Examination of HLA-DRB1*15-linked candidate antigens in Still's disease with and without lung disease and features of drug hypersensitivity.

OBJECTIVE: Lung disease in systemic juvenile idiopathic arthritis and adult-onset Still's disease (Still's-LD) is a severe manifestation strongly associated with HLA-DRB1*15 alleles and features of drug hypersensitivity reactions (fDHR), including eosinophilia, non-Still's rashes, and elevated liver function tests. Despite the high morbidity and mortality of these phenomena, pathogenesis remains poorly understood. This study investigates whether Still's-LD and fDHR are associated with pathogenic antigens through hypersensitivity reactions to Aspergillus fumigatus, for which HLA-DRB1*15 is a known risk allele, or drug reaction with eosinophilia and systemic symptoms (DRESS), which is frequently associated with human herpesvirus reactivation. METHODS: Pediatric and adult subjects were drawn from the NIH Still's disease cohort. Subjects with Still's-LD and/or fDHR were identified by chart review. Serum samples were analyzed for anti-Aspergillus fumigatus IgE via ImmunoCap assay and EBV, CMV, and HHV-6 antibodies by Luciferase Immunoprecipitation Systems. Subjects were screened for EBV, CMV and HHV-6 by nucleic acid amplification tests and/or Viral Transcript Usage Sensor (VIRTUS) analysis of whole blood RNAseq data. RESULTS: Fifty-four subjects were included in the study, 11 had LD and fDHR and 8 had fDHR alone. Thirty-three subjects were tested for anti-Aspergillus antibodies and all were negative. Forty-nine subjects were tested for CMV, EBV, and HHV-6 and 2 were positive for EBV, both of whom did not have Still's-LD or fDHR. CONCLUSION: The absence of anti-Aspergillus IgE antibodies and detectable herpesvirus nucleic acids in subjects with Still's-LD and fDHR does not support a mechanistic association with hypersensitivity to Aspergillus fumigatus or with human herpesvirus reactivation.