BaCKgRoUND aND aIMS: Stratified therapy has entered clinical practice in primary biliary cholangitis (PBC), with routine use of second-line therapy in nonresponders to first-line therapy with ursodeoxycholic acid (UDCA). The mechanism for nonresponse to UDCA remains, however, unclear and we lack mechanistic serum markers. The UK-PBC study was established to explore the biological basis of UDCA nonresponse in PBC and identify markers to enhance treatment.appRoaCH aND ReSUltS: Discovery serum proteomics (Olink) with targeted multiplex validation were carried out in 526 subjects from the UK-PBC cohort and 97 healthy controls. In the discovery phase, untreated PBC patients (n = 68) exhibited an inflammatory proteome that is typically reduced in scale, but not resolved, with UDCA therapy (n = 416 treated patients). Nineteen proteins remained at a significant expression level (defined using stringent criteria) in UDCA-treated patients, six of them representing a tightly linked profile of chemokines (including CCL20, known to be released by biliary epithelial cells (BECs) undergoing senescence in PBC). All showed significant differential expression between UDCA responders and nonresponders in both the discovery and validation cohorts. A linear discriminant analysis, using serum levels of C-X-C motif chemokine ligand 11 and C-C motif chemokine ligand 20 as markers of responder status, indicated a high level of discrimination with an AUC of 0.91 (CI, 0.83-0.91).CoNClUSIoNS: UDCA under-response in PBC is characterized by elevation of serum chemokines potentially related to cellular senescence and was previously shown to be released by BECs in PBC, suggesting a potential role in the pathogenesis of high-risk disease. These also have potential for development as biomarkers for identification of high-risk disease, and their clinical utility as biomarkers should be evaluated further in prospective studies. (Hepatology 2021;74:3269-3283). P rimary biliary cholangitis (PBC) is a chronic cholestatic liver disease with a significant inflammatory/immune component. (1) The condition is characterized by damage to, and eventual destruction of, the small intrahepatic bile ducts. Duct

Summary Background Current guidelines in primary biliary cholangitis ( PBC) recommend routine screening for symptoms. However, at present there are no validated practical tools suitable for screening use in practice. Aim To develop a short quality of life questionnaire for PBC Methods The short PBC HRQL questionnaire was derived and validated by analysing the PBC‐40 questionnaires from the UK‐PBC Research Cohort. Construct validity was assessed using the European Quality of Life Five Dimensions (EQ5D) questionnaire. Test‐retest analysis was done by asking a subgroup of patients to complete the questionnaire twice within 2‐4 weeks. Results A total of 2219 patients completed PBC‐40 questionnaire in 2013. Stepwise regression identified 10 questions that contributed to more than 95% of the PBC‐40 score variance and covered the main domains of PBC. The short HRQL questionnaire, PBC‐10, had good internal consistency (Cronbach's α 0.905) and item‐total correlations. PBC‐10 demonstrated no ceiling effects but a floor effect was noted. Further validation on 2502 patients who completed the PBC questionnaire in 2017 confirmed the psychometric properties of PBC‐10. Further analysis on 186 patients showed that PBC‐10 demonstrated good internal consistency (Cronbach's α = 0.936), had good reproducibility (intra‐class correlation coefficient = 0.945), good correlation with the EQ5D (r = .736), and was responsive to change. A change of 4 points in the PBC‐10 score would be considered clinically important. Conclusion PBC‐10 is a short and valid questionnaire for assessing the HRQL in patients with PBC in clinical practice.

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