Editorial

Treating autoimmune hepatitis – More science, more

progress, better therapy
Gideon M. Hirschfield1,*, Ansgar W. Lohse2

See Article, pages 576–585
DOI of original article: https://
doi.org/10.1016/j.jhep.2023.
11.032
People living with autoimmune diseases frequently
have impaired quality and quantity of life, and
usually a chronic disease course.1 Physicians
usually focus on their own areas of interest but
taking the ‘patient helicopter’ view is important to
challenge our current management paradigms.
Patients may fairly ask what do autoimmune hep-
atitis (AIH), rheumatoid arthritis, multiple sclerosis,
psoriasis, and inflammatory bowel diseases have
in common? All are immune-mediated diseases,
whose exact aetiology is unknown, all may lead to
acute flares that can be effectively managed by
corticosteroid therapy, all require long-term
maintenance immunotherapy, and all may benefit
from treatment with azathioprine. However, corti-
costeroids and azathioprine are no longer the
cornerstone of therapy for any of these diseases,
except AIH!
Patients living with the other autoimmune
conditions are offered multiple therapeutic alter-
natives based on enormous progress over de-
cades from basic and clinical immunology.2–5 AIH
may be more rare, more heterogeneous, and
more difficult to diagnose and study, but never-
theless, as a Hepatology community, we must
address concerns that we are failing our patients
in not providing them access to a plethora of
more specific drugs, both established and
emerging. Nor are we providing the data needed
to choose the right drug for the right patient at the
right time, such as addressing disease presen-
tation, disease maintenance, or disease-related
symptoms.6,7 While 50 years ago Hepatology
was leading the field with the conduct of three
randomised trials – indeed some of the earliest
randomised trials in medical history, proving the
life-saving effectiveness of corticosteroid therapy
in AIH – very few trials have been performed
since.8–12 As we debate if one corticosteroid is
better than another (budesonide vs. prednisone/
prednisolone13), all other disciplines are spoiled
for choice with a surfeit of immune-modulating
drugs – admittedly with varying efficacy and
varying side-effect profiles, but with real options
and impressive advances in care for diseases that
were previously much harder to manage
than AIH.
It is therefore most welcome that this issue of
the Journal of Hepatology includes what is so
clearly needed to provide some progress in the
field, a randomized-controlled trial on the treat-
ment of AIH.14 Romée Snijders, Anna Stoelinga
and Joost Drenth, on behalf of their co-authors,
and the Dutch Autoimmune Hepatitis Working
Group, therefore deserve much credit for
designing, recruiting, analysing, and publishing an
investigator initiated open-label randomised-
controlled trial of azathioprine vs. mycophenolate
mofetil (MMF) for the induction of remission in
treatment-naive AIH. In what is clearly a pragmatic
trial, the data supports a role for MMF in managing
AIH, extending clinical experience by providing trial
evidence. MMF with prednisolone achieved a
higher rate of biochemical remission at 24 weeks
compared to azathioprine combined with pred-
nisolone. Azathioprine use was associated with
more adverse events leading to cessation of
treatment (8 of the 31 patients in the azathioprine
arm). Thus, the difference between the two drugs
was primarily due to this difference in their tolera-
bility profile – if analysis is restricted to the patients
taking the investigational drug, i.e. the per protocol
analysis, the effectiveness (or lack of effective-
ness, considering the relatively low biochemical
remission rate) of the two drugs was very
much comparable.
It is interesting to note that the use of MMF was
evaluated in untreated patients, a very heteroge-
neous group generally, and in this study, we are
unable to evaluate how representative the enrolled
participants are because the denominator for new
patients with AIH requiring treatment across the
study sites is not available to us. The primary
endpoint was biochemical remission defined as
normalisation of serum values of alanine amino-
transferase and immunoglobulin G after 24 weeks

Keywords: Therapy; immune mediated liver disease; clinical trials; mycophenolate.

* Corresponding author. Address: Lily and Terry Horner Chair in Autoimmune Liver Disease Research, Toronto Centre for Liver Disease, Toronto General
Hospital, Toronto, Ontario, Canada.
E-mail address: gideon.hirschfield@uhn.ca (G.M. Hirschfield).
Received 14 January 2024; accepted 15 January 2024; available online 1 February 2024
https://doi.org/10.1016/j.jhep.2024.01.021

Journal of Hepatology, April 2024. vol. 80 j 534–536


of treatment. The trialists report on seventy consenting patients
(mean age 57.9 years; 72.9% female). More patients were
randomly assigned to the MMF plus prednisolone (n = 39) arm
than the azathioprine plus prednisolone (n = 31) arm. The primary
endpoint was met in 56.4% and 29.0% of patients assigned to
the MMF group and the azathioprine group, respectively (p =
0.022). The MMF group exhibited higher complete biochemical
response rates at 6 months (72.2% vs. 32.3%) but it is notable
that baseline characteristics were not matched between groups.
No serious adverse events occurred in patients who received
MMF, but serious adverse events were reported in four patients
who received azathioprine. Two patients in the MMF group and
eight patients in the azathioprine group discontinued treatment.
Whether treatment optimisation for azathioprine was ideal is
unclear, albeit a counter argument could be made that if MMF is
simply easier to use, then that itself is an important practice point.
For clinicians appraising this trial, context is important. Whilst
the findings are helpful, many will interpret this study with some
caution based on their overall treatment experience of AIH. Firstly,
MMF has for a long time been a treatment consideration in AIH. It is
a drug familiar to many, used in systemic lupus erythematosus,
post-transplant, and other autoimmune conditions. Prior evidence
has shown it has a role in AIH (as does in fact nearly any immu-
nosuppressant with some potency), but drawbacks include higher
cost than azathioprine, inability to use in women wishing to
conceive, and variation in gastrointestinal tolerability depending
on brand formulation. MMF is also a twice daily drug, unlike
azathioprine which can usually be taken once daily.
Azathioprine is ubiquitously used, cheap, and can be dose
adjusted based on drug levels. Secondly, the trial is not really
asking the right question: guidelines universally recommend
corticosteroids as the drug of choice to induce remission and
azathioprine or MMF, usually as a second-line drug if azathio-
prine is not tolerated, as maintenance therapy, but this trial is
studying remission induction. We knew in advance that MMF is
a good alternative to azathioprine in AIH, and patients who are
intolerant to azathioprine should be switched to MMF accord-
ing to all guidelines. In this trial, presumably for reasons of trial
design, patients were not switched to MMF as recommended
in the guidelines, and as is usual medical practice. More
importantly, patients are much more interested in the long-term
outcome of their treatment, and less so in the time to reach
biochemical remission. Unfortunately, the long-term questions
that patients ask us are almost impossible to answer in a
clinical trial, and thus in addition to more innovative, and better-
funded trials, we need good prospective and comprehensive
long-term registry data.
What then are the take-home messages after this trial for the
clinical gastroenterologist and hepatologist? MMF clearly is an
Affiliations
1
Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, Canada; 2Division of Medicine, University Medical
Center Hamburg-Eppendorf, Hamburg, Germany
Financial support
The authors did not receive any financial support to produce this manuscript.
Conflict of interest
GMH has consulted for Intercept, Advanz, Ipsen, Cymabay, Pliant, Mirum,
GSK, Kowa; AWL occasional lecture fees from Falk Pharma; consulting for
Journal of Hepatology, April 2024. vol. 80 j 534–536
Editorial
alternative in early treatment of AIH and has some advantages
in comparison to azathioprine, which are better tolerability, at
least in the short-term, and probably a faster mode of action.
Thus, our therapeutic armamentarium is somewhat enlarged,
albeit by a well-established old-fashioned drug with its own
considerable risk profile. The second message is that azathi-
oprine is quite frequently poorly tolerated in early treatment of
AIH and care needs to be taken when using this well-weathered
drug to improve tolerability – for example by starting with lower
doses, by giving the drug in the first weeks only on a full
stomach, and by measuring drug metabolites (6-thioguanine
and 6-methyl mercaptopurine). The third and very sobering
message is that even if the recommended or alternative drugs
are well-tolerated, just over half of patients with AIH reach
biochemical remission. We need to improve on that, and we
need to know if biochemical remission is really required, or if
mild disease activity may be preferred to possible drug side-
effects in difficult to treat patients. More importantly, we need
to know which treatments help to improve not just life-
expectancy but also quality of life.
In summary, both azathioprine and MMF are helpful tools
for our patients, but perhaps the greater point is why indeed
are we still using either drug in an era of biologics and small
molecules? In AIH we need to agree on what we are seeking
to achieve. We recognise from real-world studies that man-
agement is patchy in quality and heterogeneous in approach,
and that despite good treatment guidelines15,16 from both
EASL and AASLD very many patients are not receiving the
recommended standard of care. Much of this problem is due
to care structures and the inherent problem of rare complex
illnesses, that require access to expert centres to optimise
treatment of such a heterogeneous disease, with an even
more heterogeneous patient population of all age groups,
varying co-morbidities and varying health priorities. However,
a lack of clinical research and clinical trials is just as bigger
problem. We desperately need more clinical trials, brave pilot
studies with new agents and new drug combinations, sys-
tematic case series reporting unconventional approaches in
difficult to treat patients – and we need a closer cooperation
with both the pharmaceutical industry and the regulatory
authorities: hurdles for trials have to be lowered, we have to
design and allow more pragmatic trials that move away from
histology as gold standard, that include patient-centred
outcome measures (such as quality of life), and we have to
work more carefully with prospectively collected registry data.
All of this speaks to a need for more science17 that encom-
passes many approaches and many stakeholders. But team
science such as this will surely reap the reward of better
therapies in the future.
investigational drugs and trial design for Genfit, Merck and Roche. Coordinator of
the European Reference Network for Hepatological Diseases (ERN RARE-LIVER).
Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contributions
The authors contributed equally to the production of this manuscript.
535
Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/
j.jhep.2024.01.021.
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