CRC, 18 advanced adenomas and 18 normal colon samples were sequenced by RRBS; thetop 20 candidates were tested by MSP in independent samples including 18 IBD-CRCand 13 IBD-controls. Three novel markers (PDGFD, CHST2, SFMBT2) were selected forcomparison to BMP3 and NDRG4; all were assayed by QuARTS in stool samples from 33IBD-CRN cases (8 CRC, 8 HGD, 8 LGD ≥ 1cm, 10 LGD <1cm) and 50 IBD controls. Fourcontrols were excluded for insufficient β-actin. Median IBD disease duration was 23 years(interquartile range [IQR] 9-35) in cases and 13 (8-20) years in controls (p=0.0009). Noother significant differences were seen when comparing age, sex, inflammation severity, IBDextent or co-morbid primary sclerosing cholangitis. Marker levels were not influenced bydisease duration after stratification by case and control status. Detection rates at 90%specificity are reported (table). Conclusions: Accurate and novel methylation markers ofIBD-CRN were identified by RRBS and validated in both tissues and stools of IBD-CRNpatients and IBD controls. Non-optimized novel marker assays were comparable to estab-lished candidates. Results were minimally influenced by conventional IBD-CRN risk factors;however, a sensitive test for small polyps, such as chromoendoscopy, may be needed toclear diminutive polyps after positive sDNA.Detection of IBD-associated Colorectal Neoplasms by Methylated Stool DNA at 90% Speci-ficity

CRC, colorectal cancer; HGD, high-grade dysplasia, LGD, low-grade dysplasia

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Systematic Analysis of Factors Associated With Progression and Regression ofUlcerative Colitis in the Swiss IBD Cohort StudyEkaterina Safroneeva, Stephan R. Vavricka, Nicolas Fournier, Frank Seibold, ChristianMottet, Alex Straumann, Gerhard Rogler, Alain Schoepfer

Background: There is a lack of studies having systematically assessed in a large cohort ofpatients with ulcerative colitis (UC) the disease location over time as well as risk factorsassociated with progression or regression of disease extent. Aim: to assess disease locationover time and to evaluate associated risk factors. Methods: Data from the Swiss IBD cohortstudy were analyzed. Patients were recruited from university centers (68%), regional hospitals(14%), and private practices (18%). Disease locations over time were analyzed and riskfactor analysis for a change in disease location was performed using logistic regressionmodeling. Non parametric data are illustrated as median and interquartile range [IQR].Results: A total of 1,016 UC patients (45.6% females, median age at diagnosis 31 [23.3-40.5] years) were included. At diagnosis, UC patients presented with the following diseaselocations: 199 (19.6%) proctitis, 338 (33.3%) left sided colitis, 381 (37.5%) extensive colitis/pancolitis, and 98 (9.6%) unknown. During a median of 9 [5-16] years disease duration,a disease progression was documented in 145/1016 (14.3%) of patients, a regression in176/1016 (17.3%) of patients, whereas 624/1016 (61.4%) of patients had a stable diseaselocation (7% of patients with unknown evolution of disease location over time). Logisticregression modeling identified the following factors associated with disease progression inUC patients presenting with proctitis or left-sided UC at diagnosis: treatment with systemicsteroids (OR 2.077, 95%-CI 1.359-3.174, p = 0.001), treatment with immunomodulators(azathioprine, 6-MP, methotrexate) (OR 1.647, 95%-CI 1.119-2.424, p=0.011), treatmentwith TNF-antagonist(s) (OR 1.668, 95%-CI 1.077-2.581, p = 0.022), and treatment withcalcineurin-inhibitors (OR 3.159, 95%-CI 1.679-5.943, p < 0.001). Neither gender, age atUC diagnosis, body mass index, presence of extraintestinal manifestations, smoking statusat diagnosis, positive UC family history, nor 5-ASA treatment were associated with diseaseprogression. No specific factors were found to be associated with regression in UC patientswith extensive colitis/pancolitis or left-sided colitis at diagnosis. Conclusion: Over a medianof 9 years disease duration about two thirds of UC patients maintained the initial diseaselocation whereas one third either had a progression or a regression of the initial diseaselocation. Treatment with systemic steroids, immunomodulators, TNF-antagonists, or cal-cineurin-inhibitors was significantly associated with disease progression.

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Early Lesions in Small Intestinal Crohn's Disease (CD): An Endoscopic andConfocal Laser Endomicroscopic (CLE) AppraisalYing Kit Leung, Ying Huang

INTRODUCTION Direct observation of the intestinal microstructure has been made possiblewith the advent of high-resolution endoscopes with zoom, and CLE. In this study, we areable to characterize: 1. changes in the villus structure that surround an aphthoid ulcer; 2.demonstration of mucosal healing while on biologics; 3. identification of early lesions whenthe disease recurs. MATERIAL AND METHODS A total of 26 patients with CD or ilealulcers are enrolled. In twelve patients more than one colonoscopies were performed (10 - 51years). The patients with abdominal pain and aphthoid ulcers were treated with mesalamine &budesonide, and for severe Crohn's disease, infliximab and or thalidomide. Repeat colonosco-pies were performed at intervals that varied from 4 months to 2 years to observe the resultof the therapy. CLE was used in two patients. Results Acute inflammation of villi surroundingan aphthoid ulcer presents as a rosette of villi surrounding a central ulcer. In the severelyinflamed villi, extravasation of blood into the lamina propria is seen. The blood vessels ofthe villi become tortuous and more numerous in number. CLE demonstrated the changes

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in vascular microstructure. In inflamed villi, there is a definite increase in density of vesselswhich became curvilinear and spiral. Mucosal healing is demonstrated by reduction ordisappearance of the ulcers. We followed the ileal inflammation with sequential examinations.In one patient, marked inflammation of the terminal ileum with numerous ulcerations andprolapse of the ileal mucosa was treated with infliximab. 4 months later, colonoscopicexamination revealed marked improvement in the mucosal lesions, healing of the aphthoidulcers and reduction of villous inflammation.1.5 years later, the mucosal lesions disappeared.Infliximab was stopped. there was recurrence of inflammation and terminal ileal mucosalprolapse. Gradual increase in the mucosal inflammation was observed in subsequent endo-scopies. The mucosal lesions included: inflammation of individual villi with bleeding intothe intestinal cavity; inflammation of villi arranging in a circle around Peyer's patches withearly formation of aphthoid ulcers. In another patient thalidomide therapy was initiated andsix months after treatment the intestinal ulcers have nearly disappeared. Discussion It isgenerally believed that the earliest lesion of Crohn's disease begins as an aphthous ulcer.In this study we sequentially follow our patients who have CD or aphthoid ulcers andobserve the changes under treatment. We were able to characterize regression of inflammationand aphthoid ulcers upon treatment with biologics, and the genesis of new lesions aftercessation of the drug. Our study provides a clue as to the appearance of early lesions hencean opportunity for early treatment, and a direction towards research into pathogenesis.

A typical ileal ulcer shown with spectral enhancement. The villi surrounding the ulcerbecame globular and adherent to the underlying structures. Bleeding into the lamina propriaof inflamed villi could be seen. Blood vessels in these villi are increased and curved.

Confocal laser endomicroscopic image of inflamed villus. Layer of enterocyte has increasedpermeability to fluorescein. The blood vessels of the villi are increased and curved. Angiogene-sis is an early feature of inflamation of the villus in Crohn's disease.

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Fibrosis Does Not Increase With Disease Duration in Ulcerative ColitisJessica R. de Bruyn, Sybren L. Meijer, Manon E. Wildenberg, Gijs R. van den Brink,Geert R. D'Haens

Introduction Intestinal fibrosis in Crohn's disease is a process stimulated by chronic inflamma-tion leading to an increased presence of myofibroblasts in all layers of the intestinal wall.Ulcerative colitis (UC) is classically considered to be a purely mucosal disease althoughrarely transmural complications such as strictures and stenosis develop. Fibrogenesis in UChas not been studied systematically yet and may be a neglected phenomenon. We thereforeinvestigated whether there is a different fibrotic load in acute vs longstanding UC andwhether the degree of fibrosis in UC correlates with the severity of inflammation. MethodsColectomy specimens from all UC patients operated in our academic hospital between 2007-2012 were reviewed. Specimens from patients with recent onset refractory therapy UC(diagnosis < 2 years) and longstanding UC with dysplasia (> 10 years) were selected. Patients

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soperated for colon cancer without UC served as controls. On H&E stainings the Geboeshistological inflammatory activity score (0-22 points) was determined by an experiencedIBD pathologist. Sirius Red stainings and collagen I and III immunohistochemistry stainingswere performed for collagen, and α-smooth muscle (αSMA) for detection of myofibroblastsand smooth muscle cells. Staining intensity signals were investigated by image analysissoftware (Image J, NIH). Results We examined 13 colectomy specimens from patients withacute UC, 16 from patients with longstanding UC, and 7 colorectal cancer controls. Patientswith short disease duration had a higher Geboes score of 19 (13-20) points, versus 8.5 (2-16) points in specimens with longer disease duration (p=0.001). Acute and longstandingUC had a thicker muscularis mucosa (MM) than controls (0.10 vs 0.10 vs 0.05 mm, p=0.019). Both UC groups had less submucosal αSMA expression (number of αSMA positivevs total number of cells; 29% vs 33% vs 54%, p=0.009). Between acute and late UC therewas no difference in collagen deposition, however between UC together and controls therewas more collagen I expression in the mucosa, MM and muscularis externa (50% vs 10%,p=0.02; 28% vs 10%, p=0.048; 71% vs 20%, p=0.003). In both early and long UC duration,we did not find a correlation between inflammation or collagen deposition or MM thickness.There was a negative correlation between inflammation and αSMA positivity in the submucosa(R=-0.51, p=0.003) and MM (R=-0.37, p=0.04). Conclusion In our series of colectomyspecimens, there is more collagen deposition in UC than in controls. No association betweendisease duration and increased collagen deposition could be found. Expression of αSMAhowever is lower in UC and correlates with inflammation. Fibrosis in UC does not appearto increase significantly over time.

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Failure of Infliximab Treatment in Crohn's Disease Is Associated With thePresence of FibrosisJessica R. de Bruyn, Sybren L. Meijer, Manon E. Wildenberg, Gijs R. van den Brink,Geert R. D'Haens

Introduction Intestinal fibrosis in Crohn's disease (CD) is a process stimulated by chronicinflammation leading to an increased presence of myofibroblasts and collagen deposition inall layers of the intestinal wall. However, once the fibrotic process has been initiated itmay progress independently of inflammation. Infliximab (IFX) is a highly effective anti-inflammatory treatment in CD. Despite initial good response, considerable proportionsof patients lose response during maintenance treatment. We aimed to investigate if thisphenomenon could be explained by the presence of pre-existing fibrosis. Methods Wecollected ileocecal resection specimens from patients operated between 2005 and 2012 whohad failed IFX treatment (at least 3 gifts IFX), and from patients operated without previousIFX treatment. Demographics and pre-operative C-reactive protein (CRP) were recorded.Inflammation was scored on H&E stains by an experienced IBD pathologist (scoring range0-13 points). Sirius Red and collagen I immunohistochemistry stainings were performed forcollagen deposition, and α-smooth muscle (αSMA) for detection of myofibroblasts andsmooth muscle cells. Staining intensity was measured using image analysis software (ImageJ, NIH). Results We examined 12 specimens from patients operated after IFX failure, and20 specimens from IFX-naive patients. Median duration of IFX treatment was 77 (IQR 21-189) weeks. CRP levels did not differ between treated and non-treated patients (respectively17 (3-51) mg/L vs 6 (3-24) mg/L). Both IFX-failure and IFX-Naive groups had significantinflammation but this did not differ significantly (11 (IQR 6-12) vs 10 (IQR 7-12) points).More collagen I deposition in the IFX-failure group was found in the submucosa (numberof collagen I positive cells versus total number of cells; respectively 71% vs 57%, p=0.03),with a trend to more collagen I deposition in the mucosa and muscularis externa (respectively50% vs 30%, p=0.069 and 46% vs 23%, p=0.067). IFX-Naive patients had more αSMAexpression in the muscularis externa (39% vs 34%, p=0.01). There was a strong negativecorrelation between inflammation and submucosal αSMA positivity in patients who hadfailed IFX (R=-0.84, p=0.001). No correlation between IFX duration and inflammation orcollagen deposition was found. Conclusion In our series of ileocoecal resection specimens,there is more collagen I deposition in the submucosa with a trend in the mucosa andmuscularis externa. Moreover there is a strong negative correlation between inflammationand submucosal αSMA positivity in these patients. Fibrotic deposition could be a cause forIFX failure in CD patients.

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Patterns of Antibiotic Exposure and Clinical Disease Activity in InflammatoryBowel Disease: A 4 Year Prospective StudyJana G. Hashash, Claudia M. Ramos Rivers, Miguel Regueiro, Arthur Barrie, MarcSchwartz, Leonard Baidoo, Jason M. Swoger, Michael A. Dunn, David G. Binion

Background and Aim: The normal intestinal microbiota plays beneficial roles in protectionagainst pathogen invasion, development of the immune system and in nutrition but is also feltto play a central role in the pathogenesis of inflammatory bowel disease (IBD). Antimicrobialtreatment is known to cause both short- and long-term changes in the composition of thenormal human microbiota. The relationship between patterns of antibiotic use and overallclinical behavior in IBD has not been explored. We sought to prospectively characterizepatterns of antibiotic use (for IBD and non-IBD issues) and clinical IBD activity in a cohortof pts followed over 4 years. Methods: Prospective observational study from a longitudinalIBD natural history registry between 2009 and 2012. Demographic information, diseasetype, quality of life (QOL) as measured by SIBDQ, and healthcare utilization data wascollected. Patterns of IBD related hospitalizations, clinic visits, telephone calls, and emergencydepartment (ED) visits were analyzed. Antibiotic prescriptions were identified using electronicmedical record data and were categorized by drug class (antihelminths, macrolides, quino-lones, penicillin, cephalosporin, etc). Laboratory data was analyzed. Cumulative rates overthe 4 year study period were compared. Results: A total of 718 pts followed over 4 yearswere included (47.6% male, mean age 46.7±15.2y SD). Most pts (59.9%) had CD while38.6% had UC, and 1.5% were indeterminate. Four-hundred seventy-six (66.3%) pts wereexposed to antibiotics during the 4-year study period while 33.7% did not receive antibiotics.There was no difference in the gender or age of pts who received antibiotics compared tothose who did not. The antibiotic exposed group was more likely to include CD pts (63%

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vs. 53.7%; p 0.05), require narcotics (43.7% vs. 14.9%; p<0.0001), receive anti-depressanttherapy (43.1% vs. 18.6%; p<0.001) and require prednisone (52.7% vs. 31%; p<0.0001).There was no difference in the rates of immunomodulator use between groups, but antibioticexposed pts were more likely to be on biologic therapy (52% vs. 36.5%; p<0.0001). Antibioticexposed IBD pts had higher healthcare utilization as shown in Table 1. Antibiotic exposedIBD pts compared with non-antibiotic exposed IBD had a lower QOL (mean SIBDQ 50.2±11.5vs 56.4±9.5; p<0.0001) and higher rates of CRP elevation (49.2% vs 31.8%; p<0.0001).There were 3,559 total antibiotic prescriptions; most common were metronidazole (23.7%),quinolones (22.9%), macrolides (10.4%), penicillins (9.8%) and cephalosporins (8.4%).Conclusion: A majority of IBD pts receive antibiotic treatment and these exposed individualsdemonstrate a more severe clinical course, but the causative nature of this association isunclear. Further examination of antibiotic treatment on gut microbiome and IBD naturalhistory is warranted.Differences in healthcare utilization

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Impact of Metabolic Syndrome on Hospitalization Rate of Crohn's DiseasePatients Seen At a Tertiary Care CenterPaul S. Fitzmorris, Ioana B. Smith, Jeffrey Juneau, Euriko G. Torrazza Perez, BrandiBlackburn, Donny D. Kakati, Talha A. Malik

Background: Recent studies have suggested that markers of mesenteric inflammation, suchas increased adipose tissue, may be associated with poor outcomes in Crohn's disease (CD).As an extrapolation of this observation, this study sought to test the hypothesis that CDpatients with Metabolic Syndrome (MetS) have worse outcomes compared to CD patientswithout MetS. Methods: To test this hypothesis we designed a retrospective cohort studythat compared the outcomes of CD with MetS (primary exposed cohort) and CD patientwithout MetS (primary unexposed cohort). We also compared secondary exposed andunexposed cohorts based on presence and absence of component conditions of MetS.According to the International Diabetes Federation, MetS is defined by the presence of ≥3of 5 components: enlarged abdominal girth (which was assumed if BMI >30), type 2 diabetesmellitus (DM), hypertension (HTN), low serum high density lipoprotein levels (HDL) andhigh triglycerides (TG). Generalized Poisson Regression Model for Rate Data was performedto estimate the age-, sex- and duration of disease (DOD)-adjusted incidence rate ratio (IRR)of hospitalization, while accounting for individual periods of observation among CD patientswith and without MetS. Results: Of the 1139 patients with CD seen at our institutionbetween 2000 and 2013, 945 met the following criteria: They had data that allowed fordiagnosis of MetS at initial observation, and they were followed for at least one year. Themean DOD and mean duration of observation (DOO) were 13 years (SD=10.71) and 4 years(SD=3.52), respectively. 38 of the 945 CD patients had MetS. The rate of hospitalizationfor a CD exacerbation was 0.05/person-year among CD patients with MetS vs. 0.0002/person-year among CD patients without MetS. The results revealed that CD patients withMetS were almost twice as likely to have a CD-related hospitalization during the observationperiod compared with CD patients without MetS (IRR=1.95 95%CI=1.18-3.24 P=0.01).Regarding individual components of MetS, high TG (IRR=2.20 95%CI=1.50-3.24 p< 0.0001)and low HDL (IRR=2.18 95%CI=1.52-3.14 p< 0.0001) had the strongest association withincreased likelihood of hospitalization. DM (IRR=1.41 95%CI=0.77-2.46 p=0.267) and HTN(IRR=1.25 95%CI 0.9-1.74 p=0.18) were also associated with increased rate of CD-relatedhospitalization, although this association was not statistically significant. Initial BMI of > 30kg/m2 was not associated with increased rate of CD-related hospitalization (IRR=0.99 95%CI=0.76-1.29 p=0.947). Conclusions: CD Patients with MetS have a higher rate of CD-relatedhospitalization compared with CD Patients without MetS. This association appears to bedriven predominantly by high TG and low HDL. Future studies need to shed further lighton the role of low HDL and high TG on CD outcomes.

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The Impact of Vaccinations on Infectious Disease Incidence Among IBDPatientsMichael V. Chiorean, Danielle La Selva

Background: IBD patients on immunosuppressive therapy are at increased risk of infectionsincluding those that are preventable by vaccines. The preventive effect of standard immuniza-tions among IBD patients is unknown. Aims: to determine the rate of immunizations forcommon infections (flu, pneumonia) and the prevalence of infectious events among patientswith inflammatory bowel disease related to their immunosuppressive (IS) use and vaccinationstatus. Methods: Patients enrolled in a single institution IBD database were considered eligiblefor the study. Demographic information, IS drugs use (steroids, immunomodulators andbiologics), immunization status and the incidence of related infections (flu, pneumonia)were collected from the EMR. The rate of vaccinations was determined per calendar yearand time tertiles and time trends were estimated. All categorical variables were analyzedusing the chi-square test. Results: There were 3225 patients in the IBD database followedbetween 2007 and 2013; 47% with Crohn's disease, 45% male and 46.6% exposed to ISdrugs. The rate of any vaccination for flu and pneumonia was respectively, 47.6% and16.8% among IS users vs. 39.1% and 9.6% among non-users. There was a significant timetrend in both flu and pneumonia vaccinations (p<0.01 between first and third tertile forboth flu and pneumonia). There was a '09 spike in flu vaccination rate likely related to theemergence of H1N1. Patients older than 50 (69% vs. 39%, p<0.0001) and IS users (p<0.0001)were more likely to receive vaccines but there was no difference based on sex. The incidence