{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T08:57:09Z","timestamp":1784883429103,"version":"3.55.0"},"reference-count":106,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,18]],"date-time":"2021-04-18T00:00:00Z","timestamp":1618704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are two chronic cholestatic liver diseases affecting bile ducts that may progress to biliary cirrhosis. In the past few years, the increasing knowledge in the pathogenesis of both diseases led to a growing number of clinical trials and possible new targets for therapy. In this review, we provide an update on the treatments in clinical use and summarize the new drugs in trials for PBC and PSC patients. Farnesoid X Receptor (FXR) agonists and Pan-Peroxisome Proliferator-Activated Receptor (PPAR) agonists are the most promising agents and have shown promising results in both PBC and PSC. Fibroblast Growth Factor 19 (FGF19) analogues also showed good results, especially in PBC, while, although PBC and PSC are autoimmune diseases, immunosuppressive drugs had disappointing effects. Since the gut microbiome could have a potential role in the pathogenesis of PSC, recent research focused on molecules that could change the microbiome, with good results. The near future of the medical management of these diseases may include new treatments or a combination of multiple drugs targeting different signaling pathways at different stages of the diseases.<\/jats:p>","DOI":"10.3390\/jcm10081763","type":"journal-article","created":{"date-parts":[[2021,4,18]],"date-time":"2021-04-18T22:15:13Z","timestamp":1618784113000},"page":"1763","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities"],"prefix":"10.3390","volume":"10","author":[{"given":"Marta","family":"Mazzetti","sequence":"first","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"},{"name":"Department of Gastroenterology, Azienda Sanitaria Unica Regionale Marche Area Vasta 3, 62100 Macerata, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Marconi","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Mancinelli","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Marzioni","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4707-7374","authenticated-orcid":false,"given":"Luca","family":"Maroni","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology and Hepatology, Universit\u00e0 Politecnica delle Marche, 60126 Ancona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2017). Electronic address eee, European Association for the Study of the L: EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J. Hepatol., 67, 145\u2013172.","DOI":"10.1016\/j.jhep.2017.03.022"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S25","DOI":"10.1016\/j.jhep.2015.02.023","article-title":"New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond","volume":"62","author":"Beuers","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1146\/annurev-pharmtox-010818-021059","article-title":"Drug Therapies for Chronic Cholestatic Liver Diseases","volume":"60","author":"Wagner","year":"2020","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/ncpgasthep0521","article-title":"Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis","volume":"3","author":"Beuers","year":"2006","journal-title":"Nat. Clin. Pract. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1053\/jhep.2002.36088","article-title":"Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited","volume":"36","author":"Paumgartner","year":"2002","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1097\/MOG.0b013e328352aab2","article-title":"The biliary HCO(3)(-) umbrella: Experimental evidence revisited","volume":"28","author":"Beuers","year":"2012","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejim.2017.06.020","article-title":"Primary biliary cholangitis: Old and novel therapy","volume":"47","author":"Floreani","year":"2018","journal-title":"Eur. J. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1111\/j.1572-0241.2006.00699.x","article-title":"Prognosis of ursodeoxycholic Acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients","volume":"101","author":"Schalm","year":"2006","journal-title":"Am. J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1053\/jhep.2000.20240","article-title":"The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis","volume":"32","author":"Corpechot","year":"2000","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.jhep.2019.04.001","article-title":"Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis","volume":"71","author":"Harms","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/S2468-1253(18)30163-8","article-title":"Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: Development and validation of the UDCA Response Score","volume":"3","author":"Carbone","year":"2018","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1053\/j.gastro.2012.12.005","article-title":"Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid","volume":"144","author":"Carbone","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.dld.2017.05.001","article-title":"Primary Biliary Cholangitis: Advances in management and treatment of the disease","volume":"49","author":"Invernizzi","year":"2017","journal-title":"Dig. Liver Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1053\/j.gastro.2014.12.005","article-title":"Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid","volume":"148","author":"Hirschfield","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1056\/NEJMoa1509840","article-title":"A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis","volume":"375","author":"Nevens","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S2468-1253(19)30094-9","article-title":"Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study","volume":"4","author":"Trauner","year":"2019","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.cgh.2019.09.050","article-title":"Long-Term Obeticholic Acid Therapy Improves Histological Endpoints in Patients with Primary Biliary Cholangitis","volume":"18","author":"Bowlus","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1002\/hep.29569","article-title":"A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis","volume":"67","author":"Kowdley","year":"2018","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1136\/gutjnl-2017-315259","article-title":"The British Society of Gastroenterology\/UK-PBC primary biliary cholangitis treatment and management guidelines","volume":"67","author":"Hirschfield","year":"2018","journal-title":"Gut"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1002\/hep.30145","article-title":"Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases","volume":"69","author":"Lindor","year":"2019","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1042\/bj20020981","article-title":"Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice","volume":"369 Pt 3","author":"Kok","year":"2003","journal-title":"Biochem. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1038\/nm.2048","article-title":"PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance","volume":"15","author":"Mukundan","year":"2009","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00795-013-0017-0","article-title":"PPARgamma ligand attenuates portal inflammation in the MRL-lpr mouse: A new strategy to restrain cholangiopathy in primary biliary cirrhosis","volume":"46","author":"Nozaki","year":"2013","journal-title":"Med. Mol. Morphol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1056\/NEJMoa1714519","article-title":"A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis","volume":"378","author":"Corpechot","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/ajg.2017.287","article-title":"Effects of Bezafibrate on Outcome and Pruritus in Primary Biliary Cholangitis with Suboptimal Ursodeoxycholic Acid Response","volume":"113","author":"Reig","year":"2018","journal-title":"Am. J. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/apt.13465","article-title":"Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes","volume":"43","author":"Cheung","year":"2016","journal-title":"Aliment. Pharm. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"557","DOI":"10.17235\/reed.2018.5533\/2018","article-title":"Efficacy and safety of fenofibrate add-on therapy for patients with primary biliary cholangitis and a suboptimal response to UDCA","volume":"110","author":"Duan","year":"2018","journal-title":"Rev. Esp. Enferm. Dig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1002\/hep.20646","article-title":"Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: A three-year randomized trial","volume":"41","author":"Rautiainen","year":"2005","journal-title":"Hepatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/S0016-5085(99)70351-3","article-title":"Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: Results of a prospective double-blind trial","volume":"117","author":"Leuschner","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.jhep.2020.09.011","article-title":"A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA","volume":"74","author":"Hirschfield","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1053\/jhep.2003.50266","article-title":"Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis","volume":"38","author":"Hempfling","year":"2003","journal-title":"Hepatology"},{"key":"ref_32","unstructured":"Kowdley, K.V., Minuk, G.Y., Pagadala, M.R., Gulamhusein, A., Swain, M.G., Neff, G.W., Zogg, D., Bowlus, C.L., Agarwal, K., and Yoshida, E.M. (2019). The nonsteroidal farnesoid x receptor (FXR) agonist cilofexor improves liver biochemistry in patients with primary biliary cholangitis (PBC): A phase 2, randomized, placebo-controlled trial. Hepatology, Wiley."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S103","DOI":"10.1016\/S0168-8278(18)30426-4","article-title":"Early assessment of safety and efficacy of tropifexor, a potent non bile-acid FXR agonist, in patients with primary biliary cholangitis: An interim analysis of an ongoing phase 2 study","volume":"68","author":"Schramm","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/S2468-1253(17)30246-7","article-title":"Seladelpar (MBX-8025), a selective PPAR-delta agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: A double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study","volume":"2","author":"Jones","year":"2017","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_35","unstructured":"(2021, January 21). Treatment Efficacy and Safety of Low Dose Seladelpar, a Selective PPAR-\u03b4 Agonist, in Patients with Primary Biliary Cholan-Gitis: Twelve-Week Interim Analysis of an International, Randomized, Dose Ranging, Phase 2 Study. Available online: https:\/\/aasldpubs.onlinelibrary.wiley.com\/doi\/abs\/10.1002\/hep.29634."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e128","DOI":"10.1016\/S0618-8278(19)30226-9","article-title":"LBO-02-Elafibranor, a peroxisome proliferator-activted receptor alpha and delta agonist demonstrates favourable efficacy and safety in patients with primary biliary cholangitis and inadequate response to ursodeoxycholic acid treatment","volume":"70","author":"Pares","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1002\/hep4.1209","article-title":"NGM282 for Treatment of Patients with Primary Biliary Cholangitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial","volume":"2","author":"Mayo","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1016\/S0618-8278(19)30002-7","article-title":"Efficacy of GKT831 in patients with primary biliary cholangitis and inadequate response to ursodeoxycholic acid: Interim efficacy results of a phase 2 clinical trial","volume":"70","author":"Dalekos","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/hep.24748","article-title":"Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid","volume":"55","author":"Tsuda","year":"2012","journal-title":"Hepatology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/ajg.2013.51","article-title":"B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid","volume":"108","author":"Myers","year":"2013","journal-title":"Am. J. Gastroenterol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1002\/hep.30099","article-title":"Rituximab Is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A Phase 2 Randomized Controlled Trial","volume":"70","author":"Khanna","year":"2019","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/hep.28359","article-title":"Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: A proof-of-concept study","volume":"64","author":"Hirschfield","year":"2016","journal-title":"Hepatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jaut.2019.04.005","article-title":"Therapeutic trials of biologics in primary biliary cholangitis: An open label study of abatacept and review of the literature","volume":"101","author":"Bowlus","year":"2019","journal-title":"J. Autoimmun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"273","DOI":"10.15403\/jgld.2014.1121.273.icz","article-title":"Effect of S-adenosyl-L-methionine on liver biochemistry and quality of life in patients with primary biliary cholangitis treated with ursodeoxycholic acid. A prospective, open label pilot study","volume":"27","author":"Wunsch","year":"2018","journal-title":"J. Gastrointestin. Liver Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.aohep.2019.09.009","article-title":"Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies","volume":"19","author":"Gerussi","year":"2020","journal-title":"Ann. Hepatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1111\/liv.14490","article-title":"A novel non-bile acid FXR agonist EDP-305 potently suppresses liver injury and fibrosis without worsening of ductular reaction","volume":"40","author":"An","year":"2020","journal-title":"Liver Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1053\/j.gastro.2016.01.038","article-title":"Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-alpha and -delta, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening","volume":"150","author":"Ratziu","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_48","first-page":"49","article-title":"Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches","volume":"8","author":"Galoosian","year":"2020","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1159\/000371670","article-title":"Bile Acids as Hormones: The FXR-FGF15\/19 Pathway","volume":"33","author":"Kliewer","year":"2015","journal-title":"Dig. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1002\/hep.30810","article-title":"Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development","volume":"71","author":"Schumacher","year":"2020","journal-title":"Hepatology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1002\/hep.28257","article-title":"Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice","volume":"63","author":"Zhou","year":"2016","journal-title":"Hepatology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/nri1312","article-title":"NOX enzymes and the biology of reactive oxygen","volume":"4","author":"Lambeth","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.1002\/hep.25938","article-title":"Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent","volume":"56","author":"Aoyama","year":"2012","journal-title":"Hepatology"},{"key":"ref_54","first-page":"84","article-title":"Combined treatment with ursodeoxycholic acid and prednisone in primary biliary cirrhosis","volume":"44","author":"Wolfhagen","year":"1994","journal-title":"Neth. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/S0168-8278(98)80254-7","article-title":"Triple therapy with ursodeoxycholic acid, prednisone and azathioprine in primary biliary cirrhosis: A 1-year randomized, placebo-controlled study","volume":"29","author":"Wolfhagen","year":"1998","journal-title":"J. Hepatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1056\/NEJM199005173222003","article-title":"A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis","volume":"322","author":"Wiesner","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1002\/hep.20897","article-title":"Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis","volume":"42","author":"Combes","year":"2005","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1097\/01.mcg.0000177235.36640.21","article-title":"Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid","volume":"39","author":"Treiber","year":"2005","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1002\/hep.26979","article-title":"IL-12\/Th1 and IL-23\/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy","volume":"59","author":"Yang","year":"2014","journal-title":"Hepatology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/cei.12193","article-title":"Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis","volume":"174","author":"Tanaka","year":"2013","journal-title":"Clin. Exp. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.jhep.2017.05.009","article-title":"norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis","volume":"67","author":"Fickert","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/hep.29888","article-title":"Na(+) -taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice","volume":"68","author":"Slijepcevic","year":"2018","journal-title":"Hepatology"},{"key":"ref_63","first-page":"293","article-title":"Primary Sclerosing Cholangitis, Part 1: Epidemiology, Etiopathogenesis, Clinical Features, and Treatment","volume":"14","author":"Tabibian","year":"2018","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_64","unstructured":"European Society of Gastrointestinal Endoscopy, and European Association for the Study of the Liver (2017). Role of endoscopy in primary sclerosing cholangitis: European Society of Gastrointestinal Endoscopy (ESGE) and European Association for the Study of the Liver (EASL) Clinical Guideline. J. Hepatol., 66, 1265\u20131281."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/0168-8278(90)90281-U","article-title":"Ursodeoxycholic acid for primary sclerosing cholangitis","volume":"11","author":"Chazouilleres","year":"1990","journal-title":"J. Hepatol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1002\/hep.1840140516","article-title":"Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: A 30-month pilot study","volume":"14","author":"Senior","year":"1991","journal-title":"Hepatology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1002\/hep.1840160315","article-title":"Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: A placebo-controlled trial","volume":"16","author":"Beuers","year":"1992","journal-title":"Hepatology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1053\/gast.2001.27965","article-title":"A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis","volume":"121","author":"Mitchell","year":"2001","journal-title":"Gastroenterology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1053\/j.gastro.2005.08.017","article-title":"High-dose ursodeoxycholic acid in primary sclerosing cholangitis: A 5-year multicenter, randomized, controlled study","volume":"129","author":"Olsson","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1002\/hep.23082","article-title":"High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis","volume":"50","author":"Lindor","year":"2009","journal-title":"Hepatology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1111\/j.1872-034X.2009.00527.x","article-title":"Ursodeoxycholic acid in primary sclerosing cholangitis: Meta-analysis of randomized controlled trials","volume":"39","author":"Shi","year":"2009","journal-title":"Hepatol. Res."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Poropat, G., Giljaca, V., Stimac, D., and Gluud, C. (2011). Bile acids for primary sclerosing cholangitis. Cochrane Database Syst. Rev., CD003626.","DOI":"10.1002\/14651858.CD003626.pub2"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1111\/j.1365-2036.2011.04822.x","article-title":"Meta-analysis: Ursodeoxycholic acid for primary sclerosing cholangitis","volume":"34","author":"Triantos","year":"2011","journal-title":"Aliment. Pharm. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1136\/gutjnl-2018-317993","article-title":"British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis","volume":"68","author":"Chapman","year":"2019","journal-title":"Gut"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.jhep.2020.02.033","article-title":"A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis","volume":"73","author":"Kowdley","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1002\/hep.30509","article-title":"The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients with Primary Sclerosing Cholangitis","volume":"70","author":"Trauner","year":"2019","journal-title":"Hepatology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.jhep.2018.10.035","article-title":"Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial","volume":"70","author":"Hirschfield","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1097\/MCG.0000000000000591","article-title":"Combination Therapy of All-Trans Retinoic Acid with Ursodeoxycholic Acid in Patients with Primary Sclerosing Cholangitis: A Human Pilot Study","volume":"51","author":"Assis","year":"2017","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1002\/jhbp.281","article-title":"Prospective study of bezafibrate for the treatment of primary sclerosing cholangitis","volume":"22","author":"Mizuno","year":"2015","journal-title":"J. Hepatobiliary Pancreat. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1002\/hep.30237","article-title":"Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results with Insights on the Natural History of the Disease","volume":"69","author":"Muir","year":"2019","journal-title":"Hepatology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.cgh.2019.05.013","article-title":"Effects of Vedolizumab in Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases","volume":"18","author":"Lynch","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1097\/MJT.0000000000000102","article-title":"Prospective Clinical Trial of Rifaximin Therapy for Patients with Primary Sclerosing Cholangitis","volume":"24","author":"Tabibian","year":"2017","journal-title":"Am. J. Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/ajg.2008.14","article-title":"Minocycline in the treatment of patients with primary sclerosing cholangitis: Results of a pilot study","volume":"104","author":"Silveira","year":"2009","journal-title":"Am. J. Gastroenterol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.14309\/ajg.0000000000000115","article-title":"Fecal Microbiota Transplantation in Patients with Primary Sclerosing Cholangitis: A Pilot Clinical Trial","volume":"114","author":"Allegretti","year":"2019","journal-title":"Am. J. Gastroenterol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1080\/00365521.2019.1611917","article-title":"Efficacy and safety of curcumin in primary sclerosing cholangitis: An open label pilot study","volume":"54","author":"Eaton","year":"2019","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/j.1365-2036.2011.04926.x","article-title":"The safety and efficacy of oral docosahexaenoic acid supplementation for the treatment of primary sclerosing cholangitis\u2014A pilot study","volume":"35","author":"Martin","year":"2012","journal-title":"Aliment. Pharm. Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.jhep.2017.06.024","article-title":"24-Norursodeoxycholic acid in patients with primary sclerosing cholangitis: A new \u201curso saga\u201d on the horizon?","volume":"67","author":"Chazouilleres","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.jhep.2018.12.006","article-title":"NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A nebulous matter","volume":"70","author":"Tabibian","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1002\/hep.28256","article-title":"Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process","volume":"63","author":"Ponsioen","year":"2016","journal-title":"Hepatology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1194\/jlr.M005546","article-title":"Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR\/RXR-dependent and independent mechanisms","volume":"51","author":"Cai","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.clinre.2018.06.009","article-title":"Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French-Spanish experience","volume":"42","author":"Lemoinne","year":"2018","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"S428","DOI":"10.1016\/S0168-8278(16)00694-2","article-title":"Serum lysyl oxidase-like-2 (SLOXL2) levels correlate with disease severity in patients with primary sclerosing cholangitis","volume":"64","author":"Muir","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1136\/gutjnl-2016-312473","article-title":"Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal","volume":"66","author":"Ikenaga","year":"2017","journal-title":"Gut"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/nm.2208","article-title":"Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment","volume":"16","author":"Spangler","year":"2010","journal-title":"Nat. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1016\/j.jhep.2017.07.022","article-title":"Primary sclerosing cholangitis\u2014A comprehensive review","volume":"67","author":"Karlsen","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1172\/JCI73722","article-title":"Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis","volume":"125","author":"Weston","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e015081","DOI":"10.1136\/bmjopen-2016-015081","article-title":"Investigating the safety and activity of the use of BTT1023 (Timolumab), in the treatment of patients with primary sclerosing cholangitis (BUTEO): A single-arm, two-stage, open-label, multi-centre, phase II clinical trial protocol","volume":"7","author":"Arndtz","year":"2017","journal-title":"BMJ Open"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1002\/hep4.1619","article-title":"Efficacy and Safety of Cenicriviroc in Patients with Primary Sclerosing Cholangitis: PERSEUS Study","volume":"5","author":"Eksteen","year":"2021","journal-title":"Hepatol. Commun."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.jhep.2018.05.018","article-title":"Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice","volume":"69","author":"Guicciardi","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1016\/j.jhep.2017.05.007","article-title":"Targeting the gut-liver axis in liver disease","volume":"67","author":"Wiest","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1111\/apt.14525","article-title":"Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease","volume":"47","author":"Christensen","year":"2018","journal-title":"Aliment. Pharm. Ther."},{"key":"ref_102","first-page":"178","article-title":"The Intestinal Microbiome in Human Health and Disease","volume":"131","author":"Dupont","year":"2020","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1136\/gutjnl-2015-310500","article-title":"The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls","volume":"66","author":"Kummen","year":"2017","journal-title":"Gut"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1111\/1751-2980.12788","article-title":"Precision medicine in primary sclerosing cholangitis","volume":"20","author":"Maurice","year":"2019","journal-title":"J. Dig. Dis."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1111\/apt.12232","article-title":"Randomised clinical trial: Vancomycin or metronidazole in patients with primary sclerosing cholangitis\u2014A pilot study","volume":"37","author":"Tabibian","year":"2013","journal-title":"Aliment. Pharm. Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"457","DOI":"10.15403\/jgld.2014.1121.254.rah","article-title":"A Triple Blinded, Randomized, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Oral Vancomycin in Primary Sclerosing Cholangitis: A Pilot Study","volume":"25","author":"Rahimpour","year":"2016","journal-title":"J. Gastrointestin. Liver Dis."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/8\/1763\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:49:28Z","timestamp":1760161768000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/8\/1763"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,18]]},"references-count":106,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["jcm10081763"],"URL":"https:\/\/doi.org\/10.3390\/jcm10081763","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,18]]}}}