Tuesday 13 October 2009
Cryopyrinopathies are three disorders, which overlap in their clinical expression, arise from gain-of-function mutations of the gene encoding cryopyrin, an essential component of the inflammasome.
As a result of these mutations, hyperactivation of the inflammasome results in increased caspase-1 generation leading to hypersecretion of IL-1 Another proinflammatory event, activation of IL-6, is mediated via NF-β. The phenotypic differences among the three cryopyrinopathies are related to variation in the biological effects of the 41 known mutations of the cryopyrin gene. The cryopyrinopathies are inherited as autosomal dominants.
Familial Cold Autoinflammatory Syndrome
Familial Cold Autoinflammatory Syndrome (FCAS) is the mildest of the three cryopyrinopathies. Symptoms often develop in childhood and tend to worsen with age. Approximately 150 cases of FCAS have been identified in the United States. Patients tend to live in the mid-southern states, south of winter freezing and north of constant exposure to air conditioning in the summertime. Exposure to cold typically brings on a pruritic, painful rash (9). Conjunctivitis, fever, joint symptoms, fatigue and headache may be part of clinical syndrome. Hearing loss, a more constant feature of the more severe cryopyrinopathies, is rare. Amyloidosis develops in fewer than 5% of patients. Anakinra is the agent of choice in treating FCAS.
Muckle-Wells Syndrome (MWS) is encountered mainly in Europe. Its onset occurs during the first two decades of life. Triggers to inflammatory attacks other than exposure to cold include stress and exercise. In addition to episodes of fever, rash, arthralgias, abdominal pain and conjunctivitis, MWS patients develop progressive sensi-neural sensorineural deafness. As many as 25% of them will be burdened with the nephropathy of amyloidosis. Again, anakinra is the current choice of drug to control the inflammatory attacks. It may also play a role in protecting against amyloid deposition.
Neonatal Onset Multisystem Inflammatory Disease
Neonatal Onset Multisystem Inflammatory Disease (NOMID) bears an alternate complex descriptive name, CINCA (Chronic Infantile Neurological Cutaneous and Articular syndrome). It is the most severe of the cryopyrinopathies (12). Along with fevers, rash, and hearing loss, NOMID patients experience major deforming joint disease, uveitis, chronic meningitis, cerebral atrophy and delayed development. They, too, are susceptible to amyloidosis. Death within the first two decades occurs in 20% of NOMID patients. In addition to anakinra, other therapies that may suppress disease progression include steroids, etanercept, possibly thalidomide, as well as a newly developed humanized anti IL-6 receptor monoclonal antibody.
Aksentijevich I, et al. The clinical continuum of cryopyrinopathies: Novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007 Mar 28;56(4):1273– 1285.
Prieur AM. Quartier dit Maire P Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008 Sep;4(9):481–9. Epub 2008 Jul 29.