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

Figure 1 Pathogenesis of autoimmune hepatitis and pharmacological targets. Immunopathogenesis of autoimmune hepatitis (AIH) involves adaptive and innate immune systems. Molecular mimicry and breakdown of self-antigenic tolerance lead to activation of B and T cells. B cells in turn stimulate plasma cells which secret autoantibodies. Cytotoxic T cells and autoantibodies lead to hepatotoxicity. Immunosuppressive therapies target various pathways of the pathogenesis in AIH as depicted in the figure. Methotrexate, azathioprine, 6-mercaptopurine, and 6-thioguanine interfere with cell cycles and arrest the proliferation of B and T cells. Infliximab is a chimeric anti-tumor necrosis factor antibody that acts on the downstream inflammatory pathways. Rituximab and belimumab deplete B cells and attenuate B-cell-mediated activations of plasma cells. Calcineurin inhibitors like tacrolimus and cyclosporine preferably act on T cell proliferation. Sirolimus is a mammalian target of rapamycin inhibitor that ameliorates helper T cells-mediated tissue damage in the liver cells. MMF: Mycophenolate mofetil; 6-MP: 6-mercaptopurine; 6-TG: 6-thioguanine; IL: Interleukin; m-TOR: Mammalian-target of rapamycin; IFNγ: Interferon-gamma; CTL: Cytotoxic T lymphocytes; TNF: Tumor necrosis factor.