Abstract: We identified 74 trials including 5902 participants that met the inclusion criteria of this review. A total of 46 trials (4274 participants) provided information for one or more outcomes. All the trials were at high risk of bias in one or more domains. Overall, all the evidence was low or very low quality. The proportion of participants with symptoms varied from 19.9% to 100% in the trials that reported this information. The proportion of participants who were antimitochondrial antibody (AMA) positive ranged from 80.8% to 100% in the trials that reported this information. It appeared that most trials included participants who had not received previous treatments or included participants regardless of the previous treatments received. The follow-up in the trials ranged from 1 to 96 months. The proportion of people with mortality (maximal follow-up) was higher in the methotrexate group versus the no intervention group (OR 8.83, 95% CI 1.01 to 76.96; 60 participants; 1 trial; low quality evidence). The proportion of people with mortality (maximal follow-up) was lower in the azathioprine group versus the no intervention group (OR 0.56, 95% CI 0.32 to 0.98; 224 participants; 2 trials; I2 = 0%; low quality evidence). However, it has to be noted that a large proportion of participants (25%) was excluded from the trial that contributed most participants to this analysis and the results were not reliable. There was no evidence of a difference in any of the remaining comparisons. The proportion of people with serious adverse events was higher in the D-penicillamine versus no intervention group (OR 28.77, 95% CI 1.57 to 526.67; 52 participants; 1 trial; low quality evidence). The proportion of people with serious adverse events was higher in the obeticholic acid plus ursodeoxycholic acid (UDCA) group versus the UDCA group (OR 3.58, 95% CI 1.02 to 12.51; 216 participants; 1 trial; low quality evidence). There was no evidence of a difference in any of the remaining comparisons for serious adverse events (proportion) or serious adverse events (number of events). None of the trials reported health-related quality of life at any time point. Funding: nine trials had no special funding or were funded by hospital or charities; 31 trials were funded by pharmaceutical companies; and 34 trials provided no information on source of funding. Based on very low quality evidence, there is currently no evidence that any intervention is beneficial for primary biliary cholangitis. However, the follow-up periods in the trials were short and there is significant uncertainty in this issue. Further well-designed randomised clinical trials are necessary. Future randomised clinical trials ought to be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid post-randomisation dropouts or planned cross-overs; should have sufficient follow-up period (e.g. five or 10 years or more); and use clinically important outcomes such as mortality, health-related quality of life, cirrhosis, decompensated cirrhosis, and liver transplantation. Alternatively, very large groups of participants should be randomised to facilitate shorter trial duration.

Plain-language summary: We identified 74 randomised clinical trials (5902 participants). Of these, 46 randomised clinical trials (4274 participants) provided information for one or more measures (outcomes). The trials included people with primary biliary cholangitis with and without symptoms; with and without antimitochondrial antibody (AMA) (an indicator of primary biliary cholangitis) regardless of whether they received previous treatments. The average follow-up period in the trials ranged from one month to eight years in the trials that reported this information. Funding: nine trials receive no additional funding or were funded by parties with no vested interest in the results. Thirty-one trials were partially or fully funded by the pharmaceutical companies that would benefit based on the results of the trial. The source of funding was not available from the remaining trials. The overall quality of evidence was very low and all the trials were at high risk of bias, which means that there is possibility of making wrong conclusions overestimating benefits or underestimating harms of one treatment or the other because of the way that the trials were conducted. There was no reliable evidence of decrease in the deaths between any of the interventions versus no intervention. There was no evidence of decrease in serious complications or complications of any severity between any of the treatments and no treatment. None of the trials reported health-related quality of life (a measure of a person's satisfaction with their life and health) at any time point. Overall, there is currently no evidence of benefit of any intervention in primary biliary cholangitis. There is significant uncertainty in this issue and further high-quality randomised clinical trials are required.