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.

Figure 2 Indication of second- and third-line immunosuppressive therapy in patients with autoimmune hepatitis. Following primary immunosuppressive therapy, response to treatment should be assessed after 2–4 weeks. After checking drug compliance, concomitant etiology should be ruled out if patients do not respond to primary therapy. Subsequently, second- and third-line immunosuppressive therapy should be chosen. 6-MP: 6-mercaptopurine; 6-TG: 6-thioguanine; MASLD: Metabolic dysfunction-associated steatotic liver disease; AIH: Autoimmune hepatitis; PBC: Primary biliary cholangitis; DILI: Drug-induced liver injury; ArLD: Alcohol-related liver disease.

Figure 3 Managing patients with autoimmune hepatitis who are intolerant or refractory to azathioprine or 6-mercaptopurine. Azathioprine and 6-mercaptopurine are associated with bone marrow suppression and hepatotoxicity. Baseline TPMT and NUDT-15 genetic polymorphism testing is advocated to avoid myelosuppression. It should be avoided in patients who are homozygous for both enzymes. About 10%–20% of patients who are intolerant to azathioprine can be salvaged with 6-MP or MMF; however, AZA-refractory cases do not respond well to 6-MP. They will often require a third line of therapy or MMF. Metabolite assays can help guide us regarding the need for allopurinol. 6-MMP: 6-methylmercaptopurine; 6-MP: 6-mercaptopurine; 6-TG: 6-thioguanine; TPMT: Thiopurine methyltransferase; AZA: Azathioprine; MMF: Mycophenolate mofetil.