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Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities
Primary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. Patients bear a significant risk of cholangiocarcinoma...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Singapore
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242240/ https://www.ncbi.nlm.nih.gov/pubmed/32222826 http://dx.doi.org/10.1007/s00535-020-01681-z |
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author | Vesterhus, Mette Karlsen, Tom Hemming |
author_facet | Vesterhus, Mette Karlsen, Tom Hemming |
author_sort | Vesterhus, Mette |
collection | PubMed |
description | Primary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. Patients bear a significant risk of cholangiocarcinoma and colorectal cancer, and frequently have concomitant inflammatory bowel disease and autoimmune disease manifestations. To date, no medical therapy has proven significant impact on clinical outcomes and most patients ultimately need liver transplantation. Several treatment strategies have failed in the past and whilst prescription of ursodeoxycholic acid (UDCA) prevails, controversy regarding benefits remains. Lack of statistical power, slow and variable disease progression, lack of surrogate biomarkers for disease severity and other challenges in trial design serve as critical obstacles in the development of effective therapy. Advances in our understanding of PSC pathogenesis and biliary physiology over recent years has however led to a surge of clinical trials targeting various mechanistic compartments and currently raising hopes for imminent changes in patient management. Here, in light of pathophysiology, we outline and critically evaluate emerging treatment strategies in PSC, as tested in recent or ongoing phase II and III trials, stratified per a triad of targets of nuclear and membrane receptors regulating bile acid metabolism, immune modulators, and effects on the gut microbiome. Furthermore, we revisit the UDCA trials of the past and critically discuss relevant aspects of clinical trial design, including how the choice of endpoints, alkaline phosphatase in particular, may affect the future path to novel, effective PSC therapeutics. |
format | Online Article Text |
id | pubmed-7242240 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Singapore |
record_format | MEDLINE/PubMed |
spelling | pubmed-72422402020-06-03 Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities Vesterhus, Mette Karlsen, Tom Hemming J Gastroenterol Review Primary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. Patients bear a significant risk of cholangiocarcinoma and colorectal cancer, and frequently have concomitant inflammatory bowel disease and autoimmune disease manifestations. To date, no medical therapy has proven significant impact on clinical outcomes and most patients ultimately need liver transplantation. Several treatment strategies have failed in the past and whilst prescription of ursodeoxycholic acid (UDCA) prevails, controversy regarding benefits remains. Lack of statistical power, slow and variable disease progression, lack of surrogate biomarkers for disease severity and other challenges in trial design serve as critical obstacles in the development of effective therapy. Advances in our understanding of PSC pathogenesis and biliary physiology over recent years has however led to a surge of clinical trials targeting various mechanistic compartments and currently raising hopes for imminent changes in patient management. Here, in light of pathophysiology, we outline and critically evaluate emerging treatment strategies in PSC, as tested in recent or ongoing phase II and III trials, stratified per a triad of targets of nuclear and membrane receptors regulating bile acid metabolism, immune modulators, and effects on the gut microbiome. Furthermore, we revisit the UDCA trials of the past and critically discuss relevant aspects of clinical trial design, including how the choice of endpoints, alkaline phosphatase in particular, may affect the future path to novel, effective PSC therapeutics. Springer Singapore 2020-03-28 2020 /pmc/articles/PMC7242240/ /pubmed/32222826 http://dx.doi.org/10.1007/s00535-020-01681-z Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Review Vesterhus, Mette Karlsen, Tom Hemming Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities |
title | Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities |
title_full | Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities |
title_fullStr | Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities |
title_full_unstemmed | Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities |
title_short | Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities |
title_sort | emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242240/ https://www.ncbi.nlm.nih.gov/pubmed/32222826 http://dx.doi.org/10.1007/s00535-020-01681-z |
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