Current status of understanding the pathogenesis and management of patients with NOMID/CINCA.
ABSTRACT 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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ABSTRACT: Neonatal onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous and articular (CINCA) syndrome is a rare, early-onset autoinflammatory disorder and the most severe form of cryopyrin-associated periodic syndrome, which is associated with overproduction of interleukin (IL)-1β. This is a case report of a 70-day-old boy, who was diagnosed with NOMID/CINCA syndrome and who has been treated with anti-IL-1β monoclonal antibody (canakinumab) since then, despite his early infancy. The patient presented with fever, aseptic meningitis, and rash. The clinical manifestations combined with the elevated acute-phase reactants strengthened the suspicion of the diagnosis of NOMID/CINCA syndrome. Specific immunologic workup revealed high levels of serum amyloid A and IL-6. The clinical diagnosis was confirmed by the detection of a de novo mutation of the CIAS1/NLR3 gene (p.Thr348Met), and canakinumab was started at a dose of 4 mg/kg, higher than the recommended dose for older age. White blood cell, serum amyloid A, C-reactive protein, and IL-6 levels quickly decreased and became normal within a month, and the clinical condition of the patient improved significantly. The infant remains without recurrence of disease or further complications and with satisfactory mental development with anti-IL-1β monoclonal antibody treatment for >2 years. This report indicates the importance of early diagnosis of NOMID/CINCA syndrome and medication with IL-1 blockers as soon as possible for the improvement of the prognosis of cryopyrin-associated periodic syndrome and of a better patient outcome.Pediatrics 10/2014; 134(5). DOI:10.1542/peds.2013-3185 · 5.30 Impact Factor
Article: Neonatal treatment of CINCA syndrome[Show abstract] [Hide abstract]
ABSTRACT: Chronic Infantile Neurological Cutaneous Articular (CINCA) syndrome, also called Neonatal Onset Multisystem Inflammatory Disease (NOMID) is a chronic disease with early onset affecting mainly the central nervous system, bones and joints and may lead to permanent damage. We report two preterm infants with severe CINCA syndrome treated by anti-interleukin-1 in the neonatal period, although, so far, no experience with this treatment in infants younger than three months of age has been reported. A review of the literature was performed with focus on treatment and neonatal features of CINCA syndrome. Two cases suspected to have CINCA syndrome were put on treatment with anakinra in the early neonatal period due to severe clinical presentation. We observed a rapid and persistent decline of clinical signs and systemic inflammation and good drug tolerance. Diagnosis was confirmed in both cases by mutations in the NLRP3/CIAS1-gene coding for cryopyrin. As particular neonatal clinical signs polyhydramnios and endocardial overgrowth are to be mentioned. We strongly suggest that specific treatment targeting interleukin-1 activity should be started early. Being well tolerated, it can be introduced already in neonates presenting clinical signs of severe CINCA syndrome in order to rapidly control inflammation and to prevent life-long disability.Pediatric Rheumatology 12/2014; 12:52. DOI:10.1186/1546-0096-12-52 · 1.62 Impact Factor
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ABSTRACT: There is an expanding role for interleukin (IL)-1 in diseases from gout to cancer. More than any other cytokine family, the IL-1 family is closely linked to innate inflammatory and immune responses. This linkage is because the cytoplasmic segment of all members of the IL-1 family of receptors contains a domain, which is highly homologous to the cytoplasmic domains of all toll-like receptors (TLRs). This domain, termed "toll IL-1 receptor (TIR) domain," signals as does the IL-1 receptors; therefore, inflammation due to the TLR and the IL-1 families is nearly the same. Fundamental responses such as the induction of cyclo-oxygenase type 2, increased surface expression of cellular adhesion molecules and increased gene expression of a broad number of inflammatory molecules characterizes IL-1 signal transduction as it does for TLR agonists. IL-1β is the most studied member of the IL-1 family because of its role in mediating autoinflammatory disease. However, a role for IL-1α in disease is being validated because of the availability of a neutralizing monoclonal antibody to human IL-1α. There are presently three approved therapies for blocking IL-1 activity. Anakinra is a recombinant form of the naturally occurring IL-1 receptor antagonist, which binds to the IL-1 receptor and prevents the binding of IL-1β as well as IL-1α. Rilonacept is a soluble decoy receptor that neutralizes primarily IL-1β but also IL-1α. Canakinumab is a human monoclonal antibody that neutralizes only IL-1β. Thus, a causal or significant contributing role can be established for IL-1β and IL-1α in human disease.