From the Guidelines
NLRP3 plays a crucial role in the pathogenesis of autoinflammatory diseases, including cryopyrin-associated periodic syndromes (CAPS), which encompasses familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular (NOMID/CINCA) syndrome. The NLRP3 gene is responsible for encoding a protein that forms the inflammasome complex, leading to the activation of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β) 1.
Key Points
- NLRP3-associated autoinflammatory diseases are characterized by recurrent episodes of inflammation, fever, and organ damage, with CAPS being the most common phenotype 2.
- The diagnosis of NLRP3-associated autoinflammatory diseases is based on clinical features, genetic testing, and laboratory findings, including elevated levels of IL-1β and other inflammatory markers 3.
- Treatment options for NLRP3-associated autoinflammatory diseases include IL-1β inhibitors, such as canakinumab, rilonacept, and anakinra, which have been shown to be effective in reducing inflammation and improving quality of life in patients with CAPS and other NLRP3-associated diseases 1.
Treatment Recommendations
- Canakinumab is recommended as a first-line treatment for CAPS, with a dosing regimen of 2-8 mg/kg every 8 weeks for pediatric patients and 150-600 mg every 8 weeks for adult patients 1.
- Rilonacept and anakinra may also be considered as treatment options for CAPS, although their use may be limited by side effects and availability 1.
- Regular monitoring of disease activity, laboratory parameters, and side effects is essential to optimize treatment and improve patient outcomes in NLRP3-associated autoinflammatory diseases 2.
From the FDA Drug Label
The NLRP3 protein is an important component of the inflammasome and regulates the protease caspase-1 and controls the activation of IL-1β. Mutations in NLRP3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation IL-1β production by macrophages is triggered by uric acid (monosodium urate monohydrate) crystals in the joint and surrounding tissue through activation of the NLRP3 inflammasome complex. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has an important role in the systemic inflammation and manifestations of NOMID
The role of NLRP3 is to:
- Regulate the protease caspase-1
- Control the activation of IL-1β
- Activate the inflammasome complex in response to stimuli such as uric acid crystals
- Contribute to the development of autoinflammatory diseases such as NOMID and CAPS when mutated 4, 5, 6
From the Research
Role of NLRP3
- NLRP3 is a key component of the innate immunity that regulates the secretion of IL-1β 7, 8, 9, 10, 11
- Mutations in the NLRP3 gene can lead to excessive inflammasome activation and subsequent overproduction of IL-1β, causing cryopyrin-associated periodic syndromes (CAPS) 7, 8, 9, 10, 11
- CAPS encompasses a spectrum of three phenotypes of increasing severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) 7, 8, 9, 10, 11
NLRP3 and Inflammasome Activation
- Gain-of-function mutations in NLRP3 promote development of CAPS by leading to constitutive activation of cryopyrin and excessive secretion of IL-1β 9, 10
- Neutrophil-specific gain-of-function mutations in Nlrp3 can trigger severe CAPS, indicating that neutrophils can represent the main cellular drivers of CAPS pathology 10
Clinical Implications
- Early diagnosis and immediate initiation of therapy are crucial to prevent severe and possible life-threatening disease sequelae in CAPS patients 7, 8, 9, 11
- Anti-IL-1 drugs, such as anakinra, rilonacept, and canakinumab, are effective in treating symptoms of almost all CAPS patients and have radically transformed their lives 7, 8, 9, 11