Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis

J Autoimmun. 2019 Jul;101:121-130. doi: 10.1016/j.jaut.2019.04.012. Epub 2019 Apr 26.

Abstract

Despite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFα or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response.

Keywords: CD28; PTPN22; Response prediction; Rheumatoid arthritis; TNFα; Targeted therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / diagnosis
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / genetics*
  • Biomarkers
  • CD28 Antigens / antagonists & inhibitors
  • Female
  • Gene Expression Regulation*
  • Humans
  • Middle Aged
  • Molecular Targeted Therapy* / methods
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors

Substances

  • Biomarkers
  • CD28 Antigens
  • Tumor Necrosis Factor-alpha
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22