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Feasibility, Precision and Reproducibility of MR Enterography for Detection ofInflammation in Crohn's Disease in a Multicenter Clinical TrialJordi Rimola, William Sandborn, Peter Higgins, Alexandre Coimbra, Timothy Lu, Paul J.Rutgeerts, Diana Luca, David H. Bruining, Severine Vermeire, Julian Panes, CynthiaSantillan, Mahmoud Al-Hawary, Jeff L. Fidler, Dirk Vanbeckevoort, Ragna A.Vanslembrouck, Laurent Peyrin-Biroulet, Valerie Laurent, Sharon O'Byrne, Alex deCrespigny

Purpose: (1) To test the feasibility of MR enterography (MRE) for objective assessment ofinflammation in patients with Crohn's Disease (CD) in a global multicenter study; (2) Toevaluate test-retest reproducibility of a quantitative MRE-based inflammation score in smallbowel (SB); and (3) To assess feasibility and tolerability of MRE with and without a colonicdistension enema. Methods: In total, 19 CD patients gave informed consent to participatein this multicenter (3 USA sites/3 European sites), local IRB-approved study. Within 14days, each patient underwent 1 ileocolonoscopy (IC) followed by 2 consecutive MREs withor without colonic distention with water enema. The MRE protocol was developed inconsensus with the participating sites: sequences included T2-weighted Fast Spin Echo,balanced Gradient Recalled Echo, and T1-weighted series pre- and post-Gd contrast. Tolera-bility questionnaire was completed following each MRE examination. All MRE images wereread centrally and a MaRIA score (Rimola et al. 2009) was assigned for each of 9 bowelsegments (4 SB, and 5 colon) as well as a global MaRIA score incorporating all bowelsegments. In the study, 332 series across 37 MRE examinations were assessed for qualityand a 5-grade quality assessment (QA) score was assigned to each MRE sequence and artifactsannotated. IC videos were centrally read and scored. Precision of MRE score was assessedfrom the paired repeated measures in 4 SB segments per patient. Overall feasibility of MREwas assessed by compliance to protocol and QA. MRE and IC concordance was assessedusing correlation analysis. Impact of colonic distension was evaluated by assessing agreementof MRE quantification of active disease using IC as the standard reference. Results: Thecompliance to the predefined MRE protocol was 97%; 86% of series scored good to excellentin quality and 97% scored fair or better in quality. Test-retest MRE scores in SB segmentsshowed an intra-class correlation of 0.96. Analysis of variance confirmed between sitevariability accounted for less than 1% of the overall variability between the two MREmeasurements. The two sets of MaRIA scores from the colon segments, with and withoutcolonic contrast, show significant correlations with CDEIS (r=0.57, p=0.018 and r=0.59,p=0.013 respectively), but not with CDAI (r=0.30, p=0.24 and r=0.29, p=0.26 respectively).The correlation of CDAI with CDEIS was r=0.14 (p=0.57). Tolerability of MRE was compara-ble to IC, with patients slightly favoring MRE without enema. Conclusion: High qualityMRE data can be acquired from a uniform MRI scanning protocol in a global multicentersetting. MRE is tolerable and inflammation scores are highly reproducible in SB.

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Predicting Mucosal Inflammatory Activity in Crohn's Disease: A New,Validated Non-Endoscopic Disease Activity IndexItta Minderhoud, Ewout W. Steyerberg, Adriaan A. van Bodegraven, Christien J. van derWoude, Daniel W. Hommes, Gerard Dijkstra, Herma Fidder, Matthijs P. Schwartz, BasOldenburg

Background and aims: Mucosal healing is presently considered one of the primary goals intreatment of Crohn's disease, but this can only be confirmed by endoscopy. We aimed todesign and validate a Crohn's disease activity index based on a combination of clinicalcharacteristics and readily available laboratory parameters, that reliably predicts the severityof mucosal inflammation. Methods: Thirteen clinical characteristics and laboratory variableswere selected for analysis. Mucosal inflammation was assessed by the Crohn's disease Endo-scopic Index of Severity. A linear regression model was based on 93 ileocolonoscopiesperformed in 82 Crohn's disease patients, and internally validated by bootstrap resampling.Subsequently, the newly developed model was validated in a cohort of 99 ileocolonoscopies.Results: The number of liquid stools during one day*0.25 + C-reactive protein (mg/L) *0.1+ platelet count (109/L) *0.01 + fecal calprotectin (mg/L) *0.001 - mean platelet volume(fL) *0.2 optimally predicted the severity of mucosal inflammation (bootstrap adjusted R2=0.50). The model demonstrated good agreement in the external validation (r =0.7), especiallyfor (ileo)colonic Crohn's disease (r = 0.8). The negative predictive value of the model was0.87. Conclusions: This newly developed non-endoscopic, disease activity index was foundto reliably predict mucosal inflammation in Crohn's disease patients. It can be expected tofacilitate clinical decision making and might prove valuable in clinical trials.

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Histological Normalization in Ulcerative Colitis: A New Treatment OutcomeBritt Christensen, Jonathan Erlich, Stephen B. Hanauer, David T. Rubin

BACKGROUND: It is a common perception that following a diagnosis of ulcerative colitis(UC), structural abnormalities of the mucosa are permanent. Histological healing has thereforebeen defined as the absence of residual mucosal inflammation with distinctive changes incrypt architectural distortion and/or atrophy, or complete normal mucosa. Despite this,complete histological normalization (CHN) has been recognised in a number of patients inour institution. The aim of this study was to examine both the prevalence and possiblepredictors of CHN and segmental histological normalization (SHN) in patients with a con-firmed diagnosis of UC. METHODS: Patients with confirmed UC who had a baseline colonos-copy with biopsies taken in each segment of the colon (rectum, left-side and right-side) andhad a follow-up colonoscopy more than one year later were identified. Demographic, clinical,histological and biochemical data were collected from case records. The primary outcomewas CHN as defined by complete normalization of mucosa without crypt architecturaldistortion in all bowel segments on follow-up colonoscopy and SHN as defined by normalmucosa in a bowel segment (right side, left side or rectum) previously shown to haveevidence of chronic UC. Variables influencing CHN and SHN were examined using the chi-square test, Wilcoxon rank-sum test and logistic regression. RESULTS: 646 patients were

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identified; 10.1% patients had CHN and 32.2% patients had SHN. (Table 1) On univariateanalysis less extensive disease on original colonoscopy (p = 0.001), disease duration morethan 10 years (p=0.029) and no previous exposure to immunomodulators (p=0.036) oranti-TNF agents (p=0.031) on final colonoscopy predicted CHN. On multivariate analysisonly a diagnosis of proctitis (AOR 3.19, 95% CI [1.53, 6.67], p=0.002) was predictive ofCHN. There was a trend for patients with disease duration greater than 10 years (p=0.054),those previously treated with cyclosporine (p=0.078) and those on duel therapy with animmunomodulator and an anti-TNF at time of colonoscopy (p=0.063) to have increasedoccurrence of CHN. Predictors of SHN on univariate analysis were pancolitis on originalcolonoscopy (p=0.047), age of diagnosis of UC ≤ 16 years (p=0.16) and current smokingat time of final colonoscopy (p=0.024). On multivariate analysis current smoking (AOR2.074, 95% CI [1.035-4.156], p=0.040) and age of diagnosis of UC ≤ 16 years (AOR 1.94,95% CI [1.08 - 3.50], p=0.028) predicted SHN. CONCLUSION: CHN and SHN are possiblewith modern treatment of UC. The strongest independent predictor of subsequent CHN inpatients with UC is limited disease extent at worst colonoscopy. Current smoking and youngerage of diagnosis independently predicts SHN. Further research needs to be undertaken todetermine if CHN or SHN are associated with improved long-term outcomes in those with UC.Table 1: Baseline Characteristics

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Faecal Calprotectin Is Superior to Faecal Lactoferrin and S100A12 As aSurrogate Marker for Post-Operative Crohn's Disease Endoscopic Recurrence.Prospective Longitudinal Endoscopic Validation. Results From the POCERStudyEmily K. Wright, Peter De Cruz, Michael A. Kamm, Amy L. Hamilton, Kathryn J. Ritchie,Soula Krejany, Steven T. Leach, Jacqueline I. Keenan, Alexandra Gorelik, Danny Liew,Lani Prideaux, Ian C. Lawrance, Jane M. Andrews, Peter A. Bampton, Miles Sparrow,Timothy H. Florin, Peter R. Gibson, Henry Debinski, Finlay A. Macrae, Rupert W. Leong,Ian Kronborg, Graham L. Radford-Smith, Warwick Selby, Michael J. Johnson, RodneyWoods, Peter R. Elliott, Sally Bell, Steven J. Brown, William Connell, Andrew S. Day,Richard B. Gearry, Paul V. Desmond

Introduction: 70% of patients require further surgery after "curative" resection for Crohn'sdisease. Early endoscopic recurrence predicts later clinical recurrence. The Post-OperativeCrohn's Endoscopic Recurrence (POCER) study has demonstrated that drug treatmentaccording to clinical risk of recurrence plus colonoscopic monitoring with treatment step-up for recurrence results in the lowest endoscopic disease recurrence. However colonoscopyis invasive. We have recently demonstrated that faecal calprotectin (FC) can be used tomonitor for disease recurrence with a cut-off of >100μg/g indicating endoscopic recurrencewith a sensitivity of 0.89 and negative predictive value (NPV) of 91% (AUC 0.762). FCcorrelates significantly with both the presence and severity of endoscopic recurrence. Weassessed the relative value of the faecal biomarkers lactoferrin (FL) and S100A12 (FS), notpreviously investigated, for detecting recurrent disease. Materials and Methods: 318 stoolsamples from 136 patients were tested for FC, FL and FS pre-operatively and 6, 12, & 18months after resection. Colonoscopy was performed at 6 and/or 18 months. Endoscopicrecurrence was assessed blindly and centrally using the Rutgeerts score. CRP and CDAIwere assessed longitudinally. Results: FL and FS concentrations were elevated pre-operatively(median FL 40.9μg/g, FS 8.4μg/g). At 6 months, FL and FS both fell (3.0μg/g and 0.9μg/g respectively) and were higher in recurrent disease than remission (5.7 v 1.6μg/g p=0.007and 2.0 v 0.8μg/g p=0.188). At combined 6 & 18 month observations the overall prevalenceof endoscopic recurrence was 42%. FL>3.4μg/g and FS>10.5μg/g indicated endoscopicrecurrence (≥ i2) with a sensitivity of 0.70 and 0.91, specificity of 0.68 and 0.12, positivepredictive value (PPV) of 53% and 35% and NPV of 81% and 71%, respectively. FL correlatedwith both endoscopic recurrence (r=0.306, p=0.008) and Rutgeerts score (r=0.384, p<0.001)but S100A12 did not (r=0.176, p=0.937 and r=0.168, p=1.000). CRP and CDAI did notcorrelate with FL, FS, endoscopic recurrence or endoscopic severity. Conclusion: Faecalcalprotectin is the optimal marker for endoscopic post-operative recurrence, with highsensitivity and negative predictive value, and is superior to CRP and CDAI. It identifieswhich patients require colonoscopy, allowing 41% of patients to avoid colonoscopy. Faecallactoferrin offers only modest sensitivity for detecting recurrent disease. Faecal S100A12 issensitive but has low specificity and NPV.

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Classification of non-IBD, Crohn's Disease and Ulcerative Colitis in a YoungPatient Population Using a Multi-Marker Diagnostic PanelSteven Lockton, Fred Princen, Sharat Singh

Background Approximately 10%-15% of inflammatory bowel disease (IBD) cases occur inindividuals younger than 18 years old. A combination of a clinical examination, imaging,endoscopy with histopathology, and laboratory testing are conventionally used to diagnosepediatric IBD. Less invasive testing methods can be especially valuable for younger patients.The use of serology to assist in IBD diagnosis has been extensively described in the literaturefor adult patients. In addition to the auto and anti-microbial antibodies typically associatedwith IBD, genetic variants as well as angiogenesis and inflammation molecules may betterhelp identify IBD. A recent study (Plevy et al., Inflamm. Bowel Dis. 19(6):1139-48 2013)demonstrated the benefit of biomarker combinations to aid in diagnosing adult IBD. However,the diagnostic value of this biomarker test to classify and stratify IBD in younger IBD patients

is not as well established. The aim of this study was to evaluate the diagnostic performanceof a biomarker test that can identify and stratify young IBD patients. Methods Samples fromwell-characterized patients were collected from 15 North American GI centers. Median agewas 15 (IQR: 13-16). Samples from 251 patients were used: 147 Crohn's disease (CD), 47ulcerative colitis (UC) and 57 non-IBD disease controls. A combination of serological markers(ASCA-IgA, ASCA-IgG, ANCA, pANCA, anti-OmpC, anti-Fla2, anti-FlaX and anti-CBir1),four gene variants (ATG16L1, NKX2-3, ECM1, and STAT3) and five inflammatory markers(CRP, SAA, ICAM, VCAM, and VEGF) were used in this evaluation. Identification of IBD,CD, and UC and was made with the aid of a machine learning model. Sensitivity, specificity,NPV, PPV and accuracy statistics were calculated for both the IBD vs. Non-IBD componentof the diagnostic model, and separately for the CD vs. UC component (for patients calledIBD by the model). Results The multi-marker biomarker diagnostic model performed inclassifying IBD, CD and UC in pediatric patients as reported in Table 1. We observed asensitivity of 86.1% and a specificity of 86% for identifying young adults with IBD. Thesensitivity and specificity for classifying CD in patients called IBD by the model was 91.9%and 75.8%, respectively. UC sensitivity and specificity was 82.1% and 90.5%, respectively.Diagnostic accuracy of the biomarkers was 86.1% for IBD vs. non-IBD, 88.2% for CD and88.9% for UC. The IBD NPV and PPV were 64.5% and 95.4% respectively. CD NPV andPPV were 73.5% and 92.7%, respectively. UC NPV and PPV were and 95.5% and 67.6%,respectively. Conclusion Our results demonstrate that a combination of serological, genetic,and inflammatory markers may be utilized for classifying non-IBD, CD, and UC in theyoung adult patient population. Further studies are required to further investigate the clinicalutility of this biomarker test.Table 1

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Agreement Among Central Readers in the Evaluation of Endoscopic DiseaseActivity in Crohn's DiseaseReena Khanna, Guangyong Zou, Geert R. D'Haens, Paul J. Rutgeerts, John W. McDonald,Marco Daperno, Brian G. Feagan, William Sandborn, Elena Dubcenco, Margaret K.Vandervoort, Allison Luo, Barrett G. Levesque

BACKGROUND: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the SimpleEndoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess disease activity;however neither instrument has been fully validated. We evaluated intra- and inter-rateragreement and identified index items responsible for the greatest amount of disagreementbetween the measures. METHODS: Video recordings of colonoscopies obtained from 50patients with CD who participated in an induction trial of a biologic therapy conducted byBristol-Myers Squibb were triplicated and randomly reviewed by 4 central readers. Inter-class correlation coefficients (ICCs) for the inter- and intra-rater agreement were calculatedfor the CDEIS, SES-CD, and a global assessment of endoscopic lesion severity (GELS). Videosmost influential to ICC estimates were identified using Cook's distance (D) statistic. A Delphiprocess identified the most common sources of disagreement. Regression of the CDEIS andSES-CD against the GELS after exclusion of these items was used to assess correlationcoefficients of the modified indices. RESULTS: Ten of 50 videos were responsible for thegreatest disagreement. The Delphi study has identified multiple areas that require greaterclarity for scoring; specifically, definitions of stenosis and scoring after balloon dilation,defining location of ulcers involving two contiguous segments, and differentiating betweenanal and rectal lesions. Statistically, interpretation of stenosis contributed the most to disagree-ment for both indices. Intra- and inter-rater ICCs for the original and modified indices(excluding stenosis from the calculation of each index for all videos) and correlation coeffi-cients with GELS were nearly identical (Tables 1 and 2). CONCLUSION: Expert centralreading of the SES-CD and CDEIS had "substantial" to "almost perfect" intra- and inter-rateragreement. However, our preliminary results indicate that 1) further efforts to standardizedefinitions of problematic items and 2) potentially, the removal of stenosis assessment fromboth the CDEIS and SES-CD may be strategies to further improve agreement. We planfuture studies to evaluate these possibilities.Table 1. Reliability estimates for the CDEIS, SES-CD, and GELS

*ICCs of <0.00, 0.00-0.20, 0.21-0.40, 0.41-0.60, 0.61-0.80, 0.81-1.00 indicate poor, slight,fair, moderate, substantial, and, almost perfect agreement, respectively. †"Modified" refersto exclusion of scoring stenosisTable 2. Correlation between the indices

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†"Modified" refers to exclusion of scoring stenosis aBetween the modified CDEIS and theoriginal SES-CD bBetween the original CDEIS and the modified SES-CD

1001

Risk of Colorectal Cancer in Patients With Sessile Serrated Adenomas/PolypsIs of the Same Magnitude or Even Higher Than in Patients With ConventionalAdenomasRune Erichsen, John A. Baron, Stephen J. Hamilton-Dutoit, Dale Snover, Emina E.Torlakovic, Trine Frøslev, Lars Pedersen, Mogens Vyberg, Stanley R. Hamilton, Henrik T.Sørensen

Background: Studies have shown dysplasia and adenocarcinoma arising from serrated precur-sor lesions such as sessile serrated adenomas/polyps (SSA/P); SSA/Ps also share molecularcharacteristics with sporadic microsatellite instable colorectal cancers (CRC). However, thereis little longitudinal evidence of CRC risk in patients with SSA/Ps and management recommen-dations for these patients are based largely on expert opinion without objective evidence.In particular, it is unknown whether patients with SSA/Ps carry a higher CRC risk thanpatients with "conventional" adenomas (CA). Methods: Using Danish medical databases, weconducted a nationwide population-based nested case-control study (1977-2006). Amongthose with a history of colonoscopy (N=272,342), we found 2,045 patients later diagnosedwith incident CRC and 8,165 controls matched on birth year and gender. We identifiedthe first polyps resected/biopsied during or after the initial colonoscopy. Lesions originallydiagnosed as hyperplastic polyps were reviewed by four expert pathologists to identifyundiagnosed SSA/Ps. We used conditional logistic regression to compute odds ratios (ORs)for CRC associated with each serrated polyp type, using patients with CAs as a referentgroup familiar to clinicians with well-developed recommendations. Results: A total of 48(2.3%) cases and 81 (1.0%) controls had at least one SSA/P. Patients with SSA/Ps, CAs, andtraditional serrated adenomas (TSA) all showed increased CRC risks in comparison withpatients with no polyps. Compared with the 722 (35.3%) cases and the 1,633 (20.1%)controls with a history of CA, the OR of CRC in patients with SSA/Ps was 1.34 (95% CI:0.92-1.95). The CRC risk was higher in women with SSA/Ps than in women with CAs (OR=2.11, 95% CI: 1.26-3-54), whereas we found no difference in risk for men (OR= 0.82, 95%CI 0.47-1.44). In addition, the CRC risk was higher for patients with SSA/Ps proximal tothe splenic flexure than among patients with proximal CAs (OR=3.83, 95%CI: 1.45-10.14);the ORs were 0.53 (95% CI: 0.20-1.45) comparing distal and 0.81 (95% CI: 0.44-1.50)comparing rectal lesions. Similarly, patients with SSA/Ps were associated with an increasedrisk of proximal colon cancer (OR=2.16, 95%CI: 1.40-3.34) but not for distal CRC (OR=0.93, 95%CI: 0.48-1.83) in comparison with those with CAs. For the 8 (0.4%) cases andthe 14 (0.2%) controls with TSAs, the OR of CRC was 1.34 (95%CI: 0.56-3.25). Conclusion:Patients with SSA/Ps had a risk of subsequent CRC of the same magnitude or even higherthan patients with CAs. These findings broadly support existing guidelines of diagnosticfollow-up for patients with SSA/Ps, but also suggest that women should undergo particularlyclose follow-up for CRC and that optimization of surveillance of the proximal colon is impor-tant.

1002

Contributions of Cigarette Smoking to the Development of Sessile SerratedAdenomas in a Distinct PopulationJames Davenport, Walter E. Smalley, Yinghao Su, Reid Ness, Wei Zheng, Martha J.Shrubsole

BACKGROUND: Sessile serrated adenomas (SSAs) are emerging as significant precursorlesions to initial and interval colorectal cancers, with estimations of ~1/3 of cancers originatingfrom a serrated polyp pathway. However, given their novelty in the fields of gastroenterologyand GI pathology, their epidemiologic risk factors for development are not fully characterized.We looked to determine whether cigarette smoking was associated with SSA risk and whetherthis differed from the association of smoking with traditional adenomas (TAs) and hyperplasticpolyps (HPs). METHODS: The Tennessee Colorectal Polyp Study is a case-control study ofcolonoscopy patients between 2003 and 2010 at two medical centers in Nashville, TN.Individuals with genetic colorectal cancer syndromes, inflammatory bowel disease, personalhistory of cancer, or history of colorectal adenomas were excluded. Controls received acolonoscopy to the cecum without evidence of polyps. Polyp tissue samples were reviewedby a study pathologist and groups were separated based on type of polyp. Following theprocedure, telephone surveys were conducted using standard questions about demographics,medication use, medical history, lifestyle factors, and dietary intake. We compared 4402control patients with 903 cases with only TAs (excluding any SSAs), 265 cases with HPs,and 139 confirmed cases of SSAs. Odds ratios (ORs) and 95% confidence intervals (CIs)were derived from logistic regression models. RESULTS: Patients found to have SSAs oncolonoscopy were more likely to be older, male, Caucasian, earn less annual income andhave a prior family history of colorectal cancer compared to controls (p<0.05 for demograph-ics). Current cigarette smoking was associated with a substantially increased risk of all typesof polyps, but was particularly strong for hyperplastic polyps (OR: 4.58, 95% CI: 3.16-6.64) and SSAs (OR 5.50, 95% CI 3.33-9.08) in comparison to never smokers and risk wasstatistically different between the polyp groups (pheterogeneity < 0.001). Duration of cigarettesmoking was also associated with an increased risk of SSAs in a dose-dependent manner(ptrend<0.001). Interestingly, recent smoking cessation (defined as < 10 years) showedsignificant risk reduction in the development of SSAs but not in HPs or TAs (OR 0.44, 95%CI 0.21-0.92 for SSAs, OR 0.70, 95% CI 0.43-1.14 for HPs, OR 0.82, 95% CI 0.58-1.16for TAs compared with current smokers). CONCLUSION: The development of sessile serratedadenomas was associated with current tobacco cigarette use and duration, but cessation of

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