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Hereditary Cryopyrin-Associated Periodic Syndromes (Cryopyrinopathies)

By

Apostolos Kontzias

, MD, Stony Brook University School of Medicine

Last full review/revision Mar 2020| Content last modified Mar 2020
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The hereditary cryopyrin-associated periodic syndromes are a group of autosomal dominant autoinflammatory conditions triggered by cold ambient temperatures; they include familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem autoinflammatory disease. Diagnosis is clinical. Treatment is with interleukin-1 beta inhibitors.

Hereditary cryopyrin-associated periodic syndromes (CAPS) represent a spectrum of progressively severe disease.

They are due to

  • Mutations in the gene encoding the protein cryopyrin, which mediates inflammation and interleukin-1 beta (IL-1 beta) processing

Cryopyrin activity is augmented, triggering increased release of IL-1 beta from the NLRP3 inflammasome; the result is inflammation and fever. The lack of a confirmed genetic mutation does not preclude the diagnosis of CAPS because 40% of patients who have neonatal-onset multisystem autoinflammatory disease, 25% who have Muckle-Wells syndrome, and 10% of who have familial cold autoinflammatory syndrome do not have identifiable mutations based on standard genetic testing. Many of these patients exhibit somatic mosaicism, causing their phenotype.

Typically, familial cold autoinflammatory syndrome (FCAS) causes a cold-induced urticarial rash accompanied by fever and sometimes arthralgias. The condition often appears in the first year of life.

Muckle-Wells syndrome (MWS) causes intermittent fevers, urticarial rash, joint pain, and progressive deafness; 25% of patients develop renal amyloidosis.

Neonatal-onset multisystem autoinflammatory disease (NOMID) tends to cause joint and limb deformities, facial deformities, chronic aseptic meningitis, cerebral atrophy, uveitis, papillary edema, delayed development, and amyloidosis, in addition to fever and a migratory urticarial rash. As many as 20% of patients die by age 20 if untreated.

Diagnosis

  • Clinical criteria

Proposed diagnostic criteria for CAPS include increased markers of inflammation and at least 2 of the following:

  • Urticarial-like rash

  • Episodes triggered by cold and/or stress

  • Sensorineural hearing loss

  • Musculoskeletal symptoms, including arthralgias, arthritis, and myalgias

  • Chronic aseptic meningitis

  • Skeletal abnormalities, including epiphyseal overgrowth and frontal bossing

These criteria have a sensitivity of 81% and specificity of 94% (1).

Diagnosis reference

Treatment

  • IL-1 beta inhibitors

Cryopyrin-associated periodic syndromes are treated with anakinra (100 mg subcutaneously once a day), rilonacept (2.2 mg/kg subcutaneously once a week), or canakinumab (150 mg subcutaneously every 8 weeks, or every 4 weeks for refractory cases; 1, 2, 3).

Treatment references

  • 1. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al: Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360(23):2416–2425, 2009. doi: 10.1056/NEJMoa0810787.

  • 2. Sibley CH, Plass N, Snow J, et al: Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: A cohort study to determine three- and five-year outcomes. Arthritis Rheum 64(7):2375–2386, 2012. doi: 10.1002/art.34409.

  • 3. Hoffman HM, Throne ML, Amar NJ, et al: Long-term efficacy and safety profile of rilonacept in the treatment of cryopyrin-associated periodic syndromes: Results of a 72-week open-label extension study. Clin Ther 34(10):2091–2103, 2012. doi: 10.1016/j.clinthera.2012.09.009. Epub 2012 Sep 29.

Drugs Mentioned In This Article

Drug Name Select Trade
ILARIS
ARCALYST
KINERET
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