{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:34:36Z","timestamp":1792607676973,"version":"4.5.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T00:00:00Z","timestamp":1654128000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T00:00:00Z","timestamp":1654128000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Patients with severe alcohol\u2010associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30\u00a0days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180\u2010day survival.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Subjects with a clinical diagnosis of severe AH (Model for End\u2010Stage Liver Disease [MELD] &gt;20, Maddrey discriminant function [MDF] &gt;32) were randomized to receive methylprednisolone (PRED; 28\u00a0days) or a combination of anakinra (14\u00a0days) plus pentoxifylline (28\u00a0days) plus zinc (COMB; 180\u00a0days). The primary endpoint was survival at 180\u00a0days. The study was designed in 2013, initiated in October 2014, and completed in March 2018. Five hundred patients were screened to randomize 104\u00a0subjects with a clinical diagnosis of AH with a MELD score &gt;20. Fifty\u2010three 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\u00a0\u00b1\u00a010.4\u00a0years; 60.6% were males, 92.3% White, and mean MELD 25.7\u00a0\u00b1\u00a03.9. Kaplan\u2010Meier survival estimate at 180 days was 67.9% in COMB and 56% in PRED (HR\u00a0=\u00a00.69; <jats:italic toggle=\"yes\">p<\/jats:italic>\u00a0=\u00a00.3001). Survival curves separated by 90\u00a0days (COMB, 69.8%; PRED, 58.0%; HR\u00a0=\u00a00.69; <jats:italic toggle=\"yes\">p<\/jats:italic>\u00a0=\u00a00.28). Survival at 28\u00a0days was similar between the COMB (83.4%) and PRED groups (81.2%; HR\u00a0=\u00a00.91; <jats:italic toggle=\"yes\">p<\/jats:italic>\u00a0=\u00a00.85). There were no unexpected serious adverse events, and incidence of infection was comparable between groups. MELD 20\u201325 and MELD &gt;26\u00a0strata showed nonsignificant treatment effects in favor of COMB.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32478","type":"journal-article","created":{"date-parts":[[2022,3,27]],"date-time":"2022-03-27T15:28:51Z","timestamp":1648394931000},"page":"1058-1068","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":102,"title":["IL\u20101 receptor antagonist plus pentoxifylline and zinc for severe alcohol\u2010associated hepatitis"],"prefix":"10.1097","volume":"76","author":[{"given":"Gyongyi","family":"Szabo","sequence":"first","affiliation":[{"name":"Department of Medicine,Beth Israel Deaconess Medical Center and Harvard Medical School,Boston,Massachusetts,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9018-7988","authenticated-orcid":false,"given":"Mack","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Texas Southwestern Medical Center,Dallas,Texas,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig J.","family":"McClain","sequence":"additional","affiliation":[{"name":"5170,Department of Medicine,University of Louisville,Louisville,Kentucky,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivasan","family":"Dasarathy","sequence":"additional","affiliation":[{"name":"Center for Microbiome and Human Health,Lerner Research Institute of the Cleveland Clinic,Cleveland,Ohio,USA"},{"name":"Department of Inflammation and Immunity,Lerner Research Institute of the Cleveland Clinic,Cleveland,Ohio,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Barton","sequence":"additional","affiliation":[{"name":"12262,Department of Population and Quantitative Health Sciences,University of Massachusetts Medical School,Worcester,Massachusetts,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur J.","family":"McCullough","sequence":"additional","affiliation":[{"name":"Center for Microbiome and Human Health,Lerner Research Institute of the Cleveland Clinic,Cleveland,Ohio,USA"},{"name":"Department of Inflammation and Immunity,Lerner Research Institute of the Cleveland Clinic,Cleveland,Ohio,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity,Lerner Research Institute of the Cleveland Clinic,Cleveland,Ohio,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimee","family":"Kroll\u2010Desrosiers","sequence":"additional","affiliation":[{"name":"12262,Department of Population and Quantitative Health Sciences,University of Massachusetts Medical School,Worcester,Massachusetts,USA"},{"name":"VA Central Western Massachusetts,Leeds,Massachusetts,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1335-5498","authenticated-orcid":false,"given":"David","family":"Tornai","sequence":"additional","affiliation":[{"name":"Department of Medicine,Beth Israel Deaconess Medical Center and Harvard Medical School,Boston,Massachusetts,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyesung Alice","family":"Min","sequence":"additional","affiliation":[{"name":"12262,Department of Population and Quantitative Health Sciences,University of Massachusetts Medical School,Worcester,Massachusetts,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Radaeva","sequence":"additional","affiliation":[{"name":"8387,National Institute on Alcohol Abuse and Alcoholism,Bethesda,Maryland,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. E. Blair","family":"Holbein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Texas Southwestern Medical Center,Dallas,Texas,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Casey","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Texas Southwestern Medical Center,Dallas,Texas,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Cuthbert","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Texas Southwestern Medical Center,Dallas,Texas,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,6,2]]},"reference":[{"key":"hep32478-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1053\/j.gastro.2016.02.042","article-title":"Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation from the NIAAA Alcoholic Hepatitis Consortia","volume":"150","year":"2016","journal-title":"Gastroenterology"},{"key":"hep32478-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.cgh.2016.08.047","article-title":"Medical management of severe alcoholic hepatitis: expert review from the clinical practice updates Committee of the AGA Institute","volume":"15","year":"2017","journal-title":"Clin Gastroenterol Hepatol"},{"key":"hep32478-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1097\/MCG.0b013e3181fdef1d","article-title":"Clinical characteristics and mortality of hospitalized alcoholic hepatitis patients in the United States","volume":"45","year":"2011","journal-title":"J Clin Gastroenterol"},{"key":"hep32478-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1097\/MCG.0000000000000161","article-title":"Trends in alcoholic hepatitis\u2010related hospitalizations, financial burden, and mortality in the United States","volume":"49","year":"2015","journal-title":"J Clin Gastroenterol"},{"key":"hep32478-bib-0005-20250824","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1002\/hep.27779","article-title":"Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis","volume":"62","year":"2015","journal-title":"Hepatology"},{"key":"hep32478-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"685","DOI":"10.7326\/0003-4819-110-9-685","article-title":"Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial","volume":"110","year":"1989","journal-title":"Ann Intern Med"},{"key":"hep32478-bib-0007-20250824","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1053\/jhep.2001.22172","article-title":"A model to predict survival in patients with end\u2010stage liver disease","volume":"33","year":"2001","journal-title":"Hepatology"},{"key":"hep32478-bib-0008-20250824","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1056\/NEJMoa1412278","article-title":"Prednisolone or pentoxifylline for alcoholic hepatitis","volume":"372","year":"2015","journal-title":"N Engl J Med"},{"key":"hep32478-bib-0009-20250824","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1056\/NEJM199202203260802","article-title":"A randomized trial of prednisolone in patients with severe alcoholic hepatitis","volume":"326","year":"1992","journal-title":"N Engl J Med"},{"key":"hep32478-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1001\/jama.2013.276300","article-title":"Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial","volume":"310","year":"2013","journal-title":"JAMA"},{"key":"hep32478-bib-0011-20250824","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1053\/j.gastro.2016.12.019","article-title":"In patients with severe alcoholic hepatitis, prednisolone increases susceptibility to infection and infection\u2010related mortality, and is associated with high circulating levels of bacterial DNA","volume":"152","year":"2017","journal-title":"Gastroenterology"},{"key":"hep32478-bib-0012-20250824","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1111\/liv.12939","article-title":"Corticosteroids and occurrence of and mortality from infections in severe alcoholic hepatitis: a meta\u2010analysis of randomized trials","volume":"36","year":"2016","journal-title":"Liver Int"},{"key":"hep32478-bib-0013-20250824","doi-asserted-by":"crossref","first-page":"237","DOI":"10.5009\/gnl.2014.8.3.237","article-title":"Host\u2010microbiome interactions in alcoholic liver disease","volume":"8","year":"2014","journal-title":"Gut Liv"},{"key":"hep32478-bib-0014-20250824","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1002\/hep.23009","article-title":"Endotoxemia and gut barrier dysfunction in alcoholic liver disease","volume":"50","year":"2009","journal-title":"Hepatology"},{"key":"hep32478-bib-0015-20250824","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.3748\/wjg.v16.i11.1321","article-title":"Alcoholic liver disease and the gut\u2010liver axis","volume":"16","year":"2010","journal-title":"World J Gastroenterol"},{"key":"hep32478-bib-0016-20250824","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.jhep.2018.10.023","article-title":"Inflammatory pathways in alcoholic steatohepatitis","volume":"70","year":"2019","journal-title":"J Hepatol"},{"key":"hep32478-bib-0017-20250824","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.jhep.2018.10.019","article-title":"Microbiome as a therapeutic target in alcohol\u2010related liver disease","volume":"70","year":"2019","journal-title":"J Hepatol"},{"key":"hep32478-bib-0018-20250824","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1172\/JCI90562","article-title":"Intestinal fungi contribute to development of alcoholic liver disease","volume":"127","year":"2017","journal-title":"J Clin Invest"},{"key":"hep32478-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/j.1530-0277.1990.tb00482.x","article-title":"Plasma tumor necrosis factor alpha predicts decreased long\u2010term survival in severe alcoholic hepatitis","volume":"14","year":"1990","journal-title":"Alcohol Clin Exp Res"},{"key":"hep32478-bib-0020-20250824","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1002\/hep.1840090302","article-title":"Increased tumor necrosis factor production by monocytes in alcoholic hepatitis","volume":"9","year":"1989","journal-title":"Hepatology"},{"key":"hep32478-bib-0021-20250824","doi-asserted-by":"crossref","first-page":"917","DOI":"10.7326\/0003-4819-112-12-917","article-title":"Increased plasma tumor necrosis factor in severe alcoholic hepatitis","volume":"112","year":"1990","journal-title":"Ann Intern Med"},{"key":"hep32478-bib-0022-20250824","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1111\/liv.13430","article-title":"Interleukin\u20101 inhibition facilitates recovery from liver injury and promotes regeneration of hepatocytes in alcoholic hepatitis in mice","volume":"37","year":"2017","journal-title":"Liver Int"},{"key":"hep32478-bib-0023-20250824","doi-asserted-by":"crossref","first-page":"3476","DOI":"10.1172\/JCI60777","article-title":"IL\u20101 receptor antagonist ameliorates inflammasome\u2010dependent alcoholic steatohepatitis in mice","volume":"122","year":"2012","journal-title":"J Clin Invest"},{"key":"hep32478-bib-0024-20250824","doi-asserted-by":"crossref","first-page":"G625","DOI":"10.1152\/ajpgi.00350.2009","article-title":"The role of zinc deficiency in alcohol\u2010induced intestinal barrier dysfunction","volume":"298","year":"2010","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep32478-bib-0025-20250824","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.3748\/wjg.15.1613","article-title":"Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial","volume":"15","year":"2009","journal-title":"World J Gastroenterol"},{"key":"hep32478-bib-0026-20250824","article-title":"Design and rationale of a multicenter defeat alcoholic steatohepatitis trial: (DASH) randomized clinical trial to treat alcohol\u2010associated hepatitis","volume":"96","year":"2020","journal-title":"Contemp Clin Trials"},{"key":"hep32478-bib-0027-20250824","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","article-title":"Research electronic data capture (REDCap)\u2014a metadata\u2010driven methodology and workflow process for providing translational research informatics support","volume":"42","year":"2009","journal-title":"J Biomed Inform"},{"key":"hep32478-bib-0028-20250824","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1002\/hep.21607","article-title":"The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids","volume":"45","year":"2007","journal-title":"Hepatology"},{"key":"hep32478-bib-0029-20250824","first-page":"38","article-title":"CONUT: a tool for controlling nutritional status. First validation in a hospital population","volume":"20","year":"2005","journal-title":"Nutr Hosp"},{"key":"hep32478-bib-0030-20250824","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.jhep.2018.11.005","article-title":"Endpoints and patient stratification in clinical trials for alcoholic hepatitis","volume":"70","year":"2019","journal-title":"J Hepatol"},{"key":"hep32478-bib-0031-20250824","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1002\/hep.29240","article-title":"Main drivers of outcome differ between short term and long term in severe alcoholic hepatitis: a prospective study","volume":"66","year":"2017","journal-title":"Hepatology"},{"key":"hep32478-bib-0032-20250824","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/s41586-019-1742-x","article-title":"Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease","volume":"575","year":"2019","journal-title":"Nature"},{"key":"hep32478-bib-0033-20250824","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1038\/ajg.2014.154","article-title":"Granulocyte colony\u2010stimulating factor in severe alcoholic hepatitis: a randomized pilot study","volume":"109","year":"2014","journal-title":"Am J Gastroenterol"},{"key":"hep32478-bib-0034-20250824","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.jhep.2017.11.017","article-title":"Application of prognostic scores in the STOPAH trial: discriminant function is no longer the optimal scoring system in alcoholic hepatitis","volume":"68","year":"2018","journal-title":"J Hepatol"},{"key":"hep32478-bib-0035-20250824","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1053\/j.gastro.2015.04.044","article-title":"Combining data from liver disease scoring systems better predicts outcomes of patients with alcoholic hepatitis","volume":"149","year":"2015","journal-title":"Gastroenterology"},{"key":"hep32478-bib-0036-20250824","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.jhep.2013.09.011","article-title":"Invasive aspergillosis in patients with severe alcoholic hepatitis","volume":"60","year":"2014","journal-title":"J Hepatol"},{"key":"hep32478-bib-0037-20250824","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1097\/MEG.0b013e3283435d76","article-title":"Prevention of hepatorenal syndrome in patients with cirrhosis and ascites: a pilot randomized control trial between pentoxifylline and placebo","volume":"23","year":"2011","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"hep32478-bib-0038-20250824","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1053\/j.gastro.2015.06.006","article-title":"Comparative effectiveness of pharmacological interventions for severe alcoholic hepatitis: a systematic review and network meta\u2010analysis","volume":"149","year":"2015","journal-title":"Gastroenterology"},{"key":"hep32478-bib-0039-20250824","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1053\/j.gastro.2018.05.011","article-title":"Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo\u2010a meta\u2010analysis of individual data from controlled trials","volume":"155","year":"2018","journal-title":"Gastroenterology"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.32478","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.32478","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.32478","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T23:04:42Z","timestamp":1756076682000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.32478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,2]]},"references-count":39,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.32478","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,2]]},"assertion":[{"value":"2021-10-14","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-10","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}