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Defining Optimal Laboratory Response Criteria in UDCA Treated Primary Biliary Cirrhosis. Results of an International Multicenter Long-term Follow-up Study

Willem J. Lammers1, H. R. van Buuren1, Albert Pares2, Gideon M. Hirschfield3, Harry L. Janssen4, Teru Kumagi4, Pietro Invernizzi5, Pier Maria Battezzati6, Annarosa Floreani7, Cyriel Y .Ponsioen8, Christophe Corpechot9, Marlyn J. Mayo10, Jayant A. Talwalkar11, Andrew K. Burroughs12, Frederik Nevens13, Andrew L. Mason14, Kris V. Kowdley15, Marjolijn Leeman1, Llorenç Caballeria2, Palak J. Trivedi3, Angela C. Cheung4, Ana Lleo5, Nora Cazzagon7, Irene Franceschet7, Kirsten Boonstra8, Elisabeth MG M. de Vries8, Raoul Poupon9, Mohamad Imam11, Giulia Pieri12, Pushpjeet Kanwar15, Keith D. Lindor11,16, Bettina E. Hansen1
1Gastroenterology & Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands; 2Liver Unit, Hospital Clίnic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain; 3NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom; 4Liver Clinic, Toronto Western&General Hospital, University Health Network, Toronto, ON, Canada; 5Liver Unit and Center for Autoimmune Liver Disease, Humanitas Clinical and Research Center, Rozzano, Italy; 6Health Sciences, Università degli Studi di Milano, Milan, Italy; 7Surgical, Oncological and Gastroenterological, University of Padua, Padua, Italy; 8Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; 9Centre de Référence des Maladies Inflammatoires des Voies Biliaires, Hôpital Saint-Antoine, APHP, Paris, France; 10Digestive and Liver diseases, UT Southwestern Medical Center, Dallas, TX; 11Gastroenterology ond Hepatology, Mayo Clinic, Rochester, MN; 12The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, United Kingdom; 13Hepatology, University Hospitals Leuven, KULeuven, Leuven, Belgium; 14Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, AB, Canada; 15Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA; 16Arizona State University, Phoenix, AZ

Background: Several biochemical criteria have been proposed to either assess the therapeutic response and long-term prognosis in ursodeoxycholic acid (UDCA)-treated primary biliary cirrhosis (PBC) patients to identify patients at greatest need for additional treatment. This study compared the prognostic utility of these criteria in a large international cohort of patients. Methods: The Global PBC Study Group is an on-going project comprising 15 North-American and European Liver Centres. Clinical characteristics, liver biochemistry and long-term outcomes were collected from individual patient data updated until December 2012.Treatment response was evaluated according to the Barcelona, Paris I&II and Rotterdam criteria after 1 yr of UDCA treatment and according to the Toronto criteria after 2 yrs (see table). Death and liver transplantation (LTX) were used as clinical endpoints. The area-under-the-receiver-operatingcurve for survival analysis (C-statistics) was used to determine model performance. Results: The database comprises 3895 PBC patients of which 2924 U D C A-treated patients with available lab measurements; mean age of 52.3 (±12.2) yrs, female: 91%, AMA+: 88%. Median follow up time was 7 (IQR 3-11) yrs. LTX-free survival was significantly better for patients responding to treatment as assessed by all of the models. Rotterdam and Paris I criteria were the most powerful predictors, hazard ratio (HR) respectively: 3.92 (3.17-4.85) and 4.25 (3.53-5.11) for non-responders versus responders. According to Rotterdam and Paris I criteria 10-yrs survival was 84.1 % and 88.1% for responders and 42.7% and 50.1% for nonresponders. Cox regression analysis showed Barcelona, Paris I, Rotterdam and Toronto criteria were independently associated with LTX-free survival (c-statistics: 0.78 (0.74-0.81)). 38% of patients responded according to all criteria (10-yrs survival: 96.7%, sensitivity: 88.6%), while 10.4% did not respond according to any criteria (10-yrs survival: 58.0%, HR=7.7 (5.510.7)). Conclusions: This analysis of a large pooled UDCAtreated PBC cohort confirms the prognostic value of previously proposed response criteria. Paris I and Rotterdam were the most powerful predictors. Four of the five criteria contribute independently in a combined analysis of prognostic significance, suggesting that the optimal response criteria await to be defined.

Barcelona (normal ALP or >40% decrease) Paris I (ALP&#8806; 3xULN, AST&#8806; 2xULN, normal bili) Rotterdam (normaliation of abnormal bili and/or albumin) Toronto (ALP<1.67xULN) Paris II (ALP&#8806; 1.5xULN, AST&#8806; 1.5xULN, normal bili)
HR no response vs response (95% CI) 1.95 (1.62-2.34)4.25(3.53-5.11)3.92 (3.17-4.85)2.60(2.13-3.17)2.99 (2.40-3.71)
at 10 year sensitivity specificity PPV NPV63% 59% 68% 53%71% 72% 75% 69%83% 59% 72% 73%66% 60% 54% 71%45% 84% 77% 57%
c-statistics (95% CI) 0.69 (0.66-0.72)0.76 (0.74-0.78)0.74 (0.71-0.78)0.71 (0.69-0.74)0.71 (0.68-0.73)

Disclosures:

Gideon M. Hirschfield - Advisory Committees or Review Panels: Centocor/J&J, Medigene, Intercept, Falk Pharma; Consulting: Lumena, Intercept

Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris

Cyriel Y. Ponsioen - Consulting: AbbVIE; Grant/Research Support: AbbVIE, Schering Plough, Dr. Falk Pharma, Tramedico Netherlands

Marlyn J. Mayo - Consulting: Mitsubishi, Regeneron; Grant/Research Support: Intercept, Lumena

Jayant A. Talwalkar - Consulting: Lumena; Grant/Research Support: Intercept, Salix, Gilead

Frederik Nevens - Grant/Research Support: Ipsen, Roche, MSD, Astellas, CAF

Andrew L. Mason - Grant/Research Support: Abbott, Gilead

Kris V. Kowdley - Advisory Committees or Review Panels: Abbott, Gilead, Merck, Novartis, Vertex; Grant/Research Support: Abbott, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria, Janssen, Merck, Mochida, Vertex

Palak J. Trivedi - Grant/Research Support: Wellcome Trust

The following people have nothing to disclose: Willem J. Lammers, H. R. van Buuren, Albert Pares, Teru Kumagi, Pietro Invernizzi, Pier Maria Battezzati, Annarosa Floreani, Christophe Corpechot, Andrew K. Burroughs, Marjolijn Leeman, Llorenç Caballeria, Angela C. Cheung, Ana Lleo, Nora Cazzagon, Irene Franceschet, Kirsten Boonstra, Elisabeth MG M. de Vries, Raoul Poupon, Mohamad Imam, Giulia Pieri, Pushpjeet Kanwar, Keith D. Lindor, Bettina E. Hansen

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Validation of Alkaline Phosphatase and Bilirubin Values as a Surrogate Endpoint in Primary Biliary Cirrhosis an International, Collaborative Study

Willem J. Lammers1, H. R. van Buuren1, Harry L. Janssen2, Pietro Invernizzi3, Pier Maria Battezzati4, Annarosa Floreani5, Gideon M. Hirschfield6, Albert Pares7, Cyriel Y. Ponsioen8, Christophe Corpechot9, Marlyn J. Mayo10, Jayant A. Talwalkar11, Andrew K. Burroughs 12, Frederik Nevens13, Andrew L. Mason14, Kris V. Kowdley15, Bibi L. Bouwen1, Teru Kumagi2, Angela C. Cheung2, Ana Lleo3, Nora Cazzagon4, Irene Franceschet4, Palak J. Trivedi6, Llorenҫ Caballeria7, Kirsten Boonstra8, Elisabeth MG M. de Vries8, Raoul Poupon9, Mohamad Imam11, Giulia Pieri12, Pushpjeet Kanwar15, Keith D. Lindor11,16, Bettina E. Hansen1
1Gastroenterology & Hepatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands; 2Liver Clinic/ Toronto Western&General Hospital, University Health Network, Toronto, ON, Canada; 3Liver Unit and Center for Autoimmune Liver Disease, Humanitas Clinical and Research Center, Rozzano, Italy; 4Health Sciences, Università degli Studi di Milano, Milan, Italy; 5Surgical, Oncological and Gastroenterological, University of Padua, Padua, Italy; 6NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom; 7Liver Unit, Hospital Clίnic/ CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain; 8Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; 9Centre de Reférénce des Maladies Inflammatoires des Voies Biliaires, Hôpital Saint-Antoine, APHP, Paris, France; 10Digestive and Liver diseases, UT Southwestern Medical Center, Dallas, TX; 11Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN; 12The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, United Kingdom; 13Hepotology, University Hospitals Leuven, KULeuven, Leuven, Belgium; 14Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, AB, Canada; 15Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA; 16Arizona State University, Phoenix, AZ

BACKGROUND: The determination of a simple, reliable surrogate endpoint for the long-term prognosis in primary biliary cirrhosis (PBC) is highly desirable. This study evaluated the utility of serum alkaline phosphatase (ALP) and bilirubin. METHODS: The Global PBC Study Group comprises 15 North-American and European Liver Centres. Uniform clinical and follow up data (until December 2012) from individual patients were assembled and assessed against death and liver transplantation (LTX). Patients were stratified by center and adjusted for gender, calendar time, age and ursodeoxycholic acid (UDCA) for Cox-regression analysis. Analyses were conducted at entry, after 1 and 2 years on UDCA or follow up (non-UDCA) in subgroups (figure). RESULTS: 3895 PBC patients (2621 with available ALP values at 1 yr), were included. 87% on UDCA, 91%female, 87%AMA+, mean age: 51.5±12.0 yrs. Median follow up period 7 (IQR 3-11)yrs. 564 patients died, 329 had liver transplants. 5-, 10- and 15-yr LTX-free-survival was 89%, 77%, 66% respectively. Bilirubin was highly predictive of outcomes, at 1 yr HR= 4.3(3.1-6.0). There was a log-linear association of ALP with LTX-free-survival (HR at entry: 1.3(1.0-1.6), 1 yr: 1.8(1.5-2.1), 2 yrs 2.0(1.7-2.4)). Higher ALP values were associated with a worse prognosis. ALP values ≥1.67xULN at entry and 1 and 2 yrs were associated with worse outcome (HR respectively: 1.9(1.6-2.4), 2.3(1.9-2.7), 2.6(2.2-3.2)). Similar results were found for a grid of cut off points. ALP≥1.67xULN was an independent prognostic marker in cases with both normal (HR 1.6(1.3-2.1)) and abnormal bilirubin (1.6(1.1-2.2)). Subgroup analyses confirmed these findings (figure). CONCLUSION: This analysis of the largest PBC database created clearly shows that bilirubin and ALP levels are correlated with survival in UDCA (un)treated PBC and provides strong evidence that these assessments make highly valid surrogate PBC endpoints.

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Disclosures:

Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris

Gideon M. Hirschfield - Advisory Committees or Review Panels: Centocor/J&J, Medigene, Intercept, Falk Pharma; Consulting: Lumena, Intercept

Cyriel Y. Ponsioen - Consulting: AbbVIE; Grant/Research Support: AbbVIE, Schering Plough, Dr. Falk Pharma, Tramedico Netherlands

Marlyn J. Mayo - Consulting: Mitsubishi, Regeneron; Grant/Research Support: Intercept, Lumena

Jayant A. Talwalkar - Consulting: Lumena; Grant/Research Support: Intercept, Salix, Gilead

Frederik Nevens - Grant/Research Support: Ipsen, Roche, MSD, Astellas, CAF

Andrew L. Mason - Grant/Research Support: Abbott, Gilead

Kris V. Kowdley - Advisory Committees or Review Panels: Abbott, Gilead, Merck, Novartis, Vertex; Grant/Research Support: Abbott, Beckman, Boeringer Ingelheim, BMS, Gilead Sciences, Ikaria, Janssen, Merck, Mochida, Vertex

Palak J. Trivedi - Grant/Research Support: Wellcome Trust

The following people have nothing to disclose: Willem J. Lammers, H. R. van Buuren, Pietro Invernizzi, Pier Maria Battezzati, Annarosa Floreani, Albert Pares, Christophe Corpechot, Andrew K. Burroughs, Bibi L. Bouwen, Teru Kumagi, Angela C. Cheung, Ana Lleo, Nora Cazzagon, Irene Franceschet, Llorenç Caballeria, Kirsten Boonstra, Elisabeth MG M. de Vries, Raoul Poupon, Mohamad Imam, Giulia Pieri, Pushpjeet Kanwar, Keith D. Lindor, Bettina E. Hansen

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Characterization of the Intestinal Microbiome in Ulcerative Colitis Patients with and without Primary Sclerosing Cholangitis

David Kevans1,2, Andrea D. Tyler1, Kristian Holm3, Kristin K. Jørgensen3, Morten H. Vatn4, Tom H. Karlsen3, Dirk Gevers5, Johannes R. Hov3, Mark S. Silverberg1,2
1Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada; 2Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada; 3Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; 4Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 5The Broad Institute of MIT and Harvard, Cambridge, MA

Background: The intestinal microbiota is implicated in the pathogenesis of inflammatory bowel disease (IBD) and may also contribute to the development of sclerosing cholangitis. The aim of this study was to compare the composition of the intestinal microbiome of patients with ulcerative colitis (UC) with and without primary sclerosing cholangitis (PSC). Methods: Patients with PSC & UC (PSC-UC) or UC (UC); and available colonic biopsies were indentified from biobanks at Mount Sinai Hospital (MSH) and Oslo University Hospital (Oslo). Subjects with a previous liver transplant; or receiving corticosteroid, immunomodulator, biologic or antibiotic therapy at the time of endoscopy; were excluded. All biopsies evaluated were from non-inflamed sigmoid colon. Study panels comprised, Oslo PSC-UC (n=20), Oslo UC (n=9) and MSH UC (n=18). Microbial DNA was extracted and the V4 hypervariable region of the 16S rRNA gene was sequenced on Illumina MiSeq (mean reads per sample: 13,435). Paired-end reads were stitched, quality trimmed, and assembled into OTUs with 97% sequence identity and assigned a genus level taxonomy using QIIME. Raw counts were converted in relative abundance and statistical comparisons between phenotypic groups conducted using LEfSe. Results: Comparing Oslo PSC-UC, Oslo UC and MSH UC panels: median age was 43, 37 and 26 years; proportion of male gender was 75%, 40% and 61%; median IBD duration was 15, 0 and 7 years; and 5ASA therapy was used in 80%, 0% and 94% of the panels; respectively. Principal coordinate analysis demonstrated that city of sample collection was the strongest determinant of taxonomic profiles hence the primary analysis evaluated only Oslo PSC-UC vs. Oslo UC panels, while a secondary analysis evaluated Oslo PSC-UC vs. MSH & Oslo UC panels. In the primary analysis increased levels of genera Granulicatella, Streptococcus, Rumminococcus and Collinsella; while a decreased level of Bacteroides; were observed comparing PSC-UC with UC samples. In the secondary analysis increased levels of genera Parabacteroides and Collinsella were observed comparing PSC-UC with UC samples. Conclusions: This is the first study, to our knowledge, to characterise the intestinal microbiota of patients with UC with and without PSC. The genus level analysis revealed differences comparing PSC-UC and UC subjects which may reflect microbial representatives of PSC pathogenesis. Increased levels of genus Collinsella observed in primary and secondary analyses are of interest due to the role of these organisms in bile acid metabolism. Functional annotations of the genus level findings and replication in independent panels are presently ongoing.

Disclosures:

David Kevans - Speaking and Teaching: Abbvie

The following people have nothing to disclose: Andrea D. Tyler, Kristian Holm, Kristin K. Jørgensen, Morten H. Vatn, Tom H. Karlsen, Dirk Gevers, Johannes R. Hov, Mark S. Silverberg

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VAP-1 activity is elevated in PSC and modulates a4B7dependent lymphocyte adhesion to HSEC under flow

Palak J. Trivedi, Chris J. Weston, Evaggelia Liaskou, Christopher Corbett, David H. Adoms
Centre for Liver Research and NIHR Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom

Background/aims: Vascular adhesion protein (VAP)−1 is an adhesion molecule which possesses potent amine oxidase activity, and deaminates dietary amines resulting in the production of H2O2.Through this function, VAP-1 leads to activation of NFқB in hepatic sinusoidal endothelium (HSEC) resulting in expression of mucosal-vascular cell-adhesion molecule-1 (MAdCAM-1); a mechanism proposed to contribute to the homing of gut-tropic lymphocytes expressing α4β7 to the liver. Given the putative role this pathway has in hepatic diseases complicating inflammatory bowel disease (IBD), we set out to quantify circulating/soluble (sVAP-1) and intrahepatic VAP-1 enzyme activity in primary sclerosing cholangitis (PSC), and evaluate the functional consequence of its inhibition on MAdCAM-1 dependent lymphocyte recruitment to HSEC. Methods: Total VAP-1 concentration was measured by ELISA. VAP-1 amine oxidase activity was quantified in human serum and explanted liver tissue using the amplex red assay. Flow-based adhesion assays were performed using human HSEC isolated from liver explants, activated with TNFα and methylamine (VAP-1 substrate), and treated with VAP-1 antibody or semicarbazide (VAP-1 enzyme inhibitor). FAC-sorted peripheral blood leucocytes expressing α4β7 were perfused over HSEC under flow rates simulating physiological shear (0.05Pa) and adhesion and transmigration quantified. Results: Patients with PSC had significantly higher circulating median VAP-1 enzyme activity (114.5pmol H2〇 2 produced/min/ml serum, IQR 100.6-134.7) than patients with IBD (60.3, IQR 38.5-73.0; P=0.006), normal controls (84.0, IQR 77.7-105.7; P=0.020) and individuals with PBC (53.9, IQR 33.0-90.9; P=0.006), and trended higher than AIH (77.6, IQR 51.0-124.5; P=0.200) (Mann-Whitney). Total sVAP-1 concentration correlated well with sVAP-1 enzyme activity (R2=0.75). Intrahepatic median VAP-1 activity was also significantly higher in PSC (97.6pmol H2O2/min/mg protein respectively, IQR 69.5-114.5) vs. PBC (24.6, IQR 18.7-27.8; P=0.029) and AIH (32.3, IQR 23.3-35.6; P=0.028) (MannWhitney). HSEC pretreatment with semicarbazide but not antibody led to a profound reduction in total α4β7+ lymphocyte adhesion (75%); however, both antibody and enzyme inhibition independently reduced transmigration by ∼50% compared to untreated HSEC. Conclusion: sVAP-1 enzyme activity is greater in PSC compared to IBD alone, normal controls, and other immune-mediated liver diseases. Intrahepatic VAP-1 enzyme activity is significantly higher in PSC compared to AIH and PBC. Inhibition of VAP-1 leads to abrogation of α4β7-mediated adhesion to HSEC, representing a putative target for therapeutic intervention in PSC.

Disclosures:

Palak J. Trivedi - Grant/Research Support: Wellcome Trust

The following people have nothing to disclose: Chris J. Weston, Evaggelia Liaskou, Christopher Corbett, David H. Adams

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Chronic antigenic stimulation may predispose to the development of IgG4-related disease of bile ducts and pancreas

Lucas Maillette de Buy Wenniger1,2 Emma L. Culver3,4, Roger W. Chapman3,4, Eleanor Barnes3,4, Ulrich Beuers1,2
1Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; 2Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, Netherlands; 3Translational Department of Gastroenterology, John Radcliffe Hospital, Oxford, United Kingdom; 4Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom

IgG4-associated cholangitis (IAC) and autoimmune pancreatitis (AIP) are the predominant manifestations of IgG4-related diseases (IgG4-RD) and are typically diagnosed in elderly men. Their pathogenesis is enigmatic. IgG4 represents the smallest fraction of total IgG in serum, is regarded as a regulatory antibody, is upregulated in chronic immune stimulation as illustrated by elevation of bee-venom-specific IgG4 in beekeepers, is unable to bind C1q, and can exchange its Fab arms. Our recent observation of clonal expansions of IgG4-switched Bcells in patients with IAC and other manifestations of IgG4-RD as evaluated by a novel next generation sequencing protocol was suggestive of prolonged antigenic stimulation (Hepatology 2013; 58: epub). As we noted a strikingly high amount of building contractors, plumbers and other ̀blue collar' workers amongst our patient population we hypothesized that IgG4-RD is caused by chronic occupational antigen exposure in the mainly elderly male patients. Using a short questionnaire directed at environmental, residential and occupational antigen exposure, we investigated the job history and history of exposure to potential harmful compounds in our two independent cohorts of IAC and AIP patients from Amsterdam and Oxford. Of the Amsterdam cohort of 25 patients, 88% had a history of blue collar work of at least one year, but often a whole career, and reported chronic exposure to potentially harmful substances. Solvents, industrial and metal dusts, pigments and oils used in the automotive industry were among the most often mentioned potential occupational and residential hazards. In a control cohort from Amsterdam of 21 patients with primary sclerosing cholangitis (PSC) only 14% reported a history of working in a ̀blue collaŕ profession. Using an identical questionnaire a trial nurse blinded to the hypothesis replicated this investigation amongst the Oxford cohort of 44 patients with established IgG4-RD and found that 61% recalled chronic exposures to similar potentially harmful compounds. In a control cohort of 27 PSC patients from Oxford with elevated (>1.4g/L) levels of serum IgG4 and no histological evidence of IAC, this percentage was 22%. Our actual findings together with our recent observation of clonal expansions of IgG4 switched B-cells in IgG4-RD provide support for the idea that chronic exposure to occupational antigens may play a key role in the initiation and/or maintenance of IgG4-RD. Our findings may yield more insight in the aetiology of this poorly understood disease and provide directions for the optimization of its therapy.

Disclosures:

Emma L. Culver - Grant/Research Support: Wellcome Trust Research Fellowship, Merck-funded Oxford AcademicFellowship

Roger W. Chapman - Advisory Committees or Review Panels: falk, takeda; Speaking and Teaching: roche; Stock Shareholder: gilead

Ulrich Beuers - Consulting: Intercept; Grant/Research Support: Zambon; Speaking and Teaching: Falk Foundation, Gilead, Roche, Scheringh, Zambon

The following people have nothing to disclose: Lucas Maillette de Buy Wenniger, Eleanor Barnes

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Genetic and clinical differences in primary sclerosing cholangitis patients with high IgG4

Natalie L. Berntsen1, Olav Klingenberg2, Kirsten M. Boberg1, Tom H Karlsen1, Johannes R. Hov1
1Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 2Department of Medical Biochemistry and Institute of Clinical Biochemistry, Oslo University Hospital, Oslo, Norway

Objective: Elevated serum concentration of IgG4 is reported in up to 10% of patients with primary sclerosing cholangitis (PSC), a heterogeneous disorder of unknown aetiology. High IgG4 is associated with more severe disease, yet with some extent of corticosteroid responsiveness. We hypothesized that these patients represent a distinct subgroup of PSC and aimed to explore clinical and genetic aspects of high IgG4 in a large Norwegian cohort. Methods: We included 263 PSC patients with stored DNA and serum available. Patients with high IgG4 were defined by cut-off levels of a) 1.35g/l (as applied in previous studies on IgG4 related disease) and b) 2.01 g/l (upper reference limit). Genotypes of the strongest genetic risk factors in PSC, HLA-B and HLA-DRB1, were available from the patients and 368 healthy controls. Results: N=47 (18%) and n=23 (9%) PSC patients had high IgG4 when applying cut-off levels of IgG4>1.35 and IgG4>2.01 respectively. The HLA-B*08 allele, consistently observed as the top genetic risk factor in PSC, was less prevalent in patients with high than low IgG4 (29% vs 42%, P=0.02, for cut-off IgG4>1.35 and 26% vs 41%, P=0.05, for cut-off IgG4>2.01). In contrast, the PSC-associated alleles HLA-B*07 and DRB1*15 were more prevalent in PSC with high than low IgG4, but only when applying the IgG4>2.01 cut-off (HLA-B*07: 24% vs 13%, P=0.04 and DRB1*15: 26% vs 14%, P=0.04, for high vs low IgG4, respectively). When comparing patients with healthy controls, HLADRB1*15 was significantly associated only with PSC with IgG4>2.01 (26% vs 15%, P=0.05), while there was no association with HLA-DRB1*15 in this PSC population as a whole (P=0.90). Clinically, IgG4>1.35 was associated with shorter liver transplantation free survival (P=0.05) and shorter survival to the end-point of death only (P=0.007), while there were no differences between high and low IgG4 regarding gender (87% vs 75% male, P=0.09) or inflammatory bowel disease (IBD) (82% vs 82%). However, in patients with high IgG4 (>1.35), HLA-B*08 was more prevalent in patients with than without IBD (35% vs 6%, P=0.03), while IBD did not define genetically different subgroups in patients with low IgG4.Conclusions: We report for the first time on genetic associations for elevated IgG4 levels in PSC. Our findings suggest that the phenotypic heterogeneity represented by the IgG4 response contribute to the complex HLA associations observed in PSC. The possibility that elevated IgG4 concentration designate a genetic as well as clinical subgroup should be taken into account in further studies, ultimately aiming to identify patients suitable for immunosuppressive therapy or other treatment options.

Disclosures:

The following people have nothing to disclose: Natalie L. Berntsen, Olav Klingenberg, Kirsten M. Boberg, Tom H. Karlsen, Johannes R. Hov