Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA

Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Building 10, Room 6D-47B, 10 Center Drive, Bethesda, MD 20892, USA.
Current Rheumatology Reports (Impact Factor: 2.87). 04/2011; 13(2):123-31. DOI: 10.1007/s11926-011-0165-y
Source: PubMed


Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and arthritis (CINCA) syndrome is the most severe clinical phenotype in the spectrum of cryopyrin- (NLRP3/NALP3) associated periodic syndromes (CAPS). The study of patients with NOMID/CINCA has been instrumental in characterizing the extent of organ-specific inflammatory manifestations and damage that can occur with chronic interleukin (IL)-1β overproduction. Mutations in CIAS1/NLRP3 lead to constitutive activation of the "NLRP3 inflammasome," an intracellular platform that processes and secretes increased amounts of IL-1β. The pivotal role of IL-1β in NOMID/CINCA has been demonstrated in several clinical studies using IL-1--blocking agents that lead to rapid resolution of the inflammatory disease manifestations. NOMID/CINCA is a monogenic autoinflammatory syndrome; and the discovery of the role of IL-1 in NOMID has led to the exploration in the role of IL-1 in other disorders including gout and Type II diabetes. The inflammation in NOMID/CINCA is continuous with intermittent flares, and organ manifestations encompus the central nervous system, eye, inner ear, and bones. This review discusses updates on the pathogenesis of NOMID/CAPS, emerging long term-outcome data regarding IL-1--blocking agents that have influenced our considerations for optimal treatment, and a monitoring approach tailored to the patient's disease severity and organ manifestations.

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Available from: Raphaela Goldbach-Mansky
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    • "About 30 to 50% of patients who present CAPS clinical picture, responding impressively to IL-1 blocking agents, are negative for any mutations in the NLRP3 gene. Recent reports have shown the presence of somatic mosaicism in circulating leukocytes and epithelial cells of such “mutation-negative” patients; the extent to which mosaicism in mutation-negative cases can account for CAPS phenotype is a lively field of investigation [64]. "
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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.
    Full-text · Article · Jul 2014 · Mediators of Inflammation
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    • "Thus, genetic testing is necessary for diagnosis of CAPS.2 CAPS is an autosomal dominant disease and the syndrome generally presents in early childhood.3 Clinical findings include urticarial-like rash, periodic fever, inflammation of the central nervous system, meningitis, optic disc swelling, deafness, and arthropathy.3–5 Ocular manifestations of CAPS are not fully understood, although it is known to cause optic disc changes, anterior uveitis, and corneal involvement.4 "
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    ABSTRACT: Cryopyrin-associated periodic syndrome (CAPS) is a group of rare hereditary autoinflammatory diseases caused by mutations of the NLRP3 gene, and leads to excessive production of the proinflammatory cytokine, interleukin-lβ. A 35-year-old male presented with recurrent symptoms of urticarial-like rash, periodic fever, arthralgia, headache, and eye redness. His best-corrected visual acuity was 1.0 OD and 0.9 OS. Slit-lamp examination showed conjunctival and episcleral injection in both eyes. Ophthalmoscopy revealed obvious bilateral optic disc swelling and retinal vascular sheathing around the optic discs. Spectral domain optical coherence tomography also showed obvious optic disc swelling. Steroid and nonsteroidal anti-inflammatory drugs did not improve these symptoms. Genetic testing detected a heterozygous mutation of c.907G>A. Thus, the patient was genetically confirmed with CAPS. Visual acuity did not decrease for 3 years, although the optic discs became white in color. CAPS should therefore be distinguished from other disorders when examining optic disc swelling and/or uveitis patients with urticarial-like rash and periodic fever.
    Full-text · Article · Aug 2013 · Clinical ophthalmology (Auckland, N.Z.)
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    • "Approximately 60% of CINCA/NOMID patients carry heterozygous germline missense mutations in the NLRP3 coding region (mutation-positive patients).7 More than 80 different disease-causing mutations have been reported to date.8 "
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    ABSTRACT: Chronic infantile neurological cutaneous and articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease and is caused by a heterozygous germline gain-of-function mutation in the NLRP3 gene. We recently found a high incidence of NLRP3 somatic mosaicism in apparently mutation-negative CINCA/NOMID patients using subcloning and subsequent capillary DNA sequencing. It is important to rapidly diagnose somatic NLRP3 mosaicism to ensure proper treatment. However, this approach requires large investments of time, cost, and labour that prevent routine genetic diagnosis of low-level somatic NLRP3 mosaicism. We developed a routine pipeline to detect even a low-level allele of NLRP3 with statistical significance using massively parallel DNA sequencing. To address the critical concern of discriminating a low-level allele from sequencing errors, we first constructed error rate maps of 14 polymerase chain reaction products covering the entire coding NLRP3 exons on a Roche 454 GS-FLX sequencer from 50 control samples without mosaicism. Based on these results, we formulated a statistical confidence value for each sequence variation in each strand to discriminate sequencing errors from real genetic variation even in a low-level allele, and thereby detected base substitutions at an allele frequency as low as 1% with 99.9% or higher confidence.
    Full-text · Article · Jan 2012 · DNA Research
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