Bezafibrate Improves GLOBE and UK-PBC Scores and Long-Term Outcomes in Patients With Primary Biliary Cholangitis.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
26
03
2018
accepted:
02
02
2019
pubmed:
10
2
2019
medline:
1
7
2020
entrez:
10
2
2019
Statut:
ppublish
Résumé
In Japan, bezafibrate (BF) is a second-line agent for primary biliary cholangitis (PBC) that is refractory to ursodeoxycholic acid (UDCA) treatment. From a retrospective cohort (n = 873) from the Japan PBC Study Group, we enrolled 118 patients who had received UDCA monotherapy for at least 1 year followed by combination therapy with UDCA+BF for at least 1 year. GLOBE and UK-PBC scores after UDCA monotherapy (i.e., immediately before UDCA+BF combination therapy) were compared with those after 1 year of UDCA+BF combination therapy. The real outcomes of enrolled patients estimated by Kaplan-Meier analysis were compared with the predicted outcomes calculated using GLOBE and UK-PBC scores. In addition, the hazard ratio of BF treatment was calculated using propensity score analysis. The mean GLOBE score before the combination therapy was 0.504 ± 0.080, which improved significantly to 0.115 ± 0.085 (P < 0.0001) after 1 year of combination therapy. The real liver transplant-free survival of enrolled patients was significantly better than that predicted by GLOBE score before introducing BF. Combination therapy did not significantly improve the real rates of liver transplantation or liver-related death compared with those predicted by UK-PBC risk score before introducing BF, but the predicted risk was significantly reduced by the addition of BF (P < 0.0001). Cox regression analysis with inverse probability of treatment weighting showed that the addition of BF significantly reduced the hazard of liver transplant or liver-related death in patients who, after 1 year of UDCA monotherapy, had normal serum bilirubin (adjusted hazard ratio 0.09, 95% confidence interval 0.01-0.60, P = 0.013). Conclusion: Addition of BF to UDCA monotherapy improves not only GLOBE and UK-PBC scores but also the long-term prognosis of PBC patients, especially those with early-stage PBC.
Substances chimiques
Ursodeoxycholic Acid
724L30Y2QR
Bezafibrate
Y9449Q51XH
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2035-2046Subventions
Organisme : Ministry of Health, Labour and Welfare of Japan
ID : Health and Labor Sciences Research Grant
Pays : International
Informations de copyright
© 2019 by the American Association for the Study of Liver Diseases.
Références
Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ, et al. Primary biliary cirrhosis. Hepatology 2009;50:291-308.
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237-267.
Working Subgroup for Clinical Practice Guidelines for Primary Biliary Cirrhosis. 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.
Oka H, Toda G, Ikeda Y, Hashimoto N, Hasumura Y, Kamimura T, et al. A multi-center double-blind controlled trial of ursodeoxycholic acid for primary biliary cirrhosis. Gastroenterol Jpn 1990;25:774-780.
Matsuzaki Y, Tanaka N, Osuga T, Aikawa T, Shoda J, Doi M, et al. Improvement of biliary enzyme levels and itching as a result of long-term administration of ursodeoxycholic acid in primary biliary cirrhosis. Am J Gastroenterol 1990;85:15-23.
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;324:1548-1554.
Ikegami T, Matsuzaki Y. Ursodeoxycholic acid: mechanism of action and novel clinical applications. Hepatol Res 2008;38:123-131.
Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005;128:297-303.
Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology 2006;130:715-720.
Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008;48:871-877.
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;136:1281-1287.
Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009;89:147-191.
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;375:631-643.
Samur S, Klebanoff M, Banken R, Pratt DS, Chapman R, Ollendorf DA, et al. Long-term clinical impact and cost-effectiveness of obeticholic acid for the treatment of primary biliary cholangitis. Hepatology 2017;65:920-928.
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;57:1931-1941.
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;16:12-18.
Miyaguchi S, Ebinuma H, Imaeda H, Nitta Y, Watanabe T, Saito H, et al. A novel treatment for refractory primary biliary cirrhosis? Hepatogastroenterology 2000;47:1518-1521.
Nakai S, Masaki T, Kurokohchi K, Deguchi A, Nishioka M. Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary cirrhosis: a preliminary study. Am J Gastroenterol 2000;95:326-327.
Ohmoto K, Mitsui Y, Yamamoto S. Effect of bezafibrate in primary biliary cirrhosis: a pilot study. Liver 2001;21:223-224.
Yano K, Kato H, Morita S, Takahara O, Ishibashi H, Furukawa R. Is bezafibrate histologically effective for primary biliary cirrhosis? Am J Gastroenterol 2002;97:1075-1077.
Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients? J Gastroenterol 2003;38:573-578.
Itakura J, Izumi N, Nishimura Y, Inoue K, Ueda K, Nakanishi H, et al. Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis. Hepatol Res 2004;29:216-222.
Iwasaki S, Ohira H, Nishiguchi S, Zeniya M, Kaneko S, Onji M, et al. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: a prospective, multicenter study. Hepatol Res 2008;38:557-564.
Ghonem NS, Boyer JL. Fibrates as adjuvant therapy for chronic cholestatic liver disease: its time has come. Hepatology 2013;57:1691-1693.
Hazzan R, Tur-Kaspa R. Bezafibrate treatment of primary biliary cirrhosis following incomplete response to ursodeoxycholic acid. J Clin Gastroenterol 2010;44:371-373.
Lens S, Leoz M, Nazal L, Bruguera M, Pares A. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int 2014;34:197-203.
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;378:2171-2181.
Reig A, Sese P, Pares A. Effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with suboptimal ursodeoxycholic acid response. Am J Gastroenterol 2018;113:49-55.
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;149:1804-1812.
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;63:930-950.
Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat Med 2014;33:1242-1258.
Hosonuma K, Sato K, Yamazaki Y, Yanagisawa M, Hashizume H, Horiguchi N, et al. A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia. Am J Gastroenterol 2015;110:423-431.
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;136:1281-1287.
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;105:2186-2194.
Corpechot C, Chazouilleres O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol 2011;55:1361-1367.
Papastergiou V, Tsochatzis EA, Rodriguez-Peralvarez M, Thalassinos E, Pieri G, Manousou P, et al. Biochemical criteria at 1 year are not robust indicators of response to ursodeoxycholic acid in early primary biliary cirrhosis: results from a 29-year cohort study. Aliment Pharmacol Ther 2013;38:1354-1364.
Yang F, Yang Y, Wang Q, Wang Z, Miao Q, Xiao X, et al. The risk predictive values of UK-PBC and GLOBE scoring system in Chinese patients with primary biliary cholangitis: the additional effect of anti-gp210. Aliment Pharmacol Ther 2017;45:733-743.
Tanaka A, Komori A, Abe M, Inao M, Namisaki T, Hashimoto N, et al. Are the Globe and UK-PBC scores also effective for predicting risk in patients treated with bezafibrate in addition to ursodeoxycholic acid? A validation study in Japan. J Hepatol 2018;68:S5.
Tanaka A, Hirohara J, Nakanuma Y, Tsubouchi H, Takikawa H. Biochemical responses to bezafibrate improve long-term outcome in asymptomatic patients with primary biliary cirrhosis refractory to UDCA. J Gastroenterol 2015;50:675-682.
Ohira H, Sato Y, Ueno T, Sata M. Fenofibrate treatment in patients with primary biliary cirrhosis. Am J Gastroenterol 2002;97:2147-2149.
Dohmen K, Mizuta T, Nakamuta M, Shimohashi N, Ishibashi H, Yamamoto K. Fenofibrate for patients with asymptomatic primary biliary cirrhosis. World J Gastroenterol 2004;10:894-898.
Liberopoulos EN, Florentin M, Elisaf MS, Mikhailidis DP, Tsianos E. Fenofibrate in primary biliary cirrhosis: a pilot study. Open Cardiovasc Med J 2010;4:120-126.
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;33:235-242.
Han XF, Wang QX, Liu Y, You ZR, Bian ZL, Qiu DK, et al. Efficacy of fenofibrate in Chinese patients with primary biliary cirrhosis partially responding to ursodeoxycholic acid therapy. J Dig Dis 2012;13:219-224.
Grigorian AY, Mardini HE, Corpechot C, Poupon R, Levy C. Fenofibrate is effective adjunctive therapy in the treatment of primary biliary cirrhosis: a meta-analysis. Clin Res Hepatol Gastroenterol 2015;39:296-306.
Zhang Y, Li S, He L, Wang F, Chen K, Li J, et al. Combination therapy of fenofibrate and ursodeoxycholic acid in patients with primary biliary cirrhosis who respond incompletely to UDCA monotherapy: a meta-analysis. Drug Des Devel Ther 2015;9:2757-2766.
Cheung AC, Lapointe-Shaw L, Kowgier M, Meza-Cardona J, Hirschfield GM, Janssen HL, et al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther 2016;43:283-293.
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;61:3037-3044.
van Hoogstraten HJ, Hansen BE, van Buuren HR, ten Kate FJ, van Berge-Henegouwen GP, Schalm SW for the Dutch Multi-Centre PBC Study Group. Prognostic factors and long-term effects of ursodeoxycholic acid on liver biochemical parameters in patients with primary biliary cirrhosis. J Hepatol 1999;31:256-262.