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 |
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Authors: | Email author" target="_blank">Patricia?WooEmail author Nicholas?Wilkinson Anne-Marie?Prieur Taunton?Southwood Valentina?Leone Polly?Livermore Helena?Wythe David?Thomson Tadamitsu?Kishimoto |
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Institution: | (1) NHS Trust, Great Ormond Street Hospital, London, UK;(2) Hopital Necker Enfants Malades, Paris, France;(3) NHS Trust, University of Birmingham and Birmingham Children's Hospital, Birmingham, UK;(4) Chugai Pharma Europe Ltd, London, UK;(5) Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan |
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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 (≤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 ≥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. |
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