Pharmacological interventions for primary biliary cholangitis: an attempted network meta-analysis.
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ABSTRACT:
SUBMITTER: Saffioti F
PROVIDER: S-EPMC6464661 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and objective: Pruritus is a common complication in patients with primary biliary cholangitis (PBC). The pathogenesis is not clear, and also the precise therapeutic measures remain alluring. In order to systematically evaluate the efficacy and safety of drug interventions in the treatment of pruritus associated with PBC, this systemic review and meta-analysis was conducted. Methods: The randomized controlled trials (RCTs) on drug interventions in the treatment of pruritus associated with primary cholangitis were searched in the electronic databases of PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov. Two researchers independently screened the literature, extracted and integrated the data, and assessed the bias risk of the selected literature, according to the Cochrane handbook. Finally, the STATA 15.0 software was used for the meta-analysis. Results: A total of 23 RCTs involving 2,194 patients were studied, that included 12 pharmacological interventions. In terms of itching relief, compared with placebo, UDCA, methotrexate and GSK2330672 had a definite effect in improving pruritus (pruritus remission rate before and after treatment, p < 0.05). In terms of serum indexes, compared with placebo group, UDCA, OCA, rifampicin, cyclosporine, NGM282, seladelpar and colchicine may improve blood alkaline phosphatase (ALP) (p < 0.05), but only rifampicin showed low heterogeneity. UDCA, bezafibrate, OCA, rifampicin, NGM282 and others may improve blood γ-glutamyl transpeptidase (γ-GGT) (p < 0.05), but due to the high heterogeneity and the limitation of research samples, a clear conclusion cannot be drawn. In terms of adverse events, except high (>15 mg/kg/day) and low doses (<13 mg/kg/day) of UDCA increased the incidence of adverse events, there were no risk of increasing the incidence of adverse events compared with placebo (p > 0.05), and a moderate dose of UDCA (13-15 mg/kg/day) and malotilate (1,500 mg/day) may also help in reducing the incidence of adverse events (p < 0.05). Conclusion: UDCA, methotrexate and GSK2330672 may relieve itching in patients with PBC, but there is a lack of robust evidence to support their effect on ALP or γ-GGT. Due to the heterogeneity in the published studies, based on the present review, we cannot explicitly recommend any specific drug for the treatment of PBC-related pruritus. Systematic Review Registration: link-https://osf.io/2g8ya, identifier 10.17605/OSF.IO/2G8YA.
| S-EPMC9631940 | biostudies-literature
Project description: Not available
| S-EPMC6464620 | biostudies-literature
Project description:Ursodeoxycholic acid (UDCA) is the first-line therapy used for the treatment of PBC. In recent years, new pharmacological agents have been proposed for PBC therapy to cure UDCA-non-responders. Obeticholic acid (OCA) is registered in many countries for PBC, and fibrates also seem to be effective in ameliorating biochemistry alteration and symptoms typical of PBC. Moreover, a variety of new agents, acting with different mechanisms of action, are under clinical evaluation for PBC treatment, including PPAR agonists, anti-NOX agents, immunomodulators, and mesenchymal stem cell transplantation. Since an insufficient amount of data is currently available about the effect of these novel approaches on robust clinical endpoints, such as transplant-free survival, their clinical approval needs to be supported by the consistent improvement of these parameters. The intensive research in this field will hopefully lead to a novel treatment landscape for PBC in the near future, with innovative therapies based on the combination of multiple agents acting on different pathogenetic mechanisms.
| S-EPMC9405864 | biostudies-literature
Project description:The standard therapy for primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA) which has shown to improve hepatic biochemistry, delay histological progression and improve transplant-free survival. Approximately 30-40% of patients do not respond or are intolerant to UDCA. Obeticholic acid, a farnesoid X receptor (FXR) agonist is the only agent approved by the Food and Drug Administration for patients who do not respond to UDCA. Recently, combination therapy with UDCA and bezafibrate has been shown to improve biochemistry and both GLOBE and UK-PBC score in patients with an inadequate response to UDCA. More recently, new pharmacological agents have been included in Phase 2 and Phase 3 trials: PPAR agonists, non-bile acid FXR agonists, anti-NOX agents, immunomodulators and mesenchymal stem cells transplantation. This review gives an overview on the current experimental pharmacological agents employed in the treatment of PBC.
| S-EPMC7751712 | biostudies-literature
Project description:Purpose of reviewPrimary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease.Recent findingsPBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses.SummaryPBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.
| S-EPMC7879833 | biostudies-literature
Project description: Not available
| S-EPMC6040118 | biostudies-literature
Project description:The connection between gene polymorphisms of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and primary biliary cholangitis (PBC) is still vague and blurred. The purpose of this study is to precisely estimate the association of the polymorphisms of CTLA4 with the risk of PBC by using a meta-analysis.PubMed and the Chinese National Knowledge Infrastructure (CNKI) database were used to search correlative literatures, and the documents which were about the relationships between the polymorphisms of CTLA4 (rs231775, rs231725, rs3087243, and rs5742909) and PBC were collected as of June 2016. The strength of correlation based on odds ratios (ORs) and its 95% confidence intervals (95%CIs) was computed by STATA.Generally, in rs231775, a significant risk was found in G allele, the value of OR was 1.32, and its 95%CI was 1.19 to 1.47. The same situation was found in A allele of rs231725, the value of OR was 1.33, and its 95%CI was 1.22 to 1.45. As genotypic level, different genotypic models were also found to have obvious relevance with PBC in rs231775 and rs231725. No obvious connections were found in other SNPs.This study indicated that the polymorphisms of rs231775 and rs231725 would be the risk factors of PBC.
| S-EPMC5470032 | biostudies-literature
Project description:ObjectiveThe diagnostic value of antinuclear antibodies (ANAs) including anti-gp210 and anti-sp100 for primary biliary cholangitis/cirrhosis (PBC) has been widely reported. However, their diagnostic performances for antimitochondrial antibody- (AMA-) negative PBC were less well elucidated. Therefore, the aim of the current meta-analysis was to evaluate the diagnostic accuracy of ANAs in patients with AMA-negative PBC.Materials and methodsLiterature on the diagnostic value of biomarkers for AMA-negative PBC was systematically searched in PubMed, MEDLINE, EMBASE, and the Cochrane Library. The qualities of the retrieved studies were assessed by the Quality Assessment of Diagnostic Accuracy Studies-version 2 (QUADAS-2) scale. Pooled sensitivity and specificity of the biomarkers were calculated with random-effects models. The areas under the summary receiver operating characteristic (AUSROC) curves were used to evaluate the overall diagnostic performance of ANAs.ResultsA total of 11 studies (400 AMA-negative PBC patients and 6217 controls) were finally included in the meta-analysis. ANAs had an overall sensitivity of 27% (95% CI: 20%, 35%) and specificity of 98% (95% CI: 97%, 99%). The pooled sensitivities for anti-gp210 and anti-sp100 were 23% (95% CI: 13%, 37%) and 25% (95% CI: 13%, 43%), respectively, and their specificities were 99% (95% CI: 97%, 100%) and 97% (95% CI: 93%, 98%), respectively.ConclusionsANAs exhibited high specificity but low sensitivity and therefore could be used as reliable biomarkers to reduce the necessity of liver histology.
| S-EPMC6590611 | biostudies-literature
Project description:Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response.
| S-EPMC4935759 | biostudies-literature
Project description:Primary biliary cholangitis (PBC) causes chronic and persistent cholestasis in the liver, eventually resulting in cirrhosis and hepatic failure without appropriate treatment. PBC mainly develops in middle-aged women, but it is also common in young women and men. PBC is considered a model of autoimmune disease because of the presence of diseasespecific autoantibodies, that is, antimitochondrial antibodies (AMAs), intense infiltration of mononuclear cells into the bile ducts, and a high prevalence of autoimmune diseases such as comorbidities. Histologically, PBC is characterized by degeneration and necrosis of intrahepatic biliary epithelial cells surrounded by a dense infiltration of mononuclear cells, coined as chronic non-suppurative destructive cholangitis, which leads to destructive changes and the disappearance of small- or medium-sized bile ducts. Since 1990, early diagnosis with the detection of AMAs and introduction of ursodeoxycholic acid as first-line treatment has greatly altered the clinical course of PBC, and liver transplantation-free survival of patients with PBC is now comparable to that of the general population.
| S-EPMC7820210 | biostudies-literature