studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 515A
616
Association between elevated serum IgG4 (sIgG4) concentrations
and the phenotype of patients with primary
sclerosing cholangitis (PSC)
Michael P. Manns 1 , Bertus Eksteen 2 , Mitchell L. Shiffman 3 , Cynthia
Levy 4 , Kris V. Kowdley 5 , Aldo J. Montano-Loza 6 , Harry L. Janssen
7 , Robert P. Myers 8 , Dora Ding 8 , Mani Subramanian 8 , John
G. McHutchison 8 , Michael R. Charlton 9 , Christopher L. Bowlus 10 ,
Andrew J. Muir 11 , Roger W. Chapman 12 ; 1 Hannover Medical
School, Hannover, Germany; 2 University of Calgary, Calgary, AB,
Canada; 3 Liver Institute of Virginia, Richmond, VA; 4 University of
Miami, Miami, FL; 5 Swedish Medical Center, Seattle, WA; 6 University
of Alberta, Edmonton, AB, Canada; 7 University of Toronto,
Toronoto, ON, Canada; 8 Gilead Sciences, Inc., Foster City, CA;
9 Intermountain Medical Center, Salt Lake City, UT; 10 University of
California at Davis, Sacramento, CA; 11 Duke Clinical Research
Institute, Durham, NC; 12 University of Oxford, Oxford, United
Kingdom
Background: Elevated sIgG4 has been reported in 9-15% of
PSC patients and is associated with a more aggressive disease
course. Our aim was to compare the characteristics
of PSC patients with elevated and normal sIgG4. Methods:
We measured sIgG4 (BN II System; Siemens, Malvern, PA)
in PSC patients enrolled in a phase 2b trial of simtuzumab.
Corticosteroid and/or anti-TNF-α therapies were prohibited.
The associations between elevated sIgG4 (>140 mg/dL) with
demographics, body mass index (BMI), ulcerative colitis (UC),
use of ursodeoxycholic acid (UDCA), liver biochemistry, Fibro-
Test, ELF, sLOXL2 (VIDAS® LOXL2; bioMérieux, Marcy L’Etoile,
France), liver fibrosis staged by the Ishak classification, and
Mayo risk score (MRS) were determined. MRCP data will be
available at the time of presentation. Results: Among 234
patients, 34 (14.5%) had elevated sIgG4. These patients were
older than those with normal sIgG4, but sex, race, UC, and use
of UDCA did not differ between groups (Table). Although liver
biochemistry did not differ, patients with elevated sIgG4 had
lower serum albumin and higher platelet levels compared with
those with normal sIgG4. FibroTest, ELF and sLOXL2, the proportion
of patients with bridging fibrosis or cirrhosis, and MELD
and MRS were similar between groups. A sensitivity analysis
examining a sIgG4 cut-off of >201 mg/dL revealed similar
findings. Conclusions: A small proportion of PSC patients have
elevated sIgG4. In this clinical trial cohort, the sIgG4 level
does not have a significant impact on PSC phenotype including
disease severity assessed biochemically, histologically, or
according to conventional prognostic indices.
Characteristics of PSC Patients According to sIgG4
Median (IQR) or % (n).
Disclosures:
Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim,
Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/
Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim,
BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK,
Novartis
Mitchell L. Shiffman - Advisory Committees or Review Panels: Merck, Gilead,
Boehringer-Ingelheim, Bristol-Myers-Squibb, Abbvie, Janssen, Acchillion; Consulting:
Roche/Genentech; Grant/Research Support: Merck, Gilead, Boehringer-Ingelheim,
Bristol-Myers-Squibb, Abbvie, Beckman-Coulter, Achillion, Lumena,
Intercept, Novartis, Gen-Probe; Speaking and Teaching: Roche/Genentech,
Merck, Gilead, Abbvie, Janssen, Bayer
Kris V. Kowdley - Advisory Committees or Review Panels: Achillion, BMS, Evidera,
Gilead, Merck, Novartis, Trio Health, Abbvie; Grant/Research Support:
Evidera, Gilead, Immuron, Intercept, Tobira; Speaking and Teaching: Abbvie,
Gilead
Harry L. Janssen - Consulting: AbbVie, Bristol Myers Squibb, GSK, Gilead Sciences,
Innogenetics, Merck, Medtronic, Novartis, Roche, Janssen, Medimmune,
ISIS Pharmaceuticals, Tekmira; Grant/Research Support: AbbVie, Bristol Myers
Squibb, Gilead Sciences, Innogenetics, Merck, Medtronic, Novartis, Roche,
Janssen, Medimmune
Robert P. Myers - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Sciences, Inc.
Mani Subramanian - Employment: Gilead Sciences
John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Michael R. Charlton - Grant/Research Support: GIlead Sciences, Merck, Janssen,
AbbVie, Novartis
Christopher L. Bowlus - Advisory Committees or Review Panels: Gilead Sciences,
Inc; Grant/Research Support: Gilead Sciences, Inc, Intercept Pharmaceuticals,
Bristol Meyers Squibb, Takeda, Lumena, Merck; Speaking and Teaching: Gilead
Sciences, Inc
Andrew J. Muir - Advisory Committees or Review Panels: BMS, Gilead, Janssen,
Merck; Consulting: Theravance; Grant/Research Support: Abbvie, Abbvie, BMS,
Gilead, Janssen, Merck, Achillion, Lumena
The following authors have nothing to disclose: Bertus Eksteen, Cynthia Levy,
Aldo J. Montano-Loza, Dora Ding, Roger W. Chapman
617
Modeling biliary fluid dynamics reveals possible mechanism
for dose-response and personalization of UDCA
treatment in PSC
Oleksandr Ostrenko 1 , Fabian Segovia-Miranda 2 , Mario Brosch 6 ,
Wiebke Erhart 5 , Kirstin Meyer 2 , Georg Kretzschmar 3 , Christoph
Jüngst 4 , Frank Lammert 4 , Marino Zerial 2 , Clemens Schafmayer 5 ,
Lutz Brusch 1 , Jochen Hampe 6 ; 1 Center for Information Services
and High Performance Computing, Technische Universität Dresden,
Dresden, Germany; 2 Max Planck Institute of Molecular Cell
Biology and Genetics, Dresden, Germany; 3 Molecular Cell Physiology
and Endocrinology, Institute of Zoology, Technische Universität
Dresden, Dresden, Germany; 4 Saarland University Medical
Center, Homburg, Germany; 5 University Hospital Schleswig Holstein,
Kiel, Germany; 6 TU Dresden, University Hospital Dresden,
Dresden, Germany
Background: Primary sclerosing cholangitis (PSC) is a progressive
liver disease characterized by fibroobliterative destruction
of the intra- and/or extra-hepatic bile ducts. Combined with
immune-mediated insults to the bile duct, biliary flow obstruction
might lead to pressure damage to the biliary epithelium
and may drive further disease progression. Currently, the only
and controversial medical treatment is the choleretic drug
ursodeoxycholic acid (UDCA). However, while moderate doses
(10-15mg/kg/day) of UDCA might improve liver function tests
and histology, high-dose UDCA has been demonstrated to
increase mortality in a RCT, thereby calling UDCA treatment
in question. Aims: Develop a hydrodynamic model of biliary
pressure and flow to assess the effect of UDCA on biliary pressure
in normal liver and PSC. Methods: A recently developed
theory of bile secretion and transport was applied to UDCA
treatment. UDCA reduces bile viscosity (1) and increases solute
concentration and consequently osmotic water influx into bile