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Cryopyrinopathies: update on pathogenesis and treatment

Abstract

Cryopyrinopathies are a group of rare autoinflammatory diseases that includes familial cold autoinflammatory syndrome, Muckle–Wells syndrome and chronic infantile neurologic cutaneous articular syndrome (also termed neonatal-onset multisystemic inflammatory disease). These syndromes were initially considered to be distinct disease entities despite some clinical similarities; however, mutations of the same gene have since been found in all three cryopyrinopathies. These diseases, therefore, are not separate but represent a continuum of subphenotypes. The gene in question, CIAS1 (now renamed NLRP3) encodes NALP3 (also known as cryopyrin). NALP3 is an important mediator of inflammation and interleukin 1β processing. New therapies based on biologic agents that specifically target interleukin 1β are currently being developed. These new agents have provided very encouraging results for patients with these long-lasting inflammatory conditions—which used to be considered refractory to treatment. The development of therapeutic options for these cryopyrinopathies illustrates effective translation of basic science to clinical practice and the convergence of human genetics and targeted therapies.

Key Points

  • The autoinflammatory conditions FCAS, MWS and CINCA (NOMID) are autosomal-dominant or sporadic syndromes that represent a continuum of subphenotypes (FCAS is the mildest condition, CINCA/NOMID the most severe)

  • FCAS, MWS and CINCA (NOMID) are caused by mutations of the same gene, CIAS1 (now termed NLRP3), which encodes NALP3, also known as cryopyrin, an important mediator of inflammation and interleukin 1β processing

  • Promising new therapies based on biologic agents that target interleukin 1β, are currently under investigation for the treatment of patients with these cryopyrinopathies

  • Treatment of CINCA (NOMID) is more complex than that of other cryopyrinopathies because patients with CINCA (NOMID) have severe disease and the broadest range of symptoms

  • The potential risk of serious infections during treatment with interleukin 1 antagonists has to be considered, especially in the pediatric population; this risk may be exacerbated by use of high-affinity, long-acting molecules

  • The development of therapeutic options for these cryopyrinopathies illustrates the effective translation of basic science to clinical practice and the convergence of human genetics and targeted therapy

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Figure 1: Skin rash in a patient with cryopyrinopathy.
Figure 2: Overgrowth arthropathy in a patient with CINCA (NOMID).
Figure 3: The NALP3 inflammasome.

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Acknowledgements

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Neven, B., Prieur, AM. & dit Maire, P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Rev Rheumatol 4, 481–489 (2008). https://doi.org/10.1038/ncprheum0874

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