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

Lewis, M. J. et al. (2019) Molecular portraits of early rheumatoid arthritis identify clinical and treatment response phenotypes. Cell Reports, 28(9), 2455-2470.e5. (doi: 10.1016/j.celrep.2019.07.091) (PMID:31461658) (PMCID:PMC6718830)

Abstract

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.

• Item Type: Articles
• Additional Information: The PEAC was supported by funding from the UK Medical Research Council (MRC) (grant number G0800648). Core work associated with this project was supported by grants from Arthritis Research UK (Experimental Arthritis Treatment Centre, grant number 20022) and Barts and The London School of Medicine and Dentistry charity (grant number 523/819) and from Genentech, MRC, and Arthritis Research UK (ARUK) by their joint funding of Maximizing Therapeutic Utility in Rheumatoid Arthritis (MATURA) (grant numbers MR/K015346/1 and 20670 respectively). The project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure (grant number MR/L016311/1). This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham.
• Keywords: PEAC, Pathobiology of Early Arthritis Cohort study, RNA sequencing, ectopic lymphoid structures, lymphoid neogenesis, personalized medicine, rheumatoid arthritis, synovial biopsy, transcriptomics.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McInnes, Professor Iain
• Authors: Lewis, M. J., Barnes, M. R., Blighe, K., Goldmann, K., Rana, S., Hackney, J. A., Ramamoorthi, N., John, C. R., Watson, D. S., Kummerfeld, S. K., 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, I. B., Buckley, C. D., Choy, E., Taylor, P. C., Townsend, M. J., and Pitzalis, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Cell Reports
• Publisher: Elsevier
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Published Online: 27 August 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Cell Reports 28(9):2455-2470.e5
• Publisher Policy: Reproduced under a Creative Commons License