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].

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.

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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