Novel Treatment Strategies for Primary Biliary Cholangitis

Abstract

Despite the presumed immunological pathogenesis of primary biliary cholangitis, no clear or even harmful consequences have resulted from treatments designed to modify the immunological condition. Ursodeoxycholic acid (13–16 mg/kg/d) has, however, clear favorable effects that not only improve biochemical cholestasis, but also delay histological progression. Long-term treatment with ursodeoxycholic acid is associated with excellent transplant-free survival in cases showing a biochemical response at 1 year. Data on the effects of obeticholic acid and fibrates are encouraging. Moreover, recent pilot studies evaluating several biological agents targeting immunity such as different monoclonal antibodies and other drugs that modulate cholestasis are under investigation, although with limited results at present.

Keywords

ursodeoxycholic acid - fibrates - budesonide - obeticholic acid

• References

• 1 Beuers U, Gershwin ME, Gish RG , et al. Changing nomenclature for PBC: from ‘cirrhosis’ to ‘cholangitis’. Gastroenterology 2015; 149 (6) 1627-1629
• 2 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51 (2) 237-267
• 3 Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology 2009; 50 (1) 291-308
• 4 Parés A, Rodés J. Natural history of primary biliary cirrhosis. Clin Liver Dis 2003; 7 (4) 779-794
• 5 Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet 2015; 386 (10003): 1565-1575
• 6 Jones DE. Pathogenesis of primary biliary cirrhosis. Gut 2007; 56 (11) 1615-1624
• 7 Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol 2013; 8: 303-330
• 8 Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 2006; 3 (6) 318-328
• 9 Poupon R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Clin Res Hepatol Gastroenterol 2012; 36 (Suppl. 01) S3-S12
• 10 Poupon R, Chrétien Y, Poupon RE, Ballet F, Calmus Y, Darnis F. Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis?. Lancet 1987; 1 (8537): 834-836
• 11 Poupon RE, Balkau B, Eschwège E, Poupon R ; UDCA-PBC Study Group. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med 1991; 324 (22) 1548-1554
• 12 Lindor KD, Dickson ER, Baldus WP , et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 1994; 106 (5) 1284-1290
• 13 Heathcote EJ, Cauch-Dudek K, Walker V , et al. The Canadian multicenter double-blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994; 19 (5) 1149-1156
• 14 Combes B, Carithers Jr RL, Maddrey WC , et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1995; 22 (3) 759-766
• 15 Parés A, Caballería L, Rodés J , et al; UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. J Hepatol 2000; 32 (4) 561-566
• 16 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 (1) 12-16
• 17 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
• 18 Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 1999; 354 (9184): 1053-1060
• 19 Gong Y, Huang Z, Christensen E, Gluud C. Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review and meta-analysis of randomized clinical trials using Bayesian approach as sensitivity analyses. Am J Gastroenterol 2007; 102 (8) 1799-1807
• 20 Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2012; 12: CD000551
• 21 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
• 22 Angulo P, Dickson ER, Therneau TM , et al. Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a randomized trial. J Hepatol 1999; 30 (5) 830-835
• 23 Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology 2006; 130 (3) 715-720
• 24 Corpechot C, Abenavoli L, Rabahi N , et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008; 48 (3) 871-877
• 25 Kuiper EM, Hansen BE, de Vries RA , et al; Dutch PBC Study Group. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology 2009; 136 (4) 1281-1287
• 26 Kumagi T, Guindi M, Fischer SE , et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol 2010; 105 (10) 2186-2194
• 27 Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol 2011; 55 (6) 1361-1367
• 28 Zhang LN, Shi TY, Shi XH , et al. Early biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis: results of a 14-year cohort study. Hepatology 2013; 58 (1) 264-272
• 29 Lammers WJ, van Buuren HR, Hirschfield GM , 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 (6) 1338-49.e5 , quiz e15
• 30 Lammers WJ, Hirschfield GM, Corpechot C , 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 (7) 1804-1812.e4
• 31 Carbone M, Sharp SJ, Flack S , et al; UK-PBC Consortium. 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
• 32 Cavazza A, Caballería L, Floreani A , et al. Incidence, risk factors, and survival of hepatocellular carcinoma in primary biliary cirrhosis: comparative analysis from two centers. Hepatology 2009; 50 (4) 1162-1168
• 33 Kuiper EM, Hansen BE, Adang RP , et al; Dutch PBC Study Group. Relatively high risk for hepatocellular carcinoma in patients with primary biliary cirrhosis not responding to ursodeoxycholic acid. Eur J Gastroenterol Hepatol 2010; 22 (12) 1495-1502
• 34 Jackson H, Solaymani-Dodaran M, Card TR, Aithal GP, Logan R, West J. Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: a population-based cohort study. Hepatology 2007; 46 (4) 1131-1137
• 35 Trivedi PJ, Lammers WJ, van Buuren HR , et al; Global PBC Study Group. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut 2016; 65 (2) 321-329
• 36 Pellicciari R, Fiorucci S, Camaioni E , et al. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 2002; 45 (17) 3569-3572
• 37 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 (1) 147-191
• 38 Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008; 7 (8) 678-693
• 39 Trauner M, Halilbasic E. Nuclear receptors as new perspective for the management of liver diseases. Gastroenterology 2011; 140 (4) 1120-1125.e1 , 12
• 40 Fiorucci S, Antonelli E, Rizzo G , et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 2004; 127 (5) 1497-1512
• 41 Nevens F, Andreone P, Mazzella G , et al; POISE Study Group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016; 375 (7) 631-643
• 42 Hirschfield GM, Mason A, Luketic V , et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148 (4) 751-61.e8
• 43 Kowdley KV, Jones D, Luketic V , et al. An international study evaluating the farnesoid X receptor agonist obeticholic acid as monotherapy in PBC. J Hepatol 2011; 54: S13
• 44 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 (10) 2990-2992
• 45 Miyaguchi S, Ebinuma H, Imaeda H , et al. A novel treatment for refractory primary biliary cirrhosis?. Hepatogastroenterology 2000; 47 (36) 1518-1521
• 46 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 (1) 326-327
• 47 Ohmoto K, Mitsui Y, Yamamoto S. Effect of bezafibrate in primary biliary cirrhosis: a pilot study. Liver 2001; 21 (3) 223-224
• 48 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 (4) 1075-1077
• 49 Ohira H, Sato Y, Ueno T, Sata M. Fenofibrate treatment in patients with primary biliary cirrhosis. Am J Gastroenterol 2002; 97 (8) 2147-2149
• 50 Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients?. J Gastroenterol 2003; 38 (6) 573-578
• 51 Akbar SM, Furukawa S, Nakanishi S, Abe M, Horiike N, Onji M. Therapeutic efficacy of decreased nitrite production by bezafibrate in patients with primary biliary cirrhosis. J Gastroenterol 2005; 40 (2) 157-163
• 52 Kita R, Takamatsu S, Kimura T, Kokuryu H, Osaki Y, Tomono N. Bezafibrate may attenuate biliary damage associated with chronic liver diseases accompanied by high serum biliary enzyme levels. J Gastroenterol 2006; 41 (7) 686-692
• 53 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 (6) 894-898
• 54 Itakura J, Izumi N, Nishimura Y , et al. Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis. Hepatol Res 2004; 29 (4) 216-222
• 55 Iwasaki S, Ohira H, Nishiguchi S , et al; Study Group of Intractable Liver Diseases for Research on a Specific Disease, Health Science Research Grant, Ministry of Health, Labour and Welfare of Japan. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study. Hepatol Res 2008; 38 (6) 557-564
• 56 Walker LJ, Newton J, Jones DE, Bassendine MF. Comment on biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2009; 49 (1) 337-338 , author reply 338
• 57 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
• 58 Hazzan R, Tur-Kaspa R. Bezafibrate treatment of primary biliary cirrhosis following incomplete response to ursodeoxycholic acid. J Clin Gastroenterol 2010; 44 (5) 371-373
• 59 Levy C, Peter JA, Nelson DR , et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther 2011; 33 (2) 235-242
• 60 Lens S, Leoz M, Nazal L, Bruguera M, Parés A. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int 2014; 34 (2) 197-203
• 61 Hosonuma K, Sato K, Yamazaki Y , 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 (3) 423-431
• 62 Cheung AC, Lapointe-Shaw L, Kowgier M , 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 (2) 283-293
• 63 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 (3) 296-306
• 64 Reig A, Sese P, Pares A. Long-term therapy with bezafibrate and ursodeoxycholic acid is insufficient for preventing disease progression in patients with advanced primary biliary cirrhosis. J Hepatol 2015; 62: S806
• 65 Reig A, Pérez-Cormenzana M, Sesé P, Mayo R, Castro A, Pares A. Bezafibrate alleviates pruritus and decreases specific circulating metabolites in patients with primary biliary cholangitis. J Hepatol 2016; 64: S429 (abstract)
• 66 Harms MH, Cheung AC, van Buuren HR , et al. Comparable beneficial effects of beza- and fenofibrate in primary biliary cholangitis. An international study in UDCA-treated patients. Hepatology 2016; 63: 108A-109A
• 67 Matsumoto T, Miyazaki H, Nakahashi Y , et al. Multidrug resistance3 is in situ detected in the liver of patients with primary biliary cirrhosis, and induced in human hepatoma cells by bezafibrate. Hepatol Res 2004; 30 (3) 125-136
• 68 Honda A, Ikegami T, Nakamuta M , et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology 2013; 57 (5) 1931-1941
• 69 Ghonem NS, Assis DN, Boyer JL. Fibrates and cholestasis. Hepatology 2015; 62 (2) 635-643
• 70 Xie M-H, Holcomb I, Deuel B , et al. FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine 1999; 11 (10) 729-735
• 71 Zhang JH, Nolan JD, Kennie SL , et al. Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids. Am J Physiol Gastrointest Liver Physiol 2013; 304 (10) G940-G948
• 72 Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 2014; 11 (1) 55-67
• 73 Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-deficient mice. Hepatology 2016; 63 (3) 914-929
• 74 Luo J, Ko B, To C , et al. Hepatoprotective effects of NGM282 compared to obeticholic acid and bezafibrate in mouse models of cholestasis. J Hepatol 2014; 60: S531 (Abstract)
• 75 Mayo M, Wigg A, Roberts S , et al. NGM282, a novel variant of FGF-19, demonstrates biologic activity in primary biliary cirrhosis patients with an incomplete response to ursodeoxycholic acid: results of a phase 2 multicenter, randomized, double blinded, placebo controlled trial. Hepatology 2015; 62: 263A
• 76 Weinberg SL, Burckhardt G, Wilson FA. Taurocholate transport by rat intestinal basolateral membrane vesicles. Evidence for the presence of an anion exchange transport system. J Clin Invest 1986; 78 (1) 44-50
• 77 Miethke AG, Zhang W, Simmons J , et al. Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice. Hepatology 2016; 63 (2) 512-523
• 78 Mayo MJ, Pockros P, Jones D , et al. Clarity: A phase 2, randomized, doublé-blind, placebo-controlled study of lopixibat chloride (formerly LUM001), a novel apical sodium-dependent bile acid transporter inhibitor, in the treatment of primary biliary cirrhosis associated with itching. J Hepatol 2016; 64: S197 (abstract)
• 79 Kawamata Y, Fujii R, Hosoya M , et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003; 278 (11) 9435-9440
• 80 Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Häussinger D. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 2009; 50 (3) 861-870
• 81 Wang YD, Chen WD, Yu D, Forman BM, Huang W. The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor κ light-chain enhancer of activated B cells (NF-κB) in mice. Hepatology 2011; 54 (4) 1421-1432
• 82 Baghdasaryan A, Claudel T, Gumhold J , et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO⁻ ₃ output. Hepatology 2011; 54 (4) 1303-1312
• 83 Alemi F, Kwon E, Poole DP , et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 2013; 123 (4) 1513-1530
• 84 Lieu T, Jayaweera G, Zhao P , et al. The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 2014; 147 (6) 1417-1428
• 85 Hofmann AF, Zakko SF, Lira M , et al. Novel biotransformation and physiological properties of norursodeoxycholic acid in humans. Hepatology 2005; 42 (6) 1391-1398
• 86 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. Gastroenterology 2006; 130 (2) 465-481
• 87 Trauner M, Fickert P, Hirschfield G , et al. Norursodeoxycholic acid improves cholestasis in primary sclerosing cholangitis: results of a phase II dose finding study. J Hepatol 2016; 64: S208 (abstract)
• 88 Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008; 8 (9) 685-698
• 89 D'Aldebert E, Biyeyeme Bi Mve MJ, Mergey M , et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology 2009; 136 (4) 1435-1443
• 90 Agmon-Levin N, Kopilov R, Selmi C , et al. Vitamin D in primary biliary cirrhosis, a plausible marker of advanced disease. Immunol Res 2015; 61 (1-2) 141-146
• 91 Leuschner M, Güldütuna S, You T, Hübner K, Bhatti S, Leuschner U. Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J Hepatol 1996; 25 (1) 49-57
• 92 Leuschner M, Maier KP, Schlichting J , et al. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology 1999; 117 (4) 918-925
• 93 Angulo P, Jorgensen RA, Keach JC, Dickson ER, Smith C, Lindor KD. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000; 31 (2) 318-323
• 94 Rautiainen H, Kärkkäinen P, Karvonen AL , et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology 2005; 41 (4) 747-752
• 95 Rabahi N, Chrétien Y, Gaouar F , et al. Triple therapy with ursodeoxycholic acid, budesonide and mycophenolate mofetil in patients with features of severe primary biliary cirrhosis not responding to ursodeoxycholic acid alone. Gastroenterol Clin Biol 2010; 34 (4-5): 283-287
• 96 Hempfling W, Grunhage F, Dilger K, Reichel C, Beuers U, Sauerbruch T. Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis. Hepatology 2003; 38 (1) 196-202
• 97 Moritoki Y, Lian ZX, Lindor K , et al. B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice. Hepatology 2009; 50 (6) 1893-1903
• 98 Tsuda M, Moritoki Y, Lian ZX , et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology 2012; 55 (2) 512-521
• 99 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 (6) 933-941
• 100 Tajiri K, Tsuneyama K, Miyazono T, Kawai K, Minemura M, Sugiyama T. A case of primary biliary cirrhosis that progressed rapidly after treatment involving rituximab. Case Rep Gastroenterol 2013; 7 (1) 195-201
• 101 Yoshida K, Yang GX, Zhang W , et al. Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice. Hepatology 2009; 50 (5) 1494-1500
• 102 Hirschfield GM, Liu X, Xu C , et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 2009; 360 (24) 2544-2555
• 103 Hirschfield GM, Gershwin ME, Strauss R , et al; PURIFI Study Group. Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: A proof-of-concept study. Hepatology 2016; 64 (1) 189-199
• 104 Dall'Era M, Davis J. CTLA4Ig: a novel inhibitor of costimulation. Lupus 2004; 13 (5) 372-376
• 105 Ruperto N, Lovell DJ, Quartier P , et al; Paediatric Rheumatology INternational Trials Organization; Pediatric Rheumatology Collaborative Study Group. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet 2008; 372 (9636): 383-391
• 106 Dhirapong A, Yang GX, Nadler S , et al. Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology 2013; 57 (2) 708-715
• 107 Triantafillidis JK, Durakis S, Merikas E. Crohn's disease of the small bowel, complicated by primary biliary cirrhosis, Hashimoto thyroiditis, and Raynaud's phenomenon: favorable response of all disorders to adalimumab treatment. Gastroenterol Hepatol Bed Bench 2013; 6 (2) 101-105
• 108 Xu L, Shen Z, Guo L , et al. Does a betaretrovirus infection trigger primary biliary cirrhosis?. Proc Natl Acad Sci U S A 2003; 100 (14) 8454-8459
• 109 Mason AL, Farr GH, Xu L, Hubscher SG, Neuberger JM. Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis. Am J Gastroenterol 2004; 99 (12) 2348-2355
• 110 Mason AL, Lindor KD, Bacon BR, Vincent C, Neuberger JM, Wasilenko ST. Clinical trial: randomized controlled study of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol. Aliment Pharmacol Ther 2008; 28 (7) 886-894
• 111 Sun L, Wang D, Liang J , et al. Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum 2010; 62 (8) 2467-2475
• 112 Liu Y, Mu R, Wang S , et al. Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Arthritis Res Ther 2010; 12 (6) R210
• 113 Wang D, Zhang H, Liang J , et al. Effect of allogeneic bone marrow-derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model. Clin Exp Med 2011; 11 (1) 25-32
• 114 Wang L, Li J, Liu H , et al. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis. J Gastroenterol Hepatol 2013; 28 (Suppl. 01) 85-92
• 115 Wang L, Han Q, Chen H , et al. Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis. Stem Cells Dev 2014; 23 (20) 2482-2489