Pharmacological interventions for primary biliary cholangitis

Francesca Saffioti; Kurinchi Selvan Gurusamy; Leonardo Henry Eusebi; Emmanuel Tsochatzis; Brian R Davidson; Douglas Thorburn

doi:10.1002/14651858.CD011648.pub2

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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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$Trial Sequential Analysis of mortality at maximal follow‐up: azathioprine versus no intervention and colchicine versus no intervention.Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 20%), and diversity observed in the analyses (0%), the accrued sample size (224 for azathioprine versus intervention and 122 for colchicine versus no intervention) was only a small fraction of the diversity adjusted required information size (DARIS) (4580 for both comparisons); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) crossed the conventional boundaries (dotted green line) favouring azathioprine for azathioprine versus no intervention, but did not cross the conventional boundaries for colchicine versus no intervention. This indicates that there is a high risk of random errors in both these comparisons.$

Figure 4

Trial Sequential Analysis of mortality at maximal follow‐up: azathioprine versus no intervention and colchicine versus no intervention.

Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 20%), and diversity observed in the analyses (0%), the accrued sample size (224 for azathioprine versus intervention and 122 for colchicine versus no intervention) was only a small fraction of the diversity adjusted required information size (DARIS) (4580 for both comparisons); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) crossed the conventional boundaries (dotted green line) favouring azathioprine for azathioprine versus no intervention, but did not cross the conventional boundaries for colchicine versus no intervention. This indicates that there is a high risk of random errors in both these comparisons.

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$Trial Sequential Analysis of mortality at maximal follow‐up: ciclosporin versus no intervention and D‐penicillamine versus no intervention.Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 20%), and diversity observed in the analyses (82% for ciclosporin versus no intervention and 61% for D‐penicillamine versus no intervention), the accrued sample size (394 for ciclosporin versus no intervention and 423 for D‐penicillamine versus no intervention) was only a small fraction of the diversity adjusted required information size (DARIS) (25,098 for ciclosporin versus no intervention and 11,623 for D‐penicillamine versus no intervention); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) crossed the conventional boundaries (dotted green line) favouring ciclosporin for ciclosporin versus no intervention, but did not cross the conventional boundaries for D‐penicillamine versus no intervention. This indicates that there is a high risk of random errors in both these comparisons.$

Figure 5

Trial Sequential Analysis of mortality at maximal follow‐up: ciclosporin versus no intervention and D‐penicillamine versus no intervention.

Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 20%), and diversity observed in the analyses (82% for ciclosporin versus no intervention and 61% for D‐penicillamine versus no intervention), the accrued sample size (394 for ciclosporin versus no intervention and 423 for D‐penicillamine versus no intervention) was only a small fraction of the diversity adjusted required information size (DARIS) (25,098 for ciclosporin versus no intervention and 11,623 for D‐penicillamine versus no intervention); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) crossed the conventional boundaries (dotted green line) favouring ciclosporin for ciclosporin versus no intervention, but did not cross the conventional boundaries for D‐penicillamine versus no intervention. This indicates that there is a high risk of random errors in both these comparisons.

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$Trial Sequential Analysis of mortality at maximal follow‐up: colchicine plus UDCA versus UDCA.Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 7.8%), and diversity observed in the analyses (0%), the accrued sample size (160 participants) was only a small fraction of the diversity adjusted required information size (DARIS) (13,316); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) did not cross the conventional boundaries (green dotted line). This indicates that there is a high risk of random errors in both this comparison.$

Figure 6

Trial Sequential Analysis of mortality at maximal follow‐up: colchicine plus UDCA versus UDCA.

Based on an alpha error of 2.5%, power of 90% (beta error of 10%), a relative risk reduction (RRR) of 20%, a control group proportion observed in the trials (Pc = 7.8%), and diversity observed in the analyses (0%), the accrued sample size (160 participants) was only a small fraction of the diversity adjusted required information size (DARIS) (13,316); therefore, the trial sequential monitoring boundaries were not drawn. The Z‐curve (blue line) did not cross the conventional boundaries (green dotted line). This indicates that there is a high risk of random errors in both this comparison.

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Analysis 1.1

Comparison 1 Main analysis, Outcome 1 Mortality at maximal follow‐up.

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Analysis 1.2

Comparison 1 Main analysis, Outcome 2 Mortality (< 1 year).

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Analysis 1.3

Comparison 1 Main analysis, Outcome 3 Mortality (1 to 5 years).

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Analysis 1.4

Comparison 1 Main analysis, Outcome 4 Serious adverse events (proportion).

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Analysis 1.5

Comparison 1 Main analysis, Outcome 5 Serious adverse events (number of events).

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Analysis 1.6

Comparison 1 Main analysis, Outcome 6 Adverse events (proportion).

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Analysis 1.7

Comparison 1 Main analysis, Outcome 7 Adverse events (number).

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Analysis 1.8

Comparison 1 Main analysis, Outcome 8 Liver transplantation.

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Analysis 1.9

Comparison 1 Main analysis, Outcome 9 Decompensated liver disease.

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Analysis 1.10

Comparison 1 Main analysis, Outcome 10 Cirrhosis.

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Analysis 2.1

Comparison 2 Stratified by dose, Outcome 1 Mortality at maximal follow‐up.

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Analysis 2.2

Comparison 2 Stratified by dose, Outcome 2 Mortality (< 1 year).

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Analysis 2.3

Comparison 2 Stratified by dose, Outcome 3 Mortality (1 to 5 years).

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Analysis 2.4

Comparison 2 Stratified by dose, Outcome 4 Serious adverse events (proportion).

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Analysis 2.5

Comparison 2 Stratified by dose, Outcome 5 Serious adverse events (number of events).

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Analysis 2.6

Comparison 2 Stratified by dose, Outcome 6 Adverse events (proportion).

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Analysis 2.7

Comparison 2 Stratified by dose, Outcome 7 Adverse events (number).

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Analysis 2.8

Comparison 2 Stratified by dose, Outcome 8 Liver transplantation.

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Analysis 2.9

Comparison 2 Stratified by dose, Outcome 9 Decompensated liver disease.

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Analysis 2.10

Comparison 2 Stratified by dose, Outcome 10 Cirrhosis.

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Summary of findings for the main comparison. Ursodeoxycholic acid (UDCA) versus no intervention for primary biliary cholangitis

UDCA versus no intervention for primary biliary cholangitis
Patient or population: people with primary biliary cholangitis Settings: secondary or tertiary care Intervention: UDCA Comparison: no intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	No intervention	UDCA
Mortality at maximal follow‐up Follow‐up: 12 to 89 months	208 per 1000	206 per 1000 (136 to 301)	OR 0.99 (0.60 to 1.64)	734 (6 trials)	⊕⊝⊝⊝ Very low^1,2
Serious adverse events (proportion) Follow‐up: 12 to 41 months	There were no events in either group			380 (3 trials)	⊕⊝⊝⊝ Very low^1,2,3
Serious adverse events (number of events)	None of the trials reported this outcome.
Health‐related quality of life	None of the trials reported this outcome.
The basis for the assumed risk* is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; UDCA: ursodeoxycholic acid.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias in the trial(s) was high (downgraded by two levels). ² Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels). ³ There was moderate heterogeneity (downgraded by one level).

Summary of findings for the main comparison. Ursodeoxycholic acid (UDCA) versus no intervention for primary biliary cholangitis

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Summary of findings 2. Azathioprine versus no intervention for primary biliary cholangitis

Azathioprine versus no intervention for primary biliary cholangitis
Patient or population: people with primary biliary cholangitis Settings: secondary or tertiary care Intervention: azathioprine Comparison: no intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	No intervention	Azathioprine
Mortality at maximal follow‐up Follow‐up: 63 months in 1 trial and not stated in 1 trial	208 per 1000	128 per 1000 (78 to 205)	OR 0.56 (0.32 to 0.98)	224 (2 trials)	⊕⊝⊝⊝ Very low^1,2
Serious adverse events (proportion)	None of the trials reported this outcome.
Serious adverse events (number of events)	None of the trials reported this outcome.
Health‐related quality of life	None of the trials reported this outcome.
The basis for the assumed risk* is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias in the trial(s) was high (downgraded by two levels). ² Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels).

Summary of findings 2. Azathioprine versus no intervention for primary biliary cholangitis

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Summary of findings 3. Colchicine versus no intervention for primary biliary cholangitis

Colchicine versus no intervention for primary biliary cholangitis
Patient or population: people with primary biliary cholangitis Settings: secondary or tertiary care Intervention: colchicine Comparison: no intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	No intervention	Colchicine
Mortality at maximal follow‐up Follow‐up: 12 to 24 months	208 per 1000	168 per 1000 (78 to 327)	OR 0.77 (0.32 to 1.85)	122 (2 trials)	⊕⊝⊝⊝ Very low^1,2
Serious adverse events (proportion) Follow‐up: 12 months	There were no events in either group			64 (1 trial)	⊕⊝⊝⊝ Very low^1,2,3
Serious adverse events (number of events)	None of the trials reported this outcome.
Health‐related quality of life	None of the trials reported this outcome.
The basis for the assumed risk* is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias in the trial(s) was high (downgraded by two levels). ² Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels). ³ There was moderate heterogeneity (downgraded by one level).

Summary of findings 3. Colchicine versus no intervention for primary biliary cholangitis

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Summary of findings 4. Ciclosporin versus no intervention for primary biliary cholangitis

Ciclosporin versus no intervention for primary biliary cholangitis
Patient or population: people with primary biliary cholangitis Settings: secondary or tertiary care Intervention: ciclosporin Comparison: no intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	No intervention	Ciclosporin
Mortality at maximal follow‐up Follow‐up: 31 to 35 months	208 per 1000	188 per 1000 (118 to 283)	OR 0.88 (0.51 to 1.50)	390 (3 trials)	⊕⊝⊝⊝ Very low^1,2
Serious adverse events (proportion)	None of the trials reported this outcome.
Serious adverse events (number of events)	None of the trials reported this outcome.
Health‐related quality of life	None of the trials reported this outcome.
The basis for the assumed risk* is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias in the trial(s) was high (downgraded by two levels). ² Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels).

Summary of findings 4. Ciclosporin versus no intervention for primary biliary cholangitis

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Summary of findings 5. D‐Penicillamine versus no intervention for primary biliary cholangitis

D‐Penicillamine versus no intervention for primary biliary cholangitis
Patient or population: people with primary biliary cholangitis Settings: secondary or tertiary care Intervention: D‐penicillamine Comparison: no intervention
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	No intervention	D‐Penicillamine
Mortality at maximal follow‐up (Follow‐up 24 to 66 months)	208 per 1000	191 per 1000 (130 to 274)	OR 0.90 (0.57 to 1.44)	423 (5 trials)	⊕⊝⊝⊝ Very low^1,2,3
Serious adverse events (proportion) (Follow‐up 24 months)	4 per 1000	104 per 1000 (6 to 679)	OR 28.77 (1.57 to 526.67)	52 (1 trial)	⊕⊝⊝⊝ Very low^1,2,3
Serious adverse events (number of events)	None of the trials reported this outcome.
Health‐related quality of life	None of the trials reported this outcome.
The basis for the assumed risk* is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias in the trial(s) was high (downgraded by two levels). ² Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels). ³ There was moderate heterogeneity (downgraded by one level).

Summary of findings 5. D‐Penicillamine versus no intervention for primary biliary cholangitis

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Summary of findings 6. Colchicine plus ursodeoxycholic acid (UDCA) versus UDCA for primary biliary cholangitis

Colchicine plus UDCA versus UDCA for primary biliary cholangitis
Patient or population: people with primary biliary cholangitis Settings: secondary or tertiary care Intervention: colchicine + UDCA Comparison: UDCA
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	UDCA	Colchicine + UDCA
Mortality at maximal follow‐up Follow‐up: 24 months in 1 trial; not reported in 1 trial	110 per 1000	185 per 1000 (45 to 524)	OR 1.84 (0.38 to 8.91)	158 (2 trials)	⊕⊝⊝⊝ Very low^1,2
Serious adverse events (proportion) Follow‐up: not stated	14 per 1000	42 per 1000 (2 to 526)	OR 3.08 (0.12 to 78.14)	74 (1 trial)	⊕⊝⊝⊝ Very low^1,2,3
Serious adverse events (number of events)	None of the trials reported this outcome.
Health‐related quality of life	None of the trials reported this outcome.
The basis for the assumed risk* is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; UDCA: ursodeoxycholic acid.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias in the trial(s) was high (downgraded by two levels). ² Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels). ³ There was moderate heterogeneity (downgraded by one level).

Summary of findings 6. Colchicine plus ursodeoxycholic acid (UDCA) versus UDCA for primary biliary cholangitis

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Summary of findings 7. Methotrexate plus ursodeoxycholic acid (UDCA) versus UDCA for primary biliary cholangitis

Methotrexate plus UDCA versus UDCA for primary biliary cholangitis
Patient or population: people with primary biliary cholangitis Settings: secondary or tertiary care Intervention: methotrexate + UDCA Comparison: UDCA
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	UDCA	Methotrexate + UDCA
Mortality at maximal follow‐up Follow‐up: 11 to 91 months	110 per 1000	126 per 1000 (64 to 237)	OR 1.17 (0.55 to 2.51)	290 (2 trials)	⊕⊝⊝⊝ Very low^1,2
Serious adverse events (proportion)	None of the trials reported this outcome.
Serious adverse events (number of events)	None of the trials reported this outcome.
Health‐related quality of life	None of the trials reported this outcome.
The basis for the assumed risk* is the mean control group proportion across all the trials. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; UDCA: ursodeoxycholic acid.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias in the trial(s) was high (downgraded by two levels). ² Sample sizes were small and 95% confidence intervals overlapped clinically significant and clinically insignificant or no effect (downgraded by two levels). ³ There was moderate heterogeneity (downgraded by one level).

Summary of findings 7. Methotrexate plus ursodeoxycholic acid (UDCA) versus UDCA for primary biliary cholangitis

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Table 1. Characteristics of included studies arranged by comparison

Study name	No participants randomised	Post‐randomisation dropouts	No participants for whom outcome was reported	Intervention(s)	Control	Mean follow‐up period (months)
Smart 1990	20	Not stated	20	Antioxidants	No intervention	Not stated
Christensen 1985	248	63	185	Azathioprine	No intervention	63
Heathcote 1976	45	6	39	Azathioprine	No intervention	Not stated
Hoofnagle 1986	24	0	24	Chlorambucil	No intervention	52
Bodenheimer 1988	57	10	47	Colchicine	No intervention	33
Kaplan 1986	60	3	57	Colchicine	No intervention	24
Warnes 1987	64	Not stated	64*	Colchicine	No intervention	19 (median)
Bobadilla 1994	40	Not stated	40	Colchicine + UDCA	No intervention	12
Lombard 1993	349	0	349	Ciclosporin	No intervention	31 (median)
Minuk 1988	12	0	12	Ciclosporin	No intervention	Not stated
Wiesner 1990	40	11	29	Ciclosporin	No intervention	35 (median)
Dickson 1985	309	82	227	D‐Penicillamine	No intervention	60 (median)
Epstein 1979	98	Not stated	98	D‐Penicillamine	No intervention	66
Macklon 1982	60	0	60	D‐Penicillamine	No intervention	37
Matloff 1982	52	0	52	D‐Penicillamine	No intervention	24
Neuberger 1985	189	Not stated	189	D‐Penicillamine	No intervention	Not stated
Taal 1983	24	Not stated	24	D‐Penicillamine	No intervention	18
Triger 1980	35	Not stated	35	D‐Penicillamine	No intervention	Not stated
Mitchison 1989	36	0	36	Glucocorticosteroids	No intervention	36
Ueno 2005	20	Not stated	20	Lamivudine	No intervention	Not stated
Mitchison 1993	104	3	101	Malotilate	No intervention	25 (median)
Hendrickse 1999	60	Not stated	60	Methotrexate	No intervention	68
Steenbergen 1994	14	Not stated	14	Methotrexate + UDCA	No intervention	24
Mayo 2015	45	3	42	NGM282	No intervention	Not stated
Bowlus 2014	216	Not stated	216	Obeticholic acid	No intervention	12
Hirschfield 2015	165	0	165	Obeticholic acid	No intervention	3
Kowdley 2014a	59	Not stated	59	Obeticholic acid	No intervention	Not stated
Manzillo 1993a	32	Not stated	32	S‐Adenosyl methionine	No intervention	1
Manzillo 1993b	6	Not stated	6	S‐Adenosyl methionine	No intervention	2
Cash 2013	21	8	13	Simvastatin	No intervention	12
Askari 2010	28	0	28	Tetrathiomolybdate	No intervention	Not stated
McCormick 1994	18	0	18	Thalidomide	No intervention	Not stated
Arora 1990	9	Not stated	9	UDCA	No intervention	5
Battezzati 1993	88	2	86	UDCA	No intervention	6
Combes 1995a	151	0	151	UDCA	No intervention	24
Eriksson 1997	116	15	101	UDCA	No intervention	24
Heathcote 1994	222	Not stated	222	UDCA	No intervention	24
Leuschner 1989	20	0	18	UDCA	No intervention	12
Lim 1994	32	Not stated	32	UDCA	No intervention	Not stated
Lindor 1994	180	10	170	UDCA	No intervention	24
Oka 1990	52	7	45	UDCA	No intervention	Not stated
Papatheodoridis 2002	92	6	86	UDCA	No intervention	89
Pares 2000	192	0	192	UDCA	No intervention	41 (median)
Poupon 1991a	149	3	146	UDCA	No intervention	Not stated
Senior 1991	20	1	19	UDCA	No intervention	18
Turner 1994	46	0	46	UDCA	No intervention	24
Goddard 1994	57	Not stated	57	Intervention 1: UDCA Intervention 2: colchicine Intervention 3: colchicine + UDCA	No intervention	15
Wolfhagen 1998	50	Not stated	50	Azathioprine + glucocorticosteroids + UDCA	UDCA	12
Iwasaki 2008a	45	Not stated	45	Bezafibrate	UDCA	12
Kurihara 2000	24	Not stated	24	Bezafibrate	UDCA	Not stated
Hosonuma 2015	27	0	27	Bezafibrate + UDCA	UDCA	96
Iwasaki 2008b	22	Not stated	22	Bezafibrate + UDCA	UDCA	12
Kanda 2003	22	0	22	Bezafibrate + UDCA	UDCA	7
Nakai 2000	23	Not stated	23	Bezafibrate + UDCA	UDCA	12
Almasio 2000	90	6	84	Colchicine + UDCA	UDCA	Not stated
Ikeda 1996	22	0	22	Colchicine + UDCA	UDCA	24
Poupon 1996	74	Not stated	74	Colchicine + UDCA	UDCA	24
Raedsch 1993	28	8	20	Colchicine + UDCA	UDCA	24
Yokomori 2001	11	Not stated	11	Colestilan + UDCA	UDCA	Not stated
Liberopoulos 2010	10	Not stated	10	Fenofibrate + UDCA	UDCA	Not stated
Leuschner 1999	40	0	39	Glucocorticosteroids + UDCA	UDCA	24
Rautiainen 2005	77	8	69	Glucocorticosteroids + UDCA	UDCA	36
Gao 2012	79	Not stated	79	Intervention 1: glucocorticosteroids + UDCA Intervention 2: azathioprine + UDCA	UDCA	Not stated
Mason 2008	59	0	59	Lamivudine + zidovudine + UDCA	UDCA	6
Combes 2005	265	0	265	Methotrexate + UDCA	UDCA	91 (median)
Gonzalezkoch 1997	25	Not stated	25	Methotrexate + UDCA	UDCA	11
Nevens 2016	217	Not stated	216	Obeticholic acid + UDCA	UDCA	12
Ferri 1993	30	0	30	TUDCA	UDCA	6
Ma 2016	199	8	191	TUDCA	UDCA	6
Kaplan 1999	87	2	85	Colchicine	Methotrexate	24
Comparison of doses
Lindor 1997	150	Not stated	150	Intervention 1: UDCA (high) Intervention 2: UDCA (moderate)	UDCA (low)	12
Angulo 1999a	155	Not stated	155	Intervention 1: UDCA (high) Intervention 2: UDCA (moderate)	UDCA (low)	12
Van Hoogstraten 1998	61	2	59	UDCA (moderate)	UDCA (low)	Not stated
Mazzarella 2002	42	Not stated	42	UDCA (high)	UDCA (moderate)	72
TUDCA: taurodeoxycholic acid; UDCA: ursodeoxycholic acid.

Table 1. Characteristics of included studies arranged by comparison

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Table 2. Risk of bias arranged according to comparisons

Name of studies	Intervention(s)	Control	Random sequence generation	Allocation concealment	Blinding of participants and health professionals	Blinding of outcome assessors	Missing outcome bias	Selective outcome reporting	For‐profit bias	Other bias
Smart 1990	Antioxidants	No intervention	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Christensen 1985	Azathioprine	No intervention	Unclear	Unclear	Low	Low	High	High	High	Low
Heathcote 1976	Azathioprine	No intervention	Unclear	Unclear	High	High	High	High	Low	Low
Hoofnagle 1986	Chlorambucil	No intervention	Low	Low	High	High	Low	Low	Low	Low
Bodenheimer 1988	Colchicine	No intervention	Unclear	Unclear	Low	Low	High	High	High	Low
Kaplan 1986	Colchicine	No intervention	Unclear	Unclear	Unclear	Unclear	High	High	Unclear	Low
Warnes 1987	Colchicine	No intervention	Low	Low	Low	Low	Unclear	Low	Unclear	Low
Bobadilla 1994	Colchicine + UDCA	No intervention	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Lombard 1993	Ciclosporin	No intervention	Unclear	Unclear	Low	Low	Low	Low	High	Low
Minuk 1988	Ciclosporin	No intervention	Unclear	Unclear	Low	Unclear	Unclear	Low	High	Low
Wiesner 1990	Ciclosporin	No intervention	Unclear	Unclear	Low	Low	Unclear	Low	High	Low
Dickson 1985	D‐Penicillamine	No intervention	Low	Low	Low	Low	High	High	High	High
Epstein 1979	D‐Penicillamine	No intervention	Unclear	Unclear	High	High	Unclear	High	Unclear	Low
Macklon 1982	D‐Penicillamine	No intervention	Unclear	Unclear	Unclear	Unclear	Low	Low	Unclear	Low
Matloff 1982	D‐Penicillamine	No intervention	Unclear	Unclear	Unclear	Unclear	Low	Low	High	Low
Neuberger 1985	D‐Penicillamine	No intervention	Unclear	Low	Low	Low	Unclear	High	Unclear	Low
Taal 1983	D‐Penicillamine	No intervention	Unclear	Unclear	Low	Low	Unclear	Low	Unclear	Low
Triger 1980	D‐Penicillamine	No intervention	Unclear	Unclear	Unclear	Unclear	Unclear	High	High	Low
Mitchison 1989	Glucocorticosteroids	No intervention	Low	Low	High	High	Low	High	Unclear	Low
Ueno 2005	Lamivudine	No intervention	Unclear	Unclear	Low	Low	Unclear	High	Unclear	Low
Mitchison 1993	Malotilate	No intervention	Low	Low	Low	Low	High	Low	High	Low
Hendrickse 1999	Methotrexate	No intervention	Low	Low	Unclear	Unclear	Unclear	High	Unclear	Low
Steenbergen 1994	Methotrexate + UDCA	No intervention	Low	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Mayo 2015	NGM282	No intervention	Unclear	Unclear	Unclear	Unclear	High	High	High	Low
Bowlus 2014	Obeticholic acid	No intervention	Unclear	Unclear	Unclear	Unclear	Unclear	High	High	Low
Hirschfield 2015	Obeticholic acid	No intervention	Low	Unclear	Low	Low	Low	High	Unclear	High
Kowdley 2011	Obeticholic acid	No intervention	Unclear	Unclear	Unclear	Unclear	Unclear	High	High	Low
Manzillo 1993a	S‐Adenosyl methionine	No intervention	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Manzillo 1993b	S‐Adenosyl methionine	No intervention	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Cash 2013	Simvastatin	No intervention	Unclear	Low	High	High	High	High	Low	High
Askari 2010	Tetrathiomolybdate	No intervention	Low	Low	Low	Low	Low	High	Low	High
McCormick 1994	Thalidomide	No intervention	Unclear	Unclear	Low	Low	Low	High	High	Low
Arora 1990	UDCA	No intervention	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Battezzati 1993	UDCA	No intervention	Low	Low	Low	Low	High	High	Unclear	Low
Combes 1995a	UDCA	No intervention	Unclear	Unclear	Low	Low	Low	High	High	Low
Eriksson 1997	UDCA	No intervention	Unclear	Unclear	Unclear	Unclear	High	High	High	Low
Heathcote 1994	UDCA	No intervention	Unclear	Low	Low	Low	Unclear	High	High	Low
Leuschner 1989	UDCA	No intervention	Unclear	Unclear	Unclear	Unclear	High	Low	Unclear	Low
Lim 1994	UDCA	No intervention	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Lindor 1994	UDCA	No intervention	Unclear	Unclear	Low	Low	High	Low	High	Low
Oka 1990	UDCA	No intervention	Unclear	Low	Low	Low	High	High	High	Low
Papatheodoridis 2002	UDCA	No intervention	Low	Low	High	High	High	High	High	High
Pares 2000	UDCA	No intervention	Unclear	Unclear	Low	Low	Unclear	Low	High	Low
Poupon 1991a	UDCA	No intervention	Unclear	Unclear	Low	Low	High	High	High	Low
Senior 1991	UDCA	No intervention	Unclear	Unclear	Unclear	Unclear	High	High	High	Low
Turner 1994	UDCA	No intervention	Unclear	Unclear	Low	Low	Low	High	Unclear	Low
Goddard 1994	Intervention 1: UDCA Intervention 2: colchicine Intervention 3: colchicine + UDCA	No intervention	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Wolfhagen 1998	Azathioprine + glucocorticosteroids + UDCA	UDCA	Low	Low	Low	Low	Unclear	High	High	Low
Iwasaki 2008a	Bezafibrate	UDCA	Unclear	Low	High	High	Unclear	High	Low	Low
Kurihara 2000	Bezafibrate	UDCA	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Hosonuma 2015	Bezafibrate + UDCA	UDCA	Low	Low	High	High	Low	Low	Low	Low
Iwasaki 2008b	Bezafibrate + UDCA	UDCA	Unclear	Low	High	High	Unclear	High	Low	Low
Kanda 2003	Bezafibrate + UDCA	UDCA	Unclear	Unclear	Unclear	Unclear	Low	High	Unclear	Low
Nakai 2000	Bezafibrate + UDCA	UDCA	Unclear	Unclear	Unclear	Unclear	Unclear	High	Low	Low
Almasio 2000	Colchicine + UDCA	UDCA	Low	Low	Low	Low	High	High	Low	Low
Ikeda 1996	Colchicine + UDCA	UDCA	Unclear	Unclear	Unclear	Unclear	Low	High	Unclear	High
Poupon 1996	Colchicine + UDCA	UDCA	Unclear	Unclear	Low	Low	Unclear	Low	High	Low
Raedsch 1993	Colchicine + UDCA	UDCA	Unclear	Unclear	Unclear	Unclear	High	High	Unclear	Low
Yokomori 2001	Colestilan + UDCA	UDCA	Unclear	Unclear	High	High	Unclear	High	Unclear	Low
Liberopoulos 2010	Fenofibrate + UDCA	UDCA	Unclear	Unclear	High	High	Unclear	High	Unclear	Low
Leuschner 1999	Glucocorticosteroids + UDCA	UDCA	Low	Unclear	Unclear	Unclear	High	High	High	Low
Rautiainen 2005	Glucocorticosteroids + UDCA	UDCA	Unclear	Unclear	High	High	High	High	High	Low
Gao 2012	Glucocorticosteroids + UDCA Azathioprine + UDCA	UDCA	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Mason 2008	Lamivudine + zidovudine + UDCA	UDCA	Low	Low	Low	Low	Unclear	High	High	Low
Combes 2005	Methotrexate + UDCA	UDCA	Unclear	Unclear	Unclear	Unclear	Low	High	High	Low
Gonzalezkoch 1997	Methotrexate + UDCA	UDCA	Unclear	Low	Unclear	Unclear	Unclear	Low	Unclear	Low
Nevens 2016	Obeticholic acid + UDCA	UDCA	Low	Low	Low	Low	High	Low	High	Low
Ferri 1993	TUDCA	UDCA	Unclear	Unclear	Unclear	Unclear	Low	High	Unclear	Low
Ma 2016	TUDCA	UDCA	Low	Low	Low	Low	Unclear	High	High	Low
Kaplan 1999	Colchicine	Methotrexate	Unclear	Unclear	Low	Low	High	High	Unclear	Low
Comparison of doses
Lindor 1997	Intervention 1: UDCA (high) Intervention 2: UDCA (moderate)	UDCA (low)	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
Angulo 1999a	Intervention 1: UDCA (high) Intervention 2: UDCA (moderate)	UDCA (low)	Low	Low	Low	Low	Unclear	Low	Unclear	Low
Van Hoogstraten 1998	UDCA (moderate)	UDCA (low)	Low	Low	High	High	Unclear	High	High	Low
Mazzarella 2002	UDCA (high)	UDCA (moderate)	Unclear	Unclear	Unclear	Unclear	Unclear	High	Unclear	Low
TUDCA: taurodeoxycholic acid; UDCA: ursodeoxycholic acid.

Table 2. Risk of bias arranged according to comparisons

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Comparison 1. Main analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality at maximal follow‐up Show forest plot	28		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Azathioprine versus no intervention	2	224	Odds Ratio (M‐H, Fixed, 95% CI)	0.56 [0.32, 0.98]
1.2 Chlorambucil versus no intervention	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 3.28]
1.3 Colchicine versus no intervention	2	122	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.32, 1.85]
1.4 Cyclosporin versus no intervention	3	390	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.51, 1.50]
1.5 D‐Penicillamine versus no intervention	5	423	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.57, 1.44]
1.6 Glucocorticosteroids versus no intervention	1	36	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.14, 2.92]
1.7 Malotilate versus no intervention	1	101	Odds Ratio (M‐H, Fixed, 95% CI)	2.0 [0.47, 8.48]
1.8 Methotrexate versus no intervention	1	60	Odds Ratio (M‐H, Fixed, 95% CI)	8.83 [1.01, 76.96]
1.9 UDCA versus no intervention	6	734	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.60, 1.64]
1.10 Bezafibrate plus UDCA versus UDCA	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	9.67 [0.45, 207.78]
1.11 Colchicine plus UDCA versus UDCA	2	158	Odds Ratio (M‐H, Fixed, 95% CI)	1.84 [0.38, 8.91]
1.12 Methotrexate plus UDCA versus UDCA	2	290	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.55, 2.51]
1.13 Obeticholic acid plus UDCA versus UDCA	1	216	Odds Ratio (M‐H, Fixed, 95% CI)	1.55 [0.06, 38.46]
2 Mortality (< 1 year) Show forest plot	8		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Azathioprine versus no intervention	1	39	Odds Ratio (M‐H, Fixed, 95% CI)	0.58 [0.16, 2.10]
2.2 Colchicine versus no intervention	1	64	Odds Ratio (M‐H, Fixed, 95% CI)	0.86 [0.22, 3.33]
2.3 Cyclosporin versus no intervention	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 3.63]
2.4 D‐Penicillamine versus no intervention	1	189	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.35, 1.42]
2.5 Ursodeoxycholic acid (UDCA) versus no intervention	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.6 Colchicine plus UDCA versus UDCA	1	84	Odds Ratio (M‐H, Fixed, 95% CI)	1.0 [0.13, 7.45]
2.7 Methotrexate plus UDCA versus UDCA	1	25	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.8 Obeticholic acid plus UDCA versus UDCA	1	216	Odds Ratio (M‐H, Fixed, 95% CI)	1.55 [0.06, 38.46]
3 Mortality (1 to 5 years) Show forest plot	20		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Azathioprine versus no intervention	1	185	Odds Ratio (M‐H, Fixed, 95% CI)	0.56 [0.30, 1.04]
3.2 Chlorambucil versus no intervention	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 3.28]
3.3 Colchicine versus no intervention	1	58	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.22, 2.25]
3.4 Cyclosporin versus no intervention	2	378	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.54, 1.64]
3.5 D‐Penicillamine versus no intervention	4	234	Odds Ratio (M‐H, Fixed, 95% CI)	1.10 [0.59, 2.08]
3.6 Glucocorticosteroids versus no intervention	1	36	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.14, 2.92]
3.7 Malotilate versus no intervention	1	101	Odds Ratio (M‐H, Fixed, 95% CI)	2.0 [0.47, 8.48]
3.8 Methotrexate versus no intervention	1	60	Odds Ratio (M‐H, Fixed, 95% CI)	8.83 [1.01, 76.96]
3.9 UDCA versus no intervention	5	716	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.60, 1.64]
3.10 Bezafibrate plus UDCA versus UDCA	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	9.67 [0.45, 207.78]
3.11 Colchicine plus UDCA versus UDCA	1	74	Odds Ratio (M‐H, Fixed, 95% CI)	5.28 [0.24, 113.87]
3.12 Methotrexate plus UDCA versus UDCA	1	265	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.55, 2.51]
4 Serious adverse events (proportion) Show forest plot	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Colchicine versus no intervention	1	64	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 D‐Penicillamine versus no intervention	1	52	Odds Ratio (M‐H, Fixed, 95% CI)	28.77 [1.57, 526.67]
4.3 Obeticholic acid versus no intervention	1	165	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [0.21, 15.73]
4.4 UDCA versus no intervention	3	380	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 UDCA versus bezafibrate	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Bezafibrate plus UDCA versus UDCA	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 Colchicine plus UDCA versus UDCA	1	74	Odds Ratio (M‐H, Fixed, 95% CI)	3.08 [0.12, 78.14]
4.8 Lamivudine plus zidovudine plus UDCA versus UDCA	1	59	Odds Ratio (M‐H, Fixed, 95% CI)	0.47 [0.04, 5.43]
4.9 Obeticholic acid plus UDCA versus UDCA	1	216	Odds Ratio (M‐H, Fixed, 95% CI)	3.58 [1.02, 12.51]
5 Serious adverse events (number of events) Show forest plot	1		Rate Ratio (Fixed, 95% CI)	Subtotals only

5.1 Obeticholic acid plus UDCA versus UDCA	1	216	Rate Ratio (Fixed, 95% CI)	1.66 [0.75, 3.66]
6 Adverse events (proportion) Show forest plot	19		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Cyclosporin versus no intervention	3	390	Odds Ratio (M‐H, Fixed, 95% CI)	3.04 [1.98, 4.68]
6.2 D‐Penicillamine versus no intervention	2	287	Odds Ratio (M‐H, Fixed, 95% CI)	4.51 [2.56, 7.93]
6.3 Malotilate versus no intervention	1	101	Odds Ratio (M‐H, Fixed, 95% CI)	11.43 [1.40, 93.04]
6.4 Obeticholic acid versus no intervention	1	165	Odds Ratio (M‐H, Fixed, 95% CI)	4.58 [1.31, 15.95]
6.5 UDCA versus no intervention	3	380	Odds Ratio (M‐H, Fixed, 95% CI)	1.45 [0.50, 4.25]
6.6 Azathioprine plus UDCA versus UDCA	1	42	Odds Ratio (M‐H, Fixed, 95% CI)	19.67 [0.94, 413.50]
6.7 Bezafibrate versus UDCA	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.8 Bezafibrate plus UDCA versus UDCA	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	3.29 [0.12, 89.81]
6.9 Colchicine plus UDCA versus UDCA	2	42	Odds Ratio (M‐H, Fixed, 95% CI)	6.20 [0.63, 60.80]
6.10 Colestilan plus UDCA versus UDCA	1	11	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.11 Glucocorticosteroids plus UDCA versus UDCA	2	135	Odds Ratio (M‐H, Fixed, 95% CI)	5.54 [1.35, 22.84]
6.12 Methotrexate plus UDCA versus UDCA	1	25	Odds Ratio (M‐H, Fixed, 95% CI)	115.0 [4.98, 2657.48]
6.13 TauroUDCA versus UDCA	1	30	Odds Ratio (M‐H, Fixed, 95% CI)	21.0 [2.16, 204.61]
6.14 Glucocorticosteroids plus UDCA versus azathioprine plus UDCA	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	0.40 [0.08, 2.12]
7 Adverse events (number) Show forest plot	14		Rate Ratio (Random, 95% CI)	Subtotals only

7.1 Chlorambucil versus no intervention	1	24	Rate Ratio (Random, 95% CI)	3.67 [1.04, 12.87]
7.2 Cyclosporin versus no intervention	3	390	Rate Ratio (Random, 95% CI)	2.58 [1.26, 5.31]
7.3 D‐Penicillamine versus no intervention	3	303	Rate Ratio (Random, 95% CI)	2.99 [1.04, 8.63]
7.4 Malotilate versus no intervention	1	101	Rate Ratio (Random, 95% CI)	6.13 [1.38, 27.14]
7.5 Obeticholic acid versus no intervention	1	76	Rate Ratio (Random, 95% CI)	1.41 [1.13, 1.75]
7.6 Azathioprine plus glucocorticosteroids plus UDCA versus UDCA	1	50	Rate Ratio (Random, 95% CI)	1.32 [0.88, 1.97]
7.7 Bezafibrate plus UDCA versus UDCA	1	29	Rate Ratio (Random, 95% CI)	11.79 [0.65, 213.14]
7.8 Colchicine plus UDCA versus UDCA	1	24	Rate Ratio (Random, 95% CI)	5.91 [0.28, 123.08]
7.9 Methotrexate plus UDCA versus UDCA	1	27	Rate Ratio (Random, 95% CI)	30.64 [1.84, 510.76]
7.10 TauroUDCA versus UDCA	1	191	Rate Ratio (Random, 95% CI)	1.17 [0.81, 1.71]
8 Liver transplantation Show forest plot	11		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.1 Cyclosporin versus no intervention	2	378	Odds Ratio (M‐H, Fixed, 95% CI)	0.86 [0.43, 1.72]
8.2 D‐Penicillamine versus no intervention	1	189	Odds Ratio (M‐H, Fixed, 95% CI)	0.93 [0.06, 15.05]
8.3 Methotrexate versus no intervention	1	60	Odds Ratio (M‐H, Fixed, 95% CI)	0.17 [0.02, 1.58]
8.4 UDCA versus no intervention	5	640	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.48, 1.68]
8.5 Bezafibrate plus UDCA versus UDCA	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.6 Methotrexate plus UDCA versus UDCA	1	265	Odds Ratio (M‐H, Fixed, 95% CI)	0.70 [0.35, 1.39]
9 Decompensated liver disease Show forest plot	7		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 D‐Penicillamine versus no active treatment	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 UDCA versus no intervention	2	237	Odds Ratio (M‐H, Fixed, 95% CI)	1.60 [0.86, 2.98]
9.3 Azathioprine plus UDCA versus UDCA	1	42	Odds Ratio (M‐H, Fixed, 95% CI)	0.52 [0.05, 5.18]
9.4 Colchicine plus UDCA versus UDCA	1	84	Odds Ratio (M‐H, Fixed, 95% CI)	0.21 [0.04, 1.07]
9.5 Glucocorticosteroids plus UDCA versus UDCA	1	66	Odds Ratio (M‐H, Fixed, 95% CI)	0.55 [0.11, 2.69]
9.6 Methotrexate plus UDCA versus UDCA	1	265	Odds Ratio (M‐H, Fixed, 95% CI)	1.34 [0.77, 2.33]
9.7 Obeticholic acid plus UDCA versus UDCA	1	216	Odds Ratio (M‐H, Fixed, 95% CI)	1.55 [0.06, 38.46]
9.8 Glucocorticosteroids plus UDCA versus azathioprine plus UDCA	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.10, 11.18]
10 Cirrhosis Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 Azathioprine versus no intervention	1	31	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.18, 3.41]
10.2 UDCA versus no intervention	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 1.53]
10.3 Azathioprine plus glucocorticosteroids plus UDCA versus UDCA	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	0.28 [0.03, 2.90]

Comparison 1. Main analysis

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Comparison 2. Stratified by dose

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality at maximal follow‐up Show forest plot	29		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Azathioprine versus no intervention	2	224	Odds Ratio (M‐H, Fixed, 95% CI)	0.56 [0.32, 0.98]
1.2 Chlorambucil versus no intervention	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 3.28]
1.3 Colchicine versus no intervention	2	122	Odds Ratio (M‐H, Fixed, 95% CI)	0.77 [0.32, 1.85]
1.4 Cyclosporin versus no intervention	3	390	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.51, 1.50]
1.5 D‐Penicillamine versus no intervention	5	423	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.57, 1.44]
1.6 Glucocorticosteroids versus no intervention	1	36	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.14, 2.92]
1.7 Malotilate versus no intervention	1	101	Odds Ratio (M‐H, Fixed, 95% CI)	2.0 [0.47, 8.48]
1.8 Methotrexate versus no intervention	1	60	Odds Ratio (M‐H, Fixed, 95% CI)	8.83 [1.01, 76.96]
1.9 UDCA (low) versus no intervention	2	64	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.47]
1.10 UDCA (moderate) versus no intervention	4	670	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.62, 1.77]
1.11 UDCA (low) versus UDCA (high)	1	106	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.06, 17.06]
1.12 UDCA (moderate) versus UDCA (high)	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	0.36 [0.01, 9.05]
1.13 UDCA (low) plus colchicine versus UDCA (low)	1	84	Odds Ratio (M‐H, Fixed, 95% CI)	1.0 [0.13, 7.45]
1.14 UDCA (low) plus methotrexate versus UDCA (low)	1	25	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.15 UDCA (moderate) versus UDCA (low)	1	101	Odds Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.72]
1.16 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	9.67 [0.45, 207.78]
1.17 Colchicine plus UDCA (moderate) versus UDCA (moderate)	1	74	Odds Ratio (M‐H, Fixed, 95% CI)	5.28 [0.24, 113.87]
1.18 Methotrexate plus UDCA (moderate) versus UDCA (moderate)	1	265	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.55, 2.51]
1.19 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)	1	216	Odds Ratio (M‐H, Fixed, 95% CI)	1.55 [0.06, 38.46]
2 Mortality (< 1 year) Show forest plot	9		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Azathioprine versus no intervention	1	39	Odds Ratio (M‐H, Fixed, 95% CI)	0.58 [0.16, 2.10]
2.2 Colchicine versus no intervention	1	64	Odds Ratio (M‐H, Fixed, 95% CI)	0.86 [0.22, 3.33]
2.3 Cyclosporin versus no intervention	1	12	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 3.63]
2.4 D‐Penicillamine versus no intervention	1	189	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.35, 1.42]
2.5 UDCA (low) versus no intervention	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.6 UDCA (low) versus UDCA (high)	1	106	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.06, 17.06]
2.7 UDCA (moderate) versus UDCA (high)	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	0.36 [0.01, 9.05]
2.8 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)	1	216	Odds Ratio (M‐H, Fixed, 95% CI)	1.55 [0.06, 38.46]
2.9 UDCA (low) plus colchicine versus UDCA (low)	1	84	Odds Ratio (M‐H, Fixed, 95% CI)	1.0 [0.13, 7.45]
2.10 UDCA (low) plus methotrexate versus UDCA (low)	1	25	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.11 UDCA (moderate) versus UDCA (low)	1	101	Odds Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.72]
3 Mortality (1 to 5 years) Show forest plot	20		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Azathioprine versus no intervention	1	185	Odds Ratio (M‐H, Fixed, 95% CI)	0.56 [0.30, 1.04]
3.2 Chlorambucil versus no intervention	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 3.28]
3.3 Colchicine versus no intervention	1	58	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.22, 2.25]
3.4 Cyclosporin versus no intervention	2	378	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.54, 1.64]
3.5 D‐Penicillamine versus no intervention	4	234	Odds Ratio (M‐H, Fixed, 95% CI)	1.10 [0.59, 2.08]
3.6 Glucocorticosteroids versus no intervention	1	36	Odds Ratio (M‐H, Fixed, 95% CI)	0.64 [0.14, 2.92]
3.7 Malotilate versus no intervention	1	101	Odds Ratio (M‐H, Fixed, 95% CI)	2.0 [0.47, 8.48]
3.8 Methotrexate versus no intervention	1	60	Odds Ratio (M‐H, Fixed, 95% CI)	8.83 [1.01, 76.96]
3.9 UDCA (low) versus no intervention	1	46	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.47]
3.10 UDCA (moderate) versus no intervention	4	670	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.62, 1.77]
3.11 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	9.67 [0.45, 207.78]
3.12 Colchicine plus UDCA (moderate) versus UDCA (moderate)	1	74	Odds Ratio (M‐H, Fixed, 95% CI)	5.28 [0.24, 113.87]
3.13 Methotrexate plus UDCA (moderate) versus UDCA (moderate)	1	265	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.55, 2.51]
4 Serious adverse events (proportion) Show forest plot	12		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Colchicine versus no intervention	1	64	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 D‐Penicillamine versus no intervention	1	52	Odds Ratio (M‐H, Fixed, 95% CI)	28.77 [1.57, 526.67]
4.3 Obeticholic acid (high) versus no intervention	1	79	Odds Ratio (M‐H, Fixed, 95% CI)	5.14 [0.57, 46.17]
4.4 Obeticholic acid (low) versus no intervention	1	76	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 8.22]
4.5 Obeticholic acid (moderate) versus no intervention	1	86	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.05, 13.01]
4.6 UDCA (low) versus no intervention	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 UDCA (moderate) versus no intervention	2	362	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.8 UDCA (low) versus bezafibrate	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.9 Obeticholic acid (low) versus obeticholic acid (high)	1	79	Odds Ratio (M‐H, Fixed, 95% CI)	0.09 [0.00, 1.61]
4.10 Obeticholic acid (moderate) versus obeticholic acid (high)	1	89	Odds Ratio (M‐H, Fixed, 95% CI)	0.15 [0.02, 1.37]
4.11 Obeticholic acid (moderate) versus obeticholic acid (low)	1	86	Odds Ratio (M‐H, Fixed, 95% CI)	2.43 [0.10, 61.39]
4.12 Lamivudine plus zidovudine plus UDCA (moderate) versus UDCA (moderate)	1	59	Odds Ratio (M‐H, Fixed, 95% CI)	0.47 [0.04, 5.43]
4.13 UDCA (moderate) versus obeticholic acid (low) plus UDCA (moderate)	1	216	Odds Ratio (M‐H, Fixed, 95% CI)	0.28 [0.08, 0.98]
4.14 Bezafibrate plus UDCA (low) versus UDCA (low)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.15 UDCA (moderate) versus UDCA (low)	1	59	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.16 Colchicine plus UDCA (moderate) versus UDCA (moderate)	1	74	Odds Ratio (M‐H, Fixed, 95% CI)	3.08 [0.12, 78.14]
5 Serious adverse events (number of events) Show forest plot	1		Rate Ratio (Fixed, 95% CI)	Subtotals only

5.1 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)	1		Rate Ratio (Fixed, 95% CI)	1.66 [0.75, 3.66]
6 Adverse events (proportion) Show forest plot	20		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Cyclosporin versus no intervention	3	390	Odds Ratio (M‐H, Fixed, 95% CI)	3.04 [1.98, 4.68]
6.2 D‐Penicillamine versus no intervention	2	287	Odds Ratio (M‐H, Fixed, 95% CI)	4.51 [2.56, 7.93]
6.3 Malotilate versus no intervention	1	101	Odds Ratio (M‐H, Fixed, 95% CI)	11.43 [1.40, 93.04]
6.4 Obeticholic acid (high) versus no intervention	1	79	Odds Ratio (M‐H, Fixed, 95% CI)	16.6 [0.90, 305.59]
6.5 Obeticholic acid (low) versus no intervention	1	76	Odds Ratio (M‐H, Fixed, 95% CI)	1.59 [0.41, 6.17]
6.6 Obeticholic acid (moderate) versus no intervention	1	86	Odds Ratio (M‐H, Fixed, 95% CI)	8.81 [1.01, 76.73]
6.7 UDCA (low) versus no intervention	1	18	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.8 UDCA (moderate) versus no intervention	2	362	Odds Ratio (M‐H, Fixed, 95% CI)	1.45 [0.50, 4.25]
6.9 Glucocorticosteroids plus UDCA (moderate) versus azathioprine plus UDCA (moderate)	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	0.40 [0.08, 2.12]
6.10 UDCA (low) versus bezafibrate	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.11 Obeticholic acid (low) versus obeticholic acid (high)	1	79	Odds Ratio (M‐H, Fixed, 95% CI)	0.09 [0.00, 1.78]
6.12 Obeticholic acid (moderate) versus obeticholic acid (high)	1	89	Odds Ratio (M‐H, Fixed, 95% CI)	0.38 [0.02, 9.62]
6.13 Obeticholic acid (moderate) versus obeticholic acid (low)	1	86	Odds Ratio (M‐H, Fixed, 95% CI)	5.53 [0.59, 51.70]
6.14 Bezafibrate plus UDCA (low) versus UDCA (low)	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	3.29 [0.12, 89.81]
6.15 Colestilan plus UDCA (low) versus UDCA (low)	1	11	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.16 Methotrexate plus UDCA (low) versus UDCA (low)	1	25	Odds Ratio (M‐H, Fixed, 95% CI)	115.0 [4.98, 2657.48]
6.17 UDCA (moderate) versus UDCA (low)	1	59	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.18 Azathioprine plus UDCA (moderate) versus UDCA (moderate)	1	42	Odds Ratio (M‐H, Fixed, 95% CI)	19.67 [0.94, 413.50]
6.19 Colchicine plus UDCA (moderate) versus UDCA (moderate)	2	42	Odds Ratio (M‐H, Fixed, 95% CI)	6.20 [0.63, 60.80]
6.20 Glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)	2	135	Odds Ratio (M‐H, Fixed, 95% CI)	5.54 [1.35, 22.84]
6.21 TauroUDCA (moderate) versus UDCA (moderate)	1	30	Odds Ratio (M‐H, Fixed, 95% CI)	21.0 [2.16, 204.61]
7 Adverse events (number) Show forest plot	15		Rate Ratio (Fixed, 95% CI)	Subtotals only

7.1 Chlorambucil versus no intervention	1		Rate Ratio (Fixed, 95% CI)	3.67 [1.04, 12.87]
7.2 Cyclosporin versus no intervention	3		Rate Ratio (Fixed, 95% CI)	1.87 [1.51, 2.32]
7.3 D‐Penicillamine versus no intervention	3		Rate Ratio (Fixed, 95% CI)	2.64 [1.78, 3.91]
7.4 Malotilate versus no intervention	1		Rate Ratio (Fixed, 95% CI)	6.13 [1.38, 27.14]
7.5 Obeticholic acid (high) versus no intervention	1		Rate Ratio (Fixed, 95% CI)	1.91 [1.50, 2.44]
7.6 Obeticholic acid (low) versus no intervention	1		Rate Ratio (Fixed, 95% CI)	1.05 [0.80, 1.39]
7.7 Obeticholic acid (moderate) versus no intervention	1		Rate Ratio (Fixed, 95% CI)	1.25 [0.97, 1.62]
7.8 Obeticholic acid (low) versus obeticholic acid (high)	1		Rate Ratio (Fixed, 95% CI)	0.55 [0.43, 0.70]
7.9 Obeticholic acid (moderate) versus obeticholic acid (high)	1		Rate Ratio (Fixed, 95% CI)	0.66 [0.53, 0.81]
7.10 Obeticholic acid (moderate) versus obeticholic acid (low)	1		Rate Ratio (Fixed, 95% CI)	1.19 [0.93, 1.53]
7.11 UDCA (low) versus UDCA (high)	1		Rate Ratio (Fixed, 95% CI)	2.08 [0.78, 5.53]
7.12 UDCA (moderate) versus UDCA (high)	1		Rate Ratio (Fixed, 95% CI)	0.73 [0.21, 2.60]
7.13 UDCA (low) plus methotrexate versus UDCA (low)	1		Rate Ratio (Fixed, 95% CI)	30.64 [1.84, 510.76]
7.14 UDCA (moderate) versus UDCA (low)	1		Rate Ratio (Fixed, 95% CI)	0.35 [0.11, 1.10]
7.15 Azathioprine plus glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)	1		Rate Ratio (Fixed, 95% CI)	1.32 [0.88, 1.97]
7.16 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)	1		Rate Ratio (Fixed, 95% CI)	11.79 [0.65, 213.14]
7.17 Colchicine plus UDCA (moderate) versus UDCA (moderate)	1		Rate Ratio (Fixed, 95% CI)	5.91 [0.28, 123.08]
7.18 TauroUDCA (moderate) versus UDCA (moderate)	1		Rate Ratio (Fixed, 95% CI)	1.17 [0.81, 1.71]
8 Liver transplantation Show forest plot	12		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.1 Cyclosporin versus no intervention	2	378	Odds Ratio (M‐H, Fixed, 95% CI)	0.86 [0.43, 1.72]
8.2 D‐Penicillamine versus no intervention	1	189	Odds Ratio (M‐H, Fixed, 95% CI)	0.93 [0.06, 15.05]
8.3 Methotrexate versus no intervention	1	60	Odds Ratio (M‐H, Fixed, 95% CI)	0.17 [0.02, 1.58]
8.4 UDCA (low) versus no intervention	2	162	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.24, 4.06]
8.5 UDCA (moderate) versus no intervention	3	478	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.44, 1.76]
8.6 UDCA (low) versus UDCA (high)	1	106	Odds Ratio (M‐H, Fixed, 95% CI)	3.17 [0.13, 79.71]
8.7 UDCA (moderate) versus UDCA (high)	1	103	Odds Ratio (M‐H, Fixed, 95% CI)	3.37 [0.13, 84.70]
8.8 UDCA (moderate) versus UDCA (low)	1	101	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.06, 17.47]
8.9 Bezafibrate plus UDCA (moderate) versus UDCA (moderate)	1	27	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.10 Methotrexate plus UDCA (moderate) versus UDCA (moderate)	1	265	Odds Ratio (M‐H, Fixed, 95% CI)	0.70 [0.35, 1.39]
9 Decompensated liver disease Show forest plot	7		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 D‐Penicillamine versus no intervention	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 UDCA (moderate) versus no intervention	2	351	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [0.84, 2.12]
9.3 Obeticholic acid (low) plus UDCA (moderate) versus UDCA (moderate)	1	216	Odds Ratio (M‐H, Fixed, 95% CI)	1.55 [0.06, 38.46]
9.4 UDCA (low) plus colchicine versus UDCA (low)	1	84	Odds Ratio (M‐H, Fixed, 95% CI)	0.21 [0.04, 1.07]
9.5 Azathioprine plus UDCA (moderate) versus UDCA (moderate)	1	42	Odds Ratio (M‐H, Fixed, 95% CI)	0.52 [0.05, 5.18]
9.6 Glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)	1	66	Odds Ratio (M‐H, Fixed, 95% CI)	0.55 [0.11, 2.69]
9.7 Methotrexate plus UDCA (moderate) versus UDCA (moderate)	1	151	Odds Ratio (M‐H, Fixed, 95% CI)	2.00 [0.79, 5.04]
9.8 Glucocorticosteroids plus UDCA (moderate) versus azathioprine plus UDCA (moderate)	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.10, 11.18]
10 Cirrhosis Show forest plot	3		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 Azathioprine versus no intervention	1	31	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.18, 3.41]
10.2 UDCA (low) versus no intervention	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 1.53]
10.3 Azathioprine plus glucocorticosteroids plus UDCA (moderate) versus UDCA (moderate)	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	0.28 [0.03, 2.90]

Comparison 2. Stratified by dose

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