Blood molecular subtypes to guide precision treatment strategies in systemic juvenile idiopathic arthritis

Systemic juvenile idiopathic arthritis (sJIA) is the most severe subtype of JIA, with a combination of diverse clinical manifestations and a variable clinical course. A comprehensive understanding of molecular signatures at the systems level and the discovery of molecular subtypes are the initial steps toward personalized medicine in sJIA.

A blood transcriptomic dataset was collected from patients with systemic JIA (sJIA) (n = 168), polyarticular JIA (n = 254), oligoarticular JIA (n = 96), enthesitis-related arthritis (n = 40), and healthy controls (n = 220). Gene expression profiles were filtered for differentially expressed genes and unsupervised clustering, gene set enrichment, and network-based centrality analyses. The molecular signatures of three novel sJIA subgroups (designated as C1, C2, and C3) were investigated, focusing on their distinct features and treatment responses.

Neutrophil degranulation and the IL-1 signaling pathway were the shared key processes for the three subgroups. Proinflammatory signals, including TNF, IL-6, TLR, and G-CSF signaling pathways, were identified with variation across the subgroups. C1 was the most inflammatory subset with a high-risk profile for macrophage activation syndrome. The C2 subset had the most activated IL-1 and IL-18 signaling pathways. C2 and C3 have higher levels of interferon-stimulated signatures. In a canakinumab-treated dataset, treatment response was correlated with IL1B expression and NF-κB signaling pathway, and neutrophil activation-associated processes were effectively suppressed in a good responder group. GSK3B and p38 MAPK inhibitors showed a significant counteracting effect on the perturbed gene expression of sJIA.

Neutrophil activation was the key feature in active sJIA. The three molecular subtype scheme enables the formulation of precision medicine strategies in sJIA.