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Current Pediatric Reviews, 2018, 14, 187-195

REVIEW ARTICLE
ISSN: 1573-3963
eISSN: 1875-6336

Old and New Treatments for Pediatric Autoimmune Hepatitis

BENTHAM
SCIENCE

Silvia Nastasio1, Marco Sciveres2, Lorenza Matarazzo3 and Giuseppe Maggiore2,4,*

1
Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital, Harvard Medical School, Boston,
MA, USA; 2Pediatric Hepatology and Liver Transplantation, ISMETT UPMC Palermo, Palermo, Italy; 3University of
Trieste, Trieste, Italy; 4Section of Pediatrics, Department of Medical Sciences, University of Ferrara, University Hospi-
tal Arcispedale Sant’Anna, Ferrara, Italy

ARTICLEHISTORY
Received: December 26, 2017
Revised: April 16, 2018
Accepted: April 25, 2018
DOI:
10.2174/1573396314666180516130314
Abstract: Background: Autoimmune hepatitis is a rare inflammatory disease of the liver that most
frequently affects children and young adults. It is a multifactorial disease of unknown etiology,
characteristically progressive in nature, and if left untreated, may lead to cirrhosis and terminal
liver failure. It has been known for several decades now that immunosuppressive treatment con-
vincingly alters the outcome of most patients with autoimmune hepatitis and as such it should be
started as soon as diagnosis is made. Primary goals of treatment are: normalization of hepatocellu-
lar function, extinction of the hepatic necroinflammatory process, and maintenance of a stable re-
mission, thus preventing progression to cirrhosis and its complications. This article aims to review
old and new treatments for this rare chronic disorder, from the oldest and most frequently used
treatment consisting of the association of prednisone and azathioprine, to alternative medical treat-
ments, liver transplant and promising medical strategies currently under investigation.
Result and Conclusion: The review will focus on the efficacy and safety profile of each drug, as well
as on the published clinical experience with them in pediatric patients with autoimmune hepatitis.

Keywords: AIH, inflammatory disease, immunosuppressive treatment, necroinflammatory process, pediatric patients, multifac-
Current Pediatric Reviews

torial disease.

1. INTRODUCTION muscle antibody and/or antinuclear antibody, and AIH-2,

Autoimmune Hepatitis (AIH) is a rare inflammatory dis-
ease of the liver that most frequently affects children and
young adults with a preponderance in females. It is a multi-
factorial disease of unknown etiology in which environ-
mental factors act as a trigger in genetically predisposed in-
dividuals [1-4]. Recent studies have advanced the under-
standing on AIH pathogenesis demonstrating that patients
with AIH have a defect in immunoregulation. Specifically,
patients with AIH have been shown to have both numerical
and functional defects of regulatory T cells (Tregs), which
are consequently associated with an overwhelming T helper
effector responses (Teff). This imbalance between Tregs and
Teff seems to enable effector cells to initiate and perpetuate
the tissue damage seen in AIH [5, 6].
AIH is usually characterized by high serum activity of
transaminases and class G immunoglobulins, presence of
organ and non-organ specific autoantibodies and interface
hepatitis on histological examination [1-4]. The autoantibody
profile detected at diagnosis distinguishes between two types
of AIH: AIH-1, characterized by the presence of anti-smooth
characterized by anti-liver kidney microsomal antibody type
1 and/or by the presence of anti-liver cytosol type 1 antibody
[1-4].
The clinical presentation of AIH is quite variable. It
ranges from the incidental finding of elevated transaminase
levels in asymptomatic patients to acute hepatitis, acute liver
failure and insidious chronic onset with progressive fatigue,
anorexia, and intermittent jaundice.
AIH is progressive in nature and if left untreated may
lead to cirrhosis and terminal liver failure. Immunosuppres-
sive treatment convincingly alters the outcome of most pa-
tients with AIH and it should be started as soon as diagnosis
is made [7-12]. Pharmacological treatment has three main
objectives: normalization of hepatocellular function, extinc-
tion of the necroinflammatory process and maintenance of a
stable remission, thus preventing progression to cirrhosis and
its complications. Remission in AIH is defined as disappear-
ance of symptoms, normalization of aminotransferase levels,
and serum immunoglobulin G as well as negative or very
low autoantibody titer [3, 8, 13, 14].

2. CONVENTIONAL TREATMENT
*Address correspondence to this author at the Dipartimento di Scienze
Mediche-Pediatria; Azienda Ospedaliera Universitaria di Ferrara; Arcispe- Prednisolone or prednisone and azathioprine constitute
dale Sant’Anna. Via A. Moro, 8, 44124 Cona, Ferrara, Italy; Tel/Fax: + 39
0532 237383, + 39 0532 23 78 48; E-mail: giuseppe.maggiore@unife.it
the so-called conventional treatment of AIH. AIH steroid-

1875-6336/18 $58.00+.00 © 2018 Bentham Science Publishers

188 Current Pediatric Reviews, 2018, Vol. 14, No. 3
response has been known for almost 5 decades now, since
the first randomized, controlled treatment trials documented
that prednisone administered alone or in combination with
azathioprine, dramatically improves symptoms, laboratory
tests, histologic findings, and immediate survival [7, 9, 11,
15].
Corticosteroids act by binding cytoplasmic receptors
(Glucocorticoid Receptor, GR), translocating into the nu-
cleus and interacting with specific DNA sequences (Gluco-
corticoid Responsive Elements, GRE) located in the regula-
tory regions of specific genes. This interaction results in the
inhibition of T-lymphocyte activation and proliferation,
which prevents the synthesis of proinflammatory cytokines,
such as interleukin 2 and interleukin 6 [16].
Azathioprine is a pro-drug that is non-enzymatically con-
verted to 6-mercaptourine; both molecules are converted to
the pharmacologically active 6-thioguanine metabolite. The
mechanisms of action of azathioprine are complex and only
partially known: azathioprine is known to inhibit the prolif-
eration of T-lymphocytes, cytotoxic T-cells and plasma cells
by inducing the accumulation of thioguanine nucleotides
with consequent impairment of DNA and RNA synthesis.
Azathioprine has a slow onset of action likely dependent on
the slow nucleotide accumulation mechanism. An initial re-
sponse occurs within 8-12 weeks with maximal effects at-
tained after up to 6 months [17, 18].
2.1. Treatment Regimen
Prednisone (or prednisolone) is administered at 2
mg/kg/day (up to a maximum of 60 mg/day), a higher dose
than the one used in adults. Azathioprine is administered at
the initial dose of 1 mg/kg/day, which can be further in-
creased up to 2.5 mg/kg/day until a sustained biochemical
remission is achieved [1, 3, 8]. The best timing of introduc-
tion of azathioprine is still under debate.
Steroids can be started as the initial treatment with
azathioprine added later, either if the response to steroids
alone is inadequate or in order to achieve steroid withdrawal.
Alternatively, combination therapy can be initiated at the
onset of treatment with reports of increased efficacy [19]. In
addition, azathioprine has a “steroid-sparing” effect that al-
lows for a more rapid tapering of the steroid dose, thus re-
ducing the side effects related to the prolonged use of high
dose steroids. In selected cases such as acute severe AIH
steroid monotherapy is recommended because azathioprine
is potentially hepatotoxic, especially in cirrhotic and jaun-
diced patients [20].
Steroids have been shown to lead to permanent recovery
of liver function, with avoidance or delay of liver transplant,
in cirrhotic patients with AIH showing signs of LF [21]. En-
couraging results with steroid treatment were also described
in fulminant hepatic failure of autoimmune etiology suggest-
ing that a cautious trial of steroid may avoid liver transplant
in a proportion of cases [22]. However, it should be noted
that patients receiving immunosuppressive treatment are at
risk of severe infection, which has been reported as the most
frequent cause of morbidity and mortality in these patients
[21].
Nastasio et al.
Conventional treatment is associated with a measurable
clinical and laboratory improvement within 4 to 8 weeks in
over 80% of patients, however, complete normalization of
biochemical parameters may take up to several months. The
rapidity and degree of response to treatment depends on the
disease severity at onset [1,2]. Measurement of thiopurine
methyltransferase (TPMT) activity and TPMT genotyping
before initiating azathioprine therapy, proposed as a predic-
tor of drug toxicity, was not show to predict azathioprine
toxicity in adults patients with AIH [23]. In patients who are
poor azathioprine metabolizers, alternative treatments should
be considered as they can experience severe side effects with
even low doses of the drug.
Once remission is achieved, the aim is to maintain it in
the long term with the lowest possible dose of drugs. Differ-
ent treatment tapering regimes exist and should be tailored to
individual patients. A thorough clinical and biochemical
evaluation should be performed before each treatment modi-
fication.
Prednisone is first gradually decreased over a period of
several months according to the degree of the decline of
transaminase activity; the shift to alternate-day use of ster-
oids is suitable because of the lower incidence of side effect,
especially on growth [24].
In case of combined prednisone and azathioprine admini-
stration, prednisone is stopped and the patient is maintained
on azathioprine monotherapy before complete discontinuation
of treatment [1]. Azathioprine monotherapy had been demon-
strated to maintain remission in most patients with AIH [25].
The optimal duration of the immunosuppressive treat-
ment is unknown. Current recommendation is to treat for at
least two-three years, attempting withdrawal of treatment
only in case of persistent biochemical remission (normal
transaminase activity and serum IgG levels) with absent or
very low titer autoantibodies [14]. Since, in our experience,
treatment withdrawal in the first two years has been almost
constantly associated with disease relapse [8], we suggest
that a sustained remission should be maintained for at least
five years before attempting to stop treatment.
The need for a histologically documented remission be-
fore discontinuation of treatment is currently under debate,
as histological remission was not shown to be predictive of
absence of future relapses [8].
Conversely, monitoring autoantibody titre and IgG levels
plays a main role in the timing of treatment discontinuation
because their fluctuation of plasma levels correlates with the
activity of the disease [1, 2, 13].
Relapses may occur at any time during treatment and
after treatment has been discontinued, even in the absence of
triggering factors. The risk of recurrence is, however, higher
during the first two years of treatment and during adoles-
cence, possibly also linked to inadequate treatment adher-
ence during the latter [1].
About 10% of patients present poor response to conven-
tional treatment and to avoid the risk of deterioration of liver
function a third drug should be introduced. In case of further
nonresponse, the possibility of a liver transplant must be
considered.
Old and New Treatments for Pediatric Autoimmune Hepatitis
2.2. Side Effects
Prolonged steroid treatment can expose children to sig-
nificant side effects. Hyperphagia, weight gain and impaired
height growth are frequent. The high doses necessary to treat
AIH, initially or after relapses, can also cause more severe
complications such as obesity, severe growth retardation,
cataracts with visual impairment, osteoporosis and vertebral
collapse, hyperglycemia, arterial hypertension, psychosis
and serious aesthetic consequences related to the formation
of cutaneous striae and acne [1]. Such complications can
further complicate AIH treatment as they may lead to
scarce treatment adherence especially in adolescent patients.
Even though serious complications occur less frequently in
centers highly experienced in AIH treatment, close monitor-
ing of potential side effects as well as nutritional and life-
style interventions play a fundamental role in patients re-
ceiving long-term steroid treatment [26].
Azathioprine is generally considered a safe drug and its
side effects typically improve after dose reduction or after
drug discontinuation [27]. Azathioprine-related side effects
have an overall reported frequency of 10% in patients with
AIH [27, 28]. The most common one is bone marrow sup-
pression, which most frequently occurs in the form of cy-
topenia, warranting routine blood count assessment [1, 2,
28]. Other possible adverse effects are pancreatitis, nausea,
vomiting, abdominal pain, hepatotoxicity, increased suscep-
tibility to infections and other non-specific ones such as my-
algias, arthralgias, cutaneous rashes and fever. While long-
term low dose azathioprine treatment has been associated
with a 1.4-fold greater than normal increased risk of malig-
nancy, this should be weighed against the known benefits of
such treatment [28-32].
Azathioprine has been indicated as safe in pregnancy in
several reports with its use not being related to any increase
in birth defects or any other adverse consequences for the
mother or the child. Conversely, poor disease control in the
year prior to pregnancy and discontinuing treatment during
pregnancy can lead to relapse of the disease and are associ-
ated with poor pregnancy outcomes [33-37].
Table 1. Alternative treatments for pediatric autoimmune hepatitis: regimens and dosage reported in literature.
Treatments Regimens
Front-line
Cyclosporine
Salvage treatment
Mycophenolate mofetil Salvage treatment
Budesonide Front-line
Front-line
Tacrolimus
Salvage treatment
Sirolimus Salvage treatment
Rituximab Salvage treatment
Infliximab Salvage treatment
Current Pediatric Reviews, 2018, Vol. 14, No. 3 189
3. ALTERNATIVE MEDICAL TREATMENTS
Although the combination of prednisone and azathioprine
is associated with a high remission rate [1, 3, 8, 28, 38, 42],
3 to 16% of children will undergo liver transplantation de-
spite this treatment and 69 to 94% of pediatric patients will
relapse after drug withdrawal [1, 3, 39-41]. The combination
of this data with the evidence of steroid related side effects
has constituted, and currently remains a compelling reason to
refine treatment strategies and pursue new management op-
tions [43] (Tables 1 and 2).
3.1. Cyclosporine
Cyclosporine (CSA) is a powerful immunosuppressant
that has been successfully used in patients with AIH as a
short-term initial therapy alternative to steroid-azathioprine
or as a salvage treatment [1, 20]. It was initially used to pre-
vent allograft rejection in patients who received kidney, pan-
creas, liver and heart transplant. Subsequently, it was also
used for the treatment of numerous autoimmune conditions
such as uveitis, rheumatoid arthritis, and psoriasis [44-47].
CSA acts at an early stage in the antigen receptor-
induced differentiation of T-cells and blocks their activation.
Inside the cell, CSA binds with cyclophilin, a molecule be-
longing to a class of intracellular proteins called immuno-
phillins, forming a complex that inhibits calcineurin, a cyto-
plasmic phosphatase required for the activation of a T-cell-
specific transcription factor. The latter, NF-AT (nuclear fac-
tor of activated T-cells), induces transcription of interleukins
(such as IL-2, IL-3, IFN-) within activated T-Cells. CSA,
therefore, inhibits the production of these interleukins and,
consequently, the activation of T-lymphocytes [48-50].
The main side effects of CSA are reported predominately
in transplant recipients who require higher dosing. These
include nephrotoxicity, arterial hypertension and gastrointes-
tinal and neurological toxicity [51, 52].
After the first report of CSA use for the treatment of
autoimmune hepatitis in an adult patient [53], in 1987
Leichtner et al. reported the administration of CSA at 5
mg/kg/day in a 14-yr-old boy with a 5-year history of AIH
Dose
4-10 mg/Kg/day
Target trough levels: 100-300 ng/mL
20-40 mg/Kg/day
6-9 mg/day
Target trough levels: 2.5-5 ng/mL
1-2 mg/Kg/day
Target level: 4-8 ng/mL
2
375 mg/m weekly for 4 weeks, repeated depending on response
5 mg/kg 4 infusions at 4 weeks interval
190 Current Pediatric Reviews, 2018, Vol. 14, No. 3 Nastasio et al.

Table 2. Side effects of standard and alternative treatments used in autoimmune hepatitis.

Treatments Side Effects

Hyperphagia, weight gain, fat redistribution, cutaneous striae, acne, impaired height growth, severe growth retardation,
Prednisone
cataract, osteoporosis, hyperglycemia, arterial hypertension, psychosis

Azathioprine Cytopenia, pancreatitis, nausea, vomiting, abdominal pain, hepatotoxicity, malignancy

Cyclosporine Hypertrichosis, gingival hypertrophy, hypertension, nephrotoxicity

Mycophenolate mofetil Leukopenia, headache, diarrhea, diziness, hair loss

Budesonide Weight gain, fat redistribution, cutaneous striae, acne

Tacrolimus Bone marrow toxicity, neurotoxicity, nephrotoxicity, opportunistic infections

Sirolimus Pulmonary toxicity, myelosuppression, hyperlipidemia, stomatitis, edema, rash

Rituximab Infections, progressive multifocal encephalitis

Infliximab Infections, lupus-like syndrome, hepatotoxicity

type 1 refractory to corticosteroid therapy. In this patient,
ALT, AST and GGT levels were markedly reduced by 2
weeks of CSA treatment and were almost within the normal
range by 2 months. No significant side effects were noted
after 1 year of CSA administration and severe growth failure
observed during previous corticosteroid treatment reversed
with the patient displaying a catch-up growth [54].
Recently Czaja reported that since 1985, the use of CSA
has been documented in 10 reports, including a total of 133
adult patients with autoimmune hepatitis. CSA was used as a
salvage therapy and showed an overall positive response of
any degree in about 93% of patients and a negative response,
defined as no response, non-compliance, or drug intolerance
in 7% [43].
As for pediatric patients, there are only five major publi-
cations in which CSA is mostly administered for short peri-
ods, mainly to induce remission, as a bridge to a conven-
tional treatment [55-59].
In 1999 Alvarez et al. published the results of a multicen-
ter open trial involving a series of 32 treatment-naïve chil-
dren with autoimmune hepatitis mostly type 1 (28 AIH-1). In
these patients CSA was administered alone for 6 months,
followed by combined low doses of PDN and AZA for 1
month, after which CSA was discontinued. Aside from two
patients who were withdrawn from the study, 1 for non-
adherence and the other for liver failure, 25 children (78%)
normalized ALT levels within 6 months and all of them
within 1 year. CSA adverse effects were mild and disap-
peared when the drug was weaned off. This study, therefore,
represents the first systematic attempt to use CSA to induce
remission of autoimmune hepatitis, thus reducing exposure
to high doses of corticosteroids and their well-known side
effects [55].
In the same year Debray et al. published a retrospective
study limited to 15 children and adolescents with autoim-
mune hepatitis type 2, which showed that CSA, used as first-
or second-line treatment in case of conventional treatment
failure, normalized transaminase levels within 6 months in
all patients. Although side effects were mild and well toler-
ated, five patients presented a transient GFR decrease and
the authors underlined the need for long-term nephrotoxicity
surveillance [56].
In 2006 Cuarterolo et al. published a follow-up study of
84 children with autoimmune hepatitis treated with CSA for
6 months. Remission was observed in 69% of patients within
the first 6 months of CSA administration, similarly to some
large pediatric series of patients treated with prednisone or
prednisolone and azathioprine. The authors report that CSA
was well tolerated. Reported side effects include transient
hypertrichosis (55%) and gingival hypertrophy (39%). Tran-
sitory elevation of creatinine levels and hypertension were
detected only once in 9 and 4% of children respectively [57].
Furthermore CSA has been used as a salvage therapy in
children with autoimmune hepatitis and liver failure. Alvarez
et al. in 2011 analyzed the outcome of 50 treatment-naïve
children with autoimmune hepatitis and severe liver function
impairment. Patients were treated either with 2 mg/Kg/day
prednisone at doses of up to 60 mg/day or 1 mg/Kg/day
prednisone up to 40 mg/day plus CSA. CSA was discontin-
ued once a prothrombine time >50% was obtained. The ef-
fectiveness of the 2 regimens was similar (90%), with no
differences in the percentage of patients who normalized
liver function or in the time taken for recovery to occur, and
without statistical difference in infectious complications be-
tween the 2 protocols [21].
In 2004 we first reported on prolonged CSA treatment for
autoimmune liver disorders. We described our experience
with a group of 12 patients who received CSA for a mean
time of 35.6 months with a median follow-up of 6.5 years.
All patients achieved complete remission in a median period
of 4.5 weeks and safety of the drug was excellent. Side ef-
fects were indeed mild and transient: gingival hypertrophy
occurred in two patients as wells as moderate hypertrichosis,
a 20% elevation of serum creatinine occurred in only one
case. No treatment withdrawals due to side effects were re-
corded [58].
A recent meta-analysis by Zizzo et al. confirmed the effi-
cacy of cyclosporine estimating that cyclosporine has the
Old and New Treatments for Pediatric Autoimmune Hepatitis
highest short-term response rate (86%) in conventional
treatment-refractory children with autoimmune hepatitis
[59]. Larger studies on the efficacy and safety of cy-
closporine are needed to confirm such successful results over
the long-term and to understand the possible role of cy-
closporine as a maintenance treatment. Careful monitoring of
potential side effects including renal function and individual
tailoring of CSA treatment achievable with CSA through
level assessment remain key points while administering this
drug.
3.2. Mycophenolate Mofetil
Mycophenolate Mofetil (MFM) has been mainly used for
the treatment autoimmune hepatitis in adult patients intoler-
ant to azathioprine or refractory to conventional therapy
[1, 20].
MFM is a pro-drug that is metabolized in the liver and
transformed into mycophenolic acid. The latter, by inhibiting
the enzyme inosine-monophosphate dehydrogenase, impairs
the synthesis of purines and therefore of new DNA mole-
cules, with consequent antiproliferative action on activated B
and T-lymphocytes [60].
The treatment involves the administration of MFM at an
initial dose of 20 mg/kg/day, gradually increased to a maxi-
mum of 40 mg/kg/day, in addition to corticosteroids.
In 2009, Aw et al. reported that 18 of 26 (69%) children
resistant to or intolerant of conventional prednisone-
azathioprine immunosuppression had complete or partial
laboratory remission after administration of MFM and that
all patients were alive 3.5-7.6 years (median, 6.7 years) from
the onset of treatment [61]. A recent meta-analysis by Zizzo
et al. concludes that MFM is the second most effective drug
for conventional treatment-refratory children with AIH after
cyclosporine (86% vs. 36% remission rate at 6 months) [58].
Side effects are reported in 3 up to 34% of patients in-
cluding: headache, diarrhea, dizziness, hair loss and most
frequently leukopenia [1, 19].
Although MFM is a purine antagonist like azathioprine, it
is more powerful and independent from the thiopurine
methyltransferase pathway of catabolism. On the other hand,
MFM is more expensive than azathioprine and is absolutely
controindicated during pregnancy [20]. These data support
the notion that in children with AIH, refractory to standard
treatment and intolerant to CSA, the use of MFM should be
considered [62].
3.3. Budesonide
Budesonide, is a steroid that has recently emerged as an
alternative first-line treatment in association with azathio-
prine for adult patients with autoimmune hepatitis [1, 63].
When taken orally, budesonide has a 90% hepatic first
pass metabolism, which allows it to reach a high intrahepatic
concentration while limiting its systemic side effects. This
mechanism of action theoretically makes budesonide an
ideal treatment for autoimmune hepatitis. In 2013, Woy-
narowski et al. compared the effects of budesonide vs. pred-
nisone therapy, both in combination with azathioprine, on 46
pediatric patients with autoimmune hepatitis aged 9-17
Current Pediatric Reviews, 2018, Vol. 14, No. 3 191
years. Budesonide did cause fewer side effects than predni-
sone, however, after 12 months, only 46% of these patients
achieved complete remission [64]. The low proportion of
remission observed in this study compared to that reported in
other pediatric studies using prednisone and azathioprine, do
not support its use as first-line treatment of AIH [1, 65]. Fur-
thermore, it should be noted that budesonide is contraindi-
cated in cirrhotic patients because of the increased risk of
side effects.
3.4. Tacrolimus
Tacrolimus, as cyclosporine, selectively inhibits cal-
cineurin, impairing the transcription of interleukin 2 and
therefore leading to failure of T-cell clonal expansion and
differentiation. Tacrolimus is part of the mainstay of immu-
nosuppressive regimens after solid-organ transplantation. It
is 100 times more potent than cyclosporine while causing
less cosmetic side effects [66]. The administration of tac-
rolimus is, however, associated with nephrotoxicity, an in-
creased risk of post-transplant diabetes and neurological and
gastrointestinal side effects [66, 67].
There are a number of reports showing promising results
in adult patients with autoimmune hepatitis treated with tac-
rolimus both as initial and salvage treatment [68-72].
The largest series of pediatric patients receiving tac-
rolimus for the treatment of autoimmune hepatitis was pub-
lished in 2011 within an open, non-randomized, prospective,
single center study [73]. Twenty treatment-naive patients
with AIH were treated with two daily oral doses of tac-
rolimus and followed-up for 1 year with target trough levels
of 2.5-5 ng/mL. Eighty-five percent of the patients in the
study achieved complete remission, but the additional short-
term administration of low doses of prednisolone or azathio-
prine were necessary in 14 of the 17 patients. Headache
and⁄or recurrent abdominal pain were reported in 50% of
patients. Renal function remained normal in all patients. The
authors conclude that although tacrolimus monotherapy is
not sufficient to achieve complete remission in all patients, it
allows to drastically reduce the dosage of prednisolone and
azathioprine as well as most of their side effects.
Further studies are necessary to determine the efficacy
and safety of tacrolimus for the treatment of autoimmune
hepatitis in children.
3.5. Sirolimus
Sirolimus is an mTOR inhibitor that has been used after
solid organ transplantion to prevent rejection and, more re-
cently, for malignancies. This class of drugs acts by inhibit-
ing the mammalian target of rapamycin (mTOR), a protein
that has a critical role in regulating basic cellular functions,
including proliferation and survival of activated lympho-
cytes.
Major side effects of this treatment are pulmonary toxic-
ity, myelosuppression, hyperlipidemia, stomatitis, edema and
rash. There are very few clinical experiences reporting on the
use of mTOR inhibitors in treatment refractory autoimmune
hepatitis [74, 75].
192 Current Pediatric Reviews, 2018, Vol. 14, No. 3
In 2014 Kurowski et al. published a retrospective study
about 4 pediatric patients who received rescue therapy with
sirolimus after non-responding to several immunosuprressive
treatments including prednisone, azathioprine, mycophe-
nolate and tacrolimus. Sirolimus was administered to achieve
a target level of 4 to 8 ng/mL. Two of the 4 patients had im-
proved liver enzymes, with improvement of histologic in-
flammation seen in one. The authors report that there were
no side effects necessitating discontinuation of sirolimus and
that 2 patients had mouth ulcers that resolved without drug
tapering [76].
More data is necessary to better understand the potential
role of sirolimus in the treatment of autoimmune hepatitis.
3.6. Rituximab
Rituximab is a chimeric monoclonal antibody that targets
the CD20 antigen on B-cells causing B-cell depletion. It is
used to treat B-cell malignancies and autoimmune disorders
such as reumathoid arthritis [77]. The administration of ri-
tuximab has also been sucessful in isolated cases of adults
and children with autoimmune hepatitis. The most dreaded
complications associated with its use are severe bacterial and
viral infections including reactivation of Hepatitis B, latent
varicella and latent polyoma virus resulting in multifocal
leukoencephalopathy [78].
In 2013 D’Agostino et al. reported on 2 children with
severe, refractory, type 1 autoimmune hepatitis in which
rituximab, administered as rescue treatment, lead to achieve
clinical and biochemical remission without side effects [79].
Although the data is still scant, the successful use of ri-
tuximab warrants further studies in selected patients with
refractory hepatitis alongside with the strict monitoring of
the potential infective complications.
3.7. Infliximab
Infliximab is a recombinant humanized chimeric anti-
body that neutralizes the biological activity of TNF by in-
hibiting the binding of TNF with its receptors. It is used for
the treatment of several immune-mediated conditions includ-
ing Crohn disease, ulcerative colitis and rheumatoid arthritis.
As for pediatric autoimmune hepatitis, infliximab was
used in a 10 year old girl non responsive to high dose ster-
oids, azathioprine, mycophenolate and tacrolimus [80]. The
authors report that infliximab lead to achieve a sustained
biochemical response while weaning steroids, improving
quality of life and allowing deferral of liver transplantation.
The dosing schedule and efficacy profile of infliximab in the
treatment of autoimmune hepatitis still remain unknown.
Furthermore, it has been reported that infliximab increases
susceptibility to infections and immune-mediated reactions
including lupus-like syndrome as well as liver toxicity re-
sembling autoimmune hepatitis.
A recent retrospective study reviewed the records of 11
patients with Inflammatory Bowel Disease (IBD) (10 ulcera-
tive colitis) and autoimmune liver disease, mostly with auto-
immune hepatitis-sclerosing cholangitis variant. All patients
received infliximab (5mg/kg) for their IBD and 6 switched
to adalimumab due to allergic reaction or non-response.
Nastasio et al.
Liver function tests improved in 5 patients and remained
normal in 2. In this series, anti-TNF improved gut disease
in most of the patients without impairing liver function [81].
In view of potential severe side effects the use of inflixi-
mab as a rescue treatment must, however, be carefully evalu-
ated.
4. LIVER TRANSPLANT
Autoimmune hepatitis accounts for about 5% of pediatric
liver transplants with a 5-year survival rate ranging from
86% to 94% [1, 82].
Liver transplantation only represents a therapeutic option
for autoimmune hepatitis under two main circumstances:
patients presenting with acute liver failure that does not re-
spond to salvage therapy with rescue immunosuppression,
and patients with chronic end stage liver disease.
A recent study by the SPLIT group (Studies of Pediatric
Liver Transplantation) reports that children transplanted for
AIH in North America are typically female adolescents with
complications of chronic AIH type 1 and include more chil-
dren of African-American or Latino-American origin com-
pared to the overall liver transplant population. Moreover,
when patient and graft survival, infectious and metabolic
complications and re-transplantation rates where compared
in patients with or without autoimmune hepatitis, no statisti-
cally significant difference was found [83].
Although liver transplantation is an effective therapeutic
strategy, recurrence of liver disease occurs in about 20% of
patients. Recurrence of autoimmune hepatitis should be sus-
pected in case of reappearance of clinical symptoms and
signs, increase of transaminases and IgG serum levels,
autoantibody positivity, finding of interface hepatitis on liver
biopsy and steroid response. This condition appears to be
more frequent in patients transplanted for type 2 autoimmune
hepatitis and in those who have shown poor adherence to
immunosuppressive treatment [1, 84, 85].
5. FUTURE TREATMENTS
New treatment options for autoimmune hepatitis are cur-
rently being investigated. One of the most attractive targets
for cell-based immune intervention is represented by regula-
tory T-cells (Tregs).
Tregs play an important role in the pathogenesis of auto-
immune hepatitis where they have been reported to be defi-
cient in number and function [5, 6, 86-88]. A recent study
also demonstrated that in children with AIH type 2, NK cells
display an altered cytokine pattern characterized by in-
creased IFN and reduced IL-2 production, which could con-
tribute to impaired Treg function. Exposure of mononuclear
cells to IL-2 resulted in normalization of NK INF produc-
tion [89].
Infusion of autologous ex vivo expanded Tregs or their
expansion in vivo using low-dose IL-2 injections could
therefore be an effective treatment in these patients
[90-92]. An open-label trial was recently undertaken to
assess the safety and biological efficacy of low-dose IL-2
as a Treg inducer in a set of 12 autoimmune and auto-
Old and New Treatments for Pediatric Autoimmune Hepatitis
inflammatory diseases including autoimmune hepatitis
(NCT01988506).
If such treatments are proven successful, restoring self-
tolerance may become a feasible treatment end-point for
autoimmune hepatitis.
CONCLUSION
Although conventional treatment induces initial remis-
sion in the majority of patients, it is far from being consid-
ered ideal. A significant proportion of patients relapse, have
insufficient treatment response or experience intolerable side
effects. Not to mention that treatment discontinuation is very
hard to achieve. Effective and safe alternative treatment op-
tions are needed to assure a tailored successful treatment for
every patient. Collaborative multicenter investigations aimed
at a better understanding of the efficacy and safety profile of
current alternative treatments are needed before future treat-
ments aimed at restoring tolerance to hepatic autoantigens
will become available.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Study concept and design: Silvia Nastasio, Marco Sciv-
eres, Giuseppe Maggiore; Drafting of the manuscript: Silvia
Nastasio; Critical revision of the manuscript for important
intellectual content: Silvia Nastasio, Marco Sciveres,
Lorenza Matarazzo, Giuseppe Maggiore; Study supervision:
Giuseppe Maggiore.
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