title: Canakinumab reverses overexpression of inflammatory response genes in tumour necrosis factor receptor-associated periodic syndrome.
abstract: OBJECTIVE
  To explore whether gene expression profiling can identify a molecular mechanism for the clinical benefit of canakinumab treatment in patents with tumour necrosis factor receptor-associated periodic syndrome (TRAPS).
  
  
  METHODS
  Blood samples were collected from 20 patients with active TRAPS who received canakinumab 150 mg every 4 weeks for 4 months in an open-label proof-of-concept phase II study, and from 20 aged-matched healthy volunteers. Gene expression levels were evaluated in whole blood samples by microarray analysis for arrays passing quality control checks.
  
  
  RESULTS
  Patients with TRAPS exhibited a gene expression signature in blood that differed from that in healthy volunteers. Upon treatment with canakinumab, many genes relevant to disease pathogenesis moved towards levels seen in the healthy volunteers. Canakinumab downregulated the TRAPS-causing gene (TNF super family receptor 1A (TNFRSF1A)), the drug-target gene (interleukin (IL)-1B) and other inflammation-related genes (eg, MAPK14). In addition, several inflammation-related pathways were evident among the differentially expressed genes. Canakinumab treatment reduced neutrophil counts, but the observed expression differences remained after correction for this.
  
  
  CONCLUSIONS
  These gene expression data support a model in which canakinumab produces clinical benefit in TRAPS by increasing neutrophil apoptosis and reducing pro-inflammatory signals resulting from the inhibition of IL-1β. Notably, treatment normalised the overexpression of TNFRSF1A, suggesting that canakinumab has a direct impact on the main pathogenic mechanism in TRAPS.
  
  
  BACKGROUND
  NCT01242813.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Torene
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Nanguneri
authors.initials: N
authors.lastname: Nirmala
authors.affiliation: Amyloid Centre, IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Obici
authors.affiliation: Pediatric Clinic, University of Brescia and Spedali Civili, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cattalini
authors.affiliation: Galway University Hospitals, Galway, Ireland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Tormey
authors.affiliation: G Gaslini Institute, Genova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Caorsi
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Starck-Schwertz
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Letzkus
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hartmann
authors.affiliation: Novartis Pharmaceuticals, East Hanover, New Jersey, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Abrams
authors.affiliation: University College London Medical School, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Lachmann
authors.affiliation: G Gaslini Institute, Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D004334:Drug Administration Schedule; D010505:Familial Mediterranean Fever / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053583:Interleukin-1beta; D018124:Receptors, Tumor Necrosis Factor; C541220:canakinumab
keywords: Cytokines; Fever Syndromes; Inflammation