Browse by author
Lookup NU author(s): Professor David Jones, Dr Aaron Wetten, Dr Ben Barron-Millar, Dr Laura Ogle, Dr George Mells, Katherine Flack, Emeritus Professor John Kirby, Dr Jeremy Palmer, Dr Laura Jopson, Dr John Brain, Dr Graham Smith, Professor Stephen Rushton, Dr Jess Dyson
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2022 The Authors, Background: Uncertainty exists about how best to identify primary biliary cholangitis (PBC) patients who would benefit from second-line therapy. Existing, purely clinical, ursodeoxycholic acid (UDCA) response criteria accept degrees of liver biochemistry abnormality in responding patients, emerging data, however, suggest that any degree of ongoing abnormality may, in fact, be associated with an increased risk of adverse outcomes. This cohort study explores the link between response status, the biology of high-risk disease and its implications for clinical practice. Methods: Proteomics, exploring 19 markers previously identified as remaining elevated in PBC following UDCA therapy, were performed on 400 serum samples, from participants previously recruited to the UK-PBC Nested Cohort between 2014 and 2019. All participants had an established diagnosis of PBC and were taking therapeutic doses of UDCA for greater than 12 months. UDCA response status was assessed using Paris 1, Paris 2 and the POISE criteria, with additional analyses using normal liver blood tests stratified by bilirubin level. Statistical analysis using parametric t tests and 1-way ANOVA. Findings: Disease markers were statistically significantly higher in UDCA non-responders than in responders for all the UDCA response criteria, suggesting a meaningful link between biochemical disease status and disease mechanism. For each of the criteria, however, marker levels were also statistically significantly higher in responders with ongoing liver function test abnormality compared to those who had normalised their liver biochemistry. IL-4RA, IL-18-R1, CXCL11, 9 and 10, CD163 and ACE2 were consistently elevated across all responder groups with ongoing LFT abnormality. No statistically significant differences occurred between markers in normal LFT groups stratified by bilirubin level. Interpretation: This study provides evidence that any ongoing elevation in alkaline phosphatase levels in PBC after UDCA therapy is associated with some degree of ongoing disease activity. There was no difference in activity between patients with normal LFT when stratified by bilirubin. These findings suggest that if our goal is to completely control disease activity in PBC, then normalisation of alkaline phosphatase and bilirubin should be the treatment target. This would also simplify messaging around goals of therapy in PBC, benefiting both patients and clinicians. Funding: Funding by the UK Medical Research Council (Stratified Medicine Programme) and an independent research grant by Pfizer. The study funders played no role in the study design, data collection, data analyses, data interpretation or manuscript writing.
Author(s): Jones DEJ, Wetten A, Barron-Millar B, Ogle L, Mells G, Flack S, Sandford R, Kirby J, Palmer J, Brotherston S, Jopson L, Brain J, Smith GR, Rushton S, Jones R, Rushbrook S, Thorburn D, Ryder SD, Hirschfield G, Dyson JK
Publication type: Article
Publication status: Published
Journal: eBioMedicine
Year: 2022
Volume: 80
Print publication date: 01/06/2024
Online publication date: 21/05/2024
Acceptance date: 04/05/2024
Date deposited: 18/09/2024
ISSN (electronic): 2352-3964
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.ebiom.2022.104068
DOI: 10.1016/j.ebiom.2022.104068
Data Access Statement: All presented data available on request, pending approval of proposed use and signed data access agreement. Application for access to data to be made via corresponding author.
PubMed id: 35609437
Altmetrics provided by Altmetric
