A multifaceted interplay between hemophagocytosis, IL-18 and type I IFN distinguishes Still disease from other autoinflammatory diseases

Abstract

Objectives: The unknown pathophysiology and the lack of specific features for systemic Juvenile Idiopathic arthritis and adult-onset Still disease (collectively Still disease/SD) delays diagnosis and appropriate treatment. The goal of this study was to identify features and mechanisms that distinguish SD from other systemic autoinflammatory diseases (SAID).

Methods: We determined by SomaScan assay the plasma proteomes and by RNAseq the immune cell miRNA and RNA transcriptomes of 372 SAID patients. Proteomic findings were validated by ELISA assays. SD (n=72) and non-SD SAIDs (n=300) were compared to identified distinguishing features of SD. We performed integrated and unbiased analysis of all datasets using Weighted Gene Correlation Network Analysis (WGCNA) to identify feature modules that characterize SD and stratify patients.

Results: Elevated plasma heme oxygenase 1 (HO-1) and IL-18 strongly correlate and characterize SD, but do not associate with general inflammation. SD was characterized by ferroptosis in plasma, type I IFN signaling in monocyte transcriptomes and elevated NK cell miRNA-146a-5p, an IL-18 induced miRNA. Finally, we identified feature modules that distinguish SD from other SAIDs and stratify SD patients into two distinct subgroups not attributable to disease activity or inflammation, but hemophagocytosis.

Conclusions: This unprecedented large omics dataset of SAIDs, revealed that complex interactions between hemophagocytosis, IL-18 and type I IFN signaling characterize SD. Furthermore, two distinct subgroups in SD patients are distinguished by the degree of hemophagocytic activity. Finally, the large proteomics and RNAseq datasets generated in this study can serve as an invaluable resource for the further investigation SD and other SAIDs.