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原发性硬化性胆管炎药物治疗进展
DOI: 10.12449/JCH240526
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：盛夏负责文献检索，撰写论文；纪庆明负责资料分析；李昕宇、王丽宏、牛俊奇负责指导及最终定稿。
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摘要: 原发性硬化性胆管炎（PSC）是一种以慢性进行性胆管炎症为特征的胆汁淤积性疾病，在我国发病率低，预后差，尚无药物治疗能改变PSC的进程，肝移植是唯一有效治疗手段，移植后5年生存率可达85％。基于PSC现状，药物治疗面临巨大挑战。目前治疗PSC的药物尚处于临床试验阶段，初步显示出应用前景，其中熊去氧胆酸是研究最广泛、最常用的药物。除此之外，还有很多新兴药物正在研究中。本文将围绕PSC最新药物治疗进展进行概述。Abstract: Primary sclerosing cholangitis （PSC） is a cholestatic disease characterized by chronic progressive bile duct inflammation and has a low incidence rate and poor prognosis in China. There is still no drug therapy that can change the course of PSC， and liver transplantation is the only effective treatment for PSC， with a 5-year survival rate of 85% after transplantation. Drug therapy for PSC is facing great challenges based on the current status of PSC. At present， drugs for the treatment of PSC are in the stage of clinical trials and have shown certain application prospect， among which ursodeoxycholic acid is the most widely studied and commonly used drug. In addition， there are many emerging drugs in the pipeline. This article summarizes the latest advances in drug therapy for PSC.
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Key words:
- Cholangitis， Sclerosing /
- Ursodeoxycholic Acid /
- Obecholic Acid /
- Drug Therapy
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[1] European Association for the Study of the Liver. EASL Clinical Practice Guidelines on sclerosing cholangitis[J]. J Hepatol, 2022, 77( 3): 761- 806. DOI: 10.1016/j.jhep.2022.05.011. [2] LILLEMOE KD, PITT HA, CAMERON JL. Primary sclerosing cholangitis[J]. Surg Clin N Am, 1990, 70( 6): 1381- 1402. DOI: 10.1016/s0039-6109(16)45290-4. [3] LINDOR KD. Ursodiol for primary sclerosing cholangitis. mayo primary sclerosing cholangitis-ursodeoxycholic acid study group[J]. N Engl J Med, 1997, 336( 10): 691- 695. DOI: 10.1056/NEJM199703063361003. [4] OLSSON R, BOBERG KM, de MUCKADELL OS, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: A 5-year multicenter, randomized, controlled study[J]. Gastroenterology, 2005, 129( 5): 1464- 1472. DOI: 10.1053/j.gastro.2005.08.017. [5] LINDOR KD, KOWDLEY KV, LUKETIC VAC, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis[J]. Hepatology, 2009, 50( 3): 808- 814. DOI: 10.1002/hep.23082. [6] EATON JE, SILVEIRA MG, PARDI DS, et al. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis[J]. Am J Gastroenterol, 2011, 106( 9): 1638- 1645. DOI: 10.1038/ajg.2011.156. [7] TRIANTOS CK, KOUKIAS NM, NIKOLOPOULOU VN, et al. Meta-analysis: Ursodeoxycholic acid for primary sclerosing cholangitis[J]. Aliment Pharmacol Ther, 2011, 34( 8): 901- 910. DOI: 10.1111/j.1365-2036.2011.04822.x. [8] TRAUNER M, FUCHS CD, HALILBASIC E, et al. New therapeutic concepts in bile acid transport and signaling for management of cholestasis[J]. Hepatology, 2017, 65( 4): 1393- 1404. DOI: 10.1002/hep.28991. [9] 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[J]. Gastroenterology, 2006, 130( 2): 465- 481. DOI: 10.1053/j.gastro.2005.10.018. [10] FICKERT P, HIRSCHFIELD GM, DENK G, et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis[J]. J Hepatol, 2017, 67( 3): 549- 558. DOI: 10.1016/j.jhep.2017.05.009. [11] KOWDLEY KV, VUPPALANCHI R, LEVY C, et al. A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis[J]. J Hepatol, 2020, 73( 1): 94- 101. DOI: 10.1016/j.jhep.2020.02.033. [12] 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[J]. Hepatology, 2019, 70( 3): 788- 801. DOI: 10.1002/hep.30509. [13] LOOMBA R, NOUREDDI M, KOWDLEY KV, et al. Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH[J]. Hepatology, 2021, 73( 2): 625- 643. DOI: 10.1002/hep.31622. [14] SANYAL AJ, LING L, BEUERS U, et al. Potent suppression of hydrophobic bile acids by aldafermin, an FGF19 analogue, across metabolic and cholestatic liver diseases[J]. JHEP Rep, 2021, 3( 3): 100255. DOI: 10.1016/j.jhepr.2021.100255. [15] 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]. J Hepatol, 2019, 70( 3): 483- 493. DOI: 10.1016/j.jhep.2018.10.035. [16] 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]. J Clin Gastroenterol, 2017, 51( 2): e11- e16. DOI: 10.1097/MCG.0000000000000591. [17] MIZUNO S, HIRANO K, TADA M, et al. Bezafibrate for the treatment of primary sclerosing cholangitis[J]. J Gastroenterol, 2010, 45( 7): 758- 762. DOI: 10.1007/s00535-010-0204-x. [18] LEMOINNE S, PARES A, REIG A, et al. Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French-Spanish experience[J]. Clin Res Hepatol Gastroenterol, 2018, 42( 6): 521- 528. DOI: 10.1016/j.clinre.2018.06.009. [19] HATAMI B, MOSALA M, HASSANI AH, et al. Fenofibrate in primary sclerosing cholangitis; a randomized, double-blind, placebo-controlled trial[J]. Pharmacol Res Perspect, 2022, 10( 4): e00984. DOI: 10.1002/prp2.984. [20] van den HOEK AM, VERSCHUREN L, CASPERS MPM, et al. Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men[J]. Sci Rep, 2021, 11( 1): 5050. DOI: 10.1038/s41598-021-83974-8. [21] HEGADE VS, JONES DEJ, HIRSCHFIELD GM. Apical sodium-dependent transporter inhibitors in primary biliary cholangitis and primary sclerosing cholangitis[J]. Dig Dis, 2017, 35( 3): 267- 274. DOI: 10.1159/000450988. [22] BOWLUS CL, EKSTEEN B, CHEUNG AC, et al. Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study[J]. Hepatol Commun, 2023, 7( 6): e0153. DOI: 10.1097/hc9.0000000000000153. [23] CABALLERO FJ, RODRIGUES PM, LIZASO AA, et al. A3907, a systemic ASBT inhibitor, improves cholestasis in mice by inhibiting multi-organ bile acid transport and shows translational relevance to human[J]. J Hepatol, 2023, 78: S62. DOI: 10.1016/s0168-8278(23)00528-7. [24] FÄRKKILÄ M, KARVONEN AL, NURMI H, et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: A randomized placebo-controlled trial[J]. Hepatology, 2004, 40( 6): 1379- 1386. DOI: 10.1002/hep.20457. [25] TABIBIAN JH, WEEDING E, JORGENSEN RA, et al. Randomised clinical trial: Vancomycin or metronidazole in patients with primary sclerosing cholangitis-a pilot study[J]. Aliment Pharmacol Ther, 2013, 37( 6): 604- 612. DOI: 10.1111/apt.12232. [26] DAVIES YK, COX KM, ABDULLAH BA, et al. Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: An immunomodulating antibiotic[J]. J Pediatr Gastroenterol Nutr, 2008, 47( 1): 61- 67. DOI: 10.1097/MPG.0b013e31816fee95. [27] WILSON HJ, KHOKHAR F, ENOCH DA, et al. Point-prevalence survey of carbapenemase-producing Enterobacteriaceae and vancomycin-resistant enterococci in adult inpatients in a university teaching hospital in the UK[J]. J Hosp Infect, 2018, 100( 1): 35- 39. DOI: 10.1016/j.jhin.2018.06.024. [28] LINDOR KD, KOWDLEY KV, HARRISON ME, et al. ACG clinical guideline: Primary sclerosing cholangitis[J]. Am J Gastroenterol, 2015, 110( 5): 646- 659; quiz660. DOI: 10.1038/ajg.2015.112. [29] CAREY EJ, EATON J, CLAYTON M, et al. A pilot study of vidofludimus calcium for treatment of primary sclerosing cholangitis[J]. Hepatol Commun, 2022, 6( 7): 1589- 1597. DOI: 10.1002/hep4.1926. [30] LIU X, WANG HL, LIU XY, et al. Efficacy and safety of immune-modulating therapy for primary sclerosing cholangitis: A systematic review and meta-analysis[J]. Pharmacol Ther, 2022, 237: 108163. DOI: 10.1016/j.pharmthera.2022.108163. [31] ANGULO P, BATTS KP, JORGENSEN RA, et al. Oral budesonide in the treatment of primary sclerosing cholangitis[J]. Am J Gastroenterology, 2000, 95( 9): 2333- 2337. DOI: 10.1111/j.1572-0241.2000.02323.x. [32] LINDOR KD, WIESNER RH, COLWELL LJ, et al. The combination of prednisone and colchicine in patients with primary sclerosing cholangitis[J]. Am J Gastroenterol, 1991, 86( 1): 57- 61. [33] EKSTEEN B, BOWLUS CL, MONTANO-LOZA AJ, et al. Efficacy and safety of cenicriviroc in patients with primary sclerosing cholangitis: PERSEUS study[J]. Hepatol Commun, 2020, 5( 3): 478- 490. DOI: 10.1002/hep4.1619. [34] 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[J]. JHEP Rep, 2020, 2( 1): 100064. DOI: 10.1016/j.jhepr.2019.100064. [35] BARASHI N, SEGAL M, AHARON A, et al. CCL24 modulates fibrosis development in primary sclerosing cholangitis: Correlation of human serum CCL24 levels with fibrosis markers and data from the Mdr2-/- mouse model[J]. J Hepatol, 2020, 73: S486. DOI: 10.1016/s0168-8278(20)31452-5. [36] LOFTUS EV Jr, FEAGAN BG, PANACCIONE R, et al. Long-term safety of vedolizumab for inflammatory bowel disease[J]. Aliment Pharmacol Ther, 2020, 52( 8): 1353- 1365. DOI: 10.1111/apt.16060. [37] LYNCH KD, CHAPMAN RW, KESHAV S, et al. Effects of vedolizumab in patients with primary sclerosing cholangitis and inflammatory bowel diseases[J]. Clin Gastroenterol Hepatol, 2020, 18( 1): 179- 187. e 6. DOI: 10.1016/j.cgh.2019.05.013. [38] LABORDA TJ, RICCIUTO A, AUMAR M, et al. Vedolizumab therapy in children with primary sclerosing cholangitis: Data from the pediatric primary sclerosing cholangitis consortium[J]. J Pediatr Gastroenterol Nutr, 2020, 71( 4): 459- 464. DOI: 10.1097/MPG.0000000000002855. [39] 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[J]. Am J Gastroenterol, 2022, 117( 11): 1805- 1815. DOI: 10.14309/ajg.0000000000001956. [40] DECARIS ML, SCHAUB JR, CHEN C, et al. Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF[J]. Respir Res, 2021, 22( 1): 265. DOI: 10.1186/s12931-021-01863-0. [41] LITTLE R, WINE E, KAMATH BM, et al. Gut microbiome in primary sclerosing cholangitis: A review[J]. World J Gastroenterol, 2020, 26( 21): 2768- 2780. DOI: 10.3748/wjg.v26.i21.2768. -
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