| Summary: | Summary: 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. : 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. Keywords: rheumatoid arthritis, RNA sequencing, personalized medicine, synovial biopsy, ectopic lymphoid structures, lymphoid neogenesis, transcriptomics, Pathobiology of Early Arthritis Cohort study, PEAC
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