DRESS syndrome in patients with drug-induced liver injury: Characteristics and HLA risk factors.

Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) can sometimes occur in patients with drug-induced liver injury (DILI). However, detailed studies of DRESS in patients with DILI from the US are lacking. We investigated the characteristics and HLA risks for DILI who also developed DRESS.

Methods: Patients with definite, highly likely, or probable DILI enrolled into US DILI Network studies between September 2004 and August 2023 were included. DRESS was defined based on modified RegiSCAR criteria. HLA alleles were compared between DILI-DRESS cases and two control groups (DILI with non-DRESS rash [n=244] and DILI without rash [n=1637).

Results: Of 2,121 participants with DILI during the study period, 128 participants had DRESS (6%). The most frequently implicated drugs causing DRESS were trimethoprim/sulfamethoxazole, lamotrigine, phenytoin, allopurinol, and vancomycin. Compared to 1993 DILI patients without DRESS, patients with DILI + DRESS were younger (mean age 42.3 yrs vs 50.6 years), more likely to be Black (26% vs 12%), had shorter latency (median 31 days vs 47 days), higher frequency of rash (100% vs 13%), eosinophilia (55% vs 13%), and fever (76% vs 16%) (P<0.001 for all). Compared to DILI without DRESS, DILI + DRESS had more severe liver injury (severe/fatal: 45% vs 21.5%, p<0.001) and higher overall (15.6% vs 6.3%, P<0.001) and liver-related (9% vs 2.3%, p < 0.001) mortality. HLA A*32:01, HLA B*53:01 and HLA B*58:01 were significantly enriched in DILI-DRESS cases, compared to control groups.

Conclusions: Patients with DILI and DRESS are younger, more likely to be Black, had shorter time to DILI onset with more severe liver injury and higher overall and liver-related mortality. HLA A*32:01, HLA B*53:01 and HLA B*58:01 are risk factors for DILI-DRESS.