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

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

doi:10.1016/j.celrep.2019.07.091

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

Cell Rep. 2019 Aug 27;28(9):2455-2470.e5. doi: 10.1016/j.celrep.2019.07.091.

Authors

Myles J Lewis¹, Michael R Barnes², Kevin Blighe¹, Katriona Goldmann¹, Sharmila Rana³, Jason A Hackney⁴, Nandhini Ramamoorthi⁵, Christopher R John¹, David S Watson⁶, Sarah K Kummerfeld⁴, Rebecca Hands¹, Sudeh Riahi¹, Vidalba Rocher-Ros¹, Felice Rivellese¹, Frances Humby¹, Stephen Kelly¹, Michele Bombardieri¹, Nora Ng¹, Maria DiCicco¹, Désirée van der Heijde⁷, Robert Landewé⁸, Annette van der Helm-van Mil⁷, Alberto Cauli⁹, Iain B McInnes¹⁰, Christopher D Buckley¹¹, Ernest Choy¹², Peter C Taylor¹³, Michael J Townsend¹⁴, Costantino Pitzalis¹⁵

Affiliations

¹ Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
² Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Alan Turing Institute, British Library, London NW1 2DB, UK.
³ Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
⁴ Bioinformatics and Computational Biology, Genentech Research & Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.
⁵ Biomarker Discovery OMNI, Genentech Research & Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.
⁶ Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Alan Turing Institute, British Library, London NW1 2DB, UK; Oxford Internet Institute, University of Oxford, Oxford OX1 3JS, UK.
⁷ Department of Rheumatology, Leiden University Medical Center, the Netherlands.
⁸ Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, the Netherlands.
⁹ Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy.
¹⁰ Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK.
¹¹ Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences and the Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
¹² Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
¹³ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences and the Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
¹⁴ Biomarker Discovery OMNI, Genentech Research & Early Development, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: townsend.michael@gene.com.
¹⁵ Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: c.pitzalis@qmul.ac.uk.

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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Antirheumatic Agents / therapeutic use*
Arthritis, Rheumatoid / genetics
Arthritis, Rheumatoid / metabolism*
Arthritis, Rheumatoid / pathology
Databases, Factual*
Female
Humans
Interferons / blood
Interferons / genetics
Interferons / metabolism
Joints / cytology
Joints / metabolism
Male
Middle Aged
Phenotype*
Software
Transcriptome*

Substances

Antirheumatic Agents
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding