Introduction Primary sclerosing cholangitis (PSC) is a relatively uncommon hepatobiliary disorder associated with inflammatory bowel disease (IBD), wherein therapy other than transplantation remains ineffective. To understand disease course, within a goal of appropriately stratified care, the International PSC Study Group describes the natural history and clinical phenotypes across the largest cohort ever assembled.
Methods We collected individual-patient data from 1980 to 2010 (37 centres, 17 countries) and conducted risk-assessment for commonly recognised phenotypic associations.
Results Of 7,119 patients, 2,622 progressed to liver transplantation/death (LTD) (median 14·2 years) and 722 developed hepatobiliary malignancy (incidence rates: 47·5 and 13·7 per-1,000-patient-years, respectively). Cholangiocarcinoma was the most frequent malignancy (n = 596), with 38·1% of cases identified within 1 year of PSC diagnosis. Observing the patient cohort in entirety, the majority were men (65·5%), had classical/large-duct disease (89·5%), and developed IBD at some point (70·0%).
IBD consistent with Crohn’s disease (vs. ulcerative colitis) or an absence of IBD over time conferred a lower risk of LTD (time-dependent, unadjusted hazard ratio (HR): 0·61, p < 0.001; and HR:0·90, p = 0·03; respectively) and malignancy (unadj. HR:0·68, p = 0·007 and HR:0·77, p = 0·003; respectively), as did small-duct PSC (sdPSC) (unadj. HR:0·50, p < 0·001 and HR:0·40, p < 0·001; for LTD and malignancy, respectively) and female sex (unadj. HR:0·89, p = 0·018 and HR:0·70, p < 0·001; for LTD and malignancy, respectively).
On multivariable analyses assessing LTD, the impact of sdPSC over classical PSC persisted, with greater protection apparent for men (adjusted HR:0·31, p < 0·001) than women (adj. HR:0·56, p = 0·009). However, women with classical PSC expressed a lower independent risk of disease progression than men of matched PSC subtype (adj. HR:0·9, p = 0.022). IBD-phenotype retained independent stratification properties of LTD, with Crohn’s disease and IBD-absence characterising lower-risk subgroups (time-dependent adj. HR:0·69 and HR:0·89, p < 0·001 and p = 0.012; respectively). sdPSC (adj. HR:0·45, p = 0·02), Crohn’s disease (time-dependent adj. HR:0·72, p = 0·045), and IBD-absence (time-dependent adj. HR:0·72, p = 0·02) were also independently predictive of a lower HPB malignancy risk.
Conclusion Using a robust, internationally representative cohort of unique size we demonstrate how distinct, clinically meaningful phenotypes stratify outcomes in PSC. We highlight the great-unmet need for patients, and provide risk markers clinically relevant to patient care and future trial design.
Disclosure of Interest None Declared
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