title: Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy.
abstract: 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).
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Arndt H
authors.initials: AH
authors.lastname: Brachat
authors.affiliation: Cincinnati Children's Hospital Medical Center, PRCSG, Cincinnati, OH, USA.
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Grom
authors.affiliation: Wilhelmina Kinderziekenhuis, Department of Pediatric Immunology and Rheumatology, Utrecht, Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Wulffraat
authors.affiliation: Cincinnati Children's Hospital Medical Center, PRCSG, Cincinnati, OH, USA.
authors.forename: Hermine I
authors.initials: HI
authors.lastname: Brunner
authors.affiliation: Université Paris-Descartes, IMAGINE Institute, Hôpital Necker-Enfants Malades. Centre de référence national pour les Arthrites Juveniles, Unité d'Immunologie, Hématologie et Rhumatologie Pediatrique, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.affiliation: Rambam Medical Center, Department of Pediatrics B, Haifa, Israel.
authors.forename: Riva
authors.initials: R
authors.lastname: Brik
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
authors.forename: Liza
authors.initials: L
authors.lastname: McCann
authors.affiliation: Cerrahpasa Tip Fakultesi, Ic Hastaliklari ABD, Romatoloji BD, Istanbul, Turkey.
authors.forename: Huri
authors.initials: H
authors.lastname: Ozdogan
authors.affiliation: Institute of Rheumatology, Paediatric Clinic, Warsaw, Poland.
authors.forename: Lidia
authors.initials: L
authors.lastname: Rutkowska-Sak
authors.affiliation: Hospital for Sick Children, Division of Rheumatology, Toronto, ON, Canada.
authors.forename: Rayfel
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Istituto Gaetano Pini, Divisione di Reumatologia, Milano, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Gerloni
authors.affiliation: Schneider Childrens Medical Center, Pediatric Rheumatology Unit, Petach-Tikvah, Israel.
authors.forename: Liora
authors.initials: L
authors.lastname: Harel
authors.affiliation: Universidade Federal de São Paulo, Pediatrics, São Paulo, Brazil.
authors.forename: Maria
authors.initials: M
authors.lastname: Terreri
authors.affiliation: British Columbia Children's Hospital, Vancouver, BC, Canada.
authors.forename: Kristin
authors.initials: K
authors.lastname: Houghton
authors.affiliation: Universitair Ziekenhuis Gent, Centrum Voor Kinderreumatologie, Gent, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Joos
authors.affiliation: Randall Children's Hospital at Legacy Emanuel, Portland, OR, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kingsbury
authors.affiliation: Floating Hospital for Children, Rheumatology NEMC 286, Boston, MA, USA.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Lopez-Benitez
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Bek
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Schumacher
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Valentin
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Hermann
authors.initials: H
authors.lastname: Gram
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Abrams
authors.affiliation: University of Genova and Istituto Giannina Gaslini, Pediatria II-PRINTO, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.affiliation: Cincinnati Children's Hospital Medical Center, PRCSG, Cincinnati, OH, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lovell
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
authors.forename: Nanguneri R
authors.initials: NR
authors.lastname: Nirmala
authors.affiliation: Istituto Giannina Gaslini, Pediatria II-PRINTO, Genoa, Italy. nicolaruperto@gaslini.org.
authors.forename: Nicolino
authors.identifier: 0000-0001-8407-7782
authors.initials: N
authors.lastname: Ruperto
mesh_terms: D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001171:Arthritis, Juvenile / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007118:Immunoassay; D020382:Interleukin-18 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D059467:Transcriptome / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000589760:IL18 protein, human; C508600:IL6 protein, human; D020382:Interleukin-18; D015850:Interleukin-6; C541220:canakinumab
keywords: Biomarkers; Canakinumab; Gene expression; Interleukin-1β; Juvenile idiopathic arthritis; SJIA