IL‐1 receptor antagonist plus pentoxifylline and zinc for severe alcohol‐associated hepatitis

Abstract

Background and Aims Patients with severe alcohol‐associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30 days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180‐day survival. Approach and Results Subjects with a clinical diagnosis of severe AH (Model for End‐Stage Liver Disease [MELD] >20, Maddrey discriminant function [MDF] >32) were randomized to receive methylprednisolone (PRED; 28 days) or a combination of anakinra (14 days) plus pentoxifylline (28 days) plus zinc (COMB; 180 days). The primary endpoint was survival at 180 days. The study was designed in 2013, initiated in October 2014, and completed in March 2018. Five hundred patients were screened to randomize 104 subjects with a clinical diagnosis of AH with a MELD score >20. Fifty‐three patients were randomized into the COMB and 50 to the PRED treatment; 1 dropped out of the study before randomization. Mean age was 45.3 ± 10.4 years; 60.6% were males, 92.3% White, and mean MELD 25.7 ± 3.9. Kaplan‐Meier survival estimate at 180 days was 67.9% in COMB and 56% in PRED (HR = 0.69; p = 0.3001). Survival curves separated by 90 days (COMB, 69.8%; PRED, 58.0%; HR = 0.69; p = 0.28). Survival at 28 days was similar between the COMB (83.4%) and PRED groups (81.2%; HR = 0.91; p = 0.85). There were no unexpected serious adverse events, and incidence of infection was comparable between groups. MELD 20–25 and MELD >26 strata showed nonsignificant treatment effects in favor of COMB. Conclusions A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.

We need a new approach to clinical trials in alcohol‐associated hepatitis: Is there a lesson in RECOVERY?

“…In the present edition of Hepatology , Szabo et al report on a RCT consisting of a 28‐day course of methylprednisone or a combination treatment of pentoxifylline, zinc, and anakinra in patients with severe AH. [ 5 ] The combination was intended to address three putative drivers of illness in AH: renal failure, increased gut permeability, and cytokine‐mediated inflammatory injury. The primary endpoint was survival at 6 months.…”

Design of a multicenter randomized clinical trial for treatment of Alcohol-Associated Hepatitis

“…Anakinra is thought to have the potential to ameliorate liver injuries by blocking the IL-1β receptors [ 15 , 23 ]. The recent DASH trial confirmed that together with pentoxifylline and zinc, anakinra produced survival benefits similar to corticosteroids [ 17 ]. We included zinc supplements in the treatment as it is often deficient in patients with ALD [ 24 ].…”

“…This strategy was put to the test in a recent clinical trial. The Defeat Alcoholic Steatohepatitis (DASH) trial was a multicenter randomized controlled trial evaluating the effects of a combination of anakinra, an IL-1β receptor antagonist, pentoxifylline, and zinc vs. methyl-prednisolone on 30 and 90-day mortality in patients with severe AH [ 17 ]. When DASH investigators designed their trial, STOPAH results had not been published.…”

Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives

“…Combined treatment of pentoxifylline and corticosteroid has been examined in patients with AH, based on their different modes of action; however, the combination turned out to be ineffective in improving the survival rate of patients in a large randomized controlled trial [ 122 ]. Likewise, the use of pentoxifylline in combination with Anakinra, an IL-1 receptor antagonist, plus zinc showed similar survival benefits compared to methylprednisolone treatment in patients with severe AH [ 123 ]. Further, another large randomized controlled study (STOPAH) has demonstrated that patients treated with pentoxifylline showed no effect compared to the placebo group in terms of short-term mortality [ 11 ].…”