Article

Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1β Inhibition

University of North Carolina at Chapel Hill, North Carolina, United States
New England Journal of Medicine (Impact Factor: 54.42). 08/2006; 355(6):581-92. DOI: 10.1056/NEJMoa055137
Source: PubMed

ABSTRACT Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.
We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.
All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.
Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329 [ClinicalTrials.gov].).

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    • "The result is the oversecretion of IL-1␤ responsible for the inflammatory clinical manifestations. Confirming the key role of IL-1␤ in CAPS, these diseases are rapidly brought under control by treatment with IL- 1-blocking agents, either anakinra [9] [10], a soluble IL-1 receptor (rilonacept) [11], or a monoclonal antihuman IL-1␤ (canakinumab) [12] "
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    • "Indeed, in several case reports, colchicine-resistant FMF patients have shown immediate and sustained resolution of symptoms when treated with the IL-1 receptor antagonist, anakinra (Chae et al, 2006; Belkhir et al, 2007; Kuijk et al, 2007; Calligaris et al, 2008; Roldan et al, 2008). The dramatic therapeutic effect of anakinra is better known in another group of autoinflammatory diseases, the cryopyrin-associated periodic syndromes (Hawkins et al, 2003; Hoffman et al, 2004; Goldbach-Mansky et al, 2006). One issue with the treatment of anakinra is that it should be administered daily by subcutaneous injection. "
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    • "Withdrawal of anakinra treatment led to a very rapid regression of symptoms within days. Symptoms were brought under control following re-initiation of anakinra, demonstrating the requirement of daily maintenance with this drug (Goldbach-Mansky et al 2006; Hawkins et al 2006; Maksimovic et al 2008). "
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