Infliximab and alcoholic hepatitis (2004)

To the Editor: An important non–industry sponsored, randomized, controlled study is reported by Naveau and colleagues in relation to the combined use of infliximab and prednisolone in acute alcoholic hepatitis (AAH).1 However, the adverse outcome described following treatment is not in keeping with the published literature in this area, and can almost entirely be ascribed to the overall study design. Our concerns regarding this study are listed below. AAH is associated with a high risk of infection secondary to immune derangement and increased gut bacterial translocation rates,2 as evidenced by the 23 patients excluded for infection by Naveau et al. Indeed, early randomized trials of prednisolone in AAH demonstrated an infection rate of up to 50% in the placebo arm.3 The authors justify a higher dose of infliximab than normally used in Crohn's disease, suggesting that tumor necrosis factor (TNF)-α levels are higher in AAH. TNF-α levels in AAH are notably variable4-6 dependent on the assay used and the complex interaction between TNF-α with its receptors. Moreover, serious adverse events are more common with 10-mg/kg infliximab treatment in Crohn's trials7 with no additional acute benefit noted with repeated infusions. The philosophy behind targeted therapies like infliximab is to try to reduce adverse effects observed with pan-immunosuppressants, such as corticosteroids. It is clearly evident from the study by Naveau and colleagues that any positive benefit of anti-TNF therapy was lost due to a summation of the increased infection risk of both treatments. Moreover, the debate regarding corticosteroid usage in AAH persists, with limitations of use relating to bleeding, renal function, and recent history of infection, one reason for the high exclusion rate (73 of 109 eligible patients) in this study. Indeed, this positive bias might explain the low mortality rates among the placebo + steroid group compared with higher mortality rates in other AAH steroid treatment comparative trials.8 Differences exist in drug dosage, timing of therapy, and selection of patients. Naveau et al. suggest the “severe status” of their patients explains more frequent infections, albeit, apart from biopsy evidence, no additional data is provided in relation to inflammatory activity (plasma cytokine and C-reactive protein levels or systemic inflammatory response syndrome (SIRS) components). Our published pilot data in patients with AAH (n = 19)6, 9 has demonstrated a significant reduction in the high entry Maddrey and inflammatory indices score (Table 1) following a single 5-mg/kg infliximab infusion given within 72 hours of presentation. Furthermore, we demonstrate significant improvements in hemodynamic and renal function, with a total of 3 septic-related deaths in the 2 studies. As a direct impact of the Naveau study, a large UK multicenter trial of infliximab treatment in AAH has been put on hold indefinitely. However, in accordance with other published literature, we believe anti-TNF therapy administered without corticosteroids at an appropriate dose should be rigorously tested in AAH before its eventual fate is decided. Rajeshwar P Mookerjee*, Herbert Tilg , Roger Williams*, Rajiv Jalan*, * Institute of Hepatology, University College London, London, UK, Department of Gastroenterology and Hepatology, University Hospital Innsbruck, Innsbruck, Austria.