OP0013 LOSS OF SYNOVIAL TISSUE MACROPHAGE HOMEOSTASIS PRECEDES RHEUMATOID ARTHRITIS CLINICAL ONSET

Background Synovial tissue macrophages significantly contribute to Rheumatoid Arthritis, yet the precise nature/function of macrophage subsets within inflamed joint remains unexplored. Objectives To fully explore spectrum distinct activation states residing synovium RA, at risk and healthy individuals. Methods Single-cell synovial suspensions from RA (n=44), IAR (n=5), HC (n=11), PsA (n=11) OA (n=4) were obtained, examined by advanced multiparameter flow cytometric analysis, bulk RNA-sequencing, metabolic functional assays. Results Multidimensional analysis identifies enrichment CD206+CD163+ synovial-tissue co-expressing CD40 in compared synovial-tissue, with frequency CD206+CD163+CD40+ associated increased disease activity treatment response. In contrast, CX3CR1-expressing which form a protective barrier are depleted RA. Importantly this signature enriched expression coupled CX3CR1 is an early phenomenon, occurring prior clinical manifestation individuals ‘at-risk’ (IAR). RNAseq profiling sorted synovial-macrophages identified that population transcriptionally distinct, displaying unique inflammatory, phagocytic tissue-resident gene signatures, paralleled bioenergetically stable profile as indicated NAD(P)H emission. Functionally potent producers pro-inflammatory mediators (reversed CD40-signalling inhibition) induce invasive phenotype synovial-fibroblasts. These findings identify pathogenic involved shaping immune response Crucially, present pre-disease representing opportunity for diagnosis therapeutic intervention. Conclusion We have novel transcriptionally/metabolically capable contributing pathology. Uncovering molecular patterns cues transform immunoregulatory into dysfunctional inflammatory state may provide opportunities reinstate homeostasis patients. Disclosure Interests Megan Hanlon: None declared, Mary Canavan: Nuno Neto: Qingxuan Song Employee of: Janssen Pharmaceuticals, Phil Gallagher: Ronan Mullan: Conor Hurson: Barry Moran: Michael Monaghan: Sunil Nagpal Douglas Veale Consultant Janssen, Eli Lilly, Pfizer, Ursula Fearon Pfizer