title: Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement.
abstract: Eighteen Caucasian (white, Middle East and Asian) children diagnosed by paediatric rheumatologists in the UK and France as having systemic juvenile idiopathic arthritis (sJIA) were enrolled in this open label, single dose trial. All patients had evidence of continued symptoms and disease activity for at least three months while receiving >0.2 mg/kg/day of prednisolone, or its equivalent, prior to recruitment. Twelve patients also received methotrexate (< or =20 mg/m2/week). The patients were divided into three groups receiving 2, 4 or 8 mg/kg of MRA (tocilizumab) by intravenous infusion. No evidence of dose-limiting toxicity was observed and there were no dose-limiting safety issues. MRA appeared to be dramatically effective, with clinical and laboratory responses observed by 48 h post infusion, and these improvements continued well after serum MRA was undetectable. Eleven patients achieved the JIA definition of improvement (at least 3 of 6 core set criteria with a 30% improvement and no more than one worsened by 30%) and eight achieved > or =50% improvement. There were no observable differences with age. Clinical improvement in these children was observed for up to eight weeks, supporting the hypothesis that IL-6 is a key cytokine in the upregulation of genes crucial in the inflammation processes of sJIA, and the possibility of sequestration of MRA in the extra-vascular compartment needs to be considered.
authors.affiliation: Great Ormond Street Hospital, NHS Trust, London, UK. patricia.woo@ucl.ac.uk
authors.forename: Patricia
authors.initials: P
authors.lastname: Woo
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wilkinson
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Prieur
authors.forename: Taunton
authors.initials: T
authors.lastname: Southwood
authors.forename: Valentina
authors.initials: V
authors.lastname: Leone
authors.forename: Polly
authors.initials: P
authors.lastname: Livermore
authors.forename: Helena
authors.initials: H
authors.lastname: Wythe
authors.forename: David
authors.initials: D
authors.lastname: Thomson
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
mesh_terms: D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000097:blood / Q000627:therapeutic use*; D001171:Arthritis, Juvenile / Q000188:drug therapy* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007596:Joints / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D019947:Receptors, Interleukin-6; C502936:tocilizumab