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

PLoS One. 2017 Sep 1;12(9):e0183928. doi: 10.1371/journal.pone.0183928. eCollection 2017.

Abstract

Objectives: This study sought to investigate the genome-wide transcriptional effects of a combination of disease modifying anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine and hydroxychloroquine) in synovial tissues obtained from early rheumatoid arthritis (RA) patients. While combination DMARD strategies have been investigated for clinical efficacy, very little data exists on the potential molecular mechanism of action. We hypothesized that tDMARD would impact multiple biological pathways, but the specific pathways were unknown.

Methods: Paired synovial biopsy samples from early RA patients before and after 6 months of tDMARD therapy were collected by arthroscopy (n = 19). These biopsies as well as those from subjects with normal synovium (n = 28) were profiled by total RNA sequencing.

Results: Large differences in gene expression between RA and control biopsies (over 5000 genes) were identified. Despite clinical efficacy, the expression of a restricted set of less than 300 genes was reversed after 6 months of treatment. Many genes remained elevated, even in patients who achieved low disease activity. Interestingly, tDMARD downregulated genes included those involved in T cell activation and signaling and plasmablast/plasma cell differentiation and function.

Conclusions: We have identified transcriptomic signatures that characterize synovial tissue from RA patients with early disease. Analysis after 6 months of tDMARD treatment highlight consistent alterations in expression of genes related to T cell activation and plasmablast/plasma cell differentiation. These results provide novel insight into the biology of early RA and the mechanism of tDMARD action and may help identify novel drug targets to improve rates of treatment-induced disease remission.

MeSH terms

  • Adult
  • Aged
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthroscopy
  • Biopsy
  • Case-Control Studies
  • Cell Differentiation
  • Down-Regulation
  • Drug Therapy, Combination
  • Female
  • Humans
  • Hydroxychloroquine / therapeutic use
  • Lymphocyte Activation / drug effects
  • Male
  • Methotrexate / therapeutic use
  • Middle Aged
  • Plasma Cells / cytology
  • Principal Component Analysis
  • Remission Induction
  • Sequence Analysis, RNA
  • Sulfasalazine / therapeutic use
  • Synovial Membrane / drug effects*
  • Synovial Membrane / metabolism
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / drug effects
  • Transcriptome

Substances

  • Antirheumatic Agents
  • Sulfasalazine
  • Hydroxychloroquine
  • Methotrexate

Grant support

This study was supported by funding from Johnson & Johnson. The funder provided support in the form of funding for data generation and salaries for authors [AMW, YG, XY, SN], but did not have any additional role in the study design, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. MDW was supported by a National Health and Medical Research Council of Australia post-graduate scholarship.