Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra

Arthritis Rheum. 2004 Feb;50(2):607-12. doi: 10.1002/art.20033.


Objective: Mutations in the NALP3/CIAS1/PYPAF1 gene are associated with the autoinflammatory diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID), which is also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome. Molecular studies suggest that NALP3 is involved in the processing of interleukin-1beta (IL-1beta), prompting us to investigate whether IL-1 blockade may be therapeutic in patients with MWS.

Methods: We reviewed the clinical features of 3 members of a family, all of whom had MWS associated with the NALP3 variant V200M (also designated V198M), and evaluated the response of their inflammatory disease to treatment with the recombinant human IL-1 receptor antagonist anakinra. The subjects kept a diary of symptoms and underwent fortnightly clinical and laboratory assessments, including measurement of the serum amyloid A protein concentration.

Results: Each subject had fever, rashes, arthralgia, conjunctivitis, sensorineural deafness, and an intense acute-phase response characteristic of MWS. However, additional features were identified, including exacerbation of their disease by cold and neurologic manifestations, that have hitherto been described only in FCAS and NOMID, respectively. Clinical and serologic evidence of active inflammatory disease resolved rapidly and completely during treatment with anakinra.

Conclusion: The remarkable response of MWS to anakinra suggests that IL-1beta has a fundamental role in the pathogenesis of inflammation associated with mutations in the NALP3 gene, and supports study of IL-1 inhibition in patients with NOMID/CINCA syndrome or FCAS. The clinical features of the various syndromes associated with mutations in the NALP3 gene may overlap to a greater extent than has previously been recognized.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Reaction* / drug therapy
  • Acute-Phase Reaction* / genetics
  • Acute-Phase Reaction* / pathology
  • Adolescent
  • Adult
  • Antirheumatic Agents / therapeutic use*
  • Arthralgia
  • Blood Proteins / genetics
  • Carrier Proteins / genetics
  • Family Health
  • Female
  • Fever
  • Humans
  • Interleukin 1 Receptor Antagonist Protein
  • Male
  • Mutation
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pedigree
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Recombinant Proteins / therapeutic use
  • Sialoglycoproteins / therapeutic use*
  • Syndrome
  • Urticaria* / drug therapy
  • Urticaria* / genetics
  • Urticaria* / pathology


  • Antirheumatic Agents
  • Blood Proteins
  • Carrier Proteins
  • IL1RN protein, human
  • Interleukin 1 Receptor Antagonist Protein
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Receptors, Interleukin-1
  • Recombinant Proteins
  • Sialoglycoproteins