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: 55.87). 08/2006; 355(6):581-92. DOI: 10.1056/NEJMoa055137
Source: PubMed


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 In 11 patients, anakinra was withdrawn at three months until a flare occurred.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. ( number, NCT00069329 [].).

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    • "NOD-like receptors P3 is activated upon exposure to whole pathogens, but also by a number of host-derived danger signals, which are indicative of not only tissue injury (DAMPs), but also environmental irritants (Schroder and Tschopp, 2010). Mutation of NLRP3 is responsible for rare autoinflammatory diseases, collectively referred to as cryopyrin-associated periodic syndromes (CAPS; Neven et al., 2004; Ting and Davis, 2005; Jha and Ting, 2009), characterized by the hyperactivation of the inflammasome complex and increased IL-1β (Neven et al., 2004; Goldbach-Mansky et al., 2006). In addition, there is emerging evidence for the participation of the NLRP3 inflammasome as a sensor of metabolic stress (i.e., De Nardo and Latz, 2011), demyelination, and it is also involved in some neurodegenerative disorders such as the multiple sclerosis model (Jha et al., 2010) and Alzheimer’s disease (Heneka et al., 2013; Sheedy et al., 2013; Tan et al., 2013). "
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    • "We indeed found that high circulating IL-6 levels are present during active disease. In vivo, neutralization of excessive IL-1β in cryopyrinopathies and in deficiency of interleukin-1 receptor antagonist (DIRA) results in decrease in IL-6 production [10-12]. "
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