11.4, 12.7 & 13.7 yr respectively, p=0.01). There was a strong inter-relationship betweenGM-CSF Ab and both CBir1 and ASCA status that varied with age. GM-CSFp was stronglyassociated with CBirp in A1a pts (OR 3.7, p<0.001), and less so in A1b pts (OR 2.0,p<0.001). The relationship increased with increasing titres of GM-CSF Ab (q3 OR 1.8, q4OR 5.3, p<0.001). GM-CSFp also increased the likelihood of a pt being ASCAp (OR: 6.7p<0.001) across all ages. This relationship also increased with increasing GM-CSF titres(OR: q2, 2.7; q3, 6.6; q4, 26.8; p<0.0001). Disease location varied with Ab profile in theA1a group. In A1a, isolated CBir1p was associated with increased risk of extensive disease(L3, 55% vs 70% p=0.03), while the combined presence of GM-CSF Ab and CBir wasassociated with a marked increase in isolated ileal location (L1, 9.7% vs 33% p=0.002). InA1a pts negative for all AMS, GM-CSFp status was also strongly associated with L1 location(OR 4.9, p<0.002). Conclusions: Very early onset CD patients exhibit distinct AMS profiles;GM-CSF Ab modulate both AMS and disease location in this group. Collectively these resultssupport the notion of distinct pathogenesis in these pts.

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Assessment of Durability of Infliximab Maintenance Therapy in Children WithCrohn's DiseaseMarian D. Pfefferkorn, Trudy Lerer, David R. Mack, Jonathan Evans, David J. Keljo,Marsha H. Kay, Joel R. Rosh, Anthony R. Otley, Michael C. Stephens, Maria Oliva-Hemker, Neal S. Leleiko, Athos Bousvaros, Ryan Carvalho, Farhat N. Ashai-Khan,Andrew B. Grossman, Shehzad A. Saeed, Meredith C. Hitch, Michael Kappelman, BorisSudel, William A. Faubion, James Markowitz, Jeffrey S. Hyams

Background: Adult and pediatric patients with Crohn's Disease (CD) may lose response toinfliximab (IFX) maintenance therapy. Previous observations from our group showed decreas-ing numbers of pediatric patients on maintenance IFX from 93% at 1 year to 67% at 3years (IBD 2009;15:816). Aim: To identify factors associated with increased durability ofIFX therapy in children with CD. Methods: Data were obtained from the Pediatric IBDCollaborative Research Group Registry, a prospective North American observational studyof newly diagnosed children ≤16 years of age. Data are recorded at diagnosis, 30 days, andthen quarterly. Patients are managed by physician dictates, not by protocol. Disease activityis classified by physician global assessment (PGA). In this analysis all patients with CD whoreceived a 3-dose IFX induction followed by at least one infusion within 84 days of the 3rddose and who had at least 1 year of follow-up after initiation of IFX therapy were identified.Clinical and demographic characteristics, outcomes including PGA and infusion reactionswere examined. Results: 289 patients met study inclusion criteria (61% male, mean age atdiagnosis 12 ± 2.6 years (1.6-16 years), mean age at first IFX 13.2 ± 2.7 years (range 2.7-19.4 years) and mean follow-up after initial IFX dose 38 ± 22 months (12-105 months).Disease severity at diagnosis was mild in 50 (17%), moderate in 170 (59%), severe in 61(21%) and unknown in 8 (3%). Disease extent was both small and large bowel disease (L3)in 193 (67%), colonic (L2) in 74 (27%) and small intestinal (L1) in 21 (7%). Patientsremaining on maintenance IFX at 1 year were 259/289 (90%), 173/209 (83%) at 2 years,105/137 (77%) at 3 years, 68/89 (76%) at 4 years and 42/57 (74%) at 5 years. The majorityof patients remaining on IFX were corticosteroid-free with inactive/mild disease (Table).Patients < 12 years old (118/125; 94%) were more likely to remain on IFX at 1 year comparedto older patients (141/164; 86%), OR=2.75 (95% CI=1.14-6.63) p=0.025. Multivariateanalysis of gender, age at initiation of IFX, disease extent, and immunomodulator therapyduring the first quarter of IFX was not predictive of durability of IFX at 2 years, 3 years, 4years or 5 years. There were 64 infusion reactions observed in 39/289 (13%) and 14 delayedhypersensitivity reactions in 7/289 (2.4%). Conclusion: IFX therapy is durable up to 5years in a large number of pediatric CD patients (74%), with the majority remaining off ofcorticosteroids. Younger patients <12 years old are more likely to remain on IFX at 1 year;however, we found no additional patient characteristics that would predict sustained responseto IFX.Patients Remaining on Infliximab Classified According to Corticosteroid (CS) Therapyand PGA

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Prospective Multicenter Pediatric Cohort Study: Patients With Liver EnzymeElevations in the First 3 Months After Diagnosis of Inflammatory BowelDisease are at Increased Risk of Chronic Liver DiseaseAlka Goyal, Jeffrey S. Hyams, Trudy Lerer, Neal S. Leleiko, Anthony R. Otley, Anne M.Griffiths, Jonathan Evans, Joel R. Rosh, Michael C. Stephens, Athos Bousvaros, MariaOliva-Hemker, David R. Mack, Farhat N. Ashai-Khan, Marian D. Pfefferkorn, RyanCarvalho, Andrew B. Grossman, Meredith C. Hitch, Boris Sudel, Michael Kappelman,Shehzad A. Saeed, William A. Faubion, Marsha H. Kay, Marc Schaefer, James Markowitz,David J. Keljo

Background: Both autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) arefrequently associated with a diagnosis of Inflammatory Bowel Disease (IBD). Prospectiveunbiased multi-center data regarding the frequency of these disorders in the population ofpediatric patients with IBD are lacking. Aim: To determine the frequency of ALT or GGTelevation in children with IBD and concurrent or subsequent risk of AIH or PSC. Methods:Data were derived from the prospective Pediatric IBD Collaborative Research Group Registryestablished in 2002 in North America. This is an observational cohort study enrolling patientswithin 30 days of diagnosis with IBD. Data are gathered quarterly. 1786 patients were

S-37 AGA Abstracts

identified who had ALT or GGT measurements available within the first 3 months (mo)following diagnosis. The incidence of AIH and PSC concurrently or subsequently diagnosedby local clinical criteria was analyzed in these patients. Results: During longitudinal observa-tion (3.4± 2.3 yrs, median=3 yrs) of the 1786 patients, 37 patients were identified withchronic liver disease: 27 with PSC (1.5%), 3 with AIH (0.2%) and 7 with overlap syndrome(0.4%). 151/1786 patients (8%) were found to have an ALT or GGT >50 within the firstquarter of diagnosis, and 30 of these patients (20%) had chronic liver disease: AIH (3), PSC(22) or overlap (5). Only 7 out of 1635 patients (0.4%) with normal ALT and GGT in Q1were diagnosed with chronic liver disease. Liver disease was more common in Ulcerativecolitis or IBD-unspecified (UC or IBD-U) thanCrohnDisease (CD) (4.0% vs 1.2% respectively,p<.001). Children with ALT or GGT >50 in Q1 were at > 20-fold increased risk of chronicliver disease (p<0.001) Conclusions: PSC and AIH are uncommon complications of IBD,and more likely to be seen in children with UC or IBD-U than CD. While elevations in ALTor GGT within 3 months of diagnosis of IBD in children are relatively uncommon, childrenwith elevated ALT or GGT at IBD diagnosis are at greatly increased risk of a concurrent orsubsequent diagnosis of AIH or PSC.Enzyme Abnormalities in the First Three Months and Risk of Chronic Liver Disease

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Pediatric Crohn Disease Patients Who Require Ileal Resection ExhibitIncreased Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)Neutralizing Capacity in Peripheral Blood and GM-CSF Auto-AntibodyProduction by Ileal Lamina Propria CellsIngrid Jurickova, Claudia Chalk, Erin L. Bonkowski, Bruce C. Trapnell, Lee Denson

Background: GM-CSF auto-antibodies (GM-CSF Ab) are associated with stricturing behaviorand surgery in Crohn disease (CD). Patients with pulmonary alveolar proteinosis (PAP)exhibit high levels of neutralizing GM-CSF Ab. It was not known whether GM-CSF Ab inCD peripheral blood (PB) samples would also have neutralizing capacity (NC) which wouldcorrelate with complicated disease. We hypothesized that Lamina Propria Mononuclear Cells(LPMC) from affected ileal tissue would produce GM-CSF Ab and PB samples from CDpatients would exhibit GM-CSF NC. Methods: We measured serum GM-CSF Ab in 174healthy controls (HC), 302 pediatric CD patients, and 5 PAP patients. We studied 12 CDpatients undergoing ileo-cecal resection. Peripheral blood mononuclear cells (PBMC) werepurified and LPMC were isolated from ileal surgical specimens and cultured for 14 days.Total IgG and GM-CSF Ab were measured by ELISA in patient serum and day 14 PBMCand LPMC conditioned media. GM-CSF (CD116) receptor expression and GM-CSF stimula-tion (10 ng/mL for 10minutes) of granulocyte STAT5 tyrosine phosphorylation wasmeasuredby flow cytometry in whole blood samples and washed PB cells prepared from 7 HC, 45CD, and 5 PAP patients. Results: The median(IQR) serum GM-CSF Ab concentration wasincreased to 5.8(0.1,46) mcg/ml in twelve CD patients undergoing ileo-cecal resection ascompared to 0.5(0.3,1.1) mcg/mL in HC and 1.3(0.5,4) mcg/mL in CD patients withinflammatory behavior. The median(IQR) day 14 total IgG concentration in culture wasincreased from 10(5,20) mcg/mL in CD PBMC to 18(7,50)mcg/mL in CD LPMC (p=0.02).The median(IQR) day 14 GM-CSF Ab concentration in culture was increased from0.3(0.1,5)ng/mL in CD PBMC to 2.5(0.3,49)ng/mL in CD LPMC (p=0.04). CD116 receptorexpression as measured by MFI did not vary between HC and CD patients. In the subsetof forty CD patients utilized for the GM-CSF NC studies the median(IQR) serum GM-CSFAb concentration was 2(0.1,95)mcg/mL as compared to 57(38,945)mcg/mL in PAP patients(p=0.0001). GM-CSF stimulation of pSTAT5 did not vary between HC, CD, or PAP inwashed PB granulocytes in which serum was removed. However, GM-CSF stimulation ofgranulocyte pSTAT5 was reduced in whole peripheral blood (WPB) samples obtained fromCD and PAP patients. The mean(SEM) GM-CSF NC in WPB increased from 11(11)% inHC to 30(5)% in CD and 103(3)% in PAP (p<0.0001). CD patients with GM-CSF NCgreater than 25% exhibited a 42% rate of structuring disease and 33% rate of surgery ascompared to 5% and 0%, respectively for CD patients with lower GM-CSF NC (p=0.03,p=0.004, respectively). Conclusions: GM-CSF Ab production is enhanced in CD ileal LPMC.GM-CSF stimulation of pSTAT5 is intact in washed CD granulocytes. However, CD peripheralblood contains GM-CSF NC which is associated with increased rates of stricturing behaviorand surgery.

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Hes1 Promotes IL-22-Mediated Epithelial Regeneration Through Enhancementof STAT3-Dependent Transcription in Human Intestinal Epithelial CellsTatsuro Murano, Ryuichi Okamoto, Hiromichi Shimizu, Go Ito, Kiichiro Tsuchiya,Tetsuya Nakamura, Mamoru Watanabe

Background & Aims: In our previous study, we have shown that activation of Notch-Hes1signaling in intestinal epithelial cells (IECs) plays an indispensable role in regeneration ofthe inflamed intestinal mucosa. Cytokines such as IL-22 are up regulated upon intestinalinflammation, and has also been implicated in epithelial regeneration via its direct effectupon IECs. However, how these pathways co-operate or interact to promote mucosal regen-eration has never been shown. Thus, we aimed to investigate whether any interaction betweenNotch-Hes1 and IL-22/IL-22R pathway may exist in IECs, and thereby contribute to promoteregeneration of the intestinal epithelia. Methods: For the activation of Notch-Hes1 pathway,forced expression of Notch intracellular domain (NICD) or Hes1 was induced by a tetracyc-line-dependent manner, in LS174T or DLD1 cells. Also, IL-22/IL-22R pathway was activatedin those cells by addition of recombinant human IL-22. Under concomitant activation of

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