SAT0486 SERIOUS ADVERSE EVENTS OF TOCILIZUMAB IN CHILDREN WITH RHEUMATIC DISEASES – A REAL-WORLD EXPERIENCE

Abstract

Background Tocilizumab (TCZ) is a humanized monoclonal antibody that blocks interleukin 6. In children, TCZ has been approved for the treatment of systemic-onset and polyarticular course juvenile idiopathic arthritis (JIA), and is used off-label in other treatment refractory inflammatory diseases. Real-world data regarding tolerance of TCZ in children are scarce. Objectives To assess the incidence rate and type of serious adverse events in children treated with TCZ. Methods A single-center retrospective review of all consecutive patients receiving TCZ in the pediatric rheumatology division from 01/2007 to 12/2018 was performed. Inclusion criteria were a diagnosis of inflammatory rheumatic disease and treatment with at least one dose of TCZ. Patients with missing data were excluded. Serious adverse events (SAE) were defined as a life-threatening event and/or an event requiring hospital admission, leading to permanent disability or treatment discontinuation. Results A total of 70 children (39 females) were included. Thirty children had systemic JIA, 25 polyarticular course JIA, 14 systemic inflammatory disorders such as autoinflammatory syndromes and one patient severe refractory idiopathic uveitis. Median age at diagnosis was 4.2 years (IQR 2.0 – 7.3). The majority of children had received prednisone (n=56), and/or at least one biologic agent (n=63) prior to TCZ initiation. At TCZ start, children had a median age of 8.9 years (IQR 4.9 – 12.3) and disease duration of 3.2 years (IQR 0.9 – 7.4). TCZ was initiated at a 2-weekly interval in 44 children, 26 children received TCZ every 4 weeks. Fifty-eight children received concomitantly another immunosuppressive agent (prednisone (n=47) and/or methotrexate (n=20) and/or various other drugs (n=5)). A median of 26 TCZ doses were given per child (IQR 7 – 48), TCZ exposure was 146.8 patient years. Twenty-two SAE were observed in 18 (26%) children (SAE 14.9/100 patient years): 8 severe infusion reactions, 7 serious infections, 3 cutaneous reactions (toxic reaction, cutaneous vasculitis, scleroderma-like skin thickening with fasciitis), two macrophage activation syndromes, and one abnormal hepatic function and severe dizziness each. Infusion reactions occurred most frequently during the first few infusions (median during 4th infusion, IQR 3 – 5). All patients with infusion reactions had either systemic JIA (n=4) or another autoinflammatory disease (n=4). At time of infusion reaction, all children (8/8) had active disease, 7/8 had a concomitant treatment with prednisone and 2/8 additionally with cyclosporine. At last follow up, 35 (50%) children were still on TCZ, the other 35 had discontinued TCZ: 4 for remission, 13 because of inefficacy, 12 because of side effects, 3 because of both inefficacy and side effects, and 3 for other reasons. No death occurred during TCZ treatment; two patients with systemic inflammatory disease, in whom TCZ had been inefficient, died from uncontrollable disease 13 and 15 months after TCZ discontinuation, respectively. Conclusion In this cohort, serious adverse events were observed in a quarter of children with half of them having severe infusion reactions. Higher incidence rates of severe infusion reactions were observed in children with systemic JIA or autoinflammatory diseases. Ongoing careful monitoring of patients treated with TCZ, especially those with important systemic inflammation is required. Disclosure of Interests Florence Aeschlimann: None declared, Andreas Worner: None declared, Richard Mouy Consultant for: Honoraries received by Roche for Tocilizumab trial in children, Carine Wouters Grant/research support from: Grant/research support to Istituto Gaslini from GlaxoSmithKline immune-inflammation: unrestricted grant to study Blau syndrome; Roche: unrestricted rese