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Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response Phenotypes

2019; Cell Press; Volume: 28; Issue: 9 Linguagem: Inglês

10.1016/j.celrep.2019.07.091

2639-1856

Myles Lewis, Michael R. Barnes, Kevin Blighe, Katriona Goldmann, Sharmila Rana, Jason A. Hackney, Nandhini Ramamoorthi, Christopher R. John, David Watson, Sarah Kummerfeld, Rebecca Hands, Sudeh Riahi, Vidalba Rocher-Ros, Felice Rivellese, Frances Humby, Stephen Kelly, Stefano Bombardieri, Nora Ng, Maria DiCicco, Désirée van der Heijde, Robert Landewé, Annette H M van der Helm–van Mil, Alberto Cauli, Iain B. McInnes, Christopher D. Buckley, Ernest Choy, Peter C. Taylor, Michael J. Townsend, Costantino Pitzalis,

Systemic Lupus Erythematosus Research

Highlights•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 exploredSummaryThere 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.Graphical abstract