Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA
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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.
KeywordsIL-1 Autoinflammatory diseases NOMID CINCA NLRP3 CIAS1 CAPS IL-1Ra Anakinra Neonatal disorder Genetic disease
Dr. Goldbach-Mansky has received grant support from Novartis and Regeneron Pharmaceuticals.
- 1.Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002;71:198–203.PubMedCrossRefGoogle Scholar
- 2.Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002;46:3340–8.PubMedCrossRefGoogle Scholar
- 5.Infevers: an online database for autoinflammatory mutations. Available at http://fmf.igh.cnrs.fr/ISSAID/infevers/index.php. Accessed January 2011.
- 12.Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, et al. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 2010;62:258–67.PubMedCrossRefGoogle Scholar
- 14.Dollfus H, Hafner R, Hofmann HM, Russo RA, Denda L, Gonzales LD, et al. Chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease syndrome: ocular manifestations in a recently recognized chronic inflammatory disease of childhood. Arch Ophthalmol. 2000;118:1386–92.PubMedGoogle Scholar
- 21.Arostegui JI, Lopez S, Pascal M, Clemente D, Aymerich M, Balaguer F, et al. A somatic NLRP3 mutation as a cause of a sporadic case of chronic infantile neurologic, cutaneous, articular syndrome/neonatal-onset multisystem inflammatory disease: novel evidence of the role of low-level mosaicism as the pathophysiologic mechanism underlying mendelian inherited diseases. Arthritis Rheum. 2010;62:1158–66.PubMedCrossRefGoogle Scholar
- 23.Almeida MQ, Tsang KM, Cheadle C, Watkins T, Grivel JC, Nesterova M, et al. Protein kinase A regulates caspase-1 via Ets-1 in bone stromal cell-derived lesions: a link between cyclic AMP and pro-inflammatory pathways in osteoblast progenitors. Hum Mol Genet. 2011;20:165–75.PubMedCrossRefGoogle Scholar
- 30.Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2010 Dec 1 (Epub ahead of print).Google Scholar
- 42.Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008;58:2443–52.PubMedCrossRefGoogle Scholar
- 43.Goldbach-Mansky R, Shroff SD, Wilson M, Snyder C, Plehn S, Barham B, et al. A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum. 2008;58:2432–42.PubMedCrossRefGoogle Scholar
- 45.Anakinra package insert. Available at http://www.kineretrx.com/professional/pi.jsp.
- 46.Rilonacept package insert. Available at http://www.regeneron.com/ARCALYST-fpi.pdf.
- 47.Canakinumab package insert. Available at http://www.pharma.us.novartis.com/products/name/ilaris.jsp.
- 48.Piram M, Frenkel J, Gattorno M, Ozen S, Lachmann HJ, Goldbach-Mansky R et al. A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference. Ann Rheum Dis. 2010.Google Scholar