Sources & References

43 published sources for Cryopyrin-Associated Periodic Syndromes, each with evidence grades and key findings.

43 total sourcesGrade A: 13Grade B: 17Grade C: 10Grade D: 3genetics (8)pathophysiology (9)clinical (12)treatment (11)diagnosis (2)epidemiology (1)

genetics

8 sources

C7Grade Bcohort

Somatic NLRP3 mosaicism in patients with 'mutation-negative' CAPS: insights from a single centre UK cohort

Melo Gomes S, Arostegui JI, Rowczenio DM, et al. · Front Pediatr · 2025

●40% of mutation-negative CAPS have somatic mosaicism
●Allele frequencies as low as 1.9%
●Mosaicism can increase over time

C4Grade Ccase series

Late-onset cryopyrin-associated periodic syndromes caused by somatic NLRP3 mosaicism — UK single center experience

Rowczenio DM, Gomes SM, Arostegui JI, et al. · Front Immunol · 2017

●Adult-onset CAPS from somatic mosaicism
●Allele frequency 5-45%

PubMed ↗

C5Grade Cbasic research

Detection of base substitution-type somatic mosaicism of the NLRP3 gene with >99.9% statistical confidence by massively parallel sequencing

Izawa K, Hijikata A, Tanaka N, et al. · J Mol Diagn · 2012

●Deep sequencing pipeline for low-level mosaicism detection
●Can detect 1% allele frequency

PubMed ↗

C3Grade Bcohort

High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome

Tanaka N, Izawa K, Saito MK, et al. · Arthritis Rheum · 2011

●High somatic mosaicism incidence in NOMID
●International multicenter study

PubMed ↗

J7Grade Bcohort

Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France

Cuisset L, Jeru I, Duber B, et al. · Ann Rheum Dis · 2011

●French genetic epidemiology
●Mutation frequencies and founder effects
●R260W most common in MWS

PubMed ↗

B8Grade Ccase report

Somatic mosaicism of CIAS1 in a patient with chronic infantile neurologic, cutaneous, articular syndrome

Saito M, Fujisawa A, Nishikomori R, et al. · Arthritis Rheum · 2005

●First demonstration of somatic mosaicism in CAPS

PubMed ↗

C2Grade Agenetic study

De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with NOMID

Aksentijevich I, Nowak M, Mallah M, et al. · Arthritis Rheum · 2002

●De novo NLRP3 mutations in NOMID
●Genetic heterogeneity established
●50-60% of NOMID from de novo mutations

PubMed ↗

A1Grade Agenetic study

Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome

Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD · Nat Genet · 2001

●Discovery of CIAS1/NLRP3 gene
●Linked FCAS and MWS to same gene
●Identified gain-of-function mutations in NACHT domain

PubMed ↗

pathophysiology

9 sources

B1Grade Breview

The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes and innate immunity

Putnam CD, Broderick L, Bhatt DL, Hoffman HM · Immunol Rev · 2024

●Comprehensive review of NLRP3 function from CAPS to broader immunity

PubMed ↗

B2Grade Bbasic research

Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production

Molina-López C, Hurtado-Navarro L, García-Castañeda A, et al. · Nat Commun · 2024

●CAPS variants form constitutively active inflammasomes
●Basal gasdermin D cleavage demonstrated
●Responsive to MCC950 inhibitor

PubMed ↗

B3Grade Bbasic research

Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome

Karasawa T, Komada T, Yamada N, et al. · eLife · 2022

●Explains cold-triggered mechanism in FCAS
●Cryo-sensitive aggregation scaffolds inflammasome activation

PubMed ↗

B6Grade Creview

NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: from cryopyrin function to targeted therapies

Moltrasio C, Romagnuolo M, Marzano AV · Front Immunol · 2022

●Comprehensive NLRP3 structural and functional review

B10Grade Bbasic research

Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome

Broderick L, Hoffman HM · J Exp Med · 2021

●Neutrophils identified as key cellular source of IL-1β in CAPS
●Neutrophil-specific knock-in mice develop CAPS

PubMed ↗

B4Grade Breview

CAPS and NLRP3

Booshehri LM, Hoffman HM · J Clin Immunol · 2019

●Focused review linking CAPS mutations to NLRP3 function

PubMed ↗

B5Grade Abasic research

Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies

Brydges SD, Broderick L, McGeough MD, et al. · J Clin Invest · 2013

●Divergent roles of IL-1β and IL-18 in CAPS mouse models
●IL-18 independently drives skin inflammation

PubMed ↗

B7Grade Bbasic research

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

Tassi S, Carta S, Delfino L, et al. · Proc Natl Acad Sci USA · 2010

●Altered redox state in CAPS monocytes
●Spontaneous IL-1β secretion
●Spontaneous ASC speck formation

PubMed ↗

B9Grade Abasic research

Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity

Brydges SD, Mueller JL, McGeough MD, et al. · Immunity · 2009

●CAPS knock-in mouse model
●Confirmed innate immunity-driven disease
●Adaptive immunity not required

PubMed ↗

clinical

12 sources

A5Grade Breview

Diagnosis and management of the cryopyrin-associated periodic syndromes (CAPS): what do we know today?

Welzel T, Kuemmerle-Deschner JB · J Clin Med · 2021

●Comprehensive diagnostic and management review
●Current treatment algorithms

D1Grade Creview

Chronic infantile neurological cutaneous and articular (CINCA) syndrome: a review

Finetti M, Omenetti A, Federici S, et al. · Orphanet J Rare Dis · 2016

●Comprehensive CINCA/NOMID clinical review
●Organ involvement spectrum described

F6Grade Ccase series

NLRP3 A439V mutation in a large family with cryopyrin-associated periodic syndrome

Kuemmerle-Deschner JB, Verma D, Grom AA, et al. · J Rheumatol · 2016

●Detailed phenotypic description across large CAPS kindred
●Variable expressivity with same mutation

PubMed ↗

A4Grade Acohortn=136

Phenotypic and genotypic characteristics of CAPS: a series of 136 patients from the Eurofever Registry

Levy R, Gerard L, Kuemmerle-Deschner J, et al. · Ann Rheum Dis · 2015

●Largest registry study
●31 mutations in 136 patients
●Genotype-phenotype correlations established

PubMed ↗

J1Grade Creview

CAPS—pathogenesis, presentation and treatment of an autoinflammatory disease

Kuemmerle-Deschner JB · Semin Immunopathol · 2015

●Expert comprehensive review

PubMed ↗

D4Grade Bcohort

Hearing loss in Muckle-Wells syndrome

Kuemmerle-Deschner JB, Koitschev A, Ummenhofer K, et al. · Arthritis Rheum · 2013

●Systematic hearing loss characterization in MWS
●Progressive high-frequency pattern

PubMed ↗

D2Grade Creview

Current status of understanding the pathogenesis and management of patients with NOMID/CINCA

Goldbach-Mansky R · Curr Rheumatol Rep · 2011

●NIH expert review of NOMID pathogenesis
●Detailed organ involvement characterization

D5Grade Bcohortn=57

Cryopyrinopathies: otolaryngologic and audiologic manifestations

Kone-Paut I, Piram M · Otolaryngol Clin North Am · 2011

●Largest cohort for otolaryngologic features
●57 patients characterized

PubMed ↗

J2Grade Dreview

Cryopyrin-associated periodic syndromes and autoinflammation

Shinkai K, McCalmont TH, Leslie KS · Clin Exp Dermatol · 2008

●Dermatology-focused review
●Neutrophilic urticaria description

PubMed ↗

D3Grade Ccase series

Arthropathy of neonatal onset multisystem inflammatory disease (NOMID/CINCA)

Hill SC, Namde M, Engel A, et al. · Pediatr Radiol · 2007

●Imaging features of NOMID arthropathy
●Epiphyseal overgrowth characterization

PubMed ↗

F1Grade Dcase report

Urticaria, deafness and amyloidosis: a new heredo-familial syndrome

Muckle TJ, Wells M · Q J Med · 1962

●Original description of Muckle-Wells syndrome

F2Grade Dcase report

A case of cold urticaria with an unusual family history

Kile RL, Rusk HA · JAMA · 1940

●Original description of familial cold urticaria (FCAS)

treatment

11 sources

H4Grade Bcohort

Long-term safety and effectiveness of canakinumab in CAPS: results from the β-Confident Registry

Kuemmerle-Deschner JB, Ramos E, Engel K, et al. · RMD Open · 2021

●Real-world registry
●6-year safety and effectiveness data

PubMed ↗

I3Grade Cbasic research

OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation

Marchetti C, Swartzwelter B, Gamboni F, et al. · Proc Natl Acad Sci USA · 2018

●Dapansutrile — first oral NLRP3 inhibitor reaching clinical trials
●Favorable safety in Phase I

PubMed ↗

G3Grade Bcohortn=43

Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes

Kullenberg T, Löfqvist M, Leinonen M, et al. · Rheumatology · 2016

●5-year safety data
●Safe and well-tolerated
●Injection site reactions manageable

PubMed ↗

G2Grade Acohortn=26

Sustained response and prevention of damage progression in patients with NOMID treated with anakinra: 3- and 5-year outcomes

Sibley CH, Plass N, Snow J, et al. · Arthritis Rheum · 2012

●NIH 5-year follow-up
●Sustained efficacy
●Dose escalation required in some

PubMed ↗

J5Grade Breview

Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases

Dinarello CA, Simon A, van der Meer JWM · Nat Rev Drug Discov · 2012

●Broad IL-1 blockade review placing CAPS in therapeutic context

PubMed ↗

H2Grade ARCTn=166

Two-year results from a Phase III study evaluating canakinumab across CAPS phenotypes

Kuemmerle-Deschner JB, Hachulla E, Cartwright R, et al. · Ann Rheum Dis · 2011

●Phase III extension
●78% complete response across all phenotypes
●Sustained over 2 years

PubMed ↗

H3Grade ARCT

Sustained remission of symptoms and improved health-related quality of life in patients with CAPS treated with canakinumab

Koné-Paut I, Lachmann HJ, Kuemmerle-Deschner JB, et al. · Arthritis Res Ther · 2011

●QoL improvement data from canakinumab RCT
●Improved SF-36 and CHQ scores

PubMed ↗

H1Grade ARCTn=35

Use of canakinumab in the cryopyrin-associated periodic syndrome

Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. · N Engl J Med · 2009

●Landmark NEJM RCT
●97% initial response
●0% relapse on drug vs 81% on placebo

PubMed ↗

I1Grade ARCT

Efficacy and safety of rilonacept in CAPS: results from two sequential placebo-controlled studies

Hoffman HM, Throne ML, Amar NJ, et al. · Arthritis Rheum · 2008

●Pivotal RCT for rilonacept FDA approval
●Significant improvement vs placebo

PubMed ↗

G1Grade Acohortn=18

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition

Goldbach-Mansky R, Dailey NJ, Canna SW, et al. · N Engl J Med · 2006

●Landmark NEJM trial of anakinra in NOMID
●Dramatic efficacy in 18 patients
●Rapid CRP/SAA normalization

PubMed ↗

G5Grade Bcase report

Interleukin-1-receptor antagonist in the Muckle-Wells syndrome

Hawkins PN, Lachmann HJ, McDermott MF · N Engl J Med · 2003

●First report of anakinra in MWS
●Dramatic response

PubMed ↗

diagnosis

2 sources

A3Grade Acohort

Classification criteria for autoinflammatory recurrent fevers (Eurofever/PRINTO)

Gattorno M, Hofer M, Federici S, et al. · Ann Rheum Dis · 2019

●Eurofever/PRINTO classification criteria for hereditary recurrent fevers including CAPS
●Two versions: genetic+clinical and clinical-only

PubMed ↗

A2Grade Acohort

Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS)

Kuemmerle-Deschner JB, Ozen S, Tyrrell PN, et al. · Ann Rheum Dis · 2017

●Evidence-based diagnostic criteria
●Sensitivity 81%, specificity 94%
●Validated across all CAPS subtypes

PubMed ↗

epidemiology

1 sources

E1Grade Bcohort

Cryopyrin-associated periodic syndrome in Australian children and adults: epidemiological, clinical and treatment characteristics

Mehr S, Allen R, Boros C, et al. · J Paediatr Child Health · 2016

●Australian CAPS epidemiology
●Prevalence ~1/million
●Diagnostic delay data

PubMed ↗