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Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients
  1. Frances Humby1,
  2. Myles Lewis1,
  3. Nandhini Ramamoorthi2,
  4. Jason A Hackney3,
  5. Michael R Barnes1,4,
  6. Michele Bombardieri1,
  7. A. Francesca Setiadi2,
  8. Stephen Kelly1,
  9. Fabiola Bene1,
  10. Maria DiCicco1,
  11. Sudeh Riahi1,
  12. Vidalba Rocher1,
  13. Nora Ng1,
  14. Ilias Lazarou1,
  15. Rebecca Hands1,
  16. Désirée van der Heijde5,
  17. Robert B M Landewé6,7,
  18. Annette van der Helm-van Mil5,
  19. Alberto Cauli8,
  20. Iain McInnes9,
  21. Christopher Dominic Buckley10,
  22. Ernest H Choy11,
  23. Peter C Taylor12,
  24. Michael J Townsend2,
  25. Costantino Pitzalis1
  1. 1 Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
  2. 2 Biomarker Discovery OMNI, Genentech Inc, South San Francisco, California, USA
  3. 3 Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, California, USA
  4. 4 Centre for Translational Bioinformatics, William Harvey Research Institute, London, UK
  5. 5 Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
  6. 6 Amsterdam Rheumatology Center, AMC, Amsterdam, Netherlands
  7. 7 Department of Rheumatology, Zuyderland MC, Heerlen, Netherlands
  8. 8 Universita degli Studi di Cagliari, Cagliari, Italy
  9. 9 Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
  10. 10 University of Birmingham, Birmingham, UK
  11. 11 Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
  12. 12 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, Oxford, UK
  1. Correspondence to Professor Costantino Pitzalis, Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK; c.pitzalis{at}qmul.ac.uk; Dr Michael J Townsend, Biomarker Discovery OMNI, Genentech Research and Early Development, South San Francisco, USA; townsend.michael{at}gene.com

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) d iffuse-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.

  • early rheumatoid arthritis
  • synovitis
  • dmards (synthetic)
  • inflammation

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Footnotes

  • MJT and CP are joint senior authors.

  • FH, ML, NR and JAH contributed equally.

  • Handling editor Josef S Smolen

  • Contributors All authors have contributed to different degrees to patients recruitment and or data generation and or data analysis and or writing the manuscript and or revising data and or manuscript.

  • Funding This study was funded by Barts and The London School of Medicine and Dentistry Charity (grant number: 523/819); Arthritis Research UK (http://dx.doi.org/10.13039/501100000341), Experimental Arthritis Treatment Centre Grant n:20; Medical Research Council (http://dx.doi.org/10.13039/501100000265), Pathobiology of Early Arthritis Cohort (PEAC) Grant; Medical Research Council (MRC) and Arthritis Research UK (ARUK) for their joint funding of Maximizing Therapeutic Utility in Rheumatoid Arthritis (MATURA) [grant numbers MR/K015346/1, 20670, respectively].

  • Patient consent for publication Obtained.

  • Ethics approval The study has been approved by London – Dulwich Research Ethics Committee, REC reference: 05/Q0703/198.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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