Digestive Diseases and Sciences (2018) 63:1348–1354

https://doi.org/10.1007/s10620-018-5011-x

ORIGINAL ARTICLE

Tacrolimus and Mycophenolate Mofetil as Second‑Line Therapies

for Pediatric Patients with Autoimmune Hepatitis
Cumali Efe1 · Haider Al Taii2 · Henriette Ytting3 · Niklas Aehling4 · Rahima A. Bhanji5 · Hannes Hagström6 ·
Tugrul Purnak1 · Luigi Muratori7 · Mårten Werner8 · Paolo Muratori7 · Daniel Klintman9,13 · Thomas D. Schiano10 ·
Aldo J. Montano‑Loza5 · Thomas Berg4 · Fin Stolze Larsen3 · Naim Alkhouri11 · Ersan Ozaslan12 ·
Michael A. Heneghan13 · Eric M. Yoshida14 · Staffan Wahlin6

Received: 2 January 2018 / Accepted: 6 March 2018 / Published online: 22 March 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Background  We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in
pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid
and azathioprine).
Patients and Methods  We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-
eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months
(range 8–182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid
or azathioprine, and group 2 (n = 21) were non-responders to standard therapy.
Results  Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552).
In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929).
More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically
significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/
or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders
(45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects
that led to therapy withdrawal.
Conclusions  Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both
MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more
effective than MMF in patients failing previous therapy.

Keywords  Autoimmune hepatitis · Mycophenolate mofetil · Tacrolimus · Second-line · Cirrhosis · Pediatric · Liver
transplantation

Introduction
Autoimmune hepatitis (AIH) is a chronic immune-medi-
ated liver disorder characterized by elevated transaminases,
hypergammaglobulinemia, the presence of circulating
autoantibodies, and liver histology showing interface hepati-
tis [1]. AIH may present at all ages, also in childhood [2]. In
children and adolescents, AIH often has a more aggressive
disease course than in adults. Effective treatment is crucial
* Cumali Efe
drcumi21@hotmail.com
Extended author information available on the last page of the article
as AIH may rapidly progress into cirrhosis and liver failure
if remains untreated [1, 2].
Current standard treatment of AIH includes corticoster-
oids, alone or in combination with azathioprine (AZA). The
majority of AIH patients show good response to therapy
while up to 20% of patients do not respond or are intolerant
to standard treatment [3, 4]. Salvage therapies are necessary
for this group of patients. Several immunosuppressive agents
have been used with variable clinical outcomes, but there is
no well-established treatment strategy for patients who are
intolerant or who fail corticosteroid and azathioprine [5–8].
Mycophenolate mofetil (MMF) is an ester prodrug
designed to increase the bioavailability of the active

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Digestive Diseases and Sciences (2018) 63:1348–1354 1349
metabolite mycophenolic acid. Similar to AZA, MMF inhib-
its de novo purine synthesis, which results in inhibition of
both T cell and B cell lymphocyte proliferations. Tacrolimus
is a calcineurin inhibitor with potent immunosuppressive
effects on CD4 T helper cells. Tacrolimus mainly acts via
decreased production of interleukin 2, growth factors and
cytokines that are necessary for lymphocyte proliferation
[5, 9, 10]. Long-standing experiences with MMF and tac-
rolimus usage have been obtained from data in liver and
kidney transplant recipients [11]. MMF and tacrolimus are
currently the most preferred alternative therapies for adult
AIH patients who are intolerant and resistant to standard
therapy [5].
Due to the rarity of refractory AIH, data regarding the
efficacy and safety of MMF and tacrolimus have been
derived from retrospective small cohort studies or case series
[6, 12–16]. The majority of these studies have been con-
ducted with adult AIH patients, while two studies evaluated
MMF and/or tacrolimus in a subset of pediatric patients with
AIH [6, 12]. In the large international multicenter study pre-
sented here, we compared the efficacy of MMF to that of tac-
rolimus in pediatric AIH patients who were non-responsive
or intolerant to standard therapy.
Patients and Methods
Study Design
We retrospectively studied pediatric AIH patients who
received MMF or tacrolimus due to intolerance or non-
response to standard therapy. Patients were recruited from
13 centers in Europe, USA, and Canada. This study is a
sub-analysis of a large multicenter study evaluating effi-
cacy and safety of MMF and tacrolimus [8]. AIH was diag-
nosed based on a combination of serum gamma globulin or
immune globulin G (IgG) levels, circulating autoantibod-
ies, and liver biopsy findings [17]. Overlap with primary
Fig. 1  Study flowchart for
patient inclusion
sclerosing cholangitis (PSC) was defined according to sug-
gested international guidelines [18]. Patients with poor
compliance to therapy or insufficient information for an
AIH diagnosis and patients with AIH-PSC overlap (either
concomitant or consecutively) were excluded (Fig. 1).
We collected patient characteristics including, gender,
age, laboratory parameters, and histological findings at
the time of AIH diagnosis and before initiation of second-
line therapy (Table 1). We also included data on the dura-
tion and doses of standard treatment, response to standard
treatment, and reasons for switching to second-line ther-
apy. Local pathologists in the participating centers evalu-
ated liver biopsies; data from their reports were used in the
study. Fibrosis was classified according to the METAVIR
scoring system [19].
All included patients initially received standard ther-
apy (predniso(lo)ne 20–60, mg/day alone or in combina-
tion with AZA, 50–150 mg/day). The treating physicians
decided the initial and final doses of MMF and tacroli-
mus according to patient’s biochemical response and drug
blood concentrations. A switch between MMF and tacroli-
mus or a combination of these agents was also considered
for patients having a suboptimal response or patients who
developed drug side effects. AZA was discontinued in
all, except for two cases in which tacrolimus was added.
Patients received MMF at a dose of 20–40 mg/kg twice
daily and tacrolimus at a dose of 0.05–0.1 mg/kg twice
daily. The tacrolimus serum concentration was below
6.0 ng/mL in all patients during follow-up.
Patients were divided into two groups depending on
the reason for switching to MMF or tacrolimus. Group 1
included patients who were intolerant to corticosteroids or
AZA and group 2 patients who did not respond to standard
therapy. A complete biochemical response was defined as
normalization of serum aminotransferases and IgG levels
at any time within 12 months after starting therapy. Any-
thing less than a complete response was considered as a
non-response [1, 3, 4].
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1350 Digestive Diseases and Sciences (2018) 63:1348–1354

Table 1  Characteristics of patients at the time of diagnosis and before second-line therapy

Overall n = 38 MMF n = 18 Tacrolimus n = 20

Features of the study population at the time of AIH diagnosis

 Gender (female), n (%) 29 (76.3) 13 (72.2) 16 (80)
 Age (years) 13 (6–17) 12 (7–17) 14 (6–17)
 ALT × ULN 16.7 (2.9–41.2) 15.7 (2.9–41.2) 19.2 (5.7–36.0)
 AST × ULN 15.9 (3.5–38.1) 14.1 (3.5–38.1) 18.7 (4.7–35.7)
 ALP × ULN 1.5 (0.3–3.6) 1.7 (0.7–3.6) 1.3 (0.3–3.1)
 Bilirubin × ULN 2.1 (0.4–11.2) 2.5 (0.4–9.5) 1.9 (0.6–11.2)
 IgG × ULN 1.7 (0.4–3.9) 1.5 (0.6–3.2) 1.7 (0.4–3.9)
 ANA positive, n (%)a 20 (57.1) 10 (58.8) 10 (55.6)
 SMA positive, n (%)b 21 (61.8) 9 (52.9) 12 (70.6)
c
 Anti-LKM-1 positive, n (%) 3 (9.1) 2 (12.5) 1 (5.9)
 Fibrosis scores (III–IV), n (%)d 19 (55.9) 9 (52.9) 10 (58.8)
Overall MMF Tacrolimus

Characteristics of the study population before second-line therapy

 Time to second line (months) 9 (1–52) 12 (2–52) 8 (1–36)
 ALT × ULN 2.7 (0.6–21.2) 2.7 (0.6–10.5) 2.6 (0.7–21.2)
 AST × ULN 3.2 (0.5–17.8) 3.4 (0.5–10.2) 3.2 (0.7–17.8)
 ALP × ULN 1.0 (0.5–3.2) 1.1 (0.6–3.2) 0.9 (0.5–2.7)
 Bilirubin × ULN 0.9 (0.4–9.9) 0.9 (0.5–9.9) 0.9 (0.4–4.6)
 IgG × ULN 1.1 (0.6–2.1) 1.1 (0.6–2.1) 1.2 (0.7–1.8)
 Fibrosis scores (III–IV), n (%)e 7 (100) 3 (100) 4 (100)

ULN upper limit of normal

a
 ANA was available in 35
b
 SMA, in 34
c
 LKM, in 33
d
 Liver biopsy, in 34
e
 Biopsy before second-line treatment, in 7

Statistical Analysis
Visual (histograms, probability plots) and analytical meth-
ods (Kolmogorov–Smirnov/Shapiro–Wilks test) were
used to determine the normality of continuous variables.
Non-continuous variables were expressed as median (mini-
mum–maximum). The Chi-square test, where appropriate,
was used to compare the frequencies in different groups. The
Wilcoxon signed-rank test was used for comparison of initial
and final doses of corticosteroid. SPSS software version 22
(SPSS, Chicago, IL, USA) was used to perform statistical
analysis and p < 0.05 was considered statistically significant.
35 (91%) were type 1 AIH and three (9%) were type 2 AIH.
Seventeen (44.7%) were intolerant to steroid and/or AZA
(group 1), and 21 (55.3%) were non-responders to standard
therapy (group 2). Among 18 patients treated with MMF,
nine (50%) were in group 1 and nine (50%) were in group
2. Among 20 patients treated with tacrolimus, eight (40%)
were in group 1 and 12 (60%) were in group 2. Thirteen of
group 1 patients had biochemical remission when second-
line therapy was commenced. The remaining four patients
(two MMF and two tacrolimus) had significant improvement
(> 50% fall in AST/ALT levels) on standard therapy before
they were switched to second-line treatment.

Response to Second‑Line Therapy

Results
Characteristics of Study Population
A total of 49 AIH patients (< 18 years old) were identified
and 38 finally included in the study. Among the 38 patients,
The efficacy of MMF and tacrolimus in patients with AIH
is presented in Table 2. Overall, the complete response rates
were similar in MMF- and tacrolimus-treated patients (55.6
vs. 65%, p = 0.552). MMF and tacrolimus maintained a bio-
chemical response in 88.9 and 87.5% of group 1 patients,

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Digestive Diseases and Sciences (2018) 63:1348–1354 1351

Table 2  Efficacy of MMF and tacrolimus in patients with autoim-
mune hepatitis
MMF (n = 18) Tacrolimus (n = 20) P value
Response complete 10 (55.6%) 13 (65%) 0.552
(all)
Group I (n = 17) n = 9 n = 8
 Complete response 8 (88.9%) 7 (87.5%) 0.929
Group II (n = 21) n = 9 n = 12
 Complete response 2 (22.2%) 6 (50%) 0.195
respectively (p = 0.929). More group 2 patients given tac-
rolimus compared with MMF had a complete response, but
the difference was not statistically significant (50 vs. 22.2%,
p = 0.195).
The rates of complete response were lower in group 2
than in group 1 for patients treated with MMF (22.2 vs.
88.9%, p = 0.004), but the difference was not statistically sig-
nificant for tacrolimus (50.0 vs. 87.5%, p = 0.085) (Fig. 2).
Three non-responders to MMF showed a complete
response after switching to tacrolimus. A combination of
MMF and tacrolimus was used in three non-responders to
either agent (one MMF and two tacrolimus). This resulted
in a complete biochemical response in one patient.
The median serum concentrations of tacrolimus at 3, 6,
and 12 months of therapy were 4.1 ng⁄mL (range 2.6–6.2),
3.9 (range 3.1–5.9 ng⁄mL) and 4.2 (range 2.3–5.8 ng⁄mL),
respectively. The median steroid dose was decreased from
10 (2.5–20) to 3.75 (0–10) mg/day in responders to MMF
(p = 0.012), and from 12.5 (5–30) to 5 (0–10) mg/day in
responders to tacrolimus (p = 0.002). During maintenance
therapy, the steroid therapy was completely withdrawn in
four patients treated with MMF and in five patients treated
with tacrolimus.
Second‑Line Withdrawal and Side Effects
Reported side effects are presented in Table 3. Adverse
events were noted in 44.4% (8/18) of MMF-treated
patients and in 60% (12/20) of tacrolimus-treated patients
(p = 0.338). MMF was discontinued in two patients due
to leukopenia (n = 1) and abdominal pain (n = 1). MMF
was thereafter switched to standard therapy in one and to
tacrolimus in one. Tacrolimus was discontinued in three
patients due to abdominal pain (n = 1), neurologic side
effects (n = 1), and rectal bleeding (n = 1). Tacrolimus
was thereafter switched to standard therapy in one and
to MMF in two. None of the tacrolimus-treated patients
experienced hypertension or significant renal dysfunction.
Follow‑Up Duration and Outcome
The overall median follow-up time of 72 (8–182) months
was similar for patients treated with MMF 65 (12–149)
months and tacrolimus 74 (8–182) months.
At the end of the study, complete biochemical remis-
sion was achieved in 27 (71.1%) of the patients. Among
them, two patients who had cirrhosis at the time of diag-
nosis showed disease progression and underwent liver
transplantation after 74 and 123  months of follow-up.
Eleven (28.9%) patients did not enter biochemical remis-
sion. Five of these patients progressed into decompensated
cirrhosis, of which four underwent liver transplantation.
Decompensated cirrhosis was more commonly observed in
non-responders than those responders to MMF/tacrolimus
(45.5 vs. 7.4%, p = 0.006).

Table 3  Overall adverse events in AIH patients treated with MMF

and tacrolimus

MMF-treated patients (n = 18) Tacrolimus-treated patients

(n = 20)
Number of side effects 8 Number of side effects 12

Major side effects, n (%) 2 (25) Major side effects, n (%) 3 (25)
 Abdominal pain, n 1  Abdominal pain, n 1
 Cytopenias, n 1  Neurologic side effects, n 1
 Rectal bleeding, n 1
Minor side effects, n (%) 6 (75) Minor side effects, n (%) 9 (75)
 Cytopenias, n 2  Headache, n 3
Fig. 2  Therapy response rates for patients treated with MMF and  Abdominal pain, n 1  Abdominal pain, n 3
tacrolimus. MMF induced complete response in 88.9 and 22.2%  Gastroenteritis, n 1  Gastroenteritis, n 1
of intolerant and non-responders to standard therapy, respectively  Pneumonia, n 1  Pruritus 1
(p = 0.004). Tacrolimus induced complete response in 87.5 and 50%
 Herpes labialis, n 1  Headache and vomit- 1
of intolerant and non-responders to standard therapy, respectively
ing, n
(p = 0.085)

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Discussion
AIH is a chronic liver disease that affects children/adoles-
cents and adults [1]. Treatment with immunosuppression
prolongs survive in the majority of pediatric AIH patients
into adulthood [2, 20]. As for adult patients, a substan-
tial proportion of pediatric AIH patients does not respond
or is intolerant to standard therapy. This study evaluates
the efficacy and safety of MMF and tacrolimus as salvage
therapies in pediatric patients with AIH who are non-
responders or intolerant to standard therapy. The study is
based on data collected from 13 sites in Europe and North
America and represents a real-world experience. Our find-
ings, from the largest study to date, show that long-term
treatment with MMF and tacrolimus overall appear to be
effective and well tolerated in pediatric AIH patients.
A recent systematic review included reports on only
34 MMF-treated pediatric AIH patients who were either
intolerant or non-responsive to standard therapy [21]. The
review reported an overall 36% response rate to MMF
after 6 months of therapy. In our study, we found a 55.6%
response rate in patients treated with MMF. AIH is a very
heterogeneous disease, and therapy response may be seen
in a few weeks in some patients, while others respond
after 1–2 years. Earlier reported low response rates may
therefore be related to short follow-up. Aw et al. reported
an 88% response rate to MMF in 18 pediatric AIH patients
and did not find a difference in response rates between
different indications for MMF [6]. In contrast, we found
a significantly higher response rate among patients who
were responders but intolerant to standard therapy as
compared to patients who were non-responders to stand-
ard therapy. In our study, 14 intolerant patients were in
biochemical remission and four patients had significantly
improved (> 50%) aminotransferase levels when standard
therapy was switched to second-line therapy. This suggests
that patients who initially respond to standard therapy
are likely to maintain remission or to have a biochemical
response after converting therapy to MMF/tacrolimus.
Tacrolimus has been successfully used as first-line
therapy in 17 pediatric AIH [12]. The data regarding tac-
rolimus as a second-line therapy are, however, limited
[21]. Herein, we report our experience of tacrolimus as
a second-line agent in 20 children. Similar to the MMF
group, tacrolimus maintained or induced biochemical
response in the majority (87.5%) of intolerant patients,
but its efficacy decreased to 50% among patients who were
non-responsive to standard therapy.
In our study, more non-responders to standard therapy
given tacrolimus compared with MMF had a complete
response. Also, some MMF non-responders were suc-
cessfully managed either by switching to tacrolimus or
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Digestive Diseases and Sciences (2018) 63:1348–1354
by adding tacrolimus to the therapy. These findings are
in line with adult studies that have reported successful
rescue treatment with tacrolimus in AIH patients who
are resistant to other alternative therapies such as MMF,
cyclosporine, or 6-mercaptopurine [8, 22].
Drug-related adverse events were noted in 44.4% of
MMF-treated and in 60% of tacrolimus-treated patients dur-
ing follow-up. Most side effects were, however, minor and
resolved with dose adjustments. Side effects that required
treatment withdrawal were observed in two (11.1%) MMF-
treated patients and in three (15%) tacrolimus-treated
patients. The safety profile of MMF appeared to be slightly
better but due to the small sample size it is difficult to draw
definitive conclusions. For comparison, 80% of AIH patients
on corticosteroid therapy develop side effect after 2 years
of therapy and complications of AZA occur in 46% of AIH
patients. Severe or debilitating side effects that require treat-
ment withdrawal are typically observed in 13% of corticos-
teroid-treated and in 6% of AZA-treated AIH patients [1, 3,
23]. The retrospective nature of our study may overestimate
the safety profile of MMF and tacrolimus. We report all
adverse events that were noted by the treating physicians.
Some events, such as gastroenteritis, pneumonia, and herpes
labialis, may not be directly related to the immunosuppres-
sion. The teratogenic potential of MMF should be carefully
explained to all AIH patients of childbearing age. In our
study, none of MMF-treated patients had pregnancy during
the observation period.
Decompensated cirrhosis was more commonly observed
in MMF and/or tacrolimus non-responders than in patients
responding to second-line therapy. Two patients who had
baseline histological cirrhosis responded biochemically
to second-line therapy but still progressed to decompen-
sated cirrhosis. Both underwent transplantation. Adverse
outcomes are expected in some of AIH patients who are
responding to therapy. A recent study showed that histo-
logical activity may persist despite long-term biochemical
remission and that such a scenario is associated with higher
rates of fibrosis progression and increased liver-related mor-
tality [24].
Our study results need to be interpreted with caution.
It has all the limitations of a retrospective study, and as
can be expected from a study on a rare subset of patients
with a rare disease, the cohort is of limited size. The initial
doses of standard therapy and the steroid dose-tapering
protocols were not the same in all patients. The recom-
mended initial doses of AZA are also different between
USA and Europe [1, 4]. Indications, drug doses, and types
of second-line therapy were decided in a non-standardized
way. Another limitation is the definition criteria for treat-
ment response that we used in this study. The criteria for
treatment-induced remission in pediatric patients, require
normalization of laboratory findings along with negative
Digestive Diseases and Sciences (2018) 63:1348–1354 1353
or low-titer autoantibody positivity [18]. We did not have
serial evaluations of autoimmune serology (ANA, SMA,
and anti-LKM-1). Therefore, we used the adult AIH
response criteria which are less strict for pediatric disease.
Childhood AIH is mainly the domain of pediatric
hepatologists but is also managed in some adult clinics
[20]. Most pediatric AIH patients show good response to
therapy and survive into adulthood. Therefore, adult hepa-
tologists should also be familiar with this unique patient
group. Team-based efforts including a safe transition from
pediatric/adolescent to adult hepatology care are essential.
Our study reflects real-life experiences, and we hope that
it will be helpful to clinicians in the management of the
special group of pediatric AIH in which standard therapy
is not sufficient.
In conclusion, the results of this retrospective study con-
firm that MMF and tacrolimus are safe immunosuppressive
alternatives in the treatment of pediatric patients with AIH.
MMF and tacrolimus are equally effective for maintaining
remission in patients who are intolerant to standard therapy,
but due to its safety profile MMF may be the first preferred
second-line agent for these patients. Tacrolimus appears to
be more effective than MMF for patients who do not respond
to standard therapy.
Author’s contribution  SW and EMY share co-senior author-
ship. CE, SW, EMY, and EO conceptualized the study. CE,
HY, HAT, HH, SW, and TP collected and analyzed the data
and wrote the manuscript. RAB, NFM, LM, MW, FSL, PM,
DK, TDS, NA, AJML, TB, and EO contributed data and
approved the final manuscript. CE, EMY, MH, EO, and
SW interpreted data and prepared manuscript for the final
submission.
Compliance with ethical standards  Pediatr. 2013;23:302–308.
Conflict of interest  The authors declare that they have no conflict of
interest.
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Affiliations

Cumali Efe1 · Haider Al Taii2 · Henriette Ytting3 · Niklas Aehling4 · Rahima A. Bhanji5 · Hannes Hagström6 ·

Tugrul Purnak1 · Luigi Muratori7 · Mårten Werner8 · Paolo Muratori7 · Daniel Klintman9,13 · Thomas D. Schiano10 ·
Aldo J. Montano‑Loza5 · Thomas Berg4 · Fin Stolze Larsen3 · Naim Alkhouri11 · Ersan Ozaslan12 ·
Michael A. Heneghan13 · Eric M. Yoshida14 · Staffan Wahlin6

1 8
Department of Gastroenterology, Hacettepe University, Department of Public Health and Clinical Medicine, Umeå
Ankara, Turkey University, Umeå, Sweden
2 9
Department of Medicine, Cleveland Clinic Foundation, Department of Molecular and Clinical Medicine, Skåne
Cleveland, OH, USA University Hospital, Lund, Sweden
3 10
Department of Hepatology, Rigshospitalet, University Division of Liver Diseases/Transplantation Institute, The
of Copenhagen, Copenhagen, Denmark Mount Sinai Medical Center, New York, USA
4 11
Sektion Hepatologie, Klinik für Gastroenterologie und Texas Liver Institute, San Antonio, TX, USA
Rheumatologie, Universitätsklinikum Leipzig, Leipzig, 12
Department of Gastroenterology, Numune Research
Germany
and Education Hospital, Ankara, Turkey
5
Division of Gastroenterology and Liver Unit, University 13
Institute of Liver Studies, King’s College Hospital NHS
of Alberta, Alberta, Canada
Foundation Trust, Denmark Hill, London, UK
6
Hepatology Division, Centre for Digestive Diseases, 14
Division of Gastroenterology, University of British Columbia
Karolinska Institutet and Karolinska University Hospital,
and Vancouver General Hospital, Vancouver, Canada
Stockholm, Sweden
7
Centro per lo Studio e la Cura delle Malattie Autoimmuni del
Fegato e delle Vie Biliari‑Dipartimento di Scienze Mediche
e Chirurgiche (DIMEC), Alma Mater Studiorum – Università
di Bologna, Bologna, Italy

13