New treatments/targets for primary biliary cholangitis

Abstract

Primary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.

Keywords: FXR; PBC; PPAR; cholestasis; fibrates; inflammation; liver disease; obeticholic acid; ursodeoxycholic acid.

Fig. 1

Treatment algorithm for PBC. Initial staging of PBC should preferably be based on non-invasive measures including total bilirubin, ALP, aminotransferases, albumin, platelet count, liver stiffness measurement, and liver ultrasound. All patients must be treated with UDCA as a first-line treatment. Intolerance to UDCA (diarrhoea, stomach burns) may occur rarely (5%). Alternative options (OCA or fibrates) should then be considered. Assessment of biochemical response to UDCA is typically performed at 12 months of UDCA, but earlier evaluation after as few as 6 months of UDCA therapy may be proposed in patients with the most severe or symptomatic (pruritus) disease. The response criteria used must include ALP and bilirubin levels (Paris-2, Toronto, GLOBE, etc.). Abnormal levels of total and conjugated bilirubin or ALP level ≫1.5x ULN are minimal thresholds above which second-line therapies should be considered. Patients with adequate biochemical response to UDCA can be kept on UDCA monotherapy. Advanced-stage responders or those with persisting abnormal ALP might be considered for second-line therapies. In poor biochemical responders, liver biopsy should be considered when AIH-PBC variant or any other hepatic comorbidity is suspected. Addition of corticosteroids (including budesonide) is recommended in patients with AIH-PBC variant. Patients with non-regressive jaundice (bilirubin ≫5 mg/dl) or features of advanced cirrhosis (Child-Pugh B-C) should be referred for liver transplant. All remaining poor responders to UDCA should be considered for second-line therapies (i.e. OCA or fibrates) in addition to continued UDCA. Fibrates should be preferred in patients with pruritus. Second-line therapies could be switched in case of poor tolerance (pruritus for OCA; myalgia for fibrates) or combined in case of insufficient response. AIH, autoimmune hepatitis; ALP, alkaline phosphatase; OCA, obeticholic acid; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal.