A98: Rescue Treatment by Increased Doses of IL-1 Inhibitors for Macrophage Activation Syndrome in Children With Systemic Juvenile Idiopathic Arthritis.

Background/Purpose: macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (SJIA). More than half cases of MAS are steroid-resistant and required to use second-line agents, such as cyclosporine A (CsA), intravenous immunoglobulin (IVIG) and biologic agents. Known interleukin-1 (IL-1) is the key cytokine in pathogenesis of MAS and SJIA, so anti-IL-1 treatment considered as potential effective treatment. There are several publication about efficacy of increased doses of anakinra during the MAS episodes. Data about efficacy others new IL-1 blockers (canakinumab and rilonacept) for MAS in SJIA are limited. There are only several cases of MAS during and after canakinumab (CNKB) treatment of SJIA in randomized controlled trials. Methods: a retrospective study of the clinical notes, reports of laboratory investigations and radiological images. We included 3 patients with SJIA who developed MAS. First patient (Pt#1) had the severe form of MAS, resistant to high doses of steroids, IVIG, CsA. After failure of previous treatment anakinra was added, and later changed on CNKB. Second patient (Pt#2) developed SJIA flare with severe MAS after 3rd CNKB injection, resistant to high doses steroids, IVIG, required Fresh Frozen Plasma, third patient (Pt#3) developed only mild MAS after 8th CNKB injection without signs of SJIA flare. Indications for increased doses of CNKB were inefficacy of previous anti IL-1 treatment in standard and increased doses and severity of MAS (Pt#1, Pt#2) according the manufacture's manual permitted to use the maximum dose of 300 mg per injection. The initial CNKB dose before MAS was 4 mg/kg every 4 weeks in Pt#2 and Pt#3. All patient during the MAS received one single injection of increased dose of CNKB: 15 mg/kg (Pt#1), 12.5 mg/kg (Pt#2) and 7.5 mg/kg (Pt#3). CNKB was injected every 4 weeks with gradually tapering dose up to 4 mg/kg every 4 weeks. All parents signed the inform consent. Institutional Review Board affirmed this kind of treatment. Results: in Pt#1 initial treatment with standard doses of anakinra was insufficient and dose was increased up to 20 mg/kg/day with good response. Later anakinra was changed on CNKB in 1st dose 15 mg/kg every 4 weeks with gradually tapering dose up to 6 mg/kg up to now. The switching from anakinra to CNKB did not loose the efficacy. In Pt#2 after initiation of increased dose of CNKB the flare of JIA and active MAS was dramatically abrupt up to 7th day after 1st injection. Total normalization of lab tests occurred in 2 weeks. After normalization we tapered corticosteroids. In Pt#3 MAS also quickly disappeared, the normalization of lab test also occurred in 10 days. No side and adverse effects were noticed during using of increased anakinra and CNKB doses. Conclusion: SJIA and MAS are both IL-1- dependent conditions. The SJIA flare and MAS usually associated with increased production of pro-inflammatory cytokines, especially IL-1β. So we suppose that increased levels of IL-1β require increased doses of IL-1 blockers. Our data shows the efficacy and safety of increased doses of IL-1 blockers. It is necessary to provide future trials to evaluate the efficacy and safety increased doses of IL-1 blockers for treatment MAS in SJIA.