Table Info

Table 2.

Summary table of ongoing clinical trials

Drugs	Trial type	Outcome	Comment
Bezafibrate	UDCA is combined with bezafibrate in 2 years phase III RCT (NCT01654731)	The POISE criteria were met in 31% of patients compared to 0% in the placebo group and 67% normalized their alkaline phosphatase at 24 months compared to 2% in the placebo group	Bezafibrate is widely used as second-line therapy in Japan and Europe
Rituximab	A phase II trial (NCT02376335)	Was ineffective for the treatment of fatigue	-
Elafibranor	A phase III trial (NCT04526665) ELATIVE trial	51% met the primary end-point vs. 4% in placebo. 15% normalized the alkaline phosphatase	Elafibrinor has now been FDA conditionally approved (IQIRVO^®)
Seladelpar	A phase III RCT of seladelpar in patients with inadequate response to UDCA or with UDCA intolerance (NCT04620733) RESPONSE trial	61.7% met the primary end-point compared to 20% in the placebo group while 25% normalized the alkaline phosphatase	Seladelpar has now been FDA conditionally approved (LIVDELZI^®)
Volixibat	The VANTAGE trial is assessing efficacy in PBC (NCT05050136)	Trial is on-going	This drug inhibits the uptake of bile acids in the terminal ileum (IBAT inhibitor)
Linerixibat	GSK2330672, 28 days phase 2a RCT & GLIMMER, 12 weeks phase 2b RCT (NCT02966834)	This is a novel inhibitor of the apical bile acid transporter with minimal systemic absorption. It has shown promising results in reducing pruritus.	-
Probiotics	A phase 2 trial for the combination of probiotics and UDCA in those with inadequate response to UDCA monotherapy (NCT03226067)	Trial is on-going	-

IBAT: intestinal bile acid transporter; UDCA: ursodeoxycholic acid; -: not applicable

Declarations

Author contributions

MBAE, IE, and AAAA: Investigation, Writing—original draft. JLB: Writing—review & editing.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Kim WR, Lindor KD, Locke GR 3rd, Therneau TM, Homburger HA, Batts KP, et al. Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology. 2000;119:1631–6. [DOI] [PubMed]

Sood S, Gow PJ, Christie JM, Angus PW. Epidemiology of primary biliary cirrhosis in Victoria, Australia: high prevalence in migrant populations. Gastroenterology. 2004;127:470–5. [DOI] [PubMed]

Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261–73. [DOI] [PubMed]

Lleo A, Battezzati PM, Selmi C, Gershwin ME, Podda M. Is autoimmunity a matter of sex? Autoimmun Rev. 2008;7:626–30. [DOI] [PubMed]

Trivedi PJ, Hirschfield GM. Recent advances in clinical practice: epidemiology of autoimmune liver diseases. Gut. 2021;70:1989–2003. [DOI] [PubMed]

Lleo A, Jepsen P, Morenghi E, Carbone M, Moroni L, Battezzati PM, et al. Evolving Trends in Female to Male Incidence and Male Mortality of Primary Biliary Cholangitis. Sci Rep. 2016;6:25906. [DOI] [PubMed] [PMC]

John BV, Aitcheson G, Schwartz KB, Khakoo NS, Dahman B, Deng Y, et al. Male Sex Is Associated With Higher Rates of Liver-Related Mortality in Primary Biliary Cholangitis and Cirrhosis. Hepatology. 2021;74:879–91. [DOI] [PubMed]

Trivella J, John BV, Levy C. Primary biliary cholangitis: Epidemiology, prognosis, and treatment. Hepatol Commun. 2023;7:e0179. [DOI] [PubMed] [PMC]

Shaker M, Mansour N, John BV. Primary Biliary Cholangitis in Males: Pathogenesis, Clinical Presentation, and Prognosis. Clin Liver Dis. 2022;26:643–55. [DOI] [PubMed]

10.

Myers RP, Shaheen AAM, Fong A, Burak KW, Wan A, Swain MG, et al. Epidemiology and natural history of primary biliary cirrhosis in a Canadian health region: a population-based study. Hepatology. 2009;50:1884–92. [DOI] [PubMed]

11.

James OF, Bhopal R, Howel D, Gray J, Burt AD, Metcalf JV. Primary biliary cirrhosis once rare, now common in the United Kingdom? Hepatology. 1999;30:390–4. [DOI] [PubMed]

12.

Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, et al.; USA PBC Epidemiology Group. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology. 2005;42:1194–202. [DOI] [PubMed] [PMC]

13.

Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52:745–58. [DOI] [PubMed]

14.

Tanaka A, Leung PS, Gershwin ME. Environmental basis of primary biliary cholangitis. Exp Biol Med (Maywood). 2018;243:184–9. [DOI] [PubMed] [PMC]

15.

Gulamhusein AF, Juran BD, Lazaridis KN. Genome-Wide Association Studies in Primary Biliary Cirrhosis. Semin Liver Dis. 2015;35:392–401. [DOI] [PubMed] [PMC]

16.

Floreani A, Leung PSC, Gershwin ME. Environmental Basis of Autoimmunity. Clin Rev Allergy Immunol. 2016;50:287–300. [DOI] [PubMed]

17.

Bogdanos DP, Baum H, Vergani D, Burroughs AK. The role of E. coli infection in the pathogenesis of primary biliary cirrhosis. Dis Markers. 2010;29:301–11. [DOI] [PubMed] [PMC]

18.

Juran BD, Lazaridis KN. Environmental factors in primary biliary cirrhosis. Semin Liver Dis. 2014;34:265–72. [DOI] [PubMed] [PMC]

19.

Beuers U, Hohenester S, De Buy Wenniger LJM, Kremer AE, Jansen PLM, Elferink RPJO. The biliary HCO₃^– umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology. 2010;52:1489–96. [DOI] [PubMed]

20.

Hohenester S, De Buy Wenniger LM, Paulusma CC, Van Vliet SJ, Jefferson DM, Elferink RPO, et al. A biliary HCO₃^– umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology. 2012;55:173–83. [DOI] [PubMed]

21.

Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Increased expression of mitochondrial proteins associated with autophagy in biliary epithelial lesions in primary biliary cirrhosis. Liver Int. 2013;33:312–20. [DOI] [PubMed]

22.

Prieto J, Qian C, García N, Díez J, Medina JF. Abnormal expression of anion exchanger genes in primary biliary cirrhosis. Gastroenterology. 1993;105:572–8. [DOI] [PubMed]

23.

Medina JF, Martínez-Ansó, Vazquez JJ, Prieto J. Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis. Hepatology. 1997;25:12–7. [DOI] [PubMed]

24.

Prieto J, García N, Martí-Climent JM, Peñuelas I, Richter JA, Medina JF. Assessment of biliary bicarbonate secretion in humans by positron emission tomography. Gastroenterology. 1999;117:167–72. [DOI] [PubMed]

25.

Banales JM, Sáez E, Uriz M, Sarvide S, Urribarri AD, Splinter P, et al. Up-regulation of microRNA 506 leads to decreased Cl^–/HCO₃^– anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis. Hepatology. 2012;56:687–97. [DOI] [PubMed] [PMC]

26.

Harada K, Furubo S, Ozaki S, Hiramatsu K, Sudo Y, Nakanuma Y. Increased expression of WAF1 in intrahepatic bile ducts in primary biliary cirrhosis relates to apoptosis. J Hepatol. 2001;34:500–6. [DOI] [PubMed]

27.

Zhao SX, Li WC, Fu N, Zhou GD, Liu SH, Jiang LN, et al. Emperipolesis mediated by CD8⁺ T cells correlates with biliary epithelia cell injury in primary biliary cholangitis. J Cell Mol Med. 2020;24:1268–75. [DOI] [PubMed] [PMC]

28.

Arsenijevic A, Stojanovic B, Milovanovic J, Arsenijevic D, Arsenijevic N, Milovanovic M. Galectin-3 in Inflammasome Activation and Primary Biliary Cholangitis Development. Int J Mol Sci. 2020;21:5097. [DOI] [PubMed] [PMC]

29.

Balasubramaniam K, Grambsch PM, Wiesner RH, Lindor KD, Dickson ER. Diminished survival in asymptomatic primary biliary cirrhosis. A prospective study. Gastroenterology. 1990;98:1567–71. [DOI] [PubMed]

30.

Tornay AS Jr. Primary biliary cirrhosis: natural history. Am J Gastroenterol. 1980;73:223–6. [PubMed]

31.

Prince MI, Chetwynd A, Craig WL, Metcalf JV, James OFW. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut. 2004;53:865–70. [DOI] [PubMed] [PMC]

32.

Selmi C, Gershwin ME, Lindor KD, Worman HJ, Gold EB, Watnik M, et al.; USA PBC Epidemiology Group. Quality of life and everyday activities in patients with primary biliary cirrhosis. Hepatology. 2007;46:1836–43. [DOI] [PubMed] [PMC]

33.

Newton JL, Gibson GJ, Tomlinson M, Wilton K, Jones D. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology. 2006;44:91–8. [DOI] [PubMed]

34.

Düll MM, Kremer AE. Evaluation and Management of Pruritus in Primary Biliary Cholangitis. Clin Liver Dis. 2022;26:727–45. [DOI] [PubMed]

35.

Laurin JM, DeSotel CK, Jorgensen RA, Dickson ER, Lindor KD. The natural history of abdominal pain associated with primary biliary cirrhosis. Am J Gastroenterol. 1994;89:1840–3. [PubMed]

36.

Koulentaki M, Ioannidou D, Stefanidou M, Maraki S, Drigiannakis I, Dimoulios P, et al. Dermatological manifestations in primary biliary cirrhosis patients: a case control study. Am J Gastroenterol. 2006;101:541–6. [DOI] [PubMed]

37.

Ahrens EH Jr, Payne MA, Kunkel HG, Eisenmenger WJ, Blonheim SH. Primary biliary cirrhosis. Medicine (Baltimore). 1950;29:299–364. [DOI] [PubMed]

38.

Mills PR, Skerrow CJ, MacKie RM. Melanin pigmentation of the skin in primary biliary cirrhosis. J Cutan Pathol. 1981;8:404–10. [DOI] [PubMed]

39.

Cavazza A, Caballería L, Floreani A, Farinati F, Bruguera M, Caroli D, et al. Incidence, risk factors, and survival of hepatocellular carcinoma in primary biliary cirrhosis: comparative analysis from two centers. Hepatology. 2009;50:1162–8. [DOI] [PubMed]

40.

Trivedi PJ, Lammers WJ, van Buuren HR, Parés A, Floreani A, Janssen HLA, et al.; Global PBC Study Group. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut. 2016;65:321–9. [DOI] [PubMed]

41.

Raszeja-Wyszomirska J, Miazgowski T. Osteoporosis in primary biliary cirrhosis of the liver. Prz Gastroenterol. 2014;9:82–7. [DOI] [PubMed] [PMC]

42.

Sorokin A, Brown JL, Thompson PD. Primary biliary cirrhosis, hyperlipidemia, and atherosclerotic risk: a systematic review. Atherosclerosis. 2007;194:293–9. [DOI] [PubMed]

43.

Solaymani-Dodaran M, Aithal GP, Card T, West J. Risk of cardiovascular and cerebrovascular events in primary biliary cirrhosis: a population-based cohort study. Am J Gastroenterol. 2008;103:2784–8. [DOI] [PubMed]

44.

Floreani A, Cazzagon N, Franceschet I, Canesso F, Salmaso L, Baldo V. Metabolic syndrome associated with primary biliary cirrhosis. J Clin Gastroenterol. 2015;49:57–60. [DOI] [PubMed]

45.

Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69:394–419. [DOI] [PubMed]

46.

Zein CO, Angulo P, Lindor KD. When is liver biopsy needed in the diagnosis of primary biliary cirrhosis? Clin Gastroenterol Hepatol. 2003;1:89–95. [DOI] [PubMed]

47.

Joshi S, Cauch-Dudek K, Heathcote EJ, Lindor K, Jorgensen R, Klein R. Antimitochondrial antibody profiles: are they valid prognostic indicators in primary biliary cirrhosis? Am J Gastroenterol. 2002;97:999–1002. [DOI] [PubMed]

48.

Mattalia A, Quaranta S, Leung PS, Bauducci M, Van de Water J, Calvo PL, et al. Characterization of antimitochondrial antibodies in health adults. Hepatology. 1998;27:656–61. [DOI] [PubMed]

49.

Shibata M, Onozuka Y, Morizane T, Koizumi H, Kawaguchi N, Miyakawa H, et al. Prevalence of antimitochondrial antibody in Japanese corporate workers in Kanagawa prefecture. J Gastroenterol. 2004;39:255–9. [DOI] [PubMed]

50.

Kaplowitz N, Finlayson ND, Walmsley P, Thurnherr N, Javitt NB. Hepatobiliary diseases associated with serum antimitochondrial antibody (AMA). Am J Med. 1973;54:725–30. [DOI] [PubMed]

51.

Ghielmetti M, Schaufelberger HD, Mieli-Vergani G, Cerny A, Dayer E, Vergani D, et al. Acute autoimmune-like hepatitis with atypical anti-mitochondrial antibody after mRNA COVID-19 vaccination: A novel clinical entity? J Autoimmun. 2021;123:102706. [DOI] [PubMed] [PMC]

52.

Mytilinaiou MG, Meyer W, Scheper T, Rigopoulou EI, Probst C, Koutsoumpas AL, et al. Diagnostic and clinical utility of antibodies against the nuclear body promyelocytic leukaemia and Sp100 antigens in patients with primary biliary cirrhosis. Clin Chim Acta. 2012;413:1211–6. [DOI] [PubMed]

53.

Haldar D, Janmohamed A, Plant T, Davidson M, Norman H, Russell E, et al. Antibodies to gp210 and understanding risk in patients with primary biliary cholangitis. Liver Int. 2021;41:535–44. [DOI] [PubMed]

54.

Wang X, Yang Z, Ran Y, Li L, Wang B, Zhou L. Anti-gp210-positive primary biliary cholangitis: The dilemma of clinical treatment and emerging mechanisms. Ann Hepatol. 2023;28:101121. [DOI] [PubMed]

55.

Gatselis NK, Zachou K, Norman GL, Gabeta S, Papamichalis P, Koukoulis GK, et al. Clinical significance of the fluctuation of primary biliary cirrhosis-related autoantibodies during the course of the disease. Autoimmunity. 2013;46:471–9. [DOI] [PubMed]

56.

Tana MM, Shums Z, Milo J, Norman GL, Leung PS, Gershwin ME, et al. The Significance of Autoantibody Changes Over Time in Primary Biliary Cirrhosis. Am J Clin Pathol. 2015;144:601–6. [DOI] [PubMed] [PMC]

57.

Manzo-Francisco LA, Aquino-Matus J, Vidaña-Pérez D, Uribe M, Chavez-Tapia N. Systematic review and meta-analysis: Transient elastography compared to liver biopsy for staging of liver fibrosis in primary biliary cholangitis. Ann Hepatol. 2023;28:101107. [DOI] [PubMed]

58.

Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HLA, et al.; Global PBC Study Group. Development and Validation of a Scoring System to Predict Outcomes of Patients with Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy. Gastroenterology. 2015;149:1804–12.e4. [DOI] [PubMed]

59.

Carbone M, Sharp SJ, Flack S, Paximadas D, Spiess K, Adgey C, et al. The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2016;63:930–50. [DOI] [PubMed] [PMC]

60.

Roll J, Boyer JL, Barry D, Klatskin G. The prognostic importance of clinical and histologic features in asymptomatic and symptomatic primary biliary cirrhosis. N Engl J Med. 1983;308:1–7. [DOI] [PubMed]

61.

Mahl TC, Shockcor W, Boyer JL. Primary biliary cirrhosis: survival of a large cohort of symptomatic and asymptomatic patients followed for 24 years. J Hepatol. 1994;20:707–13. [DOI] [PubMed]

62.

Prince M, Chetwynd A, Newman W, Metcalf JV, James OFW. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology. 2002;123:1044–51. [DOI] [PubMed]

63.

Jones DE, Al-Rifai A, Frith J, Patanwala I, Newton JL. The independent effects of fatigue and UDCA therapy on mortality in primary biliary cirrhosis: results of a 9 year follow-up. J Hepatol. 2010;53:911–7. [DOI] [PubMed]

64.

Harms MH, van Buuren HR, Corpechot C, Thorburn D, Janssen HLA, Lindor KD, et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2019;71:357–65. [DOI] [PubMed]

65.

Lammers WJ, Van Buuren HR, Hirschfield GM, Janssen HLA, Invernizzi P, Mason AL, et al.; Global PBC Study Group. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147:1338–49.e15. [DOI] [PubMed]

66.

Locke GR 3rd, Therneau TM, Ludwig J, Dickson ER, Lindor KD. Time course of histological progression in primary biliary cirrhosis. Hepatology. 1996;23:52–6. [DOI] [PubMed]

67.

Nijhawan PK, Therneau TM, Dickson ER, Boynton J, Lindor KD. Incidence of cancer in primary biliary cirrhosis: the Mayo experience. Hepatology. 1999;29:1396–8. [DOI] [PubMed]

68.

Jones DE, Metcalf JV, Collier JD, Bassendine MF, James OF. Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes. Hepatology. 1997;26:1138–42. [DOI] [PubMed]

69.

Mendes F, Lindor KD. Antimitochondrial antibody-negative primary biliary cirrhosis. Gastroenterol Clin North Am. 2008;37:479–84. [DOI] [PubMed]

70.

Invernizzi P, Crosignani A, Battezzati PM, Covini G, De Valle G, Larghi A, et al. Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and -negative primary biliary cirrhosis. Hepatology. 1997;25:1090–5. [DOI] [PubMed]

71.

Zein CO, Beatty K, Post AB, Logan L, Debanne S, McCullough AJ. Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: A cross validated retrospective assessment. Hepatology. 2006;44:1564–71. [DOI] [PubMed]

72.

Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology. 2000;32:1196–9. [DOI] [PubMed]

73.

Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group. N Engl J Med. 1994;330:1342–7. [DOI] [PubMed]

74.

FDA adds Boxed Warning to highlight correct dosing of Ocaliva (obeticholic acid) for patients with a rare chronic liver disease [Internet]. FDA; [cited 2021 May 29]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-highlight-correct-dosing-ocaliva-obeticholic-acid-patients-rare-chronic-liver/

75.

Poupon RE, Lindor KD, Parés A, Chazouillères O, Poupon R, Heathcote EJ. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol. 2003;39:12–6. [DOI] [PubMed]

76.

John BV, Khakoo NS, Schwartz KB, Aitchenson G, Levy C, Dahman B, et al. Ursodeoxycholic Acid Response is Associated with Reduced Mortality in Primary Biliary Cholangitis with Compensated Cirrhosis. Am J Gastroenterol. 2021;116:1913–23. [DOI] [PubMed] [PMC]

77.

Hirschfield GM, Beuers U, Corpechot C, Invernizzi P, Jones D, Marzioni M, et al.; 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;67:145–72. [DOI] [PubMed]

78.

Goel A, Kim WR. Natural History of Primary Biliary Cholangitis in the Ursodeoxycholic Acid Era: Role of Scoring Systems. Clin Liver Dis. 2018;22:563–78. [DOI] [PubMed]

79.

Wilde AB, Lieb C, Leicht E, Greverath LM, Steinhagen LM, Wald de Chamorro N, et al. Real-World Clinical Management of Patients with Primary Biliary Cholangitis-A Retrospective Multicenter Study from Germany. J Clin Med. 2021;10:1061. [DOI] [PubMed] [PMC]

80.

Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, et al.; Obeticholic Acid PBC Monotherapy Study Group. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology. 2018;67:1890–902. [DOI] [PubMed] [PMC]

81.

Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al.; POISE Study Group. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N Engl J Med. 2016;375:631–43. [DOI] [PubMed]

82.

Younossi ZM, Bernstein D, Shiffman ML, Kwo P, Kim WR, Kowdley KV, et al. Diagnosis and Management of Primary Biliary Cholangitis. Am J Gastroenterol. 2019;114:48–63. [DOI] [PubMed]

83.

Trauner M, Nevens F, Shiffman ML, Drenth JPH, Bowlus CL, Vargas V, et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol Hepatol. 2019;4:445–53. [DOI] [PubMed]

84.

Kulkarni AV, Tevethia HV, Arab JP, Candia R, Premkumar M, Kumar P, et al. Efficacy and safety of obeticholic acid in liver disease-A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol. 2021;45:101675. [DOI] [PubMed]

85.

Soret P, Lam L, Carrat F, Smets L, Berg T, Carbone M, et al. Combination of fibrates with obeticholic acid is able to normalise biochemical liver tests in patients with difficult-to-treat primary biliary cholangitis. Aliment Pharmacol Ther. 2021;53:1138–46. [DOI] [PubMed]

86.

Hegade VS, Khanna A, Walker LJ, Wong LL, Dyson JK, Jones DEJ. Long-Term Fenofibrate Treatment in Primary Biliary Cholangitis Improves Biochemistry but Not the UK-PBC Risk Score. Dig Dis Sci. 2016;61:3037–44. [DOI] [PubMed]

87.

Kurihara T, Niimi A, Maeda A, Shigemoto M, Yamashita K. Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid. Am J Gastroenterol. 2000;95:2990–2. [DOI] [PubMed]

88.

Levy C, Peter JA, Nelson DR, Keach J, Petz J, Cabrera R, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther. 2011;33:235–42. [DOI] [PubMed]

89.

Corpechot C, Chazouillères O, Rousseau A, Le Gruyer A, Habersetzer F, Mathurin P, et al. A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis. N Engl J Med. 2018;378:2171–81. [DOI] [PubMed]

90.

Tanaka A, Hirohara J, Nakano T, Matsumoto K, Chazouillères O, Takikawa H, et al. Association of bezafibrate with transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2021;75:565–71. [DOI] [PubMed]

91.

Shu Y, Song Y, Bai T, Pan X, Shang H, Yang L, et al. Predictive Model of Ursodeoxycholic Acid Treatment Response in Primary Biliary Cholangitis. J Clin Transl Hepatol. 2021;9:187–93. [DOI] [PubMed] [PMC]

92.

Murillo Perez CF, Harms MH, Lindor KD, van Buuren HR, Hirschfield GM, Corpechot C, et al.; GLOBAL PBC Study Group. Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase. Am J Gastroenterol. 2020;115:1066–74. [DOI] [PubMed]

93.

Gong Y, Gluud C. Colchicine for primary biliary cirrhosis. Cochrane Database Syst Rev. 2004;2:1465–858. [DOI] [PubMed]

94.

Hendrickse MT, Rigney E, Giaffer MH, Soomro I, Triger DR, Underwood JC, et al. Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial. Gastroenterology. 1999;117:400–7. [DOI] [PubMed]

95.

Dickson ER, Fleming TR, Wiesner RH, Baldus WP, Fleming CR, Ludwig J, et al. Trial of penicillamine in advanced primary biliary cirrhosis. N Engl J Med. 1985;312:1011–5. [DOI] [PubMed]

96.

Talwalkar JA, Angulo P, Keach JC, Petz JL, Jorgensen RA, Lindor KD. Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid. J Clin Gastroenterol. 2005;39:168–71. [PubMed]

97.

Tsuda M, Moritoki Y, Lian ZX, Zhang W, Yoshida K, Wakabayashi K, et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology. 2012;55:512–21. [DOI] [PubMed]

98.

Myers RP, Swain MG, Lee SS, Shaheen AAM, Burak KW. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol. 2013;108:933–41. [DOI] [PubMed]

99.

Khanna A, Jopson L, Howel D, Bryant A, Blamire A, Newton JL, et al. Rituximab Is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A Phase 2 Randomized Controlled Trial. Hepatology. 2019;70:1646–57. [DOI] [PubMed]

100.

Eckmann JD, Chedid V, Quinn KP, Bonthu N, Nehra V, Raffals LE. De Novo Colitis Associated with Rituximab in 21 Patients at a Tertiary Center. Clin Gastroenterol Hepatol. 2020;18:252–3. [DOI] [PubMed]

101.

Jones D, Boudes PF, Swain MG, Bowlus CL, Galambos MR, Bacon BR, 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;2:716–26. [DOI] [PubMed]

102.

Kowdley KV, Bowlus CL, Levy C, Akarca US, Alvares-da-Silva MR, Andreone P, et al.; ELATIVE Study Investigators’ Group. Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis. N Engl J Med. 2024;390:795–805. [DOI] [PubMed]

103.

Hirschfield GM, Bowlus CL, Mayo MJ, Kremer AE, Vierling JM, Kowdley KV, et al.; RESPONSE Study Group. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis. N Engl J Med. 2024;390:783–94. [DOI] [PubMed]

104.

Assis DN. Advancing Second-Line Treatment for Primary Biliary Cholangitis. N Engl J Med. 2024;390:853–4. [DOI] [PubMed]

105.

Vuppalanchi R, González-Huezo MS, Payan-Olivas R, Muñoz-Espinosa LE, Shaikh F, Pio Cruz-Lopez JL, et al. A Multicenter, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of Saroglitazar in Patients with Primary Biliary Cholangitis. Clin Transl Gastroenterol. 2021;12:e00327. [DOI] [PubMed] [PMC]

106.

Levy C, Kendrick S, Bowlus CL, Tanaka A, Jones D, Kremer AE, et al.; GLIMMER Study Group. GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients with Pruritus. Clin Gastroenterol Hepatol. 2023;21:1902–12.e13. [DOI] [PubMed]

107.

Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Aspects Med. 2017;56:54–65. [DOI] [PubMed]

108.

Degirolamo C, Rainaldi S, Bovenga F, Murzilli S, Moschetta A. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep. 2014;7:12–8. [DOI] [PubMed]

109.

European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51:237–67. [DOI] [PubMed]

110.

Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E, et al.; International Autoimmune Hepatitis Group. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol. 2011;54:374–85. [DOI] [PubMed]

111.

Kim WR, Lake JR, Smith JM, Schladt DP, Skeans MA, Harper AM, et al. OPTN/SRTR 2016 Annual Data Report: Liver. Am J Transplant. 2018;18:172–253. [DOI] [PubMed]

112.

Carbone M, Bufton S, Monaco A, Griffiths L, Jones DE, Neuberger JM. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study. J Hepatol. 2013;59:490–4. [DOI] [PubMed]

113.

Pells G, Mells GF, Carbone M, Newton JL, Bathgate AJ, Burroughs AK, et al. The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort. J Hepatol. 2013;59:67–73. [DOI] [PubMed] [PMC]

114.

Tandon P, Rowe BH, Vandermeer B, Bain VG. The efficacy and safety of bile Acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritus. Am J Gastroenterol. 2007;102:1528–36. [DOI] [PubMed]

115.

De Vries E, Bolier R, Goet J, Parés A, Verbeek J, De Vree M, et al.; Netherlands Association for the Study of the Liver-Cholestasis Working Group. Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial. Gastroenterology. 2021;160:734–43.e6. [DOI] [PubMed]

116.

Hussain AB, Samuel R, Hegade VS, Jones DE, Reynolds NJ. Pruritus secondary to primary biliary cholangitis: a review of the pathophysiology and management with phototherapy. Br J Dermatol. 2019;181:1138–45. [DOI] [PubMed]

117.

Hamburg SM, Piers DA, van den Berg AP, Slooff MJ, Haagsma EB. Bone mineral density in the long term after liver transplantation. Osteoporos Int. 2000;11:600–6. [DOI] [PubMed]

118.

Reig A, Sesé P, Parés A. Effects of Bezafibrate on Outcome and Pruritus in Primary Biliary Cholangitis with Suboptimal Ursodeoxycholic Acid Response. Am J Gastroenterol. 2018;113:49–55. [DOI] [PubMed]

119.

Abu Rajab M, Kaplan MM. Statins in primary biliary cirrhosis: are they safe? Dig Dis Sci. 2010;55:2086–8. [DOI] [PubMed]

120.

Klion FM, Fabry TL, Palmer M, Schaffner F. Prediction of survival of patients with primary biliary cirrhosis. Examination of the Mayo Clinic model on a group of patients with known endpoint. Gastroenterology. 1992;102:310–3. [DOI] [PubMed]

121.

Montano-Loza AJ, Hansen BE, Corpechot C, Roccarina D, Thorburn D, Trivedi P, et al.; Global PBC Study Group. Factors Associated with Recurrence of Primary Biliary Cholangitis After Liver Transplantation and Effects on Graft and Patient Survival. Gastroenterology. 2019;156:96–107.e1. [DOI] [PubMed]

122.

Pedersen MR, Greenan G, Arora S, Murali AR, Mayo MJ. Ursodeoxycholic Acid Decreases Incidence of Primary Biliary Cholangitis and Biliary Complications After Liver Transplantation: A Meta-Analysis. Liver Transpl. 2021;27:866–75. [DOI] [PubMed]

123.

Montano-Loza AJ, Wasilenko S, Bintner J, Mason AL. Cyclosporine A protects against primary biliary cirrhosis recurrence after liver transplantation. Am J Transplant. 2010;10:852–8. [DOI] [PubMed]