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Lewis, Myles J.; Barnes, Michael R.; Blighe, Kevin; Goldmann, Katriona; Rana, Sharmila; Hackney, Jason A.; Ramamoorthi, Nandhini; John, Christopher R.; Watson, David S.; Kummerfeld, Sarah K.; Hands, Rebecca; Riahi, Sudeh; Rocher-Ros, Vidalba; Rivellese, Felice; Humby, Frances; Kelly, Stephen; Bombardieri, Michele; Ng, Nora; DiCicco, Maria; van der Heijde, Désirée; Landewé, Robert; van der Helm-van Mil, Annette; Cauli, Alberto; McInnes, Iain B.; Buckley, Christopher D.; Choy, Ernest; Taylor, Peter C.; Townsend, Michael J.; Pitzalis, Costantino
Cell reports, 08/2019, Volume: 28, Issue: 9Journal Article
There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website (https://peac.hpc.qmul.ac.uk/) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage. Display omitted •Deep phenotyping and RNA-seq of early rheumatoid arthritis individuals pre-treatment•Synovial plasma cell gene expression predicts future progressive joint damage on X-ray•Blood interferon gene signature associates with synovial B and plasma cell infiltration•Interactive website enables RNA-seq and clinical data to be fully explored Lewis et al. use histology and RNA-seq of synovial biopsies from a cohort of early rheumatoid arthritis individuals to identify three histological pathotypes and reveal gene modules associated with disease severity and clinical response.
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