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.


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 ( 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*


  • Antirheumatic Agents
  • Interferons