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Comparative Study
. 2017 Jun;152(8):1975-1984.e8.
doi: 10.1053/j.gastro.2017.02.038. Epub 2017 Mar 6.

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

Tobias J Weismüller  1 , Palak J Trivedi  2 , Annika Bergquist  3 , Mohamad Imam  4 , Henrike Lenzen  5 , Cyriel Y Ponsioen  6 , Kristian Holm  7 , Daniel Gotthardt  8 , Martti A Färkkilä  9 , Hanns-Ulrich Marschall  10 , Douglas Thorburn  11 , Rinse K Weersma  12 , Johan Fevery  13 , Tobias Mueller  14 , Olivier Chazouillères  15 , Kornelius Schulze  16 , Konstantinos N Lazaridis  17 , Sven Almer  18 , Stephen P Pereira  19 , Cynthia Levy  20 , Andrew Mason  21 , Sigrid Naess  22 , Christopher L Bowlus  23 , Annarosa Floreani  24 , Emina Halilbasic  25 , Kidist K Yimam  26 , Piotr Milkiewicz  27 , Ulrich Beuers  6 , Dep K Huynh  28 , Albert Pares  29 , Christine N Manser  30 , George N Dalekos  31 , Bertus Eksteen  32 , Pietro Invernizzi  33 , Christoph P Berg  34 , Gabi I Kirchner  35 , Christoph Sarrazin  36 , Vincent Zimmer  37 , Luca Fabris  38 , Felix Braun  39 , Marco Marzioni  40 , Brian D Juran  17 , Karouk Said  3 , Christian Rupp  8 , Kalle Jokelainen  9 , Maria Benito de Valle  10 , Francesca Saffioti  11 , Angela Cheung  17 , Michael Trauner  25 , Christoph Schramm  41 , Roger W Chapman  42 , Tom H Karlsen  22 , Erik Schrumpf  22 , Christian P Strassburg  43 , Michael P Manns  5 , Keith D Lindor  44 , Gideon M Hirschfield  45 , Bettina E Hansen  46 , Kirsten M Boberg  47 ; International PSC Study Group
Affiliations
Comparative Study

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

Tobias J Weismüller et al. Gastroenterology. 2017 Jun.

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.

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Conflict of interest statement

Conflicts of interest

The authors disclose no conflicts.

Figures

Figure 1
Figure 1
Study cohort: At the time of analysis data were available for 7931 patients. However, following exclusion of groups with an alternate diagnose or inadequate follow-up, the final study group consisted of 7121 patients, of which 2616 underwent LT or died, with a total of 721 developing primary HPB malignancy.
Figure 2
Figure 2
Cumulative incidence of clinical events. Kaplan-Meier estimates of (A) LT-free survival rate across the patient population and (B) incidence of all HPB malignancies. Notably, 37.8% (n = 272) of all HPB malignancies occurred in the first year of PSC diagnosis, with the vast majority being CCA during this time (incidence rate in the first year after PSC diagnosis: 2.6 cases per 100 patient-years). Patients with unknown transplantation, mortality, or malignancy status at the time of study completion were excluded from respective analysis.
Figure 3
Figure 3
Impact of patient age and gender on clinical outcome. Cox plots with regard to LT or HPB malignancy. All data are stratified by geographic region of referring center and year of diagnosis, presented according to patient age at diagnosis and weighted for patient gender, IBD phenotype at baseline, and PSC sub-phenotype (A and B); or patient gender weighted for patient age at diagnosis, IBD phenotype at baseline, and PSC sub-phenotype (C and D).
Figure 4
Figure 4
Impact of variant PSC sub-phenotypes and IBD phenotypes on clinical outcome. Cox plots with regard to LT or HPB malignancy. All data are stratified by geographic region of referring center and year of diagnosis, presented according to PSC sub-phenotype weighted for patient age at PSC diagnosis, gender, and IBD phenotype at baseline (A and B); or patient IBD phenotype at baseline weighted for age at PSC diagnosis, gender, and PSC sub-phenotype (C and D).
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