1Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, FL, USA.
2Hannover Medical School, Hannover, Germany.
3Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Canada.
Primary biliary cholangitis (PBC) is an archetypal autoimmune disease. Chronic lymphocytic cholangitis is associated with interface hepatitis, ductopenia, cholestasis and a progressive biliary fibrosis. People living with PBC are frequently symptomatic, experiencing a quality-of-life burden dominated by fatigue, itch, abdominal pain, and sicca complex. Whilst the female predominance, specific serum autoantibodies, immune mediated cellular injury, as well as genetic (HLA and non-HLA) risk factors, identify PBC as autoimmune, to date treatment has focused on cholestatic consequences. Biliary epithelial homeostasis is abnormal and contributes to disease. The impact of cholangiocyte senescence, apoptosis and impaired bicarbonate secretion enhance chronic inflammation and bile acid retention. First line therapy is a non-specific anti-cholestatic agent, ursodeoxycholic acid. For those with residual cholestasis biochemically, obeticholic acid is introduced, and this semi-synthetic FXR agonist adds choleretic, anti-fibrotic and anti-inflammatory activity. Future PBC licenced therapy will likely include PPAR pathway agonists, including specific PPAR-delta agonism (seladelpar), as well as elafibrinor and saroglitazar (both with broader PPAR agonism). These agents dovetail the clinical and trial experience for off-label bezafibrate and fenofibrate use. Symptom management is essential, and, encouragingly PPAR agonists reduce itch; IBAT inhibition (e.g., linerixibat) also appears promising for pruritus. For those where liver fibrosis is the target, NOX inhibition is being evaluated. Earlier stage therapies in development include therapy to impact immunoregulation in patients, as well other approaches to treating pruritus (e.g., antagonists of MrgprX4). Collectively the PBC therapeutic landscape is exciting. Therapy goals are increasingly proactive, individualized and aspire to rapidly achieve normal serum tests and quality of life with prevention of end-stage liver disease.