INFO - Liver toxicity associated with TNF inhibitors

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Hepatotoxicity with TNF inhibitors. In the ATTRACT trial, mild to moderate

LFT elevations (<3 x upper limit of normal [uLN]) were observed more often

in the INFLIX (37%) than placebo (29%) groups (all groups received

background MTX). In a Crohn's disease (CD) study (ACCENT I) all patients

were maintained on background immunomodulatory therapies (e.g., 6MP,

azathioprine, mycophenolate, or MTX) and were then randomized to receive

repeated doses of placebo, 5 mg/kg or 10 mg/kg of INFLIX. Hepatic enzyme

elevations were more common in the 5 or 10 mg INFLIX (42%) group compared

with placebo (36%) treated CD patients. Moderate LFTs elevations (>2 but <3

times the ULN) were seen in 24 INFLX (5mg or 10 mg/kg) patients, but only in

eight placebo patients. None went on to develop liver impairment. In the

ERA study, although most LFT elevations were seen in the MTX group, four

patients in the ETAN 10 mg group (none in the 25 mg group) developed mild to

moderate LFT elevations. Lastly, in the ADA clinical trials, nine ADA

treated patients (<4%) developed > 2 fold elevations of AST or ALT. Four of

these remained elevated during the trial. Many of these were confounded by

background MTX or DMARD use and the frequency was similar to placebo

controls. One patient with a history of fatty liver died while receiving

ADA, but was never noted to have an increased AST or ALT in the trial. These

data suggested that mild to moderate elevations of hepatic enzymes may occur

with TNF inhibitor use.

FDA post-marketing surveillance has disclosed 134 spontaneous reports of

liver failure associated with TNF inhibitor use. In their detailed review

of 50 well-documented cases (31 INFLIX, 19 ETAN) they found confounding

diagnoses or hepatoxin exposure in 43 cases (13 sepsis, eight tuberculosis

or INH use, five alcohol related, three viral hepatitis, two GVHD, six

hepatotoxic drugs, eight other). However, in seven cases (five INFLIX, two

ETAN) no other cause could be identified suggesting that TNF inhibitor use

may have lead to hepatic failure. It was noted that the chance occurrence

of liver failure in the general population is estimated to be one per

million population. Clinicians should be aware of these rare events and

report similar findings to the FDA at www.medwatch.com.

Arthur Kavanaugh, MD, J. Cush, MD, Matteson, MD, Hotline Editors -

August 2003

http://www.rheumatology.org/publications/hotline/0803chf.asp?aud=mem

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