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