#1leading
NLRP3 gain-of-function mutations cause constitutive inflammasome activation driving IL-1β-mediated autoinflammation in CAPS
15 studies·pathogenesis
98
evidence
Cryopyrin-Associated Periodic Syndromes
CAPSCryopyrinopathiesNLRP3-associated autoinflammatory diseaseFamilial cold autoinflammatory syndromeFCASMuckle-Wells syndromeMWSNeonatal-onset multisystem inflammatory diseaseNOMIDChronic infantile neurological cutaneous and articular syndromeCINCA
Cryopyrin-associated periodic syndromes (CAPS) are a spectrum of rare, inherited autoinflammatory disorders caused by gain-of-function mutations in the NLRP3 gene encoding cryopyrin. The spectrum encompasses three conditions of increasing severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID/CINCA).
Understanding Status
Pathophysiology
Well understood
90%
Treatment
Effective treatment available
80%
Genetic basis
Well characterized
80%
Epidemiology
- Total cases
- Unknown
- Mean onset
- 1 year
- Onset range
- 0–50 years
- Sex ratio (M:F)
- 1:1
- Diagnostic delay
- ~10 years
- Discovered
- 1940 (Kile & Rusk (FCAS, 1940); Muckle & Wells (MWS, 1962); Prieur & Griscelli (CINCA, 1981); Hoffman et al. (NLRP3 gene, 2001))
- Prevalence
- 1–3/1,000,000
- Classification
- Autoinflammatory, Monogenic, Inflammasomopathy
Cardinal Features
13 key symptoms and signs
| Feature | Frequency | Category | Sources |
|---|---|---|---|
Urticaria-like rash Non-pruritic, migratory, neutrophilic urticarial dermatosis present across all CAPS subtypes. Intensifies during flares. Biopsy shows perivascular and interstitial neutrophilic infiltrate without mast cell degranulation. | 95% | dermatologic | |
Recurrent fever Intermittent or chronic low-to-high grade fever; triggered by cold exposure in FCAS, spontaneous in MWS/NOMID. Resolves rapidly with IL-1 blockade. | 85% | systemic | |
Elevated CRP/SAA Persistent elevation of acute phase reactants; CRP and SAA universally elevated during flares. Key biomarkers for treatment monitoring; target normalization with IL-1 blockade. | 95% | laboratory | |
Arthralgia/arthritis Joint pain across all subtypes; ranges from episodic arthralgia to destructive arthropathy with epiphyseal overgrowth in NOMID. | 80% | musculoskeletal | |
Fatigue/malaise Chronic fatigue and general malaise associated with persistent systemic inflammation. Significantly impacts quality of life. | 80% | systemic | A5J1 |
Headache Due to increased intracranial pressure and chronic meningitis in NOMID; also present in MWS flares. | 50% | neurological | D1D2 |
Sensorineural hearing loss Progressive cochlear inflammation-mediated hearing loss; primarily MWS and NOMID subtypes. Partially reversible with early IL-1 blockade; irreversible once structural damage established. | 42% | neurological | |
Papilledema/optic involvement Optic nerve swelling, uveitis, visual impairment; primarily NOMID. Can progress to blindness if untreated. | 25% | ophthalmologic | D1D2 |
Chronic aseptic meningitis Chronic leptomeningitis with CSF neutrophilia; defining feature of NOMID. Can lead to hydrocephalus, cerebral atrophy, and intellectual disability. | 20% | neurological | D1D2 |
AA amyloidosis Systemic amyloidosis from chronic SAA elevation; primarily MWS. Can cause nephrotic syndrome and renal failure. Risk dramatically reduced with IL-1 blockade. | 20% | systemic | |
Growth retardation/short stature Chronic inflammation impairs growth; primarily NOMID. May improve with early IL-1 blockade. | 15% | systemic | D1D2 |
Cognitive impairment Intellectual disability from chronic CNS inflammation; primarily severe NOMID. | 10% | neurological | D1D2 |
Seizures Related to chronic meningitis and intracranial hypertension; NOMID. | 5% | neurological | D1 |
Hypothesis Tracker
Competing explanations ranked by evidence weight
#2competing
Somatic NLRP3 mosaicism explains disease in a subset of 'mutation-negative' CAPS patients
8 studies·genetics
72
evidence
#3competing
Neutrophils are the primary cellular source of IL-1β in CAPS
4 studies·pathogenesis
65
evidence
#4emerging
IL-18 drives CAPS skin disease independently of IL-1β
3 studies·pathogenesis
42
evidence
#5emerging
Cold-induced cryo-sensitive aggregation of mutant NLRP3 explains FCAS triggering
2 studies·pathogenesis
38
evidence
#6emerging
Modifier genes and epigenetic factors determine CAPS severity within shared genotypes
3 studies·genetics
35
evidence
Open Questions
Why do patients with the same NLRP3 mutation develop different CAPS subtypes (FCAS vs MWS vs NOMID)?
The same amino acid substitution can produce mild episodic disease or severe chronic multisystem inflammation. Modifier genes, epigenetics, and environmental factors are suspected but none conclusively identified.
What drives disease in mutation-negative CAPS patients who also lack detectable somatic mosaicism?
Even with deep sequencing, a substantial proportion of clinically diagnosed CAPS patients remain genetically unexplained. Other inflammasome genes, epigenetic modifications, or post-translational mechanisms may be involved.
Can direct NLRP3 inhibition with oral small molecules replace lifelong injectable IL-1 blockade?
Dapansutrile is in Phase 2a clinical trials. If effective, it would fundamentally change CAPS treatment from chronic injectable biologics to an oral pill. MCC950 failed due to hepatotoxicity.
What is the optimal timing for initiating IL-1 blockade to prevent irreversible hearing loss in MWS?
Early treatment can partially reverse hearing loss, but once cochlear damage is established, it is irreversible. The critical window for intervention is unknown.
What is the long-term safety profile of lifelong IL-1 blockade started in infancy?
Current safety data extends to 5-6 years. CAPS patients require lifelong treatment, and many are treated from early infancy. Decades-long safety data for infection risk, immunogenicity, and organ effects are unavailable.
Does IL-18 represent a viable therapeutic target for CAPS patients with incomplete response to IL-1 blockade?
Mouse models show IL-18 drives skin disease independently of IL-1β. Some CAPS patients have persistent skin symptoms despite IL-1 blockade. No IL-18-targeted therapies have been tested in CAPS.
Recent Updates
Constitutive inflammasome activation in CAPS mutants characterized
Molina-López et al. (2024) demonstrated that CAPS-associated NLRP3 variants form constitutively active inflammasomes with basal gasdermin D cleavage, IL-18 release, and pyroptosis, responsive to MCC950 inhibitor (Nat Commun).
Deep sequencing reveals somatic mosaicism in 40% of mutation-negative CAPS children
Melo Gomes et al. (2025) found somatic NLRP3 mosaicism via amplicon-based deep sequencing in 4/10 mutation-negative CAPS pediatric patients, with allele frequencies as low as 1.9% (Front Pediatr).
Cryo-sensitive aggregation mechanism explains cold-triggered FCAS
Karasawa et al. (2022) showed CAPS-associated NLRP3 mutants form cryo-sensitive aggregates that scaffold inflammasome activation, providing mechanistic explanation for cold-triggered FCAS episodes (eLife).
Oral NLRP3 inhibitor dapansutrile enters clinical trials for CAPS
Dapansutrile (OLT1177), an oral NLRP3 inhibitor with favorable safety profile, is in Phase 2a clinical trial for CAPS maintenance therapy (NCT04524858), potentially replacing injectable biologics.