Still病におけるI型インターフェロンシグネチャーと肺疾患、薬剤関連免疫反応、インターフェロン関連経路の遺伝的変異との関連性

To evaluate the relationship between type I interferon (IFN-I) stimulated gene (ISG) expression, Still's disease, and the development of lung disease (LD) and drug-associated immune reactions (DAIR) to IL-1/IL-6 inhibitors.

Whole blood ISG expression was quantified by NanoString array. ISG-28 scores were calculated in consecutive patients with Still's or Still's-like disease. Exome sequencing with family-based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis.

Among 57 patients (32 children, 25 adults), 16 had elevated ISG-28 scores. This group exhibited higher prevalence of LD (0.44 vs. 0.1, p=0.007) and DAIR (0.63 vs. 0.17, p=0.003), and lower IL-6 inhibitor use (0 vs. 0.25, p=0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL-18, or current IL-1 inhibition. The combination of HLA-DRB1*15 with high ISG-28 scores associated with LD and DAIR with high specificity, while absence of both biomarkers had high negative predictive value. Candidate genes from high ISG-28 individuals were enriched in interferon-related pathways, including autophagy, IFN-I production, toll-like receptor signaling, macrophage activation, cytoskeletal organization and responses to stress.

High IFN-I expression correlates with LD and DAIR in Still's disease, linked to rare genetic variation in immune pathways. Combining high ISG-28 with HLA-DRB1*15 significantly improves post-hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN-I directed treatments in Still's disease with IFN-I signature.