Single-cell RNA-Seq resolves phenotypically heterogeneous subtypes in systemic juvenile idiopathic arthritis (SJIA)

Systemic juvenile idiopathic arthritis (SJIA) is a clinically heterogenous systemic inflammatory disorder sometimes complicated by macrophage activation syndrome (MAS) and lung disease (LD), which are thought to be driven by IFN signaling. To identify cellular sources and novel gene programs underlying SJIA pathogenesis, we performed the first in-depth single-cell RNA Sequencing (scRNA-Seq) analysis of 21 SJIA, SJIA-LD, and SJIA-MAS patient PBMCs. To define novel heterogenous patient-subtypes associated with shared transcriptional responses and associate these with clinical and diagnostic metadata, we developed the tools UDON and SATAY-UDON. These tools identify hidden patient-subtypes, including a novel Complement and IFN signaling gene program expressed by SJIA-LD monocyte populations, unravel cellular sources of IFN signaling in SJIA-MAS as CD4 T cells and monocytic cell types, and identify a previously unknown role for platelets and S100 proteins as drivers of systemic inflammation. These data provide insights into new potential therapeutic targets for SJIA complications. Single-cell RNA-Seq of PBMCs of 21 pediatric patients with SJIA from each of 4 clinical sub-types (Inactive SJIA, Active SJIA, SJIA-LD, and SJIA-MAS) and 5 age equivalent controls. ***Raw sequencing data is being submitted to dbGAP***