title: Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.
abstract: BACKGROUND
  Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA.
  
  
  METHODS
  We randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension.
  
  
  RESULTS
  At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range.
  
  
  CONCLUSIONS
  Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).
authors.affiliation: Division of Rheumatology, Department of Medicine, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Pediatrico Bambino Gesù, Rome, Italy. fabrizio.debenedetti@opbg.net
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Benedetti
authors.forename: Hermine I
authors.initials: HI
authors.lastname: Brunner
authors.forename: Nicolino
authors.initials: N
authors.lastname: Ruperto
authors.forename: Andrew
authors.initials: A
authors.lastname: Kenwright
authors.forename: Stephen
authors.initials: S
authors.lastname: Wright
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Calvo
authors.forename: Ruben
authors.initials: R
authors.lastname: Cuttica
authors.forename: Angelo
authors.initials: A
authors.lastname: Ravelli
authors.forename: Rayfel
authors.initials: R
authors.lastname: Schneider
authors.forename: Patricia
authors.initials: P
authors.lastname: Woo
authors.forename: Carine
authors.initials: C
authors.lastname: Wouters
authors.forename: Ricardo
authors.initials: R
authors.lastname: Xavier
authors.forename: Lawrence
authors.initials: L
authors.lastname: Zemel
authors.forename: Eileen
authors.initials: E
authors.lastname: Baildam
authors.forename: Ruben
authors.initials: R
authors.lastname: Burgos-Vargas
authors.forename: Pavla
authors.initials: P
authors.lastname: Dolezalova
authors.forename: Stella M
authors.initials: SM
authors.lastname: Garay
authors.forename: Rosa
authors.initials: R
authors.lastname: Merino
authors.forename: Rik
authors.initials: R
authors.lastname: Joos
authors.forename: Alexei
authors.initials: A
authors.lastname: Grom
authors.forename: Nico
authors.initials: N
authors.lastname: Wulffraat
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Zuber
authors.forename: Francesco
authors.initials: F
authors.lastname: Zulian
authors.forename: Daniel
authors.initials: D
authors.lastname: Lovell
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
mesh_terms: D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D001171:Arthritis, Juvenile / Q000097:blood / 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; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D009503:Neutropenia / Q000139:chemically induced; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D000637:Transaminases / Q000097:blood
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; D019947:Receptors, Interleukin-6; D000637:Transaminases; C502936:tocilizumab; D008727:Methotrexate