The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study
Summary: 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,...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422002493 |
| _version_ | 1818552667723530240 |
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| author | David E.J. Jones Aaron Wetten Ben Barron-Millar Laura Ogle George Mells Steven Flack Richard Sandford John Kirby Jeremy Palmer Sophie Brotherston Laura Jopson John Brain Graham R. Smith Steve Rushton Rebecca Jones Simon Rushbrook Douglas Thorburn Stephen D. Ryder Gideon Hirschfield Jessica K. Dyson |
| author_facet | David E.J. Jones Aaron Wetten Ben Barron-Millar Laura Ogle George Mells Steven Flack Richard Sandford John Kirby Jeremy Palmer Sophie Brotherston Laura Jopson John Brain Graham R. Smith Steve Rushton Rebecca Jones Simon Rushbrook Douglas Thorburn Stephen D. Ryder Gideon Hirschfield Jessica K. Dyson |
| author_sort | David E.J. Jones |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-12T09:16:10Z |
| format | Article |
| id | doaj.art-39a878808f5b4982bbbea7ab6978ff11 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-12T09:16:10Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-39a878808f5b4982bbbea7ab6978ff112022-12-22T00:29:23ZengElsevierEBioMedicine2352-39642022-06-0180104068The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort studyDavid E.J. Jones0Aaron Wetten1Ben Barron-Millar2Laura Ogle3George Mells4Steven Flack5Richard Sandford6John Kirby7Jeremy Palmer8Sophie Brotherston9Laura Jopson10John Brain11Graham R. Smith12Steve Rushton13Rebecca Jones14Simon Rushbrook15Douglas Thorburn16Stephen D. Ryder17Gideon Hirschfield18Jessica K. Dyson19Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom; Corresponding author at: Translational and Clinical Research Institute, Medical School, Framlington Place, Newcastle-upon-Tyne, NE24HH United Kingdom.Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom; Freeman Hospital, Newcastle-upon-Tyne, United KingdomTranslational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United KingdomTranslational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United KingdomDept of Human Genetics, University of Cambridge, Cambridge, United KingdomDept of Human Genetics, University of Cambridge, Cambridge, United KingdomDept of Human Genetics, University of Cambridge, Cambridge, United KingdomTranslational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United KingdomTranslational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United KingdomTranslational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United KingdomTranslational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United KingdomTranslational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United KingdomBioinformatics Support Unit (BSU), Newcastle University, Newcastle-upon-Tyne, United KingdomSchool of Natural and Environmental Science, Newcastle University, Newcastle-upon-Tyne, United KingdomLiver Unit, St James’ Hospital, Leeds, United KingdomUniversity Department of Hepatology, UEA Medical School, Norwich, United KingdomLiver Unit, Royal Free Hospital, London, United KingdomNIHR Nottingham Biomedical Research centre at Nottingham University Hospitals NHS Trust, Nottingham, United KingdomQueen Elizabeth Hospital, Birmingham, United Kingdom; Toronto Centre for Liver Disease, University of Toronto, Toronto, CanadaTranslational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, United Kingdom; Freeman Hospital, Newcastle-upon-Tyne, United KingdomSummary: 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.http://www.sciencedirect.com/science/article/pii/S2352396422002493Primary biliary cholangitisUrsodeoxycholic acidUDCAResponse criteriaParis 1 criteriaParis 2 criteria |
| spellingShingle | David E.J. Jones Aaron Wetten Ben Barron-Millar Laura Ogle George Mells Steven Flack Richard Sandford John Kirby Jeremy Palmer Sophie Brotherston Laura Jopson John Brain Graham R. Smith Steve Rushton Rebecca Jones Simon Rushbrook Douglas Thorburn Stephen D. Ryder Gideon Hirschfield Jessica K. Dyson The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study EBioMedicine Primary biliary cholangitis Ursodeoxycholic acid UDCA Response criteria Paris 1 criteria Paris 2 criteria |
| title | The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study |
| title_full | The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study |
| title_fullStr | The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study |
| title_full_unstemmed | The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study |
| title_short | The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study |
| title_sort | relationship between disease activity and udca response criteria in primary biliary cholangitis a cohort study |
| topic | Primary biliary cholangitis Ursodeoxycholic acid UDCA Response criteria Paris 1 criteria Paris 2 criteria |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422002493 |
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