Intest Res.  2023 Oct;21(4):420-432. 10.5217/ir.2023.00039.

Treatment of primary sclerosing cholangitis combined with inflammatory bowel disease

• Kim YS
• Hurley EH
• Park Y
• Ko S

• KMID: 2547192
• DOI: http://doi.org/10.5217/ir.2023.00039

Abstract

Primary sclerosing cholangitis (PSC) is a progressive cholestatic, inflammatory, and fibrotic disease that is strongly associated with inflammatory bowel disease (IBD). PSC-IBD represents a unique disease entity and patients with this disease have an increased risk of malignancy development, such as colorectal cancer and cholangiocarcinoma. The pathogenesis of PSC-IBD involves genetic and environmental factors such as gut dysbiosis and bile acids alteration. However, despite the advancement of disease characteristics, no effective medical therapy has proven to have a significant impact on the prognosis of PSC. The treatment options for patients with PSC-IBD do not differ from those for patients with PSC alone. Potential candidate drugs have been developed based on the pathogenesis of PSC-IBD, such as those that target modulation of bile acids, inflammation, fibrosis, and gut dysbiosis. In this review, we summarize the current medical treatments for PSC-IBD and the status of new emerging therapeutic agents.

Keyword

Inflammatory bowel disease; Primary sclerosing cholangitis; Therapeutics

Figure

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  Fig. 1. Therapeutic approach of primary sclerosing cholangitis (PSC) combined with inflammatory bowel disease (IBD). IBD management should be continued regardless of PSC treatment. Symptomatic care and management of complications of PSC are currently implemented, however, with the advancement of understanding of pathogenesis of PSC-IBD, several new therapeutic agents are developed and undergone the clinical trials. UDCA, ursodeoxycholic acid; TPL, transplantation; norUDCA, norursodeoxycholic acid; FXR, farnesoid X receptor; PPARs, peroxisome proliferator-activated receptors; ASBT, apical sodium-dependent bile acid transporter; LOXL2, lysyl oxidase-like 2; CCR2, C-C chemokine receptor 2; CCR5, C-C chemokine receptor 5; α4β7, alpha 4 beta 7; VAP-1, vascular adhesion protein 1; TNF, tumor necrosis factor.

Reference

1. Park SH. Update on the epidemiology of inflammatory bowel disease in Asia: where are we now? Intest Res. 2022; 20:159–164.

2. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017; 390:2769–2778.

3. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012; 142:46–54.

4. Low D, Swarup N, Okada T, Mizoguchi E. Landscape of inflammatory bowel disease in Singapore. Intest Res. 2022; 20:291–296.

5. Kaplan GG, Windsor JW. The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021; 18:56–66.

6. Mahadevan U, Silverberg MS. Inflammatory bowel diseasegastroenterology diamond jubilee review. Gastroenterology. 2018; 154:1555–1558.

7. Vavricka SR, Schoepfer A, Scharl M, Lakatos PL, Navarini A, Rogler G. Extraintestinal manifestations of inflammatory bowel disease. Inflamm Bowel Dis. 2015; 21:1982–1992.

8. Kim JM, Cheon JH. Pathogenesis and clinical perspectives of extraintestinal manifestations in inflammatory bowel diseases. Intest Res. 2020; 18:249–264.

9. Palmela C, Peerani F, Castaneda D, Torres J, Itzkowitz SH. Inflammatory bowel disease and primary sclerosing cholangitis: a review of the phenotype and associated specific features. Gut Liver. 2018; 12:17–29.

10. Rossi RE, Conte D, Massironi S. Primary sclerosing cholangitis associated with inflammatory bowel disease: an update. Eur J Gastroenterol Hepatol. 2016; 28:123–131.

11. Molodecky NA, Kareemi H, Parab R, et al. Incidence of primary sclerosing cholangitis: a systematic review and metaanalysis. Hepatology. 2011; 53:1590–1599.

12. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010; 51:660–678.

13. Singh A, Midha V, Narang V, et al. Low prevalence of primary sclerosing cholangitis in patients with inflammatory bowel disease in India. Intest Res. 2023; 21:452–459.

14. Ye BD, Yang SK, Boo SJ, et al. Clinical characteristics of ulcerative colitis associated with primary sclerosing cholangitis in Korea. Inflamm Bowel Dis. 2011; 17:1901–1906.

15. Weng MT, Shih IL, Tung CC, et al. Association of young age and male sex with primary sclerosing cholangitis in Taiwanese patients with inflammatory bowel disease. Intest Res. 2022; 20:224–230.

16. Ohta Y, Taida T, Kato J, et al. Clinical features focusing on extraintestinal manifestations in Japanese patients with inflammatory bowel diseases: far east 1000. Digestion. 2023; 104:328–334.

17. Song EM, Yang SK. Natural history of inflammatory bowel disease: a comparison between the East and the West. Intest Res. 2022; 20:418–430.

18. Park SB, Yoon JY, Cha JM. What are the different phenotypes of inflammatory bowel disease in Asia? Gut Liver. 2022; 16:676–685.

19. Schaeffer DF, Win LL, Hafezi-Bakhtiari S, Cino M, Hirschfield GM, El-Zimaity H. The phenotypic expression of inflammatory bowel disease in patients with primary sclerosing cholangitis differs in the distribution of colitis. Dig Dis Sci. 2013; 58:2608–2614.

20. Sano H, Nakazawa T, Ando T, et al. Clinical characteristics of inflammatory bowel disease associated with primary sclerosing cholangitis. J Hepatobiliary Pancreat Sci. 2011; 18:154–161.

21. Trivedi PJ, Crothers H, Mytton J, et al. Effects of primary sclerosing cholangitis on risks of cancer and death in people with inflammatory bowel disease, based on sex, race, and age. Gastroenterology. 2020; 159:915–928.

22. Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a metaanalysis. Gastrointest Endosc. 2002; 56:48–54.

23. Gulamhusein AF, Eaton JE, Tabibian JH, Atkinson EJ, Juran BD, Lazaridis KN. Duration of inflammatory bowel disease is associated with increased risk of cholangiocarcinoma in patients with primary sclerosing cholangitis and IBD. Am J Gastroenterol. 2016; 111:705–711.

24. Oh EH, Kim YJ, Kim M, Park SH, Kim TO, Park SH. Risks of colorectal cancer and biliary cancer according to accompanied primary sclerosing cholangitis in Korean patients with ulcerative colitis: a nationwide population-based study. Intest Res. 2023; 21:252–265.

25. Bowlus CL, Arrivé L, Bergquist A, et al. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology. 2023; 77:659–702.

26. 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; 24:1074–1081.

27. Hov JR, Karlsen TH. The microbiota and the gut-liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol. 2023; 20:135–154.

28. Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis: a comprehensive review. J Hepatol. 2017; 67:1298–1323.

29. Jiang X, Karlsen TH. Genetics of primary sclerosing cholangitis and pathophysiological implications. Nat Rev Gastroenterol Hepatol. 2017; 14:279–295.

30. Kim YS, Hurley EH, Park Y, Ko S. Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gut-liver axis. Exp Mol Med. 2023; 55:1380–1387.

31. Boberg KM, Egeland T, Schrumpf E. Long-term effect of corticosteroid treatment in primary sclerosing cholangitis patients. Scand J Gastroenterol. 2003; 38:991–995.

32. Talwalkar JA, Gossard AA, Keach JC, Jorgensen RA, Petz JL, Lindor RN. Tacrolimus for the treatment of primary sclerosing cholangitis. Liver Int. 2007; 27:451–453.

33. Fraga M, Fournier N, Safroneeva E, et al. Primary sclerosing cholangitis in the Swiss Inflammatory Bowel Disease Cohort Study: prevalence, risk factors, and long-term follow-up. Eur J Gastroenterol Hepatol. 2017; 29:91–97.

34. Steenstraten IC, Sebib Korkmaz K, Trivedi PJ, et al. Systematic review with meta-analysis: risk factors for recurrent primary sclerosing cholangitis after liver transplantation. Aliment Pharmacol Ther. 2019; 49:636–643.

35. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019; 114:384–413.

36. Peng X, Luo X, Hou JY, et al. Immunosuppressive agents for the treatment of primary sclerosing cholangitis: a systematic review and meta-analysis. Dig Dis. 2017; 35:478–485.

37. Hommes DW, Erkelens W, Ponsioen C, et al. A double-blind, placebo-controlled, randomized study of infliximab in primary sclerosing cholangitis. J Clin Gastroenterol. 2008; 42:522–526.

38. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a enicrivir controlled trial. Gut. 2011; 60:780–787.

39. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005; 353:2462–2476.

40. Hedin CR, Sado G, Ndegwa N, et al. Effects of tumor necrosis factor antagonists in patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2020; 18:2295–2304.

41. Tse CS, Loftus EV Jr, Raffals LE, Gossard AA, Lightner AL. Effects of vedolizumab, adalimumab and infliximab on biliary inflammation in individuals with primary sclerosing cholangitis and inflammatory bowel disease. Aliment Pharmacol Ther. 2018; 48:190–195.

42. Biron A, Beaugerie L, Chazouillères O, Kirchgesner J. Impact of thiopurines and tumour necrosis factor antagonists on primary sclerosing cholangitis outcomes in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2022; 56:857–868.

43. Jovani M, Danese S. Vedolizumab for the treatment of IBD: a selective therapeutic approach targeting pathogenic a4b7 cells. Curr Drug Targets. 2013; 14:1433–1443.

44. Na SY, Kim YS. Management of inflammatory bowel disease beyond tumor necrosis factor inhibitors: novel biologics and small-molecule drugs. Korean J Intern Med. 2022; 37:906–919.

45. Na SY, Choi CH, Song EM, et al. Korean clinical practice guidelines on biologics and small molecules for moderate-to-severe ulcerative colitis. Intest Res. 2023; 21:61–87.

46. Lynch KD, Chapman RW, Keshav S, et al. Effects of vedolizumab in patients with primary sclerosing cholangitis and inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2020; 18:179–187.

47. Caron B, Peyrin-Biroulet L, Pariente B, et al. Vedolizumab therapy is ineffective for primary sclerosing cholangitis in patients with inflammatory bowel disease: a GETAID Multicentre Cohort Study. J Crohns Colitis. 2019; 13:1239–1247.

48. Floreani A, De Martin S. Treatment of primary sclerosing cholangitis. Dig Liver Dis. 2021; 53:1531–1538.

49. Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol. 2015; 62(1 Suppl):S25–S37.

50. Beuers U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2006; 3:318–328.

51. Karlsen TH, Vesterhus M, Boberg KM. Review article: controversies in the management of primary biliary cirrhosis and primary sclerosing cholangitis. Aliment Pharmacol Ther. 2014; 39:282–301.

52. Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med. 1997; 336:691–695.

53. 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; 129:1464–1472.

54. Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009; 50:808–814.

55. Chapman MH, Thorburn D, Hirschfield GM, et al. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut. 2019; 68:1356–1378.

56. Wunsch E, Trottier J, Milkiewicz M, et al. Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis. Hepatology. 2014; 60:931–940.

57. Stiehl A, Rudolph G, Klöters-Plachky P, Sauer P, Walker S. Development of dominant bile duct stenoses in patients with primary sclerosing cholangitis treated with ursodeoxycholic acid: outcome after endoscopic treatment. J Hepatol. 2002; 36:151–156.

58. Ferreira MT, Ribeiro IB, de Moura DT, et al. Stent versus balloon dilation for the treatment of dominant strictures in primary sclerosing cholangitis: a systematic review and metaanalysis. Clin Endosc. 2021; 54:833–842.

59. Prokopič M, Beuers U. Management of primary sclerosing cholangitis and its complications: an algorithmic approach. Hepatol Int. 2021; 15:6–20.

60. Martin EF, Levy C. Timing, management, and outcomes of liver transplantation in primary sclerosing cholangitis. Semin Liver Dis. 2017; 37:305–313.

61. Gow PJ, Chapman RW. Liver transplantation for primary sclerosing cholangitis. Liver. 2000; 20:97–103.

62. Joshi D, Bjarnason I, Belgaumkar A, et al. The impact of inflammatory bowel disease post-liver transplantation for primary sclerosing cholangitis. Liver Int. 2013; 33:53–61.

63. Williamson KD, Chapman RW. New therapeutic strategies for primary sclerosing cholangitis. Semin Liver Dis. 2016; 36:5–14.

64. Fickert P, Hirschfield GM, Denk G, et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol. 2017; 67:549–558.

65. 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; 49:1972–1981.

66. Moustafa T, Fickert P, Magnes C, et al. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology. 2012; 142:140–151.

67. Modica S, Petruzzelli M, Bellafante E, et al. Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis. Gastroenterology. 2012; 142:355–365.

68. Kowdley KV, Vuppalanchi R, Levy C, et al. A randomized, placebo-controlled, phase II study of enicriviro acid for primary sclerosing cholangitis. J Hepatol. 2020; 73:94–101.

69. Trauner M, Gulamhusein A, Hameed B, et al. The nonsteroidal farnesoid X receptor agonist enicrivi (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis. Hepatology. 2019; 70:788–801.

70. 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:e11–e16.

71. 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; 42:521–528.

72. ClinicalTrials.gov [Internet]. U.S. National Library of Medicine, 2022 [cited 2023 Jul 25]. https://classic.clinicaltrials.gov/ct2/show/NCT04309773.

73. 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; 5:478–490.

74. ClinicalTrials.gov [Internet]. U.S. National Library of Medicine, 2017 [cited 2023 Jul 25]. https://classic.clinicaltrials.gov/ct2/show/NCT03035058.

75. ClinicalTrials.gov [Internet]. U.S. National Library of Medicine, 2019 [cited 2023 Jul 25]. https://clinicaltrials.gov/study/NCT02239211.

76. 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; 17:1860–1866.

77. Bergquist A, Marschall HU, 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; 4:235–241.

78. Muir AJ, Levy C, Janssen HL, et al. Simtuzumab for primary sclerosing cholangitis: phase 2 study results with insights on the natural history of the disease. Hepatology. 2019; 69:684–698.

79. Färkkilä M, Karvonen AL, Nurmi H, et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology. 2004; 40:1379–1386.

80. 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; 37:604–612.

81. ClinicalTrials.gov [Internet]. U.S. National Library of Medicine, 2022 [cited 2023 Jul 25]. https://clinicaltrials.gov/study/nct03710122.

82. Vleggaar FP, Monkelbaan JF, van Erpecum KJ. Probiotics in primary sclerosing cholangitis: a randomized placebo-controlled crossover pilot study. Eur J Gastroenterol Hepatol. 2008; 20:688–692.

83. 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; 114:1071–1079.

84. Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications: a review. Nutr J. 2014; 13:17.

85. Ghonem NS, Ananthanarayanan M, Soroka CJ, Boyer JL. Peroxisome proliferator-activated receptor α activates human multidrug resistance transporter 3/ATP-binding cassette protein subfamily B4 transcription and increases rat biliary phosphatidylcholine secretion. Hepatology. 2014; 59:1030–1042.

86. Ghonem NS, Assis DN, Boyer JL. Fibrates and cholestasis. Hepatology. 2015; 62:635–643.

87. Miyahara T, Schrum L, Rippe R, et al. Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem. 2000; 275:35715–35722.

88. Corpechot C, Chazouillères O, Rousseau A, et al. A placebocontrolled trial of bezafibrate in primary biliary cholangitis. N Engl J Med. 2018; 378:2171–2181.

89. Ponsioen CY, Kuiper H, Ten Kate FJ, van Milligen de Wit M, van Deventer SJ, Tytgat GN. Immunohistochemical analysis of inflammation in primary sclerosing cholangitis. Eur J Gastroenterol Hepatol. 1999; 11:769–774.

90. Hsu W, Zhang W, Tsuneyama K, et al. Differential mechanisms in the pathogenesis of autoimmune cholangitis versus inflammatory bowel disease in interleukin-2Ralpha(-/-) mice. Hepatology. 2009; 49:133–140.

91. Mueller T, Beutler C, Picó AH, et al. Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis. Liver Int. 2011; 31:1574–1588.

92. Harada K, Nakanuma Y. Innate immunity in the pathogenesis of cholangiopathy: a recent update. Inflamm Allergy Drug Targets. 2012; 11:478–483.

93. Zimmermann HW, Tacke F. Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis. Inflamm Allergy Drug Targets. 2011; 10:509–536.

94. Ye X, Liu S, Hu M, Song Y, Huang H, Zhong Y. CCR5 expression in inflammatory bowel disease and its correlation with inflammatory cells and β-arrestin2 expression. Scand J Gastroenterol. 2017; 52:551–557.

95. 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; 359:150–157.

96. Rockey DC. Current and future anti-fibrotic therapies for chronic liver disease. Clin Liver Dis. 2008; 12:939–962.

97. Schierwagen R, Uschner FE, Magdaleno F, Klein S, Trebicka J. Rationale for the use of statins in liver disease. Am J Physiol Gastrointest Liver Physiol. 2017; 312:G407–G412.

98. Ikenaga N, Peng ZW, Vaid KA, et al. Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut. 2017; 66:1697–1708.

99. Pollheimer MJ, Racedo S, Mikels-Vigdal A, et al. Lysyl oxidaselike protein 2 (LOXL2) modulates barrier function in cholangiocytes in cholestasis. J Hepatol. 2018; 69:368–377.

100. 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; 4:492–503.

101. 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; 77:715–728.

102. 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; 66:611–619.

103. Sabino J, Vieira-Silva S, Machiels K, et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut. 2016; 65:1681–1689.

104. Shah A, Crawford D, Burger D, et al. Effects of antibiotic therapy in primary sclerosing cholangitis with and without inflammatory bowel disease: a systematic review and metaanalysis. Semin Liver Dis. 2019; 39:432–441.

105. Quaranta G, Guarnaccia A, Fancello G, et al. Fecal microbiota transplantation and other gut microbiota manipulation strategies. Microorganisms. 2022; 10:2424.