Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients

Humby, Frances, Lewis, Myles, Ramamoorthi, Nandhini, Hackney, Jason A., Barnes, Michael R., Bombardieri, Michele, Setiadi, A. Francesca, Kelly, Stephen, Bene, Fabiola, DiCicco, Maria, Riahi, Sudeh, Rocher, Vidalba, Ng, Nora, Lazarou, Ilias, Hands, Rebecca, van der Heijde, Désirée, Landewé, Robert B. M., van der Helm-van Mil, Annette, Cauli, Alberto, McInnes, Iain, Buckley, Christopher Dominic, Choy, Ernest H. ORCID: https://orcid.org/0000-0003-4459-8609, Taylor, Peter C., Townsend, Michael J. and Pitzalis, Costantino 2019. Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients. Annals of the Rheumatic Diseases 78 (6) , pp. 761-772. 10.1136/annrheumdis-2018-214539

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Abstract

Objectives To unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes and treatment response/outcomes longitudinally. Methods 144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) underwent ultrasound-guided synovial biopsy before and 6 months after disease-modifying antirheumatic drug (DMARD) initiation. Synovial biopsies were analysed for cellular (immunohistology) and molecular (NanoString) characteristics and results compared with clinical and imaging outcomes. Differential gene expression analysis and logistic regression were applied to define variables correlating with treatment response and predicting radiographic progression. Results Cellular and molecular analyses of synovial tissue demonstrated for the first time in early RA the presence of three pathology groups: (1) lympho-myeloid dominated by the presence of B cells in addition to myeloid cells; (2) diffuse-myeloid with myeloid lineage predominance but poor in B cells nd (3) pauci-immune characterised by scanty immune cells and prevalent stromal cells. Longitudinal correlation of molecular signatures demonstrated that elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months. Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months. Patients with predominant pauci-immune pathology showed less severe disease activity and radiographic progression. Conclusions We demonstrate at disease presentation, prior to pathology modulation by therapy, the presence of specific cellular/molecular synovial signatures that delineate disease severity/progression and therapeutic response and may pave the way to more precise definition of RA taxonomy, therapeutic targeting and improved outcomes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license.
Publisher:	BMJ Publishing Group
ISSN:	0003-4967
Date of First Compliant Deposit:	3 April 2019
Date of Acceptance:	14 February 2019
Last Modified:	04 May 2023 19:57
URI:	https://orca.cardiff.ac.uk/id/eprint/121372

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