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. Overall design: Following arthrosopic surgery, single cell suspension of ~15 biopsies per individual were generated. 4 RA and 5 PsA synovial tissue samples were analysed and 4 healthy control synovial tissue samples. Healthy individuals undergoing arthroscopy during anterior cruciate ligament (ACL) reconstruction surgery were included in this study. Healthy subjects were defined as those who had no evidence of any form of arthritis on history or examination and had no cartilage damage or synovitis on knee arthroscopy.