144 The Effect of Prognostic Factors On the Maintenance of Remission in Hepatic Encephalopathy Patients Treated with Rifaximin

experience lower salary growth, indicating impaired career progression and an irreversible opportunity cost of lost productivity.

Pregnancy Outcome in Inflammatory Bowel Disease for Women Treated with Thiopurine: Cohort from the CESAME Study Jessica Coelho, Laurent Beaugerie, Jean-Frederic Colombel, Xavier Hebuterne, Eric Lerebours, Marc Lemann, Philippe Baumer, Jacques Cosnes, Arnaud Bourreille, JeanPierre Gendre, Philippe Seksik, Fabrice Carrat, Philippe Marteau

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Introduction - Few datas on safety of thiopurines for IBD treatment during pregnancy are available. The aim of this study was to evaluate the pregnancy outcome of women exposed to thiopurines. Patients and methods - 215 pregnancies in 204 women were registered and documented in the CESAME cohort between may 2004 and october 2007. Treatment informations included : last menstrual date, delivery term, pregnancy outcome details as spontaneous abortion, therapeutic abortion, prematurity (gestational age of under 37 weeks of gestation), birth weight and height, congenital abnormality, medication history during each trimester, smoking history and ethanol ingestion. Datas were compared between women exposed to thiopurines (thiopurines only or associated with another treatment - aminosalicylates, corticosteroids ou anti-TNFa-), womens receiving another drug than thiopurines and patients without any medication. Results - The median age of the women was 28.4 years old, 75.7% had a Crohn's disease (CD), 21.8% a ulcerative colitis (UC) and 2.5% an unclassified bowel disease (UIBD), with a mean disease duration of 6.8 years at inclusion. Of 215 pregnancies, there were 138 births (142 newborns because of 4 gemellary pregnancies). 86 of the 215 pregnancies (39.6%) occured with exposure to thiopurines during all or part of the pregnancy, 84 (38.7%) with exposure to other drugs and 45 (20.7%) without any IBD treatment. No significant differences were found among the 3 groups with respect to interrupted pregnancies (36%, 33% et 40% respectively) as seen on table. 29 women with CD were still smoking (18.6%), 2 with UC (2.2%). The mean birth weight was 3135g. Conclusion - The results of this large cohort indicate that thiopurine use during pregnancy is not associated with increased congenital abnormalities risk. The increased incidence of hypotrophy and prematurity under thiopurine was not significant and may correlate to the underlying disease.

Welcome: A Randomized, Double-Blind, Controlled Trial Comparing Certolizumab Pegol 400 Mg Every 2 Weeks with Every 4 Weeks for Maintenance of Response and Remission in Patients with Moderate to Severe Crohn's Disease with Secondary Failure to Infliximab William J. Sandborn, Severine Vermeire, Geert R. D'Haens, Jean-Frederic Colombel, Richard N. Fedorak, Martina E. Spehlmann, Douglas C. Wolf, Maria T. Abreu, Krassimir Mitchev, Corinne Jamoul, Paul J. Rutgeerts Background Approximately 40% of patients (pts) with Crohn's disease (CD) who respond to anti-TNF-α therapy will lose response or experience treatment-limiting immune-mediated reactions to individual anti-TNFs. A prior study showed that certolizumab pegol (CZP) 400 mg q4w is effective for maintenance of response and remission in pts with CD who were naïve to infliximab (IFX) or who had previously received IFX.1 Objective To compare the efficacy and safety of CZP 400 mg q2w with q4w for maintenance of clinical response and remission in pts with moderate to severe CD who had previously lost response or developed hypersensitivity to IFX and had responded to induction therapy with CZP. Methods WELCOME was a 26-wk, Phase IIIb, multicenter trial, comprising a 6-wk open-label induction followed by a double-blind randomized maintenance phase in responders. Pts with a CD Activity Index (CDAI) score 220-450 and a history of secondary IFX failure (loss of response or development of acute or delayed hypersensitivity reactions) received open-label induction with CZP 400 mg sc injections at Wks 0, 2, and 4. Nonresponders at Wk 6 were withdrawn. Those who were in clinical response at Wk 6 were randomized to receive maintenance with CZP 400 mg sc q2w or q4w through Wk 24. Clinical response was defined as a decrease of ≥100 points in CDAI from baseline and remission as a CDAI score of ≤150 points. Results At Wk 6, 62.0% (334/539) of pts who received open-label induction therapy with CZP were in clinical response. Of these responders, 329 entered the double-blind maintenance trial and were thus included in the modified intent-to-treat population (CZP q2w, n= 161; CZP q4w, n=168). Clinical response and remission rates at Wk 26 are shown in the table. There was no significant difference between q2w or q4w CZP dosing regimens with respect to response (CDAI decrease of ≥100 or ≥70 points from baseline [p=0.55 and p= 0.74, respectively] or remission rates [p=0.81]). No new safety signals were observed. Conclusions 62% of pts with moderate to severe CD who had previously responded to IFX and lost response or developed hypersensitivity responded to open-label induction therapy with CZP. Among pts who responded to induction therapy with CZP, continuing therapy with CZP 400 mg q4w is as effective as CZP 400 mg q2w for maintenance of response and remission at Wk 26. Reference 1. Schreiber S, et al. N Engl J Med 2007;357:239-250.

*in proportion of births. Comparisons were not significant (exact Fisher test). 142 Pregnancy Outcomes in Women Exposed to Adalimumab: the OTIS Autoimmune Diseases in Pregnancy Project Diana L. Johnson, Kenneth L. Jones, Christina D. Chambers, Elizabeth Salas INTRODUCTION: Adalimumab (ADA) is a fully human, anti-tumor necrosis factor monoclonal antibody approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, and juvenile idiopathic arthritis in the United States and elsewhere. METHODS: This report describes an ongoing study of the safety of ADA in pregnant patients conducted by the Organization of Teratology Information Specialists (OTIS). Through a prospective cohort design, women with RA treated with ADA during the first trimester of pregnancy were followed throughout pregnancy. Pregnancy outcomes were compared with those from a disease-matched group of pregnant women without ADA treatment during pregnancy, and a healthy group of women who neither had RA nor had been treated with ADA. In addition, OTIS investigators collected information on ADAexposed pregnancies that did not meet the cohort criteria, but were followed as a case series and included patients treated for other diseases, such as Crohn's, and retrospective reports. RESULTS: As of November 30, 2008, pregnancy outcomes were available for 141 women in the cohort study (Table 1). Approximately 44% of women in the ADA-exposed cohort had discontinued the medication in their first trimester, while 38% had continued the medication through delivery. Two major structural defects (5.9%) had been reported among 34 outcomes in the ADA cohort: 1 undescended testicle and 1 microcephaly. Among 53 pregnancies in the disease-matched comparison group, 2 major structural defects were reported (3.8%): 1 chromosomal abnormality and one infant with club feet. Two major structural defects (4.3%) were reported in 47 pregnancies in the healthy comparison group. Of the 109 known outcomes in the case-series group 9 (8.3%) major anomalies had been reported(data not in Table 1): 3 chromosomal anomalies, 1 spina bifida with hydrocephalus, 1 bicuspid aortic valve and agenesis of the corpus callosum, 1 ventricular septal defect, 1 congenital hip dysplasia with inguinal hernia, one non-specific heart anomaly and 1 congenital hypothyroidism. CONCLUSION: Based on these preliminary data, no concerns have been raised regarding increased risks for adverse pregnancy outcomes associated with early pregnancy exposure to ADA in the treatment of RA. Firm conclusions await accumulation of sufficient sample size in this prospective cohort study. Table 1: Pregnancy Outcomes in the Cohort Study

144 The Effect of Prognostic Factors On the Maintenance of Remission in Hepatic Encephalopathy Patients Treated with Rifaximin Samuel Sigal, F. Fred Poordad, Kimberly L. Beavers, Kunal Merchant, Shirley Huang, Audrey L. Shaw, Enoch Bortey, William P. Forbes Background and aims: Previous studies indicate that the minimally absorbed gut-selective antibiotic rifaximin is effective treatment for hepatic encephalopathy (HE). In this multinational, placebo-controlled trial, rifaximin significantly reduced the risk of breakthrough HE in the overall intent-to-treat (ITT) population by 58% (hazard ratio, 0.421; p<0.0001). This analysis investigates the potential effect of prognostic factors contributing to breakthrough HE, and their effect on the maintenance of response to rifaximin. Methods: This randomized, double-blind, placebo-controlled trial evaluated rifaximin 550 mg twice daily for 6 months in patients with a history of HE. Patients with cirrhosis and who had ≥2 episodes of HE (Conn score ≥2) within 6 months prior to screening and were currently in remission (Conn score = 0 or 1) were enrolled. Continued therapy with lactulose was permitted. The primary endpoint was time to first breakthrough HE episode (increase of Conn score to ≥ 2; or a Conn score and asterixis grade increase of 1, if baseline Conn score = 0). Prognostic factors for maintenance of response included geographic location and baseline demographics and characteristics (sex, age, race, model for end-stage liver disease (MELD) score, Conn score, prior lactulose use, diabetes at baseline, days in remission, and episodes of HE (within 6 months prior to screening) were evaluated by covariate analysis. Results: A total of 299 patients were randomized to either rifaximin (n=140) or placebo (n=159). Demographics and baseline characteristics were similar between the groups. Independent predictors of breakthrough HE included age, MELD score, lactulose use, duration of remission, and number of prior episodes of HE. After controlling for these prognostic factors it was noted that rifaximin significantly reduced the risk of breakthrough HE by 59% versus placebo (HR, 0.408; 95% CI, 0.257-0.603; p<0.0001). The most influential prognostic factors for maintenance of remission in this covariate analysis were age (p=0.022), baseline MELD score (p=0.0005). Conclusions: Rifaximin at a dose of 1100 mg/d demonstrates a highly significant protective effect (59% risk reduction) in preventing HE breakthrough during the 6-month treatment period after controlling for influential prognostic factors. This analysis further

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corroborates the protective effect of rifaximin in the ITT population. The most influential prognostic factors for maintenance of remission were age, and baseline MELD score.

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145 Enhanced TLR Signaling Breaks Endotoxin Tolerance in Human Biliary Epithelial Cells in END-Stage Chronic Inflammatory Liver Disease Tobias Mueller, Andreas Pascher, Peter Neuhaus, Bertram Wiedenmann, Thomas Berg BACKGROUND: TLR signaling in biliary epithelial cells (BECs) is tightly controlled to prevent excessive innate immune responses in the healthy liver. We examined the effect of chronic inflammation on TLR-mediated endotoxin tolerance in human BECs in patients with end-stage chronic inflammatory liver disease (ESLD), which protects the host from permanent BEC activation in the face of ubiquitous intestinal TLR ligands in the bile and portal venous blood. METHODS: We examined patients undergoing liver transplantation for immune-mediated (PBC, PSC), alcoholic and viral (chronic hepatitis B and C) ESLD. Northern blots, real-time RT-PCR, western blots and immunocytochemistry were used for mRNA and protein expression studies of innate immune proteins in whole ESLD tissue and isolated primary BECs. Flow cytometry for incorporated endotoxin, ELISAs for secreted proinflammatory mediators such as IL-6, IL-8, and MCP-1, NF-κB reporter assays and TLR over-expression studies were used for functional studies. RESULTS: Freshly isolated human BECs in ESLD showed increased TLR activation profiles and markedly enhanced ICAM-1 expression, which have recently been linked to decreased hepatic endotoxin tolerance. Whole ESLD tissue exhibited increased expression of IFN-γ and TNF-α. Affected BECs depicted activated IFN-γ-dependent genes such as CXCL9, CXCL10 and CXCL11. We also found enhanced activation of IRF-1 and STAT1 in activated BECs, which have been shown to promote TLR signaling. These findings suggested that chronic inflammation led to enhanced TLR-mediated innate immune responses and decreased endotoxin tolerance in affected BECs in ESLD. In line with this hypothesis, primary human BECs isolated from patients with early disease stages depicted normal TLR and IL-6, IL-8, MCP-1 and ICAM-1 expression. These data suggested that increased PRR signaling and diminished endotoxin tolerance in BECs did not play a role in the primary pathogenesis of these diseases and argued for a secondary phenomenon due to chronic inflammation. Further In Vitro studies confirmed that pro-inflammatory cytokines and repetitive endotoxin challenges disrupted homo- and hetero-tolerance to endotoxins in BECs. Enhanced TLR surface expression and subsequently increased endotoxin incorporation in cytokine-primed BECs contributed to increased TLR sensitivity. CONCLUSIONS: Chronic inflammation promotes a state of hyper-responsiveness to TLR ligands in ESLD and breaks the protective endotoxin tolerance in BECs. Loss of TLR tolerance appear to be especially deleterious in the face of increased intestinal endotoxin levels, which have been described in patients with ESLD of different etiologies.

* Compared to pregnant women without liver disease ** No cases in liver transplant group 147 Intraductal Ultrasonography Combined with Percutaneous Transhepatic Cholangioscopy for the Preoperative Evaluation of Longitudinal Tumor Extent in Advanced Hilar Cholangiocarcinoma Hee Man Kim, Jeong Youp Park, Kyung Sik Kim, Mi-Suk Park, Myeong-Jin Kim, Young Nyun Park, Seungmin Bang, Si Young Song, Jae Bock Chung, Seung Woo Park Background: In hilar cholangiocarcinoma, evaluation of tumor extension to secondary bifurcation is important to determine resectability. Aim: To investigate accuracy of intraductal ultrasonography (IDUS) combined with percutaneous transhepatic cholangioscopy (PTCS) for evaluation of the longitudinal extension to secondary bifurcation in advanced hilar cholangiocarcinoma with Bismuth type IIIa, IIIb and IV. Methods: Patients with hilar cholangiocarcinoma were enrolled. Patients underwent multidetector computed tomography (MDCT) and magnetic resonance cholangiography (MRC) for initial tumor staging. In case of potentially resectable tumor, percutaneous transhepatic cholangioscopy (PTCS) with biopsy was performed at the left or right bile duct in Bismuth type IIIa or IIIb, respectively, to evaluate longitudinal tumor extent. In case of suspicious Bismuth type IV, PTCS was performed at the liver section anticipated to be preserved in surgical treatment. After PTCS, IDUS was performed sequentially. Based on information from MDCT, MRC, PTCS and IDUS, surgery with curative intent was performed and histological examination was made. Results: From June 2006 to November 2008, 25 patients with hilar cholangiocarcinoma were enrolled and 20 patients were evaluable. The accuracy of MDCT, MRC, PTCS with biopsy and IDUS in assessing longitudinal tumor extent was 80.0%, 84.2%, 90.0% and 85.0%, respectively, compared with post-operative histologic findings. In 18 patients with Bismuth type IIIa, IIIb or IV, the accuracy of MDCT, MRC, PTCS with biopsy and IDUS was 77.8%, 77.8%, 94.4% and 88.9% on longitudinal tumor extent, respectively. The combination of IDUS and PTCS produced a diagnostic accuracy of 100% on longitudinal tumor extent. IDUS and PTCS with biopsy prevented an unnecessary surgery in one patient underestimated by MDCT and MRC. In two patients overestimated as Bismuth type IV by MDCT and MRC, IDUS properly evaluated Bismuth type. Conclusions: The combined modality of IDUS and PTCS with biopsy demonstrates high accuracy in assessing longitudinal tumor extent to determine resectability, which helps to make an optimal surgical plan in advanced hilar cholangiocarcinoma, especially in Bismuth type IIIa, IIIb and IV.

146 The Impact of Cirrhosis or Prior Liver Transplant On Obstetrical Outcomes: A National Study Sanjay K. Murthy, Jenny Heathcote, Geoffrey C. Nguyen Objectives: The impact of cirrhosis or prior liver transplant on maternal and fetal health during pregnancy has not been well characterized. We sought to compare health outcome rates in pregnant women with a history of cirrhosis or liver transplant to pregnant women without liver disease. Methods: A population-based cohort study of women admitted for labor and delivery to U.S. hospitals between 1998 and 2005 was conducted using data from the Nationwide Inpatient Sample database. Pregnant women with a history of cirrhosis or liver transplant were compared to pregnant women without liver disease (controls) for various obstetrical and medical health outcomes. Results: Among pregnant women, 187 women with cirrhosis and 86 women with a prior liver transplant were compared to 662,408 women without liver disease. Women with cirrhosis or prior liver transplant had higher rates of co-morbid illness and admission to an academic centre, and lower rates of private health insurance, than general obstetrical patients (p<0.0001 for all comparisons). The rates of Cesarean section, preterm delivery, peripartum infection and pregnancy-induced hypertension were higher in both groups of patients, while rates of death, venous thromboembolism, malnutrition, placental abruption and peri-partum blood transfusion were increased specifically in cirrhotic women (Table 1). The adjusted mean length of hospital stay was 32% greater among cirrhotic women (95% CI: 18% - 49%) and 30 % greater among women who were status post-liver transplant (95% CI: 13% - 50%) as compared to pregnant women without liver disease. Conclusions: Pregnant women with a history of cirrhosis or liver transplant are at higher risk of developing numerous adverse obstetrical and medical health events than women without liver disease. Further prospective studies are warranted to confirm these findings and to assess the benefit of early involvement of a multidisciplinary health care team in the care of such patients. Table 1. Adjusted Odds Ratios of Adverse Outcomes in Hospitalized Obstetrical Patients Based on Liver Status

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148 Serum TNF-α, IL-10 and IL-18 Levels and the Cytokine Releasing Activity of Cd4cd57αβTCR-Positive T Cells in HCV-Related Hepatocellular Carcinoma Patients During Tumor Progression Tatsuya Shiraki, Eiji Takayama, Hirohito Magari, Yoshiyuki Mori, Kosaku Moribata, Naoki Shingaki, Hisanobu Deguchi, Izumi Inoue, Takao Maekita, Mikitaka Iguchi, Kimihiko Yanaoka, Hideyuki Tamai, Kenji Arii, Masashi Oka, Masao Ichinose BACKGROUND:Previous studies have indicated that serum IL-18 or IL-10 levels may be significant prognostic determinants in patients with hepatocellular carcinoma (HCC) or gastric cancer. In addition, we have previously reported that an increase of CD4CD57αβ T cells in peripheral blood (PB) reduces IFN-γ production in subjects with advanced gastric cancer and that there is a significant negative correlation between the increase of CD4CD57αβ T cells and patient prognosis (Gastroenterol 2007;32:A621). In the present study, we investigated the basal serum levels of a series of cytokines (IFN-γ, TNF-α, IL-12, IL-18, and IL10) and also the kinetics and lipopolysaccharide (LPS)-stimulated cytokine releasing activity of CD4CD57αβ T cells in the PB of HCV-related HCC patients in order to determine the relationship between tumor progression and the kinetics of anti-tumor immunity in patients with HCV-related HCC. METHODS:Ninety-six HCV-related HCC patients treated between 2006 and 2008 at the Wakayama Medical University (Wakayama, Japan) were enrolled in this study [62 men, 34 women; age 71.2 ± 8.2 years (median ± SD), range 42-88 years]. A 5-ml sample of PB was collected from each patient. Aliquots of PB were incubated with LPS (final concentration, 1 μg/ml) and the culture supernatant was collected. Separated sera from PB and the culture supernatant were assayed for a series of cytokines with an ELISA kit. The proportion of CD4CD57αβ T cells among PB mononuclear cells (PBMCs) was analyzed using a flow cytometric analyzer. RESULTS:Serum cytokine levels of TNF-α, IL18 and IL-10 were significantly elevated with advancing stages of HCC, while serum IFNγ levels were undetectable throughout the stages of HCC. The releasing activity of IFN-γ from PBMCs stimulated with LPS significantly decreased in a stepwise manner with tumor progression (stage I: 69.7 ± 72.7, stage II: 19.7 ± 44.1, stage III: 12.3 ± 23.5, stage IV: 5.3 ± 5.9 IU/ml, p < 0.01). The present study, using an In Vitro culture system clearly indicated that tumor progression reduced the anti-tumor immunity of HCC patients. The numbers of CD4CD57αβ T cells increased with tumor progression in HCV-related HCC patients (stage I: 38.2 ± 23.5, stage II: 46.5 ± 39.9, stage III: 73.3 ± 48.5, IV: 33.5 ± 26.5, p < 0.01). Taken together, these results show that the increase of these T cell subjects is

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