title: In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis.
abstract: Steroids improve the outcome in alcoholic hepatitis (AH), but up to 40% of patients fail to respond adequately. Interleukin-2 (IL-2) exacerbates steroid resistance in vitro. We performed a prospective study to determine if intrinsic steroid sensitivity correlates with response to steroids in individuals with severe AH and if IL-2 receptor blockade can reverse this. Peripheral blood mononuclear cells (PBMCs) were isolated from 20 patients with AH and a Maddrey's score >32. Patients were treated with oral prednisolone plus full supportive measures. Clinical resistance to oral steroid treatment was defined as a drop in serum bilirubin of <25% within 7 days or death within 6 months. In vitro steroid resistance was measured in PBMC using the dexamethasone suppression of lymphocyte proliferation assay and repeated after the addition of the anti-IL-2 receptor (anti-CD25) monoclonal antibody, basiliximab. Suppression of lymphocyte proliferation <60% was considered to indicate steroid resistance. In all, 82% (9/11) of in vitro steroid-resistant patients were dead at 6 months as compared to 21% (2/9) of steroid-sensitive patients (P = 0.03). Similarly, 91% (10/11) of in vitro steroid-resistant patients failed to show a significant fall in bilirubin at day 7 as compared to 44% (4/9) of steroid-sensitive patients (P < 0.05). Basiliximab improved the maximal proliferation count in 91% (10/11) of in vitro steroid-resistant patients (P = 0.003).
  
  
  CONCLUSIONS
  Clinical outcome of steroid therapy in this patient cohort correlated with in vitro steroid resistance. IL-2 blockade improved in vitro steroid sensitivity. This suggests that intrinsic lack of steroid sensitivity may contribute to poor clinical response to steroids in severe AH. IL-2 receptor blockade represents a possible mechanism to overcome this.
authors.affiliation: Henry Wellcome Laboratory for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK; Department of Liver Medicine, Bristol Royal Infirmary, Bristol, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: di Mambro
authors.forename: R
authors.initials: R
authors.lastname: Parker
authors.forename: A
authors.initials: A
authors.lastname: McCune
authors.forename: F
authors.initials: F
authors.lastname: Gordon
authors.forename: C M
authors.initials: CM
authors.lastname: Dayan
authors.forename: P
authors.initials: P
authors.lastname: Collins
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000077552:Basiliximab; D001663:Bilirubin / Q000097:blood; D004351:Drug Resistance; D006519:Hepatitis, Alcoholic / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology; D011239:Prednisolone / Q000627:therapeutic use*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab; D011239:Prednisolone; D001663:Bilirubin