Loss of synovial tissue macrophage homeostasis precedes Rheumatoid Arthritis clinical onset.

This study performed an in-depth investigation into the myeloid cellular landscape in the synovium of Rheumatoid Arthritis (RA) patients, ‘individuals-at-risk’ of RA and healthy controls (HC). Flow-cytometric analysis demonstrated for the first time, the presence of a CD40-expressing CD206+CD163+ macrophage population dominating the inflamed RA synovium, associated with disease-activity and treatment response. RNAseq/metabolic analysis demonstrated that this macrophage population is transcriptionally distinct, displaying unique inflammatory, and tissue-resident gene signatures, has a stable bioenergetic profile, and regulates stromal cell responses. scRNAseq profiling of 67908 RA and HC synovial-tissue cells identified nine transcriptionally distinct macrophage-clusters. IL- 1B+CCL20+ and SPP1+MT2A+ are the principal macrophage clusters in RA synovium, displaying heightened CD40 gene expression, capable of shaping stromal cell responses, and importantly are enriched pre-disease onset. Combined these findings identify the presence of an early pathogenic myeloid signature that shapes the RA joint microenvironment and represents a unique opportunity for early diagnosis and therapeutic intervention.