AGA Abstracts W1247 Short-Term Efficacy and Safety of Adalimumab in Children with Active Crohn's Disease: A Prospective, Open Label, Single Center Trial Franca Viola, Fortunata Civitelli, Erminia Romeo, Giulia Maiella, Federica Nuti, Marina Aloi, Osvaldo Borrelli, Salvatore Cucchiara Adalimumab (ADA) (HUMIRA, Abbott ®), a fully human IgG1 anti-TNFalpha monoclonal antibody, has become an effective therapeutic option for Crohn's disease (CD) adults intoler- ant or refractory to infliximab. There are no reports on the use of ADA in pediatric CD. This study evaluated the efficacy and safety of Adalimumab (ADA) in pediatric patients (pts) with moderate to severe CD Patients and Methods: 16 CD pts, mean age (yrs) 16.3 ± 4, (6 naïve and 10 intolerant or unresponsive to Infliximab (IFX), received ADA. For induction of remission we used 160 mg (in 7 pts) or 80 mg (in 7 pts) sc at week (wk) 0, followed by 80 mg or 40 mg at wk 2, respectively. The maintenance dose was respectively 80 mg or 40 mg eow; 2 pts received an induction dose of 120 mg followed by 80 mg at week 2. Outcome measures were: clinical remission (PCDAI score <10), clinical response (decrease in the PCDAI score of > 50 %) and safety at week 2, 4 ,12 and 24. Results: mean disease duration (months) at the beginning of ADA course was 41.3 ± 27. Ten pts had previously received IFX (9.6 ± 9.3 doses), that was discontinued due to loss of efficacy (7) or intolerance (3); mean time between the last IFX dose and the beginning of ADA was 17.7±16 months. Concomitant immunosuppressors (azathioprine or methotrexate) were maintained in 5 pts; 7 were on corticosteroids at the entry into the study. All pts were able to taper and/or stop steroids at wk 12. The mean PCDAI, CRP, ESR values at wks 0, 2, 4,12 and 24 are shown in the table. Rates (%) of remission and response, at weeks 2,4,12 and 24, were, respectively, as follows: 31.2, 37.5, 68.7 and 66.7 (remission); 50, 50, 18.7 and 25 (response). In 5 pts the initial maintenance dose of 40 mg eow was increased to 80 mg eow to mantain clinical response. Only 1 pt had a serious adverse event (cutaneous infection) requiring temporary cessation of ADA; 1 pt developed psoriasis; no pt had liver, pancreas or kidney injury; 3 had temporary local burning and pain. Conclusions: Our data suggest that ADA is an effective and well tolerated therapeutic option in inducing and maintaining clinical remission in children with refractory CD, irrespective of prior IFX therapy. Mean values of PCDAI, ESR and CRP during the study period * p<0.001 § p<0.05 & p<0.01 W1248 Microarray Analyses of UC Biopsies Suggests 5asa Reduces PI3 Kinase Signaling and Beta Catenin Activation Elizabeth Managlia, Ishfaq Bhat, Badar Muneer, Terrence A. Barrett Background and Aims: Ulcerative Colitis (UC) patients have a greater incidence of colorectal cancer (CRC). Sporadic CRC often have mutations in genes involved in βcatenin and PI3K signaling. Nuclear accumulation of βcatenin has proven to be a reliable marker for intestinal epithelial progenitor/stem cells (IEPSC). Using an Ab specific for Akt phosphorylated βcatenin (pβcatenin) data from our lab shows patients with UC have increased activated IEPSCs and suggests βcatenin and PI3K signaling may be involved in inflammation-induced cancers (Sun et al DDW 2008). We therefore investigated βcatenin and PI3K signaling and the correlation to IEPSC activation in chronic inflammation. We further aimed to elucidate a potential mechanism for 5ASA related cancer prevention through its impact on these path- ways. Methods and Results: Biopsies for active UC (UCDAI>4) or normal screening were used to determine the fold increase of mRNA over normals. Untreated patients (UT) were then compared to patients on 5ASA. Each cohort had average UCDAI scores of 7 and 6 respectively. Genes of interest included the βcatenin targets cmyc and COX2. Microarray (MA) analysis of UT (n=7) compared to 5ASA (n=5) revealed no significant difference in cmyc while COX2 was reduced from 11- to 3.3-fold(p=0.02). RTPCR confirmed these results and examined the epithelial specific βcatenin targets CD44v6 and mmp7. Average CD44v6 mRNA was reduced from 3.5-(n=18) to 2.2-fold (n=19)(p=0.04) while mmp7 decreased from 1682- to 754-fold (p=0.06). MA analysis of inflammatory genes showed a decrease in IL-1β(15- to 4.2-fold)(p=0.04), while decreases in IL-6(6.6- to 2.1-fold) and IL-8(24.5- to 5.7-fold) were approaching significance(p= 0.055 and 0.059). Data was confirmed by RTPCR and iNOS was examined. iNOS decreased from 35.2- to 10.9-fold (p=0.005). Examination of genes involving the PI3K pathway showed CTGF mRNA decreased from 3.4- to 1.2- fold(p=0.03) by MA. The inhibitor PTEN and the nuclear receptor PPARγ decreased in UT and increased in 5ASA with a strong linear correlation of increased PTEN to PPARγ(r=0.98) by RTPCR. RTPCR performed on mRNA isolated after LCM revealed that CD44v6, mmp7, and PPARγ are expressed in the epithelial fraction exclusively. Conclusion: Induction of βcatenin targets in colitis was consistent with the notion that chronic intestinal inflammation activates IEPSCs. Data revealed that 5ASA inhibited βcatenin target genes and induced inhibitors of PI3K signaling, shown to enhance βcatenin activation. Taken together, these data suggest that prevention of epithelial PI3K-mediated βcatenin signaling in colitis patients contributes to chemoprevention by reducing activation of IEPSCs. A-664 AGA Abstracts W1249 Intensification of Infliximab (Ifx) Therapy in Crohn's Disease: Efficacy and Safety Maria Chaparro, P. Martínez-Montiel, Manuel Van Domselaar, Fernando Bermejo, Jl Perez- Calle, B. Casis, Antonio López-San Román, Alicia Algaba, José Maté-Jiménez, Javier P. Gisbert INTRODUCTION: The response of Crohn's disease to IFX therapy is initially high. However, a loss of efficacy is observed in some cases over time. In such patients with loss of response, an IFX therapy “intensification” has been recommended. Nevertheless, it is still unknown whether the beneficial effect of this intensification is prolonged or just transient. AIMS: 1) To study the short- and long-term response of Crohn's disease patients treated with IFX intensification (e.g., higher doses or shortened intervals). 2) To evaluate the adverse effects associated to therapy intensification. METHODS: Retrospective multicenter survey. We included Crohn's disease patients who had been treated with at least the three induction doses of the standard IFX therapy (5 mg/kg 0-2-6 w), and who later on needed treatment intensification (10 mg/kg/8w or 5 mg/kg/4w), because of loss of response. Short-term (after the first intensification dose) and the long-term (at the end of follow-up) efficacy of the intensified therapy was analyzed. Harvey-Bradshaw's index was used in luminal Crohn's disease. In fistulizing Crohn's disease, complete response was defined as closure of all fistulas, and partial response as a 50% or more reduction in the number or the debit of fistulas. Safety was evaluated by collection of adverse effects. RESULTS: We included 33 patients (mean age, 39 years; 50% male; 33% smokers; 60% with ileocolic (L3) disease; 50% with fistulizing (B3) phenotype; 70% with perianal (p) disease). The majority (70%) of the patiens was treated with immunomodulators. The mean follow-up for intensified treatment was 40 weeks (range: 16-72 w). Mean time of IFX exposure before intensification was 12 months (range: 3-29 m). On the short-term, after the first intensification dose, 83% responded (31% complete response, 52% partial response). On the long-term, after the last intensification dose, only 65% were still responding (17% complete response, 48% partial response). One patient suffered an infusion reaction after 36 doses of intensified treatment, which subsided with slower infusion. One patient suffered an episode of herpes zoster, that did not interrupt the treatment. CONCLUSIONS: The intensification of IFX therapy is sometimes necessary after a mean drug exposure of one year. A high proportion will initially respond, but 20% of all cases lose effect again a mean of 10 months after intensification. Safety profile of IFX therapy intensification is good, having no severe adverse effects. W1250 Early Experience with Adalimumab for the Treatment of IBD in An Academic Medical Center Arun C. Swaminath, Melissa H. Rosen, Lloyd Mayer, Thomas A. Ullman, Simon Lichtiger, Maria T. Abreu BACKGROUND:Anti-TNF therapy is effective for the treatment of Crohn's disease (CD). Adalimumab, at an induction dose of 160mg/80mg followed by 40mg eow is approved for treatment of refractory CD and for patients with loss of response to infliximab. AIM:The purpose of this study was to evaluate the indications for adalimumab, the proportion of CD patients that require dose escalation, and to identify factors that predict poor clinical response to adalimumab. METHODS: Patients prescribed adalimumab for CD in an academic medical center were identified by prescription logs, pre-authorization requests, and chart review. Patients were included for analysis if they had follow up of at least 6 weeks. Adalimumab dose was escalated if patients had return of symptoms prior to next dose. A single GI physician reviewed all charts. Clinical judgment (based on modified Harvey Bradshaw Index) was used to determine severity of disease. Concomitant medication use was abstracted from the charts. RESULTS: A total of 60 charts were reviewed and 50 patients met inclusion criteria. Adalimumab was used to treat CD in 49/50 (98%). Most patients had moderate 23/50 (46%) or severe 24/50 (49%) disease. Prior infliximab exposure was present in 44/ 50 (88%). Adalimumab dose escalation occurred in 14/41 (34%) within an average time of 2.2 mo (SD 1.5mo, CI 0.8). The majority of patients who required dose escalation, 9/14 (64%), did not improve clinically. Infliximab naïve patients (n=4) did not require dose escalation. Steroids could be discontinued in 3/16 (18.7%). Clinical improvement was noted in 21/50 (42%) and 1/50 (2%) patients achieved clinical remission. Adverse drug reactions necessitated drug discontinuation in 5/50 (10%) of patients. CONCLUSION: This retrospect- ive review from a single academic medical center suggests that the majority of patients who cannot be maintained on 40mg eow of adalimumab do not often benefit from an increased dose. It also suggests that use of infliximab prior to use of adalimumab decreases the likelihood of clinical response. Clinical remission was a rare event in this group. Analysis of patients on adalimumab