Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis.
OBJECTIVE
Severe alcoholic hepatitis (AH) is associated with high mortality. Tumor necrosis factor-alpha (TNFalpha) has been demonstrated to play an important role in its pathophysiology.


METHODS
Twelve patients with biopsy-confirmed AH and a Maddrey discriminant factor >32 were treated with a single infusion of the anti-TNF monoclonal antibody Infliximab at a dose of 5mg/kg body weight. Serial measurements were made for various cytokines using specific enzyme-linked immunoassays (ELISA). In four patients, liver biopsy samples were available pretreatment and on day+28 of therapy.


RESULTS
Ten of the 12 patients are alive at a median of 15 (12-20) months. Two patients died within 30 days from septicemia. Serum bilirubin levels, Maddrey score, neutrophil count and C-reactive protein fell significantly within the first month. There was an early, though not significant, decrease in plasma levels of proinflammatory cytokines (interleukins (IL)-1beta, IL-6, IL-8, interferon-gamma), whereas plasma levels of TNFalpha remained near the sensitivity limit of the assay throughout the treatment course. While TNFalpha mRNA expression in the liver did not change, expression of IL-8, a cytokine regulated mainly by TNFalpha, was almost absent on day+28.


CONCLUSIONS
Our data suggest that randomized controlled trials of anti-TNF antibody in severe AH are warranted.
Tilg
Herbert
H
Department of Medicine, Division of Gastroenterology and Hepatology, University Hospital Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. herbert.tilg@uibk.ac.at
Jalan
Rajiv
R
Kaser
Arthur
A
Davies
Nathan A
NA
Offner
Felix A
FA
Hodges
Stephen J
SJ
Ludwiczek
Othmar
O
Shawcross
Deborah
D
Zoller
Heinz
H
Alisa
Akeel
A
Mookerjee
Rajeshwar P
RP
Graziadei
Ivo
I
Datz
Christian
C
Trauner
Michael
M
Schuppan
Detlef
D
Obrist
Peter
P
Vogel
Wolfgang
W
Williams
Roger
R
D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage*; D006519:Hepatitis, Alcoholic / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000069285:Infliximab; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood / Q000235:genetics; D008099:Liver / Q000473:pathology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D012333:RNA, Messenger / Q000032:analysis; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics
D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000069285:Infliximab