Autoimmune hepatitis beyond first-line therapy: management of intolerance and treatment failure

Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease that, if untreated, may progress to advanced fibrosis, cirrhosis, and liver failure. While first-line therapy with corticosteroids and azathioprine (AZA) is standard worldwide, up to 20% of patients develop drug intolerance or fail to achieve complete biochemical remission despite optimized dosing. This mini review summarizes recent evidence for the management of intolerance and non-response in AIH, with focus on distinguishing adverse event–driven drug discontinuation from true pharmacologic failure. We discuss AZA-induced hepatotoxicity, the role of thiopurine metabolite profiling in optimizing therapy, and strategies for identifying preferential methylators. Second-line treatments, including mycophenolate mofetil, 6-mercaptopurine, thioguanine, and calcineurin inhibitors, are reviewed alongside emerging biologics such as rituximab and infliximab. This overview aims to provide clinicians with a concise, evidence-based update on therapeutic alternatives for difficult-to-treat AIH.