Muckle-Wells syndrome (MWS)

Cryopyrin-associated periodic syndromes (CAPS)

• represent a spectrum of CIAS1 gene-mediated autoinflammatory diseases characterized by recurrent systemic inflammation (1) - caused by missense mutations in the cold-induced autoinflammatory syndrome-1-gene (CIAS1), also referred to as NLRP3 or NALP3
• CAPS results from a gain-of-function mutation of the NLRP3 gene coding for cryopyrin, which forms intracellular protein complexes known as inflammasomes (2)
  • defects of the inflammasomes lead to overproduction of interleukin-1, resulting in inflammatory symptoms seen in CAPS.
• clinical spectrum of CAPS varies from mild to severe and includes the syndromes historically described as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)
• in all three phenotypes of CAPS, there is a gain-of-function mutation of the NLRP3 gene (also known as CIAS1), which is located on chromosome 1q44 and codes for cryopyrin
  • note though that as many as 40% of patients with clinical NOMID do not show mutations on this gene, implicating the involvement of other autoinflammatory genes or the involvement of genetic mosaicism (2)
• clinical manifestations of CAPS are a continuum of disease severity with overlapping phenotypic features, but can be separated on the basis of their organ manifestations and the disease triggers
  • FCAS
    • is of the mildest phenotype and was first reported in 1940 (2)
    • characterized by recurrent urticaria, arthralgia, and fever after general exposure to cold, not necessarily by touch
      • mildest form of CAPS, is characterized by recurrent and short-lived episodes of rash, fever, arthralgias, and conjunctivitis that are triggered by exposure to cold
    • symptoms occur early and in many patients within the first 6 months of life
    • most patients have a normal life span, and the development of complications from chronic inflammation such as amyloidosis and hearing loss (HL) is rare
  • MWS
    • MWS is of the intermediate phenotype and was first described in 1962 (2)
    • present with recurrent attacks of rash, fever, arthralgias, and conjunctivitis
    • disease is typically not triggered by exposure to cold
    • develop more severe ocular and central nervous system (CNS) symptoms including uveitis, episcleritis, and headaches
    • hearing loss is described in many patients in their second and third decades of life, and the development of amyloidosis has been reported in up to 30% of patients (1)
  • NOMID
    • the most severe form of CAPS and has the worst prognosis
    • hallmark of NOMID is neonatal onset of cutaneous symptoms along with end-organ damage
      • these include the "triad" of arthropathy, chronic urticaria, and central nervous system (CNS) involvement (2)
    • symptoms typically occur at birth or in early infancy and include rash, fever, and joint inflammation
      • joint manifestations vary in severity, ranging from arthralgias with swelling and effusion to debilitating arthropathy resulting from excessive bony overgrowth occurring in one-third of the patients (1)
      • ocular manifestations are severe and include uveitis, optic atrophy, and blindness
      • CNS involvementcan present as chronic headaches, papilledema, aseptic meningitis, seizures, and cerebral atrophy
• treatment with IL-1 blocking agents such as anakinra, a recombinant IL-1 receptor antagonist, has been very effective in these patients
  • a study assessed the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluated the real-world efficacy and safety of interleukin (IL)-1 inhibitors, primarily canakinumab (3):
    • concluded that:
      • initiation of anti-IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab
      • inflammatory bowel disease (IBD) may develop in CAPS following canakinumab treatment

Reference:

• Ahmadi N, Brewer CC, Zalewski C, King KA, Butman JA, Plass N, Henderson C, Goldbach-Mansky R, Kim HJ. Cryopyrin-associated periodic syndromes: otolaryngologic and audiologic manifestations. Otolaryngol Head Neck Surg. 2011 Aug;145(2):295-302.
• Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011 Feb;11(1):12-20. doi: 10.1007/s11882-010-0160-9.
• Miyamoto, T. et a.l. Clinical characteristics of cryopyrin-associated periodic syndrome and long-term real-world efficacy and tolerability of canakinumab in Japan: results of a nationwide survey. Arthritis Rheumatol. January 25th 2024.