Emerging Targets for the Treatment of Primary Sclerosing Cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is a rare, progressive cholestatic disease of unknown etiology and characterized by inflammation and stricturing of intrahepatic and/or extrahepatic bile ducts. This process leads to bile duct scarring, progressive liver fibrosis, and end-stage liver disease. PSC is often associated with a specific form of inflammatory bowel disease and patients face a significant risk of developing cholangiocarcinoma and colorectal cancer. The clinical course of PSC can differ significantly between subtypes and affected individuals, representing a major obstacle to successful medical treatment trials. Numerous innovative therapeutic targets have been identified and, at least in part, explored, including nuclear and membrane receptors regulating bile acid metabolism and transport, modulation of gut microbiota, and signaling molecules involved in liver inflammation and fibrosis. Successful drug testing in preclinical PSC models as well as positive signals from some clinical studies justify hope. However, no medical treatment has so far been proven to improve transplant-free survival or overall survival in PSC patients. Disease-modifying drugs are urgently awaited. Despite ongoing efforts to improve study designs and implement treatment trials for novel drug targets, a central breakthrough has not yet been convincingly achieved. This situation might change in the near future. This article summarizes current research efforts aimed at developing medical treatments for PSC.

Keywords

primary sclerosing cholangitis - treatment - NCA - UDCA - FXR

Publikationsverlauf

Artikel online veröffentlicht:
26. Mai 2025

• References

• 1 Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis - a comprehensive review. J Hepatol 2017; 67 (06) 1298-1323
• 2 Loftus Jr EV, Harewood GC, Loftus CG. et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005; 54 (01) 91-96
• 3 Boonstra K, Weersma RK, van Erpecum KJ. et al; EpiPSCPBC Study Group. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 2013; 58 (06) 2045-2055
• 4 Goldstein J, Levy C. Novel and emerging therapies for cholestatic liver diseases. Liver Int 2018; 38 (09) 1520-1535
• 5 Lazaridis KN, LaRusso NF. Primary sclerosing cholangitis. N Engl J Med 2016; 375 (12) 1161-1170
• 6 Trivedi PJ, Bowlus CL, Yimam KK, Razavi H, Estes C. Epidemiology, natural history, and outcomes of primary sclerosing cholangitis: a systematic review of population-based studies. Clin Gastroenterol Hepatol 2022; 20 (08) 1687-1700.e4
• 7 Carbone M, Kodra Y, Rocchetti A. et al. Primary sclerosing cholangitis: burden of disease and mortality using data from the national rare diseases registry in Italy. Int J Environ Res Public Health 2020; 17 (09) 3095
• 8 Barner-Rasmussen N, Pukkala E, Jussila A, Färkkilä M. Epidemiology, risk of malignancy and patient survival in primary sclerosing cholangitis: a population-based study in Finland. Scand J Gastroenterol 2020; 55 (01) 74-81
• 9 Trivedi PJ, Hirschfield GM. Recent advances in clinical practice: epidemiology of autoimmune liver diseases. Gut 2021; 70 (10) 1989-2003
• 10 Crothers H, Ferguson J, Quraishi MN, Cooney R, Iqbal TH, Trivedi PJ. Past, current, and future trends in the prevalence of primary sclerosing cholangitis and inflammatory bowel disease across England (2015-2027): a nationwide, population-based study. Lancet Reg Health Eur 2024; 44: 101002
• 11 Gacesa R, Kurilshikov A, Vich Vila A. et al. Environmental factors shaping the gut microbiome in a Dutch population. Nature 2022; 604 (7907) 732-739
• 12 Weismüller TJ, Trivedi PJ, Bergquist A. et al; International PSC Study Group. Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis. Gastroenterology 2017; 152 (08) 1975-1984.e8
• 13 Halliday JS, Djordjevic J, Lust M. et al. A unique clinical phenotype of primary sclerosing cholangitis associated with Crohn's disease. J Crohns Colitis 2012; 6 (02) 174-181
• 14 Mouchli MA, Singh S, Boardman L. et al. Natural history of established and de novo inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis. Inflamm Bowel Dis 2018; 24 (05) 1074-1081
• 15 Nordenvall C, Olén O, Nilsson PJ. et al. Colectomy prior to diagnosis of primary sclerosing cholangitis is associated with improved prognosis in a nationwide cohort study of 2594 PSC-IBD patients. Aliment Pharmacol Ther 2018; 47 (02) 238-245
• 16 Hartl J, Buck L, Löwe B, Toussaint A, Schramm C. Fatigue is a symptom of clinical importance in patients with primary sclerosing cholangitis (SOMA.LIV). J Hepatol 2025; 82 (01) e44-e45
• 17 Guerra I, Bujanda L, Castro J. et al; Spanish GETECCU group (ENEIDA Project). Clinical characteristics, associated malignancies and management of primary sclerosing cholangitis in inflammatory bowel disease patients: a multicentre retrospective cohort study. J Crohns Colitis 2019; 13 (12) 1492-1500
• 18 Kaplan GG, Laupland KB, Butzner D, Urbanski SJ, Lee SS. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol 2007; 102 (05) 1042-1049
• 19 Björnsson E, Lindqvist-Ottosson J, Asztely M, Olsson R. Dominant strictures in patients with primary sclerosing cholangitis. Am J Gastroenterol 2004; 99 (03) 502-508
• 20 Gotthardt DN, Rudolph G, Klöters-Plachky P, Kulaksiz H, Stiehl A. Endoscopic dilation of dominant stenoses in primary sclerosing cholangitis: outcome after long-term treatment. Gastrointest Endosc 2010; 71 (03) 527-534
• 21 Pohl J, Ring A, Stremmel W, Stiehl A. The role of dominant stenoses in bacterial infections of bile ducts in primary sclerosing cholangitis. Eur J Gastroenterol Hepatol 2006; 18 (01) 69-74
• 22 Ranieri V, Kennedy E, Walmsley M, Thorburn D, McKay K. The primary sclerosing cholangitis (PSC) wellbeing study: understanding psychological distress in those living with PSC and those who support them. PLoS One 2020; 15 (07) e0234624
• 23 Bakhshi Z, Hilscher MB, Gores GJ. et al. An update on primary sclerosing cholangitis epidemiology, outcomes and quantification of alkaline phosphatase variability in a population-based cohort. J Gastroenterol 2020; 55 (05) 523-532
• 24 Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 2013; 145 (03) 521-536
• 25 Miard C, Desfourneaux V, Dewitte M. et al. P217 usefulness of systematic liver biopsy during a surgery for inflammatory bowel disease for the diagnosis of primary sclerosing cholangitis. J Crohns Colitis 2018; 12 (Suppl. 01) S209-S10
• 26 Belle A, Laurent V, Pouillon L. et al. Systematic screening for primary sclerosing cholangitis with magnetic resonance cholangiography in inflammatory bowel disease. Dig Liver Dis 2018; 50 (10) 1012-1018
• 27 Stanich PP, Björnsson E, Gossard AA, Enders F, Jorgensen R, Lindor KD. Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. Dig Liver Dis 2011; 43 (04) 309-313
• 28 Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet 2018; 391 (10139): 2547-2559
• 29 Poetter-Lang S, Ba-Ssalamah A, Messner A. et al. Disease severity prognostication in primary sclerosing cholangitis: a validation of the Anali scores and comparison with the potential functional stricture. Eur Radiol 2024; 34 (12) 7632-7644
• 30 Selvaraj EA, Ba-Ssalamah A, Poetter-Lang S. et al. A Quantitative magnetic resonance cholangiopancreatography metric of intrahepatic biliary dilatation severity detects high-risk primary sclerosing cholangitis. Hepatol Commun 2022; 6 (04) 795-808
• 31 Poetter-Lang S, Messner A, Bastati N. et al. Diagnosis of functional strictures in patients with primary sclerosing cholangitis using hepatobiliary contrast-enhanced MRI: a proof-of-concept study. Eur Radiol 2023; 33 (12) 9022-9037
• 32 van Munster KN, Bergquist A, Ponsioen CY. Inflammatory bowel disease and primary sclerosing cholangitis: one disease or two?. J Hepatol 2024; 80 (01) 155-168
• 33 Fuentes S, Rossen NG, van der Spek MJ. et al. Microbial shifts and signatures of long-term remission in ulcerative colitis after faecal microbiota transplantation. ISME J 2017; 11 (08) 1877-1889
• 34 Dorner H, Stolzer I, Mattner J. et al. Gut pathobiont-derived outer membrane vesicles drive liver inflammation and fibrosis in primary sclerosing cholangitis-associated inflammatory bowel disease. Gastroenterology 2024; 167 (06) 1183-1197.e16
• 35 Fickert P, Lin AC, Ritschl H, Hammer N, Denk H. Portal venous branches as an anatomic railroad for a gut-bile duct-axis. J Hepatol 2023; 79 (02) e82-e84
• 36 Graham JJ, Mukherjee S, Yuksel M. et al. Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis. Hepatology 2022; 75 (03) 518-530
• 37 Hohenester S, Wenniger LM, Paulusma CC. et al. A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology 2012; 55 (01) 173-183
• 38 Gauss A, Ehehalt R, Lehmann WD. et al. Biliary phosphatidylcholine and lysophosphatidylcholine profiles in sclerosing cholangitis. World J Gastroenterol 2013; 19 (33) 5454-5463
• 39 Pollheimer MJ, Fickert P. Animal models in primary biliary cirrhosis and primary sclerosing cholangitis. Clin Rev Allergy Immunol 2015; 48 (2-3): 207-217
• 40 Ji SG, Juran BD, Mucha S. et al; UK-PSC Consortium, International IBD Genetics Consortium, International PSC Study Group. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet 2017; 49 (02) 269-273
• 41 Karlsen TH, Franke A, Melum E. et al. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology 2010; 138 (03) 1102-1111
• 42 Melum E, Franke A, Schramm C. et al. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat Genet 2011; 43 (01) 17-19
• 43 Ellinghaus D, Folseraas T, Holm K. et al. Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology 2013; 58 (03) 1074-1083
• 44 Srivastava B, Mells GF, Cordell HJ. et al; UK-PSC Consortium. Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis. Scand J Gastroenterol 2012; 47 (07) 820-826
• 45 Folseraas T, Melum E, Rausch P. et al. Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. J Hepatol 2012; 57 (02) 366-375
• 46 Hang S, Paik D, Yao L. et al. Bile acid metabolites control T_H17 and T_reg cell differentiation. Nature 2019; 576 (7785) 143-148
• 47 Trottier J, Białek A, Caron P. et al. Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: a pilot study. Dig Liver Dis 2012; 44 (04) 303-310
• 48 Chung BK, Karlsen TH, Folseraas T. Cholangiocytes in the pathogenesis of primary sclerosing cholangitis and development of cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4 Pt B): 1390-1400
• 49 Wu S, Cao Y, Lu H. et al. Aberrant peribiliary gland niche exacerbates fibrosis in primary sclerosing cholangitis and a potential therapeutic strategy. Biomed Pharmacother 2022; 153: 113512
• 50 Jalan-Sakrikar N, Guicciardi ME, O'Hara SP. et al. Central role for cholangiocyte pathobiology in cholestatic liver diseases. Hepatology 2024
• 51 De Muynck K, Vanderborght B, De Ponti FF. et al. Kupffer cells contested as early drivers in the pathogenesis of primary sclerosing cholangitis. Am J Pathol 2023; 193 (04) 366-379
• 52 Peng ZW, Ikenaga N, Liu SB. et al. Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis. Hepatology 2016; 63 (01) 217-232
• 53 Greenman R, Segal-Salto M, Barashi N. et al. CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis. JCI Insight 2023; 8 (12) e162270
• 54 Segal-Salto M, Barashi N, Katav A. et al. A blocking monoclonal antibody to CCL24 alleviates liver fibrosis and inflammation in experimental models of liver damage. JHEP Rep Innov Hepatol 2020; 2 (01) 100064
• 55 Jiang X, Karlsen TH. Genetics of primary sclerosing cholangitis and pathophysiological implications. Nat Rev Gastroenterol Hepatol 2017; 14 (05) 279-295
• 56 Tischendorf JJ, Hecker H, Krüger M, Manns MP, Meier PN. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol 2007; 102 (01) 107-114
• 57 Campsen J, Zimmerman MA, Trotter JF. et al. Clinically recurrent primary sclerosing cholangitis following liver transplantation: a time course. Liver Transpl 2008; 14 (02) 181-185
• 58 Graziadei IW, Wiesner RH, Batts KP. et al. Recurrence of primary sclerosing cholangitis following liver transplantation. Hepatology 1999; 29 (04) 1050-1056
• 59 Graziadei IW, Wiesner RH, Marotta PJ. et al. Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis. Hepatology 1999; 30 (05) 1121-1127
• 60 Harputluoglu M, Calgin MZ, Ataman E. et al. Outcomes of patients with primary sclerosing cholangitis after liver transplantation in a predominantly living donor liver transplant center. J Liver Transpl 2023; 12: 100186
• 61 Ponsioen CY. Endpoints in the design of clinical trials for primary sclerosing cholangitis. Biochim Biophys Acta Mol Basis Dis 2018; 1864 (4 Pt B): 1410-1414
• 62 Kuo A, Gomel R, Safer R, Lindor KD, Everson GT, Bowlus CL. Characteristics and outcomes reported by patients with primary sclerosing cholangitis through an online registry. Clin Gastroenterol Hepatol 2019; 17 (07) 1372-1378
• 63 Eliasson J, Lo B, Schramm C. et al. Survey uncovering variations in the management of primary sclerosing cholangitis across Europe. JHEP Rep Innov Hepatol 2022; 4 (11) 100553
• 64 Beuers U, Spengler U, Kruis W. et al. Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial. Hepatology 1992; 16 (03) 707-714
• 65 Lindor KD. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. Ursodiol for primary sclerosing cholangitis. N Engl J Med 1997; 336 (10) 691-695
• 66 Stiehl A, Walker S, Stiehl L, Rudolph G, Hofmann WJ, Theilmann L. Effect of ursodeoxycholic acid on liver and bile duct disease in primary sclerosing cholangitis. A 3-year pilot study with a placebo-controlled study period. J Hepatol 1994; 20 (01) 57-64
• 67 Olsson R, Boberg KM, de Muckadell OS. et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology 2005; 129 (05) 1464-1472
• 68 Lindor KD, Kowdley KV, Luketic VA. et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009; 50 (03) 808-814
• 69 Wunsch E, Trottier J, Milkiewicz M. et al. Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis. Hepatology 2014; 60 (03) 931-940
• 70 Lindström L, Hultcrantz R, Boberg KM, Friis-Liby I, Bergquist A. Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2013; 11 (07) 841-846
• 71 Arizumi T, Tazuma S, Isayama H. et al; Japan PSC Study Group (JPSCSG). Ursodeoxycholic acid is associated with improved long-term outcome in patients with primary sclerosing cholangitis. J Gastroenterol 2022; 57 (11) 902-912
• 72 Bowlus CL, Arrivé L, Bergquist A. et al. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77 (02) 659-702
• 73 European Association for the Study of the Liver. EASL clinical practice guidelines on sclerosing cholangitis. J Hepatol 2022; 77 (03) 761-806
• 74 Fickert P, Fuchsbichler A, Wagner M. et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2004; 127 (01) 261-274
• 75 Fickert P, Zollner G, Fuchsbichler A. et al. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 2002; 123 (04) 1238-1251
• 76 Wang Y, Zhao D, Su L. et al. Therapeutic potential of berberine in attenuating cholestatic liver injury: insights from a PSC mouse model. Cell Biosci 2024; 14 (01) 14
• 77 Nakamoto N, Sasaki N, Aoki R. et al. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat Microbiol 2019; 4 (03) 492-503
• 78 Yoshida EM. Berberine ursodeoxycholate for the treatment of primary sclerosing cholangitis: the search for the elusive pharmacologic Holy Grail will need to continue. Am J Gastroenterol 2022; 117 (11) 1762-1763
• 79 Kowdley KV, Forman L, Eksteen B. et al. A randomized, dose-finding, proof-of-concept study of berberine ursodeoxycholate in patients with primary sclerosing cholangitis. Am J Gastroenterol 2022; 117 (11) 1805-1815
• 80 Hofmann AF, Zakko SF, Lira M. et al. Novel biotransformation and physiological properties of norursodeoxycholic acid in humans. Hepatology 2005; 42 (06) 1391-1398
• 81 Fickert P, Wagner M, Marschall HU. et al. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2006; 130 (02) 465-481
• 82 Halilbasic E, Fiorotto R, Fickert P. et al. Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2−/− mice. Hepatology 2009; 49 (06) 1972-1981
• 83 Fickert P, Pollheimer MJ, Silbert D. et al. Differential effects of norUDCA and UDCA in obstructive cholestasis in mice. J Hepatol 2013; 58 (06) 1201-1208
• 84 Sombetzki M, Fuchs CD, Fickert P. et al. 24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis. J Hepatol 2015; 62 (04) 871-878
• 85 Krones E, Eller K, Pollheimer MJ. et al. NorUrsodeoxycholic acid ameliorates cholemic nephropathy in bile duct ligated mice. J Hepatol 2017; 67 (01) 110-119
• 86 Trauner M, Halilbasic E, Claudel T. et al. Potential of nor-ursodeoxycholic acid in cholestatic and metabolic disorders. Dig Dis 2015; 33 (03) 433-439
• 87 Fickert P, Hirschfield GM, Denk G. et al; European PSC norUDCA Study Group. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol 2017; 67 (03) 549-558
• 88 Al-Khaifi A, Rudling M, Angelin B. An FXR agonist reduces bile acid synthesis independently of increases in FGF19 in healthy volunteers. Gastroenterology 2018; 155 (04) 1012-1016
• 89 Zhang JH, Nolan JD, Kennie SL. et al. Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids. Am J Physiol Gastrointest Liver Physiol 2013; 304 (10) G940-G948
• 90 Verbeke L, Mannaerts I, Schierwagen R. et al. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep 2016; 6: 33453
• 91 Verbeke L, Farre R, Trebicka J. et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014; 59 (06) 2286-2298
• 92 Verbeke L, Farre R, Verbinnen B. et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol 2015; 185 (02) 409-419
• 93 Úbeda M, Lario M, Muñoz L. et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J Hepatol 2016; 64 (05) 1049-1057
• 94 Verbeke L, Nevens F, Laleman W. Steroidal or non-steroidal FXR agonists - is that the question?. J Hepatol 2017; 66 (04) 680-681
• 95 Nevens F, Andreone P, Mazzella G. et al; POISE Study Group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016; 375 (07) 631-643
• 96 Kowdley KV, Hirschfield GM, Coombs C. et al. COBALT: a confirmatory trial of obeticholic acid in primary biliary cholangitis with placebo and external controls. Am J Gastroenterol 2024
• 97 Kowdley KVBC, Levy C. et al. The AESOP trial: a randomized, double-blind, placebo-controlled, phase 2 study of obeticholic acid in patients with primary sclerosing cholangitis. Hepatology 2017; 66 (06) 1254A-1255A
• 98 John BV, Schwartz K, Levy C. et al. Impact of obeticholic acid exposure on decompensation and mortality in primary biliary cholangitis and cirrhosis. Hepatol Commun 2021; 5 (08) 1426-1436
• 99 Levy C. Evolving role of obeticholic acid in primary biliary cholangitis. Hepatology 2018; 67 (05) 1666-1668
• 100 Gege C, Kinzel O, Steeneck C, Schulz A, Kremoser C. Knocking on FXR's door: the “hammerhead”-structure series of FXR agonists - amphiphilic isoxazoles with potent in vitro and in vivo activities. Curr Top Med Chem 2014; 14 (19) 2143-2158
• 101 Fuchs CD, Sroda N, Scharnagl H. et al. Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2^{− /−} mouse model of sclerosing cholangitis. JHEP Rep Innov Hepatol 2023; 5 (11) 100874
• 102 Trauner M, Gulamhusein A, Hameed B. et al. The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis. Hepatology 2019; 70 (03) 788-801
• 103 Trauner M, Chung C, Sterling K. et al. PRIMIS: design of a pivotal, randomized, phase 3 study evaluating the safety and efficacy of the nonsteroidal farnesoid X receptor agonist cilofexor in noncirrhotic patients with primary sclerosing cholangitis. BMC Gastroenterol 2023; 23 (01) 75
• 104 Sanyal AJ, Lopez P, Lawitz EJ. et al. Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial. Nat Med 2023; 29 (02) 392-400
• 105 Schramm C, Wedemeyer H, Mason A. et al. Farnesoid X receptor agonist tropifexor attenuates cholestasis in a randomised trial in patients with primary biliary cholangitis. JHEP Rep Innov Hepatol 2022; 4 (11) 100544
• 106 Zhao H, Lv F, Liang G. et al. FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β- catenin signaling cascade via FGFR4 activation. Oncotarget 2016; 7 (12) 13575-13586
• 107 Tan Q, Li F, Wang G. et al. Identification of FGF19 as a prognostic marker and potential driver gene of lung squamous cell carcinomas in Chinese smoking patients. Oncotarget 2016; 7 (14) 18394-18402
• 108 Yoo C, Kang J, Kim D. et al. Multiplexed gene expression profiling identifies the FGFR4 pathway as a novel biomarker in intrahepatic cholangiocarcinoma. Oncotarget 2017; 8 (24) 38592-38601
• 109 Li Y, Zhang W, Doughtie A. et al. Up-regulation of fibroblast growth factor 19 and its receptor associates with progression from fatty liver to hepatocellular carcinoma. Oncotarget 2016; 7 (32) 52329-52339
• 110 Cheng K, Metry M, Felton J. et al. Diminished gallbladder filling, increased fecal bile acids, and promotion of colon epithelial cell proliferation and neoplasia in fibroblast growth factor 15-deficient mice. Oncotarget 2018; 9 (39) 25572-25585
• 111 Chen Z, Jiang L, Liang L. et al. The role of fibroblast growth factor 19 in hepatocellular carcinoma. Am J Pathol 2021; 191 (07) 1180-1192
• 112 Hirschfield GM, Chazouillères O, Drenth JP. et al. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J Hepatol 2019; 70 (03) 483-493
• 113 Cai SY, He H, Nguyen T, Mennone A, Boyer JL. Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-dependent and independent mechanisms. J Lipid Res 2010; 51 (08) 2265-2274
• 114 Cai SY, Mennone A, Soroka CJ, Boyer JL. All-trans-retinoic acid improves cholestasis in α-naphthylisothiocyanate-treated rats and Mdr2-/- mice. J Pharmacol Exp Ther 2014; 349 (01) 94-98
• 115 Assis DN, Abdelghany O, Cai SY. et al. Combination therapy of all-trans retinoic acid with ursodeoxycholic acid in patients with primary sclerosing cholangitis: a human pilot study. J Clin Gastroenterol 2017; 51 (02) e11-e16
• 116 Honda A, Ikegami T, Nakamuta M. et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology 2013; 57 (05) 1931-1941
• 117 Corpechot C, Chazouillères O, Rousseau A. et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med 2018; 378 (23) 2171-2181
• 118 European Association for the Study of the Liver. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017; 67 (01) 145-172
• 119 Kowdley KV, Bowlus CL, Levy C. et al; ELATIVE Study Investigators' Group, ELATIVE Study Investigators' Group. Efficacy and safety of elafibranor in primary biliary cholangitis. N Engl J Med 2024; 390 (09) 795-805
• 120 Jones D, Boudes PF, Swain MG. et al. Seladelpar (MBX-8025), a selective PPAR-δ 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. Lancet Gastroenterol Hepatol 2017; 2 (10) 716-726
• 121 Hirschfield GM, Bowlus CL, Mayo MJ. et al; RESPONSE Study Group. A phase 3 trial of seladelpar in primary biliary cholangitis. N Engl J Med 2024; 390 (09) 783-794
• 122 Lemoinne S, Pares A, Reig A. et al. Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French-Spanish experience. Clin Res Hepatol Gastroenterol 2018; 42 (06) 521-528
• 123 Mizuno S, Hirano K, Isayama H. et al. Prospective study of bezafibrate for the treatment of primary sclerosing cholangitis. J Hepatobiliary Pancreat Sci 2015; 22 (10) 766-770
• 124 Mizuno S, Hirano K, Tada M. et al. Bezafibrate for the treatment of primary sclerosing cholangitis. J Gastroenterol 2010; 45 (07) 758-762
• 125 Blair HA. Elafibranor: first approval. Drugs 2024; 84 (09) 1143-1148
• 126 Kim RG, Loomba R, Prokop LJ, Singh S. Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2017; 15 (10) 1521-1530.e8
• 127 Stokkeland K, Höijer J, Bottai M, Söderberg-Löfdal K, Bergquist A. Statin use is associated with improved outcomes of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2019; 17 (09) 1860-1866.e1
• 128 Bergquist AMH, Nilsson E. et al. Long term effect of simvastatin in primary sclerosing cholangitits: a placebo-controlled, double-blind, multicenter phase III study (Piscatin). Br J Gastroenterol 2022; 4 (01) 235-241
• 129 Al-Dury S, Marschall HU. Ileal bile acid transporter inhibition for the treatment of chronic constipation, cholestatic pruritus, and NASH. Front Pharmacol 2018; 9: 931
• 130 Bowlus CL, Eksteen B, Cheung AC. et al. Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: open-label pilot study. Hepatol Commun 2023; 7 (06) e0153
• 131 Gonzales E, Hardikar W, Stormon M. et al. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study. Lancet 2021; 398 (10311): 1581-1592
• 132 Thompson RJ, Arnell H, Artan R. et al. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2022; 7 (09) 830-842
• 133 Grant AJ, Lalor PF, Salmi M, Jalkanen S, Adams DH. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet 2002; 359 (9301) 150-157
• 134 Eksteen B, Miles AE, Grant AJ, Adams DH. Lymphocyte homing in the pathogenesis of extra-intestinal manifestations of inflammatory bowel disease. Clin Med (Lond) 2004; 4 (02) 173-180
• 135 Mousavere I, Kalampokis G, Fousekis F, Karayiannis P, Baltayiannis G, Christodoulou D. An overview of recent treatment options for primary sclerosing cholangitis. Ann Gastroenterol 2023; 36 (06) 589-598
• 136 Arndtz K, Corrigan M, Rowe A. et al; BUTEO trial team. 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. BMJ Open 2017; 7 (06) e015081
• 137 Trivedi PJ, Tickle J, Vesterhus MN. et al. Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner. Gut 2018; 67 (06) 1135-1145
• 138 Weston CJ, Shepherd EL, Claridge LC. et al. Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J Clin Invest 2015; 125 (02) 501-520
• 139 Lefebvre E, Moyle G, Reshef R. et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One 2016; 11 (06) e0158156
• 140 Mossanen JC, Krenkel O, Ergen C. et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology 2016; 64 (05) 1667-1682
• 141 Puengel T, Krenkel O, Kohlhepp M. et al. Differential impact of the dual CCR2/CCR5 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury. PLoS One 2017; 12 (09) e0184694
• 142 Krenkel O, Puengel T, Govaere O. et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology 2018; 67 (04) 1270-1283
• 143 Eksteen B, Bowlus CL, Montano-Loza AJ. et al. Efficacy and safety of cenicriviroc in patients with primary sclerosing cholangitis: PERSEUS study. Hepatol Commun 2020; 5 (03) 478-490
• 144 Feagan BG, Rutgeerts P, Sands BE. et al; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369 (08) 699-710
• 145 Sandborn WJ, Feagan BG, Rutgeerts P. et al; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2013; 369 (08) 711-721
• 146 Grant AJ, Lalor PF, Hübscher SG, Briskin M, Adams DH. MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology 2001; 33 (05) 1065-1072
• 147 Ala A, Brown D, Khan K. et al. Mucosal addressin cell adhesion molecule (MAdCAM-1) expression is upregulated in the cirrhotic liver and immunolocalises to the peribiliary plexus and lymphoid aggregates. Dig Dis Sci 2013; 58 (09) 2528-2541
• 148 Westerveld D, Grajo J, Beattie L, Glover S. Vedolizumab: a novel medical intervention in the treatment of primary sclerosing cholangitis. BMJ Case Rep 2017; 2017: bcr2017220351
• 149 Coletta M, Paroni M, Caprioli F. Successful treatment with vedolizumab in a patient with chronic refractory pouchitis and primary sclerosing cholangitis. J Crohns Colitis 2017; 11 (12) 1507-1508
• 150 Christensen B, Micic D, Gibson PR. et al. 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. Aliment Pharmacol Ther 2018; 47 (06) 753-762
• 151 Fox RJ, Wiendl H, Wolf C. et al. A double-blind, randomized, placebo-controlled phase 2 trial evaluating the selective dihydroorotate dehydrogenase inhibitor vidofludimus calcium in relapsing-remitting multiple sclerosis. Ann Clin Transl Neurol 2022; 9 (07) 977-987
• 152 Herrlinger KR, Diculescu M, Fellermann K. et al. Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study. J Crohns Colitis 2013; 7 (08) 636-643
• 153 Muehler A, Kohlhof H, Groeppel M, Vitt D. The selective oral immunomodulator vidofludimus in patients with active rheumatoid arthritis: safety results from the COMPONENT study. Drugs R D 2019; 19 (04) 351-366
• 154 Carey EJ, Eaton J, Clayton M. et al. A pilot study of vidofludimus calcium for treatment of primary sclerosing cholangitis. Hepatol Commun 2022; 6 (07) 1589-1597
• 155 Paik WH, Park JK, Chung MJ. et al. Safety and efficacy of HK-660S in patients with primary sclerosing cholangitis: a randomized double-blind phase 2a trial. Clin Mol Hepatol 2024
• 156 Al-Shakhshir SM, Sean M, Schregel I, Schramm C. ed. An evaluation of anti-IL23 therapy in primary sclerosing cholangitis. AASLD The Liver Meeting: 2024 ; San Diego, CA.
• 157 Garcia Moreno AS, Guicciardi ME, Wixom AQ. et al. IL-17 signaling in primary sclerosing cholangitis patient-derived organoids. Hepatol Commun 2024; 8 (06) e0454
• 158 Garcia Moreno AS, Guicciardi ME, Wixom AQ. et al. IL-17 signaling in primary sclerosing cholangitis patient-derived organoids. Res Sq. 2023. :rs.3.rs-3406046.
• 159 Gordon KB, Blauvelt A, Papp KA. et al; UNCOVER-1 Study Group, UNCOVER-2 Study Group, UNCOVER-3 Study Group. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med 2016; 375 (04) 345-356
• 160 Baeten D, Sieper J, Braun J. et al; MEASURE 1 Study Group, MEASURE 2 Study Group. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med 2015; 373 (26) 2534-2548
• 161 Elzubeir A, High J, Hammond M. et al. Assessing brodalumab in the treatment of primary sclerosing cholangitis (SABR-PSC pilot study): protocol for a single-arm, multicentre, pilot study. BMJ Open Gastroenterol 2025; 12 (01) e001596
• 162 Caron B, Jouzeau JY, Miossec P. et al. Gastroenterological safety of IL-17 inhibitors: a systematic literature review. Expert Opin Drug Saf 2022; 21 (02) 223-239
• 163 Burisch J, Eigner W, Schreiber S. et al. Risk for development of inflammatory bowel disease under inhibition of interleukin 17: a systematic review and meta-analysis. PLoS One 2020; 15 (05) e0233781
• 164 Hueber W, Sands BE, Lewitzky S. et al; Secukinumab in Crohn's Disease Study Group. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 2012; 61 (12) 1693-1700
• 165 Targan SR, Feagan B, Vermeire S. et al. A randomized, double-blind, placebo-controlled phase 2 study of brodalumab in patients with moderate-to-severe Crohn's disease. Am J Gastroenterol 2016; 111 (11) 1599-1607
• 166 Deng Z, Wang S, Wu C, Wang C. IL-17 inhibitor-associated inflammatory bowel disease: a study based on literature and database analysis. Front Pharmacol 2023; 14: 1124628
• 167 Lancaster L, Cottin V, Ramaswamy M. et al; PLN-74809-IPF-202 Trial Investigators. Bexotegrast in patients with idiopathic pulmonary fibrosis: the INTEGRIS-IPF clinical trial. Am J Respir Crit Care Med 2024; 210 (04) 424-434
• 168 Decaris ML, Schaub JR, Chen C. et al. Dual inhibition of α_vβ₆ and α_vβ₁ reduces fibrogenesis in lung tissue explants from patients with IPF. Respir Res 2021; 22 (01) 265
• 169 Trauner M, Kowdley KV, Hirschfield GM. et al. LBP-039 Oral alpha-v/beta-6 and alpha-v/beta-1 integrin inhibitor bexotegrast in primary sclerosing cholangitis: updated 12-week interim safety and efficacy analysis of the INTEGRIS-PSC phase 2a trial. J Hepatol 2024; 80: S97-S8
• 170 Kowdley KV. ed. Bexotegrast, an oral inhibitor of αvβ6 and αvβ1 integrins, was shown to improve markers and symptoms of cholestasis and stabilized markers of liver fibrosis in participants with primary sclerosing cholangitis: Week 24 results from the Phase 2 INTEGRIS-PSC trial. The Liver Meeting 2024; San Diego, CA. Late Breaking Abstract Supplement 2024.
• 171 Snir T, Greenman R, Aricha R. et al. Machine learning identifies key proteins in primary sclerosing cholangitis progression and links high CCL24 to cirrhosis. Int J Mol Sci 2024; 25 (11) 6042
• 172 Bowlus C. ed. CM-101 improved fibrosis biomarkers in patients with primary sclerosing cholangitis: The SPRING Study. The Liver Meeting 2024 ; November 15–19, 2023; San Diego, CA. Late Breaking Abstract Supplement
• 173 Lichtman SN, Keku J, Clark RL, Schwab JH, Sartor RB. Biliary tract disease in rats with experimental small bowel bacterial overgrowth. Hepatology 1991; 13 (04) 766-772
• 174 Lichtman SN, Keku J, Schwab JH, Sartor RB. Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology 1991; 100 (02) 513-519
• 175 Kummen M, Holm K, Anmarkrud JA. et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut 2017; 66 (04) 611-619
• 176 Hov JR, Karlsen TH. The microbiota and the gut-liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 2023; 20 (03) 135-154
• 177 Hole MJ, Jørgensen KK, Holm K. et al. A shared mucosal gut microbiota signature in primary sclerosing cholangitis before and after liver transplantation. Hepatology 2023; 77 (03) 715-728
• 178 Tabibian JH, Weeding E, Jorgensen RA. et al. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis - a pilot study. Aliment Pharmacol Ther 2013; 37 (06) 604-612
• 179 Ricciuto A, Liu K, El-Matary W. et al; Pediatric PSC Consortium. Oral vancomycin is associated with improved inflammatory bowel disease clinical outcomes in primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD): a matched analysis from the Paediatric PSC Consortium. Aliment Pharmacol Ther 2024; 59 (10) 1236-1247
• 180 Tabibian JH, Gossard A, El-Youssef M. et al. Prospective clinical trial of rifaximin therapy for patients with primary sclerosing cholangitis. Am J Ther 2017; 24 (01) e56-e63
• 181 Turner AM, Li L, Monk IR. et al. Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin. Nature 2024; 635 (8040) 969-977
• 182 Silveira MG, Torok NJ, Gossard AA. et al. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am J Gastroenterol 2009; 104 (01) 83-88
• 183 van Prehn J, Reigadas E, Vogelzang EH. et al; Guideline Committee of the European Study Group on Clostridioides difficile . European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin Microbiol Infect 2021; 27 (Suppl. 02) S1-S21
• 184 Allegretti JR, Kassam Z, Carrellas M. et al. Fecal microbiota transplantation in patients with primary sclerosing cholangitis: a pilot clinical trial. Am J Gastroenterol 2019; 114 (07) 1071-1079
• 185 Al-Shakhshir S, Quraishi MN, Mullish B. et al. FAecal micRobiota transplantation in primary sclerosinG chOlangitis (FARGO): study protocol for a randomised, multicentre, phase IIa, placebo-controlled trial. BMJ Open 2025; 15 (01) e095392
• 186 Lima SF, Pires S, Rupert A. et al. The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis. Cell Rep Med 2024; 5 (03) 101431
• 187 Ichikawa M, Nakamoto N, Kredo-Russo S. et al. Bacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis. Nat Commun 2023; 14 (01) 3261
• 188 Vleggaar FP, Monkelbaan JF, van Erpecum KJ. Probiotics in primary sclerosing cholangitis: a randomized placebo-controlled crossover pilot study. Eur J Gastroenterol Hepatol 2008; 20 (07) 688-692
• 189 Eaton JE, Nelson KM, Gossard AA. et al. Efficacy and safety of curcumin in primary sclerosing cholangitis: an open label pilot study. Scand J Gastroenterol 2019; 54 (05) 633-639
• 190 Baghdasaryan A, Claudel T, Kosters A. et al. Curcumin improves sclerosing cholangitis in Mdr2−/− mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation. Gut 2010; 59 (04) 521-530
• 191 Choi J, Ghoz HM, Peeraphatdit T. et al. Aspirin use and the risk of cholangiocarcinoma. Hepatology 2016; 64 (03) 785-796
• 192 Lapumnuaypol K, Tiu A, Thongprayoon C. et al. Effects of aspirin and non-steroidal anti-inflammatory drugs on the risk of cholangiocarcinoma: a meta-analysis. QJM 2019; 112 (06) 421-427
• 193 Bosetti C, Santucci C, Gallus S, Martinetti M, La Vecchia C. Aspirin and the risk of colorectal and other digestive tract cancers: an updated meta-analysis through 2019. Ann Oncol 2020; 31 (05) 558-568
• 194 García Rodríguez LA, Soriano-Gabarró M, Bromley S, Lanas A, Cea Soriano L. New use of low-dose aspirin and risk of colorectal cancer by stage at diagnosis: a nested case-control study in UK general practice. BMC Cancer 2017; 17 (01) 637