Background: Increased circulating pro-inflammatory cytokine levels correlate with mortality in severe alcohol-associated hepatitis (AH), but their kinetics during disease progression or response to treatment remain unexplored. Objective: We longitudinally assessed circulating biomarkers in a severe AH cohort enrolled in a multicenter, double-blind clinical trial. Design: Eighty-nine patients with severe AH (MELD≥20) from 4 US sites were randomly assigned to treatment with IL-1receptor antagonist (IL-1Ra) + pentoxifylline + zinc (anakinra: 47) or methylprednisolone + placebo (steroid: 42). Plasma levels of 43 indicators of AH pathology (inflammation, bacterial translocation, liver regeneration, tissue remodeling, and cell-activation) were assessed on days 0, 7, 28, 90 and 180 after enrollment, and in 27 healthy controls. Results: Baseline characteristics and cytokine levels were similar between treatment groups but significantly different compared to healthy controls. Consistent with anakinra administration, day 7 IL-1Ra levels were significantly increased in the anakinra group accompanied by elevated levels of several other cytokines. IL-1β levels were increased in the steroid group on day 28. Strong correlations were observed between IL-1α and IL-17A as well as IL-1β and IL-13 both prior to and during treatment. Although the dysregulated biomarkers demonstrated improving trends in survivors, most did not normalize by day 180. Markers associated with 90-day mortality were distinct between the treatment groups with few exceptions (IL-13—absolute level; Sonic hedgehog and sTNFR-1—level change). Conclusions: Circulating cytokine and immune biomarkers dynamically change in AH during treatment, disease progression and/or resolution. Our results highlight the importance of treatment-specific biomarkers in future clinical trials.
Tornai et al. (Fri,) studied this question.