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

TLDR

Mutations in the NALP3/CIAS1/PYPAF1 gene cause autoinflammatory syndromes such as Muckle‑Wells, FCAS, and NOMID/CINCA, and their clinical features overlap more than previously recognized. The study aimed to determine whether IL‑1 blockade could treat Muckle‑Wells syndrome. The authors reviewed three family members with the V200M NALP3 variant, monitored symptoms and serum amyloid A every two weeks, and assessed their response to the IL‑1 receptor antagonist anakinra. All three patients displayed classic MWS symptoms plus cold‑triggered flares and neurologic signs, yet their fever, rash, arthralgia, conjunctivitis, deafness, and acute‑phase markers resolved rapidly and completely with anakinra, confirming IL‑1β’s central role and supporting IL‑1 inhibition for related syndromes.

Abstract

Abstract 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‐1β (IL‐1β), 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‐1β 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.