Autoimmune hepatitis treatment in the elderly: A systematic review

Table 1 Risk of bias assessment in the included studies according to Risk Of Bias In Non-randomised Studies of Interventions scale

Biasdomains	Schram et al[6], 2001	Granito et al[21], 2005	Al-Chalabi et al[23], 2006	Czaja et al[9], 2006	Zhang et al[22], 2012	Zachou et al[20], 2016	Morii et al[24], 2017
Confounding	Moderate	Serious	Moderate	Moderate	Serious	Moderate	Moderate
Selection of participants into study	Serious	Low	Low	Moderate	Moderate	Serious	Moderate
Classification of interventions	Serious	Moderate	Moderate	Moderate	Serious	Moderate	Moderate
Deviation from intended interventions	No information	Low	No information	No information	No information	Low	Moderate
Missing data	Moderate	Moderate	Moderate	Serious	Serious	Serious	Serious
Measurement of outcomes	Low	Moderate	Moderate	Moderate	Moderate	Moderate	Moderate
Selection of the reported results	Moderate	Moderate	Moderate	Moderate	Moderate	Serious	Moderate
Overall	Serious	Serious	Moderate	Serious	Serious	Serious	Serious

Table 2 Characteristics of included studies

Author(year)	Methods	No. of patients (F:M)	Diagnostic criteria	Country	Interventions	Median FU	Outcomes	Side effects
		Elderly:Youn-ger
Schramm et al[6], 2001	Comparative Cohort Study	40 (32:8)	IAIHG (1999)	Germany	-P alone	4-164 mo	CR, relapse, all causes and liver-related death	GI symptoms, cholestasis, skin rush (AZA). VZ infection, pulmonary TB reactivation
					-P + AZA	(40 mo in elderly group)
		20 (≥ 65 yr, 50%):20			-No treatment
Granito et al[21], 2005	Comparative Cohort Study	76 (64:12)	IAIHG (1999)	Italy	-M alone	1-16 yr (5 yr) in the elderly	CR, relapse, death	None in elderly group
		20 (≥ 65 yr, 26%):56			-M + AZA
					-No treatment
Al-Chalabi et al[23], 2006	Comparative Cohort Study	164 (128:36)	IAIHG (1999)	UK	-P alone	1-28 yr (9 yr)	CR, PR, TF, relapse, deaths/OLT	Cushingoid faces, osteoporosis, T2DM, hypertension, psychoses. Cytopenia (AZA)
					-P + AZA
		43 (≥ 60 yr, 26%):121			-(P + Cyclo
					and P + D-P in young only)
Czaja et al[9], 2006	Comparative Cohort Study	205 (175:30)	IAIHG (1999)	USA	-Pp alone	(77 mo)	Remission, SR, TF, relapse, death or OLT	Not reported
					-Pp + AZA
		47 (≥ 60 yr, 23%):158			-P + AZA
					-No treatment
Zhang et al[22], 2012	Comparative Cohort Study	75 (71:4)	IAIHG (1999)	China	-P alone	6 mo-8 yr	Remission, SR, TF, relapse, death	Not reported
		36 (≥ 60 yr, 48%):39
			+ IAIHG (2008)
Zachou et al[20], 2016	Comparative Cohort Study	158 (114:44)	IAIHG (2008)	Greece	-P + MMF	3-168 mo (72) in MMF group	CR, PR, TF, relapse, liver-related death, progression during FU, OLT	Sepsis, airway infections, VZ, mild GI symptoms, cytopenia (MMF)
		45 (> 60 yr, 28%):113			-P alone
					-P + AZA
Morii et al[24], 2017	Comparative Cohort Study	71 (56:15)	IAIHG (1999)	Japan	-Pp alone	2-69 mo (31 mo)	Remission, relapses	Not reported
		28 (≥ 70 yr, 39%):43			-UDCA

IAIHG: International Autoimmune Hepatitis Group; P: Prednisolone; Pp: Prednisone; AZA: Azathioprine; M: Methylprednisolone; Cyclo: Cyclophosphamide; D-P: D-Penicillamine; MMF: Mycophenolate Mofetil; UDCA: Ursodeoxycholic acid; CR: Complete Remission; PR: Partial remission; SR: Sustained remission; TF: Treatment failure; OLT: Orthotopic liver transplantation; GI: Gastro-Intestinal; VZ: Varicella zoster; T2DM: Type 2 diabetes mellitus; TB: Tubercolosis.

Table 3 Treatment regimens

Author (year)	Treatments
Schramm et al[6], 2001	P 1 mg/kg/die
	P 1 mg/kg/die + AZA 1-1.5 mg/kg/die
	No treatment
Granito et al[21], 2005	M 1 mg/kg/die
	M 30 mg/die + AZA 50 mg/die
	No treatment
Al-Chalabi et al[23], 2006	P 20-40 mg/die
	P 20-40 mg/die + AZA (1 mg/kg/die)
	P 20-40 mg/die + Cyclo (only in the younger group)
	P 20-40 mg/die + D-P (only in the younger group)
Czaja et al[9], 2006	Pp (doses not specified)
	Pp + AZA (doses not specified)
	Investigational therapies (drugs not specified)
	No Treatment
Zhang et al[22], 2012	P (doses not specified)
	P + AZA (doses not specified)
	No treatment
Zachou et al[20], 2016	P 0,5-1 mg/kg/die + MMF 1.5-2g/die
	P 0,5-1 mg/kg/die
	P 0.5-1 mg/kg/die + AZA 1.5-2 mg/kg/die
Morii et al[24], 2017	Pp 30-40 mg/die
	UDCA (dose not specified)

P: Prednisolone; Pp: Prednisone; AZA: Azathioprine; M: Methylprednisolone; Cyclo: Cyclophosphamide; D-P: D-Penicillamine; MMF: Mycophenolate Mofetil; UDCA: Ursodeoxycholic acid.

Table 4 Outcome definitions

Author (year)	Remission	Treatment failure	Relapse
Schramm et al[6], 2001	IAIHG revised criteria (1999)	-	IAIHG revised criteria (1999)
Granito et al[21], 2005	IAIHG revised criteria (1999)	-	IAIHG revised criteria (1999)
Al-Chalabi et al[23], 2006	IAIHG revised criteria (1999)	IAIHG original criteria (1993)	IAIHG revised criteria (1999)
	PR: IAIHG original criteria (1993)
Czaja et al[9], 2006	Symptoms: Absent	Worsening of clinical, laboratory and/or histological alterations despite compliance to therapy	Symptom recurrence and increased serum AST level (> three-fold the ULN) after drug withdrawal
	AST level: Normal or near normal (< two-fold the UNL)
	Histology: Minimal/no inflammation
	SR:
	Symptoms: Absent
	Serum AST levels: Normal or below the relapse threshold
	after drug withdrawal
Zhang et al[22], 2012	Symptoms: Absent	Worsening of clinical, laboratory and/or histological alterations despite compliance to therapy	Symptom recurrence and increased serum AST level (> three-fold the ULN) after drug withdrawal
	AST levels: Normal or near normal (< two-fold the UNL)
	Histology: Minimal or no inflammation.
	SR:
	Symptoms: Absent
	AST levels: Normal or below the relapse threshold after drug withdrawal
Zachou et al[20], 2016	CR:	Persistently elevated AST and ALT (> three-fold the UNL) and/or increased IgG despite intensive immunosuppression and compliance to therapy	Rise in AST and ALT levels (> three-fold the UNL) and/or increased IgG (> 2000 mg/dL) during therapy with or without symptom recurrence after initial CR
	Symptoms: Improved
	AST, ALT, IgG levels: normal
	Histology: Minimal/no inflammation
	PR:
	ALT or AST levels: Decreased (< two-fold ULN) without achieving complete normalization and inability to withdraw or taper prednisolone
Morii et al[24], 2017	Normal serum ALT and IgG levels	-	Re-exacerbation not explicitly defined

IAIHG: International Autoimmune Hepatitis Group; ALT: Alanine transaminase; AST: Aspartate transaminases; ULN: Upper limit of normal; IgG: Immunoglobulin G; CR: Complete remission; PR: Partial remission; SR: Sustained remission.