Characterization of genetic landscape and novel inflammatory biomarkers in patients with adult‐onset Still's disease

Objective Adult‐onset Still disease (AOSD) is a systemic autoinflammatory disorder (AID) of unknown etiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large cohort with AOSD to investigate the underlying pathology and identify novel targets for potential treatment. Methods We investigated AOSD cases (n = 60) for rare germline and somatic variants using whole exome sequencing with virtual gene panels. Transcriptome profiles were investigated by bulk RNA sequencing whole blood. Cytokine profiling was performed on an extended patient cohort (n = 106) alongside measurements of NLRP3 inflammasome activation using a custom assay and type I interferon (IFN) score using a novel method. Results We observed higher than expected frequencies of rare germline variants associated with monogenic AIDs in AOSD cases (AOSD 38.4% vs healthy controls [HCs] 20.4%) and earlier onset of putative somatic variants associated with clonal hematopoiesis of indeterminate potential. Transcriptome profiling revealed a positive correlation between Still Activity Score and gene expression associated with the innate immune system. ASC/ NLRP3 specks levels and type I IFN scores were significantly elevated in AOSD cases compared with HCs ( P = 0.0001 and 0.0015, respectively), in addition to several cytokines: interleukin (IL)‐6 ( P < 0.0001), IL‐10 ( P < 0.0075), IL‐12p70 ( P = 0.0005), IL‐18 ( P < 0.0001), IL‐23 ( P < 0.0001), IFN‐α2 ( P = 0.0009), and IFNγ ( P = 0.0002). Conclusion Our study shows considerable genetic complexity within AOSD and demonstrates the potential utility of the ASC/ NLRP3 specks assay for disease stratification and targeted treatment. The enriched genetic variants identified may not by themselves be sufficient to cause disease, but may contribute to a polygenic model for AOSD.