A Polygenic Model for Still's Disease Save

Adult-onset Still's disease (AOSD) is systemic autoinflammatory disorder of unknown etiology.  It is considered among the febrile autoinflammatory etiologies. Now a cohort study shows that AOSD patients may be enriched in germline variants usually limited to monogenic autoinflammatory disorders.

Researchers studied 60 AOSD cases for rare germline and somatic variants using whole exome sequencing with virtual gene panels. Transcriptome profiles, cytokine profiling and measurements of NLRP3 inflammasome activity and Type I Interferon (IFN) scoring were assessed. 

• A higher-than-expected frequencies of rare germline variants seen monogenic autoinflammatory disorders in AOSD cases (AOSD 38.4% vs healthy controls 20.4%).
• Still's activity score (SAS) and innate gene expression were correlated. 
• ASC/NLRP3 specks levels and Type I IFN scores were significantly elevated in AOSD cases compared to healthy controls (p=0.0001)
  • Correlated also with cytokines: 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).

Stills disease is a hyperinflammatory condition of proinflammatory excess (vida infra). This study also shows genetic complexity that may AOSD, suggesting there may be several or many genetic pathways to NLRP3 inflammasome hyperactivity - with many having a clinical phenotype we label as Still's disease. 

It is also that that these genetic variants may contribute to a polygenic model for AOSD.