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 In 11 patients, anakinra was withdrawn at three months until a flare occurred.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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    ABSTRACT: Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are innate immunity sensors that provide an early/effective response to pathogenic or injury conditions. We have reported that ethanol-induced TLR4 activation triggers signaling inflammatory responses in glial cells, causing neuroinflammation and brain damage. However, it is uncertain if ethanol is able to activate NLRs /inflammasome in astroglial cells, which is the mechanism of activation, and whether there is crosstalk between both immune sensors in glial cells. Here we show that chronic ethanol treatment increases the co-localization of caspase-1 with GFAP+ cells, and up-regulates IL-1β and IL-18 in the frontal medial cortex in WT, but not in TLR4 knock-out mice. We further show that cultured cortical astrocytes expressed several inflammasomes (NLRP3, AIM2, NLRP1 and IPAF), although NLRP3 mRNA is the predominant form. Ethanol, as ATP and LPS treatments, up-regulates NLRP3 expression, and causes caspase-1 cleavage and the release of IL-1β and IL-18 in astrocytes supernatant. Ethanol-induced NLRP3/caspase-1 activation is mediated by mitochondrial (m) ROS generation because when using a specific mitochondria ROS scavenger, the mito-TEMPO (500 M) or NLRP3 blocking peptide (4g/ml) or a specific caspase-1 inhibitor, Z-YVAD-FMK (10 M), abrogates mROS release and reduces the up-regulation of IL-1β and IL-18 induced by ethanol or LPS or ATP. Confocal microscopy studies further confirm that ethanol, ATP or LPS promotes NLRP3/caspase-1 complex recruitment within the mitochondria to promote cell death by caspase-1-mediated pyroptosis, which accounts for ≈ 73 % of total cell death (≈22%) and the remaining (≈25%) die by caspase-3-dependent apoptosis. Suppression of the TLR4 function abrogates most ethanol effects on NLRP3 activation and reduces cell death. These findings suggest that NLRP3 participates, in ethanol-induced neuroinflammation and highlight the NLRP3/TLR4 crosstalk in ethanol-induced brain injury.
    Frontiers in Cellular Neuroscience 08/2014; 8:216. DOI:10.3389/fncel.2014.00216 · 4.29 Impact Factor
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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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    • "The extent of organ damage and permanent disability varies considerably among patients with FCAS, MWS, and CINCAs. Although CAPS are regularly marked by onset of symptoms during early infancy or childhood [59, 60], a case series of patients presenting with adult onset FCAS-like symptoms and carrying the low-penetrance Q703K mutation in the NLRP3 gene has recently been described [61]. Consistent with CAPS pathogenesis, linked to the constitutively increased inflammasome activity and chronic oversecretion of IL-1β, lifelong treatment with IL-1 blocking therapies is the most logical option to control organ disease and damage; different strategies to block IL-1 have been used in clinical trials, all characterized by dramatic success in bringing down episodes of fever, urticaria-like rash, joint pain, and elevations in acute-phase reactants. "
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    ABSTRACT: The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.
    Mediators of Inflammation 07/2014; 2014:948154. DOI:10.1155/2014/948154 · 3.24 Impact Factor
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