title: Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.
abstract: BACKGROUND
  Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1β monoclonal antibody, in two trials.
  
  
  METHODS
  In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA.
  
  
  RESULTS
  At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo.
  
  
  CONCLUSIONS
  These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).
authors.affiliation: Istituto Giannina Gaslini, Pediatria II, Reumatologia, Paediatric Rheumatology International Trials Organisation (PRINTO) Coordinating Center, Genoa, Italy. nicolaruperto@ospedale-gaslini.ge.it
authors.forename: Nicolino
authors.initials: N
authors.lastname: Ruperto
authors.forename: Hermine I
authors.initials: HI
authors.lastname: Brunner
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.forename: Tamás
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authors.lastname: Constantin
authors.forename: Nico
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authors.lastname: Wulffraat
authors.forename: Gerd
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authors.lastname: Horneff
authors.forename: Riva
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authors.lastname: Brik
authors.forename: Liza
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authors.lastname: McCann
authors.forename: Ozgur
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authors.lastname: Kasapcopur
authors.forename: Lidia
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authors.lastname: Rutkowska-Sak
authors.forename: Rayfel
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authors.lastname: Schneider
authors.forename: Yackov
authors.initials: Y
authors.lastname: Berkun
authors.forename: Inmaculada
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authors.lastname: Calvo
authors.forename: Muferet
authors.initials: M
authors.lastname: Erguven
authors.forename: Laurence
authors.initials: L
authors.lastname: Goffin
authors.forename: Michael
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authors.lastname: Hofer
authors.forename: Tilmann
authors.initials: T
authors.lastname: Kallinich
authors.forename: Sheila K
authors.initials: SK
authors.lastname: Oliveira
authors.forename: Yosef
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authors.lastname: Uziel
authors.forename: Stefania
authors.initials: S
authors.lastname: Viola
authors.forename: Kiran
authors.initials: K
authors.lastname: Nistala
authors.forename: Carine
authors.initials: C
authors.lastname: Wouters
authors.forename: Rolando
authors.initials: R
authors.lastname: Cimaz
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Ferrandiz
authors.forename: Berit
authors.initials: B
authors.lastname: Flato
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Gamir
authors.forename: Isabelle
authors.initials: I
authors.lastname: Kone-Paut
authors.forename: Alexei
authors.initials: A
authors.lastname: Grom
authors.forename: Bo
authors.initials: B
authors.lastname: Magnusson
authors.forename: Seza
authors.initials: S
authors.lastname: Ozen
authors.forename: Flavio
authors.initials: F
authors.lastname: Sztajnbok
authors.forename: Karine
authors.initials: K
authors.lastname: Lheritier
authors.forename: Ken
authors.initials: K
authors.lastname: Abrams
authors.forename: Dennis
authors.initials: D
authors.lastname: Kim
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Lovell
mesh_terms: D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001171:Arthritis, Juvenile / Q000150:complications / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007239:Infections / Q000139:chemically induced; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D053208:Kaplan-Meier Estimate; D055501:Macrophage Activation Syndrome / Q000209:etiology; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; D053583:Interleukin-1beta; C541220:canakinumab; D008727:Methotrexate