Management of autoimmune hepatitis: Focus on pharmacologic treatments beyond corticosteroids

Table 1 Non-standard immunosuppressive drugs used in autoimmune hepatitis

Non-standard pharmacologic treatments	Studies	Indications	Contra-indications	Outcomes
Mycophenolate mofetil, 0.5 to 3.0 g/d
Purine antagonist (inhibits inosine monophosphate dehydrogenase, limits purine nucleotides, impairs lymphocyte proliferation)	146 mo, 7 patients[35] 119 mo, 8 patients[39] 141 mo, 15 patients[40] 161.5 mo, 26 patients[56] 126 mo, 59 naïve-patients[59]	Azatioprine Intolerance Refractory AIH Front-line therapy	Pregnancy Hypersensitivity to mycophenolate mofetil, mycophenolic acid or mycophenolate sodium	Salvage[22,35-43,56]: 47% overall improvement 58% azathioprine intolerance 12% refractory disease 53% failure or side effects 40% steroid withdrawal 3%-33% Serious side effects Front-line[59]: 88% complete response 12% partial response 58% steroid withdrawal 3% serious side effects
Cyclosporin, 2 to 5 mg/kg per day
Calcineurin inhibitor (impairs NF-κB, reduces IL-2 and lymphocyte proliferation)	6 mo, 19 patients[44] 3 mo, 5 patients[45]	Refractory AIH Relapsing AIH Non-responding AIH	Rheumatoid arthritis and psoriasis: abnormal renal function, uncontolled hypertension, malignancies Psoriasis: under PUVA, UVB therapy, methotrexate Hypersensitivity to cyclosporin or to polyoxyethylated castor oil Pregnancy	Composite results[22,44,45]: 93% improvement 7% failure/side effects
Tacrolimus, 0.075 to 4 mg/kg twice a day
Calcineurin inhibitor (impairs NF-κB, reduces IL-2 and lymphocyte proliferation)	12 mo, 21 patients[46] 25 mo, 11 patients[48] 18 mo, 9 patients[49]	Refractory AIH Relapsing AIH Non-responding AIH	Hypersensitivity to tacrolimus Pregnancy	Composite results[22,46,49]: 98% improvement 2% failure/side effects
Rituximab, 1.0 g, two doses 15 d apart1
Anti-CD20 (B-cell depletion, impairs type 2 cytokine pathway, interferes with antibody-dependent cell-mediated cytotoxicities)	5 mo, 6 patients[66] case reports; data from studies for hematological malignancies, rheumatoid arthritis	Refractory AIH Relapsing AIH Non-responding AIH	Type 1 hypersensitivity or anaphylatic reaction to murine proteins Progressive multifocal leukoencephalopathy	Biochemical improvement
Infliximab, dose of 5 mg/kg at weeks 0, 2 and 6, and then every 4 to 8 wk1
Anti-TNF-α (neutralizing soluble transmembrane forms of TNF-α impairing cytotoxic type 1 cytokine pathway)	Case reports	Refractory AIH Relapsing AIH Non-responding AIH	Heart failure NYHA class III/IV Hypersensitivity to infliximab or murine proteins	Biochemical improvement
Cyclophosphamide, 1 to 1.5 mg/kg per day
Alkylating agents (covalent binding and crosslinking to deoxyribonucleic acid-DNA, ribonucleic acid-RNA and proteins)	95 mo, 94 patients with long-term auto-immune hepatitis[71]	Refractory AIH Relapsing AIH Non-responding AIH	Hypersensitivity to cyclophosphamide, urinary outflow obstructions, severe myelosuppression, severe renal or hepatic impairment, severe immunossupression Pregnancy	91% complete remission
Methotrexate, 7.5 mg/wk
Purine antagonist (inhibits the binding of dihydrofolic acid)	Case reports[52]	Refractory AIH	Hypersensitivity Breast-feeding Pregnancy	Biochemical and histologic improvement
Ursodeoxycholic acid, 13 to 15 mg/kg per day			Hypersensitivity
Immunomodulation (epimer of chenodeoxycholic acid)	6 mo, 37 patients[53]	In addition to other immunosuppressive strategies	Unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, biliary-gastrointestinal fistula, allergy to bile acids	Biochemical improvement Corticosteroid dose reduction

¹Careful is needed in women of childbearing age since those treatments have uncertain effects on reproduction and are presumable teratogenic. AIH: Autoimmune hepatitis; NF-κB: Nuclear factor kappa B; TNF-α: Tumor necrosis factor-alpha; IL-2: Interleukin-2; UVB: Ultra-violet B; PUVA: Psoralen and ultra-violet A.