Cryopyrin-associated periodic syndromes are a group of rare inflammatory diseases including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurologic cutaneous and articular syndrome (CINCA), known in the USA as neonatal-onset multisystem inflammatory disease (NOMID). These syndromes were initially described as unrelated diseases despite their similarities. In several of these syndromes, patients have similar symptoms: fever, hives-like rash, joint problems of varying severity, and general inflammatory symptoms, such as fever. Between these three syndromes, there is a sliding scale of severity. FCAS is the mildest, CINCA (NOMID) is the most severe, and patients with MWS present an intermediate clinical picture. Research into the cause of all three of these disorders has revealed that mutations in the same gene are responsible.
CAPS is very rare, but people all over the world are affected. CAPS is not contagious.
CAPS are genetic diseases. The gene responsible for the three syndromes (FCAS, MWS, CINCA/NOMID) is called CIAS1 and encodes the protein cryopyrin (aka NLRP3). This protein plays an important role in inflammatory responses. Mutations in the gene lead to increased activity of the protein, resulting in elevated inflammatory responses. These increased inflammatory responses are responsible for the clinical manifestations seen in CAPS. In 30% of patients with CINCA/NOMID, a CIAS1 mutation cannot be detected. There is some relation between the mutations and the symptoms. Mutations in patients with the mildest forms of CAPS are never found in patients with the most severe form of CAPS and vice versa. It is likely that other genetic or environmental influences may influence the severity and symptoms of the disease.
CAPS are autosomal dominant diseases, meaning that the disease is passed on by one of the parents who also has the disease and has an abnormal copy of the CIAS1 gene. Because we have two copies of each gene, the risk of an affected parent passing on a mutated copy to the child and thus passing on the disease is 50%. New mutations also occur. This means that neither of the parents has the disease and that the CIAS1 gene has spontaneously mutated in the child. In that case, the chances of the next child in the family developing CAPS are extremely low.
The rash is a key symptom in all three diseases and is usually the first visible symptom. For all forms of CAPS, the rash is similar: areas of bumps and spots that resemble hives but are usually not itchy. The severity of the rash varies from patient to patient and can also vary over time. FCAS, also known as familial cold autoinflammatory syndrome, is characterized by repeated short episodes of fever, rash and joint pain triggered by exposure to cold ambient temperatures. Other common symptoms include inflamed eyes and muscle pain. Symptoms begin 1 to 2 hours after exposure to low temperatures or after significant changes in temperature, and the duration of the attacks is usually short (less than 24 hours). These attacks pass on their own. Patients often tell that after a warm night they wake up feeling well, but that they get worse later in the day after exposure to cold. Early onset of the disease, at birth or within the first 6 months of life, is common. Inflammation is detected by blood tests during disease activity. To what extent FCAS affects the quality of life depends on the frequency and intensity of the disease symptoms. However, late complications such as deafness and amyloidosis are rare or non-existent. MWS is characterised by recurrent episodes of fever, rash, joint and eye inflammation, although fever is not always clearly present. Chronic fatigue is very frequent. There are usually no triggers for an attack, and cold rarely triggers attacks either. The course of the disease varies between patients from more typical recurrent attacks of inflammation to more permanent symptoms. As in FCAS, patients with MWS often feel worse in the evening. The first symptoms usually occur in young children, but occasionally the disease develops later in childhood. Deafness occurs in about 70% of the patients and usually begins in childhood or early adulthood. Amyloidosis is the most serious complication of MWS and develops in approximately 25% of the adult patients. This complication is caused by the deposition of amyloid, a specific protein related to inflammation. This deposition can occur in the intestine, the skin, the heart, and particularly in the kidneys. These depositions cause gradual loss of the function of the affected organ. If the kidneys are affected, amyloidosis manifests as loss of protein in the urine, followed by kidney failure. Amyloidosis is not specific to CAPS and can occur in other chronic inflammatory diseases. Inflammation is observed in the blood during inflammatory episodes or in more severe cases continuously. The impact of MWS on the quality of life varies from patient to patient. CINCA (NOMID) is associated with the most severe symptoms in this spectrum of diseases. The rash is usually the first sign and occurs at or shortly after birth. One third of the patients is too small at birth, which may or may not be due to premature birth. Fever can be intermittent, very mild or in some cases absent. Patients often suffer from fatigue. Inflammation of the bone and joints vary in severity. In approximately two third of the patients, joint pain and transient swelling of the joints only occur during flare-ups of the disease. In one third of the patients, however, severe and disabling joint damage occurs as a result of cartilage overgrowth. This can cause severe damage of the joints, with pain and limited range of motion. Knees, ankles, wrists and elbows are often affected at both sides. It leads to typical abnormalities on X-rays. Overgrowth arthropathy usually starts at a young age (before the age of three years). Abnormalities of the central nervous system (CNS) are present in almost all patients and are caused by chronic aseptic meningitis. This chronic inflammation can lead to increased brain pressure. The symptoms related to this vary in intensity and include: chronic headaches, vomiting, irritability (in young children), swelling of the optic nerve during fundoscopy (a specialised eye exam). Epilepsy (seizures) and cognitive impairment occur occasionally in severely affected patients. The eyes can also be affected by the disease; inflammation can occur both in the front and in the back of the eye. The eye symptoms can progress to partial loss of vision. Hearing impairment is common and usually occurs in adolescence or adulthood. Amyloidosis develops with increasing age in 25% of the patients. Growth retardation and delay in the development of pubertal traits may be caused by chronic inflammation. In most cases, continuous inflammation is detectable in the blood. Careful examination of patients with CAPS usually reveals an overlap of symptoms. Patients with MWS have symptoms consistent with FCAS, such as cold susceptibility (i.e. more frequent attacks in the winter), or symptoms consistent with mild central nervous system involvement, such as frequent headaches or swelling of the optic nerve, as seen in patients with CINCA (NOMID). Symptoms related to neurological involvement can become obvious in patients with increasing age. CAPS patients from the same family may show some variation in severity and symptoms. However, severe manifestations of CINCA (NOMID), such as overgrowth arthropathy or severe neurological involvement, have never been observed in relatives of patients with mild forms of CAPS (FCAS or mild MWS).
Course of the disease
There is a huge variation in severity. Patients with FCAS have a mild disease with a good long-term prognosis. Muckle-Wells patients are more severely affected, due to possible deafness and amyloidosis. CINCA/NOMID patients have the most severe disease. Within this group, variability also exists depending on the severity of neurological and joint involvement.
The diagnosis of CAPS is based on the clinical symptoms and can be confirmed by genetic testing. Distinguishing between FCAS and MWS or between MWS and CINCA (NOMID) may be difficult because of the overlapping symptoms. The diagnosis is based on the clinical symptoms and the medical history of the patient. Ophthalmologic evaluation (in particular fundoscopy), cerebrospinal fluid examination (lumbar puncture) and X-rays can help distinguish between these related diseases.
CAPS cannot be cured since they are genetic diseases. However, thanks to substantial advances in understanding the origins of these disorders, new promising treatments are under investigation.
Recent research into the genetics and physiopathology of CAPS shows that Interleukin-1 (IL-1), a powerful protein of inflammation (cytokine), is overproduced in these conditions and plays a major role in the onset of these diseases. Currently, a number of drugs that inhibit IL-1 are being developed. The first drug used in treating these disorders was anakinra (Kineret ®). It was shown to be rapidly efficient in controlling inflammation, rash, fever, pain and fatigue in all CAPS patients. This treatment also effectively improves neurological involvement. In some conditions, it may improve deafness and control amyloidosis. Unfortunately, this drug does not seem to be effective for joint damage due to overgrowth arthropathy. The required dose depends on the severity of the disease. Treatment must be started at a young age, before chronic inflammation causes irreversible organ damage, such as deafness or amyloidosis. Anakinra is given daily, via injections under the skin. Skin irritation at the site of the injections often occurs. Rilonacept (Arcalyst ®) is another anti-IL-1 drug approved in the USA for patients older than 11 years who suffer from FCAS or MWS. Rilonacept requires weekly injections under the skin. Canakinumab (Ilaris ®) is another anti-IL-1 drug recently approved by the USA authorities and by the European Medicines Agency (EMA) for CAPS patients aged 4 years and older. In MWS patients, this drug was recently found to be effective in controlling the disease manifestations when injected under the skin every 8 weeks. Because of the genetic nature of the disease, it is likely that treatment will have to be maintained for life.
CAPS is a life-long disease. The long-term prognosis of FCAS is good, but the quality of life can be affected by recurrent episodes of fever. In the Muckle-Wells syndrome, the prognosis depends on amyloidosis and the associated renal dysfunction and possible deafness. Children with CINCA may have growth disturbances. In CINCA (NOMID), the long-term prognosis depends on the severity of the neurological, neurosensorial and joint problems. Overgrowth arthropathy may result in severe disability. Premature death is possible in severely affected patients.