biostudies-literatureSzabo GNIDDK NIH HHSNIAAA NIH HHSNational Institutes of HealthNIAMS NIH HHSNIH HHSNIGMS NIH HHS1058-1068https://www.ebi.ac.uk/biostudies/studies/S-EPMC10062003biostudies-literatureUnknown76(4)<h4>Background and aims</h4>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.<h4>Approach and results</h4>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.<h4>Conclusions</h4>A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.Hepatology (Baltimore, Md.)IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis.PMC10062003P50 AA024333UO1 AA021890RO1 AA028190R21 AR 071046P50 AA024337U01 AA026938U01 AA021902U01AA021901U01 AA021901U01 AA026976U01 AA026933U01 AA026977U01AA026938R01 AA028190UO1 AA026976‐03S1U01AA021890R01 DK113196UO1 AA026933UO1 AA026976UH2 AA026970R21 AR071046R01 GM119174RO1 DK113196U01 AA021890RO1 GM119174U01 AA0218931P50AA024337UO1 AA023902UH3 AA026970McCullough AJMitchell MKroll-Desrosiers ABarton BHolbein MEBRadaeva SSzabo GMin HATornai DCuthbert JNagy LEMcClain CJDasarathy SCasey LfalseIL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis.<h4>Background and aims</h4>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.<h4>Approach and results</h4>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.<h4>Conclusions</h4>A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.2022-01-01T00:00:00Z2022 Oct2026-05-28T20:34:48.11Z2025-04-04T03:00:13.935ZS-EPMC100620033534003210.1002/hep.32478