Pharmacological interventions for primary sclerosing cholangitis

Francesca Saffioti; Kurinchi Selvan Gurusamy; Neil Hawkins; Clare D Toon; Emmanuel Tsochatzis; Brian R Davidson; Douglas Thorburn

doi:10.1002/14651858.CD011343.pub2

مداخلات دارویی در مدیریت درمانی کلانژیت اسکلروزان اولیه

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos
estudios a la espera de clasificación
estudios en curso

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: Primary sclerosing cholangitis of the intrahepatic ducts. Exclusion criteria: 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": Endoscopic retrograde cholangiopancreatography failure (n = 2). Nasobiliary tube insertion failure (n = 2). 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: Diagnosis of primary sclerosing cholangitis. 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: 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: 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. Alkaline phosphatase level at least 1.5 times above the normal value (≤ 190 U/L). Exclusion criteria: Pregnancy. Therapy for primary sclerosing cholangitis within the past 3 months with UDCA, azathioprine, chlorambucil, colchicine, cyclosporine, methotrexate, D‐penicillamine, or corticosteroids. Serum bilirubin level higher than 15 mg/dL (255 pmol/L). 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: Occurrence of serious side effects potentially attributable to the therapy. Suspected carcinoma. 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: Age older than 18 years. Clinical, biochemical, and radiological features of primary sclerosing cholangitis. Increased activity of alkaline phosphatase or gamma‐glutamyltransferase at the beginning of the study. Liver histology compatible with primary sclerosing cholangitis. Exclusion criteria: Previous biliary tract surgery (excluding simple cholecystectomy). Major extrahepatic or hilar duct stricture causing jaundice. Cholangiocarcinoma. Decompensated liver disease. Antimitochondrial antibody (AMA) positive. Pregnancy or breastfeeding. 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: Participants were terminated from the study prematurely. 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: 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: Confirmed diagnosis of primary sclerosing cholangitis by both liver histology and endoscopic retrograde cholangiopancreatography. Age between 16 and 65 years. Exclusion criteria: End‐stage liver disease with decompensation (ascites not easily controlled by diuretics, Child‐Pugh C). Other coexisting liver disease. Suspected cholangiocarcinoma. Suspected or documented malignancy. Recurrent ascending cholangitis requiring antibiotic therapy. 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: Overlapping syndrome with autoimmune hepatitis (3 participants). Liver transplantation (3 participants in the UDCA/placebo group, 1 participant in the UDCA/metronidazole group). 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: Cholangiographic or histological diagnosis of primary sclerosing cholangitis. Age older than 18 years. Alkaline phophatase at least 2 times the upper limit of normal. Exclusion criteria: Crohn's disease activity index greater than 350. Evidence of secondary sclerosing cholangitis. Evidence of other liver disease. 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. 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: Liver transplantation (1 participant in the placebo group). Dominant stenosis requiring stenting (1 participant in the infliximab group). 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: Primary sclerosing cholangitis documented by characteristic findings on endoscopic retrograde cholangiopancreatography and liver biopsy. Exclusion criteria: Cytopenia (white blood cell count < 4000 cells/mm³, platelets < 100,000 cells/mm³, or haemoglobin < 10.0 g/dL). Significant cardiac or renal disease (serum creatinine > 2 mg/dL). Pregnancy, lactation, or lack of effective contraceptive methods. Alcoholism. Signs of liver failure manifested by ascites, encephalopathy, variceal bleeding, or muscle wasting. 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: Colectomy for ulcerative colitis (1 participant in the treatment group). Non‐compliance (1 participant in the placebo group). 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: Diagnosis of primary sclerosing cholangitis based on the following criteria: Established liver disease for longer than 6 months. Serum level of alkaline phosphatase greater than 2 times the upper limit of normal. Cholangiogram demonstrating diffuse (> 25%) narrowing, irregularity, dilatation, and tortuosity of the extrahepatic biliary ductal system with or without involvement of the intrahepatic ductal system. 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: Previous biliary tract surgery (excluding simple cholecystectomy) or documented choledocholithiasis (not cholelithiasis) before the diagnosis of primary sclerosing cholangitis. Radiographic changes strongly suggestive of cholangiocarcinoma. Alcohol abuse. 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: Diagnosis of primary sclerosing cholangitis based on the following criteria: Chronic cholestasis of at least 6 months' duration. Alkaline phosphatase at least 1.5 times the upper limit of normal. Retrograde, operative, or percutaneous cholangiographic findings of intrahepatic or extrahepatic biliary duct obstruction, beading, or narrowing consistent with primary sclerosing cholangitis. Liver biopsy with compatible findings in the previous 3 months. Exclusion criteria: Treatment with ursodiol, colchicine, corticosteroids, cyclosporine, methotrexate, or penicillamine in the preceding 3 months. Anticipated need of liver transplantation within 1 year (estimated 1‐year survival ≤ 50% on the basis of the Mayo Risk score). Recurrent variceal haemorrhage, spontaneous uncontrolled encephalopathy, or ascites resistant to diuretics. Age younger than 18 years or older than 70 years. Features suggesting other liver disease or cholangiocarcinoma. History of intraductal stones or biliary tract operations aside from cholecystectomy. 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: 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: Diagnosis of primary sclerosing cholangitis based on the following criteria: Chronic cholestatic disease for at least 6 months. Serum alkaline phosphatase at least 1.5 times the upper limit of normal. Retrograde, operative, magnetic resonance, or percutaneous cholangiography revealing intrahepatic and/or extrahepatic biliary duct obstruction, beading, or narrowing within 1 year of study entry. 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: Coexistent conditions such as preexisting advanced malignancy or severe cardiopulmonary disease that would limit life expectancy to less than 2 years. Inability to provide consent. Treatment with UDCA, pentoxifylline, corticosteroids, cyclosporin, colchicine, azathioprine, methotrexate, D‐penicillamine, budesonide, nicotine, pirfenidone, or tacrolimus in the 3 months before study entry. Patients with inflammatory bowel disease requiring specific treatment in the preceding 3 months (except mesalazine compound maintenance). Anticipated need for liver transplantation within 2 years (expected survival at 2 years < 80% according to the Mayo score). Recurrent variceal bleeding, spontaneous uncontrolled encephalopathy, INR > 1.5 uncorrected by vitamin K, resistant ascites (anticipating survival < 1 year). Pregnancy or lactation. Age younger than 18 years or older than 75 years. Liver disease due to other causes. Previous intraductal stones or biliary tree surgery other than cholecystectomy, such as biliary drainage procedures, preceding the diagnosis of primary sclerosing cholangitis. 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: 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: Colon cancer (UDCA group; 1 participant). 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: Diagnosis of primary sclerosing cholangitis based on standard clinical, biochemical, histological, and radiological features. Absence of evidence of secondary cholangitis, hepatobiliary malignancy, or viral, metabolic, or autoimmune liver disease. Exclusion criteria: Age between 18 and 80 years. Treatment with UCDA in the preceding year. Previous bile duct surgery. Dominant extrahepatic or hilar duct stricture. Previous choledocholithiasis. Recurrent ascending cholangitis. Previous history of variceal haemorrhage. Decompensated liver disease. Cholangiocarcinoma. Active inflammatory bowel disease. 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: 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: Diagnosis of primary sclerosing cholangitis based on cholangiography. Age between 18 and 70 years. Body weight lower than 115 kg. Expected survival longer than 1 year. Exclusion criteria: Earlier treatment with UDCA. Planned pregnancy within the forthcoming 5 years. Alcohol abuse and other forms of abuse. 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: Participants who did not attended any follow‐up visit. 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: Age older than 18 years and younger than 66 years. 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: Symptoms of decompensated cirrhosis including ascites, hepatic encephalopathy, and variceal bleeding. Concomitant usage of corticosteroids, immunosuppressives, and other antibiotics within 3 months before the study. History of allergy to vancomycin. Considered as on the waiting list for liver transplantation. Renal failure with creatinine higher than 1.5 mg/dL. Thrombocytopenia. Different or concomitant cause of liver disease other than primary sclerosing cholangitis. Pregnancy and lactation. 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	Mortality. Adverse events. Malignancy. Liver cirrhosis. Decompensated liver disease. 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: Diagnosis of primary sclerosing cholangitis. Raised alkaline phosphatase. 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: Histological and cholangiographic findings consistent with primary sclerosing cholangitis. Cholestatic biochemical abnormalities for at least 6 months. Serum alkaline phosphatase at least 2 times the upper limit of normal. Diagnosis of ulcerative colitis (participants selected after randomisation). Exclusion criteria: Presence of oesophageal varices. Ultrasonographic or peritoneoscopic evidence of ascites. Features of liver cirrhosis at biopsy. Serum creatinine higher than 141 nmol/L or rate of iothalamate clearance lower than 60 mL/min. Uncontrolled hypertension (systolic arterial pressure > 160 mm Hg, diastolic arterial pressure > 95 mm Hg). History of neoplastic disease other than skin cancer. Previous immunosuppressive therapy (prednisolone, azathioprine, chlorambucil). 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: Previous colectomy for ulcerative colitis (2 participants in the cyclosporine group and 1 participant in the placebo group). Treatment discontinuation (1 participant in the cyclosporine group). 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: Diagnosis of primary sclerosing cholangitis made by endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, or liver biopsy. Exclusion criteria: Evidence of secondary cholangitis. Chronic viral hepatitis (B or C), autoimmune or other metabolic liver conditions. Hepatobiliary malignancy. History of cholangitis within 3 months of study entry. Use of steroids or azathioprine within the preceding 3 months. 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: One participant in each group withdrew consent. One participant in the UDCA group moved away from the area. Two participants in the combination group discontinued the study drug for personal reasons unrelated to side effects. One participant in the combination group had recurrence of chronic sinusitis. 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: 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: Treatment with any investigational agents, such as UDCA or other antibiotics, within 3 months of the study. Prior history of allergic reactions to vancomycin and/or metronidazole. Evidence of decompensated liver disease such as recurrent variceal bleeding, refractory ascites, or spontaneous hepatic encephalopathy. Anticipated need for liver transplant within 1 year as determined by Mayo Primary Sclerosing Cholangitis risk score. 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. Pregnancy or lactation. Active illicit drug or alcohol abuse. Age younger than 18 years or older than 75 years. 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: One participant stopped treatment indefinitely owing to migraine headaches and increased diarrhoea (low‐dose vancomycin group). One participant stopped treatment indefinitely owing to diarrhoea and increased fatigue (high‐dose vancomycin group). One participant stopped treatment indefinitely owing to persistent dyspepsia (low‐dose metronidazole group). One participant was severed because of non‐compliance (low‐dose metronidazole group). One participant stopped treatment indefinitely owing to nausea and flu (high‐dose metronidazole group). One participant stopped treatment indefinitely owing to dyspepsia and burning in the eyes (high‐dose metronidazole group). 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: 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]

Ir a:

estudios incluidos
estudios a la espera de clasificación
estudios en curso

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]

Ir a:

estudios incluidos
estudios excluidos
estudios en curso

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]

Ir a:

estudios incluidos
estudios excluidos
estudios a la espera de clasificación

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
Open in figure viewer Analysis 1.1 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
Open in figure viewer Analysis 1.2 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
Open in figure viewer Analysis 1.3 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
Open in figure viewer Analysis 1.4 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
Open in figure viewer Analysis 1.5 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
Open in figure viewer Analysis 1.6 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
Open in figure viewer Analysis 1.7 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
Open in figure viewer Analysis 1.8 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
Open in figure viewer Analysis 2.1 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
Open in figure viewer Analysis 2.2 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
Open in figure viewer Analysis 2.3 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
Open in figure viewer Analysis 2.4 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
Open in figure viewer Analysis 2.5 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
Open in figure viewer Analysis 2.6 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
Open in figure viewer Analysis 2.7 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
Open in figure viewer Analysis 2.8 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]

Figure 1

Study flow diagram.

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Figure 2

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

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Figure 3

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

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

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.

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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).

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Analysis 1.1

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

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Analysis 1.2

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

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

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

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Analysis 1.6

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

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Analysis 1.7

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

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Analysis 1.8

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

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Analysis 2.1

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

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Analysis 2.2

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

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Analysis 2.3

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

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Analysis 2.4

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

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Analysis 2.5

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

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Analysis 2.6

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

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Analysis 2.7

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

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Analysis 2.8

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

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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 low^1,2,3
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 low^1,2,3
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 low^1,2,3
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 low^1,2,3,4
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 low^1,2,3
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.

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

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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
Study name	Number of people in intervention group	Number of people in control group	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Vested interest bias	Overall risk of 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

Table 1. Characteristics table (according to comparisons)

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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]

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

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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]

Comparison 2. Pharmacological treatments for primary sclerosing cholangitis: stratified by ursodeoxycholic acid dose

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Referencias

منابع مطالعات واردشده در این مرور

Allison 1986 {published data only}

Bansi 1996 {published data only}

Beuers 1992 {published data only}

Cullen 2008 {published data only}

De Maria 1996 {published data only}

Farkkila 2004 {published data only}

Hommes 2008 {published data only}

Knox 1994 {published data only}

LaRusso 1988 {published data only}

Lindor 1997 {published data only}

Lindor 2009 {published data only}

Lo 1992 {published data only}

Mitchell 2001 {published data only}

Olsson 1995 {published data only}

Olsson 2005 {published data only}

Rahimpour 2016 {published data only}

Rasmussen 1998 {published data only}

Sandborn 1993 {published data only}

Sterling 2004 {published data only}

Stiehl 1989 {published data only}

Tabibian 2013 {published data only}

Trauner 2016 {published data only}

منابع مطالعات خارج‌شده از این مرور

Beuers 1998 {published data only}

Chapman 2005 {published data only}

Chapman 2009 {published data only}

Eisenburg 1997 {published data only}

Fromm 1992 {published data only}

Goldberg 1992 {published data only}

Gross 1993 {published data only}

Harnois 2001 {published data only}

Hay 2001 {published data only}

Imam 2011 {published data only}

Kuiper 2010 {published data only}

Kurihara 2003 {published data only}

Lankarani 2003 {published data only}

Lankarani 2005 {published data only}

Lindor 1995 {published data only}

Lindor 2005 {published data only}

Lindor 2009a {published data only}

Mayo 2007 {published data only}

Silveira 2008 {published data only}

Spengler 1993 {published data only}

Stiehl 1989a {published data only}

Stiehl 1989b {published data only}

Stiehl 1994 {published data only}

Stiehl 1994a {published data only}

Stiehl 1996 {published data only}

Tabibian 1989 {published data only}

Tada 2006 {published data only}

Ter Borg 2004 {published data only}

Triantos 2012 {published data only}

van de Meeberg 1996 {published data only}

van Hoogstraten 1998 {published data only}

van Hoogstraten 2000 {published data only}

Van Thiel 1992 {published data only}

Villamil 2005 {published data only}

Vleggaar 2001 {published data only}

Vleggaar 2008 {published data only}

Wagner 1971 {published data only}

منابع مطالعات در انتظار ارزیابی

Anonymous 2006 {published data only}

ISRCTN16531030 {published data only}

NCT00059202 {published data only}

منابع مطالعات در حال انجام

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

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

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

NCT01672853 {published data only}

NCT01688024 {published data only}

NCT01755507 {published data only}

NCT02177136 {published data only}

NCT02704364 {published data only}

NCT02943460 {published data only}

NCT03035058 {published data only}

منابع اضافی