Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy

Arndt H Brachat, Alexei A Grom, Nico Wulffraat, Hermine I Brunner, Pierre Quartier, Riva Brik, Liza McCann, Huri Ozdogan, Lidia Rutkowska-Sak, Rayfel Schneider, Valeria Gerloni, Liora Harel, Maria Terreri, Kristin Houghton, Rik Joos, Daniel Kingsbury, Jorge M Lopez-Benitez, Stephan Bek, Martin Schumacher, Marie-Anne ValentinHermann Gram, Ken Abrams, Alberto Martini, Daniel J Lovell, Nanguneri R Nirmala, Nicolino Ruperto, Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG)

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Canakinumab is a human anti-interleukin-1β (IL-1β) monoclonal antibody neutralizing IL-1β-mediated pathways. We sought to characterize the molecular response to canakinumab and evaluate potential markers of response using samples from two pivotal trials in systemic juvenile idiopathic arthritis (SJIA).

METHODS: Gene expression was measured in patients with febrile SJIA and in matched healthy controls by Affymetrix DNA microarrays. Transcriptional response was assessed by gene expression changes from baseline to day 3 using adapted JIA American College of Rheumatology (aACR) response criteria (50 aACR JIA). Changes in pro-inflammatory cytokines IL-6 and IL-18 were assessed up to day 197.

RESULTS: Microarray analysis identified 984 probe sets differentially expressed (≥2-fold difference; P < 0.05) in patients versus controls. Over 50% of patients with ≥50 aACR JIA were recognizable by baseline expression values. Analysis of gene expression profiles from patients achieving ≥50 aACR JIA response at day 15 identified 102 probe sets differentially expressed upon treatment (≥2-fold difference; P < 0.05) on day 3 versus baseline, including IL-1β, IL-1 receptors (IL1-R1 and IL1-R2), IL-1 receptor accessory protein (IL1-RAP), and IL-6. The strongest clinical response was observed in patients with higher baseline expression of dysregulated genes and a strong transcriptional response on day 3. IL-6 declined by day 3 (≥8-fold decline; P < 0.0001) and remained suppressed. IL-18 declined on day 57 (≥1.5-fold decline, P ≤ 0.002).

CONCLUSIONS: Treatment with canakinumab in SJIA patients resulted in downregulation of innate immune response genes and reductions in IL-6 and clinical symptoms. Additional research is needed to investigate potential differences in the disease mechanisms in patients with heterogeneous gene transcription profiles.

TRIAL REGISTRATION: Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.

Original languageEnglish
Pages (from-to)13
JournalArthritis Research and Therapy
Volume19
Issue number1
DOIs
Publication statusPublished - Jan 23 2017

Keywords

  • Adolescent
  • Antibodies, Monoclonal
  • Arthritis, Juvenile
  • Child
  • Child, Preschool
  • Down-Regulation
  • Female
  • Gene Expression Profiling
  • Humans
  • Immunoassay
  • Interleukin-18
  • Interleukin-6
  • Male
  • Oligonucleotide Array Sequence Analysis
  • Transcriptome
  • Young Adult
  • Clinical Trial, Phase III
  • Journal Article
  • Randomized Controlled Trial

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