Efficacy Of Combined Therapy In Primary Biliary Cholangitis Patients With Poor Response To Ursodeoxycholic Acid: A Bayesian Network Meta-analysis

ObjectivesUp to 40% of ursodeoxycholic acid(UDCA)-treated patients with primary biliary cholangitis(PBC)do not have an adequate clinical response.Farnesoid X receptor agonists(FXR),peroxisome proliferator activated receptor(PPAR)agonists,and fibroblast growth factor 19(FGF19)analogues were developed as adjunctive therapy for PBC patients with suboptimal response to UDCA.The aim of this network meta-analysis was to compare the efficacy of these drugs as add-on therapy for patients with PBC and a suboptimal response to UDCA.MethodsArticle retrieval was performed using on-line databases,such as Pub Med,Embase,Web of Science,and Cochrane Central Register of Controlled Trials until December 31,2020.Randomized controlled trials(RCTs)or cohort studies or case-control studies which compared different combination regimens with UDCA monotherapy were included.Network meta-analyses were conducted with ADDIS software.We estimated mean differences(MDs)for reduction of levels of hepatic biochemical markers.Consistency models were established to identify the differences among different combination therapy strategies,and cumulative probability was used to rank the included strategies.ResultsA total of 19 articles involving 1019 participants were eligible for the network meta-analysis.Treatment rankings suggested that probability that the strategy to reduce the levels of alkaline phosphatase(ALP)as adjunctive therapy was the most effective was greatest with seladelpar,and the optimal doses for the therapeutic effects are 50mg(44%)and 200mg(35%)as followed,but two doses have similar effects(MD 9.27,95% CI-70.17,87.11).Obeticholic acid(OCA)was the most effective to reduce the levels of gamma-glutamyl transpeptidase(GGT)as adjunctive therapy,and the optimal doses for the therapeutic effects are 25mg(77%),10mg(14%)and 50mg(13%)as followed,but three different doses have similar effects(MD 50.11,95% CI-16.29—110.53;MD-22.07,95% CI-88.62—6.41;MD 27.51,95% CI-36.47—88.35).Bezafibrate was the most effective strategy to reduce the levels of total bilirubin(35%)and immunoglobulins M(Ig M)(27%)as adjunctive therapy while 3mg NGM282(30%)was the most effective in terms of reducing the levels of alanine aminotransferase(ALT).ConclusionsFor UDCA-treated patients with PBC who do not have an adequate clinical response,combination therapy showed better efficacy than UDCA monotherapy in improving serum biochemical markers.As adjunctive therapy,seladelpar was the most efficacious among treatment regimens for reducing the levels of ALP,OCA was the most efficacious to reduce the levels of GGT,and bezafibrate was the most efficacious among treatment regimens for reducing the levels of TBIL and IgM.