Cryopyrin-associated periodic syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

Cryopyrin-associated periodic syndrome (CAPS) is a rare disease entity encompassing three different clinical phenotypes including Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disorder (NOMID), and familial cold autoinflammatory syndrome (FCAS). The three aforementioned phenotypes occur due to a common gene mutation.

In 1940, Dr. Kile first described Familial cold autoinflammatory syndrome (FCAS) in a family presenting with recurrent urticaria, arthralgia, and fever after general exposure to cold. In 1962, Muckle-Wells syndrome (MWS), the intermediate phenotype of cryopyrin-associated periodic syndrome (CAPS), in terms of severity, was first described by Muckle and Wells. The association between NLRP3 gene and MWS was made in 1999 by Dr. Cuisset. Neonatal-onset multi-system inflammatory disease (NOMID), the most severe phenotype of CAPS, first discovered by Dr. Lorber in 1973. CAPS was first described by Dr. Hoffman, in 2001, following the identification of the NLRP3 gene as the causative mutant gene in families with Familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS).

The cryopyrin-associated periodic syndrome may be classified according to clinical phenotype into three subtypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID)

The exact pathogenesis of cryopyrin-associated periodic syndrome is not fully understood. However, it occurs due to the dysregulation of innate immune system. NLRP3 gene encoding a protein called cryopyrin involved in the pathogenesis of this disorder.

Cryopyrin-associated periodic syndrome is caused by a mutation in the NLRP3, also known as CIAS1, gene.

Cryopyrin-associated periodic syndrome must be differentiated from other diseases that cause fever, fatigue, weight loss, arthralgia, myalgia, rash and soft tissue swelling.

The incidence cryopyrin-associated periodic syndrome is approximately 0.0343 per 100,000 individuals aged 16 years old or younger worldwide. The prevalence of cryopyrin-associated periodic syndrome is approximately 0.1 per 100,000 individuals worldwide. CAPS is usually first presented in the infancy. There is no racial predilection to cryopyrin-associated periodic syndrome. Cryopyrin-associated periodic syndrome affects men and women equally. The majority of CAPS cases are reported in Europe.

There are no established risk factors for the cryopyrin-associated periodic syndrome.

There is insufficient evidence to recommend routine screening for the cryopyrin-associated periodic syndrome.

The symptoms of neonatal-onset multisystem inflammatory disease (NOMID) usually develops during infancy, and start with symptoms such as continuous often low-grade fever, skin rash, neurological involvement, and arthropathy. Some of the possible complications include, renal failure, amyloidosis, and destructive arthropathy. Prognosis of cryopyrin-associated periodic syndrome varies according to the clinical phenotype and other factors.

Cryopyrin-associated periodic syndrome is primarily diagnosed based on the clinical presentation. Genetic analysis of NLRP3 gene is the gold standard test for the diagnosis.

The cryopyrin-associated periodic syndrome is a spectrum of three different clinical phenotypes with the mildest form being familial cold autoinflammatory syndrome (FCAS), formerly called familial cold urticaria and neonatal-onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic cutaneous and articular (CINCA) as the most severe form. Muckle-Wells syndrome (MWS) is the intermediate form of the disease in terms of severity. Symptoms of the cryopyrin-associated periodic syndrome include episodes of cold-induced fever, skin rash, and joint pain.

Physical examination of patients with the cryopyrin-associated periodic syndrome (CAPS) is usually remarkable for recurrent episodes of cold-induced fever, urticaria-like painful rash, and arthritis. Hearing loss, ophthalmologic involvement, and focal neurologic signs are more suggestive of NOMID.

An elevated concentration of serum acute-phase reactant is diagnostic of cryopyrin-associated periodic syndrome.

There are no ECG findings associated with cryopyrin-associated periodic syndrome.

There are no x-ray findings associated with the cryopyrin-associated periodic syndrome. However, an x-ray may be helpful in the diagnosis of arthropathy associated with neonatal-onset multisystem inflammatory disease (NOMID) which may indicate enlargement of the unossified physis leading to a mass-like lesion and later appearance of stippled calcifications.

There are no echocardiography/ultrasound findings associated with Cryopyrin-associated periodic syndrome.

There are no CT scan findings associated with the cryopyrin-associated periodic syndrome.

There are no MRI findings associated with the cryopyrin-associated periodic syndrome. However, an MRI may be helpful in the diagnosis of arthropathy associated with neonatal-onset multi-system inflammatory disease (NOMID) which includes enlarged, heterogenous physis with hypointense calcifications and presence of popliteal lymph node.

There are no other imaging findings associated with the cryopyrin-associated periodic syndrome.

There are no other diagnostic studies associated with cryopyrin-associated periodic syndrome.

There is no definitive treatment for cryopyrin-associated periodic syndrome; the mainstay of therapy is supportive care. Supportive therapy for cryopyrin-associated periodic syndrome includes anakinra, rilonacept, and canakinumab. Patients with NOMID are treated with anakinra, whereas patients with FCAS and MWS are treated with canakinumab. Symptomatic treatment options include nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and glucocorticoids.

Surgical intervention is not recommended for the management of the cryopyrin-associated periodic syndrome.

There are no established measures for the primary prevention of cryopyrin-associated periodic syndrome.

There are no established measures for the secondary prevention of cryopyrin-associated periodic syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

In 1940, Dr. Kile first described Familial cold autoinflammatory syndrome (FCAS) in a family presenting with recurrent urticaria, arthralgia, and fever after general exposure to cold. In 1962, Muckle-Wells syndrome (MWS), the intermediate phenotype of cryopyrin-associated periodic syndrome (CAPS), in terms of severity, was first described by Muckle and Wells. The association between NLRP3 gene and MWS was made in 1999 by Dr. Cuisset. Neonatal-onset multi-system inflammatory disease (NOMID), the most severe phenotype of CAPS, first discovered by Dr. Lorber in 1973. CAPS was first described by Dr. Hoffman, in 2001, following the identification of the NLRP3 gene as the causative mutant gene in families with Familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS).

• In 1940, Dr. Kile first described Familial cold autoinflammatory syndrome (FCAS) in a family presenting with recurrent urticaria, arthralgia, and fever after general exposure to cold.^[1]
• In 1962, Muckle-Wells syndrome (MWS), the intermediate phenotype of cryopyrin-associated periodic syndrome (CAPS), in terms of severity, was first described by Muckle and Wells.^[2]
• The association between NLRP3 gene and MWS was made in 1999 by Dr. Cuisset.^[3]
• Neonatal-onset multisystem inflammatory disease (NOMID), the most severe phenotype of CAPS, first discovered by Dr. Lorber in 1973.^[4]
• CAPS was first described by Dr. Hoffman, in 2001, following the identification of the NLRP3 gene as the causative mutant gene in families with Familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS).^[5]
• Dr. Feldmann first found the genetic association of NLRP3 gene, also known as CIAS1 gene, with phenotype of NOMID in 2002.^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

The cryopyrin-associated periodic syndrome may be classified according to clinical phenotype into three subtypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID)

• The cryopyrin-associated periodic syndrome may be classified according to clinical phenotype into three subtypes:^[1]
  • Familial cold autoinflammatory syndrome (FCAS)
  • Muckle-Wells syndrome (MWS)
  • Neonatal-onset multisystem inflammatory disease (NOMID)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

The exact pathogenesis of cryopyrin-associated periodic syndrome is not fully understood. However, it occurs due to the dysregulation of innate immune system. NLRP3 gene encoding a protein called cryopyrin involved in the pathogenesis of this disorder.

• Inflammation is the complex immunological response of vascular tissues to harmful stimuli. Normally, it protects the organism from the injurious stimuli as well as initiates the healing process for the tissue.

• The exact pathogenesis of the cryopyrin-associated periodic syndrome is not completely understood. However, it occurs due to the dysregulation of innate immune system.^[1]
• Mutations in the NLRP3 gene cause abnormal activation of the inflammasome, the molecular platform that plays a pivotal role in inflammation.
• This leads to the overexpression of the key proinflammatory cytokine, interleukin (IL)-1β.
• Excessive amounts of IL-1β triggers the uncontrolled release of inflammatory cytokines, which act synergistically with IL-1β inducing the inflammatory process. This process is mainly mediated via the recruitment and activation of neutrophils.

• Cryopyrin-associated periodic syndrome is transmitted in the autosomal dominant pattern.^[2][3]
• NLRP3 gene encoding a protein called cryopyrin (also known as nacht domain-, leucine-rich repeat- and pyrin domain-containing protein 3 [NALP3] or pyrin domain-containing apoptotic protease activating factor 1-like protein [PYPAF1] involved in the pathogenesis of this disorder.
• Cryopyrin is derived from the Greek words for icy cold and fire. The recurrent episodes of this disease are usually triggered by cold.

• Conditions associated with Familial Cold Autoinflammatory Syndrome (FCAS) include:^[4]
  • Mild hearing loss
• Conditions associated with Muckle-Wells Syndrome include:^[5]
  • Hearing loss
  • Secondary amyloidosis
• Conditions associated with Neonatal Onset Multi-system Autoinflammatory Disease (NOMID) include:^[6][4]
  • Developmental delay
  • Seizure
  • Hydrocephalus
  • Chronic aseptic meningitis
  • Uveitis
  • Pericarditis
  • Destructive arthropathy
  • Secondary amyloidosis

• Individual cutaneous lesion in CAPS are rose or red macule or papule or plaques.^[7]

• Histology of urticarial lesions consists of dense neutrophilic infiltrate in perivascular area and interstitium.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

Cryopyrin-associated periodic syndrome is caused by a mutation in the NLRP3, also known as CIAS1, gene.

• Cryopyrin-associated periodic syndrome is caused by a mutation in the NLRP3, also known as CIAS1, gene.^[1][2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

Cryopyrin-associated periodic syndrome must be differentiated from other diseases that cause fever, fatigue, weight loss, arthralgia, myalgia, rash and soft tissue swelling.

• Cryopyrin-associated periodic syndrome (CAPS) should be differentiated from other autoinflammatory disorders presenting with fever, fatigue, weight loss, arthralgia, myalgia, rash and soft tissue swelling. The differentials include the following:

Category of Disease	Diseases	Signs and symptoms														Laboratory findings
		Inheritance pattern	Fever duration	Frequency of attacks	Abdominal pain	Arthralgia/Arthritis	Chest pain	Skin rash	Myalgia/Body pain	Diarrhea/Vomiting	Neurologic manifestations	Conjunctivitis	Aphthous stomatitis	Lymphadenopathy	Splenomegaly	Complete blood count (CBC)	C- reactive protein (CRP)
																		Erythrocyte sedimentation rate (ESR)	Other findings	Genetic analysis
Autoinflammatory diseases	Familial mediterranean fever[1][2]	Autosomal recessive/dominant	12-72 h	Weekly or 3-4 times/year	+	+	+	erysipelas-like erythema	+	+	Headache	-/+	-/+	-/+	+	Leukocytosis	↑	↑	High risk for amyloidosis	Mutation in MEFV gene
	Hyper IgD with recurrent fever[2][3][4]	Autosomal recessive	3-7 days	Every 2-12 weeks	+	+	+	Diffuse maculopapular rash Polymorphous rash	+	+	Headache	–	+/-	+/-	+/-	Leukocytosis	↑	↑	Elevated srum level of IgD & IgA Chronic mevalonic aciduria	Mutation in MVK gene
	TNF receptor-associated periodic syndrome[5][6]	Autosomal dominant	3-4 weeks	Variable	+	+	–	Migrating rash with deep pain under the areas with the rash Severe pain follows the rash path in a centrifugal pattern	–	–	Headache	+	–	+/-	+	Leukocytosis	↑	↑	Periorbital edema	Mutation in TNFRSF1A gene
	Muckle-Wells Syndrome[7][8]	Autosomal dominant	2-3 days	More common during cold seasons	+	+	–	Urticaria-like rash	+	+	Headache	+	+	–	–	Leukocytosis	↑	↑	Cold-triggered attacks	Mutation in NLRP3 gene
	Familial cold urticaria[2][9]	Autosomal dominant	12-24 hours, or longer	Common in cold seasons	–	+	–	Urticaria-like rash	–	–	Headache Mild hearing loss	+	+/-	–	–	Leukocytosis	↑	↑	Cold-triggered attacks	Mutation in NLRP3 gene
	Neonatal onset multisystem inflammatory disease[2][10][11]	Autosomal dominant	Continuous	Common in cold seasons	+		+	Urticaria-like rash	+	+	Headache Aseptic meningitis Papilledema Seizure sensorineural hearing loss	+	+/-	Generalized lymphadenopathy	+	Leukocytosis	↑	↑	Intellectual disability Elevated levels of Immunoglobulins Cold-triggered attacks	Mutation in NLRP3 gene
	PSTPIP1-associated Arthritis, pyoderma gangrenosum and acne (PAPA)[12][13]	Autosomal dominant	Variable	Variable	+/-	Destructive arthritis	+/-	Pyoderma gangrenosum ulcerative lesions Severe cystic acne	+/-	+/-	–	–	–	–	–	Leukocytosis	↑	↑	High neutrophilic content of synovial fluid Negative cultures of bone and skin	Mutation in PSTPIP1 gene
	Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA)[14][15][16]	Unkown	3-6 days	Every 21-28 days	+	+	–	–	+	+	–	–	+	Cervical lymphadenopathy	–	Leukocytosis	↑	↑	Culture negative exudative pharyngitis is a classic finding	Unknown
	Blau syndrome[17][18]	Autosomal dominant	Intermittent or persistent daily fever	Variable	+/-	+	+/-	scaly plaques Non-caseating granulomatous dermatitis in Biopsy	+	+/-	Cranial neuropathies Visual problems in 80% Peripheral neuropathies	–	+	+/-	+	Leukocytosis	↑	↑	Ophthalmologic manifestations are common	Mutation in NOD2 gene

• Neonatal onset multi-system inflammatory disease (NOMID) causes a destructive arthropathy and bone disease which must be differentiated from other disorders affecting the joints such as :^[19]
  • Juvenile Rheumatoid Arthritis (JRA)
  • Chronic Recurrent Multifocal Osteomyelitis (CRMO)
  • Rickets
• Table below differentiates the aforementioned conditions:

Disease name	Age of onset	Signs/Symptoms	X-ray findings	MRI findings
NOMID/CINCA[19][8]	Early infancy	Parietal and frontal bossing Joint pain Knee valgus or varus Limb length differences Saddleback nose Contractures Urticaria-like rash Fever Chronic aseptic meningitis	Physis is the epicenter Early radiograph: enlargement of the unossified physis, resulting in a mass-like lesion Late radiograph: stippled ossification/calcification causing deformed adjacent epiphysis Possible involvement of multiple joints simultaneously or at different times	Enlarged, heterogenous physis with hypointense calcifications on T1 & T2 weighted images Heterogenous enhancement at the physis in post-gadolinium images Presence of popliteal lymph node Absence of bony erosion
Juvenile Rheumatoid Arthritis (JRA)[20][21]	Younger than 16 years old	Fever Arthritis Rash Lymphadenopathy Hepatosplenomegaly	Involvement of the articular surface of the joints Initially, soft tissue swelling and enlarged epiphyseal enlargement due to hyperemia As the disease progresses, joint space narrowing and bony erosion are the dominant features	First, joint effusion, cartilage thinning and loss Later, joint erosion and evidence of secondary osteoarthritis Potential complications such as avascular necrosis
Chronic Recurrent Multifocal Osteomyelitis (CRMO)[22][23][24]	Childhood and adolescence	Episodes of pain and joint swelling Fever may be present or not may occur as part of a syndrome or alone	Multiple symmetrical metaphyseal lesions Lesions ranges between purely osteolytic, osteolytic with a sclerotic rim, mixed lytic and sclerotic, and purely sclerotic	Early phases: marrow edema with hypointense appearance on T1-weighted images Hyperintense on T2-weighted images Synovial thickening Joint effusion Destruction of joint cartilage Subchondral bone
Rickets[25][26]	Childhood (depends on the severity of deficiency)	Delay in fontanel closure Parietal and frontal bossing Rachitic rosary Harrison sulcus (or groove) Widening of the wrist Bowing of the distal radius and ulna Progressive lateral bowing of long bones	Widening, cupping and fraying of the metaphysis Irregular and widened epiphyseal plate Periosteal reaction	High signal intensity of unossified cartilage in the physis of the primary and secondary ossification centers No mass lesion or ossification in the physis

• Familial cold autoinflammtory syndrome must be differentiated from other diseases that cause urticaria, and rash, such as:
  • Cold Contact Urticaria
  • Schnitzler Syndrome
  • Deficiency in Interleukin-1 Receptor Antagonist
  • Systemic-Onset Juvenile Idiopathic Arthritis
  • Adult-Onset Still’s Disease
• Table below differentiates the aforementioned conditions:

Disease name	Age of onset	Signs/Symptoms	Diagnostic feature(s)	Other features
Cold Contact Urticaria[27][28]	Early adulthood	Urticarial skin eruption after exposure to cold Urticaria and/or angioedema affects areas only in contact with cold Systemic symptoms may be present in case of extensive skin involvement (even anaphylaxis)	Ice cube test is positive	The wheal appears within 5 minutes of cold contact
Familial Cold Autoinflammatory Syndrome[2]	Infancy, but may be delayed until adulthood	Non-pruritic urticarial rash Fever Headache Fatigue Conjunctivitis	Ice cube test is negative	Cold-induced rash Skin biopsy shows increased neutrophils at the eccrine coils
Schnitzler Syndrome[29]	Middle age	Chronic urticarial rash Fever Arthralgia Bone pain	Monoclonal gammopathy	Rash is the presenting sign Neutrophillic infiltrate in dermis Dermographism
Deficiency in Interleukin-1 Receptor Antagonist[30]	Infancy	Pustular rash Bone pain Swollen joints Aphthous ulcers	Occurs due to mutation in IL1RN gene Pustular rash similar to pustular psoriasis	Epidermal neutrophilic pustules at hair follicles Pathergy Hyperkeratosis and acanthosis High neutrophil infiltrate of the dermis
Systemic-Onset Juvenile Idiopathic Arthritis[31]	2-16 years of age	High fever Arthralgia Generalized lymphadenopathy Splenomegaly	Evanescent rash Bright salmon-pink Morbilliform, macular rash Rash presents with onset of fever	May cause amyloidosis
Adult-Onset Still’s Disease[32]	16-35 years May affect all ages	High spiking fever Joint pain Skin rash Lymphadenopathy Splenomegaly	Evanescent salmon-colored bumpy rash Pruritic rash on the proximal limbs and trunk	More commonly seen among women May cause destructive arthritis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

The incidence cryopyrin-associated periodic syndrome is approximately 0.0343 per 100,000 individuals aged 16 years old or younger worldwide. The prevalence of cryopyrin-associated periodic syndrome is approximately 0.1 per 100,000 individuals worldwide. CAPS is usually first presented in the infancy. There is no racial predilection to cryopyrin-associated periodic syndrome. Cryopyrin-associated periodic syndrome affects men and women equally. The majority of CAPS cases are reported in Europe.

• The incidence cryopyrin-associated periodic syndrome is approximately 0.0343 per 100,000 individuals aged 16 years old or younger worldwide.^[1]

• The prevalence of cryopyrin-associated periodic syndrome is approximately 0.1 per 100,000 individuals worldwide.^[2]

• CAPS is usually first presented in the infancy. However, due to the vague nature of the symptom, diagnosis may be delayed until childhood or longer.^[3]

• There is no racial predilection to cryopyrin-associated periodic syndrome.^[4]

• Cryopyrin-associated periodic syndrome affects men and women equally.^[4]

• The majority of CAPS cases are reported in Europe.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

There are no established risk factors for the cryopyrin-associated periodic syndrome.

• There are no established risk factors for the cryopyrin-associated periodic syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

There is insufficient evidence to recommend routine screening for the cryopyrin-associated periodic syndrome.

• There is insufficient evidence to recommend routine screening for the cryopyrin-associated periodic syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]

The symptoms of neonatal-onset multisystem inflammatory disease (NOMID) usually develops during infancy, and start with symptoms such as continuous often low-grade fever, skin rash, neurological involvement, and arthropathy. Some of the possible complications include, renal failure, amyloidosis, and destructive arthropathy. Prognosis of cryopyrin-associated periodic syndrome varies according to the clinical phenotype and other factors.

• The symptoms of neonatal-onset multisystem inflammatory disease (NOMID) usually develops during infancy, and start with symptoms such as continuous often low-grade fever, skin rash, neurological involvement, and arthropathy.^[1]

• Muckle-Wells syndrome (MWS), a moderate phenotype of cryopyrin-associated periodic syndrome, manifests with a typical urticarial rash and fever.^[2]

• FCAS, the mildest form of CAPS, present in infancy with recurrent, cold-induced episodes of fever, urticaria-like skin rash, arthralgia and conjunctivitis.^[3]
• Symptoms tend to manifest in infancy, but it may present later in life, such as childhood or adolescence.^[4]
• Episodes present 1 to 3 hour after cold or cooling exposure and may take 12 to 24 hours or longer.

• Common complications of neonatal-onset multisystem inflammatory disease (NOMID) include:^[5][6]
  • Hydrocephalus and increased intracranial pressure
  • Optic nerve atrophy and progressive vision loss
  • Cognitive delay
  • Deforming arthropathy (30-40% 0f the cases)
  • Sensorineural hearing loss
  • Renal amyloidosis
• The two latter are observed more commonly among those with Muckle-Wells syndrome (MWS).^[7]

• Prognosis of cryopyrin-associated periodic syndrome varies according to the clinical phenotype and other factors.^[3]
• Factors associated with poor outcomes include:
  • Early disease onset (before the age of 6 months)
• Prognosis of NOMID is not generally good, and disabling.^[8]
• The presence of amyloidosis is associated with a particularly poor prognosis among patients with CAPS.

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