From the Guidelines
Inactivating NLRP3 can effectively treat or prevent diseases caused by its overactivation, such as cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular (NOMID/CINCA) syndrome, as supported by the 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management, and monitoring of interleukin-1 mediated autoinflammatory diseases 1.
Diseases Caused by NLRP3 Overactivation
The diseases caused by NLRP3 overactivation are primarily autoinflammatory in nature, characterized by an inappropriate activation of the immune system leading to excessive inflammation. These include:
- Familial cold autoinflammatory syndrome (FCAS)
- Muckle-Wells syndrome (MWS)
- Neonatal onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular (NOMID/CINCA) syndrome
Treatment Options
Treatment options for these diseases focus on inhibiting the interleukin-1 (IL-1) pathway, which is downstream of NLRP3 activation. According to the evidence, treatments such as Canakinumab, Rilonacept, and Anakinra are recommended for various NLRP3-associated diseases with specific dosing regimens 1.
- Canakinumab is approved for the treatment of CAPS, including FCAS and MWS, with dosing regimens of 2–8 mg/kg every 8 weeks for pediatric patients and 150–600 mg every 8 weeks for adult patients weighing over 40 kg.
- Rilonacept is also used for CAPS, with a loading dose of 4.4 mg/kg followed by a maintenance dose of 2.2 mg/kg per week for pediatric patients, and a loading dose of 320 mg followed by a maintenance dose of 160 mg per week for adult patients.
- Anakinra is used for NOMID/CINCA, with dosing ranging from 1–8 mg/kg/day.
Considerations
While inactivating NLRP3 can be beneficial in treating diseases caused by its overactivation, it's crucial to consider the potential impact on normal immune function. NLRP3 plays a role in defending against certain infections, and its long-term inhibition could increase susceptibility to these infections 1. Therefore, treatment decisions should be made carefully, weighing the benefits of NLRP3 inhibition against potential risks.
From the Research
Effects of Inactivating NLRP3 on Diseases
- Inactivating NLRP3 can potentially reduce the severity of cryopyrin-associated periodic syndromes (CAPS) by decreasing the excessive secretion of IL-1β, as CAPS is caused by mutations in the NLRP3 gene that lead to its constitutive activation 2, 3.
- The use of anti-IL-1 drugs, such as anakinra, has been effective in treating symptoms of CAPS patients and improving their quality of life, suggesting that inactivating NLRP3 can have a positive impact on the disease 2, 3.
- Recent studies have identified various molecules that participate in the activation and inactivation of NLRP3 inflammasome, which may lead to the development of new therapies directed at NLRP3-related diseases 4.
- Neutrophil-specific gain-of-function mutations in NLRP3 have been shown to promote the development of CAPS, highlighting the importance of targeting NLRP3 in neutrophils to treat the disease 5.
- Functional analysis of disease-associated variants has elucidated the mechanisms of NLRP3 activation and inhibition, which can help stratify the CAPS population for NLRP3 inhibitor clinical trials and improve diagnosis and treatment for patients with CAPS 6.
Disease-Specific Effects
- In CAPS, inactivating NLRP3 can reduce systemic inflammation, fatigue, and organ damage, such as visual and hearing impairment, neurological deterioration, and renal insufficiency 2, 3.
- In neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome), inactivating NLRP3 can improve symptoms such as fever, rash, articular manifestations, and neurologic and neurosensory involvement 3.
- Inactivating NLRP3 can also reduce the risk of secondary amyloidosis and other complications associated with CAPS and NOMID/CINCA syndrome 3.