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Triple DMARD treatment in early rheumatoid arthritis modulates synovial T cell activation and plasmablast/plasma cell

Alice M Walsh1, Mihir D Wechalekar2,3, Yanxia Guo1

  • 1Immunology, Janssen Research and Development, LLC., Spring House, Pennsylvania, United States of America.

Plos One
|September 2, 2017
PubMed
Abstract

Insights

Combination therapy for rheumatoid arthritis (RA) impacts gene expression in synovial tissue. Treatment reversed some gene changes, but many persisted, revealing insights into RA biology and drug mechanisms.

Area of Science:

  • Immunology
  • Genomics
  • Rheumatology

Background:

  • Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation.
  • Combination disease-modifying anti-rheumatic drugs (tDMARDs) are clinically effective but their molecular mechanisms remain incompletely understood.
  • Investigating gene expression in synovial tissue offers insights into RA pathogenesis and treatment response.

Purpose of the Study:

  • To explore the genome-wide transcriptional effects of tDMARDs (methotrexate, sulfasalazine, hydroxychloroquine) in early RA synovial tissue.
  • To identify specific biological pathways modulated by tDMARD therapy.
  • To understand the molecular basis of clinical response to combination RA treatment.

Main Methods:

  • Synovial biopsy samples were collected from early RA patients before and after 6 months of tDMARD therapy (n=19).
  • Samples from healthy subjects (n=28) served as controls.
  • Total RNA sequencing was performed on all biopsies to profile gene expression.

Main Results:

  • Over 5000 genes showed differential expression between RA and control synovial tissues.
  • tDMARD treatment reversed the expression of fewer than 300 genes after 6 months.
  • Genes downregulated by tDMARDs were primarily involved in T cell activation and plasmablast/plasma cell differentiation.

Conclusions:

  • Transcriptomic signatures of early RA synovial tissue were identified.
  • tDMARD treatment consistently altered genes related to T cell activation and plasmablast/plasma cell differentiation.
  • These findings offer novel insights into early RA biology, tDMARD mechanisms, and potential new drug targets.

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