title: Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis.
abstract: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC.
  
  
  
  We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates.
  
  
  
  Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002).
  
  
  
  In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: tobias.weismueller@gmx.de.
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Weismüller
authors.affiliation: National Institute for Health Research (NIHR) Birmingham, Liver Biomedical Research Centre (BRC), University of Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham Queen Elizabeth, United Kingdom.
authors.forename: Palak J
authors.initials: PJ
authors.lastname: Trivedi
authors.affiliation: Center for Digestive Diseases, Division of Hepatology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Bergquist
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Department of Internal Medicine, University of North Dakota, Grand Forks, North Dakota.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Imam
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Lenzen
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cyriel Y
authors.initials: CY
authors.lastname: Ponsioen
authors.affiliation: Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Holm
authors.affiliation: Department of Gastroenterology, Infectious Diseases and Intoxications, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gotthardt
authors.affiliation: Helsinki University, Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Martti A
authors.initials: MA
authors.lastname: Färkkilä
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: The Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom.
authors.forename: Douglas
authors.initials: D
authors.lastname: Thorburn
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center, Groningen, The Netherlands.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.affiliation: Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Fevery
authors.affiliation: Department of Internal Medicine, Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Mueller
authors.affiliation: Service d'Hépatologie, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Pierre et Marie Curie, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Chazouillères
authors.affiliation: 1st Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Kornelius
authors.initials: K
authors.lastname: Schulze
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Lazaridis
authors.affiliation: Division of Gastroenterology and Hepatology, Linköping University, Linköping; Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Almer
authors.affiliation: Institute for Liver and Digestive Health, University College London, London, United Kingdom.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Pereira
authors.affiliation: Division of Hepatology, University of Miami, Miami, Florida.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Levy
authors.affiliation: Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mason
authors.affiliation: Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Naess
authors.affiliation: Division of Gastroenterology and Hepatology, University of California Davis, Davis, California.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Bowlus
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Floreani
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
authors.forename: Emina
authors.initials: E
authors.lastname: Halilbasic
authors.affiliation: Department of Hepatology and Liver Transplantation, California Pacific Medical Center, San Francisco, California.
authors.forename: Kidist K
authors.initials: KK
authors.lastname: Yimam
authors.affiliation: Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin, Poland; Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Milkiewicz
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia.
authors.forename: Dep K
authors.initials: DK
authors.lastname: Huynh
authors.affiliation: Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Pares
authors.affiliation: Division for Gastroenterology and Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland.
authors.forename: Christine N
authors.initials: CN
authors.lastname: Manser
authors.affiliation: Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece.
authors.forename: George N
authors.initials: GN
authors.lastname: Dalekos
authors.affiliation: University of Calgary, Snyder Institute for Chronic Diseases, Alberta, AB, Canada.
authors.forename: Bertus
authors.initials: B
authors.lastname: Eksteen
authors.affiliation: Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: Department of Gastroenterology, Hepatology, and Infectiology, Medical Clinic, University of Tübingen, Germany.
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Berg
authors.affiliation: Department of Internal Medicine 1, University Hospital of Regensburg, Regensburg, Germany.
authors.forename: Gabi I
authors.initials: GI
authors.lastname: Kirchner
authors.affiliation: Department of Internal Medicine 1, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zimmer
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Fabris
authors.affiliation: Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, Campus Kiel, UKSH, Kiel, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Braun
authors.affiliation: Clinic of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Juran
authors.affiliation: Center for Digestive Diseases, Division of Hepatology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karouk
authors.initials: K
authors.lastname: Said
authors.affiliation: Department of Gastroenterology, Infectious Diseases and Intoxications, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rupp
authors.affiliation: Helsinki University, Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Kalle
authors.initials: K
authors.lastname: Jokelainen
authors.affiliation: Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Benito de Valle
authors.affiliation: The Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Saffioti
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Angela
authors.initials: A
authors.lastname: Cheung
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: 1st Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Chapman
authors.affiliation: Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Erik
authors.initials: E
authors.lastname: Schrumpf
authors.affiliation: Department of Internal Medicine I, University of Bonn, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona; Arizona State University, College of Health Solutions, Phoenix, Arizona.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Lindor
authors.affiliation: National Institute for Health Research (NIHR) Birmingham, Liver Biomedical Research Centre (BRC), University of Birmingham, United Kingdom.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada; Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada.
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Hansen
authors.affiliation: Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: kboberg@ous-hf.no.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Boberg
mesh_terms: D000328:Adult; D017677:Age Distribution; D001315:Australia / Q000453:epidemiology; D016009:Chi-Square Distribution; D015209:Cholangitis, Sclerosing / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality / Q000601:surgery; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality / Q000601:surgery; D003424:Crohn Disease / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality / Q000601:surgery; D018450:Disease Progression; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009656:North America / Q000453:epidemiology; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D017678:Sex Distribution; D013997:Time Factors; D055815:Young Adult
keywords: Autoimmune Liver Disease; Cholestasis; Immune-Mediated Liver Disease; Risk Stratification