Genomic stratification by expression of HLA-DRB4 alleles identifies differential innate and adaptive immune transcriptional patterns - A strategy to detect predictors of methotrexate response in early rheumatoid arthritis

Clin Immunol. 2016 Oct;171:50-61. doi: 10.1016/j.clim.2016.08.013. Epub 2016 Aug 26.

Abstract

Effective drug selection is the current challenge in rheumatoid arthritis (RA). Treatment failure may follow different pathomechanisms and therefore require investigation of molecularly defined subgroups. In this exploratory study, whole blood transcriptomes of 68 treatment-naïve early RA patients were analyzed before initiating MTX. Subgroups were defined by serologic and genetic markers. Response related signatures were interpreted using reference transcriptomes of various cell types, cytokine stimulated conditions and bone marrow precursors. HLA-DRB4-negative patients exhibited most distinctive transcriptional differences. Preponderance of transcripts associated with phagocytes and bone marrow activation indicated response and transcripts of T- and B-lymphocytes non-response. HLA-DRB4-positive patients were more heterogeneous, but also linked failure to increased adaptive immune response. RT-qPCR confirmed reliable candidate selection and independent samples of responders and non-responders the functional patterning. In summary, genomic stratification identified different molecular pathomechanisms in early RA and preponderance of innate but not adaptive immune activation suggested response to MTX therapy.

Keywords: Genetics; Innate and adaptive immunity; Methotrexate; Response prediction; Rheumatoid arthritis.

MeSH terms

  • Adaptive Immunity / genetics*
  • Adult
  • Aged
  • Alleles
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • Female
  • Genomics
  • HLA-DRB4 Chains / genetics*
  • Humans
  • Immunity, Innate / genetics*
  • Male
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Young Adult

Substances

  • Antirheumatic Agents
  • HLA-DRB4 Chains
  • Methotrexate