Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response Phenotypes
Lewis MJ., Barnes MR., Blighe K., Goldmann K., Rana S., Hackney JA., Ramamoorthi N., John CR., Watson DS., Kummerfeld SK., Hands R., Riahi S., Rocher-Ros V., Rivellese F., Humby F., Kelly S., Bombardieri M., Ng N., DiCicco M., van der Heijde D., Landewé R., van der Helm-van Mil A., Cauli A., McInnes IB., Buckley CD., Choy E., Taylor PC., Townsend MJ., Pitzalis C.
© 2019 The Author(s) 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.