Tu1944

Efficacy and Safety of Standard vs Low Dose Adalimumab MaintenanceTherapy As a Function of Disease Severity in Pediatric Patients With Crohn'sDisease: Subanalysis of Imagine 1Jeffrey S. Hyams, Wallace Crandall, Joel R. Rosh, Frank Ruemmele, Johanna C. Escher,Andreas Lazar, Yaqin Wang, Roopal Thakkar

Aim: Adalimumab (ADA) has been shown to be an effective treatment for inducing andmaintaining clinical remission and/or response in children with moderate to severe Crohn'sdisease (CD)1. Although the standard adult dose (SD) ADA maintenance therapy exhibitedgenerally greater efficacy than low dose (LD)1, the influence of baseline (BL) disease severityon outcomes has not been determined. Methods: In IMAgINE11, patients (pts) aged 6-17years that had a PCDAI score .30 at BL, with CD resistant or intolerant to conventionaltherapy, including prior infliximab (IFX), received open-label induction ADA at weeks (wks)0/2 according to bodyweight (≥40kg, 160/80mg;,40kg, 80/40mg). At wk4, 188 randomizedpts (ITT population) received either double-blind SD ( ≥40kg, 40mg every other wk (eow);,40kg, 20mg eow) or LD (≥40kg, 20mg eow; ,40kg, 10mg eow) maintenance therapy.After wk12, pts could move to blinded weekly (ew) dosing for disease flare or non-response.Clinical remission (PCDAI≤10) and response (PCDAI decrease ≥15 points from BL) weremeasured at wk52. Subgroup analyses by disease severity, based on the median BL PCDAIobserved for the study population (less severe CD, PCDAI,40; more severe CD, PCDAI≥40),and also by prior IFX use were performed. Non-responder imputation was used for missingdata or after switch to ew therapy. Treatment-emergent adverse events (AE) were reportedas events/100pt-years (E/100PY) for any pt receiving at least one dose of ADA. Results:Greater clinical remission and response was achieved with SD ADA therapy compared toLD at wk52 in pts with more severe disease, with the greatest difference between dosesoccurring in IFX Naïve pts. For pts with less severe CD, similar rates of remission andresponse were observed between SD and LD ADA (Table). Switch to ew dosing occurredmost frequently in pts with more severe CD receiving LD ADA (55.6%) than in pts withless severe CD receiving the same dose (43.9%). For pts receiving SD ADA, escalation toew dosing occurred in a similar percentage of pts, regardless of BL disease severity (35.9%,less severe; 38.9%, more severe). The overall rate of AEs was similar between dosing groupsfor either pt population. For pts with less severe CD, serious AEs (SAEs) were higher withSD (32.0 E/100PY) than LD ADA (17.6 E/100PY), whereas a similar rate of SAEs wasobserved between SD and LD ADA in pts with more severe disease (54.8 vs 64.5 E/100PY, respectively). No malignancies, TB, congestive heart failure or deaths were reported.Conclusion: At wk52, SD maintenance ADA was a more effective therapy than LD forchildren with more severe CD, whereas pts with less severe disease benefitted equally fromboth doses. The greatest remission and response rates were observed for IFX-Naïve pts. Theoverall safety profile was similar for SD and LD ADA treatment. 1.Hyams 2012 Gastroenter-ology;143:365Clinical outcomes in pediatric CD pts with eow SD vs eow LD ADA (ITT population)

*p≤0.05, **p≤0.01 SD vs LD, p values from Chi-square test or Fisher's exact test; ITT:intent-to-treat

Tu1945

Adalimumab Treatment Is Associated With Improved Quality of Life inPediatric Crohn's DiseaseGigi Veereman, Johanna C. Escher, Frank Ruemmele, Wallace Crandall, Andreas Lazar,Martha Skup, Mei Yang, Jingdong Chao, Parvez Mulani, Roopal Thakkar, Jeffrey S.Hyams

Background: Adalimumab (ADA) has been shown to induce response and remission inmoderate/severe Crohn's disease (CD) in children. Aim: We aimed to assess the effect ofADA treatment on health-related quality of life (HRQOL) in pediatric patients with CD.Methods: IMAgINE 1 was a 52-week, multi-center, double-blind study assessing efficacyand safety of ADA in patients aged 6-17 years withmoderate to severe CD (defined as PediatricCD Activity Index [PCDAI] .30) failing prior therapy, including infliximab. Following 4weeks of open-label induction (80 mg and 40 mg at weeks 0 and 2, respectively for patientswith bodyweight [BW] ,40 kg, or 160 mg and 80 mg for BW ≥40 kg), 188 patients wererandomized 1:1 to standard dose (20 mg, BW ,40 kg, or 40 mg, BW ≥40 kg) or low dose(10 mg, BW ,40 kg, or 20 mg, BW ≥40 kg) double-blind ADA every other week. AfterWeek 12, patients who experienced flare or nonresponse could switch to blinded weeklydosing and to standard dose open label therapy. To assess HRQOL, patients ≥10 years (N=176) completed the IMPACT III, a 35-item questionnaire with scores ranging from 35 (poor)to 175 (best), at baseline and weeks 12, 26, and 52. A change of 10.8 has been shown toindicate clinical improvement. Within group changes from baseline were assessed usingpaired t-tests at each time point (by group; by group and prior anti-TNF use; by group andWeek 4 response). Changes from baseline were compared between dose groups usingANCOVA (with group as factor, adjusting for anti-TNF exposure, Week 4 response, andbaseline IMPACT III score). Last-observation-carried-forward was used for patients whodiscontinued or dose escalated. Results: At baseline, no significant differences were observedbetween dose groups in demographics, mean PCDAI scores, and prior anti-TNF exposure.The low dose group exhibited higher mean IMPACT III scores at baseline (117.7±15.5 vs.111.6±18.7, P=.018). Both groups demonstrated significant improvements in mean IMPACTIII scores at Weeks 12, 26, and 52 (figure). Improvements were observed in each domain,particularly in the bowel symptoms domain (4.7-4.8 change from baseline by Week 12 in

S-887 AGA Abstracts

both dose groups). The effect was most pronounced in anti-TNF Naïve patients and earlyresponders. In all groups, the standard dose group demonstrated slightly more improvementcompared to low dose, but differences were not statistically significant. Conclusion: ADAtreatment was associated with improved HRQOL in pediatric patients with CD by week 12and remained over the 52-week study.

Tu1946

Use of the QuantiFERON-TB Gold in-Tube Test for Latent TuberculosisScreening in Children With Inflammatory Bowel Disease Treated WithInfliximabEugene Vortia, Victor E. Uko, Belinda Yen-Lieberman, Jill Frawley, Lara Danziger-Isakov,Barbara Kaplan, Lori Mahajan

BACKGROUND: Infliximab therapy has been linked with an increased risk of active tubercu-losis (TB), mediated by its inhibitory effect on TNF- α. As a result, latent TB screening isrecommended prior to initiation of infliximab therapy. The QuantiFERON-TB Gold In-TubeTest (QFT-GIT) (Qiagen/Cellestis, Germantown, Maryland), an interferon gamma releaseassay, is an alternative to the tuberculin skin test (TST) for latent TB screening. The QFT-GIT is specific and performed in one visit. Since immunosuppressants may suppress themitogen response (positive control) and generate indeterminate test results, there is concernabout the usefulness of this test for patients on infliximab. OBJECTIVE: To assess theprevalence of QFT-GIT indeterminate results in children ≥ 5 yrs with inflammatory boweldisease (IBD) treated with infliximab and to evaluate factors that affect mitogen response.METHODS: A single-center prospective study was performed to evaluate 93 children 5-19yrs of age with IBD receiving infliximab infusions. All subjects had blood drawn for acomplete blood count and the QFT-GIT. In addition, data was collected on demographic,anthropometric, and disease factors, as well asmedications and risk of TB exposure. RESULTS:The mean age of the 93 enrolled patients was 15.2 (±3.8) yrs. 86% had Crohn's diseaseand 14% had ulcerative colitis. The mean infliximab dosage was 6.4 ±1.8 mg/kg [range 3.8-10.2] and mean duration since the prior infliximab infusion was 44.3 (±12.7) days, [range28-76]. Mean duration since initiation of infliximab therapy was 35.1 (±26.7) months [range3-119]. In the 31 patients for whom results of TSTs before therapy was available, none hada positive result. The mean mitogen response was 9.3 (±2.2) IU/ml, with the maximumresponse (10 IU/ml) observed in 82 patients (88 %). The QFT-GIT was negative in 90patients and positive in 2 patients and both positive patients had a negative initial TST.One patient (1%) had an indeterminate result (95% CI: 0.19 % - 5.84%), which wassignificantly less than the hypothesized rate of 8% (one-sided non-inferiority test, p =0.004). None of the 17 patients receiving additional immunosuppression to infliximab hadindeterminate QFT-GIT results [prednisone (7), median dose: 0.43 mg/kg, azathioprine(14), median dose: 1.35 mg/kg and 6-mercaptopurine (1), 0.61 mg/kg]. Lower hemoglobinlevels were significantly associated with decreased mitogen response in univariable andmultivariable regression analyses (P,0.01). CONCLUSION: This is the first prospectivestudy assessing the use of the QuantiFERON-TB Gold In-Tube test in pediatric patients treatedwith infliximab. The indeterminate rate was 1%, a rate comparable to non-immunosuppressedchildren of similar age. This study suggests that this test can be a useful tool to screen forlatent TB in children on infliximab.

Tu1947

de novo Expression of the Corticotropin-Releasing Factor (CRF) Receptors inStomachs of Patients With GastritisPallavi Mhaske, Elizabeth A. Garnett, Min Liao, Melvin B. Heyman, Aditi Bhargava

Background. Components of the stress hormone systemhave been implicated in gastrointesti-nal (GI) diseases. Urocortin 1 (Ucn1) and its two GPCR receptors CRF1 and CRF2 areimportant mediators of local, peripheral inflammatory responses. Presence of the componentsof the CRF system in stomachs of pediatric patients has not been reported. Aim. To determineif Ucn1 and CRF receptors are involved in pediatric patients with gastritis. Methods. Pediatricpatients who underwent upper endoscopy with biopsies at UCSF were categorized bydiagnosis and matched by age and gender. Data collected on all patients included demograph-ics, medical history, presenting symptoms, location of disease, final diagnosis and histologicalresults. The protocol was approved by the UCSF Committee on Human Research. Paraffin-embedded sections of the stomachs were immunostained with Ucn1 and CRF1/2 receptorantibodies and sections were analyzed by confocal microscopy. Pre-adsorbed or no primaryantibodies were used as negative controls. Results. Parietal cells and a subset of endocrineG cells of the stomachs of normal males (ages 7-15) showed robust immuonreactive Ucn1(IR-Ucn1), while CRF receptor immunostaining (IR-CRF1/2) was not detected (Fig. 1). IR-Ucn1 was prominently expressed in the goblet cells and apical lining, while epithelial cellsalso expressed IR-Ucn1. This is in sharp contrast to both upper and lower GI regions ofthe same patients, where robust IR-CRF1/2 and Ucn1 is prominently detected in the duode-num, ileum and colon. In patients with gastritis, de novo expression of IR-CRF1/2 was

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