A Review on "IL-1 Receptor Antagonist Plus Pentoxifylline and Zinc for Severe Alcohol-Associated Hepatitis".

Szabo G, Mitchell M, McClain CJ, Dasarathy S, Barton B, McCullough AJ, et al. IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis. Hepatology. 2022; 76: 1058–68. Alcoholic hepatitis (AH) is a stage of alcoholic liver disease (ALD), which typically presents as tender hepatomegaly, insidious onset of jaundice, malaise, and fatigue with features of Systemic Inflammatory Response syndrome (SIRS) following prolonged and heavy alcohol consumption.1Shah NJ, Royer A, John S. Alcoholic Hepatitis. Updated 2022 Jun 11. In: StatPearls Internet. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470217/.Google Scholar,2Lucey M.R. Mathurin P. Morgan T.R. Alcoholic hepatitis.N Engl J Med. 2009; 360: 2758-2769Crossref PubMed Scopus (731) Google Scholar A value of 32 or greater as per by Maddrey's discriminant function (MDF) predicts a mortality of 20–30% within 1 month and 30–40% in 6 months3Maddrey W.C. Boitnott J.K. Bedine M.S. Weber Jr., F.L. Mezey E. White Jr., R.I. Corticosteroid therapy of alcoholic hepatitis.Gastroenterology. 1978; 75: 193-199Abstract Full Text PDF PubMed Google Scholar. Ever since Thursz et al. in 20154Thursz M.R. Richardson P. Allison M. et al.STOPAH TrialPrednisolone or pentoxifylline for alcoholic hepatitis.N Engl J Med. 2015 Apr 23; 372 (PMID: 25901427): 1619-1628https://doi.org/10.1056/NEJMoa1412278Crossref PubMed Scopus (487) Google Scholar reported modest improvement in mortality with the use of corticosteroids, it has been used to reduce the inflammatory damage. As the pathophysiology of the disease implicates pro-inflammatory cytokines IL-beta and TNF-alfa resulting from hepatocyte injury, it becomes natural to investigate the role of anti-interleukin 1 in slowing the progression of the disease. In a recent study, Szabo et al. assessed the superiority of COMB (anakinra, pentoxifylline, and zinc) over PRED (methylprednisolone) in patients with a clinical diagnosis of severe AH (Model for End-Stage Liver Disease [MELD] >20, MDF >32). They were randomized to either receive methylprednisolone for 28 days or a combination of anakinra (14 days) plus pentoxifylline (28 days) plus zinc. After a thorough screening, 104 patients were chosen in which 53 patients were randomized into the COMB and 50 to the PRED treatment. MELD 20–25 and MELD >26 strata showed nonsignificant treatment effects in favor of COMB. The primary endpoint was set to survival at 180 days. Survival at 28 days was similar between the 2 groups. They were no unexpected serious adverse events and a near-comparable incidence of infections was seen. It was concluded that the combination therapy has similar survival benefits compared to corticosteroid therapy in severe AH. Severe alcoholic hepatitis is associated with poor treatment outcomes predominantly due to a limited understanding of the pathophysiology of the disease. As a result, any therapy that is being instituted to reduce the inflammatory damage is proving to be partly beneficial. In their review, Tornai and Szabo5Tornai D. Szabo G. Emerging medical therapies for severe alcoholic hepatitis.Clin Mol Hepatol. 2020 Oct; 26 (Epub 2020 Sep 28. PMID: 32981291; PMCID: PMC7641578): 686-696https://doi.org/10.3350/cmh.2020.0145Crossref PubMed Scopus (12) Google Scholar had previously discussed the emerging medical therapeutics toward this disease. Monoclonal antibodies like anakinra (IL-1 alfa) and canakinumab (IL-1beta) block the IL receptor antibodies and reduce inflammation. Agents like N-acetylcysteine, S-adenosylmethionine, metadoxine, and so on, alleviate the oxidative stress and prevent excessive liver injury. Akriviadis et al. have proven that pentoxifylline improves hepatic and renal functioning in alcoholic hepatitis, albeit short term.6Akriviadis E. Botla R. Briggs W. Han S. Reynolds T. Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.Gastroenterology. 2000; 119: 1637-1648https://doi.org/10.1053/gast.2000.20189Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar After Kim et al.7Kim M.J. Lin W.Q. DUR-928, an endogenous regulatory molecule, exhibits anti-inflammatory and antifibrotic activity in a mouse model of NASH.in: Emerging Trends Conference: Emerging Trends in Non Alcoholic Fatty Liver Disease. 2017Google Scholar established the anti-inflammatory role of sulfated oxysterol (DUR-928) in Non-alcoholic steatohepatitis (NASH) in preclinical models, a trial is currently evaluating the efficacy of DUR-928 in alcoholic hepatitis. Through this study, with the use of anakinra, Szabo et al. have validated the role of IL-1 in the inflammatory cascade. As an anti-inflammatory, anakinra is a better and safer option as compared to tumor necrosis factor (TNF) alfa inhibitors and prednisone. Even though TNF alfa inhibitors are effective in reducing inflammation, the increased risk of infections8Tilg H. Jalan R. Kaser A. et al.Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis.J Hepatol. 2003; 38: 419-425Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar,9Poynard T. Thabut D. Chryssostalis A. Taieb J. Ratziu V. Anti-tumor necrosis factor-alpha therapy in severe alcoholic hepatitis: are large randomized trials still possible?.J Hepatol. 2003; 38: 518-520Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar outweighs the benefit. Hmoud et al.10Hmoud B.S. Patel K. Bataller R. Singal A.K. Corticosteroids and occurrence of and mortality from infections in severe alcoholic hepatitis: a meta-analysis of randomized trials.Liver Int. 2016; 36: 721-728Crossref PubMed Scopus (56) Google Scholar and many other studies have reported an increased risk for infections (bacterial and fungal) in patients taking corticosteroids10Hmoud B.S. Patel K. Bataller R. Singal A.K. Corticosteroids and occurrence of and mortality from infections in severe alcoholic hepatitis: a meta-analysis of randomized trials.Liver Int. 2016; 36: 721-728Crossref PubMed Scopus (56) Google Scholar including this study (10% (PRED) vs. 0% (COMB)). However, in the Indian setting (external validity), the two major reasons which would result in poor compliance toward therapy: (1) cost of anakinra and (2) Parenteral route of administration (SC). Also, as this study revealed nonsuperior outcomes of COMB over PRED (statistically insignificant) for a period over 28 days (as compared to corticosteroids), the rationale of prescribing COMB is weak. There are recent data11Szabo G. Mitchell M. McClain C.J. Dasarathy S. Barton B. McCullough A.J. et al.IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis.Hepatology. 2022; 76: 1058-1068Crossref PubMed Scopus (19) Google Scholar that have revealed that combination therapy of anakinra and zinc sulfate had a significantly lower 90-day survival than those treated with prednisone. Also, there was a higher incidence of acute kidney injury in the anakinra zinc sulfate group as compared to prednisone group.11Szabo G. Mitchell M. McClain C.J. Dasarathy S. Barton B. McCullough A.J. et al.IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis.Hepatology. 2022; 76: 1058-1068Crossref PubMed Scopus (19) Google Scholar The study was underpowered as only 130 patients were involved in randomization. The average BMI in 103 patients was 30.6 ± 8.0 kg/m2 which could have had a confounding effect on the liver injury. Therefore, a liver biopsy would have confirmed the diagnosis as Severe alcoholic hepatitis (SAH). The study should have elaborated on (a) the presence and severity of infection, (b) acute on chronic liver failure, and (c) other organ damage as these parameters play a crucial role in prognosis and outcomes. Lille's score which is utilized to predict corticosteroid responsiveness at day 7 and is not validated for anakinra or pentoxifylline. Also, in patients with Lille's score >0.45 at day 7, steroids were continued for 28 days. It is not clear whether interleukin 1 (IL-1) suppression causes a compensatory increase in other cytokines something which the authors could have elucidated upon through this study. Nevertheless, such studies, which assess combination therapy, need to be conducted as they help understand the disease better and as a result improve management strategies. Only through such efforts will be decipher the entire picture and the best outcomes. Shrihari Anil Anikhindi, Writing of manuscript. Akshay Anil Anikhindi, Writing of manuscript. Prof Ashish Kumar, Editing and review. Prof Anil Arora, Editing and review. None.