Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments

Table 1 Proposed schedule of prednisone tapering during remission-induction therapy in adults[25]

	Prednisone mg/d	Azathioprine
Week 1	60.0	Check transaminase levels every week before reducing the prednisone dose: if transaminase levels stop decreasing, add azathioprine 1-2 mg/kg per day, if jaundice is subsiding
Week 2	50.0
Week 3	40.0
Week 4	30.0
Week 5	25.0
Week 6	20.0
Week 7	15.0
Week 8-9	12.5
Week 10-11	10.0
If severe steroid side effects: consider reducing to 2.5 mg/d for 2 wk and then stopping prednisone

Table 2 Proposed schedule of prednisone tapering during remission-induction therapy in children[2,12]

	Prednisone mg/kg/d	Azathioprine
Week 1	2.0	Check transaminase levels every week before reducing the prednisone dose: if transaminase levels stop decreasing, add azathioprine starting with 0.5 mg/kg per day, if jaundice is subsiding, at increasing doses up to 2-2.5 mg/kg/d until biochemical control
Week 2	1.75
Week 3	1.50
Week 4	1.25
Week 5	1.00
Week 6	0.75
Week 7	0.50
Week 8-9	0.25
Week 10-11	0.10-0.20
If severe steroid side effects: consider reducing to 2.5 mg/d for 2 wk and then stopping prednisone

Table 3 Published data on autoimmune hepatitis treatment different from steroids and azathioprine in adults (from age 16)

Reference, yr	Country	Number and type of patients	Design	Outcome	Follow-up	Dose	Safety
Budesonide
Danielsson et al[79], 1994	Sweden	13 naïve	Prospective	Significant decrase of mean transaminase levels	9 mo	6-8 mg/d	Plasma cortisol reduction in cirrhotic patients
Czaja et al[80], 2000	United States	10 AZA-NR	Prospective	3/10 BR	2-12 mo	9 mg/d	All patients had side-effects
Wiegand et al[81], 2005	Germany	12 naïve	Prospective	10/12 BR	3 mo	9 mg/d	3 discontinued due to side effects
Csepregi et al[82], 2006	Germany	10 naïve 8 AZA-NR	Prospective	7/10 naïve BR 8/8 AZA-NR BR	24 wk	9 mg/d	Steroids side-effects in cirrhotic patients
Zandieh et al[83], 2008	Canada	6 AZA-INT 3 PDN-INT	Retrospective	4/6 AZA-INT CBR 3/3 PDN-INT CBR	24 wk-8 yr	1.5-9 mg/d	Not reported
Manns et al[84], 20101	Europe	208 naïve or relapsing	Prospective, randomized,	60% BR in budesonide 39% BR in PDN	6 mo	9 mg/d	Steroids side effects: 28% in budesonide arm, 53% in PDN arm
Mycophenolate mofetil
Richardson et al[177], 2000	United Kingdom	3 AZA-INT 4 AZA-NR	Retrospective	5/7 BR	46 mo	2 g/d	Leukopaenia in 1
Zolfino et al[93], 2002	United Kingdom	3 second line	Retrospective	1/3 BR	Not reported	2 g/d	Not reported
Devlin et al[94], 2004	Canada	5 second-line	Retrospective	5/5 BR	Not reported	Not reported	1 pyelonephritis
Chatur et al[95], 2005	Canada	11 second-line	Retrospective	7/11 BR	10-54 mo	0.5-2 g/d	Leukopaenia in 1, diarrhoea in 1
Czaja et al[96],2005	United States	8 first- and second line	Retrospective	0/8 CBR	12-26 mo	0.5-3 g/ d	None reported
Inductivo-Yu et al[97], 2007	United States	15 second-line	Retrospective	Significant decrease of mean transaminase levels and of histological fibrosis and inflammation	41 mo	2 g/d	None significant
Hlivko et al[98], 2008	United States	17 naïve 12 second-line	Retrospective	16/19 BR	Not reported	0.5-2 g/d	10 discontinued for side-effects
Hennes et al[99], 20082	Germany	27 AZA-INT 9 AZA-NR	Retrospective	57% AZA-INT BR 25% AZA-NR BR	16 mo	1-2 g/d	11 GI side effects
Wolf et al[178], 2009	United States	16 second-line	Retrospective	5/16 BR	Not reported	1-2 g/d	1 discontinued due to paresthesias
Sharzehi et al[100], 2010	United States	9 AZA-INT 12 AZA-NR	Retrospective	21/21 BR	12 mo	0.5-2 g/d	1 discontinued for GI side-effects
Baven-Pronk et al[101], 2011	The Netherlands	23 AZA-INT 22 AZA-NR	Retrospective	67% AZA-INT BR 13% AZA-NR BR	3-133 mo	0.5-3 g/d	6 discontinued for side-effects
Jothinami et al[102], 2014	India- United Kingdom	18 AZA-INT 2 AZA-NR	Retrospective	14 BR	5-83 mo	1-2 g/d	3 discontinued due to side-effects
Zachou et al[103], 2016	Greece	109 naïve	Prospective	83/102 BR at 3 mo	72 mo	1.5-2 g/d	2 discontinued for septicaemia; 5 dose reduction for leukopaenia or infections
Gazzola et al[179], 2016	Australia	51 AZA-INT 45 AZA-NR	Retrospective	27/49 AZA-INT BR 17/40 AZA-NR BR	Median: 31.9 mo	1-2 g/d	1 death, 2 hospitalisations, 8 GI side effects, 5 infections, 3 cytopoenia, 3 neuropsychiatric, 2 skin cancer, 1 lymphoproliferative disorder
Park et al[180], 2016	South Korea	1 AZA-INT	Retrospective	1/1 CBR	1 yr	1 g/d	None
Cyclosporine A
Mistilis et al[121], 1985	Australia	1 AZA-INT	Retrospective	1/1 BR	1 yr	Not reported	None
Paroli et al[116], 1992	Italy	3 naïve	Prospective	3/3 BR	1 yr	5 mg/kg/d	Not reported
Person et al[118], 1993	United States	1 second-line	Retrospective	BR	Not reported	Not reported	Not reported
Sherman et al[114], 1994	United States	6 AZA-NR (1 paediatric)	Retrospective	5/6 BR at 10 wk	Not reported	Not reported	1 increased serum creatinine
Senturk et al[119], 1995	India	1 second-line	Retrospective	BR	1 yr	Not reported	None
Fernandes et al[113], 1999	United States	5 AZA-NR	Retrospective	4/5 BR at 3 mo	27 mo	3-5 mg/kg/d	Minimal
Malekzadeh et al[117], 2001	Iran	9 naïve 10 second-line	Prospective	79% BR and HI	26 mo	2-5 mg/kg/d	4 discontinued due to side effects
Zolfino et al[93], 2002	United Kingdom	1 second-line	Retrospective	NR	Not reported	Serum level 100-200 μg/L	Not reported
Malekzadeh et al[181], 2012	Iran	22 steroid-intolerant or NR	Retrospective	9 BR	60 mo	Not reported	Hirsutism (frequency not reported)
Tacrolimus
Van Thiel et al[134], 1995	United States	21 naïve	Prospective	Mean 80% ALT drop at 3 months	3 mo	6.6-8 mg/d; blood levels 0.6-1.0 ng/mL	Mild mean creatinine elevation after 1 yr
Heneghan et al[137], 1999	United Kingdom	7 naïve	Prospective	BR in 86%		Not reported	Not reported
Zolfino et al[93], 2002	United Kingdom	5 AZA-NR	Retrospective	2/5 BR	Not reported	2-4 mg/d	Not reported
Aqel et al[130], 2004	United States	11 second-line	Retrospective	Normalization of mean ALT value	16 mo	0.5-1 mg/d(blood level < 6 ng/mL)	Minimal
Chatur et al[95], 2005	Canada	3 second-line	Retrospective	3/3 NR	10-54 mo	2-4 mg/d	1 discontinued for abdominal pain
Larsen et al[131], 2007	Denmark	9 AZA- or MMF-NR (1 pediatric)	Retrospective	9/9 BR	12-37 mo	2 mg/d (target blood level < 6 ng/mL)	1 mild tremor
Tannous et al[133], 2011	United States	13 second-line	Retrospective	12/13 BR	1-65 mo	2-6 mg/d (mean blood level 6 ng/mL)	1 HUS; 1 oral carcinoma
Than et al[135], 2016	German, United Kingdom	16 AZA-NR 1 AZA-INT	Retrospective	BR in most	60 mo	0.5-5 mg/d	1 LT; 4 PSC overlap
Al Taii et al[136], 20173	United States	23 second-line	Retrospective	27% CBR 41% BR		5 mg/d (mean) serum level: 6.7 ng/mL (mean)	Significant increase of serum creatinine; 1 discontinued for GI hemorrhage
Sirolimus
Chatrath et al[139], 2014	United States	5 AZA-NR	Prospective	4/5 BR	4-72 mo	2 mg/d	2 hyperlipidemia
Rubin et al[141], 2016	United States	2 second-line	Retrospective	1/2 BR	Not reported	3-6 mg/d	1 discontinued due to leg ulcer
Everolimus
Ytting et al[143], 2015	Denmark	7 second-line	Retrospective	3/7 CBR 4/7 BR	1-3 yr	0.75-1.5 mg/d (target blood levels: 3-6 ng/mL)	Minimal
Rituximab
Burak et al[144], 2013	Canada	3 AZA-NR 3 AZA-INT	Prospective	6/6 BR at 24 wk	72 wk	1000 mg on day 0 and 15	1 mild infection
Al-Busafi et al[182], 2013	Oman	1 steroid-resisitant	Retrospective	BR	Not reported	Not reported	None reported
Rubin et al[141], 2016	United States	1 second-line	Retrospective	1/1 BR	14 mo	475 mg/m2 per week	None reported
Infliximab
Weiler-Normann et al[154], 2013	Germany	11 second-line	Retrospective	8/11 BR	6 to > 40 infusions	5 mg/kg on 0, 2, 6, then every 4-8 wk	7/11 infections, 3 discontinued for side effects
Vallejo et al[156], 2014	Spain	1 AZA-NR	Retrospective	1/1 BR	3 mo	5 mg/kg given 3 times	Mild respiratory infection
6-mercaptopurine
Pratt et al[167], 1996	United States	2 AZA-INT	Retrospective	2/2 CBR, 1/2 HI	24 mo in one not reported in the other	100 mg/d	None reported
Hübener et al[168], 2016	Germany/United Kingdom	20 AZA-INT 2 AZA-NR	Retrospective	8/20 CBR 7/20 BR	18.5 mo	25-100 mg/d	4 discontinued for GI side-effects, 1 for leucopaenia
Elnegouly et al[183], 2017	Germany/Austria	17 AZA-INT	Retrospective	11/12 CBR	1 yr	25-50 mg/d	2 discontinued for side-effects
Allopurinol
Al-Shamma et al[170], 2013	United Kingdom	1 AZA-NR	Retrospective	1/1 BR	12 mo	100 mg/d	None reported
De Boer et al[171], 2013	The Netherlands	3 AZA-INT 5 AZA-NR	Retrospective	7/8 BR	13 mo	100 mg/d	1 discontinued for neuropathy
Al-Shamma et al[172], 2013	United Kingdom	1 AZA-NR	Retrospective	1/1 CBR	Not reported	100 mg/d	None reported
6-thioguanine
De Boer et al[174], 2005	The Netherlands	3 AZA-INT	Retrospective	3/3 BR	Not reported	0.3 mg/kg/d	None reported
Van den Brand et al[175], 2017	The Netherlands	6 AZA-NR 6 AZA-INT	Retrospective	Significant median ALT decrease	12-75 mo	0.3 mg/kg/d	1 nodular regenerative hyperplasia

¹The series includes 46 children (Woynarowski et al[91] 2013);

²The series includes 4 adolescents, but only overall results are reported, and youngest age at diagnosis was 13 yr;

³The series includes 6 adolescents, but only overall results are reported, and youngest age at diagnosis was 15 yr. BR: Biochemical response; AZA-NR: Azathioprine non-responder; AZA-INT: Azathioprine intolerant; CBR: Complete biochemical response; PDN: Prednisone; GI: Gastrointestinal; HI: Histological improvement; LT: Liver transplant; NR: Non-responder; ALT: Alanine aminotransferase; HUS: Haemolytic-uremic syndrome; PSC: Primary sclerosing cholangitis.

Table 4 Published data on autoimmune hepatitis treatment different from steroids and azathioprine in children

Ref.	Country	Number and type of patients (n)	Design	Outcome	Follow-up	Dose	Side effects
Budesonide
Woynarowski et al[91], 2013	Europe	46 including naïve and second-line	Prospective	16% BR AZA+BUD 15% BR AZA+PDN at 6 mo	1 yr	6-9 mg/d	More weight gain in PDN group
Mycophenolate mofetil
Lee et al[107], 2007	Malaysia	2 second-line	Retrospective	0/2 BR at 6 mo	6-18 mo	20-40 mg/kg/d	Not reported
Aw et al[106], 2009	United Kingdom	20 AZA-NR 6 AZA-INT	Retrospective	18/26 CBR	0.75-12 mo	20-40 mg/kg/d	7 Leukopaenia
Jiménenz-Rivera et al[108], 2012	Canada	12 second-line	Retrospective	Not reported	Not reported	1000-1500 mg/d	Not reported
Dehghani et al[109], 2013	Iran	5 second-line	Retrospective	5/5 BR	None reported	Not reported	Not reported
Cyclosporine A
Jackson et al[120], 1995	South Africa	1 AZA-INT	Retrospective	1/1 BR at 2 wk	19 mo	5 mg/kg/d	None
Debray et al[111], 1999	France	8 naïve 7 second-line (all type 2 AIH)	Retrospective	8/8 naïve BR 7/7 second-line (including 3 with ALF)	1-6 yr	4.7-5.6 mg/kg/d	Minimal
Ben Halima etal[122], 2002	Tunisia	1 first-line	Retrospective	1/1 BR	Not reported	Not reported	None
Sciveres et al[184], 2004	Italy	4 naïve 4 steroid/AZA-intolerant	Retrospective	8/8 BR at 2-8 wk	1.5-15 yr	4-10 mg/kg per day	2 gingival hypertrophy, 1 creatinine elevation
Cuarterolo et al[124], 2006	Agentina	86 naïve, type 1 AIH	Prospective	BR 94%	2 yr	4 mg/kg per day	8/84 creatinine elevation 3/84 hypertension
Nastasio et al[115], 2011	Italy	19 naïve1 10 second-line1	Retrospective	19/19 naïve BR at 4-18 wk 9/10 second-line BR	6.5 yr	Not reported	11 hyperthricosis, 13 gingival hypertrophy
Dehghani et al[109], 2013	Iran	3 second-line	Retrospective	3/3 BR	Not reported	Not reported	Not reported
Lee et al[107], 2015	Malaysia	2 second-line	Retrospective	1 /2 BR	6-18 mo	5 mg/kg per day, serum level 250-350 ng/mL
Zaya et al[112], 2012	Croatia	9 naïve (1 type 2 AIH)	Retrospective	7/9 BR after 1 yr	24 mo	3-5 mg/kg per day	Minor
Jiménez-Rivera et al[108], 2012	Canada	9 naïve 15 second-line	Retrospective	Not reported	4 ± 2 yr	4 ± 0.8 mg/kg per day intially 4.9 ± 1.8 mg/kg per day in follow-up	Not reported
Tacrolimus
Zolfino et al[93], 2002	United Kingdom	1 second-line	Retrospective	NR	Not reported	2 mg/d	Not reported
Marlaka et al[138], 2012	Sweden	20 naïve	Prospective	3/20 BR in monotherapy	1 yr	Target blood levels: 2.5-5 ng/ml	1 discontinued for side-effects; 2 developed IBD
Dehghani et al[109], 2013	Iran	2 second-line	Retrospective	2/2 BR	Not reported	Not reported	Not reported
Jiménez-Rivera et al[108], 2015	Canada	6 second-line	Retrospective	Not reported	Not reported	Not reported	Not reported
Sirolimus
Kurowski et al[140], 2014	United States	4 second-line	Retrospective	2/4 BR	Not reported	Not reported	2 mo ulcers
Rituximab
D’Agostino et al[150], 2013	Canada/Argentina	2 second-line	Retrospective	2/2 CBR at 3/8 mo	26-38 mo	375 mg/m2 weekly for 4 wk	None reported
Infliximab
Rajanayagam et al[158], 2013	Australia	1 second-line	Retrospective	1/1 BR	19 mo	5 mg/kg 4 infusions at 4 wk interval	LT was not prevented
6-mercaptopurine
Pratt et al[167], 1996	United States	1 AZA-NR	Retrospective	1/1 CBR and HR	36 mo	1.5 mg/kg	None reported

¹Twelve patients had additional concomintant immunosuppressive drugs. BR: Biochemical response; AZA: Azathioprine; BUD: Budesonide; PDN: Prednisone; INT: Intolerant; NR: Non-responder; AIH: Autoimmune hepatitis; ALF: Acute liver failure; IBD: Inflammatory bowel disease; LT: Liver transplant; CRB: Complete biochemical response.