Scolaris Content Display Scolaris Content Display

Intervenciones farmacológicas para la colangitis esclerosante primaria

Collapse all Expand all

References

References to studies included in this review

Allison 1986 {published data only}

Allison MC, Burroughs AK, Noone P, Summerfield JA. Biliary lavage with corticosteroids in primary sclerosing cholangitis. A clinical, cholangiographic and bacteriological study. Journal of Hepatology 1986;3(1):118‐22. CENTRAL

Bansi 1996 {published data only}

Bansi D, Christie J, Fleming K, Chapman R. High‐dose ursodeoxycholic acid in primary sclerosing cholangitis: a randomised double‐blind placebo‐controlled trial. Gastroenterology 1996;110(4):A1146. CENTRAL
Bansi D, Christie J, Fleming K, Chapman R. High‐dose ursodeoxycholic acid in primary sclerosing cholangitis: a randomised double‐blind, placebo‐controlled trial. Gut 1996;38(Suppl 1):A54. CENTRAL

Beuers 1992 {published data only}

Beuers U, Spengler U, Kruis W, Aydemir U, Wiebecke B, Heldwein W, et al. Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo‐controlled trial. Hepatology 1992;16(3):707‐14. CENTRAL
Beuers U, Spengler U, Kruis W, Aydemir Û, Heldwein W, Weinzierl M, et al. Effect of ursodeoxycholic acid in primary sclerosing cholangitis: a controlled trial [abstract]. Hepatology 1991;14(4 Pt 2):64a. CENTRAL
Spengler U, Beuers U, Kruis W, et al. Ursodeoxycholic acid in primary sclerosing cholangitis. Bile Acids and the Hepatobiliary System From Basic Science to Clinical Practice Proceedings of Falk Symposium 68th Held in Basel, Switzerland, October 12‐14, 1992.. 1993:316‐22. CENTRAL

Cullen 2008 {published data only}

Beuers U, Cullen SN, Fleming K, Rust C, Chapman RW. Tolerance and efficacy of a high‐dose treatment with urosodeoxycholic acid in primary sclerosing cholangitis. A double‐blind randomised, placebo‐controlled dose‐finding study. Zeitschrift fur Gastroenterologie 2006;44(8):760. CENTRAL
Cullen SN, Rust C, Fleming K, Beuers U, Chapman RW. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. Journal of Hepatology 2006;44(2 Suppl):S235‐6. CENTRAL
Cullen SN, Rust C, Fleming K, Edwards C, Beuers U, Chapman RW. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. Journal of Hepatology 2008;48(5):792‐800. CENTRAL

De Maria 1996 {published data only}

De Maria N, Colantoni A, Rosenbloom E, Van Thiel DH. Ursodeoxycholic acid does not improve the clinical course of primary sclerosing cholangitis over a 2‐year period. Hepatogastroenterology 1996;43(12):1472‐9. CENTRAL

Farkkila 2004 {published data only}

Farkkila M, Karvonen AL, Nurmi H, Nuutinen H, Taavitsainen M, Pikkarainen P, et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo‐controlled trial. Hepatology 2004;40(6):1379‐86. CENTRAL

Hommes 2008 {published data only}

Hommes DW, Erkelens W, Ponsioen C, Stokkers P, Rauws E, Spek M, et al. A double‐blind, placebo‐controlled, randomized study of infliximab in primary sclerosing cholangitis. Journal of Clinical Gastroenterology 2008;42(5):522‐6. CENTRAL

Knox 1994 {published data only}

Knox TA, Kaplan MM. A double‐blind controlled trial of oral‐pulse methotrexate therapy in the treatment of primary sclerosing cholangitis. Gastroenterology 1994;106(2):494‐9. CENTRAL

LaRusso 1988 {published data only}

LaRusso N, Wiesner R, Ludwig J, MacCarty R, Beaver S, Zinsmeister A, et al. Randomized trial of penicillamine in primary sclerosing cholangitis. Hepatology 1986;6(5):1205. CENTRAL
LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL, Beaver SJ, Zinsmeister AR. Prospective trial of penicillamine in primary sclerosing cholangitis. Gastroenterology 1988;95(4):1036‐42. CENTRAL

Lindor 1997 {published data only}

Hilscher M, Tabibian JH, Enders FB, Carey EJ, Lindor KD. Long‐term follow‐up of a multicenter, randomized controlled trial of ursodeoxycholic acid in primary sclerosing cholangitis. Hepatology 2015;62:509A. CENTRAL
Lindor KD. A randomized trial of ursodeoxycholic acid (UDCA) in the treatment of primary sclerosing cholangitis (PSC). Gastroenterology 1996;110(4):A1252. CENTRAL
Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis‐Ursodeoxycholic Acid Study Group. The New England Journal of Medicine 1997;336(10):691‐5. CENTRAL
Pardi DS, Loftus EV, Kremers WK, Keach J, Lindor KD. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003;124(4):889‐93. CENTRAL

Lindor 2009 {published data only}

Eaton JE, Silveira MG, Pardi DS, Sinakos E, Kowdley KV, Luketic VA, et al. High‐dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. The American Journal of Gastroenterology 2011;106(9):1638‐45. CENTRAL
Lindor KD, Enders FB, Schmoll JA, Hoskin TL, Jorgensen RL, Petz JL. Randomized, double‐blind controlled trial of high‐dose ursodeoxycholic acid (UCDA) for primary sclerosing cholangitis (PSC). Hepatology 2008;48(4Suppl):378a. CENTRAL
Lindor KD, Kowdley KV, Luketic VAC, Harrison ME, McCashland T, Befeler AS, et al. High‐dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50(3):808‐14. CENTRAL
Sinakos E, Marshall HU, Kowdley KV, Befler A, Keach J, Lindor K. Bile acid changes after high‐dose ursodeoxycholic acid treatment in primary sclerosing cholangitis: relation to disease progression. Hepatology 2010;52:197‐203. CENTRAL

Lo 1992 {published data only}

Lo SK, Herrmann R, Chapman RW, Fleming KA, Shearman J, Cusick P, et al. Ursodeoxycholic acid in primary sclerosing cholangitis: a double‐blind placebo controlled trial. Hepatology 1992;16(2 Pt 2):92a. CENTRAL

Mitchell 2001 {published data only}

Mitchell S, Bansi D, Hunt N, Christie J, Fleming K, Chapman R. High dose ursodeoxycholic acid (UDCA) in primary sclerosing cholangitis (PSC): results after two years of a randomised double‐blind, placebo‐controlled trial. Gastroenterology 1997;112(4):A1335. CENTRAL
Mitchell SA, Bansi D, Hunt N, Christie J, Fleming K, Chapman R. High dose ursodeoxycholic acid (UDCA) in primary sclerosing cholangitis (PSC): results after two years of a randomised double‐blind, placebo‐controlled trial. Gut 1997;40(Suppl 1):A29. CENTRAL
Mitchell SA, Bansi DS, Hunt N, Bergmann K, Fleming KA, Chapman RW. A preliminary trial of high‐dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology 2001;121(4):900‐7. CENTRAL

Olsson 1995 {published data only}

Olsson R, Broome U, Danielsson A, Hagerstrand I, Jarnerot G, Loof L, et al. Colchicine treatment of primary sclerosing cholangitis. Gastroenterology 1995;108(4):1199‐203. CENTRAL

Olsson 2005 {published data only}

Lindstrom L, Boberg KM, Friis‐Liby I, Hultcrantz RW, Bergquist A. A reduction in alkaline phosphatase levels is associated to improved prognosis in primary sclerosing cholangitis: a 14 year follow up of the Scandinavian ursodeoxycholic acid trial. Hepatology 2012;56:247a. CENTRAL
Lindstrom L, Boberg KM, Wikman O, Friis‐Liby I, Hultcrantz R, Prytz H, et al. High dose ursodeoxycholic acid in primary sclerosing cholangitis does not prevent colorectal neoplasia. Alimentary Pharmacology and Therapeutics 2012;35(4):451‐7. CENTRAL
Olsson R, Boberg KM, De Muckadell OS, Lindgren S, Hultcrantz R, Folvik G, et al. High‐dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5‐year multicenter, randomized, controlled study. Gastroenterology 2005;129(5):1464‐72. CENTRAL
Olsson RG, Boberg KM, Schaffalitzky de Muckadel O, Lindgren S, Hultcrantz R, Folvik G, et al. Five‐year treatment with high‐dose UDCA in PSC. Journal of Hepatology 2004;40(Suppl 1):161. CENTRAL

Rahimpour 2016 {published data only}

Rahimpour S, Nasiri‐Toosi M, Khalili H, Daryani NE, Taromlou MKN, Azizi Z. A triple blinded, randomized, placebo‐controlled clinical trial to evaluate the efficacy and safety of oral vancomycin in primary sclerosing cholangitis: a pilot study. Journal of Gastrointestinal and Liver Diseases 2016;25(4):457‐64. CENTRAL

Rasmussen 1998 {published data only}

Rasmussen HH, Tage‐Jensen U, Vyberg M, Schlichting P, Schaffalitzky de Mucadell O, Bonnevie O. Methotrexate for treatment of primary sclerosing cholangitis. Journal of Hepatology 1998;28(1 Suppl 1):128. CENTRAL

Sandborn 1993 {published data only}

Sandborn WJ, Wiesner RH, Tremaine WJ, Larusso NF. Ulcerative colitis disease activity following treatment of associated primary sclerosing cholangitis with cyclosporin. Gut 1993;34(2):242‐6. CENTRAL
Wiesner RH, Steiner B, LaRusso NF, Lindor KD, Baldus WP. A controlled clinical trial evaluating cyclosporine in the treatment of primary sclerosing cholangitis. Hepatology1991; Vol. 14, issue 4 Pt 2:63a. CENTRAL

Sterling 2004 {published data only}

Sterlin RK, Salvatori JJ, Luketic VA, Sanyal AJ, Stravitz RT, Fulcher AS, et al. A prospective, randomized controlled pilot study of ursodeoxycholic acid (UDCA) combined with mycophenolate mofetil (MMF) in the treatment of primary sclerosing cholangitis. Hepatology 2003;38(4 Suppl 1):204a. CENTRAL
Sterling RK, Salvatori JJ, Luketic VA, Sanyal AJ, Fulcher AS, Stravitz RT, et al. A prospective, randomized‐controlled pilot study of ursodeoxycholic acid combined with mycophenolate mofetil in the treatment of primary sclerosing cholangitis. Alimentary Pharmacology and Therapeutics 2004;20(9):943‐9. CENTRAL

Stiehl 1989 {published data only}

Stiehl A, Raedsch R, Rudolph G, Theilmann L. Treatment of primary sclerosing cholangitis with ursodeoxycholic acid: first results of a controlled study. Hepatology 1989;10(4):602. CENTRAL

Tabibian 2013 {published data only}

Tabibian JH, Lindor KD. Long‐term outcomes following a randomized study of oral antibiotics in primary sclerosing cholangitis. Gastroenterology 2016;150(4 Suppl 1):S1069‐S70. CENTRAL
Tabibian JH, Weeding E, Jorgensen RA, Petz JL, Keach JC, Talwalkar JA, et al. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis ‐ a pilot study. Alimentary Pharmacology and Therapeutics 2013;37(6):604‐12. CENTRAL

Trauner 2016 {published data only}

Trauner MH, Fickert P, Hirschfield G, Denk G, Altorjay I, Marschall HU, et al. Norursodeoxycholic acid (NORUDCA) improves cholestasis in primary sclerosing cholangitis (PSC) independent of ursodeoxycholic acid (UDCA) pre‐treatment and response. Hepatology 2016;64(Suppl 1):111A. CENTRAL

References to studies excluded from this review

Beuers 1998 {published data only}

Beuers U, Sackmann FM. Treatment of primary sclerosing cholangitis: drug, endoscopic, combined or no treatment at all?. Zeitschrift für Gastroenterologie 1998;36(2):189‐91. CENTRAL

Chapman 2005 {published data only}

Chapman RW. High‐dose ursodeoxycholic acid in the management of primary sclerosing cholangitis. Bile Acid Biology and Its Therapeutic Implications 2005;141:230‐41. CENTRAL

Chapman 2009 {published data only}

Chapman RW. High‐dose ursodeoxycholic acid in the treatment of primary sclerosing cholangitis: throwing the urso out with the bathwater?. Hepatology 2009;50(3):671‐3. CENTRAL

Eisenburg 1997 {published data only}

Eisenburg J. Primary sclerosing cholangitis. Ursodeoxycholic acid is without clinical effect. Fortschritte der Medizin 1997;115(18):7‐8. CENTRAL

Fromm 1992 {published data only}

Fromm H. New treatment for primary sclerosing cholangitis: promising results with ursodiol. Gastroenterology 1992;103(1):343‐4. CENTRAL

Goldberg 1992 {published data only}

Goldberg E, Gerdes H. Primary sclerosing cholangitis: is medical therapy on the way?. Gastroenterology 1992;102(2):729‐31. CENTRAL

Gross 1993 {published data only}

Gross JB. Promises, promises: ursodeoxycholic acid for primary sclerosing cholangitis. Gastroenterology 1993;104(3):941‐3. CENTRAL

Harnois 2001 {published data only}

Harnois DM, Angulo P, Jorgensen RA, Larusso NF, Lindor KD. High‐dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis. The American Journal of Gastroenterology 2001;96(5):1558‐62. CENTRAL

Hay 2001 {published data only}

Hay JE, Malinchoc M, Dickson ER. A controlled trial of calcitonin therapy for the prevention of post‐liver transplantation atraumatic fractures in patients with primary biliary cirrhosis and primary sclerosing cholangitis. Journal of Hepatology 2001;34(2):292‐8. CENTRAL

Imam 2011 {published data only}

Imam MH, Sinakos E, Gossard AA, Kowdley KV, Luketic VA, Edwyn Harrison M, et al. High‐dose ursodeoxycholic acid increases risk of adverse outcomes in patients with early stage primary sclerosing cholangitis. Alimentary Pharmacology and Therapeutics 2011;34(10):1185‐92. CENTRAL

Kuiper 2010 {published data only}

Kuiper EMM, van Erpedum KJ, Beuers U, Hansen BE, Thio HB, de Man RA, et al. The potent bile acid sequestrant colesevelam is not effective in cholestatic pruritus: results of a double‐blind, randomized, placebo‐controlled trial. Hepatology 2010;52(4):1334‐40. CENTRAL

Kurihara 2003 {published data only}

Kurihara T, Maeda A, Shigemoto M, Yamashita K, Kamatani N. Efficacy of bezafibrate in a patient with primary sclerosing cholangitis. Journal of Gastroenterology 2003;38(3):300‐1. CENTRAL

Lankarani 2003 {published data only}

Lankarani KB. Use of mycophenolate mofetil in the treatment of primary sclerosing cholangitis. Journal of Clinical Gastroenterology 2003;36(1):86. CENTRAL

Lankarani 2005 {published data only}

Lankarani KB. Mycophenolate mofetil for the treatment of primary sclerosing cholangitis. Alimentary Pharmacology & Therapeutics 2005;21(10):1279‐80. CENTRAL

Lindor 1995 {published data only}

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

Lindor 2005 {published data only}

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

Lindor 2009a {published data only}

Lindor KD. Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Bile Acid Biology and Therapeutic Actions. Vol. 165, Dordrecht: Springer, 2009:255‐8. CENTRAL

Mayo 2007 {published data only}

Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first‐line treatment for cholestatic pruritus. Hepatology 2007;45(3):666‐74. CENTRAL

Silveira 2008 {published data only}

Silveira MG, Lindor KD. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Journal of Hepatology 2008;48(5):692‐4. CENTRAL

Spengler 1993 {published data only}

Spengler U, Beuers U, Kruis W, Aydemir Û, Wiebecke B, Heldwein W, et al. Ursodeoxycholic acid in primary sclerosing cholangitis. Bile Acids and the Hepatobiliary System. From Basic Science to Clinical Practice. Proceedings of Falk Symposium 68 1993:316‐22. CENTRAL

Stiehl 1989a {published data only}

Stiehl A, Raedsch R. Treatment of primary sclerosing cholangitis with ursodeoxycholic acid. Zeitschrift fur Gastroenterologie ‐ Verhandlungsband 1989;24:136. CENTRAL

Stiehl 1989b {published data only}

Stiehl A, Raedsch R. [Treatment of primary sclerosing cholangitis with ursodeoxycholic acid]. Z Gastroenterol Verh 1989;24:136. CENTRAL

Stiehl 1994 {published data only}

Stiehl A. Ursodeoxycholic acid therapy in treatment of primary sclerosing cholangitis. Scandinavian Journal of Gastroenterology. Supplement 1994;204:59‐61. CENTRAL

Stiehl 1994a {published data only}

Stiehl A, Walker S, Stiehl L, Rudolph G, Hofmann WJ, Theilmann L. Effect of ursodeoxycholic acid on liver and bile duct disease in primary sclerosing cholangitis. A 3‐year pilot study with a placebo‐controlled study period. Journal of Hepatology 1994;20(1):57‐64. CENTRAL
Stiehl L, Rudolph G, Raedsch R, Stiehl A. Effects of ursodeoxycholic acid in patients with primary sclerosing cholangitis. Bile Acids as Therapeutic Agents. From Basic Science to Clinical Practice. Proceedings of Falk Symposium 58 1991, (37):305‐7. CENTRAL

Stiehl 1996 {published data only}

Stiehl A. Ursodeoxycholic acid in the treatment of primary sclerosing cholangitis. Italian Journal of Gastroenterology 1996;28(3):178‐80. CENTRAL

Tabibian 1989 {published data only}

Tabibian N. Rifampin as antipruritic agent in primary sclerosing cholangitis. American Journal of Gastroenterology 1989;84(3):340. CENTRAL

Tada 2006 {published data only}

Tada S, Ebinuma H, Saito H, Hibi T. Therapeutic benefit of sulfasalazine for patients with primary sclerosing cholangitis. Journal of Gastroenterology 2006;41(4):388‐9. CENTRAL

Ter Borg 2004 {published data only}

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

Triantos 2012 {published data only}

Triantos CK, Koukias N, Nikolopoulou V, Burroughs AK. Ursodeoxycholic acid in primary sclerosing cholangitis. Alimentary Pharmacology & Therapeutics 2012;35(5):622‐3. CENTRAL

van de Meeberg 1996 {published data only}

van de Meeberg PC, Wolfhagen FH, Van Berge‐Henegouwen GP, Salemans JM, Tangerman A, van Buuren HR, et al. Single or multiple dose ursodeoxycholic acid for cholestatic liver disease: biliary enrichment and biochemical response. Journal of Hepatology 1996;25(6):887‐94. CENTRAL

van Hoogstraten 1998 {published data only}

Hoogstraten HJ, Wolfhagen FH, Meeberg PC, Kuiper H, Nix GA, Becx MC, et al. Ursodeoxycholic acid therapy for primary sclerosing cholangitis: results of a 2‐year randomized controlled trial to evaluate single versus multiple daily doses. Journal of Hepatology 1998;29(3):417‐23. CENTRAL
Hoogstraten HJF, Meeberg PC, Wolfhagen FHJ, Kuiper H, Hop WCJ, Berge‐Henegouwen GP, et al. Ursodeoxycholic acid (UDCA) for primary sclerosing cholangitis (PSC): results of a 2‐year randomized controlled trial evaluating single versus multiple daily doses. Hepatology 1997;26(4 Pt 2):401a. CENTRAL
Hoogstraten HJF, Wolfhagen FJH, Meeberg PC, Buuren HR, Berge Henegouwen GP, Schalm SW. Single versus three times daily ursodeoxycholic acid (UDCA) for primary sclerosing cholangitis (PSC): results of a randomized controlled trial. European Journal of Gastroenterology and Hepatology 1996;8(Suppl 12):A 7. CENTRAL
Vleggaar FP, van Hoogstraten HJF, Boland GJ, van Steenbergen W, van Hattum J, Henegouwen GPV, et al. Treatment with budesonide or prednisone in combination with ursodeoxycholic acid (UDCA) in primary sclerosing cholangitis (PSC): a randomized controlled pilot study. Hepatology 1998;28(4):647A. CENTRAL
van Hoogstraten HJ, Wolfhagen FH, van de Meeberg PC, Kuiper H, Nix GA, Becx MC, et al. Ursodeoxycholic acid therapy for primary sclerosing cholangitis: results of a 2‐year randomized controlled trial to evaluate single versus multiple daily doses. Journal of Hepatology 1998;29(3):417‐23. CENTRAL
van Hoogstraten HJF, Wolfhagen FJH, van de Meeberg PC, van Buuren HR, Henegouwen GPB, Schalm SW. Single versus three times daily ursodeoxycholic acid (UDCA) for primary sclerosing cholangitis (PSC): results of a randomized controlled trial. Gastroenterology 1996;110(4):A1352. CENTRAL
van Hoogstraten HJF, van de Meeberg PC, Wolfhagen FHJ, Kuiper H, Hop WCJ, van Berge Henegouwen GP, et al. Ursodeoxycholic acid (UDCA) for primary sclerosing cholangitis (PSC): results of a 2‐year randomized controlled trial evaluating single versus multiple daily doses. Hepatology 1997;26(4):1089. CENTRAL

van Hoogstraten 2000 {published data only}

Hoogstraten HJ, Vleggaar FP, Boland GJ, Steenbergen W, Griffioen P, Hop WC, et al. Budesonide or prednisone in combination with ursodeoxycholic acid in primary sclerosing cholangitis: a randomized double‐blind pilot study. Belgian‐Dutch PSC Study Group. The American Journal of Gastroenterology 2000;95(8):2015‐22. CENTRAL
van Hoogstraten HJ, Vleggaar FP, Boland GJ, van Steenbergen W, Griffioen P, Hop WC, et al. Budesonide or prednisone in combination with ursodeoxycholic acid in primary sclerosing cholangitis: a randomized double‐blind pilot study. Belgian‐Dutch PSC Study Group. American Journal of Gastroenterology 2000;95(8):2015‐22. CENTRAL

Van Thiel 1992 {published data only}

Vanthiel DH, Wright HI, Gavaler JS. Ursodeoxycholic acid (UDCA) therapy for primary sclerosing cholangitis (PSC) ‐ preliminary report of a randomized controlled trial. Hepatology 1992;16(4):A62. CENTRAL

Villamil 2005 {published data only}

Villamil AG, Bandi JC, Galdame OA, Gerona S, Gadano AC. Efficacy of lidocaine in the treatment of pruritus in patients with chronic cholestatic liver diseases. The American Journal of Medicine 2005;118(10):1160‐3. CENTRAL

Vleggaar 2001 {published data only}

Vleggaar FP, Buuren HR, Berge Henegouwen GP, Hop WC, Erpecum KJ. No beneficial effects of transdermal nicotine in patients with primary sclerosing cholangitis: results of a randomized double‐blind placebo‐controlled cross‐over study. European Journal of Gastroenterology and Hepatology 2001;13(2):171‐5. CENTRAL
Vleggaar FP, Van Buuren HR, Henegouwen GPV, Van Erpecum KJ. No beneficial effects of transdermal nicotine in primary sclerosing cholangitis (PSC): results of a randomized double‐blind cross‐over study. Hepatology 1999;30(4):563A. CENTRAL

Vleggaar 2008 {published data only}

Vleggaar F, Monkelbaan J, Van Erpecum K. No beneficial effects of probiotics in primary sclerosing cholarigitis (PSC): a randomized placebo‐controlled cross‐over study. Gastroenterology 2007;132(4):A767. CENTRAL
Vleggaar FP, Monkelbaan JF, Erpecum KJ. Probiotics in primary sclerosing cholangitis: a randomized placebo‐controlled crossover pilot study. European Journal of Gastroenterology and Hepatology 2008;20(7):688‐92. CENTRAL
Vleggaar FP, Monkelbaan JF, van Erpecum KJ. No beneficial effects of probiotics in primary sclerosing cholangitis: a randomized placebo‐controlled crossover study. European Journal of Gastroenterology and Hepatology 2008;20(7):A67. CENTRAL

Wagner 1971 {published data only}

Wagner A. Azathioprine treatment in primary sclerosing cholangitis. Lancet 1971;2(7725):663‐4. CENTRAL

References to studies awaiting assessment

Anonymous 2006 {published data only}

Anonymous. Primary sclerosing cholangitis. To slow progression and reduce carcinoma risk. MMW Fortschritte der Medizin 2006;148(24):42‐3. CENTRAL

ISRCTN16531030 {published data only}

Randomised trial of low dose, medium dose and high dose ursodeoxycholic acid with placebo in primary sclerosing cholangitis. http://isrctn.com/ISRCTN16531030 (accessed 5 July 2015). CENTRAL

NCT00059202 {published data only}

Trial of high‐dose urso in primary sclerosing cholangitis. http://clinicaltrials.gov/show/NCT00059202 (accessed 5 July 2015). CENTRAL

EUCTR2012‐004170‐26‐IT {published data only}

Randomized double‐blind placebo‐controlled trial to evaluate the efficacy of N‐acetylcystein in patients with chronic pancreatitis and primary sclerosing cholangitis.. https://www.clinicaltrialsregister.eu/ctr‐search/search?query=eudract_number:2012‐004170‐26 (accessed 5 July 2015). CENTRAL

EUCTR2015‐003310‐24‐SE {published data only}

A phase 3, open‐label, randomized, prospective clinical trial evaluating the efficacy of stratified treatment with ursodeoxycholic acid (UDCA) in preventing hepatobiliary and colorectal malignancy in surveillance patients with primary sclerosing cholangitis (PSC). https://www.clinicaltrialsregister.eu/ctr‐search/trial/2015‐003310‐24/SE (accessed 22 February 2017). CENTRAL

EUCTR2015‐003392‐30‐GB {published data only}

A phase 2, randomized, double blind, placebo controlled, parallel group, multiple center study to evaluate the safety, tolerability, and efficacy of NGM282 administered for 12 weeks in patients with primary sclerosing cholangitis (PSC). https://www.clinicaltrialsregister.eu/ctr‐search/trial/2015‐003392‐30/GB/ (accessed 22 February 2017). CENTRAL

NCT01672853 {published data only}

Simtuzumab (GS‐6624) in the prevention of progression of liver fibrosis in subjects with primary sclerosing cholangitis (PSC). http://clinicaltrials.gov/show/NCT01672853 (accessed 5 July 2015). CENTRAL

NCT01688024 {published data only}

Mitomycin C therapy for patients with primary sclerosing cholangitis. http://clinicaltrials.gov/show/NCT01688024 (accessed 5 July 2015). CENTRAL

NCT01755507 {published data only}

Norursodeoxycholic acid in the treatment of primary sclerosing cholangitis NUC‐3. http://clinicaltrials.gov/show/NCT01755507 (accessed 5 July 2015). CENTRAL

NCT02177136 {published data only}

Obeticholic acid (OCA) in primary sclerosing cholangitis (PSC). https://clinicaltrials.gov/show/NCT02177136 2015 (accessed 30 June 2015). CENTRAL

NCT02704364 {published data only}

Phase 2 study of NGM282 in patients with primary sclerosing cholangitis. https://clinicaltrials.gov/ct2/show/NCT02704364 (accessed 22 February 2017). CENTRAL

NCT02943460 {published data only}

Safety, tolerability, and efficacy of GS­9674 in adults with primary sclerosing cholangitis without cirrhosis (PSC­phase 2). https://clinicaltrials.gov/ct2/show/NCT02943460 (accessed 22 February 2017). CENTRAL

NCT03035058 {published data only}

Efficacy and safety of vedolizumab intravenous (IV) in the treatment of primary sclerosing cholangitis in subjects with underlying inflammatory bowel disease. https://clinicaltrials.gov/ct2/show/NCT03035058 (accessed 22 February 2017). CENTRAL

Boonstra 2012

Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. Journal of Hepatology 2012;56(5):1181‐8.

Boonstra 2013

Boonstra K, Weersma RK, van Erpecum KJ, Rauws EA, Spanier BW, Poen AC, et al. Population‐based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 2013;58(6):2045‐55.

Chaimani 2012

Chaimani A, Salanti G. Using network meta‐analysis to evaluate the existence of small‐study effects in a network of interventions. Research Synthesis Methods 2012;3(2):161‐76.

Chaimani 2013

Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta‐analysis in STATA. PloS One 2013;8(10):e76654.

Chan 2013

Chan A‐W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža‐Jerić K, et al. Spirit 2013 statement: defining standard protocol items for clinical trials. Annals of Internal Medicine 2013;158(3):200‐7.

Chapman 2008

Chapman R, Cullen S. Etiopathogenesis of primary sclerosing cholangitis. World Journal of Gastroenterology 2008;14(21):3350‐9.

Chapman 2010

Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51(2):660‐78.

Del Re 2013

Del Re AC, Spielmans GI, Flückiger C, Wampold BE. Efficacy of new generation antidepressants: differences seem illusory. PLoS One 2013;8(6):e63509.

Demets 1987

DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987;6(3):341‐50.

DerSimonian 1986

DerSimonian R, Laird N. Meta‐analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177‐88.

Dias 2012a

Dias S, Sutton AJ, Welton NJ, Ades AE. NICE DSU Technical Support Document 3: Heterogeneity: subgroups, meta‐regression, bias and bias‐adjustment, September 2011 (last updated April 2012). www.nicedsu.org.uk/TSD3%20Heterogeneity.final%20report.08.05.12.pdf (accessed 27 March 2014).

Dias 2012b

Dias S, Welton NJ, Sutton AJ, Ades AE. NICE DSU Technical Support Document 1: Introduction to evidence synthesis for decision making, April 2011 (last updated April 2012). www.nicedsu.org.uk/TSD1%20Introduction.final.08.05.12.pdf (accessed 27 March 2014).

Dias 2014a

Dias S, Welton NJ, Sutton AJ, Ades AE. NICE DSU technical support document 2: a generalised linear modelling framework for pairwise and network meta‐analysis of randomised controlled trials, August 2011 (last updated April 2014). http://www.nicedsu.org.uk/TSD2%20General%20meta%20analysis%20corrected%2015April2014.pdf (accessed 8 October 2014).

Dias 2014b

Dias S, Welton NJ, Sutton AJ, Caldwell DM, Lu G, Ades AE. NICE DSU Technical Support Document 4: Inconsistency in networks of evidence based on randomised controlled trials, May 2011 (last updated April 2014). http://www.nicedsu.org.uk/TSD4%20Inconsistency.final.15April2014.pdf (accessed 8 October 2014).

EASL 2009

European Association for the Study of the Liver. EASL clinical practice guidelines: management of cholestatic liver diseases. Journal of Hepatology 2009;51(2):237‐67.

Egger 1997

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ 1997;315(7109):629‐34.

Epstein 2004

Epstein MP, Kaplan MM. A pilot study of etanercept in the treatment of primary sclerosing cholangitis. Digestive Diseases and Sciences 2004;49(1):1‐4.

EuroQol 2014

EuroQol. About EQ‐5D. http://www.euroqol.org/about‐eq‐5d.html (accessed 8 October 2014).

Giljaca 2010

Giljaca V, Poropat G, Stimac D, Gluud C. Glucocorticosteroids for primary sclerosing cholangitis. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD004036.pub3]

Gluud 2013

Gluud C, Nikolova D, Klingenberg SL, Alexakis N, Als‐Nielsen B, Colli A, et al. Cochrane Hepato‐Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2013, Issue 7. Art. No.: LIVER.

Gores 2013

Gores GJ, Darwish Murad S, Heimbach JK, Rosen CB. Liver transplantation for perihilar cholangiocarcinoma. Digestive Diseases 2013;31(1):126‐9.

Gross 1985

Gross JB, Ludwig J, Wiesner RH, McCall JT, LaRusso NF. Abnormalities in tests of copper metabolism in primary sclerosing cholangitis. Gastroenterology 1985;89(2):272‐8.

Guyatt 2011

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction ‐ GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4):383‐94.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane‐handbook.org.

Higgins 2012

Higgins JPT, Jackson D, Barrett JK, Lu G, Ades AE, White IR. Consistency and inconsistency in network meta‐analysis: concepts and models for multi‐arm studies. Research Synthesis Methods 2012;3(2):98‐110.

ICH‐GCP 1997

International Conference on Harmonisation Expert Working Group. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice CFR & ICH Guidelines. Vol. 1, Pennsylvania, USA: Barnett International/PAREXEL, 1997.

Jakobsen 2014

Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta‐analytic methods. BMC Medical Research Methodology 2014;14(1):120.

Jay 2011

Jay CL, Lyuksemburg V, Ladner DP, Wang E, Caicedo JC, Holl JL, et al. Ischemic cholangiopathy after controlled donation after cardiac death liver transplantation: a meta‐analysis. Annals of Surgery 2011;253(2):259‐64.

Kjaergard 2001

Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9.

Klingenberg 2006

Klingenberg SL, Chen W. D‐penicillamine for primary sclerosing cholangitis. Cochrane Database of Systematic Reviews 2006, Issue 1. [DOI: 10.1002/14651858.CD004182.pub3]

Klose 2014

Klose J, Klose MA, Metz C, Lehner F, Manns MP, Klempnauer J, et al. Outcome stagnation of liver transplantation for primary sclerosing cholangitis in the Model for End‐Stage Liver Disease era. Langenbecks Archives of Surgery 2014;399(8):1021‐9.

Koro 2013

Koro NS, Alkaade S. Role of endoscopy in primary sclerosing cholangitis. Current Gastroenterology Reports 2013;15(12):361.

Liu 2013

Liu JZ, Hov JR, Folseraas T, Ellinghaus E, Rushbrook SM, Doncheva NT, et al. Dense genotyping of immune‐related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nature Genetics 2013;45(6):670‐5.

Lu 2006

Lu G, Ades AE. Assessing evidence inconsistency in mixed treatment comparisons. Journal of the American Statistical Association 2006;101(474):447‐59.

Lundh 2017

Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2017, Issue 2. [DOI: 10.1002/14651858.MR000033.pub3]

Macaskill 2001

Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta‐analysis. Statistics in Medicine 2001;20(4):641‐54.

Mills 2012

Mills EJ, Ioannidis JP, Thorlund K, Schünemann HJ, Puhan MA, Guyatt GH. How to use an article reporting a multiple treatment comparison meta‐analysis. JAMA 2012;308(12):1246‐53.

Moher 1998

Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. Lancet 1998;352(9128):609‐13.

NCBI 2014

NCBI. Cholangitis, Sclerosing. http://www.ncbi.nlm.nih.gov/mesh/68015209 (accessed 10 June 2014).

Newell 1992

Newell DJ. Intention‐to‐treat analysis: implications for quantitative and qualitative research. International Journal of Epidemiology 1992;21(5):837‐41.

Novak 2008

Novak K, Swain MG. Role of methotrexate in the treatment of chronic cholestatic disorders. Clinics in Liver Disease 2008;12(1):81‐96.

O'Mahony 2006

O'Mahony CA, Vierling JM. Etiopathogenesis of primary sclerosing cholangitis. Seminars in Liver Disease 2006;26(1):3‐21.

OpenBUGS 3.2.3 [Computer program]

Members of OpenBUGS Project Management Group. OpenBUGS. Version 3.2.3. Members of OpenBUGS Project Management Group, 2014.

Paumgartner 2002

Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 2002;36(3):525‐31.

Pawlik 2008

Pawlik TM, Olbrecht VA, Pitt HA, Gleisner AL, Choti MA, Schulick RD, et al. Primary sclerosing cholangitis: role of extrahepatic biliary resection. Journal of the American College of Surgeons 2008;206(5):822‐30.

Perez 2009

Perez MJ, Briz O. Bile‐acid‐induced cell injury and protection. World Journal of Gastroenterology 2009;15(14):1677‐89.

Ponsioen 2016

Ponsioen CY, Chapman RW, Chazouilleres O, Hirschfield GM, Karlsen TH, Lohse AW, et al. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an international PSC study group consensus process. Hepatology 2016;63(4):1357‐67.

Poropat 2011

Poropat G, Giljaca V, Stimac D, Gluud C. Bile acids for primary sclerosing cholangitis. Cochrane Database of Systematic Reviews 2011, Issue 1. [DOI: 10.1002/14651858.CD003626.pub2]

Puhan 2014

Puhan MA, Schünemann HJ, Murad MH, Li T, Brignardello‐Petersen R, Singh JA, et al. A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta‐analysis. BMJ 2014;349:g5630.

RevMan 2014 [Computer program]

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Royle 2003

Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591‐603.

Salanti 2011

Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple‐treatment meta‐analysis: an overview and tutorial. Journal of Clinical Epidemiology 2011;64(2):163‐71.

Salanti 2012

Salanti G. Indirect and mixed‐treatment comparison, network, or multiple‐treatments meta‐analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Research Synthesis Methods 2012;3(2):80‐97.

Savović 2012a

Savović J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized controlled trials: combined analysis of meta‐epidemiological studies. Health Technology Assessment 2012;16(35):1‐82.

Savović 2012b

Savović J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized controlled trials. Annals of Internal Medicine 2012;157(6):429‐38.

Schulz 1995

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408‐12.

Schulz 2010

Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Medicine 2010;7(3):e1000251.

Stata/SE 14.2 [Computer program]

StataCorp LP. Stata/SE 14.2 for Windows[64‐bit x86‐64]. Version 14. College Station: StataCorp LP, 2017.

Stewart 2014

Stewart L. Iatrogenic biliary injuries: identification, classification, and management. Surgical Clinics of North America 2014;94(2):297‐310.

Tabibian 2014

Tabibian JH, Lindor KD. Ursodeoxycholic acid in primary sclerosing cholangitis: if withdrawal is bad, then administration is good (right?). Hepatology 2014;60(3):785‐8.

Talwalkar 2001

Talwalkar JA, Lindor KD. Natural history and prognostic models in primary sclerosing cholangitis. Best Practice & Research: Clinical Gastroenterology 2001;15(4):563‐75.

Talwalkar 2005

Talwalkar JA, Angulo P, Keach JC, Petz JL, Jorgensen RA, Lindor KD. Mycophenolate mofetil for the treatment of primary sclerosing cholangitis. American Journal of Gastroenterology 2005;100(2):308‐12.

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. 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.

Triantos 2011

Triantos CK, Koukias NM, Nikolopoulou VN, Burroughs AK. Meta‐analysis: ursodeoxycholic acid for primary sclerosing cholangitis. Alimentary Pharmacology & Therapeutics 2011;34(8):901‐10.

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.

Valero 2012

Valero V, Cosgrove D, Herman JM, Pawlik TM. Management of perihilar cholangiocarcinoma in the era of multimodal therapy. Expert Review of Gastroenterology & Hepatology 2012;6(4):481‐95.

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

Ware JE. SF‐36® Health Survey Update. http://www.sf‐36.org/tools/sf36.shtml 2014 (accessed 8 October 2014).

Wetterslev 2008

Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta‐analysis. Journal of Clinical Epidemiology 2008;61(1):64‐75.

Wood 2008

Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ 2008;336(7644):601‐5.

Wunsch 2014

Wunsch E, Trottier J, Milkiewicz M, Raszeja‐Wyszomirska J, Hirschfield GM, Barbier O, et al. Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis. Hepatology 2014;60(9):31‐940.

Yimam 2014

Yimam KK, Bowlus CL. Diagnosis and classification of primary sclerosing cholangitis. Autoimmunity Reviews 2014;13(4‐5):445‐50.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Allison 1986

Methods

Randomised clinical trial.

Participants

Country: UK.
Number randomised: 17.
Post‐randomisation drop‐outs: 6 (35.3%).
Revised sample size: 11.
Mean age: 52 years.
Females: 3 (27.3%).

Ulcerative colitis: no.

Inclusion criteria:

  1. Primary sclerosing cholangitis of the intrahepatic ducts.

Exclusion criteria:

  1. Biliary bypass procedure.

Follow‐up: 3 months after completion of 2‐week treatment.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: continuous nasobiliary irrigation with normal saline plus hydrocortisone (100 mg/d) for 2 weeks (n = 6).
Group 2: continuous nasobiliary irrigation with saline alone (1 L/d) for 2 weeks (n = 5).

Outcomes

1. Mortality.
2. Proportion of participants with any type of adverse events.
3. Proportion of participants with severe adverse events.
4. Number of any type of adverse events.
5. Number of severe adverse events.
6. Liver transplantation.

Notes

Reasons for post‐randomisation drop‐out: "technical failures":

  1. Endoscopic retrograde cholangiopancreatography failure (n = 2).

  2. Nasobiliary tube insertion failure (n = 2).

  3. Nasobiliary tubes fell out of the biliary tree during lavage (n = 2).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomised by sealed envelope to receive continuous nasobiliary irrigation with either normal saline alone or normal saline plus hydrocortisone. [.] The randomisation code was blocked to ensure an approximately equal number of patients in each group at any stage of the trial".

Allocation concealment (selection bias)

Low risk

Quote: "Patients were randomised by sealed envelope".

Comment: "Opaque sealed envelopes manually shuffled" (trial author's reply).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Patients and interpreters blinded to allocation" (trial author's reply).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Patients and interpreters blinded to allocation" (trial author's reply).

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

Low risk

Comment: No published protocol was available; mortality and liver transplantation were reported.

For‐profit bias

Low risk

Comment: "Patients were cared for and followed within normal NHS founded hospital stay. No additional grants were sought" (trial author's reply).

Other bias

Low risk

Comment: no other bias.

Bansi 1996

Methods

Randomised clinical trial.

Participants

Country: UK.
Number randomised: 23.
Post‐randomisation drop‐outs: 1 (4.3%).
Revised sample size: 22.
Mean age: 53 years.
Females: 7 (31.8%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis.

  2. Pre‐trial biopsy and cholangiography.

Exclusion criteria: not stated.

Follow‐up: 12 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: moderate‐dose UDCA (20 mg/kg/d) over the period of follow‐up of the study (n = 11).
Group 2: placebo over the period of follow‐up of the study (n = 11).

Outcomes

No outcomes of interest were reported.

Notes

Reasons for post‐randomisation drop‐out:

  1. Dominant bile duct stricture that required stenting (UDCA group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "Double‐blind placebo‐controlled trial".

Comment: Further details were not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: This information was not available.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

Unclear risk

Comment: No published protocol was available; no outcomes of interest were reported.

For‐profit bias

Unclear risk

Comment: This information was not available.

Other bias

Low risk

Comment: no other bias.

Beuers 1992

Methods

Randomised clinical trial.

Participants

Country: Germany.
Number randomised: 14.
Post‐randomisation drop‐outs: unclear.
Revised sample size: 14.
Mean age: 39 years.
Females: 3 (21.4%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis by endoscopic retrograde cholangiography, hepatobiliary histological appearance, and a cholestatic serum enzyme pattern in the absence of evidence of secondary sclerosing cholangitis, hepatobiliary malignancies, or other viral, metabolic, or autoimmune liver disease.

  2. Alkaline phosphatase level at least 1.5 times above the normal value (≤ 190 U/L).

Exclusion criteria:

  1. Pregnancy.

  2. Therapy for primary sclerosing cholangitis within the past 3 months with UDCA, azathioprine, chlorambucil, colchicine, cyclosporine, methotrexate, D‐penicillamine, or corticosteroids.

  3. Serum bilirubin level higher than 15 mg/dL (255 pmol/L).

  4. Other liver disease in addition to primary sclerosing cholangitis.

Follow‐up: 12 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: low‐dose UDCA (13‐15 mg/kg/d) over the period of follow‐up of the study (n = 6).
Group 2: identical‐appearing placebo over the period of follow‐up of the study (n = 8).

Outcomes

No outcomes of interest were reported.

Notes

Reasons for post‐randomisation drop‐out:

  1. Occurrence of serious side effects potentially attributable to the therapy.

  2. Suspected carcinoma.

  3. Decompensation of liver disease requiring liver transplantation.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were assigned with a computer generated block randomisation to receive UDCA or identical‐appearing placebo".

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The study was a double‐blind, randomized trial comparing the efficacy and safety of UDCA with that of placebo treatment…… Patients were assigned with a computer generated block randomization to receive UDCA or identical appearing placebo".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The study was a double‐blind, randomized trial comparing the efficacy and safety of UDCA with that of placebo treatment…… Patients were assigned with a computer generated block randomization to receive UDCA or identical appearing placebo".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: Two patients (1 for each group) were excluded from the analysis (withdrawal), but adverse events were reported.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; no outcomes of interest were reported.

For‐profit bias

High risk

Quote: "Patients were assigned with a computer generated block randomization to receive UDCA or identical appearing placebo in 250‐mg capsules (13 to 15 mg/kg body wt/day; provided by Dr. Falk GmbH, Frei‐burg, Germany)".

Comment: The trial was funded by a party with a vested interest in the results.

Other bias

Low risk

Comment: no other bias.

Cullen 2008

Methods

Randomised clinical trial.

Participants

Country: UK/Germany.
Number randomised: 33.
Post‐randomisation drop‐outs: 2 (6%).
Revised sample size: 31.
Mean age: 47 years.
Females: 8.

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Age older than 18 years.

  2. Clinical, biochemical, and radiological features of primary sclerosing cholangitis.

  3. Increased activity of alkaline phosphatase or gamma‐glutamyltransferase at the beginning of the study.

  4. Liver histology compatible with primary sclerosing cholangitis.

Exclusion criteria:

  1. Previous biliary tract surgery (excluding simple cholecystectomy).

  2. Major extrahepatic or hilar duct stricture causing jaundice.

  3. Cholangiocarcinoma.

  4. Decompensated liver disease.

  5. Antimitochondrial antibody (AMA) positive.

  6. Pregnancy or breastfeeding.

  7. Women of childbearing age not using safe contraception.

Follow‐up: 24 months.

Interventions

Participants were randomly assigned to 1 of 3 groups.
Group 1: low‐dose UDCA (10 mg/kg/d) plus placebo over the period of follow‐up of the study (n = 11).
Group 2: moderate‐dose UDCA (20 mg/kg/d) plus placebo over the period of follow‐up of the study (n = 11).

Group 3: high‐dose UDCA (30 mg/kg/d) over the period of follow‐up of the study (n = 9).

Outcomes

1. Number of any type of adverse events.
2. Number of severe adverse events.
3. Liver transplantation.

Notes

Reasons for post‐randomisation drop‐out:

  1. Participants were terminated from the study prematurely.

  2. No data were given other than data from the baseline visit.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "This randomisation was carried out by an independent blinded trial pharmacist in each centre using a predetermined randomisation scheme. Patient numbers were issued sequentially within a centre".

Allocation concealment (selection bias)

Low risk

Quote: "This randomisation was carried out by an independent blinded trial pharmacist in each centre using a predetermined randomisation scheme. Patient numbers were issued sequentially within a centre".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "A proportion of the capsules taken by patients in the low and standard dose arms of the trials were placebos. The trial was a randomised, double blinded, dose‐finding study".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "A proportion of the capsules taken by patients in the low and standard dose arms of the trials were placebos. The trial was a randomised, double blinded, dose‐finding study".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; mortality was not reported.

For‐profit bias

High risk

Quote: "Dr. Falk Pharma (Freiburg, Germany) provided drugs and placebos for this trial as well as financial support for the statistical calculations performed at ClinResearch (Koln, Germany), an independent institute for biostatistics of clinical trials".

Comment: The trial was funded by a party with vested interest in the results.

Other bias

Low risk

Comment: no other bias.

De Maria 1996

Methods

Randomised clinical trial.

Participants

Country: USA.
Number randomised: 59.
Post‐randomisation drop‐outs: 0 (0%).
Revised sample size: 59.
Mean age: 31 years.
Females: 17 (28.8%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Primary sclerosing cholangitis documented by endoscopic cholangiography, liver biopsy, and a battery of clinical, biochemical, and serological parameters.

Exclusion criteria: not stated.

Follow‐up: 24 months.

Interventions

Participants were randomly assigned to 1 of 3 groups.
Group 1: low‐dose UDCA (300 mg twice a day) over the period of follow‐up of the study (n = 20).
Group 2: colchicine (60 mg twice a day) over the period of follow‐up of the study (n = 19).

Group 3: no active intervention (n = 20).

Outcomes

No outcomes of interest were reported.

Notes

"No statistical differences in the various outcome measures for the colchicine and the untreated group were evident after 2 years of follow‐up. As a result, these data were collapsed as a single controlled group (n = 39) and were compared against the UDCA group (n = 20)".

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Comment: A group of participants received no treatment.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: This information was not available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: This information was not available.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; no outcomes of interest were reported.

For‐profit bias

Unclear risk

Comment: This information was not available.

Other bias

Low risk

Comment: no other bias.

Farkkila 2004

Methods

Randomised clinical trial.

Participants

Country: Finland.
Number randomised: 80.
Post‐randomisation drop‐outs: 9 (11.3%).
Revised sample size: 71.
Mean age: 39 years.
Females: 38 (53.6%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Confirmed diagnosis of primary sclerosing cholangitis by both liver histology and endoscopic retrograde cholangiopancreatography.

  2. Age between 16 and 65 years.

Exclusion criteria:

  1. End‐stage liver disease with decompensation (ascites not easily controlled by diuretics, Child‐Pugh C).

  2. Other coexisting liver disease.

  3. Suspected cholangiocarcinoma.

  4. Suspected or documented malignancy.

  5. Recurrent ascending cholangitis requiring antibiotic therapy.

  6. Pregnancy.

Follow‐up: 36 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: low‐dose UDCA (15 mg/kg/d) and placebo over the period of follow‐up of the study (n = 37).

Group 2: low‐dose UDCA (15 mg/kg/d) and metronidazole 600 to 800 mg/d over the period of follow‐up of the study (n = 34).

Outcomes

1. Number of any type of adverse events.
2. Liver transplantation.

Notes

Reasons for post‐randomisation drop‐out:

  1. Overlapping syndrome with autoimmune hepatitis (3 participants).

  2. Liver transplantation (3 participants in the UDCA/placebo group, 1 participant in the UDCA/metronidazole group).

  3. Development of cholangiocarcinoma (2 participants in the UDCA/placebo group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was done centrally with computer generated blocks".

Allocation concealment (selection bias)

Low risk

Quote: "Randomisation was done centrally with computer generated blocks".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "In this multicenter, randomized, double‐blind, placebo‐controlled trial, the patients were randomized either to UDCA and placebo (n = 41) or UDCA and MTZ (n = 39)".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "In this multicenter, randomized, double‐blind, placebo‐controlled trial, the patients were randomized either to UDCA and placebo (n = 41) or UDCA and MTZ (n = 39). Endoscopic retrograde cholangiopancreatography findings were analysed by two radiologists independently, specialised in hepatobiliary disease, and blinded to clinical data and the order of examinations".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; mortality was not reported.

For‐profit bias

High risk

Quote: "Mary and Georg C. Ehnrooth Foundation.
Medications were supplied, free of charge, by Orion Pharma and Leiras, Finland".

Comment: The trial was funded by a party with vested interest in the results: Orion Pharma produces metronidazole, and Leiras produces UDCA.

Other bias

Low risk

Comment: no other bias.

Hommes 2008

Methods

Randomised clinical trial.

Participants

Country: The Netherlands.
Number randomised: 10.
Post‐randomisation drop‐outs: 3 (30%).
Revised sample size: 7.
Mean age: 45 years.
Females: 4 (57.1%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Cholangiographic or histological diagnosis of primary sclerosing cholangitis.

  2. Age older than 18 years.

  3. Alkaline phophatase at least 2 times the upper limit of normal.

Exclusion criteria:

  1. Crohn's disease activity index greater than 350.

  2. Evidence of secondary sclerosing cholangitis.

  3. Evidence of other liver disease.

  4. Previous treatment with infliximab, treatment with any other agent targeted at tumour necrosis factor (TNF) reduction within 3 months of screening, treatment with immunosuppressive or anti‐inflammatory medication other than mesalazine derivatives.

  5. Unstable on treatment with UDCA.

Follow‐up: 13 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: infliximab (5 mg/kg) at weeks 0, 2, 6, 12, 18, and 24 (n = 4).

Group 2: placebo at weeks 0, 2, 6, 12, 18, and 24 (n = 3).

Outcomes

1. Proportion of participants with severe adverse events
2. Number of severe adverse events.

Notes

Reasons for post‐randomisation drop‐out:

  1. Liver transplantation (1 participant in the placebo group).

  2. Dominant stenosis requiring stenting (1 participant in the infliximab group).

  3. Colorectal cancer (1 participant in the infliximab group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "Patients were randomised in a 2:1 ratio to receive infliximab or placebo at weeks 0, 2, 6,12, 18, and 24".

Comment: Additional details were not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Infliximab was supplied in 20‐mL vials containing 100mg of the lyophilized concentrate; placebo was identically formulated. The infusion solution was administered by blinded investigators using an infusion set".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Infliximab was supplied in 20‐mL vials containing 100mg of the lyophilized concentrate; placebo was identically formulated. The infusion solution was administered by blinded investigators using an infusion set".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; mortality was not reported.

For‐profit bias

High risk

Quote: "Daan Hommes has served as consultant and speaker for both Centocor and Schering Plough. Supported by a Research Grant from Centocor, Inc (Malvern, USA)".

Comment: The trial was funded by a party with vested interest in the results (this company produces infliximab).

Other bias

Low risk

Comment: no other bias.

Knox 1994

Methods

Randomised clinical trial.

Participants

Country: USA.
Number randomised: 24.
Post‐randomisation drop‐outs: 3 (12.5%).
Revised sample size: 21.
Mean age: 37 years.
Females: 7 (33.3%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Primary sclerosing cholangitis documented by characteristic findings on endoscopic retrograde cholangiopancreatography and liver biopsy.

Exclusion criteria:

  1. Cytopenia (white blood cell count < 4000 cells/mm3, platelets < 100,000 cells/mm3, or haemoglobin < 10.0 g/dL).

  2. Significant cardiac or renal disease (serum creatinine > 2 mg/dL).

  3. Pregnancy, lactation, or lack of effective contraceptive methods.

  4. Alcoholism.

  5. Signs of liver failure manifested by ascites, encephalopathy, variceal bleeding, or muscle wasting.

  6. Dominant common bile duct strictures.

Follow‐up: 48 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: methotrexate 5 mg every 12 hours (15 mg/wk) for 24 months (n = 11).

Group 2: identical placebo for 24 months (n = 10).

Outcomes

No outcomes of interest were reported.

Notes

Reasons for post‐randomisation drop‐out:

  1. Colectomy for ulcerative colitis (1 participant in the treatment group).

  2. Non‐compliance (1 participant in the placebo group).

  3. Finding of an unusual bile duct mass of unknown nature seen on protocol endoscopic retrograde cholangiopancreatography (then diagnosed as cholangiocarcinoma) (1 participant in the placebo group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Quote: "The code was broken on patients who were judged to be treatment failures".

Comment: Additional details were not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "A double‐blind controlled trial of oral‐pulse methotrexate therapy in the treatment of primary sclerosing cholangitis.…Methotrexate (or placebo) was administered orally each week in three divided doses of 5 mg every 12 hours (15 mg/wk) for 2 years in a double‐blind manner. Identical methotrexate and placebo tablets were kindly provided by Lederle laboratories".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "A double‐blind controlled trial of oral‐pulse methotrexate therapy in the treatment of primary sclerosing cholangitis.Methotrexate (or placebo) was administered orally each week in three divided doses of 5 mg every 12 hours (15 mg/wk) for 2 years in a double‐blind manner. Identical methotrexate and placebo tablets were kindly provided by Lederle laboratories".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; no outcomes of interest were reported.

For‐profit bias

High risk

Quote: "Identical methotrexate and placebo tablets were kindly provided by Lederle laboratories..Supported by General Research Center grant MOlRR00054 from the National Institutes of Health and Lederle Laboratories, Pearl River, New York".

Comment: The trial was funded by a party with vested interest in the results.

Other bias

Low risk

Comment: no other bias.

LaRusso 1988

Methods

Randomised clinical trial.

Participants

Country: USA.
Number randomised: 70.
Post‐randomisation drop‐outs: unclear.
Revised sample size: 70.
Mean age: 42 years.
Females: 26 (37.1%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis based on the following criteria:

    1. Established liver disease for longer than 6 months.

    2. Serum level of alkaline phosphatase greater than 2 times the upper limit of normal.

    3. Cholangiogram demonstrating diffuse (> 25%) narrowing, irregularity, dilatation, and tortuosity of the extrahepatic biliary ductal system with or without involvement of the intrahepatic ductal system.

    4. Pre‐entry liver biopsy specimen compatible with the diagnosis of primary sclerosing cholangitis and showing cholangitis or portal hepatitis (stage I); periportal fibrosis or periportal hepatitis (stage II); septal fibrosis, bridging necrosis, or both (stage III); or biliary cirrhosis (stage IV).

Exclusion criteria:

  1. Previous biliary tract surgery (excluding simple cholecystectomy) or documented choledocholithiasis (not cholelithiasis) before the diagnosis of primary sclerosing cholangitis.

  2. Radiographic changes strongly suggestive of cholangiocarcinoma.

  3. Alcohol abuse.

  4. Malignancy other than skin cancer.

Follow‐up: 36 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: penicillamine 750 mg/d over the period of follow‐up of the study (n = 39).

Group 2: placebo over the period of follow‐up of the study (n = 31).

Outcomes

1. Mortality.
2. Number of any type of adverse events.
3. Number of severe adverse events.
4. Liver transplant.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "We initiated in 1980 a randomized double‐blind trial of penicillamine versus placebo. Patients were randomly assigned to drug or placebo groups. Randomization was weighted in favour of the drug group in anticipation of possible drug toxicity requiring severance from the study. Penicillamine and placebo (furnished to us through the courtesy of Merck Sharp & Dohme, West Point, Pa.) were dispensed in identical yellow capsules by one pharmacist".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "We initiated in 1980 a randomized double‐blind trial of penicillamine versus placebo. Patients were randomly assigned to drug or placebo groups. Randomization was weighted in favour of the drug group in anticipation of possible drug toxicity requiring severance from the study. Penicillamine and placebo (furnished to us through the courtesy of Merck Sharp & Dohme, West Point, Pa.) were dispensed in identical yellow capsules by one pharmacist".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: This information was not available.

Selective reporting (reporting bias)

Low risk

Comment: No published protocol was available; mortality and liver transplantation were reported.

For‐profit bias

High risk

Quote: "This work was supported by the Mayo Foundation, by a grant‐in‐aid from Merck Sharp & Dohme Research Laboratories and in part by a grant from the National Institutes of Health (RR585)".

Comment: The trial was funded by a party with vested interest in the results.

Other bias

Low risk

Comment: no other bias.

Lindor 1997

Methods

Randomised clinical trial.

Participants

Country: USA.
Number randomised: 105.
Post‐randomisation drop‐outs: 3 (2.9%).
Revised sample size: 102.
Mean age: 43 years.
Females: 44 (43.1%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis based on the following criteria:

    1. Chronic cholestasis of at least 6 months' duration.

    2. Alkaline phosphatase at least 1.5 times the upper limit of normal.

    3. Retrograde, operative, or percutaneous cholangiographic findings of intrahepatic or extrahepatic biliary duct obstruction, beading, or narrowing consistent with primary sclerosing cholangitis.

    4. Liver biopsy with compatible findings in the previous 3 months.

Exclusion criteria:

  1. Treatment with ursodiol, colchicine, corticosteroids, cyclosporine, methotrexate, or penicillamine in the preceding 3 months.

  2. Anticipated need of liver transplantation within 1 year (estimated 1‐year survival ≤ 50% on the basis of the Mayo Risk score).

  3. Recurrent variceal haemorrhage, spontaneous uncontrolled encephalopathy, or ascites resistant to diuretics.

  4. Age younger than 18 years or older than 70 years.

  5. Features suggesting other liver disease or cholangiocarcinoma.

  6. History of intraductal stones or biliary tract operations aside from cholecystectomy.

  7. Recurrent ascending cholangitis requiring hospitalisation more than 2 times a year.

Follow‐up: mean follow‐up 27 months (minimum 3 months).

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: low‐dose UDCA (13‐15 mg/kg/d) over the period of follow‐up of the study (n = 51).

Group 2: identical‐appearing placebo over the period of follow‐up of the study (n = 51).

Outcomes

Time to liver transplantation.

Notes

Reasons for post‐randomisation drop‐out:

  1. Missing follow‐up beyond 3 months (2 participants in the UDCA group, 1 participant in the placebo group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was carried out separately for each of the eight strata (combination of variables) with a computer generated, blocked, randomised drug/assignment schedule.
Patient groups were stratified according to histologic stage, serum bilirubin and the presence or absence of oesophageal varices".

Allocation concealment (selection bias)

Unclear risk

Comment: This information was 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 administrated".

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 administrated".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; mortality was not reported.

For‐profit bias

High risk

Quote: "Supported in part by Axcan Pharma (produces UDCA)".

Comment: The trial was funded by a party with vested interest in the results.

Other bias

Low risk

Comment: no other bias.

Lindor 2009

Methods

Randomised clinical trial.

Participants

Country: USA.
Number randomised: 150.
Post‐randomisation drop‐outs: 0 (0%).
Revised sample size: 150.
Mean age: 47 years.
Females: 64 (42.7%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis based on the following criteria:

    1. Chronic cholestatic disease for at least 6 months.

    2. Serum alkaline phosphatase at least 1.5 times the upper limit of normal.

    3. Retrograde, operative, magnetic resonance, or percutaneous cholangiography revealing intrahepatic and/or extrahepatic biliary duct obstruction, beading, or narrowing within 1 year of study entry.

    4. Liver biopsy in the previous 1 year available for review and compatible with primary sclerosing cholangitis (included fibrous cholangitis, ductopenia with periportal inflammation, and biliary fibrosis).

Exclusion criteria:

  1. Coexistent conditions such as preexisting advanced malignancy or severe cardiopulmonary disease that would limit life expectancy to less than 2 years.

  2. Inability to provide consent.

  3. Treatment with UDCA, pentoxifylline, corticosteroids, cyclosporin, colchicine, azathioprine, methotrexate, D‐penicillamine, budesonide, nicotine, pirfenidone, or tacrolimus in the 3 months before study entry.

  4. Patients with inflammatory bowel disease requiring specific treatment in the preceding 3 months (except mesalazine compound maintenance).

  5. Anticipated need for liver transplantation within 2 years (expected survival at 2 years < 80% according to the Mayo score).

  6. Recurrent variceal bleeding, spontaneous uncontrolled encephalopathy, INR > 1.5 uncorrected by vitamin K, resistant ascites (anticipating survival < 1 year).

  7. Pregnancy or lactation.

  8. Age younger than 18 years or older than 75 years.

  9. Liver disease due to other causes.

  10. Previous intraductal stones or biliary tree surgery other than cholecystectomy, such as biliary drainage procedures, preceding the diagnosis of primary sclerosing cholangitis.

  11. Recurrent ascending cholangitis requiring hospitalisation (more than 2 times/y).

Follow‐up: planned 60 months, but study stopped earlier owing to futility. Only 50 participants had a cholangiography at 60 months. Biochemical follow‐up.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: high‐dose UDCA (28‐30 mg/kg/d) continued even after primary endpoint was reached, except for liver transplantation or death (n = 76).
Group 2: identical placebo continued even after primary endpoint was reached, except for liver transplantation or death (n = 74).

Outcomes

1. Mortality.
2. Cholangiocarcinoma.
3. Liver transplant.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Computer‐based dynamic allocation used to assign patients to study groups via the coordinating centre in Rochester, MN".

Allocation concealment (selection bias)

Low risk

Quote: "Computer‐based dynamic allocation used to assign patients to study groups via the coordinating centre in Rochester, MN".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The physician, study coordinator, and patient were blinded as to whether active drug or placebo was being administered".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The physician, study coordinator, and patient were blinded as to whether active drug or placebo was being administered".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: All randomised participants were included in the group to which they were allocated (i.e. intention‐to‐treat analysis was performed).

Selective reporting (reporting bias)

Low risk

Comment: No published protocol was available; mortality and liver transplantation were reported.

For‐profit bias

High risk

Quote: "Supported by National Institute of Diabetes and Digestive and Kidney diseases Grant 56924 and Axcan Pharma (produces UDCA) as well as well as Grant M01RR00065 from the National Center for Research resources."

Comment: The trial was funded by a party with vested interest in the results.

Other bias

Low risk

Comment: no other bias.

Lo 1992

Methods

Randomised clinical trial.

Participants

Country: UK.
Number randomised: 18.
Post‐randomisation drop‐outs: 4 (22.2%).
Revised sample size: 14.
Mean age: 47 years.
Females: 7 (38.9%).

Separate data for the subgroup with ulcerative colitis: no.
Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis with cholangiography and liver biopsy.

Exclusion criteria: not stated.

Follow‐up: 24 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: low‐dose UDCA (10 mg/kg/d) over the period of follow‐up of the study (n = 7).
Group 2: placebo over the period of follow‐up of the study (n = 7).

Outcomes

No outcomes of interest were reported.

Notes

Reasons for post‐randomisation drop‐out:

  1. Colon cancer (UDCA group; 1 participant).

  2. Clinical deterioration or self‐withdrawal (placebo group; 3 participants).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: This information was not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: This information was not available.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; no outcomes of interest were reported.

For‐profit bias

Unclear risk

Comment: This information was not available.

Other bias

Low risk

Comment: no other bias.

Mitchell 2001

Methods

Randomised clinical trial.

Participants

Country: UK/Germany.
Number randomised: 26.
Post‐randomisation drop‐outs: 0 (0%).
Revised sample size: 26.
Mean age: 52 years.
Females: 7 (26.9%).

Separate data for the subgroup with ulcerative colitis: no.
Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis based on standard clinical, biochemical, histological, and radiological features.

  2. Absence of evidence of secondary cholangitis, hepatobiliary malignancy, or viral, metabolic, or autoimmune liver disease.

Exclusion criteria:

  1. Age between 18 and 80 years.

  2. Treatment with UCDA in the preceding year.

  3. Previous bile duct surgery.

  4. Dominant extrahepatic or hilar duct stricture.

  5. Previous choledocholithiasis.

  6. Recurrent ascending cholangitis.

  7. Previous history of variceal haemorrhage.

  8. Decompensated liver disease.

  9. Cholangiocarcinoma.

  10. Active inflammatory bowel disease.

  11. Any features of a coexisting liver disease or overlap syndrome.

Follow‐up: 24 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: moderate‐dose (20 mg/kg/d) UDCA over the period of follow‐up of the study (n = 13).
Group 2: identical‐appearing placebo over the period of follow‐up of the study (n = 13).

Outcomes

No outcomes of interest were reported.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "This preliminary study was designed as a double blind, randomized trial comparing the efficacy and safety of UDCA with that of placebo treatment….The placebo was an identical‐appearing capsule administered in the same quantity and manner".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "This preliminary study was designed as a double blind, randomized trial comparing the efficacy and safety of UDCA with that of placebo treatment. . .The placebo was an identical‐appearing capsule administered in the same quantity and manner".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Quote:"Patients who were lost to follow‐up or died during the study period were included in the final analysis, provided that at least one set of follow‐up data was available".

Comment: No post‐randomisation drop‐outs were reported.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; nooutcomes of interest were reported.

For‐profit bias

Unclear risk

Comment: This information was not available.

Other bias

Low risk

Comment: no other bias.

Olsson 1995

Methods

Randomised clinical trial.

Participants

Country: Sweden.
Number randomised: 84.
Post‐randomisation drop‐outs: unclear.
Revised sample size: 84.
Mean age: 42 years.
Females: 28 (37.8%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis based on typical cholangiographic appearance.

Exclusion criteria: not stated.

Follow‐up: 36 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: colchicine 1 mg/d over the period of follow‐up of the study (n = 44).
Group 2: placebo identical in appearance over the period of follow‐up of the study (n = 40).

Outcomes

1. Mortality.
2. Liver transplant.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "The randomization procedure was performed for each center using the sealed envelope technique".

Comment: Further information on sealed envelope technique is not available.

Allocation concealment (selection bias)

Unclear risk

Quote: "The randomization procedure was performed for each center using the sealed envelope technique".

Comment: Further information on sealed envelope technique is not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The results of a double‐blind, randomized, controlled study comparing colchicine with placebo for 36 months in 84 patients with PSC are reported. After giving informed consent, the patients in each center were randomized to receive 1 mg colchicine daily or a placebo identical in appearance".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "The results of a double‐blind, randomized, controlled study comparing colchicine with placebo for 36 months in 84 patients with PSC are reported. After giving informed consent, the patients in each center were randomized to receive 1 mg colchicine daily or a placebo identical in appearance".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: This information was not available.

Selective reporting (reporting bias)

Low risk

Comment: No published protocol was available; mortality and liver transplant were reported.

For‐profit bias

Unclear risk

Comment: This information was not available.

Other bias

Low risk

Comment: no other bias.

Olsson 2005

Methods

Randomised clinical trial.

Participants

Country: Sweden/Norway.
Number randomised: 219.
Post‐randomisation drop‐outs: 21 (9.6%).
Revised sample size: 198.
Mean age: 43 years.
Females: 58 (29.3%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis based on cholangiography.

  2. Age between 18 and 70 years.

  3. Body weight lower than 115 kg.

  4. Expected survival longer than 1 year.

Exclusion criteria:

  1. Earlier treatment with UDCA.

  2. Planned pregnancy within the forthcoming 5 years.

  3. Alcohol abuse and other forms of abuse.

  4. Hepatitis B or hepatitis C infection.

Follow‐up: 60 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: moderate‐dose UDCA (17‐23 mg/kg/d) over the period of follow‐up of the study (n = 97).
Group 2: placebo (250 mg gelatin capsules containing microcrystalline cellulose, cornstarch, and magnesium stearate) over the period of follow‐up of the study (n = 101).

Outcomes

1. Mortality.
2. Proportion of participants with any type of adverse events.
3. Cholangiocarcinoma.
4. Liver transplant.
5. Quality of life.

Notes

Reasons for post‐randomisation drop‐out:

  1. Participants who did not attended any follow‐up visit.

  2. Participants who never took capsules.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Low risk

Quote: "The trial code was kept at the pharmacies in the hospitals. The code was not broken until data from all patients had been collected".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "We conducted a randomized, double‐blind, placebo controlled, multicenter….At that time we had recruited 219 patients (121 from Sweden, 77 from Norway, and 21 from Denmark) who were randomized to either UDCA (in a daily dose of 17–23 mg/kg of body weight divided in 2 doses) or placebo in identical 250‐mg gelatin capsules containing microcrystalline cellulose".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "We conducted a randomized, double‐blind, placebo controlled, multicenter….At that time we had recruited 219 patients (121 from Sweden, 77 from Norway, and 21 from Denmark) who were randomized to either UDCA (in a daily dose of 17–23 mg/kg of body weight divided in 2 doses) or placebo in identical 250‐mg gelatin capsules containing microcrystalline cellulose".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

Low risk

Comment: No published protocol was available; mortality and liver transplant were reported.

For‐profit bias

High risk

Quote: "Supported by Dr Falk Pharma GmbH".

Comment: The trial was funded by a party with vested interest in the results (this company produces UDCA).

Other bias

Low risk

Comment: no other bias.

Rahimpour 2016

Methods

Randomised clinical trial.

Participants

Country: Iran.
Number randomised: 29.
Post‐randomisation drop‐outs: 0 (0%).
Revised sample size: 29.
Average age: 36 years.
Females: 12 (41.4%).
Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Age older than 18 years and younger than 66 years.

  2. Diagnosed primary sclerosing cholangitis (chronic liver disease described by advanced course of cholestasis, inflammation with intrahepatic and extrahepatic bile duct fibrosis) with cholestasis longer than 3 months, magnetic resonance cholangiopancreatography (MRCP), and pathological confirmation.

Exclusion criteria:

  1. Symptoms of decompensated cirrhosis including ascites, hepatic encephalopathy, and variceal bleeding.

  2. Concomitant usage of corticosteroids, immunosuppressives, and other antibiotics within 3 months before the study.

  3. History of allergy to vancomycin.

  4. Considered as on the waiting list for liver transplantation.

  5. Renal failure with creatinine higher than 1.5 mg/dL.

  6. Thrombocytopenia.

  7. Different or concomitant cause of liver disease other than primary sclerosing cholangitis.

  8. Pregnancy and lactation.

  9. Drug or alcohol abuse.

Follow‐up: 12 weeks after 12 weeks of treatment.

Interventions

Participants were randomly assigned to 2 groups.
Group 1: vancomycin 125 mg QDS (n = 18).
Group 2: placebo (n = 11).

Outcomes

  1. Mortality.

  2. Adverse events.

  3. Malignancy.

  4. Liver cirrhosis.

  5. Decompensated liver disease.

  6. Liver transplantation.

Notes

Trial authors provided additional information on outcomes in February 2017.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "An independent investigator who was blinded to the treatment group made random allocation cards by using computer‐generated random numbers".

Allocation concealment (selection bias)

Low risk

Quote: "Another investigator who was also blinded was responsible for the patients’ enrolments and data collection".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "We used the triple blinding method which meant that patients, investigators who were responsible for the patients’ enrolment and the analyzer of the data at the end of the study were unaware of identities to reduce the chance of bias occurrence in the study".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "We used the triple blinding method which meant that patients, investigators who were responsible for the patients’ enrolment and the analyzer of the data at the end of the study were unaware of identities to reduce the chance of bias occurrence in the study".

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Comment: No post‐randomisation drop‐outs were reported.

Selective reporting (reporting bias)

Low risk

Comment: No published protocol was available; mortality and morbidity were reported.

For‐profit bias

Low risk

Quote: "This study was supported by a grant from the Tehran University of Medical Sciences".

Other bias

Low risk

Comment: no other bias.

Rasmussen 1998

Methods

Cross‐over randomised clinical trial.

Participants

Country: Denmark.
Number randomised: 13.
Post‐randomisation drop‐outs: not stated.
Revised sample size: 13.
Mean age: not stated.
Females: not stated.

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis.

  2. Raised alkaline phosphatase.

  3. Symptoms such as pruritus, pain, jaundice.

Exclusion criteria: not stated.

Follow‐up: 24 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: methotrexate (10 mg/m2 body area/wk) for the first year followed by placebo (n = 5).
Group 2: placebo followed by methotrexate (10 mg/m2 body area/wk) (n = 8).

Outcomes

No outcomes of interest were reported before cross‐over.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: Trial authors stated double‐blind and have used placebo. However, the groups blinded were not reported.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: Trial authors stated double‐blind and have used placebo. However, the groups blinded were not reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: This information was not available.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; no outcomes of interest were reported.

For‐profit bias

Unclear risk

Comment: This information was not available.

Other bias

Low risk

Comment: no other bias.

Sandborn 1993

Methods

Randomised clinical trial.

Participants

Country: USA.
Number randomised: 35.
Post‐randomisation drop‐outs: 9 (25.7%).
Revised sample size: 26.
Mean age: 39 years.
Females: 10 (38.5%).

Separate data for the subgroup with ulcerative colitis: yes.

Inclusion criteria:

  1. Histological and cholangiographic findings consistent with primary sclerosing cholangitis.

  2. Cholestatic biochemical abnormalities for at least 6 months.

  3. Serum alkaline phosphatase at least 2 times the upper limit of normal.

  4. Diagnosis of ulcerative colitis (participants selected after randomisation).

Exclusion criteria:

  1. Presence of oesophageal varices.

  2. Ultrasonographic or peritoneoscopic evidence of ascites.

  3. Features of liver cirrhosis at biopsy.

  4. Serum creatinine higher than 141 nmol/L or rate of iothalamate clearance lower than 60 mL/min.

  5. Uncontrolled hypertension (systolic arterial pressure > 160 mm Hg, diastolic arterial pressure > 95 mm Hg).

  6. History of neoplastic disease other than skin cancer.

  7. Previous immunosuppressive therapy (prednisolone, azathioprine, chlorambucil).

  8. Coexistence of other liver disease documented at liver biopsy.

Follow‐up: final analysis performed after mean follow‐up of 34 months in the placebo group and 36 months in the cyclosporin group.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: low‐dose cyclosporin (initial dose 5 mg/kg/d) for at least 1 year (mean 2.8 years) (n = 16).
Group 2: placebo for at least 1 year (mean 3 years) (n = 10).

Outcomes

1. Numbers of any types of adverse events.
2. Cholangiocarcinoma.

Notes

Reasons for post‐randomisation drop‐out:

  1. Previous colectomy for ulcerative colitis (2 participants in the cyclosporine group and 1 participant in the placebo group).

  2. Treatment discontinuation (1 participant in the cyclosporine group).

  3. Non‐diagnosis of ulcerative colitis (5 participants).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "From 27 June 1985 to 13 July 1988, 35 patients with precirrhotic primary sclerosing cholangitis were randomly allocated to receive low dose cyclosporin (initial dose 5 mg/kg/day) or placebo in a double blind trial".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "From 27 June 1985 to 13 July 1988, 35 patients with precirrhotic primary sclerosing cholangitis were randomly allocated to receive low dose cyclosporin (initial dose 5 mg/kg/day) or placebo in a double blind trial".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs were reported.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; mortality was not reported.

For‐profit bias

High risk

Quote: "Supported by grants from the Sandoz Corporation and the Mayo Foundation".

Comment: The trial was funded by parties with vested interest in the results.

Other bias

Low risk

Comment: no other bias.

Sterling 2004

Methods

Randomised clinical trial.

Participants

Country: USA.
Number randomised: 25.
Post‐randomisation drop‐outs: 9 (36%).
Revised sample size: 16.
Mean age: 44 years.
Females: 10 (62.5%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis made by endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, or liver biopsy.

Exclusion criteria:

  1. Evidence of secondary cholangitis.

  2. Chronic viral hepatitis (B or C), autoimmune or other metabolic liver conditions.

  3. Hepatobiliary malignancy.

  4. History of cholangitis within 3 months of study entry.

  5. Use of steroids or azathioprine within the preceding 3 months.

  6. History of liver decompensation (variceal bleeding, ascites, prolongation of prothrombin time > 2 seconds, or hepatic encephalopathy).

Follow‐up: 24 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: mycophenolate mofetil 1000 mg twice/d and low‐dose UDCA (13–15 mg/kg/d) combined treatment over the period of follow‐up of the study (n = 6).
Group 2: low‐dose UDCA (13–15 mg/kg/d) over the period of follow‐up of the study (n = 10).

Outcomes

No outcomes of interest were reported.

Notes

Reasons for post‐randomisation drop‐out:

  1. One participant in each group withdrew consent.

  2. One participant in the UDCA group moved away from the area.

  3. Two participants in the combination group discontinued the study drug for personal reasons unrelated to side effects.

  4. One participant in the combination group had recurrence of chronic sinusitis.

  5. Two participants in the combination group and 1 in the UDCA alone group had progression of their liver disease and subsequent referral for liver transplantation.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Low risk

Quote: "Concealed randomisation via investigational pharmacy or by concealed envelopes" (study author's reply).

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Neither patient nor investigator was blinded to study medication".

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: "Neither patient nor investigator was blinded to study medication".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Quote: "All data were analysed by the intention‐to‐treat method".

Comment: Post‐randomisation drop‐outs were reported.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; no outcomes of interest were reported.

For‐profit bias

High risk

Quote: "Supported in part by a NIH grant to the General Clinical Research Center of Virginia Commonwealth University Medical Center, M01‐RR‐00065‐35 and by the generous support of Roche Laboratory, Nutley, NJ and Axcan Scandipharm, Birmingham, AL, USA".

Comment: The trial was funded by a party with vested interest in the results (Roche produces mycophenolate mofetil).

Other bias

Low risk

Comment: no other bias.

Stiehl 1989

Methods

Randomised clinical trial.

Participants

Country: Germany.
Number randomised: 16.
Post‐randomisation drop‐outs: 4 (25%).
Revised sample size: 12.
Mean age: data not available.
Females: data not available.

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria: not stated.

Exclusion criteria: not stated.

Follow‐up: unclear: definitive analysis planned for 12 months and interim analysis at 3 months.

Interventions

Participants were randomly assigned to 1 of 2 groups.
Group 1: low‐dose UDCA (8‐10 mg/kg/d) over the period of follow‐up of the study (n = 6).
Group 2: placebo over the period of follow‐up of the study (n = 6).

Outcomes

No outcomes of interest were reported.

Notes

Reasons for post randomisation drop‐out not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: This information was not available.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: This information was not available.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; no outcomes of interest were reported.

For‐profit bias

Unclear risk

Comment: This information was not available.

Other bias

Low risk

Comment: no other bias.

Tabibian 2013

Methods

Randomised clinical trial.

Participants

Country: USA.
Number randomised: 35.
Post‐randomisation drop‐outs: 7 (20%).
Revised sample size: 28.
Mean age: 40 years.

Females: 14 (40%).

Separate data for the subgroup with ulcerative colitis: no.

Inclusion criteria:

  1. Diagnosis of primary sclerosing cholangitis based on serum alkaline phosphatase at least 1.5 times the upper limit of normal for at least 6 months and cholangiography demonstrating intrahepatic and/or extrahepatic biliary strictures, beading, or irregularity consistent with primary sclerosing cholangitis.

Exclusion criteria:

  1. Treatment with any investigational agents, such as UDCA or other antibiotics, within 3 months of the study.

  2. Prior history of allergic reactions to vancomycin and/or metronidazole.

  3. Evidence of decompensated liver disease such as recurrent variceal bleeding, refractory ascites, or spontaneous hepatic encephalopathy.

  4. Anticipated need for liver transplant within 1 year as determined by Mayo Primary Sclerosing Cholangitis risk score.

  5. Findings highly suggestive of liver disease of an alternative or concomitant aetiology, such as chronic alcoholic liver disease, chronic hepatitis B or C infection, haemochromatosis, Wilson’s disease, alpha‐1 antitrypsin deficiency, non‐alcoholic steatohepatitis, primary biliary cirrhosis, or secondary sclerosing cholangitis.

  6. Pregnancy or lactation.

  7. Active illicit drug or alcohol abuse.

  8. Age younger than 18 years or older than 75 years.

  9. UDCA treatment in the previous 3 months.

Follow‐up: 3 months.

Interventions

Participants were randomly assigned to 1 of 4 groups.

Group 1: vancomycin 125 or 250 mg orally 4 times a day for 12 weeks (n = 15).

Group 2: metronidazole 250 or 500 mg orally 3 times a day for 12 weeks (n = 13).

Outcomes

Numbers of any types of adverse events.

Notes

Reasons for post‐randomisation drop‐out:

  1. One participant stopped treatment indefinitely owing to migraine headaches and increased diarrhoea (low‐dose vancomycin group).

  2. One participant stopped treatment indefinitely owing to diarrhoea and increased fatigue (high‐dose vancomycin group).

  3. One participant stopped treatment indefinitely owing to persistent dyspepsia (low‐dose metronidazole group).

  4. One participant was severed because of non‐compliance (low‐dose metronidazole group).

  5. One participant stopped treatment indefinitely owing to nausea and flu (high‐dose metronidazole group).

  6. One participant stopped treatment indefinitely owing to dyspepsia and burning in the eyes (high‐dose metronidazole group).

  7. One participant stopped treatment indefinitely owing to dyspepsia, diarrhoea, and anorexia (high‐dose metronidazole group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Drugs were packaged in identical gelatin capsules, and patients and investigators were blinded to the type and dose of the drug".

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "Drugs were packaged in identical gelatin capsules, and patients and investigators were blinded to the type and dose of the drug".

Incomplete outcome data (attrition bias)
All outcomes

High risk

Comment: Post‐randomisation drop‐outs may be related to the treatment that participants received.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; mortality was not reported.

For‐profit bias

Low risk

Quote: "Funded by the PSC Partners Seeking a Cure 2009–2010 Research Grant".

Other bias

Low risk

Comment: no other bias.

Trauner 2016

Methods

Randomised clinical trial.

Participants

Country: international, multi‐centric.
Number randomised: 159.
Post‐randomisation drop‐outs: not stated.
Revised sample size: 159.
Average age: not stated
Females: not stated

Inclusion criteria:

  1. Patients with primary sclerosing cholangitis and elevated alkaline phosphatase.

Follow‐up: 4 weeks after 12 weeks of treatment.

Interventions

Participants were randomly assigned to 4 groups.
Group 1: 3 randomised doses of norursodeoxycholic acid (500 mg/d, 1000 mg/d, and 1500 mg/d) (n = not stated).
Group 2: placebo (n = not stated).

Outcomes

1. Serious adverse events.

Notes

Given that the number of participants in each group was not reported, it was not possible to include this trial in the analysis. The proportion of serious adverse events was not reported so that we could report this information in a narrative manner.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk

Comment: This information was not available.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Comment: Placebo was used, but blinding was not mentioned.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: Placebo was used, but blinding was not mentioned.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Comment: This information was not available.

Selective reporting (reporting bias)

High risk

Comment: No published protocol was available; mortality was not reported.

For‐profit bias

High risk

Quote: "Employment: Dr. Falk Pharma GmbH".
Comment: Two of the co‐authors were employed by the company that manufactures the drug.

Other bias

Low risk

Comment: no other bias.

AMA = antimitochondrial antibody; PSC = primary sclerosing cholangitis; UDCA = ursodeoxycholic acid

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Beuers 1998

Not a RCT (comments on Lindor 1997).

Chapman 2005

Not a RCT.

Chapman 2009

Editorial on Lindor 2009.

Eisenburg 1997

Not an RCT.

Fromm 1992

Comment on a non‐RCT.

Goldberg 1992

Comment on a non‐RCT.

Gross 1993

Comment on a non‐RCT.

Harnois 2001

Not a RCT.

Hay 2001

The study includes transplanted patients.

Imam 2011

Not an RCT.

Kuiper 2010

No separate data for participants with primary sclerosing cholangitis.

Kurihara 2003

Not a RCT.

Lankarani 2003

Not a RCT.

Lankarani 2005

Comment on an included trial (Sterling 2004).

Lindor 1995

Not an RCT.

Lindor 2005

Not a RCT.

Lindor 2009a

Review, not a RCT.

Mayo 2007

No separate data for participants with primary sclerosing cholangitis.

Silveira 2008

Not a RCT.

Spengler 1993

Comments on Beuers 1992 and other published experiences.

Stiehl 1989a

Not a RCT.

Stiehl 1989b

Not a RCT.

Stiehl 1994

Not a RCT.

Stiehl 1994a

All participants received the same treatment (UDCA) for 1 year before the randomised period (UDCA and placebo groups).

Stiehl 1996

Review, not a RCT.

Tabibian 1989

Not a RCT.

Tada 2006

Not a RCT.

Ter Borg 2004

No separate data for participants with primary sclerosing cholangitis.

Triantos 2012

Comment on an excluded study (Imam 2011).

van de Meeberg 1996

No separate data for participants with primary sclerosing cholangitis.

van Hoogstraten 1998

No comparison between different treatments: Participants in both arms received the same dose of UDCA once a day or in divided doses.

van Hoogstraten 2000

In this RCT, participants received different types and doses of steroids in combination with UDCA.

Van Thiel 1992

Control group received colchicine or no treatment, and no separate data were available for participants who received no treatment.

Villamil 2005

No separate data for participants with primary sclerosing cholangitis.

Vleggaar 2001

Treatment was not targeted at improving outcomes related to primary sclerosing cholangitis.

Vleggaar 2008

No pharmacological agents were studied.

Wagner 1971

Not a RCT.

RCT = randomised clinical trial; UDCA = ursodeoxycholic acid

Characteristics of studies awaiting assessment [ordered by study ID]

Anonymous 2006

Methods

Awaiting full text.

Participants

Interventions

Outcomes

Notes

ISRCTN16531030

Methods

Randomised, placebo‐controlled trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

Trial of low‐dose, medium‐dose, and high‐dose ursodeoxycholic acid with placebo in primary sclerosing cholangitis.

Outcomes

Not available.

Notes

Recruitment status: completed.

NCT00059202

Methods

Randomised, double‐blind, placebo‐controlled trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

High‐dose UDCA (28‐30 mg/kg/d) vs placebo.

Outcomes

Cirrhosis, decompensated cirrhosis, cholangiocarcinoma, liver transplantation, quality of life, and mortality.

Notes

Recruitment status: completed.

UDCA = ursodeoxycholic acid

Characteristics of ongoing studies [ordered by study ID]

EUCTR2012‐004170‐26‐IT

Trial name or title

EUCTR2012‐004170‐26‐IT.

Methods

Randomised double‐blinded placebo‐controlled trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

N‐acetylcysteine 600 mg vs placebo.

Outcomes

Quality of life.

Starting date

Not stated.

Contact information

[email protected]

Notes

Not recruiting.

EUCTR2015‐003310‐24‐SE

Trial name or title

UDCAPSCSURV.

Methods

Phase 3, open‐label, randomised, prospective clinical trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

17‐23 mg/kg/d UDCA vs placebo.

Outcomes

Decompensated liver cirrhosis and liver transplantation.

Starting date

Not stated.

Contact information

hanns‐[email protected]

Notes

EUCTR2015‐003392‐30‐GB

Trial name or title

EUCTR2015‐003392‐30‐GB.

Methods

Phase 2, randomised, double‐blind, placebo‐controlled, parallel‐group, multiple‐centre study.

Participants

Patients with primary sclerosing cholangitis.

Interventions

NGM282 vs placebo.

Outcomes

No outcomes of interest for this review.

Starting date

Not stated.

Contact information

[email protected]

Notes

NCT01672853

Trial name or title

NCT01672853.

Methods

Randomised, double‐blind, placebo‐controlled trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

GS‐6624, a monoclonal antibody against Lysyl Oxidase Like 2 (LOXL2), vs placebo.

Outcomes

Adverse events.

Starting date

February 2013.

Contact information

Rob Myers, M.D. Gilead Sciences.

Notes

NCT01688024

Trial name or title

NCT01688024.

Methods

Randomised, double‐blind, placebo‐controlled trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

Mitomycin C vs placebo.

Outcomes

Adverse events.

Starting date

September 2012.

Contact information

[email protected]

Notes

NCT01755507

Trial name or title

NCT01755507.

Methods

Randomised, double‐blind, placebo‐controlled trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

Norursodeoxycholic acid vs placebo.

Outcomes

Adverse events.

Starting date

December 2012.

Contact information

[email protected]

Notes

NCT02177136

Trial name or title

NCT02177136.

Methods

Randomised, double‐blind, placebo‐controlled trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

Obeticholic acid vs placebo.

Outcomes

Adverse events.

Starting date

December 2014.

Contact information

[email protected]

Notes

NCT02704364

Trial name or title

NCT02704364.

Methods

Randomised, double‐blind, placebo‐controlled trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

NGM282 vs placebo.

Outcomes

No outcomes of interest for this review.

Starting date

February 2016.

Contact information

[email protected]

Notes

NCT02943460

Trial name or title

NCT02943460.

Methods

Randomised, double‐blind, placebo‐controlled trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

GS‐9674 vs placebo.

Outcomes

Adverse events.

Starting date

November 2016.

Contact information

GS‐US‐428‐[email protected]

Notes

NCT03035058

Trial name or title

NCT03035058.

Methods

Randomised, double‐blind, placebo‐controlled trial.

Participants

Patients with primary sclerosing cholangitis.

Interventions

Vedolizumab vs placebo.

Outcomes

No outcomes of interest for this review.

Starting date

February 2017.

Contact information

[email protected]

Notes

vs = versus

Data and analyses

Open in table viewer
Comparison 1. Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality at maximal follow‐up Show forest plot

6

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.1

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 1 Mortality at maximal follow‐up.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 1 Mortality at maximal follow‐up.

1.1 Colchicine vs placebo

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

0.44 [0.04, 5.07]

1.2 Penicillamine vs placebo

1

70

Odds Ratio (M‐H, Fixed, 95% CI)

1.18 [0.39, 3.58]

1.3 Steroids vs placebo

1

11

Odds Ratio (M‐H, Fixed, 95% CI)

3.0 [0.10, 90.96]

1.4 Ursodeoxycholic acid vs placebo

2

348

Odds Ratio (M‐H, Fixed, 95% CI)

1.51 [0.63, 3.63]

1.5 Vancomycin vs placebo

1

29

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Serious adverse events proportion Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 1.2

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 2 Serious adverse events proportion.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 2 Serious adverse events proportion.

2.1 Infliximab vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Serious adverse events number Show forest plot

3

rate ratio (Fixed, 95% CI)

Totals not selected

Analysis 1.3

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 3 Serious adverse events number.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 3 Serious adverse events number.

3.1 Infliximab vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Penicillamine vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.3 Steroids vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Adverse events proportion Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 1.4

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 4 Adverse events proportion.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 4 Adverse events proportion.

4.1 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 Ursodeoxycholic acid vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.3 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Adverse events number Show forest plot

5

rate ratio (Fixed, 95% CI)

Totals not selected

Analysis 1.5

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 5 Adverse events number.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 5 Adverse events number.

5.1 Cyclosporin vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 Penicillamine vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.3 Steroids vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.4 Ursodeoxycholic acid plus metronidazole vs ursodeoxycholic acid

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.5 Vancomycin vs metronidazole

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

6 Quality of life Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 1.6

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 6 Quality of life.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 6 Quality of life.

6.1 Ursodeoxycholic acid vs placebo

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Liver transplantation Show forest plot

7

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.7

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 7 Liver transplantation.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 7 Liver transplantation.

7.1 Colchicine vs placebo

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

0.59 [0.09, 3.71]

7.2 Penicillamine vs placebo

1

70

Odds Ratio (M‐H, Fixed, 95% CI)

1.14 [0.32, 4.01]

7.3 Steroids vs placebo

1

11

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.4 Ursodeoxycholic acid vs placebo

2

348

Odds Ratio (M‐H, Fixed, 95% CI)

0.97 [0.52, 1.81]

7.5 Vancomycin vs placebo

1

29

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.6 Ursodeoxycholic acid plus metronidazole vs ursodeoxycholic acid

1

71

Odds Ratio (M‐H, Fixed, 95% CI)

0.29 [0.03, 2.90]

8 Cholangiocarcinoma Show forest plot

4

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.8

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 8 Cholangiocarcinoma.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 8 Cholangiocarcinoma.

8.1 Cyclosporin vs placebo

1

26

Odds Ratio (M‐H, Fixed, 95% CI)

0.19 [0.01, 5.20]

8.2 Ursodeoxycholic acid vs placebo

2

348

Odds Ratio (M‐H, Fixed, 95% CI)

1.34 [0.48, 3.68]

8.3 Vancomycin vs placebo

1

29

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Open in table viewer
Comparison 2. Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality at maximal follow‐up Show forest plot

6

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 2.1

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 1 Mortality at maximal follow‐up.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 1 Mortality at maximal follow‐up.

1.1 Colchicine vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Penicillamine vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.3 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.4 Ursodeoxycholic acid (high) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.5 Ursodeoxycholic acid (moderate) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.6 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Serious adverse events proportion Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 2.2

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 2 Serious adverse events proportion.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 2 Serious adverse events proportion.

2.1 Infliximab vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Serious adverse events number Show forest plot

4

rate ratio (Fixed, 95% CI)

Totals not selected

Analysis 2.3

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 3 Serious adverse events number.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 3 Serious adverse events number.

3.1 Infliximab vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Penicillamine vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.3 Steroids vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.4 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (moderate)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.5 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (low)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.6 Ursodeoxycholic acid (moderate) vs ursodeoxycholic acid (low)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Adverse events proportion Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 2.4

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 4 Adverse events proportion.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 4 Adverse events proportion.

4.1 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 Ursodeoxycholic acid (moderate) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.3 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Adverse events number Show forest plot

6

rate ratio (Fixed, 95% CI)

Totals not selected

Analysis 2.5

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 5 Adverse events number.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 5 Adverse events number.

5.1 Cyclosporin vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 Penicillamine vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.3 Steroids vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.4 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (low)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.5 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (moderate)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.6 Ursodeoxycholic acid (low) plus metronidazole vs ursodeoxycholic acid (low)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.7 Ursodeoxycholic acid (moderate) vs ursodeoxycholic acid (low)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.8 Vancomycin vs metronidazole

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

6 Quality of life Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Analysis 2.6

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 6 Quality of life.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 6 Quality of life.

6.1 Ursodeoxycholic acid (moderate) vs placebo

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Liver transplantation Show forest plot

8

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 2.7

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 7 Liver transplantation.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 7 Liver transplantation.

7.1 Colchicine vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.2 Penicillamine vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.3 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.4 Ursodeoxycholic acid (high) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.5 Ursodeoxycholic acid (moderate) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.6 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.7 Ursodeoxycholic acid (moderate) vs ursodeoxycholic acid (low)

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.8 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (low)

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.9 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (moderate)

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.10 Ursodeoxycholic acid (low) plus metronidazole vs ursodeoxycholic acid (low)

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8 Cholangiocarcinoma Show forest plot

4

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Analysis 2.8

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 8 Cholangiocarcinoma.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 8 Cholangiocarcinoma.

8.1 Cyclosporin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.2 Ursodeoxycholic acid (high) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.3 Ursodeoxycholic acid (moderate) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.4 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Based on an alpha error of 2.5%, power of 90% (beta error of 10%), relative risk reduction (RRR) of 20%, control group proportion observed in the trials (Pc), and heterogeneity observed in the analyses, only a small fraction of the diversity‐adjusted required information size (DARIS) has been reached (required information size = 348; DARIS = 14,509 for mortality at maximal follow‐up; required information size = 348; DARIS = 35,846 for liver transplantation; required information size = 348; DARIS = 29,191 for cholangiocarcinoma), and trial sequential monitoring boundaries were not drawn. The Z‐curves (blue lines) do not cross conventional boundaries (dotted green lines). This indicates high risk of random errors for all outcomes included in this review.
Figures and Tables -
Figure 4

Based on an alpha error of 2.5%, power of 90% (beta error of 10%), relative risk reduction (RRR) of 20%, control group proportion observed in the trials (Pc), and heterogeneity observed in the analyses, only a small fraction of the diversity‐adjusted required information size (DARIS) has been reached (required information size = 348; DARIS = 14,509 for mortality at maximal follow‐up; required information size = 348; DARIS = 35,846 for liver transplantation; required information size = 348; DARIS = 29,191 for cholangiocarcinoma), and trial sequential monitoring boundaries were not drawn. The Z‐curves (blue lines) do not cross conventional boundaries (dotted green lines). This indicates high risk of random errors for all outcomes included in this review.

Network plot for mortality at maximal follow‐up. The size of the node (circle) provides a measure of the number of trials in which the particular treatment was included in one of the arms. The thickness of the line provides a measure of the number of direct comparisons between two nodes (treatments).
Figures and Tables -
Figure 5

Network plot for mortality at maximal follow‐up. The size of the node (circle) provides a measure of the number of trials in which the particular treatment was included in one of the arms. The thickness of the line provides a measure of the number of direct comparisons between two nodes (treatments).

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 1 Mortality at maximal follow‐up.
Figures and Tables -
Analysis 1.1

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 1 Mortality at maximal follow‐up.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 2 Serious adverse events proportion.
Figures and Tables -
Analysis 1.2

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 2 Serious adverse events proportion.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 3 Serious adverse events number.
Figures and Tables -
Analysis 1.3

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 3 Serious adverse events number.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 4 Adverse events proportion.
Figures and Tables -
Analysis 1.4

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 4 Adverse events proportion.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 5 Adverse events number.
Figures and Tables -
Analysis 1.5

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 5 Adverse events number.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 6 Quality of life.
Figures and Tables -
Analysis 1.6

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 6 Quality of life.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 7 Liver transplantation.
Figures and Tables -
Analysis 1.7

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 7 Liver transplantation.

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 8 Cholangiocarcinoma.
Figures and Tables -
Analysis 1.8

Comparison 1 Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose, Outcome 8 Cholangiocarcinoma.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 1 Mortality at maximal follow‐up.
Figures and Tables -
Analysis 2.1

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 1 Mortality at maximal follow‐up.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 2 Serious adverse events proportion.
Figures and Tables -
Analysis 2.2

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 2 Serious adverse events proportion.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 3 Serious adverse events number.
Figures and Tables -
Analysis 2.3

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 3 Serious adverse events number.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 4 Adverse events proportion.
Figures and Tables -
Analysis 2.4

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 4 Adverse events proportion.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 5 Adverse events number.
Figures and Tables -
Analysis 2.5

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 5 Adverse events number.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 6 Quality of life.
Figures and Tables -
Analysis 2.6

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 6 Quality of life.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 7 Liver transplantation.
Figures and Tables -
Analysis 2.7

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 7 Liver transplantation.

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 8 Cholangiocarcinoma.
Figures and Tables -
Analysis 2.8

Comparison 2 Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose, Outcome 8 Cholangiocarcinoma.

Summary of findings for the main comparison. Ursodeoxycholic acid versus placebo for primary sclerosing cholangitis

Ursodeoxycholic acid versus placebo for primary sclerosing cholangitis

Patient or population: people with primary sclerosing cholangitis
Settings: secondary or tertiary care
Intervention: ursodeoxycholic acid
Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Placebo

Ursodeoxycholic acid

Mortality

Follow‐up: 60 months

72 per 1000

105 per 1000
(47 to 220)

OR 1.51
(0.63 to 3.63)

348
(2 trials)

⊕⊝⊝⊝
very low1,2,3

Serious adverse events

No trials reported the number of participants with serious adverse events or numbers of serious adverse events.

Proportion of people with adverse events

Follow‐up: 60 months

337 per 1000

358 per 1000
(237 to 498)

OR 1.22
(0.68 to 2.17)

198
(1 trial)

⊕⊝⊝⊝
very low1,2,3

Number of adverse events

No trials reported the number of adverse events.

Health‐related quality of life

Follow‐up: 5 years

Scale: SF‐36 General Health Scale (Limits: 0 to 100; higher = better)

Mean in the placebo group was 61.10.

Mean in the ursodeoxycholic acid group was 1.30 higher (5.61 lower or 8.21 higher).

198

(1 trial)

⊕⊝⊝⊝
very low1,2,3

Liver transplantation

Follow‐up: 60 months

123 per 1000

120 per 1000
(68 to 202)

OR 0.97
(0.52 to 1.81)

348
(2 trials)

⊕⊝⊝⊝
very low1,2,3,4

Any malignancy

No trials reported this outcome.

Cholangiocarcinoma

Follow‐up: 60 months

43 per 1000

57 per 1000
(21 to 142)

OR 1.34
(0.48 to 3.68)

348
(2 trials)

⊕⊝⊝⊝
very low1,2,3

Colorectal cancer

No trials reported this outcome.

Cholecystectomy

No trials reported this outcome.

*The basis for the assumed risk is the mean control group proportion. The corresponding risk (and its 95% confidence interval) is based on 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 Downgraded one level for risk of bias: the trial(s) were at high risk of bias.
2 Downgraded one level for imprecision: the sample size was small.
3 Downgraded one level for imprecision: the confidence intervals were wide and overlapped a clinically significant reduction or increase (25% reduction or increase) and no effect.
4 Downgraded two levels for inconsistency: I2 was high and overlap of confidence intervals was poor.

Figures and Tables -
Summary of findings for the main comparison. Ursodeoxycholic acid versus placebo for primary sclerosing cholangitis
Table 1. Characteristics table (according to comparisons)

Study name

Number of people in intervention group

Number of people in control group

Risk of bias

Overall risk of bias

Random sequence generation

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data

Selective reporting

Vested interest bias

Colchicine vs placebo

Olsson 1995

44

40

Unclear

Unclear

Low

Low

Unclear

High

Unclear

High

Cyclosporin vs placebo

Sandborn 1993

16

10

Unclear

Unclear

Low

Low

High

High

High

High

Infliximab vs placebo

Hommes 2008

4

3

Unclear

Unclear

Low

Low

High

High

High

High

Methotrexate vs placebo

Knox 1994

11

10

Unclear

Unclear

Low

Low

High

High

High

High

Rasmussen 1998

5 (crossed over after 1 year)

8

(crossed over after 1 year)

Unclear

Unclear

Unclear

Unclear

Unclear

High

Unclear

High

NorUrsodeoxycholic acid vs placebo

Trauner 2016

Not stated

Not stated

Unclear

Unclear

Unclear

Unclear

Unclear

High

High

High

Penicillamine vs placebo

LaRusso 1988

39

31

Unclear

Unclear

Low

Low

Unclear

Low

High

High

Steroids vs placebo

Allison 1986

6

5

Unclear

Low

Low

Low

High

High

Low

High

UDCA (high) vs placebo

Lindor 2009

76

74

Low

Low

Low

Low

Low

High

High

High

UDCA (moderate) vs placebo

Bansi 1996

11

11

Unclear

Unclear

Unclear

Unclear

High

High

Unclear

High

Mitchell 2001

13

13

Unclear

Unclear

Low

Low

Low

High

Unclear

High

Olsson 2005

97

101

Unclear

Low

Low

Low

High

Low

High

High

UDCA (low) vs placebo

Beuers 1992

6

8

Low

Unclear

Low

Low

Unclear

High

High

High

Lindor 1997

51

51

Low

Unclear

Low

Low

High

High

High

High

Lo 1992

7

7

Unclear

Unclear

Unclear

Unclear

High

High

Unclear

High

Stiehl 1989

6

6

Unclear

Unclear

Unclear

Unclear

High

High

Unclear

High

UDCA (low) vs UDCA (moderate) vs UDCA (high)

Cullen 2008

11

11 (UDCA (moderate)) and 9 (UDCA (high))

Low

Low

Low

Low

High

High

High

High

UDCA (low) vs colchicine vs placebo

De Maria 1996

20

19 (colchicine) and 20 (placebo)

Unclear

Unclear

High

Unclear

Unclear

High

Unclear

High

UDCA (low) plus metronidazole vs UDCA (low)

Farkkila 2004

37

34

Low

Low

Low

Low

High

High

High

High

UDCA (low) plus mycophenolate vs UDCA (low)

Sterling 2004

6

10

Unclear

Unclear

High

High

Unclear

High

High

High

Vancomycin vs metronidazole

Tabibian 2013

16

13

Unclear

Unclear

Low

Low

High

High

Low

High

Vancomycin vs placebo

Rahimpour 2016

18

11

Low

Low

Low

Low

Low

High

Low

High

Figures and Tables -
Table 1. Characteristics table (according to comparisons)
Comparison 1. Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality at maximal follow‐up Show forest plot

6

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Colchicine vs placebo

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

0.44 [0.04, 5.07]

1.2 Penicillamine vs placebo

1

70

Odds Ratio (M‐H, Fixed, 95% CI)

1.18 [0.39, 3.58]

1.3 Steroids vs placebo

1

11

Odds Ratio (M‐H, Fixed, 95% CI)

3.0 [0.10, 90.96]

1.4 Ursodeoxycholic acid vs placebo

2

348

Odds Ratio (M‐H, Fixed, 95% CI)

1.51 [0.63, 3.63]

1.5 Vancomycin vs placebo

1

29

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Serious adverse events proportion Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 Infliximab vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Serious adverse events number Show forest plot

3

rate ratio (Fixed, 95% CI)

Totals not selected

3.1 Infliximab vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Penicillamine vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.3 Steroids vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Adverse events proportion Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.1 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 Ursodeoxycholic acid vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.3 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Adverse events number Show forest plot

5

rate ratio (Fixed, 95% CI)

Totals not selected

5.1 Cyclosporin vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 Penicillamine vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.3 Steroids vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.4 Ursodeoxycholic acid plus metronidazole vs ursodeoxycholic acid

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.5 Vancomycin vs metronidazole

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

6 Quality of life Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

6.1 Ursodeoxycholic acid vs placebo

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Liver transplantation Show forest plot

7

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

7.1 Colchicine vs placebo

1

84

Odds Ratio (M‐H, Fixed, 95% CI)

0.59 [0.09, 3.71]

7.2 Penicillamine vs placebo

1

70

Odds Ratio (M‐H, Fixed, 95% CI)

1.14 [0.32, 4.01]

7.3 Steroids vs placebo

1

11

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.4 Ursodeoxycholic acid vs placebo

2

348

Odds Ratio (M‐H, Fixed, 95% CI)

0.97 [0.52, 1.81]

7.5 Vancomycin vs placebo

1

29

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.6 Ursodeoxycholic acid plus metronidazole vs ursodeoxycholic acid

1

71

Odds Ratio (M‐H, Fixed, 95% CI)

0.29 [0.03, 2.90]

8 Cholangiocarcinoma Show forest plot

4

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

8.1 Cyclosporin vs placebo

1

26

Odds Ratio (M‐H, Fixed, 95% CI)

0.19 [0.01, 5.20]

8.2 Ursodeoxycholic acid vs placebo

2

348

Odds Ratio (M‐H, Fixed, 95% CI)

1.34 [0.48, 3.68]

8.3 Vancomycin vs placebo

1

29

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 1. Pharmacological treatments for primary sclerosing cholangitis: not stratified by ursodeoxycholic acid dose
Comparison 2. Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality at maximal follow‐up Show forest plot

6

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Colchicine vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Penicillamine vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.3 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.4 Ursodeoxycholic acid (high) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.5 Ursodeoxycholic acid (moderate) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.6 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Serious adverse events proportion Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 Infliximab vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Serious adverse events number Show forest plot

4

rate ratio (Fixed, 95% CI)

Totals not selected

3.1 Infliximab vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Penicillamine vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.3 Steroids vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.4 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (moderate)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.5 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (low)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3.6 Ursodeoxycholic acid (moderate) vs ursodeoxycholic acid (low)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Adverse events proportion Show forest plot

3

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.1 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 Ursodeoxycholic acid (moderate) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.3 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 Adverse events number Show forest plot

6

rate ratio (Fixed, 95% CI)

Totals not selected

5.1 Cyclosporin vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.2 Penicillamine vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.3 Steroids vs placebo

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.4 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (low)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.5 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (moderate)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.6 Ursodeoxycholic acid (low) plus metronidazole vs ursodeoxycholic acid (low)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.7 Ursodeoxycholic acid (moderate) vs ursodeoxycholic acid (low)

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

5.8 Vancomycin vs metronidazole

1

rate ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

6 Quality of life Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

6.1 Ursodeoxycholic acid (moderate) vs placebo

1

Mean Difference (IV, Fixed, 95% CI)

0.0 [0.0, 0.0]

7 Liver transplantation Show forest plot

8

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

7.1 Colchicine vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.2 Penicillamine vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.3 Steroids vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.4 Ursodeoxycholic acid (high) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.5 Ursodeoxycholic acid (moderate) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.6 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.7 Ursodeoxycholic acid (moderate) vs ursodeoxycholic acid (low)

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.8 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (low)

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.9 Ursodeoxycholic acid (high) vs ursodeoxycholic acid (moderate)

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.10 Ursodeoxycholic acid (low) plus metronidazole vs ursodeoxycholic acid (low)

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8 Cholangiocarcinoma Show forest plot

4

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

8.1 Cyclosporin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.2 Ursodeoxycholic acid (high) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.3 Ursodeoxycholic acid (moderate) vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.4 Vancomycin vs placebo

1

Odds Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 2. Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose