A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis

Abstract

for the Foie-Alcool group of the Association Française pour l'Etude du Foie (AFEF)** Tumor necrosis factor-␣ (TNF-␣) may contribute to the progression of acute alcoholic hepatitis (AAH). The aim of this study was to evaluate the efficacy of an association of infliximab and prednisolone at reducing the 2-month mortality rate among patients with severe AAH. Patients with severe AAH (Maddrey score >32) were randomly assigned to group A receiving intravenous infusions of infliximab (10 mg/kg) in weeks 0, 2, and 4; or group B receiving a placebo at the same times. All patients received prednisolone (40 mg/day) for 28 days. Blood neutrophil functional capacities were monitored over 28 days. After randomization of 36 patients, seven patients from group A and three from group B died within 2 months. The probability of being dead at 2 months was higher (not significant [NS]) in group A (39% ؎ 11%) than in group B (18% ؎ 9%). The study was stopped by the follow-up committee and the sponsor (Assistance Publique-Hôpitaux de Paris). The frequency of severe infections within 2 months was higher in group A than in group B (P < .002). This difference was potentially related to a significantly lower ex vivo stimulation capacity of neutrophils. There were no differences between the two groups in terms of Maddrey scores at any time point. In conclusion, three infusions of 10 mg/kg of infliximab in association with prednisolone may be harmful in patients with severe AAH because of the high prevalence of severe infections.

The Lille model: A new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids

“…Although data on the evolution of liver func-tion at 6 months were available for only a small number of such patients, we observed that approximately half of them still had severe liver insufficiency, with a median Child score of 8.5 (range, [6][7][8][9][10][11][12][13][14] and a median MELD score of 21.5 (range, 12-31) (data not shown). This suggests that, among live non-responders with a Lille score Ն 0.45, only half are no longer at risk of liver-induced death.…”

“…[7][8][9] In patients with DF Ն 32, several RCTs and a recent meta-analysis showed that corticosteroids improve shortterm survival. 1,5,[10][11][12][13][14] However, novel strategies or molecules are required, in light of the fact that approximately 40% of patients die at 6 months. 15 Therefore, improvement in the prediction of mortality in severe AH is warranted.…”

Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome

“…The results of studies using these drugs in patients with AH are conflicting, 14,15 and although there are some data showing benefits from anti-TNF␣ strategies, 16,17 one trial showed increased risk of infection and mortality, which resulted in early trial termination. 18 To reconcile the apparent paradox, we assessed whether neutrophils exist in a primed or fully activated state in patients with different alcoholic liver diseases [alcoholic cirrhosis and AH superimposed on cirrhosis (cirrhosisϩAH)] and studied the association of this with the development of infection and clinical outcome. We hypothesized that full activation is associated with impaired neutrophil responses to ongoing bacterial challenge rendering patients more susceptible to infection.…”

TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model

“…40 However, subsequent clinical trials with higher anti-TNF concentrations failed to have a positive effect in these patients and the studies were terminated. 41 Indeed, a primary challenge will be to achieve specificity and efficacy without having any undesirable effects. Here, cell-specific targeting could be a promising approach to improve the clinical outcome of TNF-driven diseases.…”