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Cryopyrin-Associated Periodic Syndrome

CAPS

Cryopyrin-associated periodic syndrome refers to symptoms related to mutations of the gene encoding for cryopyrin. These mainly result from a systemic inflammatory reaction and can be observed in patients suffering from the following autoimmune disorders: chronic infantile neurologic, cutaneous, and articular syndrome (CINCA syndrome), familial cold urticaria and Muckle Wells syndrome.

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Presentation

Fatigue, fever as well as recurrent urticaria-like cutaneous lesions, i.e., non-itchy, generalized macular erythema and plaques, are characteristic for all forms of CAPS. However, age of disease onset and further clinical presentation vary between FCU, MWS and CINCA patients.

  • FCU is the mildest form of CAPS, but symptoms manifest very early in life. More than 90% of affected individuals suffer from first bouts of fever and rash during their first year of life. Such bouts are induced by generalized cold exposure and may manifest with a delay of several hours or few days. It is important to note that focal cold exposure does not trigger FCU. Besides low-grade fever and rash, FCU patients typically suffer from conjunctivitis, arthralgia and myalgia. Chills, sweats, headaches and nausea have also been reported. Symptoms remit spontaneously within less than 24 hours, but frequent bouts may severely compromise life quality. Some patients suffer from several episodes per week.
  • MWS is a disease of intermediate severity and most patients first present during infancy or early childhood. Contrary to FCU, no specific trigger of relapses has been identified. Fever, rash, conjunctivitis, arthralgia and myalgia are common complaints, but patients may also present uveitis. These reversible symptoms typically remit within a few days, but a faint, generalized erythema may persist. Progressive sensorineural hearing loss is experienced by two-thirds of MWS patients [8]. Some affected individuals develop secondary amyloidosis and renal failure.
  • CINCA usually manifests in early infancy and an increased incidence has been reported for children born prematurely. CAPS-related chronic rash, polyarthritis and symptoms indicating central nervous system (CNS) involvement are generally first observed within weeks birth. With regards to the latter, headaches, vomiting and seizures as well as papilledema are most commonly registered. Over time, growth disorders and developmental delays become apparent. Visual and hearing impairment are frequently reported. Contrary to FCU and MWS, remission and recurrence is not typical for CINCA.

Of note, overlaps between the above described phenotypes have been reported [6].

Fever
  • Herein, we present the case of a 9-month-old boy with recurrent nonpruritic rashes and episodes of fever.[ncbi.nlm.nih.gov]
  • We herein report a case of a 75-year-old woman who presented with a low-grade fever, repeated cold-induced urticaria, and painful leg edemas with neutrocytosis.[ncbi.nlm.nih.gov]
  • Clinical description CAPS comprises 3 disorders on a continuum of severity: FCAS which usually has an early-onset after birth ( 20 years), and is characterized by recurrent episodes of urticarial rash triggered by exposure to cold, low-grade fever (malaise[orpha.net]
Amyloidosis
  • Some patients with CAPS develop systemic amyloidosis via an inflammatory reaction.[ncbi.nlm.nih.gov]
  • Laboratory tests disclosed nephrotic syndrome, and renal biopsy showed AA amyloidosis. He was given anakinra with improvement of arthritis.[ncbi.nlm.nih.gov]
  • Treatment is based on IL-1 antagonism, which usually results in prompt clinical response and may prevent amyloidosis.[ncbi.nlm.nih.gov]
  • Without treatment, one third of patients develop amyloidosis with consequent renal failure and death.[ncbi.nlm.nih.gov]
  • Progressive secondary amyloidosis manifests as proteinuria and is observed in the most severe cases (25% of cases). In CINCA syndrome, an increase in cytokine or neopterin levels in the cerebrospinal fluid may be detected.[orpha.net]
Fatigue
  • To identify the cause of disease in an adult patient presenting with recent-onset fevers, chills, urticaria, fatigue, and profound myalgia, who was found to be negative for cryopyrin-associated periodic syndrome (CAPS) NLRP3 mutations by conventional[ncbi.nlm.nih.gov]
  • CAPS patients experience symptoms of systemic inflammation, intense fatigue and have poor quality of life.[ncbi.nlm.nih.gov]
  • Fatigue, fever as well as recurrent urticaria-like cutaneous lesions, i.e., non-itchy, generalized macular erythema and plaques, are characteristic for all forms of CAPS.[symptoma.com]
  • Similarly to MWS, fatigue is typically a symptom more frequently than fevers.[patientworthy.com]
  • Common features include onset in infancy, severe fatigue, fever, … View Full Text Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service.[adc.bmj.com]
Chills
  • To identify the cause of disease in an adult patient presenting with recent-onset fevers, chills, urticaria, fatigue, and profound myalgia, who was found to be negative for cryopyrin-associated periodic syndrome (CAPS) NLRP3 mutations by conventional[ncbi.nlm.nih.gov]
  • CAPS are characterized by life-long, recurrent symptoms of rash, fever/chills, joint pain, eye redness/pain, and fatigue.[fiercebiotech.com]
  • Patients also can develop fever, chills, nausea, severe thirst, red eyes, headaches and joint pain. Episodes usually last up to one day. What causes the disease? CAPS are genetic diseases.[rheumatology.org]
  • In Muckle-Wells syndrome (MWS), patients develop episodic fever, chills, rash, red eyes, joint pain, and severe headaches, often after exposure to cold. Episodes last from one to three days.[rheumatology.org]
Anemia
  • Other blood tests could be taken and analyzed as well to see if a patient has leukocytosis (an increase in the number of white cells in the blood), anemia (a deficiency of red blood cells or hemoglobin in the blood), an elevated C-reactive protein level[raregenomics.org]
  • Patients with these disorders have severe fatigue, fever, and influenza-like myalgia from infancy, together with chronic anemia and inflammation of the skin, eyes, bones, joints, and meninges.[doi.org]
  • […] mouth [ more ] 0000174 Abnormality of the genital system Genital abnormalities Genital abnormality Genital anomalies Genital defects [ more ] 0000078 Abnormality of the nose Nasal abnormality 0000366 Abnormality of the voice Voice abnormality 0001608 Anemia[rarediseases.info.nih.gov]
Nausea
  • ), weight gain, injection site reactions (such as redness, swelling, warmth, or itching), and nausea.[ilaris.com]
  • Other symptoms include fever, chills, nausea, extreme thirst, headache and joint pain.[arthritis.org]
  • Patients also can develop fever, chills, nausea, severe thirst, red eyes, headaches and joint pain. Episodes usually last up to one day. What causes the disease? CAPS are genetic diseases.[rheumatology.org]
  • In familial cold autoinflammatory syndrome (FCAS), exposure to cold (including air-conditioning) and—perhaps—other environmental triggers causes a hive-like rash, fever, chills, nausea, headaches and joint pain. Episodes usually last up to one day.[rheumatology.org]
  • Chills, sweats, headaches and nausea have also been reported. Symptoms remit spontaneously within less than 24 hours, but frequent bouts may severely compromise life quality. Some patients suffer from several episodes per week.[symptoma.com]
Vomiting
  • Muckle-Wells syndrome is characterized by symptoms that come and go, including skin rash, red eyes, joint pain and severe headaches with vomiting. Episodes last between one and three days.[arthritis.org]
  • The eyes often appear as bulging, and children often have episodes of vomiting. After 1 year of age, 50% of patients develop joint pain and swelling of the bones surrounding the large joints, especially the knees.[rheumatology.org]
  • The most common side effects of ILARIS when used for the treatment of CAPS include: cold symptoms, diarrhea, flu (influenza), runny nose, headache, cough, body aches, nausea, vomiting, and diarrhea (gastroenteritis), feeling like you are spinning (vertigo[ilaris.com]
  • Some symptoms may appear as: Fever Chronic meningitis (inflammation of the membranes surrounding the brain) Headaches Seizures Vomiting Hearing loss Vision loss Intellectual disability People with CAPS often experience: Joint inflammation Swelling Cartilage[checkorphan.org]
  • The eyes often appear as bulging, and children often have episodes of vomiting. Without treatment, 50% of patients develop joint pain and swelling of the bones surrounding the large joints, especially the knees.[rheumatology.org]
Hepatosplenomegaly
  • Also, patients develop osteopathy and long-bone epiphyseal overgrowth, growth delay, and progressive sensory neural hearing loss, lymphadenopathy, with/or without hepatosplenomegaly.[clevelandclinicmeded.com]
  • Other manifestations include short stature, hepatosplenomegaly, leukocytosis, and an elevation in serum levels of amyloid A and C-reactive protein and in the erythrocyte sedimentation rate.[doi.org]
  • Patients may also present with hepatosplenomegaly, headache, arthralgias, rashes as well as oral and vaginal apthous ulcers. These symptoms disappear once the fever abates, although skin and joint manifestation can take longer to resolve.[ncbi.nlm.nih.gov]
Hearing Impairment
  • In the most severe forms, they may develop serious organ damage such as visual and hearing impairment, neurological deterioration and renal insufficiency.[ncbi.nlm.nih.gov]
  • Supportive treatment is essential to manage the global burden of the disease including learning and cognitive impairment, growth and pubertal retardation, psychological /psychiatric distress, consequences of visual and hearing impairments.[orpha.net]
  • CAPS therapy should also include supportive measures in case of visual and hearing impairment, renal damage, growth disorders and mental retardation.[symptoma.com]
Urticaria
  • We herein report a case of a 75-year-old woman who presented with a low-grade fever, repeated cold-induced urticaria, and painful leg edemas with neutrocytosis.[ncbi.nlm.nih.gov]
  • Cryopyrin-associated periodic syndrome is an autoinflammatory syndrome caused by mutations of the CIAS1 gene (currently named NLRP3), and is characterized by periodic attacks of an urticaria-like rash, fever, head-ache, conjunctivitis and arthralgia.[ncbi.nlm.nih.gov]
  • Muckle-Wells syndrome Neonatal onset multisystemic inflammatory disorder [NOMID] Replacement Code This code replaces the following previously assigned ICD-10 code(s) listed below: L50.2 - Urticaria due to cold and heat[icdlist.com]
  • This also applies to anti-histamine treatment, which is often erroneously administered to remedy urticaria-like lesions.[symptoma.com]
  • Other symptoms include periodic fever, cold-induced urticaria-like rash, chronic aseptic meningitis, polyarticular arthralgias, and renal AA amyloidosis.[ncbi.nlm.nih.gov]
Eruptions
  • Fever, limb pain, conjunctivitis, and elevation of acute phase reactants are usually associated with skin eruption.[musculoskeletalkey.com]
  • It is important to consider CAPS as a differential diagnosis of chronic spontaneous urticaria if wheallike eruptions appear and repeat starting from shortly after birth.[ci.nii.ac.jp]
  • It is characterized by a chronic urticarial eruption that starts early in infancy or childhood. The distribution of the cutaneous eruption is widespread and favors the arms and legs over the face and trunk.[mdedge.com]
  • These syndromes were initially described as distinct clinical entities despite some clinical similarities: patients often present overlapping symptoms including fever, skin eruption appearing like hives (pseudo-urticarial) and joint involvement of varying[printo.it]
  • Methods: : A 46-year old man with urticaria-like skin eruptions, periodic fever, arthralgias and sensorineural hearing loss was referred for ophthalmological evaluation. MWS was suspected.[iovs.arvojournals.org]
Erythema
  • These reversible symptoms typically remit within a few days, but a faint, generalized erythema may persist. Progressive sensorineural hearing loss is experienced by two-thirds of MWS patients.[symptoma.com]
  • A 6-month-old male developed daily erythema and wheal without apparent itch starting from the day after birth. Antihistamines did not improve his urticaria-like eruptions.[ci.nii.ac.jp]
  • […] questionnaire based cohort study. ( 29678136 ) Mulders-Manders C.M....Hakkaart-van Roijen L. 2018 5 Cryopyrin-associated periodic syndrome in early childhood can be successfully treated with interleukin-1 blockades. ( 29331074 ) Eskola V....Korppi M. 2018 6 Erythema[malacards.org]
  • Urticarial rash is present, but initially infants have diffuse erythema. Patients with NOMID tend to have persistent inflammation.[clevelandclinicmeded.com]
  • Less common features of FMF include pericarditis, scrotal swelling, myalgia, and erysipeloid erythema.[ncbi.nlm.nih.gov]
Chronic Urticaria
  • Chronic urticaria represents an important differential diagnosis for CAPS. Chronic urticaria has no obvious cause, although some factors (e.g., drugs, infections, emotional stress, and food) can serve as eliciting stimuli.[musculoskeletalkey.com]
  • Most patients present with some or all of the following manifestations: chronic urticaria, sensorineural deafness, periodic arthritis, “aguey bouts.”[accessanesthesiology.mhmedical.com]
  • NOMID/CINCA (Neonatal-onset multisystem inflammatory disease / chronic infantile neurological cutaneous articular syndrome): This is the most severe form of CAPS, with chronic urticaria with or without fever noted at birth or in the newborn period.[clinicaladvisor.com]
  • Khan, The Expanding Field of Biologics in the Management of Chronic Urticaria, The Journal of Allergy and Clinical Immunology: In Practice, 10.1016/j.jaip.2017.05.018, 5, 6, (1489-1499), (2017). I. Kone‐Paut, P. Quartier, O. Fain, G. Grateau, P.[doi.org]
Arthritis
  • Twenty-one months after starting anakinra, the arthritis has disappeared, although nephrotic-range proteinuria persisted.[ncbi.nlm.nih.gov]
  • Pertinently, this CAPS is distinct from chronic infantile neurological cutaneous and arthritis syndrome/neonatal onset multisystemic inflammatory disease syndrome and Muckle-Wells syndrome (MWS), which also result from exon 3 mutations in this gene.[ncbi.nlm.nih.gov]
  • Differential diagnosis Differential diagnosis includes systemic-onset juvenile idiopathic arthritis, rheumatoid arthritis, systemic lupus erythematosus, familial mediterranean fever, Schnitzler syndrome, PLCG2-associated antibody deficiency and immune[orpha.net]
Arthralgia
  • Cryopyrin-associated periodic syndrome is an autoinflammatory syndrome caused by mutations of the CIAS1 gene (currently named NLRP3), and is characterized by periodic attacks of an urticaria-like rash, fever, head-ache, conjunctivitis and arthralgia.[ncbi.nlm.nih.gov]
  • Other symptoms include periodic fever, cold-induced urticaria-like rash, chronic aseptic meningitis, polyarticular arthralgias, and renal AA amyloidosis.[ncbi.nlm.nih.gov]
  • Past history: at the age of 20, he complained of arthralgia/arthritis and bilateral hypoacusis. At the age of 35, he presented posterior uveitis, several episodes of conjunctivitis, and progressive loss of visual acuity.[ncbi.nlm.nih.gov]
  • The mutation-positive patients were characterized by more frequent skin rashes, ocular symptoms, arthralgia, arthritis, and severe Muckle-Wells syndrome (MWS) Disease Activity Score. Rosacea was diagnosed in 8 patients.[ncbi.nlm.nih.gov]
  • She had a history of recurrent red eye and had been suffering episodes of skin rash and arthralgia induced by cold since childhood. At examination, she showed a reticulated corneal mid-stroma.[ncbi.nlm.nih.gov]
Myalgia
  • Nine patients (69%) reported myalgia. Six patients (46%) had papilledema and a further 2 (15%) had optic disc pallor. MRI brain scan was normal in all patients.[ncbi.nlm.nih.gov]
  • To identify the cause of disease in an adult patient presenting with recent-onset fevers, chills, urticaria, fatigue, and profound myalgia, who was found to be negative for cryopyrin-associated periodic syndrome (CAPS) NLRP3 mutations by conventional[ncbi.nlm.nih.gov]
  • Besides low-grade fever and rash, FCU patients typically suffer from conjunctivitis, arthralgia and myalgia. Chills, sweats, headaches and nausea have also been reported.[symptoma.com]
  • […] triggered by exposure to cold, low-grade fever (malaise), conjunctivitis, abdominal discomfort, and arthromyalgia; MWS which usually presents at birth or later in childhood, with recurrent urticarial rash, fever, abdominal pain, arthralgia/arthritis, myalgias[orpha.net]
Presentation at Age >18 Months
  • We describe a patient with severe cryopyrin-associated periodic syndrome who presented at age 18 months with macrocephaly and moderate sensorineural hearing loss, later developing systemic sequelae.[ncbi.nlm.nih.gov]
Kidney Failure
  • They are at risk for leukemia, infections, and some develop deposits of protein aggregated called amyloid , which can lead to kidney failure and other problems. The neurologic problems are most troubling.[checkorphan.org]
  • Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated.[rarediseases.org]
Headache
  • Twelve of the 13 patients (92%) had headache, of whom 10 (77%) had features of migraine. Seven patients (54%) had sensorineural deafness. Nine patients (69%) reported myalgia.[ncbi.nlm.nih.gov]
  • The most common clinical features were musculoskeletal symptoms, headaches, and ophthalmological symptoms.[ncbi.nlm.nih.gov]
  • Neurological involvement at diagnosis, mostly headaches and hearing loss, was noted in 17 patients (71%). Two patients of the same family had abnormal brain MRI.[ncbi.nlm.nih.gov]
  • Other symptoms include fever, chills, nausea, extreme thirst, headache and joint pain.[arthritis.org]
  • Fatigue and headaches, progressive sensorineural hearing loss, renal failure and fatal compromise of the CNS account for morbidity and mortality related to these diseases.[symptoma.com]
Papilledema
  • Six patients (46%) had papilledema and a further 2 (15%) had optic disc pallor. MRI brain scan was normal in all patients.[ncbi.nlm.nih.gov]
  • A slit lamp exam versus ophthalmoscopy may reveal papilledema, uveitis, and/or subcorneal infiltrates. Bony overgrowth of the knees may be present.[rheumatologyadvisor.com]
  • With regards to the latter, headaches, vomiting and seizures as well as papilledema are most commonly registered. Over time, growth disorders and developmental delays become apparent. Visual and hearing impairment are frequently reported.[symptoma.com]
  • CNS manifestations include chronic aseptic meningitis, mental retardation, cerebral atrophy, and chronic papilledema. NOMID can result from a mutation in the CIAS1 gene, which helps control inflammation.[allergycases.blogspot.com]
  • Clinically he had short stature [Figure 1], short neck, conjunctival congestion, diffuse urticarial rash, clubbing [Figure 1] and bilateral papilledema. The rest of the examination was normal.[jpgmonline.com]
Seizure
  • Onset, severity and complications (mainly retardation, seizures, destructive arthropathy and amyloidosis) depend on the specific mutation. Diagnosis is determined by genetic tests but is often delayed due to lack of awareness.[ncbi.nlm.nih.gov]
  • […] conjunctivitis and/or uveitis, or less commonly optic nerve atrophy, cataract, glaucoma or impaired vision; 71% of cases), neurosensory hearing loss (42% of cases), neurological involvement (morning headache, papilloedema, and/or meningitis, or less commonly seizure[en.wikipedia.org]
  • Additionally, conjunctivitis, arthralgia and myalgia, progressive hearing loss, visual impairment, headaches and seizures may be observed. Disease onset is usually in infancy, childhood or adolescence.[symptoma.com]
  • Some symptoms may appear as: Fever Chronic meningitis (inflammation of the membranes surrounding the brain) Headaches Seizures Vomiting Hearing loss Vision loss Intellectual disability People with CAPS often experience: Joint inflammation Swelling Cartilage[checkorphan.org]
  • Residual neurologic symptoms such as left hemiplegia and seizures have been noted; he is receiving physiotherapy and an antiepileptic regimen.[pediatrics.aappublications.org]

Workup

Diagnosis of CAPS is often delayed and only the entirety of anamnestic data, general, ophthalmological, otological and neurological findings will eventually prompt a specific workup.

  • Besides the respective physical examinations, laboratory analyses of blood samples are helpful in CAPS diagnosis. Affected individuals typically show leukocytosis and neutrophilia as well as elevated levels of C-reactive protein and serum amyloid A. These parameters are often altered even though patients present without acute cutaneous symptoms.
  • If skin biopsies are performed, histopathological analysis generally reveals perivascular polymorphnuclear infiltrates in the dermis. The underlying phenomenon is referred to as neutrophilic epitheliotropism [9].
  • Genetic screens confirming NLRP3 mutations are considered diagnostic for CAPS. However, this approach may lack sensitivity, particularly in CINCA patients. While the vast majority of FCU and MWS patients tests positive for NLRP3 gene defects, this only applies to about half of individuals affected by the most severe phenotype of CAPS.

Further diagnostic measures may become necessary in case of CAPS-related renal failure or CNS involvement. Here, analyses of urine and/or cerebrospinal fluid may be indicated. Proteinuria and enhanced concentrations of pro-inflammatory mediators, respectively, imply advanced stages of the disease.

White Matter Lesions
  • In addition, the chronic inflammatory white matter lesions observed on brain MRI and the responsiveness to IL-1β blockade with anakinra are unusual.[ncbi.nlm.nih.gov]

Treatment

Anti-IL-1β treatment has proven effective in relieving CAPS-associated symptoms and preventing progression to end-stage renal disease or severe CNS lesions [10]. Accordingly, anakinra, canakinumab and rilonacept have been used to treat CAPS patients. Anakinra acts as an antagonist of the IL-1 receptor, canakinumab is an antibody targeting this same receptor, and rilonacept binds IL-1 without triggering the respective pro-inflammatory cascade. Common side effects are injection site reactions, gastrointestinal complaints as well as susceptibility to upper respiratory and urogenital infections [11]. However, the benefits of such treatment by far outweigh the risks, permit permanent disease control and a significant augment of life quality. The major hurdle in CAPS therapy is not the choice of an appropriate medication, but rather the timely diagnosis of the disease.

CAPS therapy should also include supportive measures in case of visual and hearing impairment, renal damage, growth disorders and mental retardation. It should be noted that common anti-inflammatory medication like non-steroidal anti-inflammatory drugs are not effective in case of CAPS. This also applies to anti-histamine treatment, which is often erroneously administered to remedy urticaria-like lesions. Corticosteroids relieve symptoms, but before long-term use of such drugs is advised, possible side effects and adverse events should be considered.

Affected families may benefit from psychological counseling.

Prognosis

FCU, MWS and CINCA are CAPS-associated entities of increasing severity. Fatigue and headaches, progressive sensorineural hearing loss, renal failure and fatal compromise of the CNS account for morbidity and mortality related to these diseases. While the former are reversible symptoms, nerve and kidney damage are common sequelae if diagnosis of CAPS is delayed. Mortality is high in CINCA patients and death often occurs during infancy.

An early diagnosis permits a timely initiation of anti-IL-1β treatment, and such therapy reduces the risk of life-threatening complications and augments life quality.

Etiology

Autoimmune disorders inducing CAPS are genetic diseases and despite all known mutations being inherited with an autosomal dominant trait, de novo mutations are common [3]. It has long since been assumed that CINCA, FCU and MWS patients all present gain-of-function mutations of the gene encoding for cryopyrin. This gene is also known as the cold-induced autoimmune syndrome (CIAS) gene or NLRP3 gene, and it is located on the long arm of chromosome 1 (position 1q44). Even though distinct mutations of this gene have been related to CAPS, a determined genetic defect may provoke any of the aforementioned phenotypes, i.e., CINCA, FCU or MWS. This observation implies that additional factors - presumably further genes or environmental conditions - contribute to symptom onset and severity. According to this hypothesis, some CAPS patients may not even show NLRP3 mutations [3]. It has to be noted though that mosaicism has been described in CAPS patients and this phenomenon may not only account for disease heterogeneity, but may also explain presumed negativity for NLRP3 mutations [4]. With regards to non-NLRP3 mutations, sequence alterations of the promoter region of the NLRP3 gene have been registered. In affected individuals, CAPS may be induced by an overexpression of cryopyrin as opposed to the increased activity of the protein observed in "classical" CAPS-related genotypes [5].

Epidemiology

According to epidemiologic studies, CAPS incidence ranges from 1 to 10 per 1,000,000 inhabitants [1]. However, true incidence rates are likely to be higher since the disease is presumably underdiagnosed: lack of awareness as well as clinical and genetic heterogeneity all complicate diagnosis of CAPS. A retrospective study that has recently been conducted in France revealed 21 different sequence variants in a total of 135 CAPS patients, almost half of them being newly described gene defects [2].

Most known CAPS patients are Caucasians and no gender predilection has been reported. Interestingly, FCU is most often diagnosed in North America while MWS seems to be more common in Europe. It is currently not known whether this results from an assignment preference or the presence of large families affected by the respective disorders [6].

Sex distribution
Age distribution

Pathophysiology

As has been indicated above, CAPS is generally provoked by gain-of-function mutations of the NLRP3 gene, and only little is known about additional genetic defects or environmental factors contributing to CAPS pathogenesis.

The NLRP3 gene encodes for an intracellular nucleotide-binding oligomerization domain-like receptor (NLR) which is activated upon recognition of danger-associated or pathogen-associated molecular patterns (DAMP and PAMP). Thus, both non-infectious stimuli and infectious agents are able to induce downstream events like caspase-1 recruitment that eventually lead to inflammasome assembly [1]. In the absence of such stimuli, the corresponding pro-inflammatory cascade should not be activated. In CAPS patients, however, the regulation of inflammasome assembly is disturbed and an increased caspase-1 activity can be observed. This enzyme mainly processes pro-IL-1β, but is also involved in IL-18 maturation. Both IL-1β and IL-18 are pro-inflammatory cytokines and they are assumed to account for the majority of CAPS-related symptoms.

IL-1β has been shown to mediate fever, inflammation and fatigue, which all contribute to CAPS patient's decreased quality of life. Accordingly, anti-IL-1β drugs have been used to treat CAPS patients [7].

Prevention

No specific measures can be recommended to prevent de novo mutations provoking CAPS. Affected families, however, may benefit from genetic counseling since the disease is inherited with an autosomal dominant trait.

Summary

As the designation "syndrome" indicates, cryopyrin-associated periodic syndrome (CAPS) refers to a symptom complex rather than to an individual pathology. CAPS patients show symptoms resulting from an autoimmune-mediated, systemic inflammatory reaction that is, in turn, provoked by an excessive production of interleukin-1β (IL-1β). This cytokine is synthesized as an inactive pro-form, and only cleavage of pro-IL-1β yields an active, pro-inflammatory mediator. Inflammasome assembly plays an important role in IL-1β maturation and in case of CAPS, the physiological regulation of NLRP3 inflammasome assembly is disturbed.

CAPS comprises several diseases, all of which are characterized by constitutive activation of the NLRP3 inflammasome. They do, however, differ in geographical distribution and mean age at symptom onset, in clinical presentation, organ compromise, severity and prognosis. In detail, the following disorders have been related to CAPS:

  • Chronic infantile neurologic, cutaneous, and articular syndrome (CINCA syndrome), in Anglo-American countries often referred to as neonatal-onset multisystem inflammatory disease (NOMID)
  • Familial cold urticaria (FCU), also known as familial cold autoinflammatory syndrome (FCAS)
  • Muckle Wells syndrome (MWS)

CAPS is a rare disorder that affects less than 10 per 1,000,000 inhabitants [1], and incidence rates of the aforementioned, single entities are accordingly even lower. Lacking awareness and disease heterogeneity - symptoms may range from fever and rash to conjunctivitis and arthralgia - often result in diagnosis delay. This is well illustrated by the fact that the mean age at symptom onset is < 1 year, whereas CAPS is generally not diagnosed before puberty.

Although diagnostic guidelines have not yet been established, recurrence of symptoms like fever and urticaria, symptom onset during the first two decades of life and elevated concentrations of C-reactive protein have been proposed as key criteria that should prompt tests for CAPS [2]. The outcome largely depends on an early initiation of treatment with anti-IL-1β drugs like anakinra, canakinumab or rilonacept, which are very effective, relieve symptoms and improve quality of life.

Patient Information

Cryopyrin-associated periodic syndrome (CAPS) refers to a rare symptom complex induced by distinct mutations of the same gene. CAPS may be considered an inflammatory disorder and a hereditary disease that varies largely in mean age at symptom onset, clinical presentation, organ compromise, severity and prognosis. Depending on the aforementioned parameters, CAPS patients may be diagnosed with familial cold urticaria (FCU); Muckle Wells syndrome (MWS); or chronic infantile neurologic, cutaneous, and articular syndrome (CINCA syndrome). However, fatigue, fever as well as recurrent rash, i.e., occurrence of non-itchy, generalized reddened and swollen patches and plaques, are characteristic for all forms of CAPS. Additionally, conjunctivitis, arthralgia and myalgia, progressive hearing loss, visual impairment, headaches and seizures may be observed. Disease onset is usually in infancy, childhood or adolescence.

CAPS-related symptoms are provoked by enhanced release of mature interleukin-1β (IL-1β), a pro-inflammatory mediator whose maturation is stimulated by the product of the mutated gene. Consequently, drugs impairing IL-1β actions are helpful to relieve symptoms and to prevent disease progression. Distinct compounds are available that interfere with binding of IL-1β to its receptor. If an appropriate therapy is initiated in a timely manner, the outcome is generally favorable. Unfortunately, diagnosis of CAPS is often delayed due to the heterogeneity of clinical presentation and underlying genetic defects.

References

Article

  1. Giat E, Lidar M. Cryopyrin-associated periodic syndrome. Isr Med Assoc J. 2014; 16(10):659-661.
  2. Cuisset L, Jeru I, Dumont B, et al. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis. 2011; 70(3):495-499.
  3. Aksentijevich I, Nowak M, Mallah M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002; 46(12):3340-3348.
  4. Saito M, Nishikomori R, Kambe N, et al. Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients. Blood. 2008; 111(4):2132-2141.
  5. Anderson JP, Mueller JL, Misaghi A, et al. Initial description of the human NLRP3 promoter. Genes Immun. 2008; 9(8):721-726.
  6. Aksentijevich I, C DP, Remmers EF, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007; 56(4):1273-1285.
  7. Koné-Paut I, Galeotti C. Current treatment recommendations and considerations for cryopyrin-associated periodic syndrome. Expert Rev Clin Immunol. 2015; 11(10):1083-1092.
  8. Kuemmerle-Deschner JB, Koitschev A, Ummenhofer K, et al. Hearing loss in Muckle-Wells syndrome. Arthritis Rheum. 2013; 65(3):824-831.
  9. Broekaert SM, Boer-Auer A, Kerl K, et al. Neutrophilic Epitheliotropism is a Histopathological Clue to Neutrophilic Urticarial Dermatosis. Am J Dermatopathol. 2016; 38(1):39-49.
  10. Kitley JL, Lachmann HJ, Pinto A, Ginsberg L. Neurologic manifestations of the cryopyrin-associated periodic syndrome. Neurology. 2010; 74(16):1267-1270.
  11. Radin A, Marbury T, Osgood G, Belomestnov P. Safety and pharmacokinetics of subcutaneously administered rilonacept in patients with well-controlled end-stage renal disease (ESRD). J Clin Pharmacol. 2010; 50(7):835-841.

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Last updated: 2019-07-11 19:59