Molecular portraits of early rheumatoid arthritis identify clinical and treatment response phenotypes

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-naïve patients, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website (http://peac.hpc.qmul.ac.uk/) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in the synovium linked to three distinct pathotypes, which imply the existence of divergent pathogenic pathways/activation states: fibroblastic pauci-immune pathotype; macrophage rich diffuse-myeloid pathotype; and a lympho-myeloid pathotype characterised by infiltration of B/T-lymphocytes and myeloid cells. Pro-myeloid inflammatory synovial gene signatures showed strong association with increased disease activity, and correlated with clinical response to initial DMARD (disease modifying antirheumatic drug) therapy, while plasma cell genes identified a poor prognosis subgroup with progressive structural damage.