Post on 19-Mar-2017
Autoimmune Hepatitis Induced by Infliximab ina Patient with Crohn’s Disease with no RelapseAfter Switching to AdalimumabMarilia Cravo,1 Rosa Silva2 and Miguel Serrano1
1 Gastroenterology Department, Instituto Portugues de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
2 Gastroenterology Department, Hospital Central do Funchal, Madeira, Portugal
Abstract Infliximab and adalimumab are anti-tumor necrosis factor (TNF) alpha agents used for treating Crohn’s
disease. Autoimmune hepatitis (AIH) is a rare complication of treatment with these drugs. We report on a
case of AIH in a patient with Crohn’s disease treated with infliximab who fully recovered after drug
withdrawal. More interestingly, because there were no other treatment options, the patient was then treated
with adalimumab without recurrence of the liver disease and with control of the intestinal disease.
1. Case Report
We present a case of a 38-year-old woman with a 20-year
history of ileocolonic Crohn’s disease, stricturing phenotype,
corticosteroid dependent, a non-responder to azathioprine or
methrotexate. The patient underwent an ileal resection with
ileotransversostomy in 1995 as a result of bowel occlusion but
remained corticosteroid dependent. Because of this, infliximab
(5mg/kg) was started in 1999, first on an on-demand basis, but
in October 2000 infliximab administration was switched to
every 8 weeks. The patient responded well but from April 2001
to January 2002, the drug was interrupted because of a planned
pregnancy. After delivery, infliximab was re-started but 10 days
after the first infusion the patient developed a delayed hyper-
sensitivity reaction that was treated with intravenous cortico-
steroids. At that moment, anti-nuclear antibody (ANA) and
anti-double-stranded DNA (dsDNA) antibodies were negative
and liver tests were normal. Infliximab therapy was suspended
again and between 2002 and 2005 the patient received azathio-
prine 3mg/kg per day but reactivation of disease with the need
for systemic corticosteroids occurred in nine instances. As
disease was mainly active at the anastomosis and in the prox-
imal colon, budesonide was introduced, but was ineffective
on a chronic basis. Because of this corticosteroid dependence
with severe morbidity (bilateral cataracts and osteoporosis), in-
fliximab therapy was re-started in 2006 (5mg/kg, every 8 weeks)
with prednisolone administration (20mg/day) the day before
and the day after. There were no further infusion reactions and
the disease was fairly well controlled, with no further need of
systemic corticosteroids and with partial mucosal healing on
colonoscopy. As a result of the progressive loss of response, the
dose of infliximab was increased to 10mg/kg and the interval of
administrations reduced to every 6 weeks. Except for transient
periods, no concomitant immunossupressant was ever used
during treatment with infliximab.
The situation remained clinically stable until September
2008 when liver function tests were found to be altered: as-
partate aminotransferase 158UI/L, alanine aminotransferase
191UI/L, as well as a hypergammaglobulinaemia of 1.94 g/dL.Bilirubin, albumin and the international normalized ratio re-
mained normal. She denied the intake of other potential hep-
atotoxic drugs and serological markers of viral infection
(hepatitis A, B and C viruses, cytomegalovirus and Epstein–Barr
virus) were all negative. ANA was positive (>1/640), homo-
genous pattern, dsDNA and antihistone antibodies were also
positive. Anti-smooth muscle and anti-liver–kidney microsome
antibodies were negative. Liver ultrasound was normal and
liver biopsy showed features of chronic hepatitis with inflam-
matory plasmocytes infiltrate in the portal tracts, interface
hepatitis and mild periportal fibrosis (figure 1). According to
the international diagnostic criteria for AIH the score was 17,
making the diagnosis of AIH definitive. Because autoantibodies
CASE REPORTBiodrugs 2010; 24 Suppl. 1: 25-27
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ª 2010 Adis Data Information BV. All rights reserved.
were previously negative, we assumed that AIH was related to
infliximab and the drug was discontinued. Treatment with
azathioprine 50mg/day and prednisolone 40mg/day was started.After corticosteroid tapering, Crohn’s disease activity was con-
trolled with budesonide 9mg/day to which the patient had
previously responded well. Liver function tests returned to
normal and the ANA titre decreased to 1/160 within 12 weeks.
In January 2009 budesonide was decreased to 6mg/day fol-
lowed by disease reactivation. Despite increasing the dosage of
azathioprine to 150mg/day (3mg/kg per day), another course
of corticosteroids was needed to control disease activity. In
April 2009, a colonoscopy was performed that showed active
disease with serpiginous ulcers mainly in the proximal colon,
although the whole colon was involved (figure 2). In this con-
text and because there were no reports of cross-toxicity between
infliximab and adalimumab in respect to AIH, inMay 2009 the
patient was started on adalimumab 160mg, followed by 80mg
at week 2, and 40mg every other week since then. As a result
of moderate disease activity adalimumab was further increased
to 40mg/week and the patient is now in remission with two to
three bowel movements per day, some fatigue but no other com-
plaints. The polymerase chain reaction value remains negative
and a colonoscopy performed in November 2009 showed mu-
cosa healing of the ulcers previously observed with just some
areas of oedema and erythema (figure 3). Liver function tests re-
main normal, gammaglobulin is 1.2 g/dL. ANA titres are be-
tween 1/160 and 1/320, anti-dsDNA and antihistone antibodies
are negative. The patient remains on azathioprine 50mg/day toprevent relapse of AIH.
2. Discussion
Both infliximab and adalimumab are extremely effective for
treating moderate to severe Crohn’s disease.[1,2] Minor side-
effects with these therapies are relatively common but serious
complications are much less common.[3-5] With respect to liver
toxicity, a few cases of toxic hepatitis and of AIH have been
reported.[3-6] In the present case, we report one additional pa-
tient who developed AIH following infliximab treatment. The
causal relationship between infliximab and AIH is supported
by the fact that liver test abnormalities and autoantibodies were
normal/negative 6 years before, when the patient developed a
delayed hypersensitivity reaction. Infliximab is thought to con-
tribute to the development of AIH by triggering the develop-
ment of autoantibodies. These characteristically include ANA
and anti-dsDNA. The fact that our patient interrupted and re-
started treatment with infliximab so many times might have
also increased the likelihood of an autoimmune event. In addi-
tion, the fact that the patient was not on azathioprine or any other
immunossupressant for most of the time that she was on in-
fliximab could also have predisposed to the development of AIH.
There is one single case of AIH in a patient with psoriatic
arthritis treated with adalimumab.[7] The patient made a full
recovery after the discontinuation of adalimumab and treat-
ment with corticosteroids. Because our patient has no other
options for treatment and already has severe morbidity from
chronic corticosteroid use, we felt that it was ethical to treat this
Fig. 1. Liver biopsy showing features suggestive of chronic hepatitis with
interface hepatitis portal infiltrate with plasmocytes and mild periportal fib-
rosis.
Fig. 2. Endoscopic findings before starting adalimumab showing a severe
active disease with serpiginous ulcers.
26 Cravo et al.
ª 2010 Adis Data Information BV. All rights reserved. Biodrugs 2010; 24 Suppl. 1
patient with adalimumab as long as close surveillance was
maintained. The fact that the patient is now on chronic aza-
thioprine therapy may also prevent a relapse of AIH.
Our case also suggests the absence of hepatic cross-toxicity
between infliximab and adalimumab. Both drugs neutralize the
activity of TNFa but they are structurally different. Infliximab
is a chimeric monoclonal antibody, whereas adalimumab is a
fully human IgG antibody against TNF. Moreover, the lack of
response to one TNFa blocker does not always predict the
effect of another.[8] Accordingly, toxicity in the individual pa-
tient may also vary between different agents. Becker et al.[9]
recently reported the lack of hepatic cross-toxicity between
infliximab and etanercept in a patient with rheumatoid arthri-
tis. Interestingly, etanercept had previously been implicated in
exacerbating a case of AIH.[10] We then recommend that liver
function tests should be checked on a regular basis in these
patients and any abnormality should alert the clinician. The
hypothesis that concomitant immunossupression helps to pre-
vent autoimmune phenomena remains to be demonstrated.
Acknowledgments
Professor Cravo received honoraria for the submission of the case re-
port, which was funded by Schering-Plough/MSD Portugal. The other
authors declare no potential conflicts of interest relevant to this case report.
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Correspondence: Prof. Marilia Cravo, Servico de Gastrenterologia, Instituto
Portugues de Oncologia Francisco Gentil, Rua Professor Lima Basto, 1099-
023 Lisboa, Portugal.
E-mail: marilia.cravo@sapo.pt
Fig. 3. Endoscopic findings after 6 months of adalimumab therapy showing
mild erythema and oedema.
Auto-immune Hepatitis in an Anti-TNF Treated Patient 27
ª 2010 Adis Data Information BV. All rights reserved. Biodrugs 2010; 24 Suppl. 1