New and emerging treatments for PBC-related pruritus

Pruritus is an early and often debilitating symptom of primary biliary cholangitis (PBC), significantly impairing quality of life through fatigue, sleep disturbance, anxiety and social withdrawal. Traditional management relies on a stepwise approach, with bile acid sequestrants as first-line therapy and rifampin, naltrexone, or sertraline for refractory cases, but these agents often provide incomplete relief and are limited by tolerability and drug-drug interaction concerns. Advances in understanding the mechanisms of cholestatic itch have expanded treatment options to include peroxisome proliferator-activated receptor (PPAR) agonists, such as seladelpar, elafibranor and bezafibrate that uniquely offer both antipruritic effects and improvement in biochemical markers of disease activity. Therapies targeting specific pruritogenic pathways now include ileal bile acid transporter (IBAT) inhibitors, one of which is now approved specifically for PBC-related pruritus, as well as κ-opioid receptor agonists, MrgprX4 antagonists, and autotaxin inhibitors. Optimal management integrates pharmacological therapy with supportive strategies, including skin care, lifestyle modifications and psychosocial support tailored to the individual patient's disease activity, symptom severity, and comorbidities. By addressing both the biological and experiential dimensions of pruritus, this comprehensive framework enables clinicians to improve symptom control and enhance overall quality of life for patients living with PBC. Emerging therapies and a mechanism-informed treatment approach offer promise for more effective, individualized care in this challenging clinical context.