原发性胆汁性胆管炎与干燥综合征的关系

肖秋凤; 费允云

doi:10.3969/j.issn.1001-5256.2021.10.002

原发性胆汁性胆管炎与干燥综合征的关系

DOI: 10.3969/j.issn.1001-5256.2021.10.002

肖秋凤^{1, 2, 3},
费允云^{1, 2, 3, ,}

1.
中国医学科学院，北京 100730
2.
北京协和医学院，北京 100730
3.
北京协和医院风湿免疫科，风湿免疫病学教育部重点实验室，北京 100730

详细信息

通信作者:
费允云，feiyunyun@pumch.cn

中图分类号: R575.22;R593.2
计量
- 文章访问数: 1183
- HTML全文浏览量: 287
- PDF下载量: 181
- 被引次数: 0
出版历程
- 收稿日期: 2021-08-13
- 录用日期: 2021-08-28
- 出版日期: 2021-10-20

The relationship between primary biliary cholangitis and Sjögren's syndrome

Qiufeng XIAO^{1, 2, 3},
Yunyun FEI^{1, 2, 3
, ,}

1.
Chinese Academy of Medical Sciences, Beijing 100730, China
2.
Peking Union Medical College, Beijing 100730, China
3.
Key Laboratory of Rheumatic Diseases, Ministry of Education, Department of Rheumatology & Immunology, Peking Union Medical College Hospital, Beijing 100730, China

摘要

摘要: 原发性胆汁性胆管炎与干燥综合征都属于慢性自身免疫上皮细胞炎症，经常合并出现。旨在对原发性胆汁性胆管炎和干燥综合征的一般特点、临床表现、血清学特点、发病机制、治疗方案以及共同特征进行综述，探究二者共同的发病机制，为开发新疗法提供思路，更好地管理患者。
- 肝硬化, 胆汁性 /
- 干燥综合征 /
- 自身免疫疾病 /
- 免疫稳态破坏
Abstract: Both primary biliary cholangitis and Sjögren's syndrome belong to chronic autoimmune epithelitis, and they often occur at the same time. This article reviews the general features, clinical manifestations, serological features, pathogenesis, treatment regimens, and common features of primary biliary cholangitis and Sjögren's syndrome and explores the common pathogenesis of the two diseases, so as to provide ideas for developing new therapies and management strategies for patients.
- Liver Cirrhosis, Biliary /
- Sjogren's Syndrome /
- Autoimmune Diseases /
- Tolerance Breakdown

HTML全文

参考文献(79)

[1]	GULAMHUSEIN AF, HIRSCHFIELD GM. Primary biliary cholangitis: Pathogenesis and therapeutic opportunities[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(2): 93-110. DOI: 10.1038/s41575-019-0226-7.
[2]	YOUNOSSI ZM, BERNSTEIN D, SHIFFMAN ML, et al. Diagnosis and management of primary biliary cholangitis[J]. Am J Gastroenterol, 2019, 114(1): 48-63. DOI: 10.1038/s41395-018-0390-3.
[3]	BRITO-ZERÓN P, BALDINI C, BOOTSMA H, et al. Sjögren syndrome[J]. Nat Rev Dis Primers, 2016, 2: 16047. DOI: 10.1038/nrdp.2016.47.
[4]	SUN Y, ZHANG W, LI B, et al. The coexistence of Sjögren's syndrome and primary biliary cirrhosis: A comprehensive review[J]. Clin Rev Allergy Immunol, 2015, 48(2-3): 301-315. DOI: 10.1007/s12016-015-8471-1.
[5]	GERSHWIN ME, SELMI C, WORMAN HJ, et al. Risk factors and comorbidities in primary biliary cirrhosis: A controlled interview-based study of 1032 patients[J]. Hepatology, 2005, 42(5): 1194-1202. DOI: 10.1002/hep.20907.
[6]	CHALIFOUX SL, KONYN PG, CHOI G, et al. Extrahepatic manifestations of primary biliary cholangitis[J]. Gut Liver, 2017, 11(6): 771-780. DOI: 10.5009/gnl16365.
[7]	HATZIS GS, FRAGOULIS GE, KARATZAFERIS A, et al. Prevalence and longterm course of primary biliary cirrhosis in primary Sjögren's syndrome[J]. J Rheumatol, 2008, 35(10): 2012-2016.
[8]	de SANTIS M, CROTTI C, SELMI C. Liver abnormalities in connective tissue diseases[J]. Best Pract Res Clin Gastroenterol, 2013, 27(4): 543-551. DOI: 10.1016/j.bpg.2013.06.016.
[9]	CHEN WQ, DAI XN, YU Y, et al. Analysis of clinical features and prognosis in patients with primary Sjögren's syndrome and autoimmune liver disease[J]. J Peking Univ(Health Sci), 2020, 52(5): 886-891. DOI: 10.19723/j.issn.1671-167X.2020.05.015. 陈伟钱, 戴小娜, 余叶, 等. 原发性干燥综合征合并自身免疫性肝病的临床特点及预后分析[J]. 北京大学学报(医学版), 2020, 52(5): 886-891. DOI: 10.19723/j.issn.1671-167X.2020.05.015.
[10]	ZHANG XD, CHEN J, HUANG CY, et al. Clinical features of liver injury patients of primary Sjiögren's syndrome with autoimmune liver diseases[J]. Med Pharm J Chin PLA, 2020, 32(11): 63-66. DOI: 10.3969/j.issn.2095-140X.2020.11.014. 张小丹, 陈杰, 黄春洋, 等. 原发性干燥综合征合并自身免疫性肝病的临床特征分析[J]. 解放军医药杂志, 2020, 32(11): 63-66. DOI: 10.3969/j.issn.2095-140X.2020.11.014.
[11]	SELMI C, MERONI PL, GERSHWIN ME. Primary biliary cirrhosis and Sjögren's syndrome: Autoimmune epithelitis[J]. J Autoimmun, 2012, 39(1-2): 34-42. DOI: 10.1016/j.jaut.2011.11.005.
[12]	WEN ZH, YAO FL, LING Q, et al. Similarities and differences between primary biliary cholangitis and Sjögren's syndrome[J]. Med J Natl Defending Forces Southwest China, 2019, 29(11): 1108-1110. DOI: 10.3969/j.issn.1004-0188.2019.11.006. 文振华, 姚芳玲, 凌青, 等. 原发性胆汁性胆管炎有无合并干燥综合征的异同[J]. 西南国防医药, 2019, 29(11): 1108-1110. DOI: 10.3969/j.issn.1004-0188.2019.11.006.
[13]	DÖRNER T, HELD C, TREBELJAHR G, et al. Serologic characteristics in primary biliary cirrhosis associated with sicca syndrome[J]. Scand J Gastroenterol, 1994, 29(7): 655-660. DOI: 10.3109/00365529409092488.
[14]	CAREY EJ, ALI AH, LINDOR KD. Primary biliary cirrhosis[J]. Lancet, 2015, 386(10003): 1565-1575. DOI: 10.1016/S0140-6736(15)00154-3.
[15]	MÆLAND E, MIYAMOTO ST, HAMMENFORS D, et al. Understanding fatigue in Sjögren's syndrome: Outcome measures, biomarkers and possible interventions[J]. Front Immunol, 2021, 12: 703079. DOI: 10.3389/fimmu.2021.703079.
[16]	VALDES-RODRIGUEZ R, ROWE B, LEE HG, et al. Chronic pruritus in primary Sjögren's syndrome: Characteristics and effect on quality of life[J]. Acta Derm Venereol, 2017, 97(3): 385-386. DOI: 10.2340/00015555-2524.
[17]	BERNACCHI E, AMATO L, PARODI A, et al. Sjögren's syndrome: A retrospective review of the cutaneous features of 93 patients by the Italian Group of Immunodermatology[J]. Clin Exp Rheumatol, 2004, 22(1): 55-62.
[18]	LENDREM D, MITCHELL S, MCMEEKIN P, et al. Do the EULAR Sjögren's syndrome outcome measures correlate with health status in primary Sjögren's syndrome?[J]. Rheumatology (Oxford), 2015, 54(4): 655-659. DOI: 10.1093/rheumatology/keu361.
[19]	GAO LX, WANG L, ZHANG FC. Clinical characteristics of primary biliary cirrhosis complicating Sjögren syndrome[J]. Natl Med J China, 2013, 93(43): 3457-3459. DOI: 10.3760/cma.j.issn.0376-2491.2013.43.013. 高丽霞, 王立, 张奉春. 原发性胆汁性肝硬化合并干燥综合征的临床特点分析[J]. 中华医学杂志, 2013, 93(43): 3457-3459. DOI: 10.3760/cma.j.issn.0376-2491.2013.43.013.
[20]	UDDENFELDT P, DANIELSSON A, FORSSELL A, et al. Features of Sjögren's syndrome in patients with primary biliary cirrhosis[J]. J Intern Med, 1991, 230(5): 443-448. DOI: 10.1111/j.1365-2796.1991.tb00470.x.
[21]	FLOREANI A, FRANCESCHET I, CAZZAGON N, et al. Extrahepatic autoimmune conditions associated with primary biliary cirrhosis[J]. Clin Rev Allergy Immunol, 2015, 48(2-3): 192-197. DOI: 10.1007/s12016-014-8427-x.
[22]	CHEN CT, TSENG YC, YANG CW, et al. Increased risks of spontaneous bacterial peritonitis and interstitial lung disease in primary biliary cirrhosis patients with concomitant Sjögren syndrome[J]. Medicine (Baltimore), 2016, 95(2): e2537. DOI: 10.1097/MD.0000000000002537.
[23]	MATTALIA A, QUARANTA S, LEUNG PS, et al. Characterization of antimitochondrial antibodies in health adults[J]. Hepatology, 1998, 27(3): 656-661. DOI: 10.1002/hep.510270303.
[24]	SHIBATA M, ONOZUKA Y, MORIZANE T, et al. Prevalence of antimitochondrial antibody in Japanese corporate workers in Kanagawa prefecture[J]. J Gastroenterol, 2004, 39(3): 255-259. DOI: 10.1007/s00535-003-1285-6.
[25]	ZANDANELL S, STRASSER M, FELDMAN A, et al. Low rate of new-onset primary biliary cholangitis in a cohort of anti-mitochondrial antibody-positive subjects over six years of follow-up[J]. J Intern Med, 2020, 287(4): 395-404. DOI: 10.1111/joim.13005.
[26]	SUN C, XIAO X, YAN L, et al. Histologically proven AMA positive primary biliary cholangitis but normal serum alkaline phosphatase: Is alkaline phosphatase truly a surrogate marker?[J]. J Autoimmun, 2019, 99: 33-38. DOI: 10.1016/j.jaut.2019.01.005.
[27]	KLATSKIN G, KANTOR FS. Mitochondrial antibody in primary biliary cirrhosis and other diseases[J]. Ann Intern Med, 1972, 77(4): 533-541. DOI: 10.7326/0003-4819-77-4-533.
[28]	GRANITO A, MURATORI P, QUARNETI C, et al. Antinuclear antibodies as ancillary markers in primary biliary cirrhosis[J]. Expert Rev Mol Diagn, 2012, 12(1): 65-74. DOI: 10.1586/erm.11.82.
[29]	REIG A, NORMAN GL, GARCIA M, et al. Novel anti-hexokinase 1 antibodies are associated with poor prognosis in patients with primary biliary cholangitis[J]. Am J Gastroenterol, 2020, 115(10): 1634-1641. DOI: 10.14309/ajg.0000000000000690.
[30]	MARIETTE X, CRISWELL LA. Primary Sjögren's syndrome[J]. N Engl J Med, 2018, 378(10): 931-939. DOI: 10.1056/NEJMcp1702514.
[31]	SKOPOULI FN, BARBATIS C, MOUTSOPOULOS HM. Liver involvement in primary Sjögren's syndrome[J]. Br J Rheumatol, 1994, 33(8): 745-748. DOI: 10.1093/rheumatology/33.8.745.
[32]	HANSEN BU, LINDGREN S, ERIKSSON S, et al. Clinical and immunological features of Sjögren's syndrome in patients with primary biliary cirrhosis with emphasis on focal sialadenitis[J]. Acta Med Scand, 1988, 224(6): 611-619. DOI: 10.1111/j.0954-6820.1988.tb19634.x.
[33]	GRANITO A, MURATORI P, MURATORI L, et al. Antibodies to SS-A/Ro-52kD and centromere in autoimmune liver disease: A clue to diagnosis and prognosis of primary biliary cirrhosis[J]. Aliment Pharmacol Ther, 2007, 26(6): 831-838. DOI: 10.1111/j.1365-2036.2007.03433.x.
[34]	TAKESHITA M, SUZUKI K, KANEDA Y, et al. Antigen-driven selection of antibodies against SSA, SSB and the centromere 'complex', including a novel antigen, MIS12 complex, in human salivary glands[J]. Ann Rheum Dis, 2020, 79(1): 150-158. DOI: 10.1136/annrheumdis-2019-215862.
[35]	KAJIO N, TAKESHITA M, SUZUKI K, et al. Anti-centromere antibodies target centromere-kinetochore macrocomplex: A comprehensive autoantigen profiling[J]. Ann Rheum Dis, 2021, 80(5): 651-659. DOI: 10.1136/annrheumdis-2020-218881.
[36]	CHANG JC, GO S, DE WAART DR, et al. Soluble adenylyl cyclase regulates bile salt-induced apoptosis in human cholangiocytes[J]. Hepatology, 2016, 64(2): 522-534. DOI: 10.1002/hep.28550.
[37]	HARADA K, FURUBO S, OZAKI S, et al. Increased expression of WAF1 in intrahepatic bile ducts in primary biliary cirrhosis relates to apoptosis[J]. J Hepatol, 2001, 34(4): 500-506. DOI: 10.1016/s0168-8278(00)00075-1.
[38]	OKUMA A, HOSHINO K, OHBA T, et al. Enhanced apoptosis by disruption of the STAT3-IκB-ζ signaling pathway in epithelial cells induces Sjögren's syndrome-like autoimmune disease[J]. Immunity, 2013, 38(3): 450-460. DOI: 10.1016/j.immuni.2012.11.016.
[39]	NAKAMURA H, TANAKA T, PRANZATELLI T, et al. Lysosome-associated membrane protein 3 misexpression in salivary glands induces a Sjögren's syndrome-like phenotype in mice[J]. Ann Rheum Dis, 2021, 80(8): 1031-1039. DOI: 10.1136/annrheumdis-2020-219649.
[40]	MEI M, QU LH, CONG X, et al. CTRP3 promotes TNF-α-induced apoptosis and barrier dysfunction in salivary epithelial cells[J]. Cell Signal, 2021, 85: 110042. DOI: 10.1016/j.cellsig.2021.110042.
[41]	AINOLA M, POROLA P, TAKAKUBO Y, et al. Activation of plasmacytoid dendritic cells by apoptotic particles-mechanism for the loss of immunological tolerance in Sjögren's syndrome[J]. Clin Exp Immunol, 2018, 191(3): 301-310. DOI: 10.1111/cei.13077.
[42]	SHIMODA S, MIYAKAWA H, NAKAMURA M, et al. CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis[J]. J Autoimmun, 2008, 31(2): 110-115. DOI: 10.1016/j.jaut.2008.05.003.
[43]	KITA H, LIAN ZX, van de WATER J, et al. Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells[J]. J Exp Med, 2002, 195(1): 113-123. DOI: 10.1084/jem.20010956.
[44]	ADAMSON TC 3rd, FOX RI, FRISMAN DM, et al. Immunohistologic analysis of lymphoid infiltrates in primary Sjögren's syndrome using monoclonal antibodies[J]. J Immunol, 1983, 130(1): 203-208.
[45]	SPENGLER U, MÖLLER A, JUNG MC, et al. T lymphocytes from patients with primary biliary cirrhosis produce reduced amounts of lymphotoxin, tumor necrosis factor and interferon-gamma upon mitogen stimulation[J]. J Hepatol, 1992, 15(1-2): 129-135. DOI: 10.1016/0168-8278(92)90024-j.
[46]	YANG CY, MA X, TSUNEYAMA K, et al. IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: Implications for therapy[J]. Hepatology, 2014, 59(5): 1944-1953. DOI: 10.1002/hep.26979.
[47]	YAO Y, MA JF, CHANG C, et al. Immunobiology of T cells in Sjögren's syndrome[J]. Clin Rev Allergy Immunol, 2021, 60(1): 111-131. DOI: 10.1007/s12016-020-08793-7.
[48]	LIASKOU E, PATEL SR, WEBB G, et al. Increased sensitivity of Treg cells from patients with PBC to low dose IL-12 drives their differentiation into IFN-γ secreting cells[J]. J Autoimmun, 2018, 94: 143-155. DOI: 10.1016/j.jaut.2018.07.020.
[49]	XIAO F, LIN X, TIAN J, et al. Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren's syndrome[J]. Cell Mol Immunol, 2017, 14(11): 924-934. DOI: 10.1038/cmi.2017.8.
[50]	VERSTAPPEN GM, CORNETH O, BOOTSMA H, et al. Th17 cells in primary Sjögren's syndrome: Pathogenicity and plasticity[J]. J Autoimmun, 2018, 87: 16-25. DOI: 10.1016/j.jaut.2017.11.003.
[51]	SZABO K, PAPP G, BARATH S, et al. Follicular helper T cells may play an important role in the severity of primary Sjögren's syndrome[J]. Clin Immunol, 2013, 147(2): 95-104. DOI: 10.1016/j.clim.2013.02.024.
[52]	VERSTAPPEN GM, NAKSHBANDI U, MOSSEL E, et al. Is the T follicular regulatory: Follicular helper T cell ratio in blood a biomarker for ectopic lymphoid structure formation in Sjögren's syndrome? Comment on the article by fonseca et al[J]. Arthritis Rheumatol, 2018, 70(8): 1354-1355. DOI: 10.1002/art.40488.
[53]	FONSECA VR, ROMÃO VC, AGUA-DOCE A, et al. The ratio of blood T follicular regulatory cells to T follicular helper cells marks ectopic lymphoid structure formation while activated follicular helper T cells indicate disease activity in primary Sjögren's syndrome[J]. Arthritis Rheumatol, 2018, 70(5): 774-784. DOI: 10.1002/art.40424.
[54]	CARGILL T, CULVER EL. The role of B cells and B cell therapies in immune-mediated liver diseases[J]. Front Immunol, 2021, 12: 661196. DOI: 10.3389/fimmu.2021.661196.
[55]	NOCTURNE G, MARIETTE X. B cells in the pathogenesis of primary Sjögren syndrome[J]. Nat Rev Rheumatol, 2018, 14(3): 133-145. DOI: 10.1038/nrrheum.2018.1.
[56]	CICHOŻ-LACH H, GRYWALSKA E, MICHALAK A, et al. Deviations in peripheral blood cell populations are associated with the stage of primary biliary cholangitis and presence of itching[J]. Arch Immunol Ther Exp (Warsz), 2018, 66(6): 443-452. DOI: 10.1007/s00005-018-0515-9.
[57]	LI Y, WANG W, TANG L, et al. Chemokine (C-X-C motif) ligand 13 promotes intrahepatic chemokine (C-X-C motif) receptor 5+ lymphocyte homing and aberrant B-cell immune responses in primary biliary cirrhosis[J]. Hepatology, 2015, 61(6): 1998-2007. DOI: 10.1002/hep.27725.
[58]	HORST AK, KUMASHIE KG, NEUMANN K, et al. Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease[J]. Cell Mol Immunol, 2021, 18(1): 92-111. DOI: 10.1038/s41423-020-00568-6.
[59]	HARADA K, van de WATER J, LEUNG PS, et al. In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: Predominance of the Th1 subset[J]. Hepatology, 1997, 25(4): 791-796. DOI: 10.1002/hep.510250402.
[60]	MARIETTE X, ROUX S, ZHANG J, et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren's syndrome[J]. Ann Rheum Dis, 2003, 62(2): 168-171. DOI: 10.1136/ard.62.2.168.
[61]	GOTTENBERG JE, SEROR R, MICELI-RICHARD C, et al. Serum levels of beta2-microglobulin and free light chains of immunoglobulins are associated with systemic disease activity in primary Sjögren's syndrome. Data at enrollment in the prospective ASSESS cohort[J]. PLoS One, 2013, 8(5): e59868. DOI: 10.1371/journal.pone.0059868.
[62]	QUARTUCCIO L, SALVIN S, FABRIS M, et al. BLyS upregulation in Sjögren's syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands[J]. Rheumatology (Oxford), 2013, 52(2): 276-281. DOI: 10.1093/rheumatology/kes180.
[63]	MAGRI G, MIYAJIMA M, BASCONES S, et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells[J]. Nat Immunol, 2014, 15(4): 354-364. DOI: 10.1038/ni.2830.
[64]	PUGA I, COLS M, BARRA CM, et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen[J]. Nat Immunol, 2011, 13(2): 170-180. DOI: 10.1038/ni.2194.
[65]	MINGUENEAU M, BOUDAOUD S, HASKETT S, et al. Cytometry by time-of-flight immunophenotyping identifies a blood Sjögren's signature correlating with disease activity and glandular inflammation[J]. J Allergy Clin Immunol, 2016, 137(6): 1809-1821. e12. DOI: 10.1016/j.jaci.2016.01.024.
[66]	SUN JL, ZHANG HZ, LIU SY, et al. Elevated EPSTI1 promote B cell hyperactivation through NF-κB signalling in patients with primary Sjögren's syndrome[J]. Ann Rheum Dis, 2020, 79(4): 518-524. DOI: 10.1136/annrheumdis-2019-216428.
[67]	LLEO A, WANG GQ, GERSHWIN ME, et al. Primary biliary cholangitis[J]. Lancet, 2020, 396(10266): 1915-1926. DOI: 10.1016/s0140-6736(20)31607-x
[68]	BJÖRK A, MOFORS J, WAHREN-HERLENIUS M. Environmental factors in the pathogenesis of primary Sjögren's syndrome[J]. J Intern Med, 2020, 287(5): 475-492. DOI: 10.1111/joim.13032.
[69]	LEONARDI A, MESSMER EM, LABETOULLE M, et al. Efficacy and safety of 0.1% ciclosporin A cationic emulsion in dry eye disease: A pooled analysis of two double-masked, randomised, vehicle-controlled phase Ⅲ clinical studies[J]. Br J Ophthalmol, 2019, 103(1): 125-131. DOI: 10.1136/bjophthalmol-2017-311801.
[70]	ZHANG X, TANG FL, LI YZ, et al. Clinical and pathological features of primary biliary cirrhosis[J]. Chin J Rheumatol, 2001, 5(2): 98-101. DOI: 10.3760/j:issn:1007-7480.2001.02.007. 张烜, 唐福林, 李永哲, 等. 原发性胆汁性肝硬化的临床及病理分析[J]. 中华风湿病学杂志, 2001, 5(2): 98-101. DOI: 10.3760/j:issn:1007-7480.2001.02.007.
[71]	Rheumatology Branch of Chinese Medical Association. Guidelines for diagnosis and treatment of Sjögren's syndrome[J]. Chin J Rheumatol, 2010, 14(11): 766-768. DOI: 10.3760/cma.j.issn.1007-7480.2010.11.011. 中华医学会风湿病学分会. 干燥综合征诊断及治疗指南[J]. 中华风湿病学杂志, 2010, 14(11): 766-768. DOI: 10.3760/cma.j.issn.1007-7480.2010.11.011.
[72]	REIG A, SESÉ P, PARÉS A. Effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with suboptimal ursodeoxycholic acid response[J]. Am J Gastroenterol, 2018, 113(1): 49-55. DOI: 10.1038/ajg.2017.287.
[73]	CAREY EJ. Progress in primary biliary cholangitis[J]. N Engl J Med, 2018, 378(23): 2234-2235. DOI: 10.1056/NEJMe1804945.
[74]	FUKUO Y, TAKAGI S, AKAISHI H, et al. Dual effects of bezafibrate on lipid metabolism and hepatobiliary enzymes[J]. Clin Drug Invest, 1997, 14(2): 125-131. DOI: 10.2165/00044011-199714020-00006.
[75]	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[J]. Hepatology, 2012, 55(2): 512-521. DOI: 10.1002/hep.24748.
[76]	MYERS RP, SWAIN MG, LEE SS, et al. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid[J]. Am J Gastroenterol, 2013, 108(6): 933-941. DOI: 10.1038/ajg.2013.51.
[77]	KHANNA A, JOPSON L, HOWEL D, et al. Rituximab is ineffective for treatment of fatigue in primary biliary cholangitis: A phase 2 randomized controlled trial[J]. Hepatology, 2019, 70(5): 1646-1657. DOI: 10.1002/hep.30099.
[78]	KAEGI C, WUEST B, SCHREINER J, et al. Systematic review of safety and efficacy of rituximab in treating immune-mediated disorders[J]. Front Immunol, 2019, 10: 1990. DOI: 10.3389/fimmu.2019.01990.
[79]	GANDOLFO S, de VITA S. Double anti-B cell and anti-BAFF targeting for the treatment of primary Sjögren's syndrome[J]. Clin Exp Rheumatol, 2019, 37 Suppl 118(3): 199-208.