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Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities.

ABSTRACT: 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.

SUBMITTER: Vesterhus M

PROVIDER: S-EPMC7242240 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities.

Vesterhus Mette M Karlsen Tom Hemming TH

Journal of gastroenterology 20200328 6

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 ...[more]

PMID: 32222826

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Project description:ObjectivesThe clinical/colonoscopic features of ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC), the prognostic impact of UC, and the utility of UC screening in PSC patients are unknown. We characterized UC associated with PSC and assessed UC's impact on the prognosis of PSC and the importance of colonoscopic UC screening in PSC patients.MethodsWe retrospectively analyzed the cases of 77 patients treated for PSC at a single center (April 2000-July 2019). We reviewed the clinical/colonoscopic profiles of the concurrent UC patients and compared the clinical profiles, survival, and primary causes of death between the patients with/without UC (n = 35/n = 42). The details of all patients' colonoscopies were reviewed.ResultsThe concurrent UC group: 17 men, 18 women, diagnosed with PSC at the mean (SD) age of 36 (17) years; 21 patients (60%) had no UC symptoms. Colonoscopy revealed pancolitis in all patients, predominantly affecting the right-sided colon in 30 patients (86%). Lesions were scattered. Backwash ileitis (n = 13, 37%) and rectal sparing (n = 18, 51%) were observed. Most patients had mild UC; some had moderate or more severe UC (median Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score 2; range, 1-5). Ludwig's stage determined by liver biopsy did not correlate with the Mayo endoscopic score for UC. The patients with UC were diagnosed with PSC at a significantly younger age than those without UC (mean (SD), 36 [17] years vs. 55 [19] years, p < 0.0001) and had a significantly higher 5-year survival rate (97.1% vs. 70.5%, p = 0.0028). UC was detected in 19 of 34 asymptomatic patients (56%) who underwent colonoscopy screening.ConclusionsOur cohort's clinical/colonoscopic features of UC associated with PSC are more moderate or severe UC than previous cases. The coexistence of UC might affect the prognosis of PSC. In this regard, colonoscopy in PSC patients is an important examination for determining prognosis. There is also asymptomatic UC in patients with PSC. In this regard, screening for colonoscopy in PSC patients is essential. When a diagnosis of PSC is made, immediate colonoscopy is a priority with UC complications in mind.

Dataset Information

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities.

Publications

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities.

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