Difficult to treat and refractory autoimmune hepatitis: Recent advances in pharmacological management

Abstract

Autoimmune hepatitis (AIH) is a rare cause of chronic liver disease. The exact pathophysiology of AIH is unknown. Breakdown of self-tolerance against hepatic antigens and molecular mimicry are often implicated in the pathogenesis of AIH. Immunosuppressive therapy is the mainstay of treatment; however, 10%–25% of patients with AIH may not respond to primary therapy. Those patients are often salvaged with second- and third-line immunosuppressive therapy. Workup for other concomitant diseases should be done for patients who fail to respond to primary immunosuppressive therapy. Concurrent metabolic dysfunction-associated steatotic liver disease, alcohol-related liver disease, overlap syndrome (AIH with primary biliary cholangitis or sclerosing cholangitis), chronic hepatitis B virus, hepatitis C virus, and human immunodeficiency virus infection should be ruled out in such cases. Targeting the concomitant etiology may lead to resolution of the clinical symptoms and induce biochemical and histological remission. Isolated AIH without other etiologies for liver injury should be managed with a higher dose of steroids, azathioprine, or other immunosuppressive agents. Second- and third-line immunosuppressive agents include mycophenolate mofetil, cyclosporine, tacrolimus, infliximab, and rituximab. Patients with AIH may present with acute severe AIH (AS-AIH) and AIH-related acute on chronic liver failure, and they often require liver transplantation. The terms refractory or difficult-to-treat AIH have been used interchangeably and have no distinct definition. Difficult-to-treat AIH includes patients with intolerable side effects, fulminant disease (AIH with acute on chronic liver failure and AS-AIH), AIH in pregnancy, and HIV infection. Patients who fail to respond to standard first-line immunosuppressive therapy should be classified as refractory AIH. This review addresses the issues in the management of difficult-to-treat AIH with recent advances in pharmacological management.

Keywords: Autoimmune hepatitis; Difficult-to-treat autoimmune hepatitis; Steroids; Azathioprine; Mycophenolate mofetil; Cirrhosis

Core Tip: Immunosuppressive therapy remains the mainstay for patients with autoimmune hepatitis (AIH). However, managing AIH in special situations, such as acute-on-chronic liver failure, pregnancy, old age, and hepatitis B and C co-infection, can be challenging. Between 10% and 20% of patients may not respond to standard first-line immunosuppressive therapy. This review focuses on the individualized management of patients with difficult-to-treat or refractory AIH and recent advances in second- and third-line immunosuppressive therapy.