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

  Muckle-Wells syndrome (MWS) causes intermittent fevers, urticarial rash, joint pain, and progressive deafness; 25% of patients develop renal amyloidosis. [merckmanuals.com]

  Other autoinflammatory disorders may also benefit from rilonacept treatment, with clinical trials in progress for systemic onset juvenile idiopathic arthritis, gout and familial mediterranean fever. [dovepress.com]

  Fever and meningitis were added, but no microorganism was identified. [pediatrics.aappublications.org]

  Fever (FMF) Tumour Necrosis Factor (TNF)-Associated Periodic Syndrome (TRAPS) Mevalonate Kinase Deficiencies: Hyper-IgD with Periodic Fever Syndrome (HIDS), and Mevoalonate Aciduria (MA) Periodic Fever, Aphthous Stomatitis, Pharyngitis, & Cervical Adenitis [coldallergy.org]

  From Wikidata Jump to navigation Jump to search syndrome Cryopyrin associated periodic fever syndrome edit Language Label Description Also known as English Cryopyrin-associated periodic syndrome syndrome Cryopyrin associated periodic fever syndrome Statements [wikidata.org]

• Amyloidosis

  Laboratory tests disclosed nephrotic syndrome, and renal biopsy showed AA amyloidosis. He was given anakinra with improvement of arthritis. [ncbi.nlm.nih.gov]

  Muckle-Wells syndrome (MWS) causes intermittent fevers, urticarial rash, joint pain, and progressive deafness; 25% of patients develop renal amyloidosis. [merckmanuals.com]

  — UDA Syndrome — Syndrome, UDA — Syndromes, UDA — UDA Syndromes — Urticaria-Deafness-Amyloidosis Syndrome — Syndrome, Urticaria-Deafness-Amyloidosis — Syndromes, Urticaria-Deafness-Amyloidosis — Urticaria Deafness Amyloidosis Syndrome — Urticaria-Deafness-Amyloidosis [mesh.kib.ki.se]

• Fatigue

  Similarly to MWS, fatigue is typically a symptom more frequently than fevers. [patientworthy.com]

  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]

  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]

  Cold, fatigue, stress, or exercise are universal triggers of acute inflammation however acute attacks may appear unprovoked. [orpha.net]

• 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]

  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]

  Intense general malaise and chills occur at the same time and lead to severe disability. [orpha.net]

  Individuals with MWS often have episodic fever, chills, and joint pain. As a result, MWS is considered a type of periodic fever syndrome. MWS is caused by a defect in the CIAS1 gene which creates the protein cryopyrin. [en.wikipedia.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]

  […] 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]

• Pneumonia

  Seven consecutive patients with cryopyrin-associated periodic syndrome experienced severe inflammation following receipt of a Streptococcus pneumoniae vaccination, according to a recently published report. [healio.com]

  Dose increased 2038 7/F Post lumbar puncture syndrome 5 months Mild No action 2042 1.3/F Pneumonia 7 months Moderate No action Patient no. [academic.oup.com]

  Severe Inflammation Following Vaccination Against Streptococcus Pneumoniae in Patients with Cryopyrin-Associated Periodic Syndromes “Pneumococcal vaccines can trigger a severe local and systemic inflammatory reaction in patients with CAPS.” [saidsupport.org]

  It has been recommended that the long-acting anti-IL-1 agents in very young children should be used in conjunction with antibiotic prophylaxis and immunisation against Streptococcus pneumoniae and Haemophilus influenzae as for post-splenectomy. [dermnetnz.org]

  […] clinical response (reduction in fever and irritability) and complete laboratory response (improved C‐reactive protein and serum amyloid A levels) to humanized anti–IL‐6 receptor antibody (MRA), but died from congestive heart failure and interstitial pneumonia [doi.org]

• Nausea

  A 43-year-old woman with MWS received the vaccine and developed fever, profuse shivering, sweating, nausea and vomiting, followed by a severe headache, photophobia and neck stiffness 4 days later. [healio.com]

  weight gain, injection site reactions (such as redness, swelling, warmth, or itching), and nausea. [ilaris.com]

  Systemic findings such as conjunctivitis, myalgia, and nausea may also be seen. Rarely, patients may experience headache, diaphoresis, drowsiness, and amyloidosis. [visualdx.com]

  Other symptoms include fever, chills, nausea, extreme thirst, headache or joint pain. [arthritis.org]

• Vomiting

  Early symptoms of NOMID may include a hive-like rash that doesn't itch, headache, bulging eyes or blindness, hearing loss, repeated vomiting or joint pain and swelling. [arthritis.org]

  A 43-year-old woman with MWS received the vaccine and developed fever, profuse shivering, sweating, nausea and vomiting, followed by a severe headache, photophobia and neck stiffness 4 days later. [healio.com]

  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]

• 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]

  Abdominal CT revealed hepatosplenomegaly with inguinal and retroperitoneal adenopathies measuring less than 1cm. [elsevier.es]

  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]

  Hearing impairment grades II to IV are considered disabling. Profound hearing impairment constitutes deafness. [ped-rheum.biomedcentral.com]

  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]

• Tinnitus

  All adult patients were additionally tested using speech audiometry, caloric vestibular stimulation and tinnitus handicap questioning. [ped-rheum.biomedcentral.com]

• Visual Impairment

  We underscore that ocular involvement in MuckleWells syndrome should be carefully assessed, since it can lead to visual impairment. [ncbi.nlm.nih.gov]

  We want to emphasize that ocular involvement in MWS should be carefully assessed, since it can lead to visual impairment. [ard.bmj.com]

  A total of 36 of the patients were diagnosed with NOMID, which is characterized by fevers, rash, headache, aseptic meningitis, hearing loss, visual impairment, and cognitive difficulties. [medpagetoday.com]

  CAPS therapy should also include supportive measures in case of visual and hearing impairment, renal damage, growth disorders and mental retardation. [symptoma.com]

  In addition, these patients have sensorineural progressive hearing loss, visual impairment due to chronic papilloedema and cognitive impairment. Approximately 20% of patients with NOMID syndrome do not survive into adulthood if untreated [ 4, 5 ]. [academic.oup.com]

• Arthritis

  Twenty-one months after starting anakinra, the arthritis has disappeared, although nephrotic-range proteinuria persisted. [ncbi.nlm.nih.gov]

  Arthritis Res Ther. 2011;13(6):R196. Tanaka N, Izawa K, Saito MK, et al. [the-rheumatologist.org]

  Arthritis Rheum 58 : 2432–2442 6. Taylor PC (2003) Anti-cytokines and cytokines in the treatment of rheumatoid arthritis. Curr Pharm Des 9 : 1095–1106 7. [nature.com]

• Arthralgia

  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]

  Conclusion: Articular symptoms encountered in CAPS are very common and found in 82% of patients with arthralgia and synovitis in knees and ankles. These symptoms are considered predominant for 20% but rarely explored by imaging. [acrabstracts.org]

  Typically, familial cold autoinflammatory syndrome (FCAS) causes a cold-induced urticarial rash accompanied by fever and sometimes arthralgias. The condition often appears in the first year of life. [merckmanuals.com]

• 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]

  Tendinopathy occurred in 13 patients (15%) and myalgia in 29 cases (33%). Only two patients had arthropathy with a typical non-inflammatory enlargement of the growth plates and epiphyses of long bones. [acrabstracts.org]

  Myalgia, arthralgias and distal edema are very common. With age, patients develop eythematous band over the hands as well as digital clubbing. [orpha.net]

• Urticaria

  A case of cold urticaria with an unusual family history. JAMA. 1940;114(12):1067–1068. Muckle TJ, Wells M. Urticaria, deafness and amyloidosis: A new heredo-familial syndrome. QJ Med. 1962 Apr;31:235–248. Prieur AM, Griscelli C. [the-rheumatologist.org]

  Cold Induced Autoinflammatory Syndrome — Familial Cold Autoinflammatory Syndrome 1 — FCAS1 — Familial Cold Urticaria — Cold Urticarias, Familial — Familial Cold Urticarias — Urticaria, Familial Cold — Urticarias, Familial Cold — Cold Urticaria, Familial [mesh.kib.ki.se]

  Case 2 A 2-year-old girl visited our hospital; she had had recurrent urticaria and arthritis (particularly at the knee joint) since birth. [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]

• Skin Rash

  Her mother and her younger sister also suffered from relapsing episodes of skin rash and fever triggered by cold as well as flares of red eye. They had developed premature hearing loss. [ncbi.nlm.nih.gov]

  […] months Urticarial rash + ND ND ND + ND – ND FCAS 31 years/F 2 years Skin rash + ND + + + ND ND ND Yamashita et al. 1987 (17) FCAS 3 years/M 2 months Skin rash + ND + – + ND ND ND CINCA 14 years/M At birth Skin rash ND ND + + ND ND ND + Inamo et al. 1994 [medicaljournals.se]

  As for FCAS, in these two diseases, the skin rash is observed only during the fever attacks, but is not induced by cold exposure. [musculoskeletalkey.com]

• Erythema

  430079001 – Cryopyrin associated periodic syndrome Look For Subscription Required Diagnostic Pearls Subscription Required Differential Diagnosis & Pitfalls Systemic-onset juvenile idiopathic arthritis Familial Mediterranean fever – recurrent erysipelas-like erythema [visualdx.com]

  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]

  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]

  With the exception of one event of injection site erythema in a patient 12–17 years, ISRs were only reported in patients 2–11 years and ⩾18 years of age. There was no difference in reporting rates of ISRs between males and females. [academic.oup.com]

• 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]

  The eruption consists of urticarial migratory plaques that may be generalized. [visualdx.com]

  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]

• Sweating

  A 43-year-old woman with MWS received the vaccine and developed fever, profuse shivering, sweating, nausea and vomiting, followed by a severe headache, photophobia and neck stiffness 4 days later. [healio.com]

  Tell your healthcare provider right away if you have any symptoms of an infection such as fever, sweats or chills, cough, flu-like symptoms, weight loss, shortness of breath, blood in your phlegm, sores on your body, warm or painful areas on your body [ilaris.com]

  Skin biopsy from the urticaria-like rash can suggest the diagnosis of a cryopyrin-associated periodic syndrome, as it shows a perivascular and sometimes peri-eccrine (around sweat gland) neutrophilic infiltrate of the reticular dermis, without mast cells [dermnetnz.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]

• 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]

  Other symptoms include fever, chills, nausea, extreme thirst, headache or joint pain. [arthritis.org]

  He also suffered from “migraine” headaches, which similarly lessened in severity as he grew older. [the-rheumatologist.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]

  Headaches were characterized as migraines or not-migraines according to the International Classification of Headache Disorders, 2nd edition. [ojrd.biomedcentral.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]

  The CNS involvement commonly encountered by ophthalmologists includes aseptic meningitis with associated papilledema, optic nerve pallor from previous episodes of papilledema, and uveitis.[2–5],[11],[12] CINCA/NOMID may also present with dry eye, conjunctivitis [tandfonline.com]

  A slit lamp exam versus ophthalmoscopy may reveal papilledema, uveitis, and/or subcorneal infiltrates. Bony overgrowth of the knees may be present. [rheumatologyadvisor.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]

  Residual neurologic symptoms such as left hemiplegia and seizures have been noted; he is receiving physiotherapy and an antiepileptic regimen. [pediatrics.aappublications.org]

  hearing loss, and neurodegeneration Congenital deafness with Labyrinthine Aplasia, Microtia ,and Microdontia (LAMM) Craniometaphyseal Dysplasia Craniosynostosis Deafness and Myopia Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation, and Seizures [genedx.com]

  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]

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.

• Neutrophilia

  Before anakinra treatment the patient showed typical clinical and serological signs of active inflammatory disease, including rash, polyarthritis of wrists and metacarpal joints, leucocytosis with neutrophilia, and a moderate acute phase response. [doi.org]

  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. [symptoma.com]

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.

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.

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].

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].

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].

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.

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.

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.

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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.
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5. Anderson JP, Mueller JL, Misaghi A, et al. Initial description of the human NLRP3 promoter. Genes Immun. 2008; 9(8):721-726.
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