Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

on behalf of the, International PSC Study Group

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Background & Aims 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. Methods 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. Results 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). Conclusions 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.

Original languageEnglish (US)
Pages (from-to)1975-1984.e8
JournalGastroenterology
Volume152
Issue number8
DOIs
StatePublished - Jun 1 2017

Fingerprint

Sclerosing Cholangitis
Inflammatory Bowel Diseases
Phenotype
Liver Transplantation
Neoplasms
Ulcerative Colitis
Crohn Disease
Disease Progression

Keywords

  • Autoimmune Liver Disease
  • Cholestasis
  • Immune-Mediated Liver Disease
  • Risk Stratification

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis. / on behalf of the; International PSC Study Group.

In: Gastroenterology, Vol. 152, No. 8, 01.06.2017, p. 1975-1984.e8.

Research output: Contribution to journalArticle

on behalf of the ; International PSC Study Group. / Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis. In: Gastroenterology. 2017 ; Vol. 152, No. 8. pp. 1975-1984.e8.
@article{0ebab007f51d459983a2c4a137a0582b,
title = "Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis",
abstract = "Background & Aims 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. Methods 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. Results 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). Conclusions 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.",
keywords = "Autoimmune Liver Disease, Cholestasis, Immune-Mediated Liver Disease, Risk Stratification",
author = "{on behalf of the} and {International PSC Study Group} and Weism{\"u}ller, {Tobias J.} and Strassburg, {Christian P.} and Trivedi, {Palak J.} and Hirschfield, {Gideon M.} and Trivedi, {Palak J.} and Annika Bergquist and Karouk Said and Mohamad Imam and Lazaridis, {Konstantinos N.} and Juran, {Brian D.} and Angela Cheung and Lindor, {Keith D.} and Weism{\"u}ller, {Tobias J.} and Henrike Lenzen and Manns, {Michael P.} and Ponsioen, {Cyriel Y.} and Ulrich Beuers and Kristian Holm and Sigrid Naess and Karlsen, {Tom H.} and Erik Schrumpf and Boberg, {Kirsten M.} and Daniel Gotthardt and Christian Rupp and F{\"a}rkkil{\"a}, {Martti A.} and Kalle Jokelainen and Marschall, {Hanns Ulrich} and {Benito de Valle}, Maria and Douglas Thorburn and Francesca Saffioti and Weersma, {Rinse K.} and Johan Fevery and Tobias Mueller and Olivier Chazouill{\`e}res and Kornelius Schulze and Christoph Schramm and Sven Almer and Pereira, {Stephen P.} and Cynthia Levy and Andrew Mason and Bowlus, {Christopher L.} and Annarosa Floreani and Emina Halilbasic and Michael Trauner and Yimam, {Kidist K.} and Piotr Milkiewicz and Piotr Milkiewicz and Huynh, {Dep K.} and Albert Pares and Keith Lindor",
year = "2017",
month = "6",
day = "1",
doi = "10.1053/j.gastro.2017.02.038",
language = "English (US)",
volume = "152",
pages = "1975--1984.e8",
journal = "Gastroenterology",
issn = "0016-5085",
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TY - JOUR

T1 - Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

AU - on behalf of the

AU - International PSC Study Group

AU - Weismüller, Tobias J.

AU - Strassburg, Christian P.

AU - Trivedi, Palak J.

AU - Hirschfield, Gideon M.

AU - Trivedi, Palak J.

AU - Bergquist, Annika

AU - Said, Karouk

AU - Imam, Mohamad

AU - Lazaridis, Konstantinos N.

AU - Juran, Brian D.

AU - Cheung, Angela

AU - Lindor, Keith D.

AU - Weismüller, Tobias J.

AU - Lenzen, Henrike

AU - Manns, Michael P.

AU - Ponsioen, Cyriel Y.

AU - Beuers, Ulrich

AU - Holm, Kristian

AU - Naess, Sigrid

AU - Karlsen, Tom H.

AU - Schrumpf, Erik

AU - Boberg, Kirsten M.

AU - Gotthardt, Daniel

AU - Rupp, Christian

AU - Färkkilä, Martti A.

AU - Jokelainen, Kalle

AU - Marschall, Hanns Ulrich

AU - Benito de Valle, Maria

AU - Thorburn, Douglas

AU - Saffioti, Francesca

AU - Weersma, Rinse K.

AU - Fevery, Johan

AU - Mueller, Tobias

AU - Chazouillères, Olivier

AU - Schulze, Kornelius

AU - Schramm, Christoph

AU - Almer, Sven

AU - Pereira, Stephen P.

AU - Levy, Cynthia

AU - Mason, Andrew

AU - Bowlus, Christopher L.

AU - Floreani, Annarosa

AU - Halilbasic, Emina

AU - Trauner, Michael

AU - Yimam, Kidist K.

AU - Milkiewicz, Piotr

AU - Milkiewicz, Piotr

AU - Huynh, Dep K.

AU - Pares, Albert

AU - Lindor, Keith

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Background & Aims 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. Methods 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. Results 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). Conclusions 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.

AB - Background & Aims 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. Methods 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. Results 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). Conclusions 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.

KW - Autoimmune Liver Disease

KW - Cholestasis

KW - Immune-Mediated Liver Disease

KW - Risk Stratification

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