Corticosteroids in severe alcohol-related hepatitis: A multicenter randomized clinical trial

Severe alcohol-related hepatitis (AH) has high short-term mortality, and corticosteroid therapy is recommended in the absence of contraindications. However, its benefit in patients with early spontaneous bilirubin improvement remains unknown. We aim at determining whether corticosteroid therapy improves survival compared with placebo in this specific population.

In this multicenter, randomized, placebo-controlled trial conducted in 10 Belgian hospitals (from February 2018 to May 2024), patients aged ≥18 yr with biopsy-proven severe AH and spontaneous bilirubin decline >10% between admission and Day 5-10 were randomized 1:1 to methylprednisolone 32 mg daily or placebo for 28 days. The primary outcome was 90-day survival; other outcomes included 30-day survival and cumulative incidence of infection at 90 days.

We analyzed 69 (49%) of the 140 planned patients (38 corticosteroid, 31 placebo). Baseline characteristics were well balanced. At 90 days, survival was 79% (95% CI 67-93%) vs. 83% (95% CI 70-98%) (hazard ratio 1.19, 95% CI 0.39-3.63, p = 0.76). Eight deaths occurred in the corticosteroid arm vs. five in the placebo arm. At 30 days, survival was 95% vs. 94% (p = 0.83). Cumulative incidence of infection at 90 days was 47% vs. 34% (subdistribution hazard ratio 1.55, 95% CI 0.72-3.34, p = 0.26). Lille score was an independent predictor of 90-day mortality.

In patients with severe AH and early spontaneous bilirubin improvement, corticosteroid therapy was not associated with improved survival, but the underpowered trial cannot exclude a benefit. A short observation period after admission may help identify patients who can be managed without corticosteroids.

Corticosteroid therapy is recommended for patients with severe alcohol-related hepatitis (AH), but whether this benefit extends to those who show early spontaneous improvement in bilirubin after admission was previously unknown. In this multicenter, randomized, placebo-controlled trial, corticosteroid therapy was not associated with improved 90-day or 30-day survival in patients with severe, biopsy-proven AH and a spontaneous bilirubin decline of >10% within 5-10 days of admission. Corticosteroids were associated with a numerically higher, though not statistically significant, risk of infection. These findings are most relevant to hepatologists and other clinicians managing severe AH, and to researchers designing future AH trials, as they identify a subgroup in whom the benefit of corticosteroids is uncertain. They support a risk-stratified approach in which a brief observation period after admission-incorporating bilirubin trend, infection screening, and liver biopsy-may help identify patients with a relatively favorable prognosis who can be spared corticosteroid therapy and its associated risks. However, because the trial was stopped early after enrolling only 69 of the 140 planned patients, it was underpowered, and a modest survival benefit of corticosteroids cannot be excluded. Therefore, these results should not be interpreted as definitive evidence against corticosteroid use in this population. Larger, adequately powered studies are required to validate these findings before informing clinical guidelines or being generalized to broader patient populations.

ClinicalTrials.gov (NCT03160651), EudraCT number: 2016-005136-16.