is unclear, but in our patient, an autoimmune/inflammatory disease of the gut may predispose to portal bacteremia/pylephlebitis, which may result in thrombosis, sclerosis, and obstruction of small- and medium-sized portal vein radicals. His long-term exposure to 6 MP/imuran is another putative precipitating factor.

MAI, The Other Mycobacterium, as a Complication from Anti-TNF Therapy in IBD

Purpose: The patient is a 61-year-old male who presented with several weeks of malaise, weight loss, and several days of vomiting. He has a 25-year history of fibrostenotic Crohn's disease, for which he underwent an ileo-cecectomy in the past. Six months prior to presentation, the patient began having weight loss, abdominal pain, and was found to have strictures and ulcers in his small bowel. He had a negative Quantiferon Gold, and was started on infliximab therapy, 5 mg/kg with a standard initiation protocol. He received a total of six infusions prior to the current presentation, most recently 3 weeks prior. He was not taking any other medications for IBD, including a 5-ASA, immunologic or steroids. On presentation, the patient reported no fever, chills, nightsweats or cough. He had his baseline abdominal pain, but continued to have regular flatus and bowel movements, as well as a normal appetite. His physical exam demonstrated a thin man with notable pallor. His oropharynx was clear, and there was no palpable cervical lymphadenopathy. He had ronchi in his right lower lobe with deep inspiration. Abdominal exam was notable for a scaphoid abdomen with mild tympanic distention, and hyperactive bowel sounds. On labs, his WBC was 12.2 K/uL with a slight left shift, and his hemoglobin was 7.5 g/dL. He had a CT of the abdomen performed, where a 3-cm mass-like opacity was seen at the right lung base abutting the pleura. He also has some thickened small bowel loops in the left upper quadrant. Microbiology data was negative for legionella or strep pneumonia, as well as negative for histoplasmosis. The patient then underwent a video-assisted thoracic surgery with removal of the mass lesion. Pathology revealed areas of fibrosis, inflammation and foci with multinucleated giant cells suggestive of granulomas. Stains for AFB and fungus were negative. On sputum cultures, one-sixth grew Micobacterium avium-intracellulare (MAI). The patient was subsequently begun on multidrug treatment of his MAI with resolution of his symptoms and return to his normal weight. Anti-TNF therapy is a well-known risk factor for tuberculosis and other granulomatous diseases. Nontuberculosis mycobacterium has been reported in rheumatologic patients, usually in those taking corticosteroids or methotrexate concomitantly, but a specific warning or testing for MAI is not standard of care for IBD patients receiving anti-TNF therapy.

Various Clinical Presentations of Eosinophilic Enteritis

Purpose: Eosinophilic enteritis is part of a broad spectrum of eosinophilic inflammatory diseases characterized by the infiltration of eosinophils to different degrees anywhere from the esophagus to the rectum. Eosinophilic esophagitis is currently the most well recognized and characterized eosinophilic disorder of the gastrointestinal tract. However, eosinophilic enteritis remains an uncommon disease with a paucity of published data. We will present three cases of eosinophilic enteritis with various clinical presentations and courses. The first case is a 47 year old gentleman presenting with right upper quadrant abdominal pain, emesis, and watery diarrhea of 4 days duration. His past medical history was significant for seizure disorder that was controlled with medications and a history of alcoholism. Laboratory studies were significant for peripheral eosinophilia. Extensive infectious work-up was negative; however, Charcot Leyden crystals were seen on stool. EGD revealed mild esophagitis, gastritis, and duodenitis. Biopsies of the duodenum were consistent with eosinophilic enteritis. Random biopsies of the normal appearing colon and terminal ileum also revealed more than 25 eosinophils per high power field. The patient was treated with a course of prednisone while as inpatient, with transition to budesonide as outpatient with resolution. The second case is a 30 year old gentleman with chronic intermittent periumbilical abdominal pain and diarrhea which had worsened over the week prior to presentation. He noted 5 bowel movements daily with occasional bright red blood in the stool with a 15 lb weight loss over the last year. CT scan revealed significant thickening of the distal ileum as well as stranding in the pelvic mesentery. Endoscopy was significant for gastric ulceration and stenosis of the terminal ileum. The patient eventually underwent laparoscopic ileocecectomy for presumed partial small bowel obstruction suspected to be secondary to fibrostenotic Crohn's disease. Review of the surgical specimens showed increased eosinophils with no signs of chronicity or architectural evidence of Crohn's disease. And finally, 26 year old female presented with 4 week history of bilateral lower extremity edema with recent extension to her waist and periorbital area. She denied abdominal pain, diarrhea, change in her bowel habits or GI blood loss. She denies a history of liver, kidney, or cardiac problems. Initial labs revealed a peripheral eosinophilia of 22% and an albumin of 1.5 without proteinuria. EGD was notable for ulcerative duodenitis. Biopsies revealed a significant portion of eosinophils. She underwent allergy testing with elimination diet resulting in the resolution of her symptoms.

Biodegradable stents: another big step in the field of non-surgical therapy for fibrostenotic Crohn's disease

Biodegradable stents: another big step in the field of non-surgical therapy for fibrostenotic Crohn's disease

An Unusual Cause of Fibrostenotic Terminal Ileal Disease

Question: A 47-year-old woman was hospitalized for a 6-month history of episodic right-sided abdominal pain, nausea, and vomiting. Pain episodes occurred every month on an average, lasted for few hours at a time, and required 3 hospital admissions. As symptoms progressed, she developed diarrhea, described as 3–4 episodes of loose, watery bowel movements per day. Her medical history included hypertension controlled with medications, hysterectomy, and cholecystectomy. Physical examination was significant only for mild tenderness on the right lower abdomen, with no hepatosplenomegaly, masses, or peritoneal signs. Liver function tests, amylase, and lipase levels were normal. Abdominal ultrasonography showed no biliary dilatation. Upper endoscopy and colonoscopy (with terminal ileal intubation) were normal. Abdominal computed tomography (CT; Figure A) showed thickening of the distal ileuma a few centimeters proximal to the ileocecal valve with mild dilation of mid distal ileum proximally. Fecal material was seen in the small bowel, indicative of stasis. A clinical diagnosis of fibrostenotic Crohn's disease involving the terminal ileum was made. She underwent laparoscopic resection of the terminal ileum and cecum. Gross specimen (Figure B) showed a strictured terminal ileal segment approximately 5-cm long (arrow), with a tortuous ileum with prominent mucosal folds. On sectioning (Figure C), several hemorrhagic foci (arrow) within the thickened bowel wall were seen. Microscopic examination (Figure D; stain: hematoxylin and eosin; original magnification, 10×) revealed thickened muscularis propria, lamina propria, and subserosa with benign endometrial glands and stroma located within the muscularis propria of the thickened segment. What is the diagnosis? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Endometriosis, defined as presence of functional endometrial glands and stroma in locations outside the uterus, can involve intraperitoneal or extraperitoneal sites. The most common site of involvement is the ovaries. It affects up to 5%–10% women of menstruating age.1Olive D.L. Schwartz L.B. Endometriosis.N Engl J Med. 1993; 328: 1759-1769Crossref PubMed Scopus (755) Google Scholar Typical symptoms include pelvic pain, infertility, and dyspareunia. Although symptoms of early disease are usually cyclical, occurring during menstruation, they may become persistent with progressive disease or with involvement of other organs. The diagnosis is based on a high clinical suspicion and a typical histology. Endometriosis of the gastrointestinal tract affects 3%–37% women with this condition and most commonly involves the rectosigmoid region.2De Ceglie A. Bilardi C. Blanchi S. et al.Acute small bowel obstruction caused by endometriosis: a case report and review of the literature.World J Gastroenterol. 2008; 14: 3430-3434Crossref PubMed Scopus (79) Google Scholar Less commonly, it involves other colonic segments, small bowel, or the appendix. Symptoms related to gastrointestinal involvement depend on the site of involvement and vary from abdominal pain, abdominal distention, tenesmus, constipation, and diarrhea. Endometriosis rarely affects mucosal surfaces making endoscopic biopsies insufficient for diagnosis.2De Ceglie A. Bilardi C. Blanchi S. et al.Acute small bowel obstruction caused by endometriosis: a case report and review of the literature.World J Gastroenterol. 2008; 14: 3430-3434Crossref PubMed Scopus (79) Google Scholar Terminal ileal involvement from endometriosis is uncommon and occurs in 1%–7% of all patients with intestinal endometriosis.2De Ceglie A. Bilardi C. Blanchi S. et al.Acute small bowel obstruction caused by endometriosis: a case report and review of the literature.World J Gastroenterol. 2008; 14: 3430-3434Crossref PubMed Scopus (79) Google Scholar Patients with terminal ileal involvement are usually young nulliparous women who present with intermittent or persistent abdominal pain. Patients with significant involvement of the terminal ileum, like our patient, can present with symptoms and imaging evidence of obstruction.3Orbuch I.K. Reich H. Orbuch M. et al.Laparoscopic treatment of recurrent small bowel obstruction secondary to ileal endometriosis.J Minim Invasive Gynecol. 2007; 14: 113-115Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In the setting of obstruction, medical therapy with danazol or gonadotropin releasing hormones serve only as temporizing measures,3Orbuch I.K. Reich H. Orbuch M. et al.Laparoscopic treatment of recurrent small bowel obstruction secondary to ileal endometriosis.J Minim Invasive Gynecol. 2007; 14: 113-115Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar and definitive treatment requires surgical resection of the involved segment of the bowel. In conclusion, endometriosis should be considered in the differential diagnosis of a young patient presenting with terminal ileal disease mimicking Crohn's disease.

Endoprosthetic management of refractory ileocolonic anastomotic strictures after resection for Crohnʼs disease: Report of nine-year follow-up and review of the literature

The role of endoluminal stenting in benign obstruction, especially for Crohn's disease (CD), is controversial, with limited data and widely disparate outcomes. The purpose of this study was to determine the long-term efficacy and safety of this technology in the treatment of fibrostenotic CD and to review the existing literature on this topic. We undertook a retrospective review of all patients undergoing endoluminal stenting for CD strictures at our institution from 2001 to 2010. Outcome measures included technical success, clinical improvement, duration of stent and luminal patency, and need for re-intervention. Five patients underwent this procedure with a 100% rate of technical and an 80% rate of clinical success. Mean follow-up was 28 months (range 3 weeks to 109 months) and mean long-term luminal patency was 34.8 months (range 4.5-109 months). There was one complication involving reobstruction which required surgical intervention and no mortalities. Endoluminal stenting of CD strictures is a safe and effective alternative to surgery which can provide lasting benefit in select patients. Further studies are necessary to clarify the full impact of this technology on long-term management of this complex disease.

Predictors of fibrostenotic Crohnʼs disease

Intestinal fibrosis is a common and serious complication of Crohn's disease (CD) and as it can occur at any time during the disease course, it is crucial to identify patients at risk. The aim is not only to understand the pathophysiology of fibrogenesis but to be able to accurately inform subjects about their disease course, design future trials of potentially useful antifibrotic therapies, and, most important, identify those CD patients at risk, with the view to early, more aggressive medical therapy. This review summarizes the current status of our understanding and ability to predict fibrostenosing CD. The review encompasses three distinct areas: genetic variants, clinical phenotypes, and serologic markers in order to develop a conceptual framework for an understanding of fibrostenotic CD. It also aims to highlight where our knowledge is insufficient in order to identify areas that require future research.

S1202 Natural History of Crohn's Disease (CD) of the Pouch After Total Proctocolectomy

Background: The natural history of CD of the pouch has not been characterized. Methods: All eligible patients with CD of the pouch were identified and included from our subspecialty Pouchitis Clinic between 2002 and 2009. Demographic & clinical variables were collected from a prospectively maintained database. Results: 206 pts with CD of the pouch consisted of 49 inflammatory, 40 fibrostenotic, and 117 fistulizing types. Pts with fistulizing CD were younger than those with fibrostenotic CD. The interval from IBD diagnosis and pouch construction was shorter in the fistulizing CD group. More pts with fistulizing CD had postoperative use of biologics (25.6% vs. 10.2% and 12.5%, p=0.028). More patients with fistulizing CD were hospitalized for pouch-related condition (21.4% vs. 15.0% and 2.0%, p=0.007). Progression of phenotypes and pouch survival are shown in Figures. Conclusions: Clinical phenotypes of Crohn's pouch can change over time. These phenotypes of CD were associated with different natural history and risk for pouch failure.

Appropriate therapy for fistulizing and fibrostenotic Crohn's disease: Results of a multidisciplinary expert panel — EPACT II

Introduction Many therapeutic decisions in the management of fistulizing and fibrostenotic Crohn's disease (CD) have to be taken without the benefit of strong scientific evidence. For this reason, explicit appropriateness criteria for CD fistula and stenosis treatment were developed by a multidisciplinary European expert panel in 2004 with the aim of making them easily available on the Internet and thus allowing individual case scenario evaluation; these criteria were updated in 2007. Methods Twelve international experts convened in Geneva, Switzerland in December 2007. Explicit clinical scenarios, corresponding to real daily practice, were rated on a 9-point scale based on evidence from the published literature and panelists' own expertise. Median ratings were stratified into three categories: appropriate (7–9), uncertain (4–6) and inappropriate (1–3). Results Overall, panelists rated 60 indications pertaining to fistulas. Antibiotics, azathioprine/6-mercaptopurine and conservative surgery are the mainstay of therapy for simple and complex fistulas. In the event of previous failure of azathioprine/6-mercaptopurine therapy, methotrexate and infliximab were considered appropriate for complex fistulas. The panel also rated 72 indications related to the management of fibrostenotic CD. The experts considered balloon dilation, if the stricture was endoscopically accessible, stricturoplasty and bowel resection to be appropriate for small bowel fibrostenotic Crohn's disease, and balloon dilation and bowel resection appropriate for fibrostenotic colonic disease. In the presence of an ileocolonic or ileorectal anastomotic stricture of < 7 cm, endoscopic balloon dilation, and bowel resection were considered appropriate. Conclusion Antibiotics, azathioprine/6-mercaptopurine, and conservative surgery are the mainstay of therapy for fistulizing Crohn's disease. Infliximab is a therapeutic option in patients without prior response to immunosuppressant therapy. In fibrostenotic Crohn's disease, endoscopic balloon dilation, if feasible, or surgical therapy should be considered. These expert recommendations are available online ( www.epact.ch). Prospective evaluation is now needed to test the validity of these appropriateness criteria in clinical practice.

Administration of adalimumab in the treatment of Crohn’s disease of the ileal pouch

Crohn's disease (CD) of the pouch can develop in patients with ileal pouch-anal anastomosis (IPAA). Scant data are available on the treatment of this disease entity. To evaluate efficacy and safety of adalimumab in treating CD of the ileal pouch. From June 2007 to June 2008, 17 IPAA patients with inflammatory (n = 10), fibrostenotic (n = 2) or fistulizing (n = 5) CD of the pouch treated with adalimumab were evaluated. Inclusion criteria were CD of the pouch who failed medical therapy and were otherwise qualified for permanent pouch diversion or excision. All qualified patients received the standard dosing regimen of subcutaneous injection adalimumab (160 mg at week 0, 80 mg at week 1, and 40 mg every other week thereafter). Complete clinical response was defined as resolution of symptoms. Partial clinical response was defined as improvement in symptoms. Endoscopic inflammation before and after therapy was recorded, using the Pouchitis Disease Activity Index (PDAI) endoscopy subscores. The median age was 36 years with 12 patients (70.6%) being male. At 4 weeks, seven patients (41.2%) had a complete symptom response and 6 (35.3%) had a partial response. There was also a significant improvement in the PDAI endoscopy subscores at week 4 (P < 0.05). At the last follow-up (median of 8 weeks), eight patients (47.1%) had a complete symptom response and 4 (23.5%) had a partial response. Four patients (23.6%) developed adverse effects. Three patients (17.7%) eventually had pouch failure after failing to respond to adalimumab therapy. Adalimumab appeared to be well-tolerated and efficacious in treating CD of the pouch in this open-labelled induction study.

Risk factors for pouch failure in patients with different phenotypes of Crohnʼs disease of the pouch

Crohn's disease (CD) of the pouch is one of the leading causes of pouch failure in patients with restorative proctocolectomy. Risk factors for pouch failure in these patients are yet to be identified. The aim of the study was to assess risk factors associated with pouch failure in patients with CD of the pouch. All patients with a confirmed diagnosis of CD of the pouch in the Pouchitis Clinic between 2002 and 2007 were evaluated. Patients with familial adenomatous polyposis, normal pouches, pouchitis, cuffitis, surgical complications, and other diseased pouch conditions were excluded. Pouch failure was defined as the requirement for a permanent diversion or pouch resection. Demographic and clinical factors were studied with univariable and multivariable analyses. A total of 137 patients with CD of the pouch were included. Twenty-two patients (16%) developed pouch failure a median of 6 years after ileostomy takedown. Four of 50 patients (8.0%) with inflammatory CD, 4 of 30 (13.3%) with fibrostenotic CD, and 14 of 57 (24.6%) with fistulizing CD had pouch failure. A Kaplan-Meier plot for time to pouch failure by CD phenotype showed a trend toward association (P = 0.054) in patients with fistulizing CD. Adjusting for age, smoking status, and the use of immunomodulators or biologics, fistulizing CD was not found to be significantly associated with a higher hazard for pouch failure. Younger age, being an ex-smoker, and the use of immunomodulators or biologics were found to increase the hazard of pouch failure. Younger age, being an ex-smoker, and the requirement for immunomodulators or biologics were associated with pouch failure. The identification of these risk factors may help delineate the natural history of CD of the pouch and shed light on proper clinical management and prognosis.

Clinical Features and Quality of Life in Patients with Different Phenotypes of Crohn's Disease of the Ileal Pouch

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. 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. 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. 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 Clinical Phenotypes of Crohn's Disease of the Ileal Pouch

Crohn's disease (CD) of the pouch can occur in patients with colectomy and ileal pouch-anal anastomosis (IPAA) originally performed for a preoperative diagnosis of ulcerative colitis. The clinical presentations of CD of the pouch are inflammatory, fibrostenotic, and fistulizing. Risk factors for clinical phenotypes of CD of the pouch have not been characterized. A total of 78 eligible patients with CD of the pouch together with 294 nonselected non-CD patients with IPAA seen in the Pouchitis Clinic were enrolled, including 28 with inflammatory CD, 18 with fibrostenotic CD, and 32 with fistulizing CD. The clinical phenotypes of CD were diagnosed based on a combined assessment of clinical, endoscopic, radiographic, and histologic features. Three separate analyses were performed, and for each analysis, the outcome of interest was having one of the phenotypes versus not having it. A stepwise selection multivariable logistic regression analysis was used. In the multivariable analysis, the risk factor for inflammatory CD was higher afferent-limb endoscopy scores (hazard ratio [HR] 1.87 95% confidence interval [CI] 1.54-2.27); the risk factors for fibrostenotic CD were higher afferent-limb (95% CI 1.81-3.48, HR 2.51) and higher cuff (95% CI 1.01-1.84, HR 1.36) endoscopy scores; and for fistulizing CD the risk factors were younger age (95% CI 0.93-0.99, HR 0.96), female gender (95% CI 1.35-6.97, HR 3.07), a preoperative diagnosis of indeterminate colitis (95% CI 1.72-9.34, HR 4.00), and no use of nonsteroidal antiinflammatory drugs (95% CI 1.31-8.25, HR 3.28). Each of the three phenotypes of CD of the pouch was associated with certain risk factors, suggesting that each of these diseases has a different etiology and disease process. The identification and management of some of the modifiable risk factors may reduce CD-related morbidity.