Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Peter C. Grayson*, Carmelo Carmona-Rivera, Lijing Xu, Noha Lim, Zhong Gao, Adam L. Asare, Ulrich Specks, John H. Stone, Philip Seo, Robert F. Spiera, Carol A. Langford, Gary S. Hoffman, Cees G. M. Kallenberg, E. William St Clair, Nadia K. Tchao, Steven R. Ytterberg, Deborah J. Phippard, Peter A. Merkel, Mariana J. Kaplan, Paul A. MonachRituximab ANCA-Associated

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

ObjectiveTo discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV.

MethodsThe source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions.

ResultsDifferential expression between responders (n=77) and nonresponders (n=35) was detected in 2,346 transcripts at the baseline visit (P

ConclusionIn AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV.

Original languageEnglish
Pages (from-to)1922-1932
Number of pages11
JournalArthritis & Rheumatology
Volume67
Issue number7
DOIs
Publication statusPublished - Jul-2015

Keywords

  • SMALL-VESSEL VASCULITIS
  • ANCA-ASSOCIATED VASCULITIS
  • WEGENERS-GRANULOMATOSIS
  • TREATMENT RESISTANCE
  • NETTING NEUTROPHILS
  • EXTRACELLULAR TRAPS
  • RELAPSE
  • TRANSCRIPTION
  • PROTEINASE-3
  • PREDICTORS

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