212 This model, available on the internet (www.lillemodel.com) may allow identification of patients who remain at high risk to be treated with other interventions. A wealth of evidence suggests that dysregulated Tyrosine Kinase Inhibitor Library clinical trial cytokines, including tumor necrosis factor alpha (TNFα) and a host of downstream cytokines play a pivotal role in the pathophysiology of AH. Thus, several agents have been studied that impact
the immunologic milieu, targeting specific cytokines, and TNFα in particular. Among the first agents to be studied was pentoxifylline, an oral phosphodiesterase inhibitor which also inhibits the production of TNFα, among other cytokines. A randomized placebo controlled clinical trial tested pentoxifylline in 101 patients with clinical evidence of severe AH.213 The in-hospital mortality in the treated ABT-263 patients was 40% lower than in the
placebo arm, with the bulk of the reduction related to a substantially lower likelihood of developing hepatorenal syndrome (HRS). HRS was responsible for 50% of the 12 deaths in the treatment arm, compared to 91.7% of the 24 deaths in the placebo group. Other specific inhibitors of TNF that have been studied include infliximab, a monoclonal chimeric anti-TNF antibody, and etanercept, a fusion protein containing the ligand-binding portion of the human TNF receptor fused to the Fc portion of human immunoglobulin G1.214 In the
first clinical trial of infliximab, 20 patients with biopsy proven alcoholic hepatitis and an MDF score between 32 and 55 (based on the original Maddrey score, which demonstrated an increased mortality at a Idelalisib score > 93) were randomized to either 5 mg/kg of infliximab plus 40 mg/day of prednisone (n = 11) or to prednisone alone.215 No substantial difference in overall mortality was found, but substantial decreases in other prognostic markers, including cytokine levels and MDF scores were seen in patients treated with combination therapy. Another trial, performed at 19 centers in France, randomized 36 patients with biopsy proven alcoholic hepatitis and an MDF ≥ 32 to prednisolone (40 mg/day for 4 weeks), versus prednisolone along with infliximab (10 mg/kg, given at study entry, and again at 2 weeks and 4 weeks after entry).216 The trial was stopped prematurely after seven deaths had occurred in the infliximab group, compared with three in the prednisolone arm. Four of the seven deaths in the infliximab arm were related to infectious etiologies, compared to one in the prednisolone group. The design, and in particular, the dose of infliximab chosen in the study, has been criticized as predisposing to these infections.