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

Table 1 Second-line immunosuppressives used in refractory autoimmune hepatitis

Drugs	Mycophenolate mofetil	Tacrolimus	Cyclosporine	Methotrexate	Sirolimus
Position in managing refractory AIH	Second line	Second line	Second line	Second line	Second line
Mechanism of action	Prodrug converted to mycophenolic acid, which inhibits purine biosynthesis and attenuate proliferation of B and T cells	Calcineurin inhibitors which suppress IL-2 production	Calcineurin inhibitors which suppress IL-2 production	Inhibition of folic acid synthesis	m-TOR inhibitor
Dose	20–40 mg/kg/d	2–6 mg/kg/d	2–4 mg/kg/d	7–20 mg/wk	1–2 mg/kg/d
Pregnancy category1	D	C	C	X	C
Adverse events	Diarrhea, cytopenia and colitis	Nephrotoxicity, gingival hypertrophy, hypertension and dyselectrolytemia	Nephrotoxicity, hyperkalemia	Bone marrow suppression, pulmonary fibrosis, and liver injury	Arthralgia, peripheral edema, skin rashes ang gastrointestinal problems
Comments	More effective for azathioprine intolerant than azathioprine refractory AIH. Current RCT shows it can be safe first-line alternative to azathioprine[61-63]	Tacrolimus was effective in 18 of 23 patients with first-line-intolerant or refractory AIH[65]	Five of six patients with steroid refractory AIH responded to cyclosporine[66,120]	Six of 11 patients responded to methotrexate after initial non-response to steroid with or without azathioprine[68,69]	Four of five patients with steroid refractory AIH responded to sirolimus[92]

¹These capital letters denote pregnancy category of the drugs.

m-TOR: Mammalian-target of rapamycin; AIH: Autoimmune hepatitis; RCT: Randomized controlled trial; IL: Interleukin.

Table 2 Third-line immunosuppressives used in refractory autoimmune hepatitis

Drugs	Infliximab	Rituximab	Belimumab
Position in managing refractory AIH	Third line	Third line	Third line
Mechanism of action	Monoclonal antibody to TNF-α	Chimeric monoclonal antibody against CD-20	B-cell-activating factor inhibitor
Dose	5 mg/kg	2 doses of 1000 mg IV administered 2 wk apart, or 375 mg/m2 rituximab	10 mg/kg
Pregnancy category1	B	C	C
Adverse events	Infectious complications can cause drug induced AIH like injury allergic reaction	Infectious complications	Infection, allergic reactions, progressive multifocal leukoencephalopathy, and mental health issues
Comments	Response rate 78% when used as a third line agent[94]	As a third line agent biochemical remission: 67%, 71% flare-free survival after median 6 yr[88-90,121]	Steroid refractory AIH. Two patients had complete biochemical response[99]

¹These capital letters denote pregnancy category of the drugs.

AIH: Autoimmune hepatitis; TNF: Tumor necrosis factor.