Autoimmune hepatitis: Towards a personalized treatment

Table 1 Pathogenesis and possible treatment targets in autoimmune hepatitis

Drug family	Medication	Remission rates	Mechanism of action	Advantages	Disadvantages	Ref.
Steroids	Prednisone	80%	CD4 + T cell sequestration in reticuloendothelial system; Inhibition of IL-1 and IL-6 synthesis; Inhibition of cell-cell adhesion molecules	Inexpensive; Widely available; Extensive experience in its use	Weight-gain; Growth stunting; Hyperglycemia; Psychosis; Osteoporosis; Arterial hypertension	Mieli-Vergani et al[17]; Mack et al[29]
	Budesonide	70%-80%		Theoretically less side-effects than prednisone	Expensive; Contraindicated in cirrhosis and liver failure; May not control autoreactive cells in peripheric lymphoid tissue	Mack et al[29]; Olivas et al[36]; Manns et al[37]; Woynarowski et al[38]
Antimetabolites	Azathioprine	80%	Purine synthesis inhibition	Extensive experience in its use	Not for induction; Bone marrow toxicity; Vomiting and gastrointestinal symptoms; Hepato-splenic T cell lymphoma	Mack et al[29]; Olivas et al[36]; Muratori et al[39]
	Mycophenolate mofetil	72%-84%	GMP, GTP, dGTP synthesis inhibition halting lymphocyte proliferation	Excellent alternative in azathioprine intolerance; Better tolerated than azathioprine; Less side effects	Not for induction; Diarrhea; Abdominal pain; Dizziness	Inductivo-Yu et al[45]; Santiago et al[50]; Snijders et al[53]
	Methotrexate	55%	Purine and pyrimidines through folate depletion	May be an alternative in azathioprine intolerance	Not for induction; Hepatotoxicity; Limited experience; Low tolerability	Haridy et al[56]
Calcineurin inhibitors	Cyclosporin A	80%-94%	Binding of immunophilins; Proinflammatory cytokine synthesis inhibition	Useful as an alternative to steroids for induction; Useful for steroid-sparing (liver failure)	Monitoring of trough levels; Nephrotoxicity; Gingival hyperplasia; Hypertrichosis; Not ideal for chronic use	Alvarez et al[67]; Malekzadeh et al[68]; Cuarterolo et al[72]
	Tacrolimus	69%-75%		Good alternative in anti-metabolite refractory patients	Same as cyclosporin A; Diabetes	Abdollahi et al[78]; Hanouneh et al[79]; Efe et al[80]; Efe et al[81]
mTOR inhibitors	Sirolimus	0% (response in 50%)	Impair dendritic cells and T cell proliferation and differentiation	Alternatives in difficult-to-treat patients; Sparing of Tregs	Anecdotical experience; Not effective in monotherapy	Kurowski et al[90]; Chatrath et al[91]
	Everolimus	0% (response in 83%)				Jannone et al[92]
B cell depletion	Anti-CD 20 (rituximab)	75%-100%	Direct decrease in antigen-presenting cells; Indirect decrease in autoreactive plasmacytes; Decrease of B cell-mediated T cell activation; Direct decrease in autoreactive T cells (belimumab only)	Useful for induction and maintenance; Ensures compliance; Steroid-sparing	Expensive; Lack of long-term safety data	D’Agostino et al[102]; Than et al[108]; Costaguta et al[110]
	Anti-BAFF (belimumab)	Unknown		Better response in other diseases than with rituximab	Ongoing trial for AIH	ClinicalTrials.gov [124]; Wise and Stohl[125]
Biologics	Anti-TNF (infliximab)	61%	Inhibits dendritic cell activation; Inhibits T helper differentiation; Inhibits cytotoxic T cells	Useful for induction and/or maintenance; Extensive experience in other diseases; Good safety profile	Anti-TNF may trigger AIH; Hepatotoxicity	Weiler-Normann et al[129]; Rajanayagam and Lewindon[130]; Weiler-Normann et al[131]
	Anti-IL1 (anakinra)	Unknown	Inhibits monocyte/macrophage activation; Inhibits fibroblast proliferation; Inhibits ROS synthesis	Experimental benefits in other forms of hepatitis; Theoretical benefits on fibrosis	Unknown efficacy in AIH; Possible hepatotoxicity	Iracheta-Vellve et al[137]; Petrasek et al[138]
	Anti-IL17 (secukinumab)	Unknown	Inhibits macrophage cytokine secretion; Inhibit endothelial cell expression of integrins and selectins; Inhibit neutrophil recruitment and decrease survival	Effective in murine models; Experimental benefits since IL-17 is central in many autoimmune disorders	Unknown efficacy in human AIH; Th17/Treg disbalance may paradoxically be detrimental in some autoimmune disorders	Zhao et al[144]; Yu et al[145]
JAK inhibitors	Tofacitinib	Unknown	Inhibition of proinflammatory cytokine synthesis	Effective in murine models; Effective in STAT gain-of-function-related AIH	Unknown efficacy in human AIH; Relatively new medications	Hadžić et al[157]; Kaneko et al[158]
Cell therapy	Chimeric antigen receptor-T cell therapy	Unknown	Selective targeting of autoreactive CD19 + cells; Cell therapy-mediated B cell depletion	Effective in B cell malignancies; Excellent safety profile; Targeted immunosuppression	Expensive therapy; Not easily available	Schett et al[169]
	Treg cell transfer	Unknown	Induction of peripherical tolerance to self-antigens; Dampening of the inflammatory response	Effective in murine models; Theoretical possibility of tolerance “resetting”; Excellent safety profile	Lack of specific self-antigens in AIH-1; Expensive therapy; Not easily available	Lapierre et al[172]; Sánchez-Fueyo et al[173]

AIH: Autoimmune hepatitis; BAFF: B-cell activating factor; CD: Cluster of differentiation; dGTP: Deoxyguanosine triphosphate; GMP: Guanosine monophosphate; GTP: Guanosine triphosphate; IL: Interleukin; JAK: Janus kinase; mTOR: Mammalian target of rapamycin; ROS: Reactive oxygen species; STAT: Signal transducer and activator of transcription; Th: T helper cell; TNF: Tumor necrosis factor; Treg: Regulatory T cell.

Table 2 Special considerations when choosing a treatment for specific populations

Population	Less-desirable options	Reasons	Available options
Obesity and metabolic syndrome	Steroids	Weight gain; Arterial hypertension; Steroid-induced hyperglycemia	Induction with cyclosporin A: Trough target of 250 ng/mL for 3 months and decrease to 200 ng/mL for the next 3 months. Tapering of cyclosporin with addition of 0.3-0.5 mg/kg daily prednisone for 3 months, and then every other day for another 3 months. Azathioprine at usual dose from the 6th month onwards; Induction with rituximab at 375 mg/m2 once a week for 4 weeks. Maintenance with the same dose every 6 months. Adapt according to lymphocyte (CD20 +) count and IgG levels
Adolescents; Eating disorders; Body dysmorphia	Steroids; CsA	Weight gain; Stretch marks; Acne; Growth stunting; Psychosis and suicidal ideation; Hypertrichosis; Gingival hyperplasia	Budesonide at doses of 9 mg for induction, with progressive tapering to 6 mg and then 3 mg. Maintenance with azathioprine: Rituximab induction as previously mentioned. Maintenance with rituximab or azathioprine; Prednisone at 0.5-1 mg/kg daily + CsA targeting 200 ng/mL for 3-6 months as induction
Concomitant autoimmune disorders	NA	Treatment should be aimed at controlling all the conditions simultaneously with the smaller number of medications possible	In antibody-mediated diseases: Rituximab at 375 mg/m2 for induction and maintenance
Inflammatory bowel disease	NA		Infliximab at 5-10 mg/kg at week 0, 2, and 6 for induction. Maintenance with a dose every 4 weeks to 8 weeks. Doses and frequencies are adapted according to IBD activity; Although not yet proven, in this scenario the use of JAK inhibitors may become useful, although no evidence exists presently
Non-compliance	Steroids; CsA; Tacrolimus	Medications with significant side effects, requiring multiple daily doses, and with a set therapeutic range are less desirable	Rituximab ensures the compliance of patients as doses are administered a few times a year and under healthcare personnel surveillance

CD: Cluster of differentiation; CsA: Cyclosporin A; IBD: Inflammatory bowel disease; JAK: Janus kinases; NA: Not applicable.