NLRP3-associated autoinflammatory disease

NLRP3-associated autoinflammatory disease, also known as cryopyrin-associated periodic syndrome (CAPS), is a spectrum of inherited autoinflammatory disorders caused by gain-of-function mutations in the NLRP3 gene (also called CIAS1 or PYPAF1), which encodes the protein cryopyrin. This protein plays a central role in the innate immune system by forming the NLRP3 inflammasome, a multiprotein complex that regulates the production of interleukin-1β (IL-1β). Mutations lead to excessive IL-1β release, resulting in systemic inflammation. The CAPS spectrum encompasses three overlapping clinical phenotypes of increasing severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological cutaneous and articular (CINCA) syndrome. The disease affects multiple body systems. Common features across the spectrum include recurrent or chronic episodes of fever, urticaria-like skin rash, joint pain and swelling, conjunctivitis, and elevated inflammatory markers (such as C-reactive protein and serum amyloid A). In FCAS, episodes are typically triggered by cold exposure and are relatively mild. MWS is characterized by progressive sensorineural hearing loss and risk of AA amyloidosis due to chronic inflammation. NOMID/CINCA, the most severe form, presents in the neonatal period with chronic aseptic meningitis, papilledema, intellectual disability, characteristic bony overgrowth (particularly of the knees and long bones), and facial dysmorphism. Without treatment, NOMID can lead to significant neurological damage and organ dysfunction. The treatment landscape has been transformed by the availability of IL-1-targeted biologic therapies. Anakinra (an IL-1 receptor antagonist), canakinumab (a monoclonal antibody against IL-1β), and rilonacept (an IL-1 trap) have demonstrated remarkable efficacy in controlling symptoms, reducing inflammation, and preventing long-term complications such as amyloidosis and hearing loss. Early diagnosis and initiation of treatment are critical to preventing irreversible organ damage. Lifelong therapy is generally required, as symptoms recur upon discontinuation of IL-1 blockade.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

Common questions about NLRP3-associated autoinflammatory disease