Jennifer M. Choi

Combination of Innate and Adaptive Immune Alterations Increased the Likelihood of Fibrostenosis in Crohn’s Disease

Background: Mutations in the nucleotide oligomerization domain‐2 (NOD2) gene and positive antibodies to microbial antigens have been found to be associated with the Crohns disease (CD) phenotype, fibrostenosis. The aim of this study was to confirm these relationships in a large cohort of CD patients and to determine the correlation between the presence of NOD2 variants and antibodies to oligomannan, CBir, outer membrane porin‐C (OmpC), and I2 in CD patients with fibrostenosis. Methods: Sera and DNA from 731 unrelated CD patients were tested for NOD2 variants (SNP 8, 12, and 13) and the antibodies. The results were correlated with CD phenotypes, fibrostenosis, internal penetrating, perianal penetrating, and ulcerative colitis (UC)‐like as well as other clinical features. Results: The presence of NOD2 allelic variants was primarily associated with fibrostenosis, secondarily with small bowel disease and small bowel surgery, and was inversely associated with UC‐like disease. This association was present in patients with a fibrostenosis only (Vienna B2) and those with both stricturing and penetrating disease. The presence and level of antibodies to microbial antigens was also associated with the fibrostenosis phenotype. In the 316 patients with fibrostenosis the prevalence of NOD2 variants was significantly correlated with the antibody titer by quartile sum score. Further, when these patients with fibrostenosis were clustered by quartile sum score, the odds ratio for fibrostenosis was significantly higher in the patients with NOD2 variant alleles within each cluster, indicating synergy. Conclusions: Defects of innate (NOD2 variants) and adaptive (antibodies to microbial antigens) immunity act synergistically to increase the risk of the fibrostenosis phenotype. (Inflamm Bowel Dis 2009;)

Presenteeism in Inflammatory Bowel Diseases: A Hidden Problem with Significant Economic Impact

Background:Indirect costs associated with impaired productivity at work (presenteeism) due to inflammatory bowel disease (IBD) are a major contributor to health expenditures. Studies estimating indirect costs in the United States did not take presenteeism into account. We aimed to quantify work limitations and presenteeism and its associated costs in an IBD population to generate recommendations to reduce presenteeism and decrease indirect costs. Methods:We performed a prospective study at a tertiary IBD center. During clinic visits, work productivity, work-related problems and adjustments, quality of life, and disease activity were assessed in patients with IBD. Work productivity and impairment were assessed in a control population as well. Indirect costs associated with lost work hours (absenteeism) and presenteeism were estimated, as well as the effect of disease activity on those costs. Results:Of the 440 included patients with IBD, 35.6% were unemployed. Significantly more presenteeism was detected in patients with IBD (62.9%) compared with controls (27.3%) (P = 0.004), with no significant differences in absenteeism. Patients in remission experienced significantly more presenteeism than controls (54.7% versus 27.3%, respectively, P < 0.01), and indirect costs were significantly higher for remissive patients versus controls (

Sa1139 Safety of Certolizumab Pegol in 2570 Crohn's Disease Patients With 4378 Patients Years at Risk: Integrated Data From the Global Clinical Program

17,766 per yr versus

Predictors of Therapeutic Remission to Thiopurines in Pediatric Inflammatory Bowel Disease

9179 per yr, respectively, P < 0.03). Only 34.3% had made adjustments to battle work-related problems such as fatigue, irritability, and decreased motivation. Conclusions:Patients with IBD in clinical remission still cope with significantly more presenteeism and work limitations than controls; this translates in higher indirect costs and decreased quality of life. The majority have not made any adjustments to battle these problems.

347 Targeting a microRNA for the Therapy of Colitis-Associated Colorectal Cancer

Back ground: The calcineurin inhibitor (CNI) tacrolimus (TAC) has been reported to be effective for induction and maintenance of remission in patients with refractory ulcerative colitis (UC). However, CNI has nephrotoxic potential leading to acute and chronic renal damage in some cases. To date, little is known about the influence of long term administration of oral TAC on renal function in patients with UC. Aim: The aim of our study was to evaluate the incidence and the severity of renal function impairment in UC patient who received TAC treatment. Methods: In this retrospective study, the medical charts of 71 adult patients with steroid-refractory UC treated with TAC between 2012 and 2014 in a single Japanese center were analyzed. In principle, TAC was orally administrated as a 2 week-induction (target trough levels 10-15ng/ml) followed by a maintenance therapy (target trough levels 5-10ng/ml). Estimated glomerular filtration rate (eGFR) was evaluated during the treatment. Acute kidney injury (AKI) was defined by the RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of function, Loss of function and End-stage kidney disease) consensus criteria using the maximal change in serum creatinine (Scr) and eGFR during the TAC treatment compared with baseline value before treatment. Results: The mean duration of TAC administration was 210 days. At 12weeks, TAC produced a clinical response in 54 patients (76.1%) and remission was achieved in 29 of those 54 (40.8%). The AKI rate during TAC treatment was 46.5% (33 of 71 patients). RIFLE class R (Scr increase > 1.5 times or eGFR decrease > 25%) accounted for 27 patients (38.0%), and RIFLE class I (Scr increase > 2 times or eGFR decrease > 50%) for six (8.5%). The AKI rate was 76.8% (10/13) in patients who had been administrated TAC for more than 1 year and 37.5% (18/48) in patients with TAC treatment within 6 months (p=0.006). After withdrawal of TAC, renal function impairment (eGFR decrease > 25%) was still observed in 10 patients (14.1%). Conclusions: Oral TAC therapy appears to be effective for patients with refractory UC. However, renal function impairment was frequently observed during this treatment. Thus, careful monitoring of renal function must be required to avoid irreversible chronic renal damage during long-term administration of TAC.

Su1105 The Development and Evaluation of Coordinated Care Pathways for Inflammatory Bowel Diseases

Background: Variation in thiopurine methyltransferase (TPMT) activity does not fully account for differences in interindividual clinical response to thiopurines in inflammatory bowel disease (IBD). Other genetic and immune biomarkers may also predict therapeutic outcomes with thiopurines. Aims: To test associations of known IBD susceptibility loci and novel “pharmacogenetic” genome-wide association study (GWAS)-identified loci, as well as clinical and immune phenotypes, with thiopurine-induced corticosteroid-free remission in IBD, and develop a predictive model of remission. Methods: Corticosteroid-free remission at 26 weeks after thiopurine initiation was defined using the Harvey Bradshaw Index (HBI) for Crohns disease (CD) and partial Mayo score for ulcerative colitis (UC). Serum was assayed for ASCA IgA and IgG, anti-OmpC, anti-CBir1, I2, and pANCA using ELISA. Clinical phenotypes included age, gender, IBD subtype (CD versus UC), disease duration at thiopurine initiation, and age at diagnosis. Genotyping was performed using Illumina technology. Univariate analyses tested associations of phenotype and genotype with remission. Stepwise logistic regression was performed to build predictive models. Results: Corticosteroid-free remission occurred in 56 of 122 subjects (45.9%) at week 26. Female gender (OR = 0.37; 95% CI: 0.18-0.77; P = 0.011) and pANCA (OR = 0.23; 95% CI: 0.06-0.87; P = 0.049) were negatively associated with corticosteroid-free remission at 26 weeks. Five known IBD susceptibility loci were associated with corticosteroid-free remission (P < 0.05) (Table 1). A single nucleotide polymorphism (SNP) at 15q31 tagging MEF2A (macrophage differentiation) and LYSMD4 (peptidoglycan binding) met the criteria for nominal association at the genome wide level for remission (OR = 9.5; P = 3E-05). The most predictive model of remission included the previously identified HLA-DRB1 locus (rs2516049), 7 novel “pharmacogenetic” GWAS loci, pANCA, disease duration, and a diagnosis of UC with an R-squared of 0.884, area under the curve [AUC] of 0.985, sensitivity of 0.929, specificity of 0.919, accuracy of 0.826, and positive likelihood ratio of 11.45. The probability of remission increased 7.3-fold when the number of predictors increased from 0-4 to 5-7 (95% CI: 2.4321.66; P = 0.0004). Conclusions: The combination of genotype with clinical and immune phenotypes is most predictive of corticosteroid-free remission after thiopurine initiation. Defining predictors of therapeutic efficacy to thiopurines may allow the identification of patients who will benefit most from this class of therapy, contributing to a more individualized approach to therapy. Table 1: SNPs associatedwith corticosteroid-free remissionwith thiopurines atweek 26.

Su1230 Remote Monitoring of IBD Disease Activity Using the Mobile Health Index (mHI): A Validation Study

Background/Aim: Mucosal healing (MH) at endoscopy is a major therapeutic goal in ulcerative colitis (UC). Endoscopy, however, is invasive, time consuming and uncomfortable. Computed tomography colonography (CTC) has emerged as a noninvasive screening procedure for colorectal neoplasia but radiation exposure is a major concern if applied to patients with UC. We aimed to examine ultra-low dose CTC (uCTC) for evaluating mucosal inflammation in patients with UC. Methods: Patients with UC underwent colonoscopy and uCTC acquired with low dose at 75 mAs or ultra-low dose at 5 mAs levels on the same day. As bowel preparation, patients took low residue diets on the previoursday and 1.8L of isotonic magnesium solution on the day. CTC images were evaluated for UC, in which selected valuables (loss of colonic haustra, luminal narrowing, bowel wall thickness, mural hyperenhancement and mesenteric hyper-vascularity in both air images or multiplanar reconstruction (MPR) images) were scored from 0 to 1 in the worst affected segment of colon, to create a novel uCTC score from 0 to 5. Endoscopic severity was evaluated by Mayo Clinic endoscopy sub-score (eMCS, 0-3) and the two score were correlated. Results: In 90 patients the median uCTC score was 3.56 (range 0-5) and eMCS 1.89 (range 0-3). The uCTC score correlated with eMCS (r = 0.727, p< 0.001). The CTC score for each Mayo e-score were as follows (mean±SD): score 0, 0.77±0.77; 1, 2.56±1.40; 2, 3.69±1.69; 3, 4.83±0.34. The uCTC score showed significant differences between endoscopic activity and MH (eMCS 0 vs 1 P<0.001; 1 vs 2 or 3, P<0.01 and <0.001, respectively). Furthermore, uCTC air images alone revealed a significant relationship with eMCS, even with ultra-low dose CTC at 5 mAs levels. Conclusion: uCTC may be a non-invasive tool to assess mucosal activity in UC and may be a technique to determine MH. Ultra-low dose CTC resolves concern about radiation exposure.