Determinants of the effectiveness of bezafibrate combined with ursodeoxycholic acid in patients with primary biliary cholangitis.
PBC
UDCA
fibrate
prognostic factors
transplantation
Journal
Hepatology research : the official journal of the Japan Society of Hepatology
ISSN: 1386-6346
Titre abrégé: Hepatol Res
Pays: Netherlands
ID NLM: 9711801
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
revised:
25
05
2023
received:
09
03
2023
accepted:
03
06
2023
medline:
9
6
2023
pubmed:
9
6
2023
entrez:
8
6
2023
Statut:
ppublish
Résumé
For patients with primary biliary cholangitis (PBC) exhibiting suboptimal responses to ursodeoxycholic acid (UDCA), obeticholic acid (OCA), and bezafibrate (BZF) are currently used and shown to improve long-term outcomes. Nevertheless, we encounter patients who die or undergo liver transplantation (LT) even with combination treatment. In this study, we explored prognostic indicators in patients receiving combination treatment of UDCA and BZF. We took advantage of the Japanese PBC registry and enrolled patients who received both UDCA and BZF therapy in 2000 or later. The covariates investigated included baseline covariates as well as treatment covariates. Two main outcomes (all-cause death or LT and liver-related death or LT) were assessed using multivariable-adjusted Cox proportional hazards models. In total, 772 patients were included. The median follow-up was 7.1 years. Using the Cox regression model, bilirubin (hazard ratio [HR] 6.85, 95% confidence interval [CI] 1.73-27.1, p = 0.006), alkaline phosphatase (HR 5.46, 95% CI 1.32-22.6, p = 0.019), and histological stage (HR 4.87, 95% CI 1.16-20.5, p = 0.031) were found associated with LT-free survival. For survival free from liver disease-related death or LT, albumin (HR 7.72, 95% CI 1.48-40.4, p = 0.016) and bilirubin (HR 14.5, 95% CI 2.37-88.5, p = 0.004) were found significantly associated. In patients with PBC receiving combination therapy, prognostic variables were similar to those in patients receiving UDCA monotherapy. These results indicate the importance of diagnosing patients with PBC at an earlier stage because of the reduced effectiveness of BZF at advanced stages.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
For patients with primary biliary cholangitis (PBC) exhibiting suboptimal responses to ursodeoxycholic acid (UDCA), obeticholic acid (OCA), and bezafibrate (BZF) are currently used and shown to improve long-term outcomes. Nevertheless, we encounter patients who die or undergo liver transplantation (LT) even with combination treatment. In this study, we explored prognostic indicators in patients receiving combination treatment of UDCA and BZF.
METHODS
METHODS
We took advantage of the Japanese PBC registry and enrolled patients who received both UDCA and BZF therapy in 2000 or later. The covariates investigated included baseline covariates as well as treatment covariates. Two main outcomes (all-cause death or LT and liver-related death or LT) were assessed using multivariable-adjusted Cox proportional hazards models.
RESULTS
RESULTS
In total, 772 patients were included. The median follow-up was 7.1 years. Using the Cox regression model, bilirubin (hazard ratio [HR] 6.85, 95% confidence interval [CI] 1.73-27.1, p = 0.006), alkaline phosphatase (HR 5.46, 95% CI 1.32-22.6, p = 0.019), and histological stage (HR 4.87, 95% CI 1.16-20.5, p = 0.031) were found associated with LT-free survival. For survival free from liver disease-related death or LT, albumin (HR 7.72, 95% CI 1.48-40.4, p = 0.016) and bilirubin (HR 14.5, 95% CI 2.37-88.5, p = 0.004) were found significantly associated.
CONCLUSION
CONCLUSIONS
In patients with PBC receiving combination therapy, prognostic variables were similar to those in patients receiving UDCA monotherapy. These results indicate the importance of diagnosing patients with PBC at an earlier stage because of the reduced effectiveness of BZF at advanced stages.
Types de publication
Journal Article
Langues
eng
Pagination
989-997Subventions
Organisme : The Ministry of Health, Labor, and Welfare of Japan
ID : JPMH20FC1023
Informations de copyright
© 2023 Japan Society of Hepatology.
Références
Lleo A, Wang GQ, Gershwin ME, Hirschfield GM. Primary biliary cholangitis. Lancet. 2020;396(10266):1915-1926. https://doi.org/10.1016/s0140-6736(20)31607-x
Tanaka A, Mori M, Matsumoto K, Ohira H, Tazuma S, Takikawa H. Increase trend in the prevalence and male-to-female ratio of primary biliary cholangitis, autoimmune hepatitis, and primary sclerosing cholangitis in Japan. Hepatol Res. 2019;49(8):881-889. https://doi.org/10.1111/hepr.13342
Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med. 1991;324(22):1548-1554. https://doi.org/10.1056/nejm199105303242204
Harms MH, van Buuren HR, Corpechot C, Thorburn D, Janssen HL, Lindor KD, et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis. J Hepatol. 2019;71(2):357-365. https://doi.org/10.1016/j.jhep.2019.04.001
Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997;113(3):884-890. https://doi.org/10.1016/s0016-5085(97)70183-5
Shi J, Wu C, Lin Y, Chen YX, Zhu L, Xie WF. Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials. Am J Gastroenterol. 2006;101(7):1529-1538. https://doi.org/10.1111/j.1572-0241.2006.00634.x
Corpechot C, Abenavoli L, Rabahi N, Chrétien Y, Andréani T, Johanet C, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871-877. https://doi.org/10.1002/hep.22428
Kuiper EM, Hansen BE, de Vries RA, den Ouden-Muller JW, van Ditzhuijsen TJ, Haagsma EB, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136(4):1281-1287. https://doi.org/10.1053/j.gastro.2009.01.003
Kumagi T, Guindi M, Fischer SE, Arenovich T, Abdalian R, Coltescu C, et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 2010;105(10):2186-2194. https://doi.org/10.1038/ajg.2010.216
Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology. 2006;130(3):715-720. https://doi.org/10.1053/j.gastro.2005.12.029
Carbone M, Mells GF, Pells G, Dawwas MF, Newton JL, Heneghan MA, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology. 2013;144(3):560-569. e7; quiz e13-4. https://doi.org/10.1053/j.gastro.2012.12.005
Carbone M, Nardi A, Flack S, Carpino G, Varvaropoulou N, Gavrila C, et al. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score. Lancet Gastroenterol Hepatol. 2018;3(9):626-634. https://doi.org/10.1016/s2468-1253(18)30163-8
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(3):930-950. https://doi.org/10.1002/hep.28017
Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HL, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015;149(7):1804-1812.e4. https://doi.org/10.1053/j.gastro.2015.07.061
Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, et al. 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(6):1338-1349. e5; quiz e15. https://doi.org/10.1053/j.gastro.2014.08.029
Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631-643. https://doi.org/10.1056/nejmoa1509840
Murillo Perez CF, Fisher H, Hiu S, Kareithi D, Adekunle F, Mayne T, et al. Greater transplant-free survival in patients receiving obeticholic acid for primary biliary cholangitis in a clinical trial setting compared to real-world external controls. Gastroenterology. 2022;163(6):1630-1642.e3. https://doi.org/10.1053/j.gastro.2022.08.054
Honda A, Ikegami T, Nakamuta M, Miyazaki T, Iwamoto J, Hirayama T, et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology. 2013;57(5):1931-1941. https://doi.org/10.1002/hep.26018
Corpechot C, Chazouilleres 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(23):2171-2181. https://doi.org/10.1056/nejmoa1714519
Iwasaki S, Tsuda K, Ueta H, Aono R, Ono M, Saibara T, et al. Bezafibrate may have a beneficial effect in pre-cirrhotic primary biliary cirrhosis. Hepatol Res. 1999;16(1):12-18. https://doi.org/10.1016/s1386-6346(99)00033-9
Working Subgroup for Clinical Practice Guidelines for Primary Biliary C. Guidelines for the management of primary biliary cirrhosis: the intractable hepatobiliary disease study Group supported by the Ministry of Health, labour and Welfare of Japan. Hepatol Res. 2014;44(Suppl S1):71-90. https://doi.org/10.1111/hepr.12270
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(3):565-571. https://doi.org/10.1016/j.jhep.2021.04.010
Nakano T, Inoue K, Hirohara J, Arita S, Higuchi K, Omata M, et al. Long-term prognosis of primary biliary cirrhosis (PBC) in Japan and analysis of the factors of stage progression in asymptomatic PBC (a-PBC). Hepatol Res. 2002;22(4):250-260. https://doi.org/10.1016/s1386-6346(01)00148-6
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):S25-S37. https://doi.org/10.1016/j.jhep.2015.02.023
Trauner M, Fuchs CD. Novel therapeutic targets for cholestatic and fatty liver disease. Gut. 2021;71(1):194-209. https://doi.org/10.1136/gutjnl-2021-324305
Colapietro F, Gershwin ME, Lleo A. PPAR agonists for the treatment of primary biliary cholangitis: old and new tales. J Transl Autoimmun. 2023;6:100188. https://doi.org/10.1016/j.jtauto.2023.100188
de Vries E, Bolier R, Goet J, Parés A, Verbeek J, de Vree M, et al. Fibrates for itch (FITCH) in fibrosing cholangiopathies: a double-blind, randomized, placebo-controlled trial. Gastroenterology. 2021;160(3):734-743.e6. https://doi.org/10.1053/j.gastro.2020.10.001
Levy C, Kendrick S, Bowlus CL, Tanaka A, Jones D, Kremer AE, et al. GLIMMER: a randomized phase 2b dose-ranging trial of linerixibat in primary biliary cholangitis patients with pruritus. Clin Gastroenterol Hepatol. 2022. https://doi.org/10.1016/j.cgh.2022.10.032
Tanaka A, Atsukawa M, Tsuji K, Notsumata K, Suyama A, Ito H, et al. Japanese subgroup analysis of GLIMMER: a global Phase IIb study of linerixibat for the treatment of cholestatic pruritus in patients with primary biliary cholangitis. Hepatol Res. 2023. https://doi.org/10.1111/hepr.13895