Background and aimsDrug development in primary sclerosing cholangitis (PSC) is challenging, giving orphan disease status and variable rates of disease progression. A potential route for new therapies is through attenuation of symptoms. However, the epidemiology of symptomatic presentations and how they inherently fluctuate over time is not known. We conducted a prospective, multicenter study (trial registration: ISRCTN:15518794) to quantify the prevalence, intensity, and variability of pruritus in PSC.Approach and resultsParticipants underwent face-to-face symptom assessment through the itch numerical rating scale (NRS) and 5D-itch tool. Clinical, radiological, and biochemical factors associated with pruritus intensity were determined, alongside the impact on health-related quality-of-life [EQ-5D-5L and chronic liver disease questionnaires (CLDQ)] over 12-week intervals (up to 48±4 weeks). In all, 220 patients participated, of whom n=116 reported pruritus, with n=56 scoring NRS worst itch ≥4. Median 5D-itch was greater in people with cirrhosis (11.0 vs. 8.0), transient elastography readings >8.0 kPa (9.5 vs. 5.0), and a history of ascending cholangitis (11.0 vs. 7.0) ( p <0.01; all). 5D-itch correlated positively with serum bilirubin, ALP, ALT, and AST; and negatively with CLDQ and EQ-5D-5L. In patients scoring NRS ≥4, 61.5% reported persistent pruritus intensity over 48 weeks. Reciprocally, 46.2% experienced a spontaneous ≥2 point reduction in NRS without the addition of a new anti-pruritic agent.ConclusionsOne in 4 PSC patients experience moderate-severe pruritus, with greater symptom intensity in those with advanced disease. Our dataset is able to serve as a reference tool to aid future interventional study design, with regard to anti-pruritus therapies in PSC.