Cryopyrin-associated periodic syndrome D59.1

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 13.12.2023

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CAPS; Cryopyrin-associated periodic syndrome

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Cryopyrin-associated periodic syndrome (CAPS) is a rare hereditary autoinflammatory disease characterized clinically by cutaneous (urticarial exanthema) and systemic inflammation of the musculoskeletal system (arthralgias) and the central nervous system. These episodes can be triggered by cold, fatigue and other stressors or spontaneously. CAPS occurs in a less severe variant as familial cold urticaria (familial cold-induced autoinflammatory syndrome [FCAS]).

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Extremely rare. About 80 patients are ill in Germany.

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The syndrome is caused by an autosomal-dominantly inherited gain-of-function mutation (GOF mutations) in the NLRP3 gene (aka CIAS1 gene/Cold-induced autoinflammatory syndrome gene/gene locus: 1q44/>170 mutations are now known). These "gain-of-function" mutations lead to abnormal activation of the NLRP3 inflammasome, as cryopyrin is an important part of the NLRTP3 inflammasome. Furthermore, cryopyrin interacts with other components, activates caspase-1 and leads to an unphysiologically increased release of IL-1β as well as to gasdermin D-dependent pyroptosis. The increased release of interleukin-1 leads to chronic recurrent fever attacks. Urticaria (also papular exanthema) and arthralgias. See also cold urticaria, familial.

Clinical features
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The symptoms within CAPS overlap clinically. Patients may present with features of more than one disease. In a retrospective cohort of 136 CAPS patients with systemic involvement from 16 countries (Levy R et al. 2013), the most common clinical features were fever (84% of cases, often with concurrent constitutional symptoms such as fatigue, malaise, mood disturbances or failure to thrive), urticarial exanthema often underlying neutrophilic dermatitis (Gusdorf L et al. 2018) ( 97% of cases), especially after exposure to cold, and musculoskeletal involvement (myalgia, arthralgia and/or arthritis or, less commonly, joint contracture, patella overgrowth, bone deformity, bone erosion and/or osteolysis - 86% of cases). Less common features included ophthalmologic involvement (conjunctivitis and/or uveitis or less commonly optic nerve atrophy, cataract, glaucoma or visual disturbances), neurosensory hearing loss and neurologic involvement (morning headache, papilledema and/or meningitis or less commonly seizures, hydrocephalus or mental retardation) and AA amyloidosis (4% of cases).

Differential diagnosis
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Most patients with CAPS have a continuous disease course, on-demand treatment is only recommended for patients with low disease activity. Once the diagnosis has been established, patients receive either on-demand treatment (only recommended for low disease activity or seasonal disease) or continuous treatment.

Targeted blockade of interleukin-1 by anakinra, canakinumab, gevokizumab and rilonacept leads to a significant improvement in symptoms.

After 3 months, patients should be examined to determine whether the target has been achieved. Treatment decisions include continuation, dose adjustments, medication changes or strategy changes. Monitoring recommendations and intervals are presented (AIDAI: Autoinflammatory Diseases Activity Index (Piram M et al. 2014); ADDI: Autoinflammatory Disease Damage Index to assess the extent of organ damage ; PGA and PPGA: Global assessment by physician and patient using a visual analog scale.

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In recent years, two further phenotypes of hereditary NLRP3 mutations have been described, autosomal dominant deafness 34 (DFN34) and keratitis fugax hereditaria (KFH), which are characterized exclusively by cochlea- or anterior eye-limited autoinflammation. The cause of these organ limitations is unclear. These phenotypes broaden the clinical and genetic spectrum of NLRP3-associated autoinflammatory diseases.

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  1. Booshehri LM et al (2019) CAPS and NLRP3. J Clin Immunol 39:277-286.
  2. Cordero MD et al. (2018) Gain of function mutation and inflammasome driven diseases in human and mouse models. J Autoimmun 91:13-22.
  3. Gusdorf L et al. (2018) Neutrophilic urticarial dermatosis: A review. Ann Dermatol Venereol 145:735-740.
  4. Levy R et al. (2015) Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry". Annals of the Rheumatic Diseases 74: 2043-2049.
  5. Moltrasio C et al. ( 2022) NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies. Front Immunol 13:1007705.
  6. Piram M et al. (2014) Validation of the auto-inflammatory diseases activity index (AIDAI) for hereditary recurrent fever syndromes. Ann Rheum Dis 73:2168-2173.
  7. Romano M et al. (2022) The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumor necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist. Ann Rheum Dis 81:907-921.


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Last updated on: 13.12.2023