Proposed therapies in primary biliary cholangitis

Abstract

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.

Cenicriviroc, a cytokine receptor antagonist, potentiates all‐trans retinoic acid in reducing liver injury in cholestatic rodents

“…Interestingly, treatment with CVC alone did not reduce cholestatic liver injury in either rodent models, including an absence of an effect on liver necrosis, fibrosis and even bile duct proliferation. This observation is consistent with reports from clinical trials in PBC patients where there was a lack of efficacy when immunosuppressive drugs were tested . However, at the molecular level, CVC treatment alone reduced hepatic expression of pro‐inflammatory cytokine Ccl2, Ccl5, Tnf‐α and IL‐6 in these cholestatic animals (Figures & ).…”

“…Recently, obeticholic acid has been approved by the FDA for treating PBC patients with inadequate responses or intolerance to UDCA, but pruritus and hyperlipidaemia are significant side effects . Therefore, there is a need for developing additional therapeutic approaches for PBC and other cholestatic disorders …”

“…7 Therefore, there is a need for developing additional therapeutic approaches for PBC and other cholestatic disorders. 5,6,8 Recent studies into the pathophysiologic mechanisms of cholestasis have indicated that bile acids cause liver injury by stimulating a cytokine-mediated inflammatory response. [9][10][11] In this process, hepatocytes with elevated levels of bile acids initiate the event by releasing pro-inflammatory cytokines that attract neutrophils and T cells which then lead to the tissue injury.…”

Primary Biliary Cholangitis: Disease Pathogenesis and Implications for Established and Novel Therapeutics

“…non-Hodgkin' s lymphoma), it has also been found to be therapeutic in various autoimmune diseases. 57 An open label study of rituximab usage in PBC included 14 patients on UDCA (without biochemical remission) who were administered two infusions (1000 mg) 2 weeks apart and followed for 72 weeks. 56 Effective B-cell depletion was achieved in 93% (13/14) subjects but response was not sustained with rebound increase in circulating plasma B-cells after 12 weeks.…”

“…IL-12 and IL-23 are the main antigens-two cytokines paramount to Th1/Th17 signaling in PBC. 57 A phase II multicenter study evaluating the efficacy and safety of ustekinumab in 20 PBC subjects revealed no significant improvement in ALP at 12 or 28 weeks with ustekinumab therapy (NCT0138997). Other clinical trials ongoing evaluating various immunomodulatory agents in PBC refractory to UDCA include: CTLA-4 Ig (abatacept, NCT02078882) and CD40-anatagonist monoclonal antibody (FFP104, NCT02193360).…”