Cryopyrinopathies: update on pathogenesis and treatment

Summary and Introduction


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.


Cryopyrinopathies are autoinflammatory diseases characterized by recurrent bouts of systemic inflammation that involve several tissues, including joints and skin. Unlike autoimmune diseases, autoinflammatory syndromes are not associated with antigen-specific T-cell responses or high titers of autoantibodies, but are related to disorders of the innate immune system.[1] The full list of autoinflammatory syndromes can be seen in Box 1 . Most of the genes associated with the syndromes listed in Box 1 encode proteins that are important mediators of apoptosis, inflammation and cytokine processing. This Review focuses on cryopyrinopathies: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome

(MWS), and chronic infantile neurological cutaneous articular syndrome (CINCA; also known as neonatal-onset multisystemic inflammatory disease, abbreviated to NOMID). These three autoinflammatory syndromes are closely related, both genetically and in terms of clinical symptoms. Clinical characteristics, mechanisms of disease, and new treatment options for these syndromes are discussed in this Review.

Clinical Manifestations

FCAS, MWS and CINCA (NOMID) were originally described as distinct clinical entities despite the fact that their symptoms overlap; patients often present with fever, pseudourticarial skin rash, and joint involvement of varying severity associated with neutrophil-mediated inflammation and an intense acute-phase response. In reality, these three syndromes exist on a continuum of severity; FCAS is the mildest condition, CINCA (NOMID) the most severe, and MWS has an intermediate-severity phenotype.

Clinical characteristics of FCAS, MWS and CINCA (NOMID) are given in Table 1 and detailed below. The skin rash-a key symptom of all three diseases-is usually the first notable manifestation and develops shortly after birth or in early infancy. This rash exhibits the same clinical and histological characteristics regardless of syndrome: it is migratory, maculopapular, urticaria – like and usually nonpruritic. A few patients report a burning sensation. The intensity of the skin rash can vary from patient to patient and with disease activity.

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Cryopyrinopathies: update on pathogenesis and treatment