Review
Copyright ©The Author(s) 2017.
World J Gastroenterol. Sep 7, 2017; 23(33): 6030-6048
Published online Sep 7, 2017. doi: 10.3748/wjg.v23.i33.6030
Table 1 Proposed schedule of prednisone tapering during remission-induction therapy in adults[25]
Prednisone mg/dAzathioprine
Week 160.0Check 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 250.0
Week 340.0
Week 430.0
Week 525.0
Week 620.0
Week 715.0
Week 8-912.5
Week 10-1110.0
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/dAzathioprine
Week 12.0Check 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 21.75
Week 31.50
Week 41.25
Week 51.00
Week 60.75
Week 70.50
Week 8-90.25
Week 10-110.10-0.20
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, yrCountryNumber and type of patientsDesignOutcomeFollow-upDoseSafety
Budesonide
Danielsson et al[79], 1994Sweden13 naïveProspectiveSignificant decrase of mean transaminase levels9 mo6-8 mg/dPlasma cortisol reduction in cirrhotic patients
Czaja et al[80], 2000United States10 AZA-NRProspective3/10 BR2-12 mo9 mg/dAll patients had side-effects
Wiegand et al[81], 2005Germany12 naïveProspective10/12 BR3 mo9 mg/d3 discontinued due to side effects
Csepregi et al[82], 2006Germany10 naïve 8 AZA-NRProspective7/10 naïve BR 8/8 AZA-NR BR24 wk9 mg/dSteroids side-effects in cirrhotic patients
Zandieh et al[83], 2008Canada6 AZA-INT 3 PDN-INTRetrospective4/6 AZA-INT CBR 3/3 PDN-INT CBR24 wk-8 yr1.5-9 mg/dNot reported
Manns et al[84], 20101Europe208 naïve or relapsingProspective, randomized,60% BR in budesonide 39% BR in PDN6 mo9 mg/dSteroids side effects: 28% in budesonide arm, 53% in PDN arm
Mycophenolate mofetil
Richardson et al[177], 2000United Kingdom3 AZA-INT 4 AZA-NRRetrospective5/7 BR46 mo2 g/dLeukopaenia in 1
Zolfino et al[93], 2002United Kingdom3 second lineRetrospective1/3 BRNot reported2 g/dNot reported
Devlin et al[94], 2004Canada5 second-lineRetrospective5/5 BRNot reportedNot reported1 pyelonephritis
Chatur et al[95], 2005Canada11 second-lineRetrospective7/11 BR10-54 mo0.5-2 g/dLeukopaenia in 1, diarrhoea in 1
Czaja et al[96],2005United States8 first- and second lineRetrospective0/8 CBR12-26 mo0.5-3 g/ dNone reported
Inductivo-Yu et al[97], 2007United States15 second-lineRetrospectiveSignificant decrease of mean transaminase levels and of histological fibrosis and inflammation41 mo2 g/dNone significant
Hlivko et al[98], 2008United States17 naïve 12 second-lineRetrospective16/19 BRNot reported0.5-2 g/d10 discontinued for side-effects
Hennes et al[99], 20082Germany27 AZA-INT 9 AZA-NRRetrospective57% AZA-INT BR 25% AZA-NR BR16 mo1-2 g/d11 GI side effects
Wolf et al[178], 2009United States16 second-lineRetrospective5/16 BRNot reported1-2 g/d1 discontinued due to paresthesias
Sharzehi et al[100], 2010United States9 AZA-INT 12 AZA-NRRetrospective21/21 BR12 mo0.5-2 g/d1 discontinued for GI side-effects
Baven-Pronk et al[101], 2011The Netherlands23 AZA-INT 22 AZA-NRRetrospective67% AZA-INT BR 13% AZA-NR BR3-133 mo0.5-3 g/d6 discontinued for side-effects
Jothinami et al[102], 2014India- United Kingdom18 AZA-INT 2 AZA-NRRetrospective14 BR5-83 mo1-2 g/d3 discontinued due to side-effects
Zachou et al[103], 2016Greece109 naïveProspective83/102 BR at 3 mo72 mo1.5-2 g/d2 discontinued for septicaemia; 5 dose reduction for leukopaenia or infections
Gazzola et al[179], 2016Australia51 AZA-INT 45 AZA-NRRetrospective27/49 AZA-INT BR 17/40 AZA-NR BRMedian: 31.9 mo1-2 g/d1 death, 2 hospitalisations, 8 GI side effects, 5 infections, 3 cytopoenia, 3 neuropsychiatric, 2 skin cancer, 1 lymphoproliferative disorder
Park et al[180], 2016South Korea1 AZA-INTRetrospective1/1 CBR1 yr1 g/dNone
Cyclosporine A
Mistilis et al[121], 1985Australia1 AZA-INTRetrospective1/1 BR1 yrNot reportedNone
Paroli et al[116], 1992Italy3 naïveProspective3/3 BR1 yr5 mg/kg/dNot reported
Person et al[118], 1993United States1 second-lineRetrospectiveBRNot reportedNot reportedNot reported
Sherman et al[114], 1994United States6 AZA-NR (1 paediatric)Retrospective5/6 BR at 10 wkNot reportedNot reported1 increased serum creatinine
Senturk et al[119], 1995India1 second-lineRetrospectiveBR1 yrNot reportedNone
Fernandes et al[113], 1999United States5 AZA-NRRetrospective4/5 BR at 3 mo27 mo3-5 mg/kg/dMinimal
Malekzadeh et al[117], 2001Iran9 naïve 10 second-lineProspective79% BR and HI26 mo2-5 mg/kg/d4 discontinued due to side effects
Zolfino et al[93], 2002United Kingdom1 second-lineRetrospectiveNRNot reportedSerum level 100-200 μg/LNot reported
Malekzadeh et al[181], 2012Iran22 steroid-intolerant or NRRetrospective9 BR60 moNot reportedHirsutism (frequency not reported)
Tacrolimus
Van Thiel et al[134], 1995United States21 naïveProspectiveMean 80% ALT drop at 3 months3 mo6.6-8 mg/d; blood levels 0.6-1.0 ng/mLMild mean creatinine elevation after 1 yr
Heneghan et al[137], 1999United Kingdom7 naïveProspectiveBR in 86%Not reportedNot reported
Zolfino et al[93], 2002United Kingdom5 AZA-NRRetrospective2/5 BRNot reported2-4 mg/dNot reported
Aqel et al[130], 2004United States11 second-lineRetrospectiveNormalization of mean ALT value16 mo0.5-1 mg/d(blood level < 6 ng/mL)Minimal
Chatur et al[95], 2005Canada3 second-lineRetrospective3/3 NR10-54 mo2-4 mg/d1 discontinued for abdominal pain
Larsen et al[131], 2007Denmark9 AZA- or MMF-NR (1 pediatric)Retrospective9/9 BR12-37 mo2 mg/d (target blood level < 6 ng/mL)1 mild tremor
Tannous et al[133], 2011United States13 second-lineRetrospective12/13 BR1-65 mo2-6 mg/d (mean blood level 6 ng/mL)1 HUS; 1 oral carcinoma
Than et al[135], 2016German, United Kingdom16 AZA-NR 1 AZA-INTRetrospectiveBR in most60 mo0.5-5 mg/d1 LT; 4 PSC overlap
Al Taii et al[136], 20173United States23 second-lineRetrospective27% CBR 41% BR5 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], 2014United States5 AZA-NRProspective4/5 BR4-72 mo2 mg/d2 hyperlipidemia
Rubin et al[141], 2016United States2 second-lineRetrospective1/2 BRNot reported3-6 mg/d1 discontinued due to leg ulcer
Everolimus
Ytting et al[143], 2015Denmark7 second-lineRetrospective3/7 CBR 4/7 BR1-3 yr0.75-1.5 mg/d (target blood levels: 3-6 ng/mL)Minimal
Rituximab
Burak et al[144], 2013Canada3 AZA-NR 3 AZA-INTProspective6/6 BR at 24 wk72 wk1000 mg on day 0 and 151 mild infection
Al-Busafi et al[182], 2013Oman1 steroid-resisitantRetrospectiveBRNot reportedNot reportedNone reported
Rubin et al[141], 2016United States1 second-lineRetrospective1/1 BR14 mo475 mg/m2 per weekNone reported
Infliximab
Weiler-Normann et al[154], 2013Germany11 second-lineRetrospective8/11 BR6 to > 40 infusions5 mg/kg on 0, 2, 6, then every 4-8 wk7/11 infections, 3 discontinued for side effects
Vallejo et al[156], 2014Spain1 AZA-NRRetrospective1/1 BR3 mo5 mg/kg given 3 timesMild respiratory infection
6-mercaptopurine
Pratt et al[167], 1996United States2 AZA-INTRetrospective2/2 CBR, 1/2 HI24 mo in one not reported in the other100 mg/dNone reported
Hübener et al[168], 2016Germany/United Kingdom20 AZA-INT 2 AZA-NRRetrospective8/20 CBR 7/20 BR18.5 mo25-100 mg/d4 discontinued for GI side-effects, 1 for leucopaenia
Elnegouly et al[183], 2017Germany/Austria17 AZA-INTRetrospective11/12 CBR1 yr25-50 mg/d2 discontinued for side-effects
Allopurinol
Al-Shamma et al[170], 2013United Kingdom1 AZA-NRRetrospective1/1 BR12 mo100 mg/dNone reported
De Boer et al[171], 2013The Netherlands3 AZA-INT 5 AZA-NRRetrospective7/8 BR13 mo100 mg/d1 discontinued for neuropathy
Al-Shamma et al[172], 2013United Kingdom1 AZA-NRRetrospective1/1 CBRNot reported100 mg/dNone reported
6-thioguanine
De Boer et al[174], 2005The Netherlands3 AZA-INTRetrospective3/3 BRNot reported0.3 mg/kg/dNone reported
Van den Brand et al[175], 2017The Netherlands6 AZA-NR 6 AZA-INTRetrospectiveSignificant median ALT decrease12-75 mo0.3 mg/kg/d1 nodular regenerative hyperplasia
Table 4 Published data on autoimmune hepatitis treatment different from steroids and azathioprine in children
Ref.CountryNumber and type of patients (n)DesignOutcomeFollow-upDoseSide effects
Budesonide
Woynarowski et al[91], 2013Europe46 including naïve and second-lineProspective16% BR AZA+BUD 15% BR AZA+PDN at 6 mo1 yr6-9 mg/dMore weight gain in PDN group
Mycophenolate mofetil
Lee et al[107], 2007Malaysia2 second-lineRetrospective0/2 BR at 6 mo6-18 mo20-40 mg/kg/dNot reported
Aw et al[106], 2009United Kingdom20 AZA-NR 6 AZA-INTRetrospective18/26 CBR0.75-12 mo20-40 mg/kg/d7 Leukopaenia
Jiménenz-Rivera et al[108], 2012Canada12 second-lineRetrospectiveNot reportedNot reported1000-1500 mg/dNot reported
Dehghani et al[109], 2013Iran5 second-lineRetrospective5/5 BRNone reportedNot reportedNot reported
Cyclosporine A
Jackson et al[120], 1995South Africa1 AZA-INTRetrospective1/1 BR at 2 wk19 mo5 mg/kg/dNone
Debray et al[111], 1999France8 naïve 7 second-line (all type 2 AIH)Retrospective8/8 naïve BR 7/7 second-line (including 3 with ALF)1-6 yr4.7-5.6 mg/kg/dMinimal
Ben Halima etal[122], 2002Tunisia1 first-lineRetrospective1/1 BRNot reportedNot reportedNone
Sciveres et al[184], 2004Italy4 naïve 4 steroid/AZA-intolerantRetrospective8/8 BR at 2-8 wk1.5-15 yr4-10 mg/kg per day2 gingival hypertrophy, 1 creatinine elevation
Cuarterolo et al[124], 2006Agentina86 naïve, type 1 AIHProspectiveBR 94%2 yr4 mg/kg per day8/84 creatinine elevation 3/84 hypertension
Nastasio et al[115], 2011Italy19 naïve1 10 second-line1Retrospective19/19 naïve BR at 4-18 wk 9/10 second-line BR6.5 yrNot reported11 hyperthricosis, 13 gingival hypertrophy
Dehghani et al[109], 2013Iran3 second-lineRetrospective3/3 BRNot reportedNot reportedNot reported
Lee et al[107], 2015Malaysia2 second-lineRetrospective1 /2 BR6-18 mo5 mg/kg per day, serum level 250-350 ng/mL
Zaya et al[112], 2012Croatia9 naïve (1 type 2 AIH)Retrospective7/9 BR after 1 yr24 mo3-5 mg/kg per dayMinor
Jiménez-Rivera et al[108], 2012Canada9 naïve 15 second-lineRetrospectiveNot reported4 ± 2 yr4 ± 0.8 mg/kg per day intially 4.9 ± 1.8 mg/kg per day in follow-upNot reported
Tacrolimus
Zolfino et al[93], 2002United Kingdom1 second-lineRetrospectiveNRNot reported2 mg/dNot reported
Marlaka et al[138], 2012Sweden20 naïveProspective3/20 BR in monotherapy1 yrTarget blood levels: 2.5-5 ng/ml1 discontinued for side-effects; 2 developed IBD
Dehghani et al[109], 2013Iran2 second-lineRetrospective2/2 BRNot reportedNot reportedNot reported
Jiménez-Rivera et al[108], 2015Canada6 second-lineRetrospectiveNot reportedNot reportedNot reportedNot reported
Sirolimus
Kurowski et al[140], 2014United States4 second-lineRetrospective2/4 BRNot reportedNot reported2 mo ulcers
Rituximab
D’Agostino et al[150], 2013Canada/Argentina2 second-lineRetrospective2/2 CBR at 3/8 mo26-38 mo375 mg/m2 weekly for 4 wkNone reported
Infliximab
Rajanayagam et al[158], 2013Australia1 second-lineRetrospective1/1 BR19 mo5 mg/kg 4 infusions at 4 wk intervalLT was not prevented
6-mercaptopurine
Pratt et al[167], 1996United States1 AZA-NRRetrospective1/1 CBR and HR36 mo1.5 mg/kgNone reported