Budesonide versus Prednisone with Azathioprine for the Treatment of

Autoimmune Hepatitis in Children and Adolescents

Marek Woynarowski, MD1, Antal Nemeth, MD2, Yaacov Baruch, MD3, Sibylle Koletzko, MD4, Michael Melter, MD5,
Burkhard Rodeck, MD6, Christian P. Strassburg, MD7, Markus Prols, MD8, Ma1gorzata Wozniak, MD1,
and Michael P. Manns, MD7, on behalf of the European Autoimmune Hepatitis-Budesonide Study Group*
Objective To compare the effect of budesonide vs prednisone therapy both in combination with azathioprine in
pediatric patients with autoimmune hepatitis (AIH).

Study design Forty-six patients with AIH (11 males and 35 females) aged 9-17 years were enrolled in a 6-month,
prospective, double-blind, randomized, active-controlled, multicenter phase IIb study evaluating budesonide
(n = 19; 3 mg twice or 3 times daily) vs prednisone (n = 27; 40 mg/day tapered to 10 mg/day), both with azathioprine
(1-2 mg/kg/day), followed by a further 6 months of open-label budesonide therapy. The primary efficacy endpoint
was complete biochemical remission (normal serum alanine aminotransferase and aspartate aminotransferase
levels) without predefined steroid-specific side effects.
Results We observed no statistically significant difference in the percentage of patients who met the primary
endpoint between the budesonide (3 of 19; 16%) and prednisone groups (4 of 27; 15%) after 6 months, nor in
the percentage of patients who experienced biochemical remission (budesonide, 6 of 19 [32%]; prednisone, 9 of
27 [33%]), lack of steroid-specific side effects (budesonide, 10 of 19 [53%]; prednisone, 10 of 27 [37%]).
The mean weight gain was 1.2  3.5 kg in the budesonide group and 5.1  4.9 kg in the prednisone group
(P = .006). A total of 42 patients received open-label budesonide treatment for another 6 months. After 12 months,
46% of these patients achieved complete remission.
Conclusion Oral budesonide with azathioprine can induce and maintain remission in pediatric patients with AIH
and may be considered an alternative therapy to prednisone. The treatment causes fewer side effects and does not
lead to weight gain; however, it may be less effective than prednisone in inducing remission. (J Pediatr
2013;163:1347-53).
See editorial, p 1246

utoimmune hepatitis (AIH) is a chronic progressive liver disease associated with significant morbidity and mortality.1 It
occurs at all ages and affects predominately females, and is particularly aggressive in children and adolescents.2,3
Untreated, the prognosis for active AIH is poor, with 5- and 10-year survival rates between 50% and 10%, respectively.4
The estimated prevalence of AIH per 1 million population is 107 in Sweden,5 170 in Norway,6 and 189 in New Zealand.7 In
Poland, the estimated prevalence is 40 cases per 1 million pediatric patients,8 hindering the ability to perform controlled,
randomized, and adequately powered trials in patients with AIH.
Therapy with corticosteroids alone or in combination with azathioprine has been shown to induce remission and improve
survival9; 20% of children with AIH type 1 can successfully discontinue treatment.2,10 Steroid therapy does not cure the disease,
however, and relapses are common after discontinuation.11,12 Thus, many children continue remission maintenance therapy
with azathioprine.13 Consequently, patients with AIH require long-term treatment and are at risk for side effects of steroids or,
less frequently, azathioprine.
Experience with other immunosuppressive therapy in children with AIH is
limited, and no controlled, randomized trials have been reported. Cyclosporine
From the Childrens Health Memorial Institute, Warsaw,
Poland; Karolinska University Hospital, Stockholm,
A was found to induce biochemical remission in treatment-nave children14,15;
Sweden; Rambam Health Care Campus, Haifa, Israel;
Dr v Hauner Kinderspital, Ludwig Maximilians University
however, another study showed that despite biochemical improvement, none
of Munich, Munich, Germany; University Hospital
Regensburg, Germany; Christians Childrens Hospital
of the patients fulfilled the criteria for discontinuing therapy.16 Tacrolimus has
Osnabr
uck, Germany; University Hospital Bonn,
had limited efficacy in children with AIH and is probably insufficient to achieve
Germany; and Dr Falk Pharma, Freiburg, Germany
17
*A list of members of European AIH-Budesonide Study
complete remission. Mycofenolate mofetil may be considered as rescue therapy
1

Group is available at www.jpeds.com (Appendix).

AIH
ALT
AST
NS

Autoimmune hepatitis
Alanine aminotransferase
Aspartate aminotransferase
Not significant

Supported by Dr Falk Pharma (BUC-38/AIH). M.P. is

employed by Dr Falk Pharma. M.M. is a consultant to Dr
Falk Pharma and receives grant support and lecture fees.
The other authors declare no conflicts of interest.
Registered with ClinicalTrials.gov: NCT 00838214.
0022-3476/$ - see front matter. Copyright 2013 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.05.042

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in children resistant to standard immunosuppression.18

Treatment with these medications may be accompanied by
significant unwanted effects, and thus they are used in
treatment-resistant patients, not as first-line therapy.19
A potential alternative to standard prednisone therapy for
AIH is the use of topical steroids such as budesonide, which
has a 90% first-pass effect in the noncirrhotic liver.20 The
experience with budesonide in patients with AIH is limited.
Two studies concluded that budesonide is effective and has
a low rate of side effects,21,22 whereas another study reported
lack of efficacy in inducing remission and a high rate of side
effects.23 However, Czaja and Lindor23 explored budesonide
in difficult-to-treat patients with AIH in whom previous
therapy with standard of care had failed. These 3 studies
were open-label, not randomized, and included low numbers
of patients. The first large, multicenter, randomized trial
comparing budesonide with prednisone, both in combination with azathioprine demonstrated that oral budesonide
in combination with azathioprine effectively achieves and
maintains remission in 60% of noncirrhotic patients with
AIH in conjunction with a low rate of steroid-specific side
effects.24 The population studied by Manns et al24 included
208 adult and pediatric patients with a first diagnosis of acute
AIH or a relapse of therapy following previously diagnosed
disease and no cirrhosis present. The aim of this study was
to compare oral budesonide with oral prednisone in combination with azathioprine after 6 months in a double-blind
treatment period and to describe the outcome after a
subsequent 6 months of budesonide open-label treatment
in children and adolescents with AIH.

Methods
Patients with AIH aged 9-17 years were included in this
analysis. The diagnosis of AIH was established according to
the criteria of the International Autoimmune Hepatitis
Group.25 Patients enrolled in the study had either a first
diagnosis of acute AIH or had experienced a relapse of
previously diagnosed AIH based on liver biopsy analysis
performed within 12 months before screening. Patients had
serum alanine aminotransferase (ALT) and/or serum
aspartate aminotransferase (AST) levels at least twice the
upper limit of normal, along with elevated levels of
gammaglobulins and IgG. All patients exhibited normal
thiopurinemethyltransferase activity, normal levels of adrenocorticotrophic hormone, a1-antitrypsin, ceruloplasmin,
and serum copper.
The Institutional Review Boards of each participating
center approved the study protocol. Legal representatives of
minor patients and parents whenever required by local
regulations provided written informed consent. The study
was conducted in accordance with the Declaration of
Helsinki and Good Clinical Practice guidelines. An external
data and safety monitoring board reviewed the results of the
2 interim analyses and made recommendations to the sponsor.
Exclusion criteria included the presence of hepatitis A, B,
C, D, E, or G virus infection; primary biliary cirrhosis;
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primary sclerosing cholangitis; Wilson disease; hemochromatosis; cirrhosis; fulminant liver failure; recent treatment
with drugs with known liver toxicity; and parenteral
administration of blood or blood products within 6 months
before screening.
This study is a subanalysis of the large multicenter
randomized trial comparing budesonide with prednisone,
both in combination with azathioprine.24 It was a 6-month
double-blind, double-dummy controlled study (segment A)
with a further 6-month open-label phase (segment B)
(Figure 1; available at www.jpeds.com). Sequential
randomization to 1 of 2 possible treatment arms was 1:1.
During segment A, patients were randomly assigned to
receive either budesonide (3 mg 3 times daily or 3 mg twice
daily after biochemical remission) or prednisone (starting
dose 40 mg/day, tapered to 10 mg/day according to a fixed
high-dose or a low-dose regimen for early treatment
responders) (Figure 1). Patients who experienced
biochemical remission after 3 months in segment A (ie,
normal ALT and AST values after 3 months of therapy)
were eligible to enter segment B. Patients without
biochemical remission at month 6 also could proceed to
segment B at the investigators discretion. During segment
B, all patients were treated with budesonide (3 mg 2 or
3 times daily). Azathioprine was administered at a dose of
1-2 mg/kg/day throughout both segments A and B.
Safety variables, including adverse events, predefined
steroid-specific side effects (moon face, acne, buffalo
hump, hirsutism, striae, diabetes, glaucoma, and elevated
intraocular pressure), laboratory values, vital signs, and complete physical examination results, were assessed throughout
the study.
Study Endpoints
The primary efficacy endpoint was complete response to
therapy, defined as complete biochemical remission at the
patients last visit in segment A and the absence of predefined
steroid-specific side effects throughout segment A. Secondary
endpoints included complete biochemical remission and the
occurrence or absence of steroid-specific side effects. In
addition, complete response, biochemical response, and the
absence of steroid-specific side effects were described at
month 12 of the study in all patients receiving both
budesonide and azathioprine and in patients who had
switched from prednisone to budesonide after month 6.
Changes in body weight between baseline and the month
6 visit and between the month 6 and month 12 visits were
documented in patients receiving budesonide and in those
who had switched from prednisone to budesonide.
Statistical Analyses
The study power was first calculated for the core study
including all patients, adult and pediatric. We anticipated
complete response rates of 35% in the budesonide group and
17.5% in the prednisone group. With 102 evaluable patients
per treatment group, a 1-sided c2 test at an a-level of 2.5 %
had a power of 80% to detect a difference as assumed.24
Woynarowski et al

ORIGINAL ARTICLES

November 2013

Table. Demographic and baseline characteristics of patients randomized to the budesonide arm or prednisone arm
Budesonide (n = 19)
Sex, n (%)
Male
Female
Ethnic origin, n (%)
Caucasian
Other
Age at screening, years, mean (range)
Age at AIH onset, years, mean (range)
Body mass index, kg/m2, mean (range)
AIH score, mean  SD
Extrahepatic manifestations, n (%)
Liver function parameters, mean  SD
Total bilirubin concentration, mg/dL (normal: <1.10 mg/dL)
ALT activity, U/L (normal: females, 10-35 U/L; males, 10-50 U/L)
AST activity, U/L (normal: females, 10-35 U/L; males, 10-50 U/L)
Alkaline phosphatase activity, U/L (normal: females, 35-104 U/L; males, 40-129 U/L)
GGT activity, U/L (normal: females, 39-100 U/L; males, 66-100 U/L)
Liver biopsy assessment, n (%)
Interface hepatitis
Predominantly lymphocytic infiltrate
Rosetting of liver cells
Biliary changes
Immunoglobulins, mean  SD
Gammaglobulin concentration, g/dL (normal: 0.58-1.52 g/dL)
IgG concentration, mg/dL (normal: 700-1600 mg/dL)
Autoantibodies, n (%)
ANA-positive
SMA-positive
LKM-positive
SLA-positive
AIH history, n (%)
Treatment-naive
Disease relapse

8 (42)
11 (58)

Prednisone (n = 27)
3 (11)*
24 (89)

10 (100)
0
13.2 (9-17)
10.7 (4-13)
20.6 (15.3-31.6)
17.6 (3.5)
3 (16)

27 (100)
0
14.2 (11-17)
12.7 (7-14)
20.4 (14.7-37.1)
18.6 (3.0)
2 (7)

1.59  1.89
339  398
314  401
303  161
127  99

2.61  2.62
511  571
425  467
277  185
118  114

12 (63.2)
13 (68.4)
1 (5.3)
0

20 (74.1)
16 (59.3)
0
0

2.67  1.09
2760  940

2.79  1.06
2910  1077

12 (63)
14 (74)
1 (5)
3 (16)

16 (60)
18 (67)
2 (7)
4 (17)

6 (32)
13 (68)

17 (63)
10 (27)

GGT, gamma-glutamyl transpeptidase; ANA, antinuclear antibodies; SMA, antismooth muscle antibodies; LKM, liver-kidney microsome antibodies; SLA, soluble liver antigen antibodies.
*P = .01.
P = .03.

A subset of all patients in the overall study cohort was

analyzed; thus, the analysis sets are much smaller. Descriptive
statistical methods were used to analyze all variables. Onesided asymptotic c2 tests for comparing 2 rates and singlesample t tests were applied for the statistical analysis of the
results. Two-sided tests were used to compare results in the
treatment groups. Statistical analyses were performed by
ClinResearch (Aptiv Solutions GmbH; Cologne, Germany).

Results
Of the 208 patients enrolled in the study, 46 completed
segment A and were evaluable (the intention to treat analysis
group). This group comprised 11 males and 35 females, aged
9-17 years at screening (mean  SD, 13.8  2.2 years) and at
age 4-14 years at diagnosis of AIH (mean, 11.8  2.7 years).
Segment B was completed by 18 of 19 patients in the budesonide group and by 24 of 27 patients in the prednisone group.
The proportion of females was lower in the budesonide
group compared with the prednisone group (58% vs 89%;
P < .05), as was the proportion of treatment-nave patients
(32% vs 63%; P = .03). No other demographic and baseline
characteristic differed significantly between the 2 groups
(Table). Treatment compliance was assessed by a pill count

at each study visit. Calculated compliance for all treatments

applied was approximately 95% in both groups.
Efficacy
At the last segment A visit, the primary efficacy endpoint
complete response to therapy without steroid-specific side
effectswas achieved by 3 of 19 (16%) of the budesonidetreated patients and in 4 of 27 (15%) of the prednisonetreated patients. Biochemical remission at this time point
in the study was achieved in 6 of 19 (32%) in the budesonide
group and in 9 of 27 (33%) of those in the prednisone group.
Differences in complete and biochemical responses between
the 2 groups at the end of segment A were not statistically
significant (Figure 2, A).
At the last visit of segment B, complete remission and
biochemical remission were achieved in 9 of 18 (50%)
patients in the budenoside group and in 10 of 24 (42%)
patients in the prednisone group. The difference were not
statistically significant (Figure 2, B).
Mean ALT concentration decreased between baseline and
month 6 from 338 U/L to 53 U/L in the budesonide group
(P < .001) and from 510 U/L to 74 U/L in the prednisone
group (P < .001). The reduction in mean ALT activity during
segment A proceeded slightly faster in the prednisone group

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Vol. 163, No. 5

Figure 2. Complete response rate (defined as serum AST and ALT levels within normal ranges and absence of steroid-specific
side effects) and biochemical response at A, the end of month 6 and B, the end of month 12.

than in the budesonide group; however, the differences did

not attain statistical significance at any point in segment A.
Response to treatment was greater during segment B,
and mean ALT activity remained low in both groups
(Figure 3, A).
Mean IgG concentrations decreased between baseline and
month 6 in both the budesonide group (from 2760 to 1884
mg/dL; P < .001) and the prednisone group (from 2910 to
1682 mg/dL; P < .001). The initial decrease was faster in
the prednisone group than in the budesonide group, with a

statistically significant difference between the 2 groups at

week 4 (2260 vs 1750 mg/dL; P = .016). There were no
statistically significant differences between the budesonide
and prednisone groups at months 3 and 6 during segment
A. IgG concentration remained stable during segment B in
both groups (Figure 3, B).
Safety and Tolerability
Both study medications were well tolerated. Segment
A treatment-emergent adverse effects in the budesonide

Figure 3. Changes in A, mean serum ALT activity and B, mean IgG concentration in subjects randomized to budesonide or to
prednisone during segments A and B of the study. *Pooled T-test.
1350

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ORIGINAL ARTICLES

November 2013
(n = 19) and prednisone (n = 27) groups included moon face
(11% vs 44%; P = .01), acne (21% vs 26%; P = not significant
[NS]), and skin striae (5% vs 11%; P = NS). At month 6, the
proportion of patients without predefined steroid-specific
side effects was slightly, but not statistically significantly,
higher in the budesonide group (53% vs 37%; P = NS). At
month 12, there was no between-group difference in the proportion of patients without predefined steroid-specific side
effects (95% vs 96%; P = NS). Weight gain at month 6 was
significantly lower in the budesonide group (1.2 vs 5.1 kg;
P = .006). During segment B, mean body weight increased
slightly (0.5 kg) in the budesonide group, but dropped markedly in the prednisone group ( 2.8 kg; P < .001) (Figure 4).

Discussion
For decades, the management of AIH was based on
prednisone alone or in combination with azathioprine in
adults26-29 and children.30 The definition of AIH remission
varies among studies, and may involve clinical, biochemical,
immunologic, and histological status assessment. Alvarez
et al14 defined AIH remission as normal serum ALT, and
Cuarterolo et al15 defined it as normal ALT in the absence
of clinical symptoms. The outcome measure used by Aw
et al18 was normalized serum AST activity. Some authors
define the endpoint as complete or nearly complete normalization of aminotransferase activity.16 The definition of complete clinical recovery provided by Mieli-Vergani et al31
includes normal transaminase activity, normal IgG, negative
or extremely low autoantibody titers, and histological resolution of liver inflammation. Biochemical remission can be
achieved within weeks or months, whereas histopathological
improvement takes much longer. When a single variable,
such as aminotransferase normalization, is the outcome

Figure 4. Changes of mean body weight from baseline at month

6 and 12 in patients randomized to budesonide or to prednisone
and switched to budesonide after month 6. *Two sample t-test
(two-sided); **paired t-test.

measure, the remission rate with standard corticosteroids

and azathioprine therapy reaches 80%.
The treatment response noted in the present study is lower
than the 80% previously reported in children.10,12,31 This
difference most likely can be attributed to the unique
definition of treatment response that we used in the core study
analysis and in this subanalysis of the pediatric population.
Our definition was determined a priori as a primary efficacy
endpoint and included normal ALT and AST levels and the
absence of predefined steroid-specific side effects.
The introduction of innovative therapies in the pediatric
population is usually delayed, because most new medications
are tested only in adults. The experience with innovative
therapies in children is limited, especially when the number
of affected patients is too small to conduct a sufficiently powered study that is also randomized and controlled. Several previous pediatric studies have documented a similar efficacy of
prednisone and azathioprine-based regimens in children and
adults30,32; however, the recommended doses in children are
higher than those in adults.31 Response to treatment with corticosteroids with or without azathioprine is generally excellent
in children, and normalized liver values have been reported in
up to 90%, but achieving this may take several months.11
In a previous prospective randomized controlled study
that included adults and pediatric patients with AIH, we
demonstrated that budesonide in combination with azathioprine was capable of inducing and maintaining remission in
60%.24 We found a significantly lower incidence of steroidspecific side effects with budesonide and azathioprine
combination therapy compared with standard prednisone
therapy.24 Pediatric patients accounted for approximately
25% of the total study population (46 of 208); however,
that study did not include an age-related comparison.
The present study protocol was prepared following
guidelines for an adult population with AIH in accordance
with the current American Association for the Study of the
Liver practice guidelines.19 The initial prednisone dose was
lower than that recommended for pediatric populations,31
and azathioprine was initiated at the beginning of the study,
a schedule not generally recommended owing to potential
hepatotoxicity.2,11 This factor must be taken into account
when examining the results of this subanalysis.
The original trial was designed to test for the superiority of
budesonide over prednisone in treating AIH. Statistical
power was calculated for the original study and required a
cohort of 200 subjects. A much smaller pediatric population
was analyzed in the present study, making the study underpowered. Our results can be subjected to post hoc descriptive
statistical testing only. In addition, comparisons of results in
other subgroups of this pediatric population, such as sex,
history, or type of the disease, would make little sense and
are thus were not undertaken. With this approach in the
overall study, budesonide was superior to prednisone at
month 6 with respect to the rates of complete response
(47% vs 18%) and a biochemical response (60% vs 39%).24
These results were not confirmed in the present study, which
found no differences between the budesonide and prednisone

Budesonide versus Prednisone with Azathioprine for the Treatment of Autoimmune Hepatitis in Children and Adolescents

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groups in complete remission (16% vs 18%) and biochemical

remission (32% vs 33%). Our data show that after 6 months
of treatment with budesonide, the response rates in the
children and adolescents did not attain those seen in adults.
Response rates after treatment with prednisone were similar
in pediatric and adult patients. The low numbers of randomized patients with a new AIH diagnosis (eg, treatment-nave
children and adolescents) might be the reason for the low
overall response rate seen in this subgroup analysis.
Continuing budesonide therapy in the pediatric patients
for 12 months raised the complete and biochemical response
rate to 50%. Continuous improvement in the proportion of
patients with both complete and biochemical responses was
also observed in patients who were switched from prednisone
to budesonide after 6 months. Thus, although budesonide
was not superior to prednisone in inducing remission, it
was capable of maintaining remission in both treatment
groups.
Budesonide therapy was well tolerated in the main study
cohort as well as in the pediatric subpopulation. The
differences in the rate of subjects with steroid-specific side
effects at 6 months in the children and adolescents failed to
reach statistical significance (53% vs 37%). The rate of
steroid-specific side effects decreased in both groups; at the
end of the 12-month study period, almost all patients were
free of predefined steroid-specific side effects.
In the main study cohort, we documented an increase in
body weight in 6% of the patients in the budesonide group
and in 19% of those in the prednisone group.24 The interpretation of body mass changes in children and adolescents
is much more complex than in adults, because growth and
pubertal status must be taken into account. Our study
observation period was relatively short, and the comparison
groups were similar in terms of age. Nonetheless, weight
gain was statistically higher in the prednisone group
compared with the budesonide group (5.1 kg vs 1.2 kg). Patients who remained on budesonide continued to gain body
weight until the end of the study, and those switched from
prednisone to budesonide lost body weight between months
6 and 12. We found a pronounced increase in body mass
index in the prednisone group, which was partially reversed
after switching to budesonide treatment. Thus, the changes
in body mass index corresponded to changes in body
weight. There were no relevant changes in height during
the observation period in either treatment group. This
finding might be interpreted as a return to normal growth
variables and a reduction in steroid-induced weight gain
from prednisone.
There is a need to develop a safe and efficient therapy for
pediatric patients with AIH.33 The number of children
treated in this study was too small to justify recommending
budesonide as standard therapy in noncirrhotic children
with AIH. However, in children and adolescents with severe
steroid-related side effects, we believe that budesonide may
be considered as maintenance therapy. Further studies in
pediatric patients with AIH aimed at examining different
doses of budesonide compared with standard pediatric
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Vol. 163, No. 5

immunosuppressive regimens are needed to assess the
long-term effects and benefits of budesonide on the course
of this devastating disease. n
Submitted for publication Nov 11, 2012; last revision received Apr 25, 2013;
accepted May 17, 2013.
Reprint requests: Marek Woynarowski, MD, Department of Gastroenterology,
Hepatology, and Feeding Disorders, Childrens Health Memorial Institute, Al.
Dzieci Polskich 20, 04-730 Warsaw, Poland. E-mail: m.woynarowski@czd.pl

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Budesonide versus Prednisone with Azathioprine for the Treatment of Autoimmune Hepatitis in Children and Adolescents

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Vol. 163, No. 5

Appendix
Members of the European AIH-Budesonide Study Group
include:
Childrens Health Memorial Institute, Warsaw, Poland:
Beata Oralewska, MD
Karolinska University Hospital, Stockholm, Sweden: Bj
orn
Fischler, MD and Henrik Arnell, MD
Rambam-Health Care Campus, Haifa, Israel: Ella Veitsman, MD and Rafael Enat, MD
Dr v Hauner Kinderspital, Ludwig Maximilians University
of Munich, Germany: Philip Bufler, MD, Martin Alberer,
MD, Thomas Lang, MD
University Hospital Regensburg, Germany: Eva-Doreen
Pfister, MD
Christian Childrens Hospital Osnabr
uck, Germany:
Martin Eilers, MD.

Figure 1. Design of a multicenter phase IIb study evaluating prednisone and azathioprine against budesonide and azathioprine
in AIH. Segment A: 6 months double-blind, randomized, active-controlled phase of the study with budesonide or prednisone
tapered at subsequent visits as indicated. Segment B: 6 months open label budesonide and azathioprine therapy phase of the
study. Patients randomized to budesonide and azathioprine in Segment A continued their therapy and those randomized to
prednisone and azathioprine in segment A were switched to budesonide and azathioprine in segment B. *Months 7-12 all patients received budesonide (3 mg TID/BID); **patients showing biochemical remission after 3 months of treatment could continue
with Segment B. BID, twice daily; TID, three times daily.

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