Refractory autoimmune hepatitis in children: Considerations for assessment and management

Table 1 Definitions of treatment outcomes in autoimmune hepatitis

Ref.	Outcomes	Definition
Mack et al[2], 2020; Pape et al[8], 2022	Biochemical remission; complete biochemical response	Normal aspartate aminotransferase, alanine amino transferase and immunoglobulin G levels
Mack et al[2], 2020	Histological remission	Absence of inflammation in liver tissue after treatment
Mieli-Vergani et al[3], 2018	Complete remission	Normal aspartate aminotransferase, alanine amino transferase and immunoglobulin G levels; anti-nuclear antibody/anti-smooth muscle antibody- negative or low titer (< 1:20); anti-liver-kidney microsomal antibody type 1 and anti-liver cytosol type 1 antibody - < 1:10 or negative
Mack et al[2], 2020	Treatment intolerance	Inability to continue maintenance therapy due to drug-related side effects
Mack et al[2], 2020	Incomplete response	Improvement of laboratory and histological findings that are insufficient to satisfy criteria for remission
Pape et al[8], 2022	Non-response	Failure to achieve a more than 50% reduction of alanine amino transferase within 4 weeks of treatment
Mack et al[2], 2020	Treatment failure	Worsening laboratory or histological findings despite compliance with standard therapy
Mack et al[2], 2020	Relapse	Exacerbation of disease activity after induction of remission and drug withdrawal (or nonadherence)
Mieli-Vergani et al[3], 2018	Refractory	Intolerant of or unresponsive to standard immunosuppression

Table 2 Considerations for assessing patients with refractory autoimmune hepatitis

	Considerations for assessing patients with refractory autoimmune hepatitis
1	Confirm compliance/rule out non-adherence
2	Re-evaluate the diagnosis of AIH and evaluate for liver diseases which can mimic biochemical and/or histological features of AIH
3	Assess for extra-hepatic co-morbidities

AIH: Autoimmune hepatitis.

Table 3 Scoring system by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition for the diagnosis of juvenile autoimmune hepatitis

Criteria	Titre or level	Points
Positive autoantibodies1,2
Antinuclear antibodies (ANA) or anti-smooth muscle	≥ 1:20	+ 1
antibodies (SMA)	≥ 1:80	+ 2
Anti-liver kidney microsomal type 1 (anti-LKM1)	≥ 1:10	+ 1
	≥ 1:80	+ 2
Anti-liver cytosol type 1 (anti-LC1) antibody		+ 2
Anti-soluble liver antigen (anti-SLA)		+ 2
Anti-perinuclear neutrophil cytoplasmic antibody (pANCA)		+ 1
Immunoglobulin G (IgG)
	> ULN	+ 1
	> 1.2 × the ULN	+ 2
Histological features3
	Compatible with AIH	+ 1
	Typical of AIH	+ 2
Absence of viral hepatitis, Wilson disease, metabolic associated steatotic liver disease, drug exposure		+ 2
Presence of extrahepatic autoimmunity		+ 1
Family history of autoimmune disease		+ 1
Cholangiography
	Normal	+ 2
	Abnormal	- 2

¹Antibodies measured by indirect immunofluorescence on a composite rodent substrate (i.e., kidney, liver or stomach).

²Addition of points achieved for antinuclear antibody, smooth muscle antibody, anti-liver kidney microsomal antibody type 1 antibodies, liver cytosol antibody type 1, and anti-soluble liver antigen cannot exceed a maximum of 2 points.

³Typical histological features are those contained in the revised diagnostic criteria of the International Autoimmune Hepatitis Group, principally interface hepatitis.

AIH: Autoimmune hepatitis; ANA: Antinuclear antibody; SMA: Smooth muscle antibody; LKM-1: Liver kidney microsomal antibody type 1; LC-1: Liver cytosol antibody type 1; pANCA: Perinuclear antineutrophil cytoplasmic antibody; IgG: Immunoglobulin G; ULN: Upper limit of normal.

Table 4 Differential diagnosis in refractory autoimmune hepatitis

Differential diagnosis in refractory autoimmune hepatitis
Primary sclerosing cholangitis
Viral infections
Wilsons disease
Hereditary hemochromatosis
Coeliac disease
Alpha one antitrypsin deficiency
Inflammatory bowel disease
Metabolic dysfunction-associated steatotic liver disease
Drug-induced autoimmune-like hepatitis
Genetic defects of immune regulation
Extrahepatic immune disorders (thyroid disorders, systemic lupus erythematosus)

Table 5 Immunosuppressive therapies used in children for refractory autoimmune hepatitis

Medication		Route of administration	Dose in children	Trough level	Adjuvant therapy indicated
Mycophenolate mofetil	Second line	Oral	10 mg/kg/dose twice daily; maximum dose 20 mg/kg/dose twice daily	Not applicable	Yes- steroid
Tacrolimus	Second or third line	Oral	0.05 mg/kg/day- adjusted as per trough level	Initial serum trough levels 6-8 ng/mL, tapering to 3-5 ng/mL	Yes- steroid
Cyclosporine A	Third or fourth line	Oral	4 mg/kg twice daily- adjusted as per trough level	Initial trough levels at 200-250 ng/mL, tapering to trough levels < 120 ng/mL after full biochemical remission	Yes- steroid
Sirolimus	Third/fourth line	Oral	Initial dose 1-2 mg/m2 body surface area	Trough level of 4 ng/mL to 8 ng/mL	Yes- steroid
Rituximab	Third/fourth line	Intravenous infusion	375 mg/m2 2-4 doses every alternate week or fortnightly; further doses of rituximab might be needed 4-6 monthly	Not measurable. Surveillance of CD20+ B-cells is recommended; immunoglobulin supplementation may be necessary	Yes- steroid
Infliximab	Third/fourth line	Intravenous infusion	5 mg/kg infliximab is infusions at 0, after two weeks, and after six weeks of initial infusion, and thereafter every four to eight weeks depending on laboratory and clinical course	Data not available	Yes- steroid

Table 6 Examples of ongoing trials in autoimmune hepatitis

Ref.		Treatment	Mechanism of action	Stage of development
Mack et al[2], 2020; Whitehead and Kriegermeier[42], 2020; Reau et al[48], 2024	1	Zetomipzomib	Immunoproteasome inhibitor	Phase 2
	2	Ianalumab, Belimumab	Antibody-dependent cellular cytotoxicity mediated B-cell depletion through B-cell activating factor inhibition	Phase 2/3
	3	JKB-122	Toll-like receptor-4 inhibition	Phase 2
	4	Mesenchymal stromal cells	Induction of regulatory T-cell differentiation and suppression of lymphocyte activation	Phase 1/2
	5	Synthetic preimplantation factor (s-PIF)	Creation of immunosuppressive and immunomodulatory environment of pregnancy	Phase 1