title: Pharmacological interventions for primary biliary cholangitis: an attempted network meta-analysis.
abstract: Primary biliary cholangitis (previously primary biliary cirrhosis) is a chronic liver disease caused by the destruction of small intra-hepatic bile ducts resulting in stasis of bile (cholestasis), liver fibrosis, and liver cirrhosis. The optimal pharmacological treatment of primary biliary cholangitis remains uncertain.
  
  
  
  To assess the comparative benefits and harms of different pharmacological interventions in the treatment of primary biliary cholangitis through a network meta-analysis and to generate rankings of the available pharmacological interventions according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, assessed the comparative benefits and harms of different interventions using standard Cochrane methodology.
  
  
  
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to February 2017 to identify randomised clinical trials on pharmacological interventions for primary biliary cholangitis.
  
  
  
  We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with primary biliary cholangitis. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention.
  
  
  
  We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, Pond Street, Hampstead, London, UK, NW3 2QG.|Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University of Messina, Via Consolare Valeria, 1, Messina, Messina, Italy, 98125.
authors.forename: Francesca
authors.initials: F
authors.lastname: Saffioti
authors.affiliation: Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UK, NW3 2PF.
authors.forename: Kurinchi Selvan
authors.initials: KS
authors.lastname: Gurusamy
authors.affiliation: The Royal Free Sheila Sherlock Liver Centre, Royal Free Hampstead NHS Foundation Trust and UCL Institute of Liver and Digestive Health, London, UK.|Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
authors.forename: Leonardo Henry
authors.initials: LH
authors.lastname: Eusebi
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, Pond Street, Hampstead, London, UK, NW3 2QG.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tsochatzis
authors.affiliation: Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UK, NW3 2PF.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Davidson
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, Pond Street, Hampstead, London, UK, NW3 2QG.
authors.forename: Douglas
authors.initials: D
authors.lastname: Thorburn
mesh_terms: D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use; D002635:Chenodeoxycholic Acid / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D002756:Cholagogues and Choleretics / Q000009:adverse effects / Q000627:therapeutic use; D002761:Cholangitis / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D002908:Chronic Disease; D003078:Colchicine / Q000009:adverse effects / Q000627:therapeutic use; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use; D008928:Mitochondria / Q000276:immunology; D010396:Penicillamine / Q000009:adverse effects / Q000627:therapeutic use; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic; D014580:Ursodeoxycholic Acid / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D002756:Cholagogues and Choleretics; D007166:Immunosuppressive Agents; C464660:obeticholic acid; D002635:Chenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D016572:Cyclosporine; D010396:Penicillamine; D001379:Azathioprine; D003078:Colchicine; D008727:Methotrexate