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Intervenciones farmacológicas para la colangitis biliar primaria

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Referencias

Referencias de los estudios incluidos en esta revisión

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Almasio 2000 {published data only}

Almasio P, Provenzano G, Battezzati PM, Podda M, Todros L, Rosina F, et al. The Italian multi‐centre randomized controlled trial of UDCA vs colchicine plus UDCA in symptomatic primary biliary cholangitis. Hepatology 1994;20(4 (Pt 2)):73. CENTRAL
Almasio PL, Floreani A, Chiaramonte M, Provenzano G, Battezzati P, Crosignani A, et al. Multicentre randomized placebo‐controlled trial of UDCA with or without colchicine in symptomatic primary biliary cholangitis. Alimentary Pharmacology & Therapeutics 2000;14(12):1645‐52. CENTRAL
Battezzati PM, Zuin M, Crosignani A, Allocca M, Invernizzi P, Selmi C, et al. Ten‐year combination treatment with colchicine and UDCA for primary biliary cholangitis: a double‐blind, placebo‐controlled trial on symptomatic patients. Alimentary Pharmacology & Therapeutics 2001;15(9):1427‐34. CENTRAL
Podda M, Almasio P, Battezzati PM, Crosignani A. Long‐term effect of the administration of UDCA alone or with colchicine in patients with primary biliary cholangitis: a double‐blind multicentre study. 68th Falk Symposium; 1992 Oct 12‐14; Basel, Switzerland. 1993:310‐5. CENTRAL

Angulo 1999a {published data only}

Angulo P, Dickson ER, Therneau TM, Jorgensen RA, Smith C, DeSotel CK, et al. Comparison of three doses of UDCA in the treatment of primary biliary cholangitis: a randomized trial. Journal of Hepatology 1999;30(5):830‐5. CENTRAL

Arora 1990 {published data only}

Arora R, Batta AK, Salen G, O'Brien C, Senior JR. Effect of ursodiol on bile acid conjugation in patients with primary biliary cholangitis. Hepatology 1990;12(4 (Pt 2)):994. CENTRAL
Batta AK, Arora R, Salen G, Katz S. UDCA improves liver function and reduces serum and urinary endogenous bile acids in primary biliary cholangitis. Hepatology 1988;8(5):1221. CENTRAL
Batta AK, Arora R, Salen G, O'Brien C, Senior JR. Effect or ursodiol on biliary bile acid composition and conjugation in patients with primary biliary cholangitis. Gastroenterology 1990;98(2 (Pt 2)):A567. CENTRAL

Askari 2010 {published data only}

Askari F, Innis D, Dick RB, Hou GQ, Marrero J, Greenson J, et al. Treatment of primary biliary cholangitis with tetrathiomolybdate: results of a double‐blind trial. Translational Research 2010;155(3):123‐30. CENTRAL

Battezzati 1993 {published data only}

Anonymous. UDCA (UDCA) for symptomatic primary biliary cholangitis (PBC): a double‐blind multicenter trial. Journal of Hepatology 1989;9(Suppl 1):S44. CENTRAL
Battezzati PM, Podda M, Bianchi FB, Naccarato R, Orlandi F, Surrenti C, et al. UDCA for symptomatic primary biliary cholangitis. Preliminary analysis of a double‐blind multicenter trial. Italian multicenter group for the study of UDCA in PBC. Journal of Hepatology 1993;17(3):332‐8. CENTRAL
Podda M, Battezzati PM, Crosignani A, Bianchi FB, Fusconi M, Chiaramonte M, et al. UDCA (UDCA) for symptomatic primary biliary cholangitis (PBC): a double‐blind multicenter trial. Hepatology 1989;10(4):639. CENTRAL

Bobadilla 1994 {published data only}

Bobadilla J, Vargas F, Dehesa M, Zapata L, Kaplan M, Nava R, et al. Colchicine and ursodiol in the treatment of primary biliary cholangitis. Hepatology 1994;20(4 (Pt 2)):332a. CENTRAL

Bodenheimer 1988 {published data only}

Bodenheimer H, Schaffner F, Pezzullo J. Evaluation of colchicine therapy in primary biliary cholangitis. Gastroenterology 1988;95(1):124‐9. CENTRAL
Bodenheimer H, Schaffner F, Pezzullo J. A randomized double‐blind controlled trial of colchicine in primary biliary cholangitis. Hepatology 1985;5(5):968. CENTRAL
Bodenheimer H, Schaffner F, Pezzullo J. Colchicine therapy in primary biliary cholangitis. Hepatology 1986;6(5):1172. CENTRAL
Zifroni A, Schaffner F. Long‐term follow‐up of patients with primary biliary cholangitis on colchicine therapy. Hepatology 1991;14(6):990‐3. CENTRAL

Bowlus 2014 {published data only}

Bowlus CL, Pockros PJ, Drenth J, Floreani A, Vincent C, Luketic VA, et al. Obeticholic acid in PBC patients: the utility of titration based on therapeutic response and tolerability. Hepatology 2014;60:353a. CENTRAL

Cash 2013 {published data only}

Cash WJ, O'Neill S, O'Donnell ME, McCance DR, Young IS, McEneny J, et al. Randomized controlled trial assessing the effect of simvastatin in primary biliary cholangitis. Liver International 2013;33(8):1166‐74. CENTRAL

Christensen 1985 {published data only}

Christensen E, Neuberger J, Crowe J. Beneficial effect of azathioprine and prediction of prognosis in primary biliary cholangitis. Final results of an international trial. Gastroenterology 1985;89(5):1084‐91. CENTRAL
Christensen E, Neuberger J, Crowe J, Popper H, Portmann B, Deniach D, et al. Azathioprine in primary biliary cholangitis: late results of an international trial. Liver 1984;4(1):81. CENTRAL
Christensen E, Neuberger J, Crowe J, Popper H, Portmann B, Doniach D, et al. Azathioprine in primary biliary cholangitis: late results of an international trial. Gut 1983;24(10):A995‐6. CENTRAL
Crowe J, Christensen E, Smith M. Azathioprine in primary biliary cholangitis: a preliminary report of an international trial. Gastroenterology 1980;78(5 I):1005‐10. CENTRAL

Combes 1995a {published data only}

Carithers RL, Luketic VA, Peters M, Zetterman RK, Garcia‐Tsao G, Munoz SJ. Extended follow‐up of patients in the US multicenter trial of UDCA for primary biliary cholangitis. Gastroenterology 1996;110(Suppl 4):A1163. CENTRAL
Combes B, Carithers RL, Maddrey WC, Lin D, McDonald MF, Wheeler DE, et al. A randomized, double‐blind, placebo‐controlled trial of UDCA in primary biliary cholangitis. Hepatology 1995;22(3):759‐66. CENTRAL
Combes B, Carithers RL, Maddrey WC, Munoz S, Garcia‐Tsao G, et al. Biliary bile acids in primary biliary cholangitis: effect of UDCA. Hepatology 1999;29(6):1649‐54. CENTRAL
Combes B, Carithers RL, McDonald MF, Maddrey WC, Munoz SJ, Boyer JL, et al. UDCA therapy in patients with primary biliary cholangitis. Hepatology 1991;14(4 (Pt 2)):91a. CENTRAL
Combes B, Carithers RL, Maddrey WC, Munoz SJ, McDonald MF, Garcia‐Tsao G. A randomized, double‐blind, placebo‐controlled trial of UDCA in primary biliary cholangitis. 68th Falk Symposium; 1992 Oct 12‐14; Basel, Switzerland. 1993:289‐91. CENTRAL
Combes B, Carithers RL, Maddrey WC, Munoz SJ, McDonald MF, Garcia‐Tsao G, et al. A randomized, double‐blind, placebo‐controlled trial of UDCA (UDCA) in primary biliary cholangitis. Hepatology 1993;18(4 (Pt 2)):175a. CENTRAL
Combes B, Markin RS, Wheeler DE, Rubin R, West AB, Mills AS, et al. The effect of UDCA on the florid duct lesion of primary biliary cholangitis. Hepatology 1999;30(3):602‐5. CENTRAL

Combes 2005 {published data only}

Combes B, Emerson SS, Flye NL. The primary biliary cholangitis (PBC) ursodiol (UDCA) plus methotrexate (MTX) or its placebo study (PUMPS) ‐ a multicenter randomized trial. Hepatology 2003;38(4):210A‐1A. CENTRAL
Combes B, Emerson SS, Flye NL, Munoz SJ, Luketic VA, Mayo MJ, et al. Methotrexate (MTX) plus UDCA (UDCA) in the treatment of primary biliary cholangitis. Hepatology 2005;42(5):1184‐93. CENTRAL
Munoz S, Carithers R, Emerson SS, Flye N, Kowdley K, Combes B. Absence of pulmonary toxicity in primary biliary cholangitis (PBC) treated with methotrexate and ursodiol. Hepatology 1998;28(Suppl 4):392a. CENTRAL
NCT00004784. Phase III randomized study of ursodiol with vs without methotrexate for primary biliary cholangitis. clinicaltrials.gov/ct2/show/NCT00004784 (date first received: 24 February 2000). CENTRAL

Dickson 1985 {published data only}

Deering TB, Dickson ER, Fleming CR. Effect of D penicillamine on copper retention in patients with primary biliary cholangitis. Gastroenterology 1977;72(6):1208‐12. CENTRAL
Dickson ER. The syndrome of primary biliary cholangitis. Journal of Rheumatology ‐ Supplement 1981;7:121‐3. CENTRAL
Dickson ER, Fleming CR, Geall MG. A double blind controlled study using D‐penicillamine in chronic cholangiolitic hepatitis (primary biliary cholangitis). Gastroenterology 1977;72(5 II):A‐26. CENTRAL
Dickson ER, Fleming TR, Wiesner RH. Trial of penicillamine in advanced primary biliary cholangitis. New England Journal of Medicine 1985;312(16):1011‐5. CENTRAL
Dickson ER, Wiesner RH, Baldus WP, Fleming CR, Ludwig JL. D‐penicillamine improves survival and retards histologic progression in primary biliary‐cirrhosis. Gastroenterology 1982;82(5 Part 2):1225. CENTRAL
Fleming CR, Ludwig J, Dickson ER. Asymptomatic primary biliary cholangitis. Presentation, histology, and results with D‐penicillamine. Mayo Clinic Proceedings 1978;53(9):587‐93. CENTRAL
Locke GR, Therneau TM, Ludwig J, Dickson ER, Lindor KD. Time course of histological progression in primary biliary cholangitis. Hepatology 1996;23(1):52‐6. CENTRAL
Powell FC, Rogers RS, Dickson ER. Primary biliary cholangitis and lichen planus. Journal of the American Academy of Dermatology 1983;9(4):540‐5. CENTRAL

Epstein 1979 {published data only}

Epstein G, De Williers D, Jain S, Potter BJ, Thomas HC, Sherlock S. Effect of penicillamine on immune complexes and immunoglobulins in primary biliary cholangitis (PBC). Gut 1978;19(Suppl 3):A994. CENTRAL
Epstein O, Cook D, Jain S, Sherlick S. D‐Penicillamine in primary biliary cholangitis (PBC) ‐ an untested (and untestable?) treatment. Gut 1984;25:A1134. CENTRAL
Epstein O, Cook DG, Jain S, McIntyre N, Sherlock S. D‐Penicillamine and clinical‐trials in PBC. Hepatology 1984;4(5):1032. CENTRAL
Epstein O, Cook DG, Jain S, Sherlock S. D‐Penicillamine in PBC ‐ an untested (and untestable?) treatment. Journal of Hepatology 1985;1(Suppl 1):S49. CENTRAL
Epstein O, De Villiers D, Jain S. Reduction of immune complexes and immunoglobulins induced by D‐penicillamine in primary biliary cholangitis. New England Journal of Medicine 1979;300(6):274‐8. CENTRAL
Epstein O, Jain S, Lee RG. D‐Penicillamine treatment improves survival in primary biliary cholangitis. Lancet 1981;1(8233):1275‐7. CENTRAL
Epstein O, Jain S, Lee RG, Cook DG, Boss AM, Scheuer PJ, et al. D‐Penicillamine treatment improves survival in primary biliary‐cirrhosis. Gut 1981;22(5):A433‐A. CENTRAL
Jain S, McGee JD, Scheuer PJ, Samourian S, Sherlock S. A controlled trial of D‐penicillamine therapy in primary biliary cholangitis and chronic active hepatitis. Digestion 1976;14:523. CENTRAL
Jain S, Scheuer PJ, Samourian S. A controlled trial of D‐penicillamine therapy in primary biliary cholangitis. Lancet 1977;1(8016):831‐4. CENTRAL
Jain S, Scheur PJ, Samourian S, McGee JD, Sherlock S. A controlled trial of D‐penicillamine therapy in primary biliary cholangitis. Gut 1976;17(Suppl 2):822. CENTRAL

Eriksson 1997 {published data only}

Eriksson LS, Olsson R, Glauman H, Prytz H, Befrits H, Lindgren S, et al. UDCA (UDCA) in patients with primary biliary cholangitis (PBC): results of a two‐year randomized placebo‐controlled study (abstract). Scandinavian Journal of Gastroenterology 1995;30(Suppl 209):35. CENTRAL
Eriksson LS, Olsson R, Glauman H, Prytz H, Befrits R, Ryden BO, et al. UDCA treatment in patients with primary biliary cholangitis. A Swedish multicentre, double‐blind, randomized controlled study. Scandinavian Journal of Gastroenterology 1997;32(2):179‐86. CENTRAL

Ferri 1993 {published data only}

Ferri F, Bernocchi P, Fedeli S. [Taurodeoxycholic acid in the treatment of primary biliary cholangitis. A controlled study in comparison to UDCA]. Clinica Terapeutica 1993;143(4):321‐6. CENTRAL

Gao 2012 {published data only}

Gao LX, Zhang FC, Wang L, Zhang X, Liu B. The clinical observation of different therapeutic strategies in combined primary biliary cholangitis and Sjogren syndrome. Chung‐Hua Nei Ko Tsa Chih 2012;51(11):851‐4. CENTRAL

Goddard 1994 {published data only}

Goddard C, Smith A, Hunt L, Halder T, Hillier V, Rowan B, et al. Surrogate markers of response in a trial of UDCA (UDCA) and colchicine in primary biliary cholangitis (PBC). Gut 1995;36(Suppl 1):A30. CENTRAL
Goddard CJR, Hunt L, Smith A, Followfield G, Rowan B, Warnes TW. A trial of UDCA (UDCA) and colchicine in primary biliary cholangitis (PBC). Hepatology 1994;20(4 (Pt 2)):151a. CENTRAL

Gonzalezkoch 1997 {published data only}

Gonzalezkoch A, Brahm J, Antezana C, Smok G, Cumsille MA. The combination of UDCA and methotrexate for primary biliary cholangitis is not better than UDCA alone. Journal of Hepatology 1997;27(1):143‐9. CENTRAL

Heathcote 1976 {published data only}

Heathcote J, Ross A, Sherlock S. A prospective controlled trial of azathioprine in primary biliary cholangitis. Gastroenterology 1976;70(5 PT.1):656‐60. CENTRAL
Ross A, Sherlock S. A controlled trial of azathioprine in primary biliary cholangitis. Gut 1971;12(2):770. CENTRAL
Ross A, Sherlock S. A trial of azathioprine in primary biliary cholangitis. Gut 1970;11(12):1058. CENTRAL

Heathcote 1994 {published data only}

Heathcote EJ, Cauch‐Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, et al. The Canadian multicenter double‐blind randomized controlled trial of UDCA in primary biliary cholangitis. Hepatology 1994;19(5):1149‐56. CENTRAL
Heathcote EJL, Cauch K, Walker V, Bailey RJ, Blendis LM, Ghent CN, et al. The Canadian multicenter double‐blind randomized controlled trial of UDCA in primary biliary‐cirrhosis. Hepatology 1992;16(4):A91. CENTRAL
Heathcote EJL, Cauch K, Walker V, Blendis LM, Pappas SC, Wanless IR. A double‐blind randomized controlled multicentre trial of UDCA in primary biliary cholangitis: results from a 1991 interim analysis. 68th Falk Symposium; 1992 Oct 12‐14; Basel, Switzerland. 1993:294‐8. CENTRAL
Neuman MG, Cameron RG, Haber JA, Katz GG, Blendis LM. An electron microscopic and morphometric study of ursodeoxycholic effect in primary biliary cholangitis. Liver 2002;22(3):235‐44. CENTRAL
Neuman MG, Cameron RG, Shear NH, Blendis LM. Electron microscopic study on antifibrotic effects of ursodeoxycholate treatment in primary biliary cholangitis. Bile Acids and Cholestasis 1999;108:254‐69. CENTRAL
Worobetz LJ, Cauch‐Dudek K, Heathcote EJ. The effect of UDCA (UDCA) on anti‐mitochondrial antibody (AMA) titre in primary biliary cholangitis (PBC). Gastroenterology 1995;108(4 Suppl 3):A1200. CENTRAL

Hendrickse 1999 {published data only}

Giaffer MH, Hendrickse M, Soomoro I, Triger DR, Underwood JCE, Gleeson D. Low‐dose methotrexate in treatment of primary biliary cholangitis. Gut 1995;36(Suppl 1):A30. CENTRAL
Hendrickse M, Rigney E, Giaffer MH, Soomoro I, Triger DR, Underwood JC, et al. Low‐dose methotrexate in primary biliary cholangitis: long‐term results of a placebo‐controlled trial. Hepatology 1997;26(4):479. CENTRAL
Hendrickse MT, Rigney E, Giaffer MH, Soomro I, Triger DR, Underwood JC, et al. Low‐dose methotrexate is ineffective in primary biliary cholangitis: long‐term results of a placebo‐controlled trial. Gastroenterology 1999;117(2):400‐7. CENTRAL

Hirschfield 2015 {published data only}

Hirschfield G, Kowdley K, Mason A, Luketic V, Gordon S, Vincent C, et al. Long‐term (LT) therapy of a farnesoid X receptor (FXR) agonist obeticholic acid (OCA) maintains biochemical response in primary biliary cholangitis (PBC). Journal of Hepatology 2012;56:S372. CENTRAL
Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, et al. Efficacy of obeticholic acid in patients with primary biliary cholangitis and inadequate response to UDCA. Gastroenterology 2015;148(4):751‐61.e8. CENTRAL
Luketic V, Gordon SG, Vincent C, Chapman R, Mayo M, Kowdley K, et al. The FXR agonist obeticholic acid improves a transplant free survival‐proven biochemical response criterion in placebo controlled primary biliary cholangitis studies. Journal of Hepatology 2014;60(1 (Suppl 1)):S193‐4. CENTRAL
Luketic VA, Invernizzi P, Trauner M, Regula J, Mazzella G, Strasser SI, et al. Efficacy of obeticholic acid in primary biliary cholangitis as assessed by response criteria associated with clinical outcome: a poise analysis. Hepatology 2014;60:355a‐6a. CENTRAL
Marschall H, Luketic VA, Mason AL, Lindor KD, Hirschfield GM, Gordon SC, et al. The farnesoid X receptor (FXR) agonist obeticholic acid (INT‐747, 6α‐ethyl chenodeoxycholic acid) in combination with UDCA (UDCA) increases plasma FGF‐19 concentrations but not bile acid concentration or profile in primary biliary cholangitis (PBC). Hepatology 2010;52(Suppl S1):355a. CENTRAL
Mason AL, Lindor KD, Bacon BR, Vincent C, Neuberger JM, Wasilenko ST. Multi‐center, double blind, randomized controlled trial of zidovudine and lamivudine (Combivir) therapy for patients with primary biliary cholangitis. Hepatology 2007;46(4):264A. CENTRAL

Hoofnagle 1986 {published data only}

Hoofnagle JH, Davis GL, Schafer DF, Peters M, Avigan MI, Pappas SC, et al. Randomized trial of chlorambucil for primary biliary cholangitis. Gastroenterology 1986;91(6):1327‐34. CENTRAL
Hoofnagle JH, Davis GL, Schafer DF, Peters MG, Avigan MI, Hanson RG, et al. Randomized trial of chlorambucil for primary biliary‐cirrhosis. Hepatology 1984;4(5):1062. CENTRAL

Hosonuma 2015 {published data only}

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 UDCA and bezafibrate in patients with primary biliary cholangitis and dyslipidaemia. American Journal of Gastroenterology 2015;110(3):423‐31. CENTRAL
Sato K, Hosonuma K, Yamazaki Y, Yanagisawa M, Hashizume H, Horiguchi N, et al. Long‐term prognosis of combination therapy with UDCA and bezafibrate for primary biliary cholangitis: a prospective, multicenter, randomized controlled study. Hepatology International 2014;8(1 (Suppl 1)):S15. CENTRAL

Ikeda 1996 {published data only}

Ikeda T, Tozuka S, Noguchi O, Kobayashi F, Sakamoto S, Marumo F, et al. Effects of additional administration of colchicine in UDCA‐treated patients with primary biliary cholangitis: a prospective randomized study. Journal of Hepatology 1996;24(1):88‐94. CENTRAL

Iwasaki 2008a {published data only}

Iwasaki S, Ohira H, Nishiguchi S, Zeniya M, Kaneko S, Onji M, et al. The efficacy of UDCA and bezafibrate combination therapy for primary biliary cholangitis: a prospective, multicenter study. Hepatology Research 2008;38(6):557‐64. CENTRAL

Iwasaki 2008b {published data only}

Iwasaki S, Ohira H, Nishiguchi S, Zeniya M, Kaneko S, Onji M, et al. The efficacy of UDCA and bezafibrate combination therapy for primary biliary cholangitis: a prospective, multicenter study. Hepatology Research 2008;38(6):557‐64. CENTRAL

Kanda 2003 {published data only}

Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients?. Journal of Gastroenterology 2003;38(6):573‐8. CENTRAL

Kaplan 1986 {published data only}

Johnston DE, Kaplan MM, Miller KB, Connors CM, Milford EL. Histocompatibility antigens in primary biliary cholangitis. American Journal of Gastroenterology 1987;82(11):1127‐9. CENTRAL
Kaplan MM, Alling DW, Wolfe HJ, Zimmerman HJ. Colchicine is effective in the treatment of primary biliary cholangitis. Hepatology 1985;5(5):967. CENTRAL
Kaplan MM, Alling DW, Zimmerman HJ, Wolfe HJ, Sepersky RA, Hirsch GE, et al. A prospective trial of colchicine for primary biliary cholangitis. (abstract). Acta Gastroenterologica Belgica 1987;50(3):382. CENTRAL
Kaplan MM, Alling DW, Zimmerman HJ, Wolfe HJ, Sepersky RA, Hirsch GS, et al. A prospective trial of colchicine for primary biliary cholangitis. New England Journal of Medicine 1986;315(23):1448‐54. CENTRAL
Miller LC, Kaplan MM. Serum interleukin‐2 and tumor necrosis factor‐alpha in primary biliary cholangitis: decrease by colchicine and relationship to HLA‐DR4. American Journal of Gastroenterology 1992;87(4):465‐70. CENTRAL

Kaplan 1999 {published data only}

Kaplan M, Schmid C, McKusick A, Provenzale D, Sharma A, Sepe T. Double blind trial of methotrexate (MTX) versus colchicine (COLCH) in primary biliary cholangitis (PBC). Hepatology 1993;18(4 (Pt 2)):176a. CENTRAL
Kaplan MM, Dickstein G, Schmid C. Methotrexate (MTX) improves histology in primary biliary cholangitis (PBC). Hepatology 1994;20(4 (Pt 2)):152a. CENTRAL
Kaplan MM, Schmid C, Provenzale D, Sharma A, Dickstein G, McKusick A. A prospective trial of colchicine and methotrexate in the treatment of primary biliary cholangitis. Gastroenterology 1999;117(5):1173‐80. CENTRAL
Miller LC, Sharma A, McKusick AF, Tassoni JP, Dinarello CA, Kaplan MM. Synthesis of interleukin‐1 beta in primary biliary cholangitis: relationship to treatment with methotrexate or colchicine and disease progression. Hepatology 1995;22(2):518‐24. CENTRAL
NCT00004748. Phase III randomized, double‐blind, placebo‐controlled study of low‐dose oral methotrexate vs colchicine for primary biliary cholangitis. www.clinicaltrials.gov/ct2/show/NCT00004748 Date first received: 24 February 2000. CENTRAL
Sharma A, Provenzale D, McKusick A, Kaplan MM. Interstitial pneumonitis after low‐dose methotrexate therapy in primary biliary cholangitis. Gastroenterology 1994;107(1):266‐70. CENTRAL

Kowdley 2011 {published data only}

Kowdley K, Jones D, Luketic V, Chapman R, Burroughs A, Hirschfield G, et al. An international study evaluating the farnesoid X receptor agonist obeticholic acid as monotherapy in PBC. Journal of Hepatology 2011;54:S13. CENTRAL

Kurihara 2000 {published data only}

Kurihara T, Niimi A, Maeda A, Shigemoto M, Yamashita K. Bezafibrate in the treatment of primary biliary cholangitis: comparison with UDCA. American Journal of Gastroenterology 2000;95(10):2990‐2. CENTRAL

Leuschner 1989 {published data only}

Guldutuna S, Leuschner U, Imhof M, Zimmer G. Treatment of chronic active hepatitis and primary biliary cholangitis with UDCA. Zeitschrift Fur Gastroenterologie 1992;30 Suppl 1:49‐54. CENTRAL
Leuschner U, Fischer H, Guldutuna S, Kurtz W, Gatzen M, Hellstern A. Does UDCA (UDCA) influence cell membrane architecture in patients with primary biliary cholangitis (PBC)?. Gastroenterology 1989;96(5 (Pt 2)):A621. CENTRAL
Leuschner U, Fischer H, Hubner K. [UDCA in the treatment of primary biliary cholangitis: results of a controlled study]. Zeitschrift fur Gastroenterologie ‐ Verhandlungsband 1989;24:133. CENTRAL
Leuschner U, Fischer H, Kurtz W, Guldutuna S, Hubner K, Hellstern A, et al. UDCA in primary biliary cholangitis: results of a controlled double‐blind trial. Gastroenterology 1989;97(5):1268‐74. CENTRAL
Leuschner U, Fisher H, Hübner K, Güldütuna S, Gatzen M, Hellstern A. UDCA (UDCA) treatment of primary biliary cholangitis: clinical and histological results of a controlled study. 52nd Falk Symposium; 1988 Jun 9‐11; Freiburg, Germany 1989;41:355‐8. CENTRAL

Leuschner 1999 {published data only}

Leuschner M, Maier KP, Schlichting J, Strahl R, Herrmann G, Dahm HH, et al. Combination of UDCA (UDCA) with budesonide (BUD) is superior to UDCA‐mono‐therapy in primary biliary cholangitis (PBC). Journal of Hepatology 1999;30(Suppl 1):57. CENTRAL
Leuschner M, Maier KP, Schlichting J, Strahl R, Herrmann G, Dahm HH, et al. UDCA (UDCA) and budesonide (BUD) in the treatment of primary biliary cholangitis (PBC): a prospective double‐blind trial. Hepatology 1999;30(4):471a. CENTRAL
Leuschner M, Maier KP, Schlichting J, Strahl R, Herrmann G, Dahm HH, et al. [UDCA (UDCA)‐placebo versus UDCA‐budesonide by primary biliary cholangitis (PBC). A double‐blind study]. Zeitschrift fur Gastroenterologie 1999;37(9):897. CENTRAL
Leuschner M, Maier KP, Schlichting J, Strahl S, Herrmann G, Dahm HH, et al. Oral budesonide and UDCA for treatment of primary biliary cholangitis: results of a prospective double‐blind trial. Gastroenterology 1999;117(4):918‐25. CENTRAL

Liberopoulos 2010 {published data only}

Liberopoulos EN, Florentin M, Elisaf MS, Mikhailidis DP, Tsianos E. Fenofibrate in primary biliary cholangitis: a pilot study. Open Cardiovascular Medicine Journal 2010;4:120‐6. CENTRAL

Lim 1994 {published data only}

Lim AG, Jazrawi RP, Maxwell JD, Northfield TC. UDCA (UDCA) improves hepatic excretion in primary biliary cholangitis (PBC). Gut 1994;35(S5):S11. CENTRAL
Lim AG, Jazrawi RP, Petroni ML, Pereira S, Maxwell JD, Northfield TC. T‐lymphocyte activation in primary biliary cholangitis: effects of UDCA. Falk Symposium XIII International Bile Acid Meeting 1994;80:147. CENTRAL

Lindor 1994 {published data only}

Balan V, Dickson ER, Jorgensen RA, Lindor KD. Effect of UDCA on serum lipids of patients with primary biliary cholangitis. Mayo Clinic Proceedings 1994;69(10):923‐9. CENTRAL
Batts KP, Jorgensen RA, Dickson ER, Hofmann AF, Rossi SS, Ludwig J, et al. The effects of UDCA on hepatic inflammation and histologic stage in patients with primary biliary cholangitis. Hepatology 1993;18(4 (Pt 2)):175a. CENTRAL
Batts KP, Jorgensen RA, Dickson ER, Lindor KD. Effects of UDCA on hepatic inflammation and histological stage in patients with primary biliary cholangitis. American Journal of Gastroenterology 1996;91(11):2314‐7. CENTRAL
Dickson ER, Lindor KD, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh PA. Ursodiol is effective therapy for patients with primary biliary cholangitis. 68th Falk Symposium; 1992 Oct 12‐14; Basel, Switzerland. 1993:292‐3. CENTRAL
Jorgensen RA, Dickson ER, Hofmann AF, Rossi SS, Lindor KD. Characterisation of patients with a complete biochemical response to UDCA. Gut 1995;36(6):935‐8. CENTRAL
Lacerda MA, Lindor KD, Jorgensen RA, Rossi SS, Hofmann AF, Salen GR, et al. Dissimilar patterns of serum and biliary bile‐acids in primary biliary‐cirrhosis (PBC) patients treated with UDCA (UDCA). Hepatology 1993;18(4):A174. CENTRAL
Laurin JM, DeSotel CK, Jorgensen RA, Dickson ER, Lindor KD. The natural history of abdominal pain associated with primary biliary cholangitis. American Journal of Gastroenterology 1994;89(10):1840‐3. CENTRAL
Lindor KD, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh PA, Dickson ER. UDCA (UDCA) is beneficial therapy for patients with primary biliary cholangitis (PBC). Hepatology 1992;16(2 (Pt 2)):91a. CENTRAL
Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh PA, et al. UDCA in the treatment of primary biliary cholangitis. Gastroenterology 1994;106(5):1284‐90. CENTRAL
Lindor KD, Janes CH, Crippin JS, Jorgensen RA, Dickson ER. Bone disease in primary biliary cholangitis: does UDCA make a difference?. Hepatology 1995;21(2):389‐92. CENTRAL
Lindor KD, Jorgensen RA, Dickson ER. UDCA delays the onset of esophageal varices in primary biliary cholangitis. Hepatology 1995;22(4 (Pt 2)):125a. CENTRAL
Lindor KD, Jorgensen RA, Therneau TM, Malinchoc M, Dickson ER. UDCA delays the onset of esophageal varices in primary biliary cholangitis. Mayo Clinic Proceedings 1997;72(12):1137‐40. CENTRAL
Lindor KD, Lacerda MA, Jorgensen RA, DeSotel CK, Batta AK, Salen G, et al. Relationship between biliary and serum bile acids and response to UDCA in patients with primary biliary cholangitis. American Journal of Gastroenterology 1998;93(9):1498‐504. CENTRAL
Siegel JL, Jorgensen R, Angulo P, Lindor KD. Treatment with UDCA is associated with weight gain in patients with primary biliary cholangitis. Journal of Clinical Gastroenterology 2003;37(2):183‐5. CENTRAL
Zukowski TH, Jorgensen RA, Dickson ER, Lindor KD. Autoimmune conditions associated with primary biliary cholangitis: response to UDCA therapy. American Journal of Gastroenterology 1998;93(6):958‐61. CENTRAL

Lindor 1997 {published data only}

Lindor KD, Jorgensen R, Therneau TM, Smith C, Mahoney DW, Dickson ER. Comparison of three different doses of UDCA in the treatment of primary biliary cholangitis: a randomized trial. Hepatology 1997;26(4):1240. CENTRAL

Lombard 1993 {published data only}

Guanabens N, Pares A, Navasa M, Martinez de Osaba MJ, Hernandez ME, Munoz J, et al. Cyclosporin a increases the biochemical markers of bone remodeling in primary biliary cholangitis. Journal of Hepatology 1994;21(1):24‐8. CENTRAL
Guañabens N, Parés A, Navasa M, Rivera F, Muñoz J, Rodés J. Influence of cyclosporin a in bone metabolism in primary biliary cholangitis. Revista Española de Reumatología 1990;17(Suppl 1):14‐5. CENTRAL
Lombard M, Portmann B, Neuberger J, Williams R, Tygstrup N, Ranek L, et al. Cyclosporin a treatment in primary biliary cholangitis: results of a long‐term placebo controlled trial. Gastroenterology 1993;104(2):519‐26. CENTRAL
Lombard M, Portmann BP, Tygstrup N, Ranek L, Larsen HR, Trepo C, et al. Cyclosporin a in primary biliary cholangitis: results of a long‐term placebo controlled trial and effect on survival. Hepatology 1990;12(4 (Pt 2)):872. CENTRAL

Ma 2016 {published data only}

Ma H, Zeng M, Han Y, Yan H, Tang H, Sheng J, et al. A multicenter, randomized, double‐blind trial comparing the efficacy and safety of TUDCA and UDCA in Chinese patients with primary biliary cholangitis. Medicine 2016;95(47):e5391. CENTRAL

Macklon 1982 {published data only}

Bassendine M, Macklon A, Mulcahy R, James O. Controlled trial of high and low dose D‐penicillamine (DP) in primary biliary cholangitis (PBC): results at three years. Gut 1982;23:A909. CENTRAL
Macklon AF, Bassendine MF, James OFW. Controlled trial of D‐penicillamine in primary biliary cholangitis: incidence of side effects and relation to dose. Hepatology 1982;2(1):166. CENTRAL

Manzillo 1993a {published data only}

Manzillo G, Piccinino F, Surrenti C, Frezza M, Grazie C. Double‐blind, placebo‐controlled study with parenteral and oral S‐adenosyl‐L‐methionine (SAMe) in primary biliary cholangitis. II United European Gastroenterology Week 1993:A337. CENTRAL

Manzillo 1993b {published data only}

Manzillo G, Piccinino F, Surrenti C, Frezza M, Grazie C. Double‐blind, placebo‐controlled study with parenteral and oral S‐adenosyl‐L‐methionine (SAMe) in primary biliary cholangitis. II United European Gastroenterology Week 1993:A337. CENTRAL

Mason 2008 {published data only}

Mason A, Luketic V, Lindor K, Hirschfield G, Gordon S, Mayo M. Farnesoid‐x receptor agonists: a new class of drugs for the treatment of PBC? An international study evaluating the addition of INT‐747 to UDCA. Journal of Hepatology 2010;52(Suppl 1):S1‐S2. CENTRAL
Mason AL, Lindor KD, Bacon BR, Vincent C, Neuberger JM, Vvasilenko ST. Clinical trial: randomized controlled study of zidovudine and lamivudine for patients with primary biliary cholangitis stabilized on ursodiol. Alimentary Pharmacology & Therapeutics 2008;28(7):886‐94. CENTRAL

Matloff 1982 {published data only}

Matloff D, Resnick R, Alpert E, Kaplan M. D‐Penicillamine does not alter the course of primary biliary cholangitis. Clinical Research 1979;27:579A. CENTRAL
Matloff DS, Alpert E, Resnick RH, Kaplan MM. A prospective trial of D‐penicillamine in primary biliary cholangitis. New England Journal of Medicine 1982;306(6):319‐26. CENTRAL

Mayo 2015 {published data only}

Mayo MJ, Wigg AJ, Roberts SK, Arnold H, Hassanein TI, Leggett BA, et al. NGM282, a novel variant of FGF‐19, demonstrates biologic activity in primary biliary cholangitis patients with an incomplete response to UDCA: results of a phase 2 multicenter, randomized, double blinded, placebo controlled trial. Hepatology 2015;62:263A‐4A. CENTRAL

Mazzarella 2002 {published data only}

Enrico R, Federica B, Andrea L, Patrizia S, Roda A, Mazzella G. Treatment of early (I‐II stage) primary biliary cholangitis (PBC): high versus standard UDCA doses after 15 years follow‐up. A randomized open controlled trial. Hepatology 2011;54(4 (Suppl)):1209a. CENTRAL
Mazzarella G, Azzolini F, Casanova S, Giovanelli S, Ferrara F, Liva S, et al. Standard vs high dose UDCA in PBC: efficacy on liver function tests and histology after six years of treatment in a randomised controlled trial. Gastroenterology 2002;123(1):66. CENTRAL

McCormick 1994 {published data only}

McCormick PA, Scott F, Epstein O, Burroughs AK, Scheuer PJ, McIntyre N. Thalidomide as therapy for primary biliary cholangitis: a double‐blind placebo controlled pilot study. Journal of Hepatology 1994;21(4):496‐9. CENTRAL

Minuk 1988 {published data only}

Hanley DA, Ayer LM, Gundberg CM, Minuk GY. Parameters of calcium metabolism during a pilot study of cyclosporin a in patients with symptomatic primary biliary cholangitis. Clinical & Investigative Medicine ‐ Medecine Clinique et Experimentale 1991;14(4):282‐7. CENTRAL
Minuk G, Bohme C, Burgess E, Hershfield N, Kelly J, Shaffer E, et al. A prospective, double‐blind, randomized, controlled trial of cyclosporine a in primary biliary‐cirrhosis. Hepatology 1987;7(5):1119. CENTRAL
Minuk G, Bohme C, Burgess E, Hershfield N, Kelly J, Shaffer E, et al. A prospective, randomized, placebo‐controlled study of cyclosporine a in primary biliary‐cirrhosis. Clinical and Investigative Medicine ‐ Medecine Clinique et Experimentale 1987;10(4):B131. CENTRAL
Minuk GY, Bohme CE, Burgess E, Hershfield NB, Kelly JK, Shaffer EA, et al. Pilot study of cyclosporin a in patients with symptomatic primary biliary cholangitis. Gastroenterology 1988;95(5):1356‐63. CENTRAL
Parsons HG, Thirsk JE, Frohlich J, Dias V, Minuk GY. Effect of cyclosporin a on serum lipids in primary biliary cholangitis patients. Clinical & Investigative Medicine ‐ Medecine Clinique et Experimentale 1989;12(6):386‐91. CENTRAL

Mitchison 1989 {published data only}

Mitchison HC, Bassendine MF, Malcolm AJ, Watson AJ, Record CO, James OF. A pilot, double‐blind, controlled 1‐year trial of prednisolone treatment in primary biliary cholangitis: hepatic improvement but greater bone loss. Hepatology 1989;10(4):420‐9. CENTRAL
Mitchison HC, Bassendine MF, Watson AJ, Record CO, James OFW. Double blind placebo‐controlled trial of prednisolone treatment in primary biliary cholangitis (PBC): a 3 year update. Journal of Hepatology 1989;9(1):P4. CENTRAL
Mitchison HC, Palmer JM, Bassendine MF, Watson AJ, Record CO, James OF. A controlled trial of prednisolone treatment in primary biliary cholangitis. Three‐year results. Journal of Hepatology 1992;15(3):336‐44. CENTRAL
Mitchison HC, Watson AJ, Bassendine MF, Record CO, James OFW. A pilot double blind controlled trial of prednisolone treatment in primary biliary cholangitis (PBC). Journal of Hepatology 1986;3(Suppl 1):S28. CENTRAL

Mitchison 1993 {published data only}

Buuren HR, Schalm SW. Beneficial effect of malotilate on primary biliary cholangitis (PBC): results of a multicentre controlled trial. Journal of Hepatology 1989;9(Suppl 1):S28. CENTRAL
Mitchison HC, Mutimer DJ, James OFW, Triger DR, Moller B, Hopf U, et al. The results of a randomized double blind controlled trial evaluating malotilate in primary biliary cholangitis. Journal of Hepatology 1993;17(2):227‐35. CENTRAL

Nakai 2000 {published data only}

Nakai S, Masaki T, Kurokohchi K, Deguchi A, Nishioka M. Combination therapy of bezafibrate and UDCA in primary biliary cholangitis: a preliminary study. American Journal of Gastroenterology 2000;95(1):326‐7. CENTRAL
Nakai S, Masaki T, Morita T, Deguchi A, Nishioka M. The effect of bezafibrate in patients with primary biliary cholangitis. Hepatology 1999;30(4 Suppl):566a. CENTRAL

Neuberger 1985 {published data only}

Neuberger J, Christensen E, Popper H, Portmann B, Caballeri J, Rodes J, et al. D‐Penicillamine in primary biliary cholangitis: preliminary results of an international trial. Gut 1983;24(10):A968. CENTRAL
Neuberger J, Christensen E, Popper H, Portmann B, Caballeri J, Rodes J, et al. D‐Penicillamine in primary biliary cholangitis: preliminary results of an international trial. Liver 1984;4(1):74. CENTRAL
Neuberger J, Christensen E, Portmann B, Caballeria J, Rodes J, Ranek L, et al. Double blind controlled trial of D‐penicillamine in patients with primary biliary cholangitis. Gut 1985;26(2):114‐9. CENTRAL

Nevens 2016 {published data only}

Andreone P, Mazzella G, Invernizzi P, Floreani A, Picaro LA, Adorini L. Efficacy and safety of obeticholic acid in patients with primary biliary cirrhosis: an analysis of the Italian patients from a phase 3, randomized, placebo controlled study. Digestive and Liver Disease 2016;48:e81. CENTRAL
Andreone P, Mazzella G, Strasser SI, Bowlus CL, Invernizzi P, Drenth J, et al. The FXR agonist obeticholic acid (OCA) improves liver biochemistry parameters correlated with clinical benefit across a range of patient characteristics. Hepatology 2014;60:360a. CENTRAL
Hirschfield GM, Floreani A, Trivedi PJ, Pencek R, Liberman A, Marmon T, et al. Long‐term effect of obeticholic acid on transient elastography and AST to platelet ratio index in patients with PBC. Hepatology 2017;64(1 Suppl S1):110A‐1A. CENTRAL
Mayo M, Kremer AE, Beuers U, Marmon T, Hooshmand‐Rad R, Pencek R, et al. Mitigation of pruritus during obeticholic acid treatment in patients with primary biliary cirrhosis: strategies and successes. Gastroenterology 2016;150(4 Suppl):S1072. CENTRAL
Nevens F, Andreone P, Mazzella G, Strasser S, Bowlus C, Invernizzi P, et al. The first primary biliary cholangitis (PBC) phase 3 trial in two decades‐an international study of the FXR agonist obeticholic acid in PBC patients. Journal of Hepatology 2014;60(1 Suppl 1):S525‐6. CENTRAL
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. New England Journal of Medicine 2016;375(7):631‐43. CENTRAL
Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus CL, Invernizzi P, et al. An international phase 3 study of the FXR agonist obeticholic acid in PBC patients: effects on markers of cholestasis associated with clinical outcomes and hepatocellular damage. Hepatology 2014;60:347a‐8a. CENTRAL
Pares A, Pencek R, Peters Y, Marmon T, MacConell L, Adorini L, et al. FXR agonism with obeticholic acid may attenuate bone mineral density decrease in subjects with primary biliary cirrhosis. Journal of hepatology 2015;62:S786. CENTRAL
Pencek R, Lutz K, Marmon T, MacConell L. Evaluation of the posology of obeticholic acid (OCA) in patients with PBC. Hepatology 2015;62:525a‐6a. CENTRAL
Peters Y, Hooshmand‐Rad R, Pencek R, Owens‐Grillo J, Marmon T, MacConell L, et al. Long‐term safety of OCA in patients with PBC. Hepatology 2015;62:530a. CENTRAL
Peters Y, Hooshmand‐Rad R, Pencek R, Owens‐Grillo J, Marmon T, Macconell L, et al. Long‐term safety of obeticholic acid in patients with primary biliary cirrhosis. Digestive and Liver Disease 2016;48:e117‐8. CENTRAL
Pockros PJ, Reddy KG, Owens‐Grillo J, Marmon T, MacConell L. Efficacy of obeticholic acid in patients with primary biliary cholangitis and renal impairment. Hepatology 2017;64(1 Suppl S1):205A. CENTRAL
Trauner M, Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus CL, et al. Sustained improvement in the markers of cholestasis in an open label long term safety extension study of obeticholic acid in primary biliary cirrhosis patients. Hepatology 2015;62:511a‐2a. CENTRAL
Vierling JM, Hirschfield GM, Jones D, Groszmann RJ, Kowdley KV, Pencek R, et al. Efficacy of obeticholic acid treatment in patients with primary biliary cholangitis with cirrhosis. Hepatology 2017;64(1 Suppl S1):187A. CENTRAL

Oka 1990 {published data only}

Oka H, Toda G, Ikeda Y, Hashimoto N, Hasumura Y, Kamimura T, et al. A multi‐center double‐blind controlled trial of UDCA for primary biliary cholangitis. Gastroenterologia Japonica 1990;25(6):774‐80. CENTRAL
Toda G, Oka H, Hasumura Y, Kamimura T, Ohat Y, Tsuji T, et al. A multicenter double‐blind controlled trial of UDCA for primary biliary cholangitis in Japan. XI International Bile Acid Meeting Bile Acids as Therapeutic Agents ‐ From Basic Science to Clinical Practice 1990:76. CENTRAL

Papatheodoridis 2002 {published data only}

Hadziyannis S. Long‐term treatment of primary biliary cholangitis with UDCA: the third year of a controlled trial. XI International Bile Acid Meeting Bile Acids as Therapeutic Agents ‐ From Basic Science to Clinical Practice 1990:57‐8. CENTRAL
Hadziyannis S, Hadziyannis E. A randomised controlled trial of UDCA (UDCA) in primary biliary cholangitis (PBC). Hepatology 1988;8(5):1421. CENTRAL
Hadziyannis S, Hadziyannis E, Lianidou E, Makris A. Long‐term treatment of primary biliary cholangitis with UDCA: the third year of a controlled trial. Bile Acids as Therapeutic Agents From Basic Science to Clinical Practice Falk Symposium 58 1990:287‐96. CENTRAL
Hadziyannis SJ, Hadziyannis ES, Makris A. A randomized controlled trial of UDCA (UDCA) in primary biliary cholangitis (PBC). European Journal of Clinical Investigation 1989;19(Pt 2):A15. CENTRAL
Hadziyannis SJ, Hadziyannis ES, Makris A. A randomized controlled trial of UDCA (UDCA) in primary biliary cholangitis (PBC). Hepatology 1989;10(4):580. CENTRAL
Papatheodoridis GV, Deutsch M, Hadziyannis E, Tzakou A, Hadzivannis SJ. Ursodeoxycholic‐acid for primary biliary cholangitis: final results of a 12‐year prospective, randomised, controlled trial. Journal of Hepatology 2000;32:40. CENTRAL
Papatheodoridis GV, Hadziyannis ES, Deutsch M, Hadziyannis SJ. UDCA for primary biliary cholangitis: final results of a 12‐year, prospective, randomized, controlled trial. American Journal of Gastroenterology 2002;97(8):2063‐70. CENTRAL

Pares 2000 {published data only}

Pares A. Long‐term treatment of primary biliary cholangitis with UDCA: results of a randomized, double‐blind, placebo‐controlled trial. Journal of Hepatology 1997;26(Suppl 1):S166. CENTRAL
Pares A, Caballeria L, Bruguera M, Rodes J. Factors influencing historical progression of early primary biliary cholangitis effect of UDCA (abstract). Journal of Hepatology 2001;34(1):189‐90. CENTRAL
Pares A, Caballeria L, Rodes J. Long‐term UDCA treatment delays progression of mild primary biliary cholangitis (abstract). Journal of Hepatology 2001;34(1):187‐8. CENTRAL
Pares A, Caballeria L, Rodes J, Bruguera M, Rodrigo L, Garcia‐Plaza A, et al. Long‐term effects of UDCA in primary biliary cholangitis: results of a double‐blind controlled multicentric trial. UDCA‐cooperative group from the Spanish Association for the Study of the Liver. Journal of Hepatology 2000;32(4):561‐6. CENTRAL

Poupon 1991a {published data only}

Calmus Y, Poupon R. UDCA (UDCA) in the treatment of chronic cholestatic diseases. Biochimie 1991;73(10):1335‐8. CENTRAL
Huet PM, Huet J, Hotte S. Long term effect of UDCA (UDCA) on hepatic function and portal hypertension in primary biliary cholangitis (PBC). Hepatology 1994;20(4 (Pt 2)):202a. CENTRAL
Huet PM, Willems B, Huet J, Poupon R. Effects of UDCA (UDCA) on hepatic function and portal hypertension in primary biliary cholangitis (PBC). Hepatology 1990;12(4 (Pt 2)):907. CENTRAL
Poupon R, Chazouilleres O, Balkau B, Poupon RE. Clinical and biochemical expression of the histopathological lesions of primary biliary cholangitis. UDCA‐PBC Group. Journal of Hepatology 1999;30(3):408‐12. CENTRAL
Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cholangitis. New England Journal of Medicine 1991;324(22):1548‐54. CENTRAL
Poupon RE, Balkau B, Guechot J, Heintzmann F. Predictive factors in UDCA‐treated patients with primary biliary cholangitis: role of serum markers of connective tissue. Hepatology 1994;19(3):635‐40. CENTRAL
Poupon RE, Balkau B, Poupon R. Beneficial effect of UDCA (UDCA) in primary biliary cholangitis (PBC) final results of the French Canadian trial. Hepatology 1990;12(4 (Pt 2)):872. CENTRAL
Poupon RE, Chretien Y, Balkau B, Niard AM, Poupon R. Ursodeoxycholic therapy for primary biliary cholangitis: a four year controlled study. Hepatology 1992;16(2 (Pt 2)):91a. CENTRAL
Poupon RE, Chretien Y, Poupon R, Paumgartner G. Serum bile acids in primary biliary cholangitis: effect of UDCA therapy. Hepatology 1993;17(4):599‐604. CENTRAL
Poupon RE, Eschwege E, Poupon R. UDCA for the treatment of primary biliary cholangitis. Interim analysis of a double‐blind multicentre randomized trial. The UDCA‐PBC Study Group. Journal of Hepatology 1990;11(1):16‐21. CENTRAL
Poupon RE, Ouguerram K, Chretien Y, Verneau C, Eschwege E, Magot T, et al. Cholesterol‐lowering effect of UDCA in patients with primary biliary cholangitis. Hepatology 1993;17(4):577‐82. CENTRAL
Poupon RE, Ouguerram K, Chretien Y, Verneau C, Eschwege E, Magot T, et al. [Hypocholesterolemic properties of UDCA in patients with primary biliary cholangitis]. Medecine & Chirurgie Digestives 1995;24(3):163‐4. CENTRAL
Poupon RE, Poupon R. UDCA (UDCA) for treatment of primary biliary cholangitis (PBC): interim analysis of a double‐blind multicenter randomized trial. Hepatology 1989;10(4):639. CENTRAL

Poupon 1996 {published data only}

Huet P, Willems B, Huet J, Poupon R. Effects of UDCA (UDCA) on hepatic function and portal hypertension in primary biliary cholangitis (PBC). XII International Bile Acid Meeting Bile Acids and the Hepatobiliary System from Basic Science to Clinical Practice Falk Symposium No 68 1992:118. CENTRAL
Huet PM, Huet J, Deslauriers J. Long‐term UDCA (UDCA) and colchicine (C) treatment in primary biliary cholangitis (PBC): effect on hepatic function and portal hypertension. Canadian Journal of Gastroenterology 1996;10(Suppl A):S47. CENTRAL
Huet PM, Huet J, Poupon RE, Deslauriers J. The combination of UDCA (UDCA) and colchicine (C) for patients with primary biliary cholangitis (PBC): effect on hepatic function and portal hypertension. Hepatology 1996;23(1):I‐49. CENTRAL
Poupon RE, Huet PM, Poupon R, Bonnand AM, Nhieu JT, Zafrani ES. A randomized trial comparing colchicine and UDCA combination to UDCA in primary biliary cholangitis. UDCA‐PBC Study Group. Hepatology 1996;24(5):1098‐103. CENTRAL
Poupon RE, Niard AM, Huet PM, Miguet JP, Mathieuchandelier C, Doffoel M, et al. A randomized trial comparing the combination UDCA (UDCA) and colchicine to UDCA alone in primary biliary‐cirrhosis. Hepatology 1994;20(4):A151. CENTRAL

Raedsch 1993 {published data only}

Raedsch R, Stiehl A, Walker S, Rudi J, Schlenker T, Gerteis C. Controlled study on the effects of a combined colchicine plus UDCA treatment in primary biliary cholangitis. 68th Falk Symposium; 1992 Oct 12‐14; Basel, Switzerland. 1993:303‐9. CENTRAL
Raedsch R, Stiehl A, Walker S, Scherrmann JM, Kommerell B. [Combined colchicine plus UDCA‐treatment of primary biliary cholangitis: results of a placebo‐controlled double‐blind study]. Zeitschrift Fur Gastroenterologie 1992;30(Suppl 1):55‐7. CENTRAL
Raedsch R, Stiehl A, Walker S, Theilmann L, Kommerell B. Effects of UDCA and colchicine plus UDCA in primary biliary cholangitis: a double‐blind pilot study. Bile Acids as Therapeutic Agents From Basic Science to Clinical Practice Falk Symposium 58 1991, (36):301‐4. CENTRAL
Raedsch R, Stiehl A, Walker S, Theilmann L, Kommerell B. Influence of UDCA and URSO plus colchicine on primary biliary cholangitis: a double‐blind controlled pilot study. Klinische Wochenschrift 1991;69(Suppl 23):84. CENTRAL

Rautiainen 2005 {published data only}

Rautiainen H, Farkkila M, Neuvonen M, Sane T, Karvonen AL, Nurm H, et al. Pharmacokinetics and bone effects of budesonide in primary biliary cholangitis. Alimentary Pharmacology & Therapeutics 2006;24(11‐12):1545‐52. CENTRAL
Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P, Nuutinen H, et al. Budesonide combined with UDCA to improve liver histology in primary biliary cholangitis: a three‐year randomized trial. Hepatology 2005;41(4):747‐52. CENTRAL

Senior 1991 {published data only}

O'Brien CB, Senior JR, Sternlieb JM, Sample M, Saul SM, Arora R. Ursodiol treatment of primary biliary cholangitis. Gastroenterology 1990;98(2 (Pt 2)):A617. CENTRAL
Senior JR, O'Brien C. Mortality risk indices as outcome measures of the effectiveness of UDCA treatment of cholestatic liver diseases. Bile Acids as Therapeutic Agents From Basic Science to Clinical Practice Falk Symposium 58 1991:273‐85. CENTRAL
Senior JR, O'Brien CB, Dickson ER. Effect of oral ursodiol treatment on the predicted probability of mortality in primary biliary cholangitis. Hepatology 1990;12(2):438. CENTRAL

Smart 1990 {published data only}

Smart HL, Cann PA, Thuluvath PJ, Triger DR. A double blind placebo controlled study of antioxidants in primary biliary cholangitis (PBC). Gut 1990;31(10):A1184. CENTRAL

Steenbergen 1994 {published data only}

Steenbergen W, Sciot R, Eycken P, Desmet V, Fevery J. Combined treatment with methotrexate and UDCA in primary biliary cholangitis (PBC). Journal of Hepatology 1994;21(Suppl 1):S89. CENTRAL
Steenbergen W, Sciot R, Eyken P, Desmet V, Fevery J. Methotrexate alone or in combination with UDCA as possible treatment in primary biliary cholangitis. Cholestatic Liver diseases: New Strategies for Prevention and Treatment of Hepatobiliary and Cholestatic Liver Diseases Falk Symposium 75 1994:246‐54. CENTRAL
Van Steenbergen W, Sciot R, Van Eyken P, Desmet V, Fevery J. Combined treatment with methotrexate and UDCA in non‐cirrhotic primary biliary cholangitis. Acta Clinica Belgica 1996;51(1):8‐18. CENTRAL

Taal 1983 {published data only}

Taal BG, Schalm SW. Prednisone plus D‐penicillamine, D‐penicillamine and placebo compared in primary biliary‐cirrhosis syndrome. Gastroenterology 1981;80(5 Part 2):1351. CENTRAL
Taal BG, Schalm SW, Kate FWJ. Double‐blind controlled study of penicillamine in primary biliary cholangitis: dose‐dependent effects. Nederlands Tijdschrift voor Geneeskunde 1982;126(12):547. CENTRAL
Taal BG, Schalm SW, Ten Kate FW, Van Berge Henegouwen GP, Brandt KH. Low therapeutic value of D‐penicillamine in a short‐term prospective trial in primary biliary cholangitis. Liver 1983;3(6):345‐52. CENTRAL

Triger 1980 {published data only}

Triger DR, Manifold IH, Cloke P, Underwood JCE. D‐Penicillamine in primary biliary cholangitis: two year results of a single centre, doubled‐blind controlled trial. Gut 1980;21(10):A919‐20. CENTRAL

Turner 1994 {published data only}

Myszor M, Turner I, Mitshison H, Bennett M, Burt AD, James OFW. No symptomatic or histological benefit from UDCA treatment in PBC after 1 year controlled pilot study. Hepatology 1990;12(2):415. CENTRAL
Turner IB, Myszor M, Mitchison HC, Bennett MK, Burt AD, James OF. A two year controlled trial examining the effectiveness of UDCA in primary biliary cholangitis. Journal of Gastroenterology & Hepatology 1994;9(2):162‐8. CENTRAL

Ueno 2005 {published data only}

Ueno Y, Moritoki Y, Kanno N, Fukushima K, Yamagiwa Y, Kogure T, et al. Randomized double blind control trial of reverse transcriptase inhibitor for the treatment of UDCA‐resistant PBC. Gastroenterology 2005;128(4):A775‐A. CENTRAL

Van Hoogstraten 1998 {published data only}

Hoogstraten HJF, Smet MBM, Renooij W, Hop WCJ, Berge‐Henegouwen GP, Schalm SW. A randomized controlled trial evaluating therapy with UDCA in daily doses of 10 mg/kg versus 20 mg/kg in primary biliary cholangitis. European Journal of Gastroenterology & Hepatology 1998;10(12):A7. CENTRAL
Van Hoogstraten HJF, De Smet MBM, Renooij W, Breed JGS, Engels L, Den Ouden‐Muller JW, et al. A randomized trial in primary biliary cholangitis comparing UDCA in daily doses of either 10 mg/kg or 20 mg/kg. Alimentary Pharmacology & Therapeutics 1998;12(10):965‐71. CENTRAL
Van Hoogstraten HJF, De Smet MBM, Renooij W, Hop WCJ, Van Buuren HR, VanBerge‐Henegouwen GP. A randomized controlled trial evaluating therapy with UDCA in daily doses of 10 mg/kg versus 20 mg/kg in primary biliary cholangitis. Gastroenterology 1998;114(4):A1358‐A. CENTRAL

Warnes 1987 {published data only}

Warnes T, Babbs C, Smith A, Lee F, Haboubi NY, Johnson PJ, et al. A controlled trial of colchicine in primary biliary cholangitis (PBC). Journal of Hepatology 1985;1(Suppl 2):S348. CENTRAL
Warnes TW, Goddard CJR, Smith A, Rowan BP, Hunt L. Liver function and prognosis in primary biliary cholangitis: 'sharp' and 'blunt' tests and the influence of colchicine treatment on survival. Hepatology 1996;23(1):I‐82. CENTRAL
Warnes TW, Smith A, Lee F, Haboubi NY, Johnson PJ, Hunt L. A controlled trial of colchicine in primary biliary cholangitis. Hepatology 1984;4(5):1022. CENTRAL
Warnes TW, Smith A, Lee FI, Haboubi NY, Johnson PJ, Hunt L. A controlled trial of colchicine in primary biliary cholangitis. Trial design and preliminary report. Journal of Hepatology 1987;5(1):1‐7. CENTRAL

Wiesner 1990 {published data only}

Wiesner RH, Dickson ER, Lindor KD, Jørgensen R, LaRusso NF, Baldus W. A controlled clinical trial evaluating cyclosporin in the treatment of primary biliary cholangitis: a preliminary report. Hepatology 1987;7(5):1025. CENTRAL
Wiesner RH, Ludwig J, Lindor KD, Jorgensen RA, Baldus WP, Homburger HA, et al. A controlled trial of cyclosporine in the treatment of primary biliary cholangitis. New England Journal of Medicine 1990;322(20):1419‐24. CENTRAL

Wolfhagen 1998 {published data only}

Hoogstraten H, Wolfhagen FHJ, Berge Henegouwen GP, Schalm SW, Kate FJW, Hop WCJ, et al. Combined bile acid‐immunosuppressive therapy for primary biliary cholangitis. Results of a 1‐year multi centre, placebo controlled trial. European Journal of Gastroenterology & Hepatology 1996;8(Suppl 12):A 41. CENTRAL
Lim AG, Wolfhagen FH, Verma A, Van Buuren HR, Jazrawi RP, Levy JH, et al. Soluble intercellular adhesion molecule‐1 in primary biliary cholangitis: effect of UDCA and immunosuppressive therapy. European Journal of Gastroenterology & Hepatology 1997;9(2):155‐61. CENTRAL
Lim AG, Wolfhagen FHJ, Verma A, Buuren HR, Jazrawi RP, Levy JH, et al. Soluble intercellular adhesion molecule 1 in primary biliary cholangitis: effect of UDCA and immunosuppressive therapy. Hepatology 1995;22(4 (Pt 2)):124a. CENTRAL
Lim AG, Wolfhagen FHJ, Verma A, Buuren HR, Jazrawi RP, Northfield TC. Soluble intercellular adhesion molecule‐1 in primary biliary cholangitis: effect of UDCA, prednisone and azathioprine. Falk Symposium Bile Acids and Immunology 1995;86:9. CENTRAL
Lim AG, Wolfhagen FHJ, Verma A, Jazrawi RP, Bururen HR, Levy JH, et al. Combination UDCA and immunosuppressive therapy for the treatment of primary biliary cholangitis. Gut 1995;37(Suppl 2):A27. CENTRAL
Van Hoogstraten HJF, Wolfhagen FHJ, Henegouwen GPB, Schalm SW, tenKate FJW, Hop WCJ. Combined bile acid ‐ immunosuppressive therapy for primary biliary cholangitis. Results of a 1‐year multi centre, placebo controlled trial. Hepatology 1996;24(4 Suppl):167. CENTRAL
Wolfhagen FHJ, Buuren HR, Berge Henegouwen GP, Hattum J, Ouden JW, Kerbert MJ, et al. A randomized placebo‐controlled trial with prednisone/azathioprine in addition to UDCA in primary biliary cholangitis. Journal of Hepatology 1994;21(Suppl 1):S49. CENTRAL
Wolfhagen FHJ, Buuren HR, Berge‐Henegouwen GP, Hattum J, Ouden JW, Kerbert MJ. Prednisone/azathioprine treatment in primary biliary cholangitis (PBC) a randomized, placebo‐controlled trial. Netherlands Journal of Surgery 1995;46:A10. CENTRAL
Wolfhagen FHJ, Lim AG, Verma A, Buuren HR, Jazrawi RP, Northfield TC, et al. Soluble ICAM‐1 in primary biliary cholangitis (PBC) during combined treatment with UDCA, prednisone and azathioprine. Netherlands Journal of Surgery 1995;47:A29‐30. CENTRAL
Wolfhagen FHJ, Van Hoogstraten HJF, Van Buuren HR, Van Berge‐Henegouwen GP, Ten Kate FJW, Hop WCJ, et al. Triple therapy with UDCA, prednisone and azathioprine in primary biliary cholangitis: A 1‐year randomized, placebo‐controlled study. Journal of Hepatology 1998;29(5):736‐42. CENTRAL

Yokomori 2001 {published data only}

Yokomori H, Oda M, Ishii H. Effects of UDCA and colestilan versus UDCA alone on serum bile acids and pruritus: a randomized, open‐label study. Current Therapeutic Research ‐ Clinical and Experimental 2001;62(3):221‐9. CENTRAL

Referencias de los estudios excluidos de esta revisión

Ir a:

Angulo 1999b {published data only}

Angulo P, Batts KP, Therneau TM, Jorgensen RA, Dickson ER, Lindor KD. Long‐term UDCA delays histological progression in primary biliary cholangitis. Hepatology 1999;29(3):644‐7. CENTRAL

Angulo 1999c {published data only}

Angulo P, Lindor KD, Therneau TM, Jorgensen RA, Malinchoc M, Kamath PS, et al. Utilization of the Mayo risk score in patients with primary biliary cholangitis receiving UDCA. Liver 1999;19(2):115‐21. CENTRAL

Angulo 2002 {published data only}

Angulo P, Petz JL, Jorgensen RA, Lindor KD. A randomized, cross‐over study evaluating single‐ and multiple‐daily dosage schedules of UDCA in primary biliary cholangitis. Gastroenterology 2002;122(4):A629. CENTRAL

Attili 1994 {published data only}

Attili AF, Rusticali A, Varriale M, Carli L, Repice AM, Callea F. Effect of UDCA on serum enzymes and liver histology in patients with chronic active hepatitis ‐ a 12 month double‐blind, placebo‐controlled trial. Journal of Hepatology 1994;20(3):315‐20. CENTRAL

Avezov 2004a {published data only}

Avezov SA, Mansurova F. [Efficacy of combined use of UDCA and heptral in the treatment of primary biliary cholangitis]. Klinicheskaia Meditsina 2004;82(2):46‐9. CENTRAL

Avezov 2004b {published data only}

Avezov SA, Mansurov F. [Efficacy of combined administration of UDCA and hepthral in the treatment of primary biliary cholangitis]. Klinicheskaia Meditsina 2004;82(3):55‐8. CENTRAL

Bach 2003 {published data only}

Bach N, Bodian C, Bodenheimer H, Croen E, Berk PD, Thung SN, et al. Methotrexate therapy for primary biliary cholangitis. American Journal of Gastroenterology 2003;98(1):187‐93. CENTRAL

Batta 1989 {published data only}

Batta AK, Salen G, Arora R, Shefer S, Tint GS, Abroon J, et al. Effect of UDCA on bile acid metabolism in primary biliary cholangitis. Hepatology 1989;10(4):414‐9. CENTRAL

Beukers 1988 {published data only}

Beukers R, Schalm SW. Effect of cyclosporine and cyclosporine plus prednisone in primary biliary cholangitis. Transplantation Proceedings 1988;20(3 Suppl 4):340‐3. CENTRAL

Blanche 1994 {published data only}

Blanche P, Sicard D. Methotrexate for polymyositis associated with primary biliary cholangitis. Clinical & Experimental Rheumatology 1994;12(6):694. CENTRAL

Bonis 2006 {published data only}

Bonis PA, Kaplan M. Methotrexate for treatment of primary biliary cholangitis. Hepatology 2006;43(3):632; author reply 633. CENTRAL

Borum 1990 {published data only}

Borum M, Fromm H. UDCA in the treatment of primary biliary cholangitis: first controlled data. Hepatology 1990;12(1):172‐3. CENTRAL

Bray 1991 {published data only}

Bray GP, Padova C, Tredger JM, Williams R. A comparison of S‐adenosylmethionine (SAMe), rifampicin (R) and UDCA (UDCA) in primary biliary cholangitis (PBC): interim results. Journal of Hepatology 1991;13(Suppl 2):S101. CENTRAL

Carbone 2016 {published data only}

Carbone M, Jones D, Mells GF, Pencek R, Marmon T, Shapiro D. Predicted risk of end stage liver disease with continued standard of care and subsequent addition of obeticholic acid in patients with PBC. Hepatology 2016;63 (1 Suppl 1):184A‐5A. CENTRAL

Chazouilleres 1995 {published data only}

Chazouilleres O, Legendre C, StMaur P, Ismail PR, Poupon R. Histological course of primary biliary cholangitis (PBC) treated with UDCA (UDCA). Hepatology 1995;22(4 (Pt 2)):125a. CENTRAL

Christensen 1986 {published data only}

Christensen E, Neuberger J, Crowe J, Portmann B, Williams R, Altman DG, et al. Azathioprine and prognosis in primary biliary cholangitis. Gastroenterology 1986;90(2):508‐9. CENTRAL

Combes 1989 {published data only}

Combes B. Prednisolone for primary biliary cholangitis ‐ good news, bad news. Hepatology 1989;10(4):511‐3. CENTRAL

Combes 2004 {published data only}

Combes B, Luketic VA, Peters MG, Zetterman RK, Garcia‐Tsao G, Munoz SJ, et al. Prolonged follow‐up of patients in the U.S. Multicenter trial of UDCA for primary biliary cholangitis. American Journal of Gastroenterology 2004;99(2):264‐8. CENTRAL

Combes 2005b {published data only}

Combes B. Reflections on therapeutic trials in primary biliary cholangitis. Hepatology 2005;42(5):1009. CENTRAL

Copaci 2001 {published data only}

Copaci I, Micu L, Cojocaru L. UDCA and methotrexate for primary biliary cholangitis. Journal of Hepatology 2001;34(1):59. CENTRAL

Corpechot 2000 {published data only}

Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of UDCA therapy on liver fibrosis progression in primary biliary cholangitis. Hepatology 2000;32(6):1196‐9. CENTRAL

Corpechot 2001 {published data only}

Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of UDCA therapy on liver fibrosis progression in primary biliary cholangitis. European Journal of Gastroenterology & Hepatology 2001;13(1):90. CENTRAL

Crosignani 1996a {published data only}

Crosignani A, Larghi A, Invernizzi P, Battezzati PM, DeValle G, Zuin M, et al. Tauroursodeoxycholic and UDCAs for the treatment of primary biliary cholangitis: a crossover study. Hepatology 1996;23(1):P111. CENTRAL

Crosignani 1996b {published data only}

Crosignani A, Battezzati PM, Setchell KDR, Invernizzi P, Covini G, Zuin M, et al. TauroUDCA for treatment of primary biliary cholangitis ‐ a dose‐response study. Digestive Diseases and Sciences 1996;41(4):809‐15. CENTRAL

Degott 1999 {published data only}

Degott C, Zafrani ES, Callard P, Balkau B, Poupon RE, Poupon R. Histopathological study of primary biliary cholangitis and the effect of UDCA treatment on histology progression. Hepatology 1999;29(4):1007‐12. CENTRAL

De la Mora 1994 {published data only}

De la Mora G, Bobadilla J, Romero P, Rodríguez‐Leal G, Morán S, Kershenobich D, et al. Does treatment with UDCA (UDCA) really diminish cholesterol serum levels in primary biliary cholangitis (PBC)?. Hepatology 1994;19:571. CENTRAL

Dickson 1991 {published data only}

Dickson ER, Lindor KD. Beneficial effects of UDCA in an open trial of patients with primary biliary cholangitis. Bile Acids as Therapeutic Agents From Basic Science to Clinical Practice Falk Symposium 58 1991, (32):271‐2. CENTRAL

Emond 1996 {published data only}

Emond M, Carithers RL, Luketic VA, Peters M, Zetterman RK, Garcia‐Tsao G. Does UDCA improve survival in patients with primary biliary cholangitis? Comparison of outcome in the US multicenter trial to expected survival using the Mayo Clinic prognostic model. Hepatology 1996;24(4 (Pt 2)):168a. CENTRAL

Fischer 1967 {published data only}

Fischer JA, Schmid M. Treatment of primary biliary cholangitis with azathioprine. Lancet 1967;1(7487):421‐4. CENTRAL

Golovanova 2010 {published data only}

Golovanova EV, Khomeriki SG, Petrakov AV, Serova TI. Budesonide in treatment of patients with cross primary biliary cholangitis and autoimmune hepatitis. Eksperimental'Naia i Klinicheskaia Gastroenterologiia 2010, (8):113‐7. CENTRAL

Heathcote 1993 {published data only}

Heathcote EJL, Cauch K, Walker V, Blendism LM, Ghent CN, Pappas SC. A four‐year follow‐up study of UDCA therapy for primary biliary cholangitis. Gastroenterology 1993;104(4 (Pt 2)):A914. CENTRAL

Heathcote 1995 {published data only}

Heathcote EJ, Lindor KD, Poupon R, Cauchdudek K, Dickson ER, Trout R, et al. Combined analysis of French, American and Canadian randomized controlled trials of UDCA therapy in primary biliary cholangitis. Gastroenterology 1995;108(4 Suppl 3):A1082. CENTRAL

Hirschfield 2011 {published data only}

Hirschfield GM, Mason AL, Gordon SC, Luketic VA, Mayo M, Vincent C, et al. A long term safety extension trial of the farnesoid x receptor (FXR) agonist obeticholic acid (OCA) and UDCA in primary biliary cholangitis (PBC). Hepatology 2011;54(S1):429a. CENTRAL

Hishon 1982 {published data only}

Hishon S, Tobin G, Ciclitira PJ. A clinical trial of levamisole in primary biliary cholangitis. Postgraduate Medical Journal 1982;58(685):701‐3. CENTRAL

Howat 1966 {published data only}

Howat HT, Ralston AJ, Varley H, Wilson JA. The late results of long‐term treatment of primary biliary cholangitis by corticosteroids. Revue Internationale d' Hepatologie 1966;16(2):227‐38. CENTRAL

Hwang 1993 {published data only}

Hwang SJ, Chan CY, Lee SD, Wu JC, Tsay SH, Lo KJ. UDCA in the treatment of primary biliary cholangitis: a short‐term, randomized, double‐blind controlled, cross‐over study with long‐term follow up. Journal of Gastroenterology & Hepatology 1993;8(3):217‐23. CENTRAL

Invernizzi 1996 {published data only}

Invernizzi A, Setchell DDR, Crosignani A, Larghi A, Battezzatti PM, O'Connell N, et al. Comparison between tauroursodeoxycholic and UDCAs in patients with primary biliary cholangitis: a cross over study. Hepatology 1996;24(4 (Pt 2)):168a. CENTRAL

Invernizzi 2015 {published data only}

Invernizzi P, Pencek R, Marmon T, MacConell L, Shapiro D. Integrated efficacy summary for obeticholic acid in subjects with primary biliary cholangitis. Journal of Hepatology 2015;62:S778. CENTRAL

Itakura 2004 {published data only}

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 cholangitis. Hepatology Research 2004;29(4):216‐22. CENTRAL

Jazrawi 1999 {published data only}

Jazrawi RP, Verma A, Ahmed HA, Northfield TC. Effect of UDCA on cholestatic features and complications of primary biliary cholangitis. Bile Acids and Cholestasis 1999;108:231‐46. CENTRAL

Jones 2006 {published data only}

Jones DE, Bhala N, Newton JL. Reflections on therapeutic trials in primary biliary cholangitis: a quality of life oriented counter‐view. Hepatology 2006;43(3):633; Author reply 634. CENTRAL

Jorgensen 2002 {published data only}

Jorgensen R, Angulo P, Dickson ER, Lindor KD. Results of long‐term ursodiol treatment for patients with primary biliary cholangitis. American Journal of Gastroenterology 2002;97(10):2647‐50. CENTRAL

Joshi 2002 {published data only}

Joshi S, Cauch‐Dudek K, Wanless IR, Lindor KD, Jorgensen R, Batts K, et al. Primary biliary cholangitis with additional features of autoimmune hepatitis: response to therapy with UDCA. Hepatology 2002;35(2):409‐13. CENTRAL

Kaplan 1993 {published data only}

Kaplan MM. New strategies needed for treatment of primary biliary cholangitis?. Gastroenterology 1993;104(2):651‐3. CENTRAL

Kaplan 1998 {published data only}

Kaplan M. Primary biliary cholangitis. Lancet 1998;351(9097):216. CENTRAL

Kaplan 2004 {published data only}

Kaplan MM, Cheng S, Price LL, Bonis PA. A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cholangitis: ten‐year results. Hepatology 2004;39(4):915‐23. CENTRAL

Kaplan 2009 {published data only}

Kaplan MM, Poupon R. Treatment with immunosuppressives in patients with primary biliary cholangitis who fail to respond to ursodiol. Hepatology 2009;50(2):652. CENTRAL

Kisand 1996 {published data only}

Kisand KE, Karvonen AL, Vuoristo M, Farkkila M, Lehtola J, Inkovaara J, et al. UDCA treatment lowers the serum level of antibodies against pyruvate dehydrogenase and influences their inhibitory capacity for the enzyme complex in patients with primary biliary cholangitis. Journal of Molecular Medicine 1996;74(5):269‐72. CENTRAL

Kisand 1998 {published data only}

Kisand KE, Kisand KV, Karvonen AL, Vuoristo M, Mattila J, Makinen J, et al. Antibodies to pyruvate dehydrogenase in primary biliary cholangitis: correlation with histology. APMIS 1998;106(9):884‐92. CENTRAL

Kowdley 2014a {published data only}

Kowdley K, Hirschfield G, Chapman R, Vincent C, Jones D, Pares A, et al. Long‐term treatment of primary biliary cholangitis with the FXR agonist obeticholic acid shows durable efficacy. Journal of Hepatology 2014;60(1 Suppl 1):S192‐3. CENTRAL

Kowdley 2014b {published data only}

Kowdley KV, Pencek R, Marmon T, Shapiro D, Hooshmand‐Rad R. FXR agonist obeticholic acid: sustained improvement in markers of cholestasis and long‐term safety in patients with primary biliary cholangitis through 4 years. Hepatology 2014;60:361a. CENTRAL

Kowdley 2015 {published data only}

Kowdley KV, Shah H, Mason A, Luketic VA, Pencek R, Marmon T, et al. Long‐term safety and efficacy of obeticholic acid treatment in primary biliary cirrhosis after more than 4 years of treatment. Hepatology 2015;62:521a‐2a. CENTRAL

Kugler 1991 {published data only}

Kugler CF, Fleig WE. [Placebo‐controlled double‐blind study of cyclosporin a in primary biliary cholangitis]. Zeitschrift Fur Gastroenterologie 1991;29(12):663‐4. CENTRAL

Kurihara 2002 {published data only}

Kurihara T, Maeda A, Shigemoto M, Yamashita K, Hashimoto E. Investigation into the efficacy of bezafibrate against primary biliary cholangitis, with histological references from cases receiving long term monotherapy. American Journal of Gastroenterology 2002;97(1):212‐4. CENTRAL

Lampe 1972 {published data only}

Lampe K, Hudepohl M, Schopen RD. [Immunosuppressive therapy of chronic aggressive hepatitis and primary biliary cholangitis]. Medizinische Klinik 1972;67(15):527‐34. CENTRAL

Larghi 1997 {published data only}

Larghi A, Crosignani A, Battezzati PM, De Valle G, Allocca M, Invernizzi P, et al. Ursodeoxycholic and tauro‐UDCAs for the treatment of primary biliary cholangitis: a pilot crossover study. Alimentary Pharmacology & Therapeutics 1997;11(2):409‐14. CENTRAL

Lee 2003 {published data only}

Lee YM, Kaplan MM. Efficacy of colchicine in patients with primary biliary cholangitis poorly responsive to ursodiol and methotrexate. American Journal of Gastroenterology 2003;98(1):205‐8. CENTRAL

Leung 2010 {published data only}

Leung J, Bonder A, Sasson M, Bonis P, Kaplan M. 19‐year follow‐up of patients in a double‐blind trial of colchicine plus ursodiol versus methotrexate plus ursodiol in the treatment of primary biliary cholangitis. Gastroenterology 2010;1:S218. CENTRAL

Leung 2011 {published data only}

Leung J, Bonis PA, Kaplan MM. Colchicine or methotrexate, with ursodiol, are effective after 20 years in a subset of patients with primary biliary cholangitis. Clinical Gastroenterology & Hepatology 2011;9(9):776‐80. CENTRAL

Leuschner 1990 {published data only}

Leuschner U, Güldütuna S, Fischer H, Hellstern A, Hübner K. UDCA in the treatment of primary biliary cholangitis: the Frankfurt experience. Strategies for the treatment of hepatobiliary diseases Falk symposium 53 1990, (9):83‐90. CENTRAL

Leuschner 1993a {published data only}

Leuschner M, Güldütuna S, Imhof M, Bhati S, You T, Leuschner U. UDCA therapy in primary biliary cholangitis. 68th Falk Symposium; 1992 Oct 12‐14; Basel, Switzerland 1993:299‐302. CENTRAL

Leuschner 1993b {published data only}

Leuschner M, Guldutuna S, Benjaminov A, Hubner K, Leuschner U. Interim evaluation of a prospective double‐blind trial of UDCA (UDCA) versus UDCA plus prednisolone in primary biliary cholangitis (PBC). Gastroenterology 1993;104(4):A938. CENTRAL

Leuschner 1996a {published data only}

Leuschner M, Guldutuna S, You T, Hubner K, Bhatti S, Leuschner U. UDCA and prednisolone versus UDCA and placebo in the treatment of early stages of primary biliary cholangitis. Journal of Hepatology 1996;25(1):49‐57. CENTRAL

Leuschner 1996b {published data only}

Leuschner M, Guldutuna S, Hubner K, You T, Leuschner U. UDCA (UDCA) and prednisolone in the treatment of primary biliary cholangitis (PBC). Results of a controlled double‐blind trial. Gastroenterology 1996;110(4):A1250. CENTRAL

Leuschner 1997 {published data only}

Leuschner U, Maier KP, Guldutuna S, Parte‐Peterhans S, Leuschner M. UDCA in combination with prednisolone or budesonide in the therapy of primary biliary cholangitis. Bile Acids in Hepatobiliary Diseases: Basic Research and Clinical Application 1997;93:299‐302. CENTRAL

Leuschner 1998 {published data only}

Leuschner U, Maier P, Schitling J, Strahl R, Herrmann G, Leuschner M. UDCA and budesonide in the treatment of primary biliary cholangitis. XV International Bile Acid Meeting Bile Acids and Cholestasis Vol 1998;Falk Symposium 108:60‐1. CENTRAL

Levy 2004 {published data only}

Levy C, Angulo P. UDCA and long‐term survival in primary biliary cholangitis. American Journal of Gastroenterology 2004;99(2):269‐70. CENTRAL

Licinio 2015 {published data only}

Licinio R, Facciorusso A, Castellaneta NM, Di Leo A. Combination therapy of UDCA and bezafibrate in patients with primary biliary cholangitis: the end of the steroid era in autoimmune liver diseases?. American Journal of Gastroenterology 2015;110(7):1086. CENTRAL

Lim 2000 {published data only}

Lim AG, Jazrawi RP, Ahmed HA, Northfield TC. UDCA ‐ an immunomodulator in primary biliary cholangitis?. Bile Acids in Hepatobiliary Disease 2000;110B:30‐5. CENTRAL

Lindor 1994a {published data only}

Lindor KD, Jorgensen RA, Anderson ML, Gores GJ, Baldus WP, Dickson ER. The combination of UDCA (UDCA) and methotrexate (MTX) for patients with primary biliary cholangitis (PBC): the results of a pilot study. Hepatology 1994;20(4 (Pt 2)):202. CENTRAL

Lindor 1995a {published data only}

Lindor KD, Therneau TM, Jorgensen RA, Malinochoc M, Dickson ER. Effects of UDCA (UDCA) on survival in patients with primary biliary‐cirrhosis (PBC). Gastroenterology 1995;108(4 Suppl 3):A1111. CENTRAL

Lindor 1995b {published data only}

Lindor KD, Dickson ER, Jorgensen RA, Anderson ML, Wiesner RH, Gores GJ, et al. The combination of UDCA and methotrexate for patients with primary biliary cholangitis: the results of a pilot study. Hepatology 1995;22(4 I):1158‐62. CENTRAL

Lindor 1995c {published data only}

Lindor K. Long‐term experience with UDCA for patients with primary biliary cholangitis and primary sclerosing cholangitis. International Falk Workshop Bile Acids in Liver Diseases 1995:141‐5. CENTRAL

Lindor 1996 {published data only}

Lindor KD, Therneau TM, Jorgensen RA, Malinchoc M, Dickson ER. Effects of UDCA on survival in patients with primary biliary cholangitis. Gastroenterology 1996;110(5):1515‐8. CENTRAL

Lindor 2000 {published data only}

Lindor KD, Poupon R, Poupon R, Heathcote EJ, Therneau T. UDCA for primary biliary cholangitis. Lancet 2000;355(9204):657‐8. CENTRAL

Lindor 2005 {published data only}

Lindor KD. Dose effect of UDCA used in the treatment of primary biliary cholangitis and primary sclerosing cholangitis. Bile Acid Biology and Its Therapeutic Implications 2005;141:225‐9. CENTRAL

Lindor 2007 {published data only}

Lindor K. UDCA for the treatment of primary biliary cholangitis. New England Journal of Medicine 2007;357(15):1524‐9. CENTRAL

Lytvyak 2015 {published data only}

Lytvyak E, Montano‐Loza AJ, Saxinger L, Mason A. Combination anti‐retroviral therapy provides reduction in human betaretrovirus load and durable biochemical responses in patients with primary biliary cholangitis. Hepatology 2015;62:528A. CENTRAL

Lytvyak 2016 {published data only}

Lytvyak E, Montano‐Loza AJ, Mason AL. Combination antiretroviral studies for patients with primary biliary cirrhosis. World Journal of Gastroenterology 2016;22(1):349‐60. CENTRAL

Miettinen 1993 {published data only}

Miettinen TA, Farkkila M, Vuoristo M, Karvonen AL, Leino R, Lehtola J. Improvement of serum noncholesterol sterols may indicate retarded progression of primary biliary cholangitis (PBC) in a randomized placebo controlled two‐year trial with colchicine and UDCA. Gastroenterology 1993;104(4 (Pt 2)):A954. CENTRAL

Miettinen 1995 {published data only}

Miettinen TA, Farkkila M, Vuoristo M, Karvonen AL, Leino R, Lehtola J, et al. Serum cholestanol, cholesterol precursors, and plant sterols during placebo‐controlled treatment of primary biliary cholangitis with UDCA or colchicine. Hepatology 1995;21(5):1261‐8. CENTRAL

Muntoni 2010 {published data only}

Muntoni S, Rojkind M, Muntoni S. Colchicine reduces procollagen III and increases pseudocholinesterase in chronic liver disease. World Journal of Gastroenterology 2010;16(23):2889‐94. CENTRAL

Nikolaidis 2006 {published data only}

Nikolaidis N, Kountouras J, Giouleme O, Tzarou V, Chatzizisi O, Patsiaoura K, et al. Colchicine treatment of liver fibrosis. Hepato‐Gastroenterology 2006;53(68):281‐5. CENTRAL

Ohmoto 2001 {published data only}

Ohmoto K, Mitsui Y, Yamamoto S. Effect of bezafibrate in primary biliary cholangitis: a pilot study. Liver 2001;21(3):223‐4. CENTRAL

Ohmoto 2006 {published data only}

Ohmoto K, Yoshioka N, Yamamoto S. Long‐term effect of bezafibrate on parameters of hepatic fibrosis in primary biliary cholangitis. Journal of Gastroenterology 2006;41(5):502‐3. CENTRAL

Pan 2013 {published data only}

Pan XL, Zhao L, Li L, Li AH, Ye J, Yang L, et al. Efficacy and safety of TUDCA in the treatment of liver cirrhosis: a double‐blind randomized controlled trial. Journal of Huazhong University of Science and Technology‐Medical Sciences 2013;33(2):189‐94. CENTRAL

Pares 2009 {published data only}

Pares A. Excellent long‐term survival in patients with primary biliary cholangitis treated with UDCA. Bile Acid Biology and Therapeutic Actions 2009;165:259‐69. CENTRAL

Podda 1989 {published data only}

Podda M, Ghezzi C, Battezzati PM, Bertolini E, Crosignani A, Petroni ML, et al. Effect of different doses of UDCA in chronic liver disease. Digestive Diseases & Sciences 1989;34(12 Suppl):59S‐65S. CENTRAL

Poupon 1989 {published data only}

Poupon R, Poupon R, the UDCA‐PBCG. UDCA for primary biliary cholangitis. International Lugano Symposium on Biliary Physiology and Diseases: Strategies for the Treatment of Hepatobiliary Diseases Falk Symposium No 531989, issue 22. CENTRAL

Poupon 1990 {published data only}

Poupon R, Poupon R, The UDCA‐PBCG. UDCA in the treatment of primary biliary cholangitis. Strategies for the treatment of hepatobiliary diseases. Falk Symposium 53 1990:79‐81. CENTRAL

Poupon 1991b {published data only}

Poupon RE, Balkau B, Eschwege E, Poupon R, Kaplan MM. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cholangitis. Annals of Internal Medicine 1991;115(6 Suppl 2):48. CENTRAL

Poupon 1994 {published data only}

Poupon RE, Poupon R, Balkau B. Ursodiol for the long‐term treatment of primary biliary cholangitis. The UDCA‐PBC study group. New England Journal of Medicine 1994;330(19):1342‐7. CENTRAL

Poupon 1997 {published data only}

Poupon RE, Lindor KD, CauchDudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of UDCA in primary biliary cholangitis. Gastroenterology 1997;113(3):884‐90. CENTRAL

Poupon 1999 {published data only}

Poupon RE, Bonnand AM, Chretien Y, Poupon R. Ten‐year survival in UDCA‐treated patients with primary biliary cholangitis. The UDCA‐PBC study group. Hepatology 1999;29(6):1668‐71. CENTRAL

Poupon 2003 {published data only}

Poupon RE, Lindor KD, Pares A, Chazouilleres O, Poupon R, Heathcote EJ. Combined analysis of the effect of treatment with UDCA on histologic progression in primary biliary cholangitis. Journal of Hepatology 2003;39(1):12‐6. CENTRAL

Raedsch 1989 {published data only}

Raedsch R, Stiehl A, Hopf U, Moller B. [Effect of UDCA treatment on primary biliary cholangitis]. Zeitschrift fur Gastroenterologie ‐ Verhandlungsband 1989;24:125‐7. CENTRAL

Reed 1982 {published data only}

Reed M. Penicillamine therapy 'encouraging' in primary biliary cholangitis study. JAMA 1982;248(1):11‐2. CENTRAL

Robson 1994 {published data only}

Robson SC, Neuberger JM, Williams R. The influence of cyclosporine a therapy on sex hormone levels in pre‐ and post‐menopausal women with primary biliary cholangitis. Journal of Hepatology 1994;21(3):412‐6. CENTRAL

Roda 2002 {published data only}

Roda E, Azzaroli F, Nigro G, Piazza F, Jaboli F, Ferrara F, et al. Improved liver tests and greater biliary enrichment with high dose UDCA in early stage primary biliary cholangitis. Digestive & Liver Disease 2002;34(7):523‐7. CENTRAL

Savolainen 1983 {published data only}

Savolainen ER, Miettinen TA, Pikkarainen P, Salaspuro MP, Kivirikko KI. Enzymes of collagen synthesis and type III procollagen aminopropeptide in the evaluation of D‐penicillamine and medroxyprogesterone treatments of primary biliary cholangitis. Gut 1983;24(2):136‐42. CENTRAL

Schaffner 1982 {published data only}

Schaffner F, Sternlieb I, Sachs H. A 2 dose level randomized double‐blind controlled trial of penicillamine in primary biliary cholangitis ‐ the 1st 2 years. Hepatology 1982;2(5):714. CENTRAL

Setchell 1994 {published data only}

Setchell KDR, Rodrigues C, Podda M, Crosignani A. TauroUDCA (TUDCA) appears more effective than UDCA at displacing hydrophobic bile acids from the bile acid pool of patients with primary biliary cholangitis (PBC). Hepatology 1994;20(4 (Pt 2)):150a. CENTRAL

Setchell 1996 {published data only}

Setchell KDR, Rodrigues CMP, Podda M, Crosignani A. Metabolism of orally administered TUDCA in patients with primary biliary cholangitis. Gut 1996;38(3):439‐46. CENTRAL

Stellaard 1979 {published data only}

Stellaard F, Bolt MG, Boyer JL, Klein PD. Phenobarbital treatment in primary biliary cholangitis. Differences in bile acid composition between responders and nonresponders. Journal of Laboratory & Clinical Medicine 1979;94(6):853‐61. CENTRAL

Taal 1985 {published data only}

Taal BG, Schalm SW. Cryoglobulins in primary biliary cholangitis: prevalence and modulation by immunosuppressive therapy. Zeitschrift Fur Gastroenterologie 1985;23(5):228‐34. CENTRAL

Tang 2008 {published data only}

Tang HH, Chen YJ, Tong GD, Zhou DQ, He JS, Zhou XZ, et al. [Efficacy of UDCA combined with Tongdan Decoction in treatment of patients with primary biliary cholangitis]. World Chinese Journal of Digestology 2008;16(13):1417‐24. CENTRAL

Tong 2012 {published data only}

Tong GD, Tang HH, Wei CS, Chen YJ, He JS, Zhou XZ, et al. Efficacy of UDCA combined with Tongdan Decoction on immunological indices and histopathological changes in primary biliary cholangitis patients. Chinese Journal of Integrative Medicine 2012;18(1):16‐22. CENTRAL

Verma 1999 {published data only}

Verma A, Jazrawi RP, Ahmed HA, Davis T, Bland JM, Benson M, et al. Optimum dose of UDCA in primary biliary cholangitis. European Journal of Gastroenterology & Hepatology 1999;11(10):1069‐76. CENTRAL

Verma 2000 {published data only}

Verma A, Jazrawi RP, Ahmed HA, Northfield TC. The optimum dose of UDCA in primary biliary cholangitis. Bile Acids in Hepatobiliary Disease 2000;110B:25‐9. CENTRAL

Vogel 1988 {published data only}

Vogel W, Kathrein H, Judmaier G, Braunsteiner H. Deterioration of primary biliary cholangitis during treatment with UDCA. Lancet 1988;1(8595):1163. CENTRAL

Vuoristo 1995 {published data only}

Vuoristo M, Farkkila M, Karvonen AL, Leino R, Lehtola J, Makinen J, et al. A placebo‐controlled trial of primary biliary cholangitis treatment with colchicine and UDCA. Gastroenterology 1995;108(5):1470‐8. CENTRAL

Vuoristo 1997 {published data only}

Vuoristo M, Farkkila M, Gylling H, Karvonen AL, Leino R, Lehtola J, et al. Expression and therapeutic response related to apolipoprotein e polymorphism in primary biliary cholangitis. Journal of Hepatology 1997;27(1):136‐42. CENTRAL

Wiesner 1994 {published data only}

Wiesner RH. Progression of primary biliary cholangitis on UDCA. Gastroenterology 1994;106(2):555. CENTRAL

Wolfhagen 1995 {published data only}

Wolfhagen FH, Van Buuren HR, Schalm SW, Ten Kate FJ, Van Hattum J, Eskens FA, et al. Can UDCA induce disease remission in primary biliary cholangitis? The Dutch Multicentre PBC Study Group. Journal of Hepatology 1995;22(3):381. CENTRAL

Yan 2007 {published data only}

Yan G, Erik C, Gluud C. The long‐term beneficial effects of UDCA in primary biliary cholangitis are highly questionable. American Journal of Gastroenterology 2007;102(2):464‐5. CENTRAL

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Yano K, Kato H, Morita S, Takahara O, Ishibashi H, Furukawa R. Is bezafibrate histologically effective for primary biliary cholangitis?. American Journal of Gastroenterology 2002;97(4):1075‐7. CENTRAL

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Zuin M, Grandinetti G, Camisasca M, Boga E, Ravizza L, Molteni P. A comparison of cholestyramine and diethylaminoethyl‐dextran for the treatment of hyperlipidemia and pruritus of primary biliary cholangitis. Current Therapeutic Research, Clinical and Experimental 1991;49(4):659‐65. CENTRAL

Referencias de los estudios en espera de evaluación

Ir a:

O'Brian 1990 {published data only}

O'Brian C, Senior J, Sternlieb J, Saul S. Caution: not all patients with primary biliary cholangitis may successfully be treated by ursodiol. Second International Meeting on Pathochemistry, Pathophysiology and Pathomechanisms of the Biliary System and New Strategies for the Treatment of Hepato‐biliary Diseases 1990:208. CENTRAL

Zaman 2006 {published data only}

Zaman A. Methotrexate in combination with UDCA is ineffective in the treatment of primary biliary cholangitis: commentary. Evidence‐Based Gastroenterology 2006;7(1):21‐2. CENTRAL

ChiCTR‐IPR‐16008935 {unpublished data only}

Biochemical Response of PBC‐AIH Overlap Syndrome Induced by Ursodeoxycholic Acid Only or Combination Therapy of Immunosuppressive Agents. Ongoing study Not stated..

EUCTR2015‐002698‐39‐GB {unpublished data only}

A 12‐Week, Double‐Blind, Randomized, Placebo‐Controlled, Phase 2 Study to Evaluate the Effects of Two Doses of MBX‐8025 in Subjects with Primary Biliary Cirrhosis (PBC) and an Inadequate Response to Ursodeoxycholic Acid (UDCA).. Ongoing study Not stated..

NCT02308111 {published and unpublished data}

Lindor K, Hansen B, Pencek R, Hooshmand‐Rad R, Marmon T, MacConell L, et al. A phase 3b, double blind, placebo controlled study evaluating the effect of obeticholic acid on clinical outcomes in subjects with primary biliary cholangitis at elevated risk of progression to liver transplant or death. Journal of Hepatology 2015;62:S850‐1. CENTRAL

NCT02701166 {unpublished data only}

The Effect of Bezafibrate on Cholestatic Itch. Ongoing studyFebruary 2016..

NCT02823353 {unpublished data only}

Fenofibrate in Combination with Ursodeoxycholic Acid in Primary Biliary Cirrhosis: a Randomized Control Study. Ongoing studyJanuary 2016..

NCT02823366 {unpublished data only}

Fenofibrate for Patients with Primary Biliary Cirrhosis who had an Inadequate Response to Ursodeoxycholic Acid. Ongoing studyJanuary 2016..

NCT02937012 {unpublished data only}

Efficacy and Security of Bezafibrate in Patients with Primary Biliary Cirrhosis without Biochemical Response to Ursodeoxycholic Acid: a Randomized, Double‐blind, Placebo‐controlled Trial. Ongoing studyOctober 2016..

NCT02943447 {unpublished data only}

A Phase 2, Randomized, Double‐Blind, Placebo Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS‐9674 in Subjects with Primary Biliary Cholangitis without Cirrhosis. Ongoing studyDecember 2016..

NCT02965911 {unpublished data only}

A Randomized Controlled Clinical Trial on the Efficacy and Safety of Fenofibrate Combined with Ursodeoxycholic Acid in PBC Patients with an Incomplete Biochemical Response to UDCA. Ongoing studyJanuary 2016..

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Baldursdottir TR, Bergmann OM, Jonasson JG, Ludviksson BR, Axelsson TA, Bjornsson ES. The epidemiology and natural history of primary biliary cholangitis: a nationwide population‐based study. European Journal of Gastroenterology and Hepatology 2012;24(7):824‐30.

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Talwalkar JA, Angulo P, Keach JC, Petz JL, Jorgensen RA, Lindor KD. Mycophenolate mofetil for the treatment of primary biliary cholangitis in patients with an incomplete response to UDCA. Journal of Clinical Gastroenterology 2005;39(2):168‐71.

Talwalkar 2006

Talwalkar JA, Donlinger JJ, Gossard AA, Keach JC, Jorgensen RA, Petz JC, et al. Fluoxetine for the treatment of fatigue in primary biliary cholangitis: a randomized, double‐blind controlled trial. Digestive Diseases and Sciences 2006;51(11):1985‐91.

Ter Borg 2004

Ter Borg PC, Van Os E, Van den Broek WW, Hansen BE, Van Buuren HR. Fluvoxamine for fatigue in primary biliary cholangitis and primary sclerosing cholangitis: a randomised controlled trial [ISRCTN88246634]. BMC Gastroenterology 2004;4:13.

Thorlund 2011

Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen, Denmark. Available from www.ctu.dk/tsa2011:1‐115.

Thorlund 2012

Thorlund K, Mills EJ. Sample size and power considerations in network meta‐analysis. Systematic Reviews 2012;1:41.

TSA 2011 [Computer program]

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen. TSA version 0.9. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen, 2011.

Turner 2012

Turner RM, Davey J, Clarke MJ, Thompson SG, Higgins JP. Predicting the extent of heterogeneity in meta‐analysis, using empirical data from the Cochrane Database of Systematic Reviews. International Journal of Epidemiology 2012;41(3):818‐27.

Van Valkenhoef 2012

Van Valkenhoef G, Lu G, De Brock B, Hillege H, Ades AE, Welton NJ. Automating network meta‐analysis. Research Synthesis Methods 2012;3(4):285‐99.

Ware 2014

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Wetterslev 2008

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Wetterslev 2017

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Yin 2015

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Zhang 2015

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

Almasio 2000

Methods

Randomised clinical trial.

Participants

Country: Italy.

Number randomised: 90.

Post‐randomisation dropouts: 6 (6.7%).

Revised sample size: 84.

Mean age: 54 years.

Females: 81 (96.4%).

Symptomatic participants: 84 (100%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: symptomatic participants only.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • People with biliary obstruction.

  • Anticipated requirement for liver transplantation in 1 year.

  • Pregnancy.

  • Aged < 18 years or > 70 years.

  • Coexisting liver disease.

  • Anticipated life expectancy < 3 years.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) + colchicine (n = 42).

Further details: UDCA: 250 mg BD for 3 years + colchicine: 1 mg/day for 3 years.

Group 2: UDCA (low) (n = 42).

Further details: UDCA: 250 mg BD for 3 years.

Outcomes

Mortality, decompensated liver disease.

Notes

Reasons for post‐randomisation dropouts: adverse effects and low compliance.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Colchicine, 1 mg daily, or an indistinguishable placebo were randomly assigned to patients according to a computer‐generated list developed separately for each centre".

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was performed by a central study unit…".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used and authors stated double‐blind.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used and authors stated double‐blind.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

Low risk

Comment: no money received for the trial; the drug was provided by Abc Farmaceutici S.p.a (author's reply).

Other bias

Low risk

Comment: no other bias noted.
Angulo 1999a

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 155.

Post‐randomisation dropouts: not stated.

Revised sample size: 155.

Mean age: 53 years.

Females: 130 (83.9%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • People with decompensated cirrhosis.

  • Hepatocellular carcinoma.

  • Concomitant immunosuppressive regimen.

  • Other major diseases unrelated to primary biliary cholangitis.

  • Alcohol abuse.

  • Low compliance.

Interventions

Participants were randomly assigned to 3 groups.

Group 1: UDCA (low) (n = 52).

Further details: UDCA: 5 mg/kg/day to 7 mg/kg/day; duration: 1 to 2 years.

Group 2: UDCA (moderate) (n = 49).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day; duration: 1 to 2 years.

Group 3: UDCA (high) (n = 54).

Further details: UDCA: 23 mg/kg/day to 25 mg/kg/day; duration: 1 to 2 years.

Outcomes

Mortality, adverse events, liver transplantation.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was carried out separately for each of the eight strata with a computer‐generated, blocked, randomized drug assignment schedule".

Allocation concealment (selection bias)

Low risk

Quote: "Patients were randomized by a statistician (D.W.M.), and the drug was provided by a pharmacist who was not involved in the patient's clinical evaluation or follow‐up".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The patients, physicians, nurses, and study coordinator were unaware throughout the study which dose was being administered. To assure blindness patients received the same number of tablets by mixing UDCA‐tablets with placebo‐tablets in a ratio defined by their assigned dose; therefore, the number of tablets taken per day according to the body weight was exactly the same regardless of the dose assigned".
Comment: identical placebo used and authors stated double‐blind.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used and authors stated double‐blind.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: unclear whether all participants randomised were included in the analysis.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other risk of bias.
Arora 1990

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 9.

Post‐randomisation dropouts: not stated.

Revised sample size: 9.

Mean age: not stated.

Females: not stated.

Symptomatic participants: 9 (100%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 5 months.

Inclusion criteria

  • Symptom status: symptomatic participants only.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) (n = 5).

Further details: UDCA: 10 mg/kg/day for 5 months.

Group 2: placebo (n = 4).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: placebo used and authors stated double blind; however, unclear whether identical placebo used.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: placebo used and authors stated double blind; however, unclear whether identical placebo used.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other risk of bias.
Askari 2010

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 28.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 28.

Mean age: 54 years.

Females: 26 (92.9%).

Symptomatic participants: not stated.

AMA positive: 27 (96.4%).

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Did not take UDCA in the previous 3 months.

  • Decompensated cirrhosis.

  • Required renal dialysis.

  • Pregnant or nursing.

  • Had a serious illness of other types such as uncontrolled congestive heart failure, severe diabetic neuropathy, severe pulmonary disease, advanced cancer, etc.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: tetrathiomolybdate (n = 13).

Further details: tetrathiomolybdate: 10 mg/day to 120 mg/day based on serum ceruloplasmin levels; duration: not stated.

Group 2: placebo (n = 15).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The patients were assigned to the placebo arm or the tetrathiomolybdate arm using a table of random numbers".

Allocation concealment (selection bias)

Low risk

Quote: "Central allocation by pharmacy" (author's reply).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used and authors stated double‐blind.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used and authors stated double‐blind.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote: "There were not post‐randomisation drop‐outs" (author's reply).

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Low risk

Quote: "Supported by Grant FD‐02590‐02 from the U.S. Food and Drug Administration's Orphan Products Office, the General Clinical Research Center of the University of Michigan Hospitals, Grant MO1‐ RR000042 from the National Institutes of Health, and Grant Ul1‐ RR024986 Clinical and Translational Science Awards".

Other bias

High risk

Comment: unclear whether the participants continued to take UDCA in both groups.
Battezzati 1993

Methods

Randomised clinical trial.

Participants

Country: Italy.

Number randomised: 88.

Post‐randomisation dropouts: 2 (2.3%).

Revised sample size: 86.

Mean age: 55 years.

Females: 78 (90.7%).

Symptomatic participants: 86 (100%).

AMA positive: 77 (89.5%).

Responders: not stated.

Mean follow‐up period (for all groups): minimum 6 months.

Inclusion criteria

  • Symptom status: symptomatic participants only.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Serum bilirubin levels > 10 mg/dL.

  • Decompensated liver disease.

  • Evidence of malignancy.

  • Alcohol abuse.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) (n = 42).

Further details: UDCA: 250 mg BD for 6 months.

Group 2: placebo (n = 44).

Outcomes

None of the outcomes of interest reported.

Notes

Reasons for post‐randomisation dropouts: lost to follow‐up.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization of treatment assignments was performed separately for each centre: patients were consecutively given indistinguishable medications, which had been assigned by the central pharmacy according to a computer‐ generated list. UDCA and an identical‐appearing placebo were obtained through the courtesy of ABC Farmaceutici, Torino, Italy".

Allocation concealment (selection bias)

Low risk

Quote: "Randomization of treatment assignments was performed separately for each centre: patients were consecutively given indistinguishable medications, which had been assigned by the central pharmacy according to a computer‐ generated list. UDCA and an identical‐appearing placebo were obtained through the courtesy of ABC Farmaceutici, Torino, Italy".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Randomization of treatment assignments was performed separately for each centre: patients were consecutively given indistinguishable medications, which had been assigned by the central pharmacy according to a computer‐ generated list. UDCA and an identical‐appearing placebo were obtained through the courtesy of ABC Farmaceutici, Torino, Italy".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Randomization of treatment assignments was performed separately for each centre: patients were consecutively given indistinguishable medications, which had been assigned by the central pharmacy according to a computer‐ generated list. UDCA and an identical‐appearing placebo were obtained through the courtesy of ABC Farmaceutici, Torino, Italy".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other risk of bias.
Bobadilla 1994

Methods

Randomised clinical trial.

Participants

Country: Mexico.

Number randomised: 40.

Post‐randomisation dropouts: not stated.

Revised sample size: 40.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) + colchicine (n = 21).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day for 1 year + colchicine: 1 mg/day for 5 days in a week for 1 year.

Group 2: placebo (n = 19).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although placebo used in double‐blind trial, unclear whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although placebo used in double‐blind trial, unclear whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Bodenheimer 1988

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 57.

Post‐randomisation dropouts: 10 (17.5%).

Revised sample size: 47.

Mean age: 52 years.

Females: not stated.

Symptomatic participants: 45 (95.7%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): 33 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: colchicine (n = 28).

Further details: colchicine: 0.6 mg BD orally for 5 years.

Group 2: placebo (n = 29).

Outcomes

None of the outcomes of interest reported.

Notes

Reasons for post‐randomisation dropouts: non‐compliance.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The design of our trial was that of a double‐blind, randomized evaluation of colchicine (0.6 mg) twice daily compared with an identically appearing placebo".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The design of our trial was that of a double‐blind, randomized evaluation of colchicine (0.6 mg) twice daily compared with an identically appearing placebo".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Quote: "The colchicine and placebo tablets were prepared and generously supplied by Eli Lilly and Company, Indianapolis, Ind".

Other bias

Low risk

Comment: no other source of bias.
Bowlus 2014

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 216.

Post‐randomisation dropouts: not stated.

Revised sample size: 216.

Mean age: 56 years.

Females: 197 (91.2%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 3 groups.

Group 1: obeticholic acid (low) (n = 73).

Further details: obeticholic acid (low): 5 mg orally for 12 months; frequency not stated.

Group 2: obeticholic acid (low) (n = 73).

Further details: obeticholic acid (low): 10 mg orally for 12 months; frequency not stated.

Group 3: placebo (n = 70).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although placebo was used in double‐blind trial, unclear whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although placebo was used in double‐blind trial, unclear whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Comment: Several authors had advised pharmaceutical companies or were employees of pharmaceutical company.

Other bias

Low risk

Comment: no other source of bias.
Cash 2013

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 21.

Post‐randomisation dropouts: 8 (38.1%).

Revised sample size: 13.

Mean age: 55 years.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: 13 (100%).

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA‐positive participants only.

  • Response status: not stated.

Exclusion criteria

  • Aged < 19 years or > 76 years.

  • Cholesterol < 5 mmol/L.

  • Known hypertension.

  • Diabetes mellitus.

  • History of cardiovascular disease.

  • Already prescribed lipid‐lowering agents or hormonal preparations.

  • Pregnancy.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: simvastatin (n = 7).

Further details: simvastatin: 20 mg/day orally for 12 months.

Group 2: placebo (n = 6).

Outcomes

None of the outcomes of interest reported.

Notes

Reasons for post‐randomisation dropouts: adverse effects.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Low risk

Quote: "Patient treatment randomization and allocation was performed independently by the Department of Research Pharmacology in the Royal Victoria Hospital at the initial baseline visit".

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "The patients were blinded but the healthcare providers were not" (author's reply).

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Outcome assessors were not blinded" (author's reply).

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Low risk

Quote: "Financial support: The Royal Victoria Hospital Liver Support Group".

Other bias

High risk

Quote: "Patients were allowed to continue previous prescriptions for primary biliary cholangitis. It was not clear whether this was balanced across groups".

Christensen 1985

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 248.

Post‐randomisation dropouts: 63 (25.4%).

Revised sample size: 185.

Mean age: 55 years.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Mean follow‐up period (for all groups): minimum 63 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • No antimetabolites in the previous 6 months.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: azathioprine (n = 98).

Further details: azathioprine: escalating doses up to a maximum of 100 mg/day; duration: not stated.

Group 2: placebo (n = 87).

Outcomes

Mortality.

Notes

Reasons for post‐randomisation dropouts: lost to follow‐up.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Quote: "Patients were randomized to azathioprine or placebo separately for each centre and for each sex by the sealed envelope technique".

Comment: further details of sealed envelope technique were not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used and authors stated double‐blind.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used and authors stated double‐blind.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

High risk

Quote: "This work was also supported by the Wellcome Foundation. J.N. was supported by Ciba‐Geigy Ltd".

Other bias

Low risk

Comment: no other source of bias.
Combes 1995a

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 151.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 151.

Mean age: 49 years.

Females: 134 (88.7%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Other exclusion criteria

  • Recurrent bleeds from oesophagogastric varices, spontaneous encephalopathy, or diuretic‐resistant ascites.

  • Serum bilirubin ≥ 20 mg/dL.

  • Pregnancy.

  • Aged < 19 years.

  • Findings of other causes of liver disease.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) (n = 77).

Further details: UDCA: 10 mg/kg/day to 12 mg/kg/day for 2 years.

Group 2: placebo (n = 74).

Outcomes

Decompensated liver disease.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Quote: "Supported in part by a research grant from Ciba‐Geigy".

Other bias

Low risk

Comment: no other risk of bias.
Combes 2005

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 265.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 265.

Mean age: 51 years.

Females: 245 (92.5%).

Symptomatic participants: not stated.

AMA positive: 265 (100%).

Responders: not stated.

Median follow‐up period (for all groups): 91 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: AMA‐positive participants only.

  • Response status: not stated.

Exclusion criteria

  • People with advanced biliary cirrhosis.

  • People with decompensated cirrhosis.

  • Aged < 19 years or > 69 years.

  • History of alcohol abuse.

  • Pregnant or unwilling to use contraception.

  • Use of immunosuppressive agents.

  • Renal or pulmonary dysfunction.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) + methotrexate (n = 132).

Further details: UDCA: 15 mg/kg/day for 2 years + methotrexate: 2.5 mg orally once a week.

Group 2: UDCA (moderate) (n = 133).

Further details: UDCA: 15 mg/kg/day for 2 years.

Outcomes

Mortality, liver transplantation, decompensated liver disease.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: placebo used in this double‐blind trial; however, the authors did not state whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: placebo used in this double‐blind trial; however, the authors did not state whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

High risk

Quote: "By provision of UDCA by Ciba‐Geigy Corporation, and subsequently Novartis; by provision of methotrexate and its placebo by Lederle Laboratories, and subsequently Wyeth‐Ayerst Laboratories".

Other bias

Low risk

Comment: no other source of bias.
Dickson 1985

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 309.

Post‐randomisation dropouts: 82 (26.5%).

Revised sample size: 227.

Mean age: not stated.

Females: 200 (88.1%).

Symptomatic participants: 182 (80.2%).

AMA positive: not stated.

Responders: not stated.

Median follow‐up period (for all groups): 60 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • People with severe hepatitis.

  • Evidence of inflammatory bowel disease.

  • Malignant condition other than skin cancer.

  • Evidence of prior or present extrahepatic obstruction.

  • Use of cholestatic or hepatotoxic drugs.

  • Excessive alcohol intake.

  • Presence of hepatitis B antigen.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: D‐penicillamine (n = 111).

Further details: D‐penicillamine: 1000 mg/day; duration: not stated.

Group 2: placebo (n = 116).

Outcomes

Adverse events.

Notes

Reasons for post‐randomisation dropouts: histological stages < 3; alcoholism.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly assigned to drug or placebo groups according to a table of random numbers".

Allocation concealment (selection bias)

Low risk

Quote: "Penicillamine and placebo (furnished to us through the courtesy of Merck Sharp and Dohme, West Point, Pa.) were dispensed in identical yellow capsules by a central pharmacist".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

High risk

Quote: "Penicillamine and placebo (furnished to us through the courtesy of Merck Sharp and Dohme, West Point, Pa.) were dispensed in identical yellow capsules by a central pharmacist".

Other bias

High risk

Comment: authors presented the results of only a subgroup of participants without explaining the reason for this.

Epstein 1979

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 98.

Post‐randomisation dropouts: not stated.

Revised sample size: 98.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): mean: 66 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: D‐penicillamine (n = 61).

Further details: D‐penicillamine: 600 mg/day to 900 mg/day for 12 months.

Group 2: placebo (n = 37).

Outcomes

Mortality.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "The original double‐blind design of the trial was discontinued after a year because both major and minor side effects identified treated patients".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "The original double‐blind design of the trial was discontinued after a year because both major and minor side effects identified treated patients".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Eriksson 1997

Methods

Randomised clinical trial.

Participants

Country: Sweden.

Number randomised: 116.

Post‐randomisation dropouts: 15 (12.9%).

Revised sample size: 101.

Mean age: 57 years.

Females: 99 (98%).

Symptomatic participants: 39 (38.6%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • People with severe end‐stage liver disease.

  • Pregnancy.

  • Alcohol or drug abuse.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) (n = 60).

Further details: UDCA: 500 mg/day for 24 months.

Group 2: placebo (n = 56).

Outcomes

Liver transplantation.

Notes

Reasons for post‐randomisation dropouts: adverse effects, alcoholic hepatitis, liver transplantation, death.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: placebo used in this double‐blind trial; however, the authors did not state whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: placebo used in this double‐blind trial; however, the authors did not state whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Quote: "We acknowledge the financial support from Meda AB, Searle AB, and the Swedish Medical Research Council (03x‐4793)".

Other bias

Low risk

Comment: no other source of bias.
Ferri 1993

Methods

Randomised clinical trial.

Participants

Country: Italy.

Number randomised: 30.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 30.

Mean age: 53 years.

Females: 27 (90%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 6 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • People with decompensated cirrhosis.

  • Extrahepatic biliary obstruction.

  • Severe kidney or heart disease.

  • Neoplasms.

  • Pregnancy or breastfeeding.

  • Excessive alcohol consumption.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: TUDCA (moderate) (n = 15).

Further details: TUDCA: 13 mg/day to 15 mg/day for 6 months.

Group 2: UDCA (moderate) (n = 15).

Further details: UDCA: 13 mg/day to 15 mg/day for 6 months.

Outcomes

Adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: information not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: information not available.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: adverse events, the only outcome of interest reported in this study were available from all randomised participants.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Gao 2012

Methods

Randomised clinical trial.

Participants

Country: China.

Number randomised: 79.

Post‐randomisation dropouts: not stated.

Revised sample size: 79.

Mean age: 53 years.

Females: 77 (97.5%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Other inclusion criteria

  • Only people with Sjogren's syndrome were included.

Exclusion criteria

  • People with decompensated cirrhosis.

  • Aged > 70 years.

  • Other autoimmune diseases.

Interventions

Participants were randomly assigned to 3 groups.

Group 1: UDCA (moderate) (n = 29).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day; duration: not stated.

Group 2: UDCA (moderate) + glucocorticosteroids (n = 37).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day; duration: not stated + prednisolone: 7.5 mg/day; duration: not stated.

Group 3: UDCA (moderate) + azathioprine (n = 13).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day; duration: not stated + azathioprine: 1 mg/kg/day; duration: not stated.

Outcomes

Adverse events, decompensated liver disease.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: information not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: information not available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Goddard 1994

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 57.

Post‐randomisation dropouts: not stated.

Revised sample size: 57.

Mean age: not stated.

Females: not stated.

Symptomatic participants: 30 (52.6%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): 15 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 4 groups.

Group 1: UDCA (low) (n = not stated).

Further details: UDCA: 10 mg/kg/day; duration: not stated.

Group 2: colchicine (n = not stated).

Further details: colchicine: 1 mg/day; duration: not stated.

Group 3: UDCA (low) + colchicine (n = not stated).

Further details: UDCA: 10 mg/kg/day; duration: not stated + colchicine: 1 mg/day; duration: not stated.

Group 4: placebo (n = not stated).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: placebo used; however, the authors did not mention blinding.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: placebo used; however, the authors did not mention blinding.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Gonzalezkoch 1997

Methods

Randomised clinical trial.

Participants

Country: Chile.

Number randomised: 25.

Post‐randomisation dropouts: not stated.

Revised sample size: 25.

Mean age: 50 years.

Females: 25 (100%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 11 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Other concomitant liver or biliary diseases.

  • Decompensated cirrhosis.

  • Presence of other serious diseases (e.g. diabetes mellitus, chronic renal insufficiency).

  • Need to use additional medications.

  • Pregnancy.

  • Any pharmacological therapy during the previous 6 months.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) + methotrexate (n = 13).

Further details: UDCA: 250 mg BD for 48 weeks + methotrexate: 10 mg/week given over 48 hours each week for 48 months.

Group 2: UDCA (low) (n = 12).

Further details: UDCA: 250 mg BD for 48 weeks.

Outcomes

Mortality, adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Low risk

Quote: "A physician who was blinded to the treatment, followed them up clinically, evaluated clinical symptoms, adverse side effects, complications and compliance".

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: placebo used in this double‐blind trial; however, the authors did not state whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: placebo used in this double‐blind trial; however, the authors did not state whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Heathcote 1976

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 45.

Post‐randomisation dropouts: 6 (13.3%).

Revised sample size: 39.

Mean age: 51 years.

Females: not stated.

Symptomatic participants: 39 (100%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: symptomatic participants only.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Established cirrhosis or liver failure.

  • Presence of oesophageal varices.

  • Recurrent suppurative infections.

  • Treatment with other immunosuppressants.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: azathioprine (n = 19).

Further details: azathioprine: 2 mg/kg; frequency and duration: not stated.

Group 2: control (n = 20).

Outcomes

Mortality, cirrhosis.

Notes

Reasons for post‐randomisation dropouts: adverse events, wrong diagnosis.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Quote: "Patients were randomly allocated to the treatment or control group, using the sealed envelope technique".

Comment: further details of sealed envelope technique not available.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "No placebo was given to the control patients".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "No placebo was given to the control patients".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

Low risk

Quote: "This work was supported by the Medical Research Council and the Ingram Fund".

Other bias

Low risk

Comment: no other source of bias.
Heathcote 1994

Methods

Randomised clinical trial.

Participants

Country: Canada.

Number randomised: 222.

Post‐randomisation dropouts: not stated.

Revised sample size: 222.

Mean age: 56 years.

Females: 206 (92.8%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Aged < 18 years.

  • On transplant list.

  • Needed to take enzyme‐inducing drugs.

  • Pregnant.

  • Other medical illnesses with anticipated life expectancy < 5 years.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) (n = 111).

Further details: UDCA: 14 mg/kg/day for 2 years.

Group 2: placebo (n = 111).

Outcomes

Mortality, liver transplantation.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was done separately at each centre by the study pharmacist using consecutive identification numbers, and patients were stratified according to whether they were symptomatic or asymptomatic".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Once informed consent was obtained from the patients, double‐blind randomization to UDCA or an identical placebo (1 : 1) was conducted".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Once informed consent was obtained from the patients, double‐blind randomization to UDCA or an identical placebo (1 : 1) was conducted".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: unclear whether the authors have reported the outcomes on all randomised participants.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

High risk

Quote: "Study medications kindly provided by Interfalk Canada and Jouveinal Inc., Quebec, Canada".

Other bias

Low risk

Comment: no other source of bias.
Hendrickse 1999

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 60.

Post‐randomisation dropouts: not stated.

Revised sample size: 60.

Mean age: 57 years.

Females: 55 (91.7%).

Symptomatic participants: 57 (95%).

AMA positive: 51 (85%).

Responders: not stated.

Mean follow‐up period (for all groups): minimum 68 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Advanced liver disease.

  • Continuing or recent alcohol abuse.

  • Immunosuppressive drugs in the previous 6 months.

  • Contemplation of pregnancy.

  • Haematological abnormalities.

  • Other serious medical illness that might cause liver dysfunction or limit life expectancy.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: methotrexate (n = 30).

Further details: methotrexate: 2.5 mg 3 times weekly for 6 years.

Group 2: placebo (n = 30).

Further details: placebo: 3 times weekly for 6 years.

Outcomes

Mortality, liver transplantation.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomized in groups of 10 by a random‐number technique, operated by the hospital pharmacy, to receive 2.5 mg MTX [methotrexate] or identical placebo tablets, both supplied by Lederle Laboratories, on Friday, Saturday, and Sunday of each week for up to 6 years".

Allocation concealment (selection bias)

Low risk

Quote: "Patients were randomized in groups of 10 by a random‐number technique, operated by the hospital pharmacy, to receive 2.5 mg MTX or identical placebo tablets, both supplied by Lederle Laboratories, on Friday, Saturday, and Sunday of each week for up to 6 years".

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: placebo used in this double‐blind trial; however, the authors did not state whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: placebo used in this double‐blind trial; however, the authors did not state whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor morbidity reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Hirschfield 2015

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 165.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 165.

Mean age: 55 years.

Females: 157 (95.2%).

Symptomatic participants: not stated.

AMA positive: 134 (81.2%).

Responders: 0 (0%).

Mean follow‐up period (for all groups): all participants followed up for 3 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: non‐responders only.

Exclusion criteria

  • Advanced liver disease or decompensated liver disease.

  • Immunosuppressive drugs in the previous 3 months.

  • Other concomitant liver diseases.

Interventions

Participants were randomly assigned to 3 groups.

Group 1: obeticholic acid (low) (n = 38).

Further details: obeticholic acid (low): 10 mg for 85 days; frequency not stated.

Group 2: obeticholic acid (moderate) (n = 48).

Further details: obeticholic acid (moderate): 25 mg for 85 days; frequency not stated.

Group 3: obeticholic acid (high) (n = 41).

Further details: obeticholic acid (high): 50 mg for 85 days; frequency not stated.

Group 4: placebo (n = 38).

Outcomes

Adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The computerized randomization schedule used a block size of 4 at each center".

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

High risk

Quote: "Patients received varying doses of UDCA".
Hoofnagle 1986

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 24.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 24.

Mean age: 47 years.

Females: 23 (95.8%).

Symptomatic participants: 24 (100%).

AMA positive: 22 (91.7%).

Responders: not stated.

Mean follow‐up period (for all groups): 52 months.

Inclusion criteria

  • Symptom status: symptomatic participants only.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Advanced liver disease or decompensated liver disease.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: chlorambucil (n = 13).

Further details: chlorambucil: 2 mg OD; duration: not stated.

Group 2: control (n = 11).

Outcomes

Mortality, adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomized by random numbers (generated by pharmacy) to either chlorambucil or no therapy. Pre‐computer age. They were kept in envelopes" (author's reply).

Allocation concealment (selection bias)

Low risk

Quote: "Patients were randomized by random numbers (generated by pharmacy) to either chlorambucil or no therapy. Pre‐computer age. They were kept in envelopes" (author's reply).

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Not a blinded study" (author's reply).

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "The outcomes were not blinded" (author's reply).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

Low risk

Quote: "The study was funded by the NIH intramural program" (author's reply).

Other bias

Low risk

Comment: no other source of bias.
Hosonuma 2015

Methods

Randomised clinical trial.

Participants

Country: Japan.

Number randomised: 27.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 27.

Mean age: 64 years.

Females: 22 (81.5%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: 0 (0%).

Mean follow‐up period (for all groups): minimum: 96 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: non‐responders only.

Other inclusion criteria

  • People with dyslipidaemia.

Exclusion criteria

  • Other liver diseases, e.g. alcoholic liver disease.

  • Obstructive biliary disease.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) + bezafibrate (n = 13).

Further details: UDCA: 12 mg/kg/day to 15 mg/kg/day; duration: not stated + bezafibrate: 400 mg/day; duration: not stated.

Group 2: UDCA (moderate) (n = 14).

Further details: UDCA: 12 mg/kg/day to 15 mg/kg/day; duration: not stated.

Outcomes

Mortality, adverse events, liver transplantation.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Sealed opaque envelopes" (author's reply).

Allocation concealment (selection bias)

Low risk

Quote: "These patients were randomly allocated to treatment with either UDCA alone (the UDCA group) or with the combination therapy (the UDCA+BF [bezafibrate] group), according to sequential sealed envelopes in blocks of four to ensure equal randomization for the duration of the study".

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "However, our study was an unblinded, open trial and was therefore not free from bias".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "However, our study was an unblinded, open trial and was therefore not free from bias".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

Low risk

Comment: mortality and adverse events reported.

For‐profit bias

Low risk

Quote: "This study was supported by the authors' own research funds".

Other bias

Low risk

Comment: no other source of bias.
Ikeda 1996

Methods

Randomised clinical trial.

Participants

Country: Japan.

Number randomised: 22.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 22.

Mean age: 61 years.

Females: 19 (86.4%).

Symptomatic participants: 7 (31.8%).

AMA positive: 22 (100%).

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: AMA‐positive participants only.

  • Response status: not stated.

Exclusion criteria

  • Other liver diseases.

  • No immunosuppressants or hepatotoxic drugs in the previous 6 months.

  • Alcohol or drug abuse.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) + colchicine (n = 10).

Further details: UDCA: 9 mg/kg/day to 15 mg/kg/day for 2 years + colchicine: 1 mg/day for 2 years.

Group 2: UDCA (moderate) (n = 12).

Further details: UDCA: 9 mg/kg/day to 15 mg/kg/day for 2 years.

Outcomes

Adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: information not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: information not available.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

Unclear risk

Quote: "Part of the present study was supported by a grant from the Intractable Liver Diseases Research Committee, the Ministry of Health and Welfare, Japan".

Comment: unclear how the remaining part of the funds were obtained.

Other bias

High risk

Comment: dose range for UDCA was very wide.
Iwasaki 2008a

Methods

Randomised clinical trial.

Participants

Country: Japan.

Number randomised: 45.

Post‐randomisation dropouts: not stated.

Revised sample size: 45.

Mean age: 56 years.

Females: 37 (82.2%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Cirrhosis.

  • Advanced liver disease or decompensated cirrhosis.

  • Renal insufficiency.

  • Malignancy.

  • Pregnancy.

  • Aged < 19 years.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: bezafibrate (n = 20).

Further details: bezafibrate: 400 mg/day for 52 weeks.

Group 2: UDCA (low) (n = 25).

Further details: UDCA: 600 mg/day for 52 weeks.

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Low risk

Quote: "Consecutive patients from these hospitals were randomized centrally at the Kanagawa Dental University and were enrolled into the study if they met the following criteria".

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "A randomized, open study design was used because there was no suitable placebo for bezafibrate available".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "A randomized, open study design was used because there was no suitable placebo for bezafibrate available".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Low risk

Quote: "The Ministry of Health, Labour and Welfare of Japan supported this study from 2002 to 2004 with a Health Science Research Grant on a Specific Disease (Study of Intractable Liver Diseases) to chief scientist Gotaro Toda".

Other bias

Low risk

Comment: no other bias.
Iwasaki 2008b

Methods

Randomised clinical trial.

Participants

Country: Japan.

Number randomised: 22.

Post‐randomisation dropouts: not stated.

Revised sample size: 22.

Mean age: 54 years.

Females: 19 (86.4%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: 0 (0%).

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: non‐responders only.

Exclusion criteria

  • Cirrhosis.

  • Advanced liver disease or decompensated cirrhosis.

  • Renal insufficiency.

  • Malignancy.

  • Pregnancy.

  • Aged < 19 years.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) + bezafibrate (n = 10).

Further details: UDCA: 600 mg/day for 52 weeks + bezafibrate: 400 mg/day for 52 weeks.

Group 2: UDCA (low) (n = 12).

Further details: UDCA: 600 mg/day for 52 weeks.

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Low risk

Quote: "Consecutive patients from these hospitals were randomized centrally at the Kanagawa Dental University and were enrolled into the study if they met the following criteria".

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "A randomized, open study design was used because there was no suitable placebo for bezafibrate available".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "A randomized, open study design was used because there was no suitable placebo for bezafibrate available".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Low risk

Quote: "The Ministry of Health, Labour and Welfare of Japan supported this study from 2002 to 2004 with a Health Science Research Grant on a Specific Disease (Study of Intractable Liver Diseases) to chief scientist Gotaro Toda".

Other bias

Low risk

Comment: no other bias.
Kanda 2003

Methods

Randomised clinical trial.

Participants

Country: Japan.

Number randomised: 22.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 22.

Mean age: 56 years.

Females: 19 (86.4%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: 0 (0%).

Mean follow‐up period (for all groups): minimum 7 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: non‐responders only.

Other inclusion criteria

  • Treatment with UDCA for ≥ 6 months prior the study.

  • Prior compliance with UDCA therapy.

Exclusion criteria

  • Other chronic liver diseases or decompensated liver disease.

  • Previous colchicine, corticosteroid, or immunosuppressive treatment.

  • Thyroid or renal dysfunction.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) + bezafibrate (n = 11).

Further details: UDCA: 600 mg/day for 6 months + bezafibrate: 400 mg/day for 52 weeks.

Group 2: UDCA (low) (n = 11).

Further details: UDCA: 600 mg/day for 6 months.

Outcomes

Adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: information not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: information not available.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: mortality was not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other bias.
Kaplan 1986

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 60.

Post‐randomisation dropouts: 3 (5%).

Revised sample size: 57.

Mean age: not stated.

Females: 57 (100%).

Symptomatic participants: 45 (78.9%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Concomitant debilitating cardiovascular illness.

  • End‐stage cirrhosis.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: colchicine (n = 28).

Further details: colchicine: 0.6 mg BD for ≥ 2 years.

Group 2: placebo (n = 29).

Outcomes

Mortality.

Notes

Reasons for post‐randomisation dropouts: adverse effects, despondent about treatment.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: authors stated that this was a double‐blind trial and used a placebo; however, they did not state whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: authors stated that this was a double‐blind trial and used a placebo; however, they did not state whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other bias.
Kaplan 1999

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 87.

Post‐randomisation dropouts: 2 (2.3%).

Revised sample size: 85.

Mean age: 51 years.

Females: 82 (96.5%).

Symptomatic participants: 71 (83.5%).

AMA positive: 77 (90.6%).

Responders: not stated.

Mean follow‐up period (for all groups): minimum 24 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • End‐stage liver failure.

  • History of alcohol abuse.

  • Administration of drugs associated with chronic liver disease.

  • Contemplation of pregnancy.

  • Other serious medical illnesses such as renal or heart disease that may cause liver dysfunction or shorten life expectancy.

  • Hypersplenism.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: colchicine (n = 43).

Further details: colchicine: 0.6 mg BD for 2 years.

Group 2: methotrexate (n = 42).

Further details: methotrexate: 15 mg/week orally.

Outcomes

None of the outcomes of interest reported.

Notes

Reasons for post‐randomisation dropouts: withdrawal from study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Both the patients and investigators were blinded to the treatment assignments".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Both the patients and investigators were blinded to the treatment assignments".

Comment: authors stated that this was a double‐blind trial and used a placebo; however, they did not state whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other bias.
Kowdley 2011

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 59.

Post‐randomisation dropouts: not stated.

Revised sample size: 59.

Mean age: 55 years.

Females: 50 (84.7%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 3 groups.

Group 1: obeticholic acid (low) (n = 20).

Further details: obeticholic acid (low): 10 mg OD for 12 weeks.

Group 2: obeticholic acid (high) (n = 16).

Further details: obeticholic acid (high): 50 mg OD for 12 weeks.

Group 3: placebo (n = 23).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although this was a double‐blind trial and placebo was used, unclear whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although this was a double‐blind trial and placebo was used, unclear whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Comment: some of the coauthors were from the pharmaceutical industry.

Other bias

Low risk

Comment: no other source of bias.
Kurihara 2000

Methods

Randomised clinical trial.

Participants

Country: Japan.

Number randomised: 24.

Post‐randomisation dropouts: not stated.

Revised sample size: 24.

Mean age: 60 years.

Females: 23 (95.8%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Cirrhosis.

  • Advanced liver disease or decompensated cirrhosis.

  • Renal insufficiency.

  • Malignancy.

  • Pregnancy.

  • Aged < 19 years of age.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: bezafibrate (n = 12).

Further details: bezafibrate: 400 mg/day for 1 year.

Group 2: UDCA (low) (n = 12).

Further details: UDCA: 600 mg/day for 1 year.

Outcomes

Adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: information not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: information not available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other bias.
Leuschner 1989

Methods

Randomised clinical trial.

Participants

Country: Germany.

Number randomised: 20.

Post‐randomisation dropouts: 2 (10%).

Revised sample size: 18.

Mean age: not stated.

Females: 18 (100%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Decompensated liver cirrhosis.

  • Chronic pancreatitis.

  • Taking immunosuppressive drugs, glucocorticosteroids, or sex hormones.

  • Taking other drugs for treatment of liver diseases or known to cause hepatotoxicity.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) (n = 10).

Further details: UDCA: 10 mg/kg/day for 9 months.

Group 2: placebo (n = 8).

Outcomes

Mortality, adverse events.

Notes

Reasons for post‐randomisation dropouts: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although placebo was used in this double‐blind trial, unclear whether identical placebo used.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although placebo was used in this double‐blind trial, unclear whether identical placebo used.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Leuschner 1999

Methods

Randomised clinical trial.

Participants

Country: Germany.

Number randomised: 40.

Post‐randomisation dropouts: 1 (2.5%).

Revised sample size: 39.

Mean age: 58 years.

Females: 37 (94.9%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Decompensated liver cirrhosis.

  • Diabetes mellitus.

  • Glaucoma.

  • Previous history of duodenal or gastric ulcer.

  • Pregnancy.

  • Hypertension.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) + corticosteroids (n = 20).

Further details: UDCA: 10 mg/kg/day to 15 mg/kg/day for 2 years + budesonide: 3 mg 3 times daily for 2 years.

Group 2: UDCA (moderate) (n = 19).

Outcomes

None of the outcomes of interest reported.

Notes

Reasons for post‐randomisation dropouts: personal reasons.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Complete randomization was done according to Rancode + (version 3.1; IDV‐Co., Marsaglia and Bray, Gauting, Germany)".

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although placebo was used in this double‐blind trial, unclear whether identical placebo used.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although placebo was used in this double‐blind trial, unclear whether identical placebo used.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Quote: "UDCA, budesonide, and placebo were provided by Dr. Falk Pharma GmbH (Freiburg, Germany)".

Other bias

Low risk

Comment: no other source of bias.
Liberopoulos 2010

Methods

Randomised clinical trial.

Participants

Country: Greece.

Number randomised: 10.

Post‐randomisation dropouts: not stated.

Revised sample size: 10.

Mean age: 57 years.

Females: 8 (80%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: 0 (0%).

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: non‐responders only.

Exclusion criteria

  • Cardiovascular disease.

  • Diabetes mellitus.

  • Cancer.

  • Renal disease.

  • Hypothyroidism.

  • Recent lipid‐lowering agent use.

  • Agents that affect lipid metabolism.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) + fenofibrate (n = 6).

Further details: UDCA: 600 mg/day for 8 weeks + fenofibrate: 200 mg/day for 8 weeks.

Group 2: UDCA (low) (n = 4).

Further details: UDCA: 600 mg/day for 8 weeks.

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Continue open‐label UDCA".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Continue open‐label UDCA".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Quote: "This study was conducted independently; no company or institution supported it financially. Some of the authors have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies".
Comment: unclear whether the authors were in the advisory board of related pharmaceutical companies.

Other bias

Low risk

Comment: no other source of bias.
Lim 1994

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 32.

Post‐randomisation dropouts: not stated.

Revised sample size: 32.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) (n = not stated).

Further details: UDCA: 10 mg/kg/day to 12 mg/kg/day; duration: not stated.

Group 2: placebo (n = not stated).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although a placebo was used in this double‐blind trial, unclear whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although a placebo was used in this double‐blind trial, unclear whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Lindor 1994

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 180.

Post‐randomisation dropouts: 10 (5.6%).

Revised sample size: 170.

Mean age: 53 years.

Females: 160 (94.1%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • People with decompensated cirrhosis.

  • Hepatocellular carcinoma.

  • Concomitant immunosuppressive regimen.

  • Other major diseases unrelated to primary biliary cholangitis.

  • Alcohol abuse.

  • Low compliance.

  • Recurrent variceal haemorrhage, intractable ascites, spontaneous encephalopathy.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) (n = 86).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day; duration: not stated.

Group 2: placebo (n = 84).

Outcomes

Mortality, adverse events, liver transplantation.

Notes

Reasons for post‐randomisation dropouts: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The patients, physicians, nurses, and study coordinators were blinded as to whether active drug or placebo was being administered".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The patients, physicians, nurses, and study coordinators were blinded as to whether active drug or placebo was being administered".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

High risk

Quote: "Supported by Falk Pharma and Interfalk".

Other bias

Low risk

Comment: no other risk of bias.
Lindor 1997

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 150.

Post‐randomisation dropouts: not stated.

Revised sample size: 150.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA positive participants only.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 3 groups.

Group 1: UDCA (low) (n = not stated).

Further details: UDCA: 5 mg/kg/day to 7 mg/kg/day; duration: not stated.

Group 2: UDCA (moderate) (n = not stated).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day; duration: not stated.

Group 3: UDCA (high) (n = not stated).

Further details: UDCA: 22 mg/kg/day to 25 mg/kg/day; duration: not stated.

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: information not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: information not available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other risk of bias.
Lombard 1993

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 349.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 349.

Mean age: 54 years.

Females: 298 (85.4%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Median follow‐up period (for all groups): 31 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Significant renal impairment.

  • Serious non‐hepatic or malignant disease limiting life expectancy.

  • Inability to attend for regular follow‐up.

  • Consideration for a liver transplant.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: ciclosporin (n = 176).

Further details: ciclosporin: 3 mg/kg/day to maintain levels at 150 ng/mL by polyclonal radioimmunoassay or 75 ng/mL by monoclonal radioimmunoassay.

Group 2: placebo (n = 173).

Outcomes

Mortality, adverse events, liver transplantation.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Quote: "Sealed envelopes" (author's reply).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

High risk

Quote: "The authors are grateful to Sandoz Pharmaceuticals, Basle, Switzerland and their international sub‐offices for supplying Sandimmune and placebo for this study and for their support throughout. The authors are grateful to Sandoz Pharmaceuticals, Basle, Zerland and their international sub‐offices for supplying Sandimmune and placebo for this study and for their support throughout".

Other bias

Low risk

Comment: no other source of bias.
Ma 2016

Methods

Randomised clinical trial.

Participants

Country: China.

Number randomised: 199.

Post‐randomisation dropouts: 8 (4.0%).

Revised sample size: 191.

Mean age: 51 years.

Females: 167 (83.9%).

Symptomatic participants: 38 (19.9%).

AMA positive: 187 (97.9%).

Responders: not stated.

Mean follow‐up period (for all groups): all participants: 6 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Advanced or decompensated liver disease.

  • Pregnancy or breastfeeding.

  • Other causes of liver diseases.

  • Serious comorbidities.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) (n = 66).

Further details: UDCA: 250 mg 3 times daily for 24 weeks.

Group 2: TUDCA (moderate) (n = 125).

Further details: TUDCA: 250 mg 3 times daily for 24 weeks.

Outcomes

Adverse events.

Notes

Reason for drop‐outs: not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A centralized telecommunication‐based interactive voice response system was used for patient randomization after patient eligibility was determined through clinical and laboratory screening assessments".

Allocation concealment (selection bias)

Low risk

Quote: "A centralized telecommunication‐based interactive voice response system was used for patient randomization after patient eligibility was determined through clinical and laboratory screening assessments".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: unclear whether all participants were included in the analysis.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

High risk

Quote: "This study was sponsored by the Beijing Trendful Kangjian Medical Information Consulting Co., Ltd. and the Major Science and Technology Special Project of China Twelfth Five‐year Plan (2012ZX10002003). Registration Number: NCT01829698".

Other bias

Low risk

Comment: no other source of bias.
Macklon 1982

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 60.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 60.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): 37 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: D‐penicillamine (n = 41).

Further details: D‐penicillamine: 250 mg/day or 1 g/day; duration: not stated.

Group 2: placebo (n = 19).

Outcomes

Mortality, adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although placebo was used, there is no mention of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although placebo was used, there is no mention of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other bias.
Manzillo 1993a

Methods

Randomised clinical trial.

Participants

Country: Italy.

Number randomised: 32.

Post‐randomisation dropouts: not stated.

Revised sample size: 32.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 1 month.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: SAMe (n = 16).

Further details: SAMe: 800 mg/day IV for 2 weeks.

Group 2: placebo (n = 16).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although placebo was used, there was no mention of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although placebo was used, there was no mention of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other bias.
Manzillo 1993b

Methods

Randomised clinical trial.

Participants

Country: Italy.

Number randomised: 6.

Post‐randomisation dropouts: not stated.

Revised sample size: 6.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 2 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: SAMe (n = 3).

Further details: SAMe: 1600 mg/day orally for 8 weeks.

Group 2: placebo (n = 3).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although placebo was used, there was no mention of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although placebo was used, there was no mention of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other bias.
Mason 2008

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 59.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 59.

Mean age: 56 years.

Females: 58 (98.3%).

Symptomatic participants: not stated.

AMA positive: 59 (100%).

Responders: 0 (0%).

Mean follow‐up period (for all groups): all participants followed up for 6 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA‐positive participants only.

  • Response status: non‐responders only.

Other exclusion criteria

  • Advanced or decompensated liver disease.

  • Use of immunosuppressants or anti‐inflammatory drugs in previous 3 months.

  • Significant renal impairment.

  • Excessive alcohol consumption.

  • Pregnant, breastfeeding, or not using contraceptives in sexually active women of child‐bearing age.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: lamivudine + zidovudine + UDCA (moderate) (n = 30).

Further details: lamivudine: 150 mg BD for 6 months + zidovudine: 300 mg BD for 6 months + UDCA: 13 mg/kg/day to 15 mg/kg/day for 6 months.

Group 2: UDCA (moderate) (n = 29).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day for 6 months.

Outcomes

Adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was performed centrally at the University of Alberta by a dynamic randomization" (author's reply).

Allocation concealment (selection bias)

Low risk

Quote: "Sealed opaque envelopes" (author's reply).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Dilan Clinical Packaging Ltd (Mississauga, ON, Canada) coded samples ensuring that the investigators and patients were blinded to the treatment".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Dilan Clinical Packaging Ltd (Mississauga, ON, Canada) coded samples ensuring that the investigators and patients were blinded to the treatment".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

High risk

Quote: "This study was funded in full by GlaxoSmithKline and Axcan Pharma".

Other bias

Low risk

Comment: no other bias.
Matloff 1982

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 52.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 52.

Mean age: 52 years.

Females: 48 (92.3%).

Symptomatic participants: not stated.

AMA positive: 42 (80.8%).

Responders: not stated.

Mean follow‐up period (for all groups): minimum 24 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: D‐penicillamine (n = 26).

Further details: D‐penicillamine: 1 g/day; duration: not stated.

Group 2: placebo (n = 26).

Outcomes

Mortality, adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although placebo was used in this double‐blind trial, there was no mention about identical placebo.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although placebo was used in this double‐blind trial, there was no mention about identical placebo.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

High risk

Quote: "We are indebted to Merck, Sharp and Dohme Research Laboratories for providing the D‐penicillamine and placebo tablets".

Other bias

Low risk

Comment: no other bias.
Mayo 2015

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 45.

Post‐randomisation dropouts: 3 (6.7%).

Revised sample size: 42.

Mean age: 56 years.

Females: 38 (90.5%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: NGM282 (n = 27).

Further details: NGM282: 0.3 mg/day or 3 mg/day SC for 28 days.

Group 2: placebo (n = 15).

Outcomes

None of the outcomes of interest reported.

Notes

Reasons for post‐randomisation dropouts: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although placebo was used in this double‐blind trial, unclear whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although placebo was used in this double‐blind trial, unclear whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Quote: "Grant/Research Support: Intercept, Salix, NGM, Lumena, Gilead".

Other bias

Low risk

Comment: no other bias.
Mazzarella 2002

Methods

Randomised clinical trial.

Participants

Country: Italy.

Number randomised: 42.

Post‐randomisation dropouts: not stated.

Revised sample size: 42.

Mean age: not stated.

Females: 37 (88.1%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 72 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (high) (n = 21).

Further details: UDCA (high): 30 mg/kg/day for 6 years.

Group 2: UDCA (moderate) (n = 21).

Further details: UDCA (moderate): 10.5 mg/kg/day for 6 years.

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: information not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: information not available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other bias.
McCormick 1994

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 18.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 18.

Mean age: 60 years.

Females: 14 (77.8%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Premenopausal or unsterilised women.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: thalidomide (n = 10).

Further details: thalidomide: 100 mg/day for 6 months.

Group 2: placebo (n = 8).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Quote: "Thalidomide and identical placebo tablets were supplied by Penn Pharmaceuticals Ltd".

Other bias

Low risk

Comment: no other bias.
Minuk 1988

Methods

Randomised clinical trial.

Participants

Country: Canada.

Number randomised: 12.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 12.

Mean age: 55 years.

Females: 11 (91.7%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: ciclosporin (n = 6).

Further details: ciclosporin: maintain serum radioimmunoassay dosage between 100 ng/mL and 200 ng/mL for 12 months.

Group 2: placebo (n = 6).

Outcomes

Mortality, adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Quote: "…patients were randomized by sealed envelope to receive either cyclosporin A or placebo".
Comment: further details of the sealed envelope method not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although a placebo was used, there was no mention about blinding.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: although a placebo was used, there was no mention about blinding.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

High risk

Comment: the drugs were provided by the pharmaceutical company.

Other bias

Low risk

Comment: no other bias.
Mitchison 1989

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 36.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 36.

Mean age: 55 years.

Females: 33 (91.7%).

Symptomatic participants: 35 (97.2%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 36 months.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Aged > 70 years.

  • Treatment for primary biliary cirrhosis in the preceding 4 months.

  • Early liver disease.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: glucocorticosteroids (n = 19).

Further details: prednisolone: 10 mg/day for 36 months (loading dose was used).

Group 2: placebo (n = 17).

Outcomes

Mortality.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were paired according to the presence or absence of cirrhosis, their age by decade, menopausal status (for women) and their serum bilirubin (greater or less than 30 µmoles per litre)".

Comment: minimisation used.

Allocation concealment (selection bias)

Low risk

Quote: "Patients were paired according to the presence or absence of cirrhosis, their age by decade, menopausal status (for women) and their serum bilirubin (greater or less than 30 µmoles per litre)".

Comment: minimisation used.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Study was double‐blind for the first year, single blind thereafter (patients were blinded)".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Study was double‐blind for the first year, single blind thereafter (patients were blinded)".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other bias.
Mitchison 1993

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 104.

Post‐randomisation dropouts: 3 (2.9%).

Revised sample size: 101.

Mean age: 54 years.

Females: 93 (92.1%).

Symptomatic participants: 101 (100%).

AMA positive: not stated.

Responders: not stated.

Median follow‐up period (for all groups): 25 months.

Inclusion criteria

  • Symptom status: symptomatic participants only.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Aged > 65 years.

  • Immunosuppressive drugs in the preceding 6 months.

  • Advanced liver disease or decompensated liver disease.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: malotilate (n = 52).

Further details: malotilate: 500 mg 3 times daily; mean duration: 23 months.

Group 2: placebo (n = 49).

Outcomes

Mortality, adverse events.

Notes

Reasons for post‐randomisation dropouts: elementary data not available.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Random sequence was generated by the trial statistician with tables with random numbers" (author's reply).

Allocation concealment (selection bias)

Low risk

Quote: "Sequentially numbered identical containers" (author's reply).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Both patients and doctors were unaware of the nature of the tablets".
Comment: placebo used to achieve blinding.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Both patients and doctors were unaware of the nature of the tablets".
Comment: placebo used to achieve blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

High risk

Quote: "The study was supported in part by Zyma S.A., Nyon, Switzerland, and by Nihon Nohyaku, Tokyo, Japan".

Other bias

Low risk

Comment: no other source of bias.
Nakai 2000

Methods

Randomised clinical trial.

Participants

Country: Japan.

Number randomised: 23.

Post‐randomisation dropouts: not stated.

Revised sample size: 23.

Mean age: 57 years.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) + bezafibrate (n = 13).

Further details: UDCA: 600 mg/day; duration: not stated + bezafibrate: 400 mg/day; duration: not stated.

Group 2: UDCA (low) (n = 10).

Further details: UDCA: 600 mg/day; duration: not stated.

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: information not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: information not available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Low risk

Quote: "This work was supported by a Grant‐in‐Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan".

Other bias

Low risk

Comment: no other source of bias.
Neuberger 1985

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 189.

Post‐randomisation dropouts: not stated.

Revised sample size: 189.

Mean age: not stated.

Females: 174 (92.1%).

Symptomatic participants: 172 (91%).

AMA positive: 163 (86.2%).

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Taking azathioprine in the previous 6 months.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: D‐penicillamine (n = 98).

Further details: D‐penicillamine: 1200 mg/day; duration: not stated.

Group 2: placebo (n = 91).

Outcomes

Mortality, liver transplantation.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Low risk

Quote: "Opaque sealed envelopes" (author's reply).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Double blind trial, identical appearing placebo" (author's reply).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Assessors were blinded, identical placebo" (author's reply).

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

Unclear risk

Quote: "Not pharmaceutical funding" (author's reply).

Other bias

Low risk

Comment: no other source of bias.
Nevens 2016

Methods

Randomised clinical trial.

Participants

Country: multicentric; international.

Number randomised: 217.

Post‐randomisation dropouts: 1.

Revised sample size: 216.

Mean age: 56 years.

Females: 196 (90.7%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: 0 (0%).

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: non‐responders only.

  • Aged > 18 years.

  • Alkaline phosphatase level ≥ 1.67 times the upper limit of the normal range or an abnormal total bilirubin level < 2 times the upper limit of the normal range.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: obeticholic acid (low) + UDCA (moderate) (n = 143).

Further details: obeticholic acid: 5 mg to 10 mg for 1 year + UDCA: 13 mg/kg/day to 15 mg/kg/day for 1 year.

Group 2: UDCA (moderate) (n = 73).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day for 1 year.

Outcomes

Mortality, adverse events.

Notes

Reasons for post‐randomisation dropouts: withdrawal from study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "On a predefined randomization code (generated by the Sponsor or designee) using an IWRS".

Allocation concealment (selection bias)

Low risk

Quote: "The randomization number will be recorded in the CRF and will serve for patient identification and for assignment of appropriate study medication and bottle number(s) by the IWRS".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used and authors stated double‐blind.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used and authors stated double‐blind.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

High risk

Quote: "Supported by Intercept Pharmaceuticals".
Comment: trial funded by industrial sources which might benefit by the nature of the results.

Other bias

Low risk

Comment: no other source of bias.
Oka 1990

Methods

Randomised clinical trial.

Participants

Country: Japan.

Number randomised: 52.

Post‐randomisation dropouts: 7 (13.5%).

Revised sample size: 45.

Mean age: 59 years.

Females: 41 (91.1%).

Symptomatic participants: 17 (37.8%).

AMA positive: 41 (91.1%).

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: symptomatic and asymptomatic participants.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Advanced liver disease or decompensated liver disease.

  • Pregnancy.

  • Complications from illnesses other than primary biliary cholangitis.

  • Use of treatment for primary biliary cholangitis within the past 3 months.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) (n = 22).

Further details: UDCA: 600 mg/day for 24 weeks.

Group 2: placebo (n = 23).

Outcomes

None of the outcomes of interest reported.

Notes

Reasons for post‐randomisation dropouts: worsening liver disease, lack of compliance.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Low risk

Quote: "The patients were allocated to two groups, a UDCA group and a placebo group, by a single monitor according to a randomization scheme in which the number of patients allocated to two groups tended to be equal".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Quote: "UDCA and placebo tablets were generously furnished by Tokyo Tanabe Pharmaceutical Company".

Other bias

Low risk

Comment: no other source of bias.
Papatheodoridis 2002

Methods

Randomised clinical trial.

Participants

Country: Greece.

Number randomised: 92.

Post‐randomisation dropouts: 6 (6.5%).

Revised sample size: 86.

Mean age: 54 years.

Females: 77 (89.5%).

Symptomatic participants: 86 (100%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): 89 months.

Inclusion criteria

  • Symptom status: symptomatic participants only.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Extrahepatic biliary obstruction.

  • Other liver diseases.

  • Aged > 70 years.

  • Immunosuppression within previous 12 months.

  • Advanced or decompensated liver disease.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) (n = 43).

Further details: UDCA: 12 mg/kg//day to 15 mg/kg//day for ≥ 2 years.

Group 2: control (n = 43).

Outcomes

Mortality, liver transplantation, decompensated liver disease.

Notes

Reasons for post‐randomisation dropouts: not stated.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was carried out by serially numbered sealed envelopes containing random table numbers 14 patients crossed over from placebo to UDCA".

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was carried out by serially numbered sealed envelopes containing random table numbers 14 patients crossed over from placebo to UDCA".

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Patients and healthcare providers were not blinded" (author's reply).

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "The outcome assessors were not blinded" (author's reply).

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts in the initial report.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

High risk

Quote: "Support for this work was provided during the first 2 years of the study by a research grant the pharmaceutical company Galenica Hellas and by the Greek Ministry of Health and Welfare".

Other bias

High risk

Comment: 14 participants crossed over from placebo to UDCA.
Pares 2000

Methods

Randomised clinical trial.

Participants

Country: Spain.

Number randomised: 192.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 192.

Mean age: 54 years.

Females: 179 (93.2%).

Symptomatic participants: not stated.

AMA positive: 172 (89.6%).

Responders: not stated.

Median follow‐up period (for all groups): 41 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Aged > 72 years.

  • Immunosuppression within previous 6 months.

  • Life expectancy < 6 months.

  • Pregnancy.

  • Drug addiction.

  • Other liver diseases.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) (n = 99).

Further details: UDCA 14 mg/kg/day to 16 mg/kg/day; duration: 25 to 73 months.

Group 2: placebo (n = 93).

Outcomes

Mortality, adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: unclear whether all participants were included in the analysis.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

High risk

Quote: "We are indebted to Zambon S. A., Laboratorio Farmaceutico for supplying the UDCA and placebo capsules, and for the invaluable administrative support".

Other bias

Low risk

Comment: no other risk of bias.
Poupon 1991a

Methods

Randomised clinical trial.

Participants

Country: France.

Number randomised: 149.

Post‐randomisation dropouts: 3 (2%).

Revised sample size: 146.

Mean age: 56 years.

Females: 134 (91.8%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Received any of the following drugs during the previous 6 months: ursodiol, azathioprine, chlorambucil, colchicine, corticosteroids, D‐penicillamine, and ciclosporin.

  • Serum bilirubin concentration > 150 μmol/L.

  • Serum albumin concentration < 25 g/L.

  • Past or active gastrointestinal bleeding from oesophageal varices.

  • Evidence of past or present extrahepatic obstruction of the bile ducts.

  • Excessive alcohol consumption (> 50 g/day).

  • Positive test for hepatitis B surface antigen.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) (n = 73).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day for 2 years.

Group 2: placebo (n = 73).

Outcomes

None of the outcomes of interest reported.

Notes

Reasons for post‐randomisation dropouts: bilirubin > 300 μmol/L, ascites, other coexisting disease.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Quote: "This work was supported in part by Synthélabo‐Recherche and in Canada by Jouveinal and Interfalk".

Other bias

Low risk

Comment: no other source of bias.
Poupon 1996

Methods

Randomised clinical trial.

Participants

Country: France.

Number randomised: 74.

Post‐randomisation dropouts: not stated.

Revised sample size: 74.

Mean age: 54 years.

Females: 63 (85.1%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Received any of the following drugs during the previous 6 months: ursodiol, azathioprine, chlorambucil, colchicine, corticosteroids, D‐penicillamine, and ciclosporin.

  • Serum bilirubin concentration > 150 μmol/L.

  • Serum albumin concentration < 25 g/L.

  • Past or active gastrointestinal bleeding from oesophageal varices.

  • Evidence of past or present extrahepatic obstruction of the bile ducts.

  • Excessive alcohol consumption (> 50 g/day).

  • Other identified causes of liver or biliary diseases.

  • Aged ≥ 75 years.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) + colchicine (n = 37).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day for 2 years + colchicine: 1 mg/day for 5 days in a week for 2 years.

Group 2: UDCA (moderate) (n = 37).

Further details: UDCA: 13 mg/kg/day to 15 mg/kg/day for 2 years.

Outcomes

Mortality, adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: unclear whether all randomised participants were included for analysis.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

High risk

Quote: "Supported in part by Laboratoires Houde (France) and Jouveinal (Canada)".

Other bias

Low risk

Comment: no other source of bias.
Raedsch 1993

Methods

Randomised clinical trial.

Participants

Country: Germany.

Number randomised: 28.

Post‐randomisation dropouts: 8 (28.6%).

Revised sample size: 20.

Mean age: 54 years.

Females: 20 (100%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) + colchicine (n = 8).

Further details: UDCA: 10 mg/kg/day to 12 mg/kg/day for 24 months + colchicine: 1 mg/day for 24 months.

Group 2: UDCA (moderate) (n = 12).

Further details: UDCA: 10 mg/kg/day to 12 mg/kg/day for 24 months.

Outcomes

Adverse events.

Notes

Reasons for post‐randomisation dropouts: adverse events, lost to follow‐up.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although a placebo used in this double‐blind trial, unclear whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although a placebo used in this double‐blind trial, unclear whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Rautiainen 2005

Methods

Randomised clinical trial.

Participants

Country: Finland.

Number randomised: 77.

Post‐randomisation dropouts: 8 (10.4%).

Revised sample size: 69.

Mean age: 53 years.

Females: 60 (87%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 36 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Aged < 18 years or > 70 years.

  • Pregnancy or inadequate contraceptive use.

  • Systemic immunosuppressive use.

  • Other liver diseases.

  • Cirrhosis.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) + glucocorticosteroids (n = 37).

Further details: UDCA: 15 mg/kg/day for 3 years + budesonide: 6 mg/day for 3 years.

Group 2: UDCA (moderate) (n = 32).

Further details: UDCA: 15 mg/kg/day for 3 years.

Outcomes

Adverse events.

Notes

Reasons for post‐randomisation dropouts: adverse effects, death, refused follow‐up biopsy.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Quote: "Randomization was done centrally at Helsinki University Hospital with sealed envelopes in a block of 10".

Comment: further details of sealed envelope technique not available.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Study design was randomized but open because placebo for budesonide was not available for us".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Study design was randomized but open because placebo for budesonide was not available for us".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

High risk

Quote: "Medication was supplied free of charge by AstraZeneca Finland (budesonide, Entocort) and Leiras Finland (UDCA, Adursal)".

Other bias

Low risk

Comment: no other source of bias.
Senior 1991

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 20.

Post‐randomisation dropouts: 1 (5%).

Revised sample size: 19.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 18 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) (n = 9).

Further details: UDCA (low): 8 mg/kg/day to 12 mg/kg/day for 6 months.

Group 2: placebo (n = 10).

Outcomes

None of the outcomes of interest reported.

Notes

Reasons for post‐randomisation dropouts: had coexisting gallstones.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although a placebo used in this double‐blind trial, unclear whether the placebo was identical.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although a placebo used in this double‐blind trial, unclear whether the placebo was identical.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: there were post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

High risk

Quote: "and ursodiol supplies provided by Ciba‐Geigy Corporation".

Other bias

Low risk

Comment: no other source of bias.
Smart 1990

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 20.

Post‐randomisation dropouts: not stated.

Revised sample size: 20.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: antioxidants (n = not stated).

Further details: antioxidant: cocktail of vitamin E 100 mg, zinc 135 mg, and selenium 100 μg daily; duration: not stated.

Group 2: placebo (n = not stated).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: although a placebo was used, no mention of blinding made.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: although a placebo was used, no mention of blinding made.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Steenbergen 1994

Methods

Randomised clinical trial.

Participants

Country: Belgium.

Number randomised: 14.

Post‐randomisation dropouts: not stated.

Revised sample size: 14.

Mean age: 51 years.

Females: 12 (85.7%).

Symptomatic participants: not stated.

AMA positive: 13 (92.9%).

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA‐positive and AMA‐negative participants.

  • Response status: not stated.

Exclusion criteria

  • Presence of cirrhosis.

  • Excessive alcohol consumption.

  • Other viral diseases.

  • Mental disorders.

  • Pregnancy.

  • Chronic infection.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) + methotrexate (n = 8).

Further details: UDCA: 500 mg/day; duration: not stated + methotrexate: 15 mg/week; duration: not stated.

Group 2: control (n = 6).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Using a random number table…".

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: information not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: information not available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Taal 1983

Methods

Randomised clinical trial.

Participants

Country: Netherlands.

Number randomised: 24.

Post‐randomisation dropouts: not stated.

Revised sample size: 24.

Mean age: 49 years.

Females: 23 (95.8%).

Symptomatic participants: 24 (100%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 18 months.

Inclusion criteria

  • Symptom status: symptomatic participants only.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Advanced or decompensated liver disease.

  • Use of cholestatic drug in the previous 6 months.

  • Associated inflammatory bowel disease.

  • Neoplasm within last 5 years.

  • Pregnancy.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: D‐penicillamine (n = 11).

Further details: D‐penicillamine: 250 mg/day to 1000 mg/day (escalating dose) and then 500 mg/day: total duration: 1 year.

Group 2: placebo (n = 13).

Outcomes

Mortality, adverse events, decompensated liver disease.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

Low risk

Comment: mortality and adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Triger 1980

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 35.

Post‐randomisation dropouts: not stated.

Revised sample size: 35.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: D‐penicillamine (n = not stated).

Further details: D‐penicillamine: 250 mg to 875 mg (escalating dose).

Group 2: placebo (n = not stated).

Outcomes

Mortality.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: in this double‐blind trial, unclear whether the placebo was identical to active treatment.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: in this double‐blind trial, unclear whether the placebo was identical to active treatment.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

High risk

Quote: "The UDCA and placebo tablets were generously donated by Thames Laboratories, Wrexham, Wales".

Other bias

Low risk

Comment: no other source of bias.
Turner 1994

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 46.

Post‐randomisation dropouts: 0 (0%).

Revised sample size: 46.

Mean age: 58 years.

Females: 44 (95.7%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): all participants followed up for 24 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) (n = 22).

Further details: UDCA: 10 mg/kg/day for 2 years.

Group 2: placebo (n = 24).

Outcomes

Mortality, liver transplantation, cirrhosis.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: no post‐randomisation dropouts.

Selective reporting (reporting bias)

High risk

Comment: adverse events not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Ueno 2005

Methods

Randomised clinical trial.

Participants

Country: Japan.

Number randomised: 20.

Post‐randomisation dropouts: not stated.

Revised sample size: 20.

Mean age: not stated.

Females: 16 (80%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: 0 (0%).

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: non‐responders only

Exclusion criteria

  • Aged < 20 years or > 70 years.

  • History of antiretroviral or steroid treatment.

  • Renal dysfunction.

  • Other causes of liver damage.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: lamivudine (n = not stated).

Further details: lamivudine: 100 mg/day for 3 months.

Group 2: placebo (n = not stated).

Outcomes

None of the outcomes of interest reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: neither mortality nor adverse events reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Van Hoogstraten 1998

Methods

Randomised clinical trial.

Participants

Country: Netherlands.

Number randomised: 61.

Post‐randomisation dropouts: 2 (3.3%).

Revised sample size: 59.

Mean age: 57 years.

Females: 55 (93.2%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: 0 (0%).

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: non‐responders only.

Exclusion criteria

  • Decompensated liver disease.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) (n = 32).

Further details: UDCA (low): 10 mg/kg/day for 6 months.

Group 2: UDCA (moderate) (n = 27).

Further details: UDCA (moderate): 20 mg/kg/day for 6 months.

Outcomes

Adverse events.

Notes

Reasons for post‐randomisation dropouts: developed liver failure, lost to follow‐up.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Tables with random numbers" (author's reply).

Allocation concealment (selection bias)

Low risk

Quote: "Opaque closed envelopes" (author's reply).

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "randomised open controlled trial".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "randomised open controlled trial".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

High risk

Quote: "This study was supported in part by Zambon Nederland BV, Amersfoort, the Netherlands".

Other bias

Low risk

Comment: no other source of bias.
Warnes 1987

Methods

Randomised clinical trial.

Participants

Country: UK.

Number randomised: 64.

Post‐randomisation dropouts: not stated.

Revised sample size: 64.

Mean age: not stated.

Females: not stated.

Symptomatic participants: not stated.

AMA positive: 64 (100%).

Responders: not stated.

Median follow‐up period (for all groups): 19 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: AMA‐positive participants only.

  • Response status: not stated.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: colchicine (n = 34).

Further details: colchicine: 0.5 mg BD; duration: not stated.

Group 2: placebo (n = 30).

Outcomes

Mortality, adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "To ensure that treatment groups were comparable, patients were stratified according to serum bilirubin level at entry (A, < 19/µmol/1; B, 20‐34/ µmol/L; C, 35‐102/µmol/L; D, >102/µmol/1). The first patient in any pair was allocated by the staff pharmacist to the treatment or placebo group by reference to random tables. The pair was completed when another patient, in the same bilirubin group and with an age within 5 years of the first patient, was entered into the study. The second member of the pair was allocated to the alternative treatment group. The study was double‐blind".
Comment: minimisation method used.

Allocation concealment (selection bias)

Low risk

Quote: "To ensure that treatment groups were comparable, patients were stratified according to serum bilirubin level at entry (A, < 19/µmol/1; B, 20‐34/ µmol/L; C, 35‐102/µmol/L; D, >102/µmol/1). The first patient in any pair was allocated by the staff pharmacist to the treatment or placebo group by reference to random tables. The pair was completed when another patient, in the same bilirubin group and with an age within 5 years of the first patient, was entered into the study. The second member of the pair was allocated to the alternative treatment group. The study was double‐blind".
Comment: minimisation method used.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.
Wiesner 1990

Methods

Randomised clinical trial.

Participants

Country: USA.

Number randomised: 40.

Post‐randomisation dropouts: 11 (27.5%).

Revised sample size: 29.

Mean age: 46 years.

Females: 28 (96.6%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: not stated.

Median follow‐up period (for all groups): 35 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Cirrhosis or advanced liver disease.

  • Renal dysfunction.

  • Uncontrolled hypertension.

  • Neoplastic disease.

  • Skin cancer.

  • Previous immunosuppressive therapy.

  • Other liver diseases.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: ciclosporin (n = 19).

Further details: ciclosporin: 4 mg/kg/day.

Group 2: placebo (n = 10).

Outcomes

Mortality, adverse events, liver transplantation.

Notes

Reasons for post‐randomisation dropouts: follow‐up < 1 year.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

Low risk

Comment: mortality and morbidity reported.

For‐profit bias

High risk

Quote: "Supported by a grant from Sandoz and by the Mayo foundation".

Other bias

Low risk

Comment: no other source of bias.
Wolfhagen 1998

Methods

Randomised clinical trial.

Participants

Country: Netherlands.

Number randomised: 50.

Post‐randomisation dropouts: not stated.

Revised sample size: 50.

Mean age: 52 years.

Females: 45 (90%).

Symptomatic participants: not stated.

AMA positive: not stated.

Responders: 0 (0%).

Mean follow‐up period (for all groups): all participants followed up for 12 months.

Inclusion criteria

  • Symptom status: not stated.

  • AMA status: not stated.

  • Response status: non‐responders only.

Exclusion criteria

  • Advanced or decompensated liver disease.

  • Alcohol abuse.

  • Other causes of liver disease.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (moderate) + azathioprine + glucocorticosteroids (n = 26).

Further details: UDCA: 10 mg/kg/day for 6 months + azathioprine: 50 mg/day for 6 months + prednisolone: 10 mg/day for 6 months.

Group 2: UDCA (moderate) (n = 24).

Further details: UDCA: 10 mg/kg/day for 6 months.

Outcomes

Adverse events, cirrhosis.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Tables with random numbers" (author's reply).

Allocation concealment (selection bias)

Low risk

Quote: "Opaque closed envelopes" (author's reply).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: identical placebo used in this double‐blind trial.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

High risk

Quote: "Supported by…Zambon Nederland B.v. and Glaxo Wellcome Research and Development Ltd".

Other bias

Low risk

Comment: no other source of bias.
Yokomori 2001

Methods

Randomised clinical trial.

Participants

Country: Japan.

Number randomised: 11.

Post‐randomisation dropouts: not stated.

Revised sample size: 11.

Mean age: 54 years.

Females: 9 (81.8%).

Symptomatic participants: 11 (100%).

AMA positive: not stated.

Responders: not stated.

Mean follow‐up period (for all groups): not stated.

Inclusion criteria

  • Symptom status: symptomatic participants only.

  • AMA status: not stated.

  • Response status: not stated.

Exclusion criteria

  • Advanced or decompensated liver disease.

  • Pregnancy.

  • Treatment with immunosuppressants or other drugs that interfere with bile secretion.

  • Severe complications other than primary biliary cholangitis.

Interventions

Participants were randomly assigned to 2 groups.

Group 1: UDCA (low) + colestilan (n = 5).

Further details: UDCA: 600 mg/day for 8 weeks + colestilan: 6.42 mg/day for 4 weeks.

Group 2: UDCA (low) (n = 6).

Further details: UDCA: 600 mg/day for 8 weeks.

Outcomes

Adverse events.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: information not available.

Allocation concealment (selection bias)

Unclear risk

Comment: information not available.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "open‐label".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "open‐label".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: information not available.

Selective reporting (reporting bias)

High risk

Comment: mortality not reported.

For‐profit bias

Unclear risk

Comment: information not available.

Other bias

Low risk

Comment: no other source of bias.

AMA: antimitochondrial antibody; BD: twice daily; IV: intravenous; OD: once daily; SAMe: S‐adenosyl methionine; SC: subcutaneous; TUDCA: taurodeoxycholic acid; UDCA: ursodeoxycholic acid.

Characteristics of excluded studies [ordered by study ID]

Ir a:

Study

Reason for exclusion

Angulo 1999b

Long‐term follow‐up of participants included in an included trial (Lindor 1994), but the randomisation was not maintained.

Angulo 1999c

Long‐term follow‐up of participants included in an included trial (Lindor 1994), but the randomisation was not maintained.

Angulo 2002

Comparison of different administration schedules of the same dose of UDCA.

Attili 1994

Not in people with primary biliary cholangitis.

Avezov 2004a

Not a randomised clinical trial.

Avezov 2004b

Not a randomised clinical trial.

Bach 2003

Not a randomised clinical trial.

Batta 1989

Not a randomised clinical trial.

Beukers 1988

Not a randomised clinical trial.

Blanche 1994

Not a randomised clinical trial.

Bonis 2006

Not a randomised clinical trial.

Borum 1990

Not a primary study (editorial).

Bray 1991

Cross‐over RCT; no results presented before cross‐over.

Carbone 2016

Long‐term follow‐up of Nevens 2016, but excluded because randomisation not maintained.

Chazouilleres 1995

Not a randomised clinical trial.

Christensen 1986

Not a primary study (letter to editor).

Combes 1989

Not a primary study (editorial).

Combes 2004

Not a primary study (editorial).

Combes 2005b

Long‐term follow‐up of participants in an included RCT (Combes 1995a); however, all participants received the intervention after the end of the initial study.

Copaci 2001

Not a randomised clinical trial.

Corpechot 2000

Long‐term follow‐up of an included trial (Poupon 1991a); however, all participants received the active intervention at the end of the trial period.

Corpechot 2001

Not a primary study (editorial).

Crosignani 1996a

Cross‐over RCT; no outcomes of interest reported before cross‐over.

Crosignani 1996b

In this RCT of different doses of TUDCA, participants who were intolerant to the drug were replaced. This affected the randomisation.

De la Mora 1994

No separate data on people who were randomised (included non‐randomised participants in the results).

Degott 1999

Long‐term follow‐up of an included trial (Poupon 1991a); however, all participants received the active intervention at the end of the trial period.

Dickson 1991

No separate data on people who were randomised (included non‐randomised participants in the results).

Emond 1996

Long‐term follow‐up of an included trial (Combes 1995a); however, all participants received the active intervention at the end of the trial period.

Fischer 1967

Not a randomised clinical trial.

Golovanova 2010

Not a randomised clinical trial.

Heathcote 1993

Not a randomised clinical trial.

Heathcote 1995

Not a primary study.

Hirschfield 2011

Not a randomised clinical trial.

Hishon 1982

Not a randomised clinical trial.

Howat 1966

Not a randomised clinical trial.

Hwang 1993

Cross‐over RCT; none of the outcomes of interest reported prior to cross‐over.

Invernizzi 1996

Cross‐over RCT, no results presented before cross‐over.

Invernizzi 2015

Not a primary study.

Itakura 2004

Not a primary study.

Jazrawi 1999

Not a randomised clinical trial.

Jones 2006

Not a primary study (letter to editor).

Jorgensen 2002

Long‐term follow‐up of an included trial (Lindor 1994); however, all participants received the active intervention at the end of the trial period.

Joshi 2002

Not a primary study.

Kaplan 1993

Not a primary study (editorial).

Kaplan 1998

Not a primary study (letter to editor).

Kaplan 2004

Long‐term follow‐up of an included trial (Kaplan 1999), but the treatment was changed at the completion of the RCT.

Kaplan 2009

Not a primary study (letter to editor).

Kisand 1996

Quasi‐randomised study (allocation by case numbers).

Kisand 1998

Quasi‐randomised study (allocation by case numbers).

Kowdley 2014a

Not a randomised clinical trial.

Kowdley 2014b

Not a randomised clinical trial.

Kowdley 2015

Long‐term follow‐up of Kowdley 2011, but excluded because randomisation was not maintained.

Kugler 1991

Not a primary study (commentary).

Kurihara 2002

Not a randomised clinical trial.

Lampe 1972

Not a randomised clinical trial.

Larghi 1997

Cross‐over RCT; no results presented before cross‐over.

Lee 2003

Not a randomised clinical trial.

Leung 2010

Long‐term follow‐up of a subgroup of participants in an included trial (Kaplan 1999), where additional interventions were added after completion of the trial period.

Leung 2011

Long‐term follow‐up of a subgroup of participants in an included trial (Kaplan 1999), where additional interventions were added after completion of the trial period.

Leuschner 1990

Not a primary study (review).

Leuschner 1993a

Not a primary study (review).

Leuschner 1993b

Quasi‐randomised study (allocation by alternation).

Leuschner 1996a

Quasi‐randomised study (allocation by alternation).

Leuschner 1996b

Quasi‐randomised study (allocation by alternation).

Leuschner 1997

Not a primary study (review).

Leuschner 1998

Not a primary study (review).

Levy 2004

Not a primary study (editorial).

Licinio 2015

Not a primary study (letter to editor).

Lim 2000

Not a randomised clinical trial.

Lindor 1994a

Not a randomised clinical trial

Lindor 1995a

Long‐term follow‐up an included RCT (Lindor 1994); however, all participants received the intervention after the completion of the RCT.

Lindor 1995b

Not a randomised clinical trial.

Lindor 1995c

Not a primary study (review).

Lindor 1996

Long‐term follow‐up an included RCT (Lindor 1994); however, all participants received the intervention after the completion of the RCT.

Lindor 2000

Not a primary study (letter to editor).

Lindor 2005

Not a primary study (review).

Lindor 2007

Not a primary study (review).

Lytvyak 2015

Cross‐over RCT; no outcomes reported prior to cross‐over.

Lytvyak 2016

Not a randomised clinical trial

Miettinen 1993

Quasi‐randomised study (allocation by case numbers).

Miettinen 1995

Quasi‐randomised study (allocation by case numbers).

Muntoni 2010

Only 4 participants in this trial had primary biliary cholangitis and separate data not available for these 4 participants.

Nikolaidis 2006

Only 5 participants had primary biliary cholangitis and only 1 of them received placebo. Separate data not available on these participants.

Ohmoto 2001

Not a randomised clinical trial.

Ohmoto 2006

Not a randomised clinical trial.

Pan 2013

Only 5 participants had primary biliary cholangitis. Separate data not available for these participants.

Pares 2009

Not a randomised clinical trial.

Podda 1989

Cross‐over study of different doses of UDCA; outcomes not reported at the end of first treatment.

Poupon 1989

Not a primary study (review).

Poupon 1990

Not a primary study (review).

Poupon 1991b

Not a primary study (commentary).

Poupon 1994

Long‐term follow‐up of an included trial (Poupon 1991a); however, all participants received the active intervention at the end of the trial period.

Poupon 1997

Not a primary study.

Poupon 1999

Not a randomised clinical trial.

Poupon 2003

Not a primary study.

Raedsch 1989

Not a randomised clinical trial.

Reed 1982

Not a primary study (editorial).

Robson 1994

Not a randomised clinical trial.

Roda 2002

Not a randomised clinical trial.

Savolainen 1983

Unclear whether this was a randomised clinical trial.

Schaffner 1982

Comparison of 2 doses of D‐penicillamine with no other treatment as comparator.

Setchell 1994

In this RCT of different doses of TUDCA, participants who were intolerant to the drug were replaced. This affected the randomisation.

Setchell 1996

In this RCT of different doses of TUDCA, participants who were intolerant to the drug were replaced. This affected the randomisation.

Stellaard 1979

Not a randomised clinical trial.

Taal 1985

Not a randomised clinical trial.

Tang 2008

Not a pharmacological agent.

Tong 2012

Not a pharmacological agent.

Verma 1999

Cross‐over RCT; no results presented before cross‐over.

Verma 2000

Not a primary study (review).

Vogel 1988

Not a randomised clinical trial.

Vuoristo 1995

Quasi‐randomised study (allocation by case numbers).

Vuoristo 1997

Quasi‐randomised study (allocation by case numbers).

Wiesner 1994

Not a randomised clinical trial.

Wolfhagen 1995

Not a randomised clinical trial.

Yan 2007

Not a primary study (letter to editor).

Yano 2002

Not a randomised clinical trial.

Zuin 1991

Symptomatic treatment of dyslipidaemia associated with primary biliary cholangitis.

TUDCA: taurodeoxycholic acid; UDCA: ursodeoxycholic acid.

Characteristics of studies awaiting assessment [ordered by study ID]

Ir a:

O'Brian 1990

Methods

Full text not available.

Participants

Interventions

Outcomes

Notes
Zaman 2006

Methods

Full text not available.

Participants

Interventions

Outcomes

Notes

Characteristics of ongoing studies [ordered by study ID]

Ir a:

ChiCTR‐IPR‐16008935

Trial name or title

Biochemical Response of PBC‐AIH Overlap Syndrome Induced by Ursodeoxycholic Acid Only or Combination Therapy of Immunosuppressive Agents

Methods

Randomised parallel clinical trial

Participants

People with primary biliary cholangitis and autoimmune hepatitis overlap syndrome.

Interventions

Group 1: UDCA + immunosuppression

Further details: not provided.

Group 2: UDCA.

Further details: not provided.

Outcomes

Adverse events

Starting date

Not stated.

Contact information

[email protected]

Notes

Status: recruiting.
EUCTR2015‐002698‐39‐GB

Trial name or title

A 12‐Week, Double‐Blind, Randomized, Placebo‐Controlled, Phase 2 Study to Evaluate the Effects of Two Doses of MBX‐8025 in Subjects with Primary Biliary Cirrhosis (PBC) and an Inadequate Response to Ursodeoxycholic Acid (UDCA).

Methods

Randomised, placebo‐controlled, double‐blind clinical trial.

Participants

People with primary biliary cholangitis (non‐responders).

Interventions

Group 1: MBX‐8025.

Further details: not provided.

Group 2: placebo.

Outcomes

None of the outcomes of interest for this review measured in this trial.

Starting date

Not stated.

Contact information

[email protected]

Notes

Status: recruiting.
NCT02308111

Trial name or title

A Phase 3b, Double‐Blind, Randomized, Placebo‐Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Patients With Primary Biliary Cirrhosis

Methods

Phase 3, double‐blind, randomised, placebo‐controlled, multicentre study.

Participants

People with primary biliary cholangitis.

Interventions

Group 1: obeticholic acid.

Further details: obeticholic acid 5 mg to 10 mg tablets once daily for the duration of the study based on tolerability at 3 months.

Group 2: placebo.

Further details: 1 tablet daily for the remainder of the study.

Outcomes

Mortality, liver transplantation, liver decompensation, hepatocellular carcinoma.

Starting date

December 2014.

Contact information

[email protected]

Notes

Status: recruiting.
NCT02701166

Trial name or title

The Effect of Bezafibrate on Cholestatic Itch

Methods

Double‐blind, randomised, placebo‐controlled clinical trial.

Participants

People with primary biliary cholangitis.

Interventions

Group 1: bezafibrate.

Further details: bezafibrate 400 mg/day.

Group 2: placebo.

Outcomes

None of the outcomes of interest for this review are measured in this trial.

Starting date

February 2016.

Contact information

[email protected]

Notes

Status: recruiting.
NCT02823353

Trial name or title

Fenofibrate in Combination with Ursodeoxycholic Acid in Primary Biliary Cirrhosis: a Randomized Control Study

Methods

Phase 3, open‐label, randomised clinical trial.

Participants

People with primary biliary cholangitis.

Interventions

Group 1: UDCA + fenofibrate.

Further details: not provided.

Group 2: UDCA.

Further details: not provided.

Outcomes

None of the outcomes of interest for this review are measured in this trial.

Starting date

January 2016.

Contact information

[email protected]

Notes

Status: recruiting.
NCT02823366

Trial name or title

Fenofibrate for Patients with Primary Biliary Cirrhosis who had an Inadequate Response to Ursodeoxycholic Acid

Methods

Phase 3, open‐label, randomised clinical trial.

Participants

People with primary biliary cholangitis.

Interventions

Group 1: UDCA + fenofibrate

Further details: not provided.

Group 2: UDCA.

Further details: not provided.

Outcomes

None of the outcomes of interest for this review measured in this trial.

Starting date

January 2016.

Contact information

[email protected]

Notes

Status: recruiting.

May be the same as NCT02823353.

NCT02937012

Trial name or title

Efficacy and Security of Bezafibrate in Patients with Primary Biliary Cirrhosis without Biochemical Response to Ursodeoxycholic Acid: a Randomized, Double‐blind, Placebo‐controlled Trial

Methods

Randomised, double‐blind, placebo‐controlled clinical trial.

Participants

People with primary biliary cholangitis (non‐responders).

Interventions

Group 1: UDCA + bezafibrate.

Further details: bezafibrate 200 mg capsule every 12 hours + UDCA 13 mg/kg/day to 15 mg/kg/day for 12 months.

Group 2: UDCA + placebo.

Further details: placebo capsule (for bezafibrate 200 mg capsule) every 12 hours + UDCA 13 mg/kg/day to 15 mg/kg/day for 12 months.

Outcomes

Quality of life.

Starting date

October 2016.

Contact information

[email protected]

[email protected]

Notes

Status: recruiting.
NCT02943447

Trial name or title

A Phase 2, Randomized, Double‐Blind, Placebo Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS‐9674 in Subjects with Primary Biliary Cholangitis without Cirrhosis

Methods

Randomised, double‐blind, placebo‐controlled clinical trial.

Participants

People with primary biliary cholangitis.

Interventions

Group 1: GS‐9674.

Further details: GS‐9674 30 mg for 12 weeks.

Group 2: placebo.

Outcomes

Adverse events.

Starting date

December 2016.

Contact information

GS‐US‐427‐[email protected]

Notes

Status: recruiting.
NCT02965911

Trial name or title

A Randomized Controlled Clinical Trial on the Efficacy and Safety of Fenofibrate Combined with Ursodeoxycholic Acid in PBC Patients with an Incomplete Biochemical Response to UDCA

Methods

Open‐label, randomised clinical trial.

Participants

People with primary biliary cholangitis.

Interventions

Group 1: fenofibrate + UDCA.

Further details: UDCA 13 mg/kg/day to 15 mg/kg/day + fenofibrate 200 mg once daily for 12 months.

Group 2: UDCA.

Further details: UDCA 13 mg/kg/day to 15 mg/kg/day.

Outcomes

None of the outcomes of interest for this review measured in this trial.

Starting date

January 2016.

Contact information

[email protected]

Notes

Status: recruiting.

UDCA: ursodeoxycholic acid.

Data and analyses

Open in table viewer
Comparison 1. Main analysis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality at maximal follow‐up Show forest plot

28

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.1
Comparison 1 Main analysis, Outcome 1 Mortality at maximal follow‐up.

Comparison 1 Main analysis, Outcome 1 Mortality at maximal follow‐up.

1.1 Azathioprine versus no intervention

2

224

Odds Ratio (M‐H, Fixed, 95% CI)

0.56 [0.32, 0.98]

1.2 Chlorambucil versus no intervention

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.28]

1.3 Colchicine versus no intervention

2

122

Odds Ratio (M‐H, Fixed, 95% CI)

0.77 [0.32, 1.85]

1.4 Cyclosporin versus no intervention

3

390

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.51, 1.50]

1.5 D‐Penicillamine versus no intervention

5

423

Odds Ratio (M‐H, Fixed, 95% CI)

0.90 [0.57, 1.44]

1.6 Glucocorticosteroids versus no intervention

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

0.64 [0.14, 2.92]

1.7 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

2.0 [0.47, 8.48]

1.8 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

8.83 [1.01, 76.96]

1.9 UDCA versus no intervention

6

734

Odds Ratio (M‐H, Fixed, 95% CI)

0.99 [0.60, 1.64]

1.10 Bezafibrate plus UDCA versus UDCA

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

9.67 [0.45, 207.78]

1.11 Colchicine plus UDCA versus UDCA

2

158

Odds Ratio (M‐H, Fixed, 95% CI)

1.84 [0.38, 8.91]

1.12 Methotrexate plus UDCA versus UDCA

2

290

Odds Ratio (M‐H, Fixed, 95% CI)

1.17 [0.55, 2.51]

1.13 Obeticholic acid plus UDCA versus UDCA

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

2 Mortality (< 1 year) Show forest plot

8

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.2
Comparison 1 Main analysis, Outcome 2 Mortality (< 1 year).

Comparison 1 Main analysis, Outcome 2 Mortality (< 1 year).

2.1 Azathioprine versus no intervention

1

39

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.16, 2.10]

2.2 Colchicine versus no intervention

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.86 [0.22, 3.33]

2.3 Cyclosporin versus no intervention

1

12

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.63]

2.4 D‐Penicillamine versus no intervention

1

189

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.35, 1.42]

2.5 Ursodeoxycholic acid (UDCA) versus no intervention

1

18

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.6 Colchicine plus UDCA versus UDCA

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.13, 7.45]

2.7 Methotrexate plus UDCA versus UDCA

1

25

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.8 Obeticholic acid plus UDCA versus UDCA

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

3 Mortality (1 to 5 years) Show forest plot

20

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.3
Comparison 1 Main analysis, Outcome 3 Mortality (1 to 5 years).

Comparison 1 Main analysis, Outcome 3 Mortality (1 to 5 years).

3.1 Azathioprine versus no intervention

1

185

Odds Ratio (M‐H, Fixed, 95% CI)

0.56 [0.30, 1.04]

3.2 Chlorambucil versus no intervention

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.28]

3.3 Colchicine versus no intervention

1

58

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.22, 2.25]

3.4 Cyclosporin versus no intervention

2

378

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.54, 1.64]

3.5 D‐Penicillamine versus no intervention

4

234

Odds Ratio (M‐H, Fixed, 95% CI)

1.10 [0.59, 2.08]

3.6 Glucocorticosteroids versus no intervention

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

0.64 [0.14, 2.92]

3.7 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

2.0 [0.47, 8.48]

3.8 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

8.83 [1.01, 76.96]

3.9 UDCA versus no intervention

5

716

Odds Ratio (M‐H, Fixed, 95% CI)

0.99 [0.60, 1.64]

3.10 Bezafibrate plus UDCA versus UDCA

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

9.67 [0.45, 207.78]

3.11 Colchicine plus UDCA versus UDCA

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

5.28 [0.24, 113.87]

3.12 Methotrexate plus UDCA versus UDCA

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

1.17 [0.55, 2.51]

4 Serious adverse events (proportion) Show forest plot

11

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.4
Comparison 1 Main analysis, Outcome 4 Serious adverse events (proportion).

Comparison 1 Main analysis, Outcome 4 Serious adverse events (proportion).

4.1 Colchicine versus no intervention

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 D‐Penicillamine versus no intervention

1

52

Odds Ratio (M‐H, Fixed, 95% CI)

28.77 [1.57, 526.67]

4.3 Obeticholic acid versus no intervention

1

165

Odds Ratio (M‐H, Fixed, 95% CI)

1.83 [0.21, 15.73]

4.4 UDCA versus no intervention

3

380

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.5 UDCA versus bezafibrate

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.6 Bezafibrate plus UDCA versus UDCA

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.7 Colchicine plus UDCA versus UDCA

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

3.08 [0.12, 78.14]

4.8 Lamivudine plus zidovudine plus UDCA versus UDCA

1

59

Odds Ratio (M‐H, Fixed, 95% CI)

0.47 [0.04, 5.43]

4.9 Obeticholic acid plus UDCA versus UDCA

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

3.58 [1.02, 12.51]

5 Serious adverse events (number of events) Show forest plot

1

Rate Ratio (Fixed, 95% CI)

Subtotals only
Analysis 1.5
Comparison 1 Main analysis, Outcome 5 Serious adverse events (number of events).

Comparison 1 Main analysis, Outcome 5 Serious adverse events (number of events).

5.1 Obeticholic acid plus UDCA versus UDCA

1

216

Rate Ratio (Fixed, 95% CI)

1.66 [0.75, 3.66]

6 Adverse events (proportion) Show forest plot

19

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.6
Comparison 1 Main analysis, Outcome 6 Adverse events (proportion).

Comparison 1 Main analysis, Outcome 6 Adverse events (proportion).

6.1 Cyclosporin versus no intervention

3

390

Odds Ratio (M‐H, Fixed, 95% CI)

3.04 [1.98, 4.68]

6.2 D‐Penicillamine versus no intervention

2

287

Odds Ratio (M‐H, Fixed, 95% CI)

4.51 [2.56, 7.93]

6.3 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

11.43 [1.40, 93.04]

6.4 Obeticholic acid versus no intervention

1

165

Odds Ratio (M‐H, Fixed, 95% CI)

4.58 [1.31, 15.95]

6.5 UDCA versus no intervention

3

380

Odds Ratio (M‐H, Fixed, 95% CI)

1.45 [0.50, 4.25]

6.6 Azathioprine plus UDCA versus UDCA

1

42

Odds Ratio (M‐H, Fixed, 95% CI)

19.67 [0.94, 413.50]

6.7 Bezafibrate versus UDCA

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.8 Bezafibrate plus UDCA versus UDCA

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

3.29 [0.12, 89.81]

6.9 Colchicine plus UDCA versus UDCA

2

42

Odds Ratio (M‐H, Fixed, 95% CI)

6.20 [0.63, 60.80]

6.10 Colestilan plus UDCA versus UDCA

1

11

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.11 Glucocorticosteroids plus UDCA versus UDCA

2

135

Odds Ratio (M‐H, Fixed, 95% CI)

5.54 [1.35, 22.84]

6.12 Methotrexate plus UDCA versus UDCA

1

25

Odds Ratio (M‐H, Fixed, 95% CI)

115.0 [4.98, 2657.48]

6.13 TauroUDCA versus UDCA

1

30

Odds Ratio (M‐H, Fixed, 95% CI)

21.0 [2.16, 204.61]

6.14 Glucocorticosteroids plus UDCA versus azathioprine plus UDCA

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.12]

7 Adverse events (number) Show forest plot

14

Rate Ratio (Random, 95% CI)

Subtotals only
Analysis 1.7
Comparison 1 Main analysis, Outcome 7 Adverse events (number).

Comparison 1 Main analysis, Outcome 7 Adverse events (number).

7.1 Chlorambucil versus no intervention

1

24

Rate Ratio (Random, 95% CI)

3.67 [1.04, 12.87]

7.2 Cyclosporin versus no intervention

3

390

Rate Ratio (Random, 95% CI)

2.58 [1.26, 5.31]

7.3 D‐Penicillamine versus no intervention

3

303

Rate Ratio (Random, 95% CI)

2.99 [1.04, 8.63]

7.4 Malotilate versus no intervention

1

101

Rate Ratio (Random, 95% CI)

6.13 [1.38, 27.14]

7.5 Obeticholic acid versus no intervention

1

76

Rate Ratio (Random, 95% CI)

1.41 [1.13, 1.75]

7.6 Azathioprine plus glucocorticosteroids plus UDCA versus UDCA

1

50

Rate Ratio (Random, 95% CI)

1.32 [0.88, 1.97]

7.7 Bezafibrate plus UDCA versus UDCA

1

29

Rate Ratio (Random, 95% CI)

11.79 [0.65, 213.14]

7.8 Colchicine plus UDCA versus UDCA

1

24

Rate Ratio (Random, 95% CI)

5.91 [0.28, 123.08]

7.9 Methotrexate plus UDCA versus UDCA

1

27

Rate Ratio (Random, 95% CI)

30.64 [1.84, 510.76]

7.10 TauroUDCA versus UDCA

1

191

Rate Ratio (Random, 95% CI)

1.17 [0.81, 1.71]

8 Liver transplantation Show forest plot

11

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.8
Comparison 1 Main analysis, Outcome 8 Liver transplantation.

Comparison 1 Main analysis, Outcome 8 Liver transplantation.

8.1 Cyclosporin versus no intervention

2

378

Odds Ratio (M‐H, Fixed, 95% CI)

0.86 [0.43, 1.72]

8.2 D‐Penicillamine versus no intervention

1

189

Odds Ratio (M‐H, Fixed, 95% CI)

0.93 [0.06, 15.05]

8.3 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

0.17 [0.02, 1.58]

8.4 UDCA versus no intervention

5

640

Odds Ratio (M‐H, Fixed, 95% CI)

0.90 [0.48, 1.68]

8.5 Bezafibrate plus UDCA versus UDCA

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.6 Methotrexate plus UDCA versus UDCA

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

0.70 [0.35, 1.39]

9 Decompensated liver disease Show forest plot

7

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.9
Comparison 1 Main analysis, Outcome 9 Decompensated liver disease.

Comparison 1 Main analysis, Outcome 9 Decompensated liver disease.

9.1 D‐Penicillamine versus no active treatment

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 UDCA versus no intervention

2

237

Odds Ratio (M‐H, Fixed, 95% CI)

1.60 [0.86, 2.98]

9.3 Azathioprine plus UDCA versus UDCA

1

42

Odds Ratio (M‐H, Fixed, 95% CI)

0.52 [0.05, 5.18]

9.4 Colchicine plus UDCA versus UDCA

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

0.21 [0.04, 1.07]

9.5 Glucocorticosteroids plus UDCA versus UDCA

1

66

Odds Ratio (M‐H, Fixed, 95% CI)

0.55 [0.11, 2.69]

9.6 Methotrexate plus UDCA versus UDCA

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

1.34 [0.77, 2.33]

9.7 Obeticholic acid plus UDCA versus UDCA

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

9.8 Glucocorticosteroids plus UDCA versus azathioprine plus UDCA

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.10, 11.18]

10 Cirrhosis Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 1.10
Comparison 1 Main analysis, Outcome 10 Cirrhosis.

Comparison 1 Main analysis, Outcome 10 Cirrhosis.

10.1 Azathioprine versus no intervention

1

31

Odds Ratio (M‐H, Fixed, 95% CI)

0.79 [0.18, 3.41]

10.2 UDCA versus no intervention

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

0.15 [0.01, 1.53]

10.3 Azathioprine plus glucocorticosteroids plus UDCA versus UDCA

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.03, 2.90]
Open in table viewer
Comparison 2. Stratified by dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality at maximal follow‐up Show forest plot

29

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 2.1
Comparison 2 Stratified by dose, Outcome 1 Mortality at maximal follow‐up.

Comparison 2 Stratified by dose, Outcome 1 Mortality at maximal follow‐up.

1.1 Azathioprine versus no intervention

2

224

Odds Ratio (M‐H, Fixed, 95% CI)

0.56 [0.32, 0.98]

1.2 Chlorambucil versus no intervention

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.28]

1.3 Colchicine versus no intervention

2

122

Odds Ratio (M‐H, Fixed, 95% CI)

0.77 [0.32, 1.85]

1.4 Cyclosporin versus no intervention

3

390

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.51, 1.50]

1.5 D‐Penicillamine versus no intervention

5

423

Odds Ratio (M‐H, Fixed, 95% CI)

0.90 [0.57, 1.44]

1.6 Glucocorticosteroids versus no intervention

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

0.64 [0.14, 2.92]

1.7 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

2.0 [0.47, 8.48]

1.8 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

8.83 [1.01, 76.96]

1.9 UDCA (low) versus no intervention

2

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.33 [0.03, 3.47]

1.10 UDCA (moderate) versus no intervention

4

670

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.62, 1.77]

1.11 UDCA (low) versus UDCA (high)

1

106

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.06, 17.06]

1.12 UDCA (moderate) versus UDCA (high)

1

103

Odds Ratio (M‐H, Fixed, 95% CI)

0.36 [0.01, 9.05]

1.13 UDCA (low) plus colchicine versus UDCA (low)

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.13, 7.45]

1.14 UDCA (low) plus methotrexate versus UDCA (low)

1

25

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.15 UDCA (moderate) versus UDCA (low)

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

0.35 [0.01, 8.72]

1.16 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

9.67 [0.45, 207.78]

1.17 Colchicine plus UDCA (moderate) versus UDCA (moderate)

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

5.28 [0.24, 113.87]

1.18 Methotrexate plus UDCA (moderate) versus UDCA (moderate)

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

1.17 [0.55, 2.51]

1.19 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

2 Mortality (< 1 year) Show forest plot

9

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 2.2
Comparison 2 Stratified by dose, Outcome 2 Mortality (< 1 year).

Comparison 2 Stratified by dose, Outcome 2 Mortality (< 1 year).

2.1 Azathioprine versus no intervention

1

39

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.16, 2.10]

2.2 Colchicine versus no intervention

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.86 [0.22, 3.33]

2.3 Cyclosporin versus no intervention

1

12

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.63]

2.4 D‐Penicillamine versus no intervention

1

189

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.35, 1.42]

2.5 UDCA (low) versus no intervention

1

18

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.6 UDCA (low) versus UDCA (high)

1

106

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.06, 17.06]

2.7 UDCA (moderate) versus UDCA (high)

1

103

Odds Ratio (M‐H, Fixed, 95% CI)

0.36 [0.01, 9.05]

2.8 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

2.9 UDCA (low) plus colchicine versus UDCA (low)

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.13, 7.45]

2.10 UDCA (low) plus methotrexate versus UDCA (low)

1

25

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.11 UDCA (moderate) versus UDCA (low)

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

0.35 [0.01, 8.72]

3 Mortality (1 to 5 years) Show forest plot

20

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 2.3
Comparison 2 Stratified by dose, Outcome 3 Mortality (1 to 5 years).

Comparison 2 Stratified by dose, Outcome 3 Mortality (1 to 5 years).

3.1 Azathioprine versus no intervention

1

185

Odds Ratio (M‐H, Fixed, 95% CI)

0.56 [0.30, 1.04]

3.2 Chlorambucil versus no intervention

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.28]

3.3 Colchicine versus no intervention

1

58

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.22, 2.25]

3.4 Cyclosporin versus no intervention

2

378

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.54, 1.64]

3.5 D‐Penicillamine versus no intervention

4

234

Odds Ratio (M‐H, Fixed, 95% CI)

1.10 [0.59, 2.08]

3.6 Glucocorticosteroids versus no intervention

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

0.64 [0.14, 2.92]

3.7 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

2.0 [0.47, 8.48]

3.8 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

8.83 [1.01, 76.96]

3.9 UDCA (low) versus no intervention

1

46

Odds Ratio (M‐H, Fixed, 95% CI)

0.33 [0.03, 3.47]

3.10 UDCA (moderate) versus no intervention

4

670

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.62, 1.77]

3.11 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

9.67 [0.45, 207.78]

3.12 Colchicine plus UDCA (moderate) versus UDCA (moderate)

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

5.28 [0.24, 113.87]

3.13 Methotrexate plus UDCA (moderate) versus UDCA (moderate)

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

1.17 [0.55, 2.51]

4 Serious adverse events (proportion) Show forest plot

12

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 2.4
Comparison 2 Stratified by dose, Outcome 4 Serious adverse events (proportion).

Comparison 2 Stratified by dose, Outcome 4 Serious adverse events (proportion).

4.1 Colchicine versus no intervention

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 D‐Penicillamine versus no intervention

1

52

Odds Ratio (M‐H, Fixed, 95% CI)

28.77 [1.57, 526.67]

4.3 Obeticholic acid (high) versus no intervention

1

79

Odds Ratio (M‐H, Fixed, 95% CI)

5.14 [0.57, 46.17]

4.4 Obeticholic acid (low) versus no intervention

1

76

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 8.22]

4.5 Obeticholic acid (moderate) versus no intervention

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

0.79 [0.05, 13.01]

4.6 UDCA (low) versus no intervention

1

18

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.7 UDCA (moderate) versus no intervention

2

362

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.8 UDCA (low) versus bezafibrate

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.9 Obeticholic acid (low) versus obeticholic acid (high)

1

79

Odds Ratio (M‐H, Fixed, 95% CI)

0.09 [0.00, 1.61]

4.10 Obeticholic acid (moderate) versus obeticholic acid (high)

1

89

Odds Ratio (M‐H, Fixed, 95% CI)

0.15 [0.02, 1.37]

4.11 Obeticholic acid (moderate) versus obeticholic acid (low)

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

2.43 [0.10, 61.39]

4.12 Lamivudine plus zidovudine plus UDCA (moderate) versus UDCA (moderate)

1

59

Odds Ratio (M‐H, Fixed, 95% CI)

0.47 [0.04, 5.43]

4.13 UDCA (moderate) versus obeticholic acid (low) plus UDCA (moderate)

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.08, 0.98]

4.14 Bezafibrate plus UDCA (low) versus UDCA (low)

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.15 UDCA (moderate) versus UDCA (low)

1

59

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.16 Colchicine plus UDCA (moderate) versus UDCA (moderate)

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

3.08 [0.12, 78.14]

5 Serious adverse events (number of events) Show forest plot

1

Rate Ratio (Fixed, 95% CI)

Subtotals only
Analysis 2.5
Comparison 2 Stratified by dose, Outcome 5 Serious adverse events (number of events).

Comparison 2 Stratified by dose, Outcome 5 Serious adverse events (number of events).

5.1 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)

1

Rate Ratio (Fixed, 95% CI)

1.66 [0.75, 3.66]

6 Adverse events (proportion) Show forest plot

20

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 2.6
Comparison 2 Stratified by dose, Outcome 6 Adverse events (proportion).

Comparison 2 Stratified by dose, Outcome 6 Adverse events (proportion).

6.1 Cyclosporin versus no intervention

3

390

Odds Ratio (M‐H, Fixed, 95% CI)

3.04 [1.98, 4.68]

6.2 D‐Penicillamine versus no intervention

2

287

Odds Ratio (M‐H, Fixed, 95% CI)

4.51 [2.56, 7.93]

6.3 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

11.43 [1.40, 93.04]

6.4 Obeticholic acid (high) versus no intervention

1

79

Odds Ratio (M‐H, Fixed, 95% CI)

16.6 [0.90, 305.59]

6.5 Obeticholic acid (low) versus no intervention

1

76

Odds Ratio (M‐H, Fixed, 95% CI)

1.59 [0.41, 6.17]

6.6 Obeticholic acid (moderate) versus no intervention

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

8.81 [1.01, 76.73]

6.7 UDCA (low) versus no intervention

1

18

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.8 UDCA (moderate) versus no intervention

2

362

Odds Ratio (M‐H, Fixed, 95% CI)

1.45 [0.50, 4.25]

6.9 Glucocorticosteroids plus UDCA (moderate) versus azathioprine plus UDCA (moderate)

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.12]

6.10 UDCA (low) versus bezafibrate

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.11 Obeticholic acid (low) versus obeticholic acid (high)

1

79

Odds Ratio (M‐H, Fixed, 95% CI)

0.09 [0.00, 1.78]

6.12 Obeticholic acid (moderate) versus obeticholic acid (high)

1

89

Odds Ratio (M‐H, Fixed, 95% CI)

0.38 [0.02, 9.62]

6.13 Obeticholic acid (moderate) versus obeticholic acid (low)

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

5.53 [0.59, 51.70]

6.14 Bezafibrate plus UDCA (low) versus UDCA (low)

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

3.29 [0.12, 89.81]

6.15 Colestilan plus UDCA (low) versus UDCA (low)

1

11

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.16 Methotrexate plus UDCA (low) versus UDCA (low)

1

25

Odds Ratio (M‐H, Fixed, 95% CI)

115.0 [4.98, 2657.48]

6.17 UDCA (moderate) versus UDCA (low)

1

59

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.18 Azathioprine plus UDCA (moderate) versus UDCA (moderate)

1

42

Odds Ratio (M‐H, Fixed, 95% CI)

19.67 [0.94, 413.50]

6.19 Colchicine plus UDCA (moderate) versus UDCA (moderate)

2

42

Odds Ratio (M‐H, Fixed, 95% CI)

6.20 [0.63, 60.80]

6.20 Glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)

2

135

Odds Ratio (M‐H, Fixed, 95% CI)

5.54 [1.35, 22.84]

6.21 TauroUDCA (moderate) versus UDCA (moderate)

1

30

Odds Ratio (M‐H, Fixed, 95% CI)

21.0 [2.16, 204.61]

7 Adverse events (number) Show forest plot

15

Rate Ratio (Fixed, 95% CI)

Subtotals only
Analysis 2.7
Comparison 2 Stratified by dose, Outcome 7 Adverse events (number).

Comparison 2 Stratified by dose, Outcome 7 Adverse events (number).

7.1 Chlorambucil versus no intervention

1

Rate Ratio (Fixed, 95% CI)

3.67 [1.04, 12.87]

7.2 Cyclosporin versus no intervention

3

Rate Ratio (Fixed, 95% CI)

1.87 [1.51, 2.32]

7.3 D‐Penicillamine versus no intervention

3

Rate Ratio (Fixed, 95% CI)

2.64 [1.78, 3.91]

7.4 Malotilate versus no intervention

1

Rate Ratio (Fixed, 95% CI)

6.13 [1.38, 27.14]

7.5 Obeticholic acid (high) versus no intervention

1

Rate Ratio (Fixed, 95% CI)

1.91 [1.50, 2.44]

7.6 Obeticholic acid (low) versus no intervention

1

Rate Ratio (Fixed, 95% CI)

1.05 [0.80, 1.39]

7.7 Obeticholic acid (moderate) versus no intervention

1

Rate Ratio (Fixed, 95% CI)

1.25 [0.97, 1.62]

7.8 Obeticholic acid (low) versus obeticholic acid (high)

1

Rate Ratio (Fixed, 95% CI)

0.55 [0.43, 0.70]

7.9 Obeticholic acid (moderate) versus obeticholic acid (high)

1

Rate Ratio (Fixed, 95% CI)

0.66 [0.53, 0.81]

7.10 Obeticholic acid (moderate) versus obeticholic acid (low)

1

Rate Ratio (Fixed, 95% CI)

1.19 [0.93, 1.53]

7.11 UDCA (low) versus UDCA (high)

1

Rate Ratio (Fixed, 95% CI)

2.08 [0.78, 5.53]

7.12 UDCA (moderate) versus UDCA (high)

1

Rate Ratio (Fixed, 95% CI)

0.73 [0.21, 2.60]

7.13 UDCA (low) plus methotrexate versus UDCA (low)

1

Rate Ratio (Fixed, 95% CI)

30.64 [1.84, 510.76]

7.14 UDCA (moderate) versus UDCA (low)

1

Rate Ratio (Fixed, 95% CI)

0.35 [0.11, 1.10]

7.15 Azathioprine plus glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)

1

Rate Ratio (Fixed, 95% CI)

1.32 [0.88, 1.97]

7.16 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)

1

Rate Ratio (Fixed, 95% CI)

11.79 [0.65, 213.14]

7.17 Colchicine plus UDCA (moderate) versus UDCA (moderate)

1

Rate Ratio (Fixed, 95% CI)

5.91 [0.28, 123.08]

7.18 TauroUDCA (moderate) versus UDCA (moderate)

1

Rate Ratio (Fixed, 95% CI)

1.17 [0.81, 1.71]

8 Liver transplantation Show forest plot

12

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 2.8
Comparison 2 Stratified by dose, Outcome 8 Liver transplantation.

Comparison 2 Stratified by dose, Outcome 8 Liver transplantation.

8.1 Cyclosporin versus no intervention

2

378

Odds Ratio (M‐H, Fixed, 95% CI)

0.86 [0.43, 1.72]

8.2 D‐Penicillamine versus no intervention

1

189

Odds Ratio (M‐H, Fixed, 95% CI)

0.93 [0.06, 15.05]

8.3 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

0.17 [0.02, 1.58]

8.4 UDCA (low) versus no intervention

2

162

Odds Ratio (M‐H, Fixed, 95% CI)

0.99 [0.24, 4.06]

8.5 UDCA (moderate) versus no intervention

3

478

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.44, 1.76]

8.6 UDCA (low) versus UDCA (high)

1

106

Odds Ratio (M‐H, Fixed, 95% CI)

3.17 [0.13, 79.71]

8.7 UDCA (moderate) versus UDCA (high)

1

103

Odds Ratio (M‐H, Fixed, 95% CI)

3.37 [0.13, 84.70]

8.8 UDCA (moderate) versus UDCA (low)

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.06, 17.47]

8.9 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.10 Methotrexate plus UDCA (moderate) versus UDCA (moderate)

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

0.70 [0.35, 1.39]

9 Decompensated liver disease Show forest plot

7

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 2.9
Comparison 2 Stratified by dose, Outcome 9 Decompensated liver disease.

Comparison 2 Stratified by dose, Outcome 9 Decompensated liver disease.

9.1 D‐Penicillamine versus no intervention

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 UDCA (moderate) versus no intervention

2

351

Odds Ratio (M‐H, Fixed, 95% CI)

1.33 [0.84, 2.12]

9.3 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

9.4 UDCA (low) plus colchicine versus UDCA (low)

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

0.21 [0.04, 1.07]

9.5 Azathioprine plus UDCA (moderate) versus UDCA (moderate)

1

42

Odds Ratio (M‐H, Fixed, 95% CI)

0.52 [0.05, 5.18]

9.6 Glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)

1

66

Odds Ratio (M‐H, Fixed, 95% CI)

0.55 [0.11, 2.69]

9.7 Methotrexate plus UDCA (moderate) versus UDCA (moderate)

1

151

Odds Ratio (M‐H, Fixed, 95% CI)

2.00 [0.79, 5.04]

9.8 Glucocorticosteroids plus UDCA (moderate) versus azathioprine plus UDCA (moderate)

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.10, 11.18]

10 Cirrhosis Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only
Analysis 2.10
Comparison 2 Stratified by dose, Outcome 10 Cirrhosis.

Comparison 2 Stratified by dose, Outcome 10 Cirrhosis.

10.1 Azathioprine versus no intervention

1

31

Odds Ratio (M‐H, Fixed, 95% CI)

0.79 [0.18, 3.41]

10.2 UDCA (low) versus no intervention

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

0.15 [0.01, 1.53]

10.3 Azathioprine plus glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.03, 2.90]

Study flow diagram.
Figuras y tablas -
Figure 1

Study flow diagram.

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Trial Sequential Analysis of mortality at maximal follow‐up: azathioprine versus no intervention and colchicine versus no intervention.Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 20%), and diversity observed in the analyses (0%), the accrued sample size (224 for azathioprine versus intervention and 122 for colchicine versus no intervention) was only a small fraction of the diversity adjusted required information size (DARIS) (4580 for both comparisons); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) crossed the conventional boundaries (dotted green line) favouring azathioprine for azathioprine versus no intervention, but did not cross the conventional boundaries for colchicine versus no intervention. This indicates that there is a high risk of random errors in both these comparisons.
Figuras y tablas -
Figure 4

Trial Sequential Analysis of mortality at maximal follow‐up: azathioprine versus no intervention and colchicine versus no intervention.

Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 20%), and diversity observed in the analyses (0%), the accrued sample size (224 for azathioprine versus intervention and 122 for colchicine versus no intervention) was only a small fraction of the diversity adjusted required information size (DARIS) (4580 for both comparisons); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) crossed the conventional boundaries (dotted green line) favouring azathioprine for azathioprine versus no intervention, but did not cross the conventional boundaries for colchicine versus no intervention. This indicates that there is a high risk of random errors in both these comparisons.

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Trial Sequential Analysis of mortality at maximal follow‐up: ciclosporin versus no intervention and D‐penicillamine versus no intervention.Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 20%), and diversity observed in the analyses (82% for ciclosporin versus no intervention and 61% for D‐penicillamine versus no intervention), the accrued sample size (394 for ciclosporin versus no intervention and 423 for D‐penicillamine versus no intervention) was only a small fraction of the diversity adjusted required information size (DARIS) (25,098 for ciclosporin versus no intervention and 11,623 for D‐penicillamine versus no intervention); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) crossed the conventional boundaries (dotted green line) favouring ciclosporin for ciclosporin versus no intervention, but did not cross the conventional boundaries for D‐penicillamine versus no intervention. This indicates that there is a high risk of random errors in both these comparisons.
Figuras y tablas -
Figure 5

Trial Sequential Analysis of mortality at maximal follow‐up: ciclosporin versus no intervention and D‐penicillamine versus no intervention.

Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 20%), and diversity observed in the analyses (82% for ciclosporin versus no intervention and 61% for D‐penicillamine versus no intervention), the accrued sample size (394 for ciclosporin versus no intervention and 423 for D‐penicillamine versus no intervention) was only a small fraction of the diversity adjusted required information size (DARIS) (25,098 for ciclosporin versus no intervention and 11,623 for D‐penicillamine versus no intervention); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) crossed the conventional boundaries (dotted green line) favouring ciclosporin for ciclosporin versus no intervention, but did not cross the conventional boundaries for D‐penicillamine versus no intervention. This indicates that there is a high risk of random errors in both these comparisons.

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Trial Sequential Analysis of mortality at maximal follow‐up: colchicine plus UDCA versus UDCA.Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 7.8%), and diversity observed in the analyses (0%), the accrued sample size (160 participants) was only a small fraction of the diversity adjusted required information size (DARIS) (13,316); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) did not cross the conventional boundaries (green dotted line). This indicates that there is a high risk of random errors in both this comparison.
Figuras y tablas -
Figure 6

Trial Sequential Analysis of mortality at maximal follow‐up: colchicine plus UDCA versus UDCA.

Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 7.8%), and diversity observed in the analyses (0%), the accrued sample size (160 participants) was only a small fraction of the diversity adjusted required information size (DARIS) (13,316); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) did not cross the conventional boundaries (green dotted line). This indicates that there is a high risk of random errors in both this comparison.

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Comparison 1 Main analysis, Outcome 1 Mortality at maximal follow‐up.
Figuras y tablas -
Analysis 1.1

Comparison 1 Main analysis, Outcome 1 Mortality at maximal follow‐up.

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Comparison 1 Main analysis, Outcome 2 Mortality (< 1 year).
Figuras y tablas -
Analysis 1.2

Comparison 1 Main analysis, Outcome 2 Mortality (< 1 year).

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Comparison 1 Main analysis, Outcome 3 Mortality (1 to 5 years).
Figuras y tablas -
Analysis 1.3

Comparison 1 Main analysis, Outcome 3 Mortality (1 to 5 years).

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Comparison 1 Main analysis, Outcome 4 Serious adverse events (proportion).
Figuras y tablas -
Analysis 1.4

Comparison 1 Main analysis, Outcome 4 Serious adverse events (proportion).

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Comparison 1 Main analysis, Outcome 5 Serious adverse events (number of events).
Figuras y tablas -
Analysis 1.5

Comparison 1 Main analysis, Outcome 5 Serious adverse events (number of events).

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Comparison 1 Main analysis, Outcome 6 Adverse events (proportion).
Figuras y tablas -
Analysis 1.6

Comparison 1 Main analysis, Outcome 6 Adverse events (proportion).

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Comparison 1 Main analysis, Outcome 7 Adverse events (number).
Figuras y tablas -
Analysis 1.7

Comparison 1 Main analysis, Outcome 7 Adverse events (number).

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Comparison 1 Main analysis, Outcome 8 Liver transplantation.
Figuras y tablas -
Analysis 1.8

Comparison 1 Main analysis, Outcome 8 Liver transplantation.

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Comparison 1 Main analysis, Outcome 9 Decompensated liver disease.
Figuras y tablas -
Analysis 1.9

Comparison 1 Main analysis, Outcome 9 Decompensated liver disease.

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Comparison 1 Main analysis, Outcome 10 Cirrhosis.
Figuras y tablas -
Analysis 1.10

Comparison 1 Main analysis, Outcome 10 Cirrhosis.

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Comparison 2 Stratified by dose, Outcome 1 Mortality at maximal follow‐up.
Figuras y tablas -
Analysis 2.1

Comparison 2 Stratified by dose, Outcome 1 Mortality at maximal follow‐up.

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Comparison 2 Stratified by dose, Outcome 2 Mortality (< 1 year).
Figuras y tablas -
Analysis 2.2

Comparison 2 Stratified by dose, Outcome 2 Mortality (< 1 year).

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Comparison 2 Stratified by dose, Outcome 3 Mortality (1 to 5 years).
Figuras y tablas -
Analysis 2.3

Comparison 2 Stratified by dose, Outcome 3 Mortality (1 to 5 years).

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Comparison 2 Stratified by dose, Outcome 4 Serious adverse events (proportion).
Figuras y tablas -
Analysis 2.4

Comparison 2 Stratified by dose, Outcome 4 Serious adverse events (proportion).

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Comparison 2 Stratified by dose, Outcome 5 Serious adverse events (number of events).
Figuras y tablas -
Analysis 2.5

Comparison 2 Stratified by dose, Outcome 5 Serious adverse events (number of events).

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Comparison 2 Stratified by dose, Outcome 6 Adverse events (proportion).
Figuras y tablas -
Analysis 2.6

Comparison 2 Stratified by dose, Outcome 6 Adverse events (proportion).

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Comparison 2 Stratified by dose, Outcome 7 Adverse events (number).
Figuras y tablas -
Analysis 2.7

Comparison 2 Stratified by dose, Outcome 7 Adverse events (number).

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Comparison 2 Stratified by dose, Outcome 8 Liver transplantation.
Figuras y tablas -
Analysis 2.8

Comparison 2 Stratified by dose, Outcome 8 Liver transplantation.

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Comparison 2 Stratified by dose, Outcome 9 Decompensated liver disease.
Figuras y tablas -
Analysis 2.9

Comparison 2 Stratified by dose, Outcome 9 Decompensated liver disease.

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Comparison 2 Stratified by dose, Outcome 10 Cirrhosis.
Figuras y tablas -
Analysis 2.10

Comparison 2 Stratified by dose, Outcome 10 Cirrhosis.

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Summary of findings for the main comparison. Ursodeoxycholic acid (UDCA) versus no intervention for primary biliary cholangitis

UDCA versus no intervention for primary biliary cholangitis

Patient or population: people with primary biliary cholangitis

Settings: secondary or tertiary care

Intervention: UDCA

Comparison: no intervention

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

No intervention

UDCA

Mortality at maximal follow‐up

Follow‐up: 12 to 89 months

208 per 1000

206 per 1000
(136 to 301)

OR 0.99
(0.60 to 1.64)

734
(6 trials)

⊕⊝⊝⊝
Very low1,2

Serious adverse events (proportion)

Follow‐up: 12 to 41 months

There were no events in either group

380
(3 trials)

⊕⊝⊝⊝
Very low1,2,3

Serious adverse events (number of events)

None of the trials reported this outcome.

Health‐related quality of life

None of the trials reported this outcome.

*The basis for the assumed risk is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio; UDCA: ursodeoxycholic acid.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias in the trial(s) was high (downgraded by two levels).
2 Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels).

3 There was moderate heterogeneity (downgraded by one level).

Figuras y tablas -
Summary of findings for the main comparison. Ursodeoxycholic acid (UDCA) versus no intervention for primary biliary cholangitis
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Summary of findings 2. Azathioprine versus no intervention for primary biliary cholangitis

Azathioprine versus no intervention for primary biliary cholangitis

Patient or population: people with primary biliary cholangitis

Settings: secondary or tertiary care

Intervention: azathioprine

Comparison: no intervention

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

No intervention

Azathioprine

Mortality at maximal follow‐up

Follow‐up: 63 months in 1 trial and not stated in 1 trial

208 per 1000

128 per 1000
(78 to 205)

OR 0.56
(0.32 to 0.98)

224
(2 trials)

⊕⊝⊝⊝
Very low1,2

Serious adverse events (proportion)

None of the trials reported this outcome.

Serious adverse events (number of events)

None of the trials reported this outcome.

Health‐related quality of life

None of the trials reported this outcome.

*The basis for the assumed risk is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias in the trial(s) was high (downgraded by two levels).
2 Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels).

Figuras y tablas -
Summary of findings 2. Azathioprine versus no intervention for primary biliary cholangitis
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Summary of findings 3. Colchicine versus no intervention for primary biliary cholangitis

Colchicine versus no intervention for primary biliary cholangitis

Patient or population: people with primary biliary cholangitis

Settings: secondary or tertiary care

Intervention: colchicine

Comparison: no intervention

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

No intervention

Colchicine

Mortality at maximal follow‐up

Follow‐up: 12 to 24 months

208 per 1000

168 per 1000
(78 to 327)

OR 0.77
(0.32 to 1.85)

122
(2 trials)

⊕⊝⊝⊝
Very low1,2

Serious adverse events (proportion)

Follow‐up: 12 months

There were no events in either group

64
(1 trial)

⊕⊝⊝⊝
Very low1,2,3

Serious adverse events (number of events)

None of the trials reported this outcome.

Health‐related quality of life

None of the trials reported this outcome.

*The basis for the assumed risk is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias in the trial(s) was high (downgraded by two levels).
2 Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels).

3 There was moderate heterogeneity (downgraded by one level).

Figuras y tablas -
Summary of findings 3. Colchicine versus no intervention for primary biliary cholangitis
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Summary of findings 4. Ciclosporin versus no intervention for primary biliary cholangitis

Ciclosporin versus no intervention for primary biliary cholangitis

Patient or population: people with primary biliary cholangitis

Settings: secondary or tertiary care

Intervention: ciclosporin

Comparison: no intervention

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

No intervention

Ciclosporin

Mortality at maximal follow‐up

Follow‐up: 31 to 35 months

208 per 1000

188 per 1000
(118 to 283)

OR 0.88
(0.51 to 1.50)

390
(3 trials)

⊕⊝⊝⊝
Very low1,2

Serious adverse events (proportion)

None of the trials reported this outcome.

Serious adverse events (number of events)

None of the trials reported this outcome.

Health‐related quality of life

None of the trials reported this outcome.

*The basis for the assumed risk is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias in the trial(s) was high (downgraded by two levels).
2 Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels).

Figuras y tablas -
Summary of findings 4. Ciclosporin versus no intervention for primary biliary cholangitis
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Summary of findings 5. D‐Penicillamine versus no intervention for primary biliary cholangitis

D‐Penicillamine versus no intervention for primary biliary cholangitis

Patient or population: people with primary biliary cholangitis

Settings: secondary or tertiary care

Intervention: D‐penicillamine

Comparison: no intervention

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

No intervention

D‐Penicillamine

Mortality at maximal follow‐up

(Follow‐up 24 to 66 months)

208 per 1000

191 per 1000
(130 to 274)

OR 0.90
(0.57 to 1.44)

423
(5 trials)

⊕⊝⊝⊝
Very low1,2,3

Serious adverse events (proportion)

(Follow‐up 24 months)

4 per 1000

104 per 1000
(6 to 679)

OR 28.77
(1.57 to 526.67)

52
(1 trial)

⊕⊝⊝⊝
Very low1,2,3

Serious adverse events (number of events)

None of the trials reported this outcome.

Health‐related quality of life

None of the trials reported this outcome.

*The basis for the assumed risk is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias in the trial(s) was high (downgraded by two levels).
2 Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels).

3 There was moderate heterogeneity (downgraded by one level).

Figuras y tablas -
Summary of findings 5. D‐Penicillamine versus no intervention for primary biliary cholangitis
Ir a la tabla de la revisión
Summary of findings 6. Colchicine plus ursodeoxycholic acid (UDCA) versus UDCA for primary biliary cholangitis

Colchicine plus UDCA versus UDCA for primary biliary cholangitis

Patient or population: people with primary biliary cholangitis

Settings: secondary or tertiary care

Intervention: colchicine + UDCA

Comparison: UDCA

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

UDCA

Colchicine + UDCA

Mortality at maximal follow‐up

Follow‐up: 24 months in 1 trial; not reported in 1 trial

110 per 1000

185 per 1000
(45 to 524)

OR 1.84
(0.38 to 8.91)

158
(2 trials)

⊕⊝⊝⊝
Very low1,2

Serious adverse events (proportion)

Follow‐up: not stated

14 per 1000

42 per 1000
(2 to 526)

OR 3.08
(0.12 to 78.14)

74
(1 trial)

⊕⊝⊝⊝
Very low1,2,3

Serious adverse events (number of events)

None of the trials reported this outcome.

Health‐related quality of life

None of the trials reported this outcome.

*The basis for the assumed risk is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio; UDCA: ursodeoxycholic acid.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias in the trial(s) was high (downgraded by two levels).
2 Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels).

3 There was moderate heterogeneity (downgraded by one level).

Figuras y tablas -
Summary of findings 6. Colchicine plus ursodeoxycholic acid (UDCA) versus UDCA for primary biliary cholangitis
Ir a la tabla de la revisión
Summary of findings 7. Methotrexate plus ursodeoxycholic acid (UDCA) versus UDCA for primary biliary cholangitis

Methotrexate plus UDCA versus UDCA for primary biliary cholangitis

Patient or population: people with primary biliary cholangitis

Settings: secondary or tertiary care

Intervention: methotrexate + UDCA

Comparison: UDCA

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

UDCA

Methotrexate + UDCA

Mortality at maximal follow‐up

Follow‐up: 11 to 91 months

110 per 1000

126 per 1000
(64 to 237)

OR 1.17
(0.55 to 2.51)

290
(2 trials)

⊕⊝⊝⊝
Very low1,2

Serious adverse events (proportion)

None of the trials reported this outcome.

Serious adverse events (number of events)

None of the trials reported this outcome.

Health‐related quality of life

None of the trials reported this outcome.

*The basis for the assumed risk is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio; UDCA: ursodeoxycholic acid.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Risk of bias in the trial(s) was high (downgraded by two levels).
2 Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels).

3 There was moderate heterogeneity (downgraded by one level).

Figuras y tablas -
Summary of findings 7. Methotrexate plus ursodeoxycholic acid (UDCA) versus UDCA for primary biliary cholangitis
Ir a la tabla de la revisión
Table 1. Characteristics of included studies arranged by comparison

Study name

No participants randomised

Post‐randomisation dropouts

No participants for whom outcome was reported

Intervention(s)

Control

Mean follow‐up period (months)

Smart 1990

20

Not stated

20

Antioxidants

No intervention

Not stated

Christensen 1985

248

63

185

Azathioprine

No intervention

63

Heathcote 1976

45

6

39

Azathioprine

No intervention

Not stated

Hoofnagle 1986

24

0

24

Chlorambucil

No intervention

52

Bodenheimer 1988

57

10

47

Colchicine

No intervention

33

Kaplan 1986

60

3

57

Colchicine

No intervention

24

Warnes 1987

64

Not stated

64*

Colchicine

No intervention

19 (median)

Bobadilla 1994

40

Not stated

40

Colchicine + UDCA

No intervention

12

Lombard 1993

349

0

349

Ciclosporin

No intervention

31 (median)

Minuk 1988

12

0

12

Ciclosporin

No intervention

Not stated

Wiesner 1990

40

11

29

Ciclosporin

No intervention

35 (median)

Dickson 1985

309

82

227

D‐Penicillamine

No intervention

60 (median)

Epstein 1979

98

Not stated

98

D‐Penicillamine

No intervention

66

Macklon 1982

60

0

60

D‐Penicillamine

No intervention

37

Matloff 1982

52

0

52

D‐Penicillamine

No intervention

24

Neuberger 1985

189

Not stated

189

D‐Penicillamine

No intervention

Not stated

Taal 1983

24

Not stated

24

D‐Penicillamine

No intervention

18

Triger 1980

35

Not stated

35

D‐Penicillamine

No intervention

Not stated

Mitchison 1989

36

0

36

Glucocorticosteroids

No intervention

36

Ueno 2005

20

Not stated

20

Lamivudine

No intervention

Not stated

Mitchison 1993

104

3

101

Malotilate

No intervention

25 (median)

Hendrickse 1999

60

Not stated

60

Methotrexate

No intervention

68

Steenbergen 1994

14

Not stated

14

Methotrexate + UDCA

No intervention

24

Mayo 2015

45

3

42

NGM282

No intervention

Not stated

Bowlus 2014

216

Not stated

216

Obeticholic acid

No intervention

12

Hirschfield 2015

165

0

165

Obeticholic acid

No intervention

3

Kowdley 2014a

59

Not stated

59

Obeticholic acid

No intervention

Not stated

Manzillo 1993a

32

Not stated

32

S‐Adenosyl methionine

No intervention

1

Manzillo 1993b

6

Not stated

6

S‐Adenosyl methionine

No intervention

2

Cash 2013

21

8

13

Simvastatin

No intervention

12

Askari 2010

28

0

28

Tetrathiomolybdate

No intervention

Not stated

McCormick 1994

18

0

18

Thalidomide

No intervention

Not stated

Arora 1990

9

Not stated

9

UDCA

No intervention

5

Battezzati 1993

88

2

86

UDCA

No intervention

6

Combes 1995a

151

0

151

UDCA

No intervention

24

Eriksson 1997

116

15

101

UDCA

No intervention

24

Heathcote 1994

222

Not stated

222

UDCA

No intervention

24

Leuschner 1989

20

0

18

UDCA

No intervention

12

Lim 1994

32

Not stated

32

UDCA

No intervention

Not stated

Lindor 1994

180

10

170

UDCA

No intervention

24

Oka 1990

52

7

45

UDCA

No intervention

Not stated

Papatheodoridis 2002

92

6

86

UDCA

No intervention

89

Pares 2000

192

0

192

UDCA

No intervention

41 (median)

Poupon 1991a

149

3

146

UDCA

No intervention

Not stated

Senior 1991

20

1

19

UDCA

No intervention

18

Turner 1994

46

0

46

UDCA

No intervention

24

Goddard 1994

57

Not stated

57

Intervention 1: UDCA
Intervention 2: colchicine
Intervention 3: colchicine + UDCA

No intervention

15

Wolfhagen 1998

50

Not stated

50

Azathioprine + glucocorticosteroids + UDCA

UDCA

12

Iwasaki 2008a

45

Not stated

45

Bezafibrate

UDCA

12

Kurihara 2000

24

Not stated

24

Bezafibrate

UDCA

Not stated

Hosonuma 2015

27

0

27

Bezafibrate + UDCA

UDCA

96

Iwasaki 2008b

22

Not stated

22

Bezafibrate + UDCA

UDCA

12

Kanda 2003

22

0

22

Bezafibrate + UDCA

UDCA

7

Nakai 2000

23

Not stated

23

Bezafibrate + UDCA

UDCA

12

Almasio 2000

90

6

84

Colchicine + UDCA

UDCA

Not stated

Ikeda 1996

22

0

22

Colchicine + UDCA

UDCA

24

Poupon 1996

74

Not stated

74

Colchicine + UDCA

UDCA

24

Raedsch 1993

28

8

20

Colchicine + UDCA

UDCA

24

Yokomori 2001

11

Not stated

11

Colestilan + UDCA

UDCA

Not stated

Liberopoulos 2010

10

Not stated

10

Fenofibrate + UDCA

UDCA

Not stated

Leuschner 1999

40

0

39

Glucocorticosteroids + UDCA

UDCA

24

Rautiainen 2005

77

8

69

Glucocorticosteroids + UDCA

UDCA

36

Gao 2012

79

Not stated

79

Intervention 1: glucocorticosteroids + UDCA
Intervention 2: azathioprine + UDCA

UDCA

Not stated

Mason 2008

59

0

59

Lamivudine + zidovudine + UDCA

UDCA

6

Combes 2005

265

0

265

Methotrexate + UDCA

UDCA

91 (median)

Gonzalezkoch 1997

25

Not stated

25

Methotrexate + UDCA

UDCA

11

Nevens 2016

217

Not stated

216

Obeticholic acid + UDCA

UDCA

12

Ferri 1993

30

0

30

TUDCA

UDCA

6

Ma 2016

199

8

191

TUDCA

UDCA

6

Kaplan 1999

87

2

85

Colchicine

Methotrexate

24

Comparison of doses

Lindor 1997

150

Not stated

150

Intervention 1: UDCA (high)

Intervention 2: UDCA (moderate)

UDCA (low)

12

Angulo 1999a

155

Not stated

155

Intervention 1: UDCA (high)

Intervention 2: UDCA (moderate)

UDCA (low)

12

Van Hoogstraten 1998

61

2

59

UDCA (moderate)

UDCA (low)

Not stated

Mazzarella 2002

42

Not stated

42

UDCA (high)

UDCA (moderate)

72

TUDCA: taurodeoxycholic acid; UDCA: ursodeoxycholic acid.
Figuras y tablas -
Table 1. Characteristics of included studies arranged by comparison
Ir a la tabla de la revisión
Table 2. Risk of bias arranged according to comparisons

Name of studies

Intervention(s)

Control

Random sequence generation

Allocation concealment

Blinding of participants and health professionals

Blinding of outcome assessors

Missing outcome bias

Selective outcome reporting

For‐profit bias

Other bias

Smart 1990

Antioxidants

No intervention

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Christensen 1985

Azathioprine

No intervention

Unclear

Unclear

Low

Low

High

High

High

Low

Heathcote 1976

Azathioprine

No intervention

Unclear

Unclear

High

High

High

High

Low

Low

Hoofnagle 1986

Chlorambucil

No intervention

Low

Low

High

High

Low

Low

Low

Low

Bodenheimer 1988

Colchicine

No intervention

Unclear

Unclear

Low

Low

High

High

High

Low

Kaplan 1986

Colchicine

No intervention

Unclear

Unclear

Unclear

Unclear

High

High

Unclear

Low

Warnes 1987

Colchicine

No intervention

Low

Low

Low

Low

Unclear

Low

Unclear

Low

Bobadilla 1994

Colchicine + UDCA

No intervention

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Lombard 1993

Ciclosporin

No intervention

Unclear

Unclear

Low

Low

Low

Low

High

Low

Minuk 1988

Ciclosporin

No intervention

Unclear

Unclear

Low

Unclear

Unclear

Low

High

Low

Wiesner 1990

Ciclosporin

No intervention

Unclear

Unclear

Low

Low

Unclear

Low

High

Low

Dickson 1985

D‐Penicillamine

No intervention

Low

Low

Low

Low

High

High

High

High

Epstein 1979

D‐Penicillamine

No intervention

Unclear

Unclear

High

High

Unclear

High

Unclear

Low

Macklon 1982

D‐Penicillamine

No intervention

Unclear

Unclear

Unclear

Unclear

Low

Low

Unclear

Low

Matloff 1982

D‐Penicillamine

No intervention

Unclear

Unclear

Unclear

Unclear

Low

Low

High

Low

Neuberger 1985

D‐Penicillamine

No intervention

Unclear

Low

Low

Low

Unclear

High

Unclear

Low

Taal 1983

D‐Penicillamine

No intervention

Unclear

Unclear

Low

Low

Unclear

Low

Unclear

Low

Triger 1980

D‐Penicillamine

No intervention

Unclear

Unclear

Unclear

Unclear

Unclear

High

High

Low

Mitchison 1989

Glucocorticosteroids

No intervention

Low

Low

High

High

Low

High

Unclear

Low

Ueno 2005

Lamivudine

No intervention

Unclear

Unclear

Low

Low

Unclear

High

Unclear

Low

Mitchison 1993

Malotilate

No intervention

Low

Low

Low

Low

High

Low

High

Low

Hendrickse 1999

Methotrexate

No intervention

Low

Low

Unclear

Unclear

Unclear

High

Unclear

Low

Steenbergen 1994

Methotrexate + UDCA

No intervention

Low

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Mayo 2015

NGM282

No intervention

Unclear

Unclear

Unclear

Unclear

High

High

High

Low

Bowlus 2014

Obeticholic acid

No intervention

Unclear

Unclear

Unclear

Unclear

Unclear

High

High

Low

Hirschfield 2015

Obeticholic acid

No intervention

Low

Unclear

Low

Low

Low

High

Unclear

High

Kowdley 2011

Obeticholic acid

No intervention

Unclear

Unclear

Unclear

Unclear

Unclear

High

High

Low

Manzillo 1993a

S‐Adenosyl methionine

No intervention

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Manzillo 1993b

S‐Adenosyl methionine

No intervention

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Cash 2013

Simvastatin

No intervention

Unclear

Low

High

High

High

High

Low

High

Askari 2010

Tetrathiomolybdate

No intervention

Low

Low

Low

Low

Low

High

Low

High

McCormick 1994

Thalidomide

No intervention

Unclear

Unclear

Low

Low

Low

High

High

Low

Arora 1990

UDCA

No intervention

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Battezzati 1993

UDCA

No intervention

Low

Low

Low

Low

High

High

Unclear

Low

Combes 1995a

UDCA

No intervention

Unclear

Unclear

Low

Low

Low

High

High

Low

Eriksson 1997

UDCA

No intervention

Unclear

Unclear

Unclear

Unclear

High

High

High

Low

Heathcote 1994

UDCA

No intervention

Unclear

Low

Low

Low

Unclear

High

High

Low

Leuschner 1989

UDCA

No intervention

Unclear

Unclear

Unclear

Unclear

High

Low

Unclear

Low

Lim 1994

UDCA

No intervention

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Lindor 1994

UDCA

No intervention

Unclear

Unclear

Low

Low

High

Low

High

Low

Oka 1990

UDCA

No intervention

Unclear

Low

Low

Low

High

High

High

Low

Papatheodoridis 2002

UDCA

No intervention

Low

Low

High

High

High

High

High

High

Pares 2000

UDCA

No intervention

Unclear

Unclear

Low

Low

Unclear

Low

High

Low

Poupon 1991a

UDCA

No intervention

Unclear

Unclear

Low

Low

High

High

High

Low

Senior 1991

UDCA

No intervention

Unclear

Unclear

Unclear

Unclear

High

High

High

Low

Turner 1994

UDCA

No intervention

Unclear

Unclear

Low

Low

Low

High

Unclear

Low

Goddard 1994

Intervention 1: UDCA
Intervention 2: colchicine
Intervention 3: colchicine + UDCA

No intervention

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Wolfhagen 1998

Azathioprine + glucocorticosteroids + UDCA

UDCA

Low

Low

Low

Low

Unclear

High

High

Low

Iwasaki 2008a

Bezafibrate

UDCA

Unclear

Low

High

High

Unclear

High

Low

Low

Kurihara 2000

Bezafibrate

UDCA

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Hosonuma 2015

Bezafibrate + UDCA

UDCA

Low

Low

High

High

Low

Low

Low

Low

Iwasaki 2008b

Bezafibrate + UDCA

UDCA

Unclear

Low

High

High

Unclear

High

Low

Low

Kanda 2003

Bezafibrate + UDCA

UDCA

Unclear

Unclear

Unclear

Unclear

Low

High

Unclear

Low

Nakai 2000

Bezafibrate + UDCA

UDCA

Unclear

Unclear

Unclear

Unclear

Unclear

High

Low

Low

Almasio 2000

Colchicine + UDCA

UDCA

Low

Low

Low

Low

High

High

Low

Low

Ikeda 1996

Colchicine + UDCA

UDCA

Unclear

Unclear

Unclear

Unclear

Low

High

Unclear

High

Poupon 1996

Colchicine + UDCA

UDCA

Unclear

Unclear

Low

Low

Unclear

Low

High

Low

Raedsch 1993

Colchicine + UDCA

UDCA

Unclear

Unclear

Unclear

Unclear

High

High

Unclear

Low

Yokomori 2001

Colestilan + UDCA

UDCA

Unclear

Unclear

High

High

Unclear

High

Unclear

Low

Liberopoulos 2010

Fenofibrate + UDCA

UDCA

Unclear

Unclear

High

High

Unclear

High

Unclear

Low

Leuschner 1999

Glucocorticosteroids + UDCA

UDCA

Low

Unclear

Unclear

Unclear

High

High

High

Low

Rautiainen 2005

Glucocorticosteroids + UDCA

UDCA

Unclear

Unclear

High

High

High

High

High

Low

Gao 2012

Glucocorticosteroids + UDCA
Azathioprine + UDCA

UDCA

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Mason 2008

Lamivudine + zidovudine + UDCA

UDCA

Low

Low

Low

Low

Unclear

High

High

Low

Combes 2005

Methotrexate + UDCA

UDCA

Unclear

Unclear

Unclear

Unclear

Low

High

High

Low

Gonzalezkoch 1997

Methotrexate + UDCA

UDCA

Unclear

Low

Unclear

Unclear

Unclear

Low

Unclear

Low

Nevens 2016

Obeticholic acid + UDCA

UDCA

Low

Low

Low

Low

High

Low

High

Low

Ferri 1993

TUDCA

UDCA

Unclear

Unclear

Unclear

Unclear

Low

High

Unclear

Low

Ma 2016

TUDCA

UDCA

Low

Low

Low

Low

Unclear

High

High

Low

Kaplan 1999

Colchicine

Methotrexate

Unclear

Unclear

Low

Low

High

High

Unclear

Low

Comparison of doses

Lindor 1997

Intervention 1: UDCA (high)

Intervention 2: UDCA (moderate)

UDCA (low)

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

Angulo 1999a

Intervention 1: UDCA (high)

Intervention 2: UDCA (moderate)

UDCA (low)

Low

Low

Low

Low

Unclear

Low

Unclear

Low

Van Hoogstraten 1998

UDCA (moderate)

UDCA (low)

Low

Low

High

High

Unclear

High

High

Low

Mazzarella 2002

UDCA (high)

UDCA (moderate)

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

Low

TUDCA: taurodeoxycholic acid; UDCA: ursodeoxycholic acid.
Figuras y tablas -
Table 2. Risk of bias arranged according to comparisons
Ir a la tabla de la revisión
Comparison 1. Main analysis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality at maximal follow‐up Show forest plot

28

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Azathioprine versus no intervention

2

224

Odds Ratio (M‐H, Fixed, 95% CI)

0.56 [0.32, 0.98]

1.2 Chlorambucil versus no intervention

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.28]

1.3 Colchicine versus no intervention

2

122

Odds Ratio (M‐H, Fixed, 95% CI)

0.77 [0.32, 1.85]

1.4 Cyclosporin versus no intervention

3

390

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.51, 1.50]

1.5 D‐Penicillamine versus no intervention

5

423

Odds Ratio (M‐H, Fixed, 95% CI)

0.90 [0.57, 1.44]

1.6 Glucocorticosteroids versus no intervention

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

0.64 [0.14, 2.92]

1.7 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

2.0 [0.47, 8.48]

1.8 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

8.83 [1.01, 76.96]

1.9 UDCA versus no intervention

6

734

Odds Ratio (M‐H, Fixed, 95% CI)

0.99 [0.60, 1.64]

1.10 Bezafibrate plus UDCA versus UDCA

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

9.67 [0.45, 207.78]

1.11 Colchicine plus UDCA versus UDCA

2

158

Odds Ratio (M‐H, Fixed, 95% CI)

1.84 [0.38, 8.91]

1.12 Methotrexate plus UDCA versus UDCA

2

290

Odds Ratio (M‐H, Fixed, 95% CI)

1.17 [0.55, 2.51]

1.13 Obeticholic acid plus UDCA versus UDCA

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

2 Mortality (< 1 year) Show forest plot

8

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Azathioprine versus no intervention

1

39

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.16, 2.10]

2.2 Colchicine versus no intervention

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.86 [0.22, 3.33]

2.3 Cyclosporin versus no intervention

1

12

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.63]

2.4 D‐Penicillamine versus no intervention

1

189

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.35, 1.42]

2.5 Ursodeoxycholic acid (UDCA) versus no intervention

1

18

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.6 Colchicine plus UDCA versus UDCA

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.13, 7.45]

2.7 Methotrexate plus UDCA versus UDCA

1

25

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.8 Obeticholic acid plus UDCA versus UDCA

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

3 Mortality (1 to 5 years) Show forest plot

20

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Azathioprine versus no intervention

1

185

Odds Ratio (M‐H, Fixed, 95% CI)

0.56 [0.30, 1.04]

3.2 Chlorambucil versus no intervention

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.28]

3.3 Colchicine versus no intervention

1

58

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.22, 2.25]

3.4 Cyclosporin versus no intervention

2

378

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.54, 1.64]

3.5 D‐Penicillamine versus no intervention

4

234

Odds Ratio (M‐H, Fixed, 95% CI)

1.10 [0.59, 2.08]

3.6 Glucocorticosteroids versus no intervention

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

0.64 [0.14, 2.92]

3.7 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

2.0 [0.47, 8.48]

3.8 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

8.83 [1.01, 76.96]

3.9 UDCA versus no intervention

5

716

Odds Ratio (M‐H, Fixed, 95% CI)

0.99 [0.60, 1.64]

3.10 Bezafibrate plus UDCA versus UDCA

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

9.67 [0.45, 207.78]

3.11 Colchicine plus UDCA versus UDCA

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

5.28 [0.24, 113.87]

3.12 Methotrexate plus UDCA versus UDCA

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

1.17 [0.55, 2.51]

4 Serious adverse events (proportion) Show forest plot

11

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Colchicine versus no intervention

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 D‐Penicillamine versus no intervention

1

52

Odds Ratio (M‐H, Fixed, 95% CI)

28.77 [1.57, 526.67]

4.3 Obeticholic acid versus no intervention

1

165

Odds Ratio (M‐H, Fixed, 95% CI)

1.83 [0.21, 15.73]

4.4 UDCA versus no intervention

3

380

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.5 UDCA versus bezafibrate

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.6 Bezafibrate plus UDCA versus UDCA

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.7 Colchicine plus UDCA versus UDCA

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

3.08 [0.12, 78.14]

4.8 Lamivudine plus zidovudine plus UDCA versus UDCA

1

59

Odds Ratio (M‐H, Fixed, 95% CI)

0.47 [0.04, 5.43]

4.9 Obeticholic acid plus UDCA versus UDCA

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

3.58 [1.02, 12.51]

5 Serious adverse events (number of events) Show forest plot

1

Rate Ratio (Fixed, 95% CI)

Subtotals only

5.1 Obeticholic acid plus UDCA versus UDCA

1

216

Rate Ratio (Fixed, 95% CI)

1.66 [0.75, 3.66]

6 Adverse events (proportion) Show forest plot

19

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

6.1 Cyclosporin versus no intervention

3

390

Odds Ratio (M‐H, Fixed, 95% CI)

3.04 [1.98, 4.68]

6.2 D‐Penicillamine versus no intervention

2

287

Odds Ratio (M‐H, Fixed, 95% CI)

4.51 [2.56, 7.93]

6.3 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

11.43 [1.40, 93.04]

6.4 Obeticholic acid versus no intervention

1

165

Odds Ratio (M‐H, Fixed, 95% CI)

4.58 [1.31, 15.95]

6.5 UDCA versus no intervention

3

380

Odds Ratio (M‐H, Fixed, 95% CI)

1.45 [0.50, 4.25]

6.6 Azathioprine plus UDCA versus UDCA

1

42

Odds Ratio (M‐H, Fixed, 95% CI)

19.67 [0.94, 413.50]

6.7 Bezafibrate versus UDCA

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.8 Bezafibrate plus UDCA versus UDCA

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

3.29 [0.12, 89.81]

6.9 Colchicine plus UDCA versus UDCA

2

42

Odds Ratio (M‐H, Fixed, 95% CI)

6.20 [0.63, 60.80]

6.10 Colestilan plus UDCA versus UDCA

1

11

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.11 Glucocorticosteroids plus UDCA versus UDCA

2

135

Odds Ratio (M‐H, Fixed, 95% CI)

5.54 [1.35, 22.84]

6.12 Methotrexate plus UDCA versus UDCA

1

25

Odds Ratio (M‐H, Fixed, 95% CI)

115.0 [4.98, 2657.48]

6.13 TauroUDCA versus UDCA

1

30

Odds Ratio (M‐H, Fixed, 95% CI)

21.0 [2.16, 204.61]

6.14 Glucocorticosteroids plus UDCA versus azathioprine plus UDCA

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.12]

7 Adverse events (number) Show forest plot

14

Rate Ratio (Random, 95% CI)

Subtotals only

7.1 Chlorambucil versus no intervention

1

24

Rate Ratio (Random, 95% CI)

3.67 [1.04, 12.87]

7.2 Cyclosporin versus no intervention

3

390

Rate Ratio (Random, 95% CI)

2.58 [1.26, 5.31]

7.3 D‐Penicillamine versus no intervention

3

303

Rate Ratio (Random, 95% CI)

2.99 [1.04, 8.63]

7.4 Malotilate versus no intervention

1

101

Rate Ratio (Random, 95% CI)

6.13 [1.38, 27.14]

7.5 Obeticholic acid versus no intervention

1

76

Rate Ratio (Random, 95% CI)

1.41 [1.13, 1.75]

7.6 Azathioprine plus glucocorticosteroids plus UDCA versus UDCA

1

50

Rate Ratio (Random, 95% CI)

1.32 [0.88, 1.97]

7.7 Bezafibrate plus UDCA versus UDCA

1

29

Rate Ratio (Random, 95% CI)

11.79 [0.65, 213.14]

7.8 Colchicine plus UDCA versus UDCA

1

24

Rate Ratio (Random, 95% CI)

5.91 [0.28, 123.08]

7.9 Methotrexate plus UDCA versus UDCA

1

27

Rate Ratio (Random, 95% CI)

30.64 [1.84, 510.76]

7.10 TauroUDCA versus UDCA

1

191

Rate Ratio (Random, 95% CI)

1.17 [0.81, 1.71]

8 Liver transplantation Show forest plot

11

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

8.1 Cyclosporin versus no intervention

2

378

Odds Ratio (M‐H, Fixed, 95% CI)

0.86 [0.43, 1.72]

8.2 D‐Penicillamine versus no intervention

1

189

Odds Ratio (M‐H, Fixed, 95% CI)

0.93 [0.06, 15.05]

8.3 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

0.17 [0.02, 1.58]

8.4 UDCA versus no intervention

5

640

Odds Ratio (M‐H, Fixed, 95% CI)

0.90 [0.48, 1.68]

8.5 Bezafibrate plus UDCA versus UDCA

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.6 Methotrexate plus UDCA versus UDCA

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

0.70 [0.35, 1.39]

9 Decompensated liver disease Show forest plot

7

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

9.1 D‐Penicillamine versus no active treatment

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 UDCA versus no intervention

2

237

Odds Ratio (M‐H, Fixed, 95% CI)

1.60 [0.86, 2.98]

9.3 Azathioprine plus UDCA versus UDCA

1

42

Odds Ratio (M‐H, Fixed, 95% CI)

0.52 [0.05, 5.18]

9.4 Colchicine plus UDCA versus UDCA

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

0.21 [0.04, 1.07]

9.5 Glucocorticosteroids plus UDCA versus UDCA

1

66

Odds Ratio (M‐H, Fixed, 95% CI)

0.55 [0.11, 2.69]

9.6 Methotrexate plus UDCA versus UDCA

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

1.34 [0.77, 2.33]

9.7 Obeticholic acid plus UDCA versus UDCA

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

9.8 Glucocorticosteroids plus UDCA versus azathioprine plus UDCA

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.10, 11.18]

10 Cirrhosis Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

10.1 Azathioprine versus no intervention

1

31

Odds Ratio (M‐H, Fixed, 95% CI)

0.79 [0.18, 3.41]

10.2 UDCA versus no intervention

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

0.15 [0.01, 1.53]

10.3 Azathioprine plus glucocorticosteroids plus UDCA versus UDCA

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.03, 2.90]
Figuras y tablas -
Comparison 1. Main analysis
Ir a la tabla de la revisión
Comparison 2. Stratified by dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality at maximal follow‐up Show forest plot

29

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Azathioprine versus no intervention

2

224

Odds Ratio (M‐H, Fixed, 95% CI)

0.56 [0.32, 0.98]

1.2 Chlorambucil versus no intervention

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.28]

1.3 Colchicine versus no intervention

2

122

Odds Ratio (M‐H, Fixed, 95% CI)

0.77 [0.32, 1.85]

1.4 Cyclosporin versus no intervention

3

390

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.51, 1.50]

1.5 D‐Penicillamine versus no intervention

5

423

Odds Ratio (M‐H, Fixed, 95% CI)

0.90 [0.57, 1.44]

1.6 Glucocorticosteroids versus no intervention

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

0.64 [0.14, 2.92]

1.7 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

2.0 [0.47, 8.48]

1.8 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

8.83 [1.01, 76.96]

1.9 UDCA (low) versus no intervention

2

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.33 [0.03, 3.47]

1.10 UDCA (moderate) versus no intervention

4

670

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.62, 1.77]

1.11 UDCA (low) versus UDCA (high)

1

106

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.06, 17.06]

1.12 UDCA (moderate) versus UDCA (high)

1

103

Odds Ratio (M‐H, Fixed, 95% CI)

0.36 [0.01, 9.05]

1.13 UDCA (low) plus colchicine versus UDCA (low)

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.13, 7.45]

1.14 UDCA (low) plus methotrexate versus UDCA (low)

1

25

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.15 UDCA (moderate) versus UDCA (low)

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

0.35 [0.01, 8.72]

1.16 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

9.67 [0.45, 207.78]

1.17 Colchicine plus UDCA (moderate) versus UDCA (moderate)

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

5.28 [0.24, 113.87]

1.18 Methotrexate plus UDCA (moderate) versus UDCA (moderate)

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

1.17 [0.55, 2.51]

1.19 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

2 Mortality (< 1 year) Show forest plot

9

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Azathioprine versus no intervention

1

39

Odds Ratio (M‐H, Fixed, 95% CI)

0.58 [0.16, 2.10]

2.2 Colchicine versus no intervention

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.86 [0.22, 3.33]

2.3 Cyclosporin versus no intervention

1

12

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.63]

2.4 D‐Penicillamine versus no intervention

1

189

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.35, 1.42]

2.5 UDCA (low) versus no intervention

1

18

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.6 UDCA (low) versus UDCA (high)

1

106

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.06, 17.06]

2.7 UDCA (moderate) versus UDCA (high)

1

103

Odds Ratio (M‐H, Fixed, 95% CI)

0.36 [0.01, 9.05]

2.8 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

2.9 UDCA (low) plus colchicine versus UDCA (low)

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

1.0 [0.13, 7.45]

2.10 UDCA (low) plus methotrexate versus UDCA (low)

1

25

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.11 UDCA (moderate) versus UDCA (low)

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

0.35 [0.01, 8.72]

3 Mortality (1 to 5 years) Show forest plot

20

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Azathioprine versus no intervention

1

185

Odds Ratio (M‐H, Fixed, 95% CI)

0.56 [0.30, 1.04]

3.2 Chlorambucil versus no intervention

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 3.28]

3.3 Colchicine versus no intervention

1

58

Odds Ratio (M‐H, Fixed, 95% CI)

0.71 [0.22, 2.25]

3.4 Cyclosporin versus no intervention

2

378

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.54, 1.64]

3.5 D‐Penicillamine versus no intervention

4

234

Odds Ratio (M‐H, Fixed, 95% CI)

1.10 [0.59, 2.08]

3.6 Glucocorticosteroids versus no intervention

1

36

Odds Ratio (M‐H, Fixed, 95% CI)

0.64 [0.14, 2.92]

3.7 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

2.0 [0.47, 8.48]

3.8 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

8.83 [1.01, 76.96]

3.9 UDCA (low) versus no intervention

1

46

Odds Ratio (M‐H, Fixed, 95% CI)

0.33 [0.03, 3.47]

3.10 UDCA (moderate) versus no intervention

4

670

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.62, 1.77]

3.11 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

9.67 [0.45, 207.78]

3.12 Colchicine plus UDCA (moderate) versus UDCA (moderate)

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

5.28 [0.24, 113.87]

3.13 Methotrexate plus UDCA (moderate) versus UDCA (moderate)

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

1.17 [0.55, 2.51]

4 Serious adverse events (proportion) Show forest plot

12

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Colchicine versus no intervention

1

64

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 D‐Penicillamine versus no intervention

1

52

Odds Ratio (M‐H, Fixed, 95% CI)

28.77 [1.57, 526.67]

4.3 Obeticholic acid (high) versus no intervention

1

79

Odds Ratio (M‐H, Fixed, 95% CI)

5.14 [0.57, 46.17]

4.4 Obeticholic acid (low) versus no intervention

1

76

Odds Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 8.22]

4.5 Obeticholic acid (moderate) versus no intervention

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

0.79 [0.05, 13.01]

4.6 UDCA (low) versus no intervention

1

18

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.7 UDCA (moderate) versus no intervention

2

362

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.8 UDCA (low) versus bezafibrate

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.9 Obeticholic acid (low) versus obeticholic acid (high)

1

79

Odds Ratio (M‐H, Fixed, 95% CI)

0.09 [0.00, 1.61]

4.10 Obeticholic acid (moderate) versus obeticholic acid (high)

1

89

Odds Ratio (M‐H, Fixed, 95% CI)

0.15 [0.02, 1.37]

4.11 Obeticholic acid (moderate) versus obeticholic acid (low)

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

2.43 [0.10, 61.39]

4.12 Lamivudine plus zidovudine plus UDCA (moderate) versus UDCA (moderate)

1

59

Odds Ratio (M‐H, Fixed, 95% CI)

0.47 [0.04, 5.43]

4.13 UDCA (moderate) versus obeticholic acid (low) plus UDCA (moderate)

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.08, 0.98]

4.14 Bezafibrate plus UDCA (low) versus UDCA (low)

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.15 UDCA (moderate) versus UDCA (low)

1

59

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.16 Colchicine plus UDCA (moderate) versus UDCA (moderate)

1

74

Odds Ratio (M‐H, Fixed, 95% CI)

3.08 [0.12, 78.14]

5 Serious adverse events (number of events) Show forest plot

1

Rate Ratio (Fixed, 95% CI)

Subtotals only

5.1 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)

1

Rate Ratio (Fixed, 95% CI)

1.66 [0.75, 3.66]

6 Adverse events (proportion) Show forest plot

20

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

6.1 Cyclosporin versus no intervention

3

390

Odds Ratio (M‐H, Fixed, 95% CI)

3.04 [1.98, 4.68]

6.2 D‐Penicillamine versus no intervention

2

287

Odds Ratio (M‐H, Fixed, 95% CI)

4.51 [2.56, 7.93]

6.3 Malotilate versus no intervention

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

11.43 [1.40, 93.04]

6.4 Obeticholic acid (high) versus no intervention

1

79

Odds Ratio (M‐H, Fixed, 95% CI)

16.6 [0.90, 305.59]

6.5 Obeticholic acid (low) versus no intervention

1

76

Odds Ratio (M‐H, Fixed, 95% CI)

1.59 [0.41, 6.17]

6.6 Obeticholic acid (moderate) versus no intervention

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

8.81 [1.01, 76.73]

6.7 UDCA (low) versus no intervention

1

18

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.8 UDCA (moderate) versus no intervention

2

362

Odds Ratio (M‐H, Fixed, 95% CI)

1.45 [0.50, 4.25]

6.9 Glucocorticosteroids plus UDCA (moderate) versus azathioprine plus UDCA (moderate)

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.12]

6.10 UDCA (low) versus bezafibrate

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.11 Obeticholic acid (low) versus obeticholic acid (high)

1

79

Odds Ratio (M‐H, Fixed, 95% CI)

0.09 [0.00, 1.78]

6.12 Obeticholic acid (moderate) versus obeticholic acid (high)

1

89

Odds Ratio (M‐H, Fixed, 95% CI)

0.38 [0.02, 9.62]

6.13 Obeticholic acid (moderate) versus obeticholic acid (low)

1

86

Odds Ratio (M‐H, Fixed, 95% CI)

5.53 [0.59, 51.70]

6.14 Bezafibrate plus UDCA (low) versus UDCA (low)

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

3.29 [0.12, 89.81]

6.15 Colestilan plus UDCA (low) versus UDCA (low)

1

11

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.16 Methotrexate plus UDCA (low) versus UDCA (low)

1

25

Odds Ratio (M‐H, Fixed, 95% CI)

115.0 [4.98, 2657.48]

6.17 UDCA (moderate) versus UDCA (low)

1

59

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

6.18 Azathioprine plus UDCA (moderate) versus UDCA (moderate)

1

42

Odds Ratio (M‐H, Fixed, 95% CI)

19.67 [0.94, 413.50]

6.19 Colchicine plus UDCA (moderate) versus UDCA (moderate)

2

42

Odds Ratio (M‐H, Fixed, 95% CI)

6.20 [0.63, 60.80]

6.20 Glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)

2

135

Odds Ratio (M‐H, Fixed, 95% CI)

5.54 [1.35, 22.84]

6.21 TauroUDCA (moderate) versus UDCA (moderate)

1

30

Odds Ratio (M‐H, Fixed, 95% CI)

21.0 [2.16, 204.61]

7 Adverse events (number) Show forest plot

15

Rate Ratio (Fixed, 95% CI)

Subtotals only

7.1 Chlorambucil versus no intervention

1

Rate Ratio (Fixed, 95% CI)

3.67 [1.04, 12.87]

7.2 Cyclosporin versus no intervention

3

Rate Ratio (Fixed, 95% CI)

1.87 [1.51, 2.32]

7.3 D‐Penicillamine versus no intervention

3

Rate Ratio (Fixed, 95% CI)

2.64 [1.78, 3.91]

7.4 Malotilate versus no intervention

1

Rate Ratio (Fixed, 95% CI)

6.13 [1.38, 27.14]

7.5 Obeticholic acid (high) versus no intervention

1

Rate Ratio (Fixed, 95% CI)

1.91 [1.50, 2.44]

7.6 Obeticholic acid (low) versus no intervention

1

Rate Ratio (Fixed, 95% CI)

1.05 [0.80, 1.39]

7.7 Obeticholic acid (moderate) versus no intervention

1

Rate Ratio (Fixed, 95% CI)

1.25 [0.97, 1.62]

7.8 Obeticholic acid (low) versus obeticholic acid (high)

1

Rate Ratio (Fixed, 95% CI)

0.55 [0.43, 0.70]

7.9 Obeticholic acid (moderate) versus obeticholic acid (high)

1

Rate Ratio (Fixed, 95% CI)

0.66 [0.53, 0.81]

7.10 Obeticholic acid (moderate) versus obeticholic acid (low)

1

Rate Ratio (Fixed, 95% CI)

1.19 [0.93, 1.53]

7.11 UDCA (low) versus UDCA (high)

1

Rate Ratio (Fixed, 95% CI)

2.08 [0.78, 5.53]

7.12 UDCA (moderate) versus UDCA (high)

1

Rate Ratio (Fixed, 95% CI)

0.73 [0.21, 2.60]

7.13 UDCA (low) plus methotrexate versus UDCA (low)

1

Rate Ratio (Fixed, 95% CI)

30.64 [1.84, 510.76]

7.14 UDCA (moderate) versus UDCA (low)

1

Rate Ratio (Fixed, 95% CI)

0.35 [0.11, 1.10]

7.15 Azathioprine plus glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)

1

Rate Ratio (Fixed, 95% CI)

1.32 [0.88, 1.97]

7.16 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)

1

Rate Ratio (Fixed, 95% CI)

11.79 [0.65, 213.14]

7.17 Colchicine plus UDCA (moderate) versus UDCA (moderate)

1

Rate Ratio (Fixed, 95% CI)

5.91 [0.28, 123.08]

7.18 TauroUDCA (moderate) versus UDCA (moderate)

1

Rate Ratio (Fixed, 95% CI)

1.17 [0.81, 1.71]

8 Liver transplantation Show forest plot

12

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

8.1 Cyclosporin versus no intervention

2

378

Odds Ratio (M‐H, Fixed, 95% CI)

0.86 [0.43, 1.72]

8.2 D‐Penicillamine versus no intervention

1

189

Odds Ratio (M‐H, Fixed, 95% CI)

0.93 [0.06, 15.05]

8.3 Methotrexate versus no intervention

1

60

Odds Ratio (M‐H, Fixed, 95% CI)

0.17 [0.02, 1.58]

8.4 UDCA (low) versus no intervention

2

162

Odds Ratio (M‐H, Fixed, 95% CI)

0.99 [0.24, 4.06]

8.5 UDCA (moderate) versus no intervention

3

478

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.44, 1.76]

8.6 UDCA (low) versus UDCA (high)

1

106

Odds Ratio (M‐H, Fixed, 95% CI)

3.17 [0.13, 79.71]

8.7 UDCA (moderate) versus UDCA (high)

1

103

Odds Ratio (M‐H, Fixed, 95% CI)

3.37 [0.13, 84.70]

8.8 UDCA (moderate) versus UDCA (low)

1

101

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.06, 17.47]

8.9 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)

1

27

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.10 Methotrexate plus UDCA (moderate) versus UDCA (moderate)

1

265

Odds Ratio (M‐H, Fixed, 95% CI)

0.70 [0.35, 1.39]

9 Decompensated liver disease Show forest plot

7

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

9.1 D‐Penicillamine versus no intervention

1

24

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

9.2 UDCA (moderate) versus no intervention

2

351

Odds Ratio (M‐H, Fixed, 95% CI)

1.33 [0.84, 2.12]

9.3 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)

1

216

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [0.06, 38.46]

9.4 UDCA (low) plus colchicine versus UDCA (low)

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

0.21 [0.04, 1.07]

9.5 Azathioprine plus UDCA (moderate) versus UDCA (moderate)

1

42

Odds Ratio (M‐H, Fixed, 95% CI)

0.52 [0.05, 5.18]

9.6 Glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)

1

66

Odds Ratio (M‐H, Fixed, 95% CI)

0.55 [0.11, 2.69]

9.7 Methotrexate plus UDCA (moderate) versus UDCA (moderate)

1

151

Odds Ratio (M‐H, Fixed, 95% CI)

2.00 [0.79, 5.04]

9.8 Glucocorticosteroids plus UDCA (moderate) versus azathioprine plus UDCA (moderate)

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

1.06 [0.10, 11.18]

10 Cirrhosis Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

10.1 Azathioprine versus no intervention

1

31

Odds Ratio (M‐H, Fixed, 95% CI)

0.79 [0.18, 3.41]

10.2 UDCA (low) versus no intervention

1

22

Odds Ratio (M‐H, Fixed, 95% CI)

0.15 [0.01, 1.53]

10.3 Azathioprine plus glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)

1

50

Odds Ratio (M‐H, Fixed, 95% CI)

0.28 [0.03, 2.90]
Figuras y tablas -
Comparison 2. Stratified by dose
Ir a la tabla de la revisión