Background/Purpose: Cryopyrin-Associated Periodic Syndromes (CAPS) include a group of rare inherited autoinflammatory diseases consisting of Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome and the most severe form, Neonatal-Onset Multisystem Inflammatory Disease (NOMID). Anakinra is an IL-1-receptor antagonist blocking the biologic activity of naturally occurring IL-1 which has been proven effective and safe in the treatment of severe CAPS^1,2. The objective of the present analysis was to describe anakinra dose adjustments in patients with severe CAPS.

Methods: A prospective, open-label, single arm 60-month study of anakinra was conducted at the National Institutes of Health and the main efficacy and safety findings have been reported earlier^1,2. The patients were stratified by age at anakinra treatment initiation: infants/toddlers (<2 years), children (2-11 years), adolescents (12-18 years) and adults (>18 years). The initial starting dose of 1-2 mg/kg/day of anakinra was either maintained or adjusted during the study depending on clinical response. For patients with inadequate clinical response or a disease flare, the dose could be increased by 0.5-1 mg/kg for up to a maximum of 10 mg/kg/day. The dose increases were estimated with a Mixed Model for Repeated Measures (MMRM).. References: ¹Goldbach-Mansky et al. NEJM. 2006;355:581-92. ²Sibley et al. Arthritis Rheum. 2012;64:2375-86.

Results: 43 patients (13 infants/toddlers, 18 children, 12 adolescents/adults) were included in the study and exposed to anakinra: 26 started on doses <1.5 mg/kg/day and 17 on ≥1.5 mg/kg/day. For 90% of the patients enrolled during the first 3 years of the study the starting dose was <1.5 mg/kg/day, while for the majority of the patients enrolled later (68%) the starting dose was ≥1.5 mg/kg/day. During the study, the treatment doses increased and the estimated mean maintenance dose at Month 60 was similar across age groups, ranging from 3.0 to 3.8 mg/kg/day (mean 3.3 mg/kg/day). On average, the dose was increased by 0.5 mg/kg/day for the first time at Month 6 and thereafter at Month 18 and 36. The actual dose range during the study was 0.9-7.6 mg/kg/day, with the highest dose maintained for 15 months followed by a decrease thereafter. The doses were not only increased for preventing disease flares e.g. rash, fever and elevated CRP but also to preserve organ function, e.g. hearing and vision. Comparable numbers of adverse events were reported for low (<3.5 mg/kg/day; total anakinra exposure 128.0 patient years) and high (≥3.5 mg/kg/day; total anakinra exposure 31.9 patient years) doses; 7.9 events per patient year for low doses and 6.8 for high doses. There was no correlation between development of anakinra anti-drug antibodies and dose adjustments.

Conclusion: Anakinra doses were adjusted based on clinical response in order to achieve systemic inflammatory remission and absence of organ inflammation. In one patient doses up to 7.6 mg/kg/day were needed to control CNS inflammation. Dose adjustments were well tolerated with adverse event reporting rates similar in patients on doses <3.5 and ≥3.5mg/kg/day.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dose-adjustment-of-anakinra-kineret-based-on-clinical-response-in-patients-with-severe-cryopyrin-associated-periodic-syndromes/