Cryopyrin-Associated Autoinflammatory Syndromes (CAPS) are a group of illnesses related to defects in the protein cryopyrin (also called NLRP3). These diseases differ in the systems involved and in the severity of the disease. CAPS is rare, found in about one in 360,000 to 1,000,000 people. Familial cold autoinflammatory syndrome (FCAS) is the mildest condition, Muckle-Wells syndrome (MWS) may cause long-term complications, and neonatal onset multisystem inflammatory disease (NOMID) is the most severe and presents shortly after birth. Males and females are both affected, and all ethnic groups can be affected.
Cryopyrin-associated autoinflammatory syndromes (CAPS) consist of three diseases related to a defect in the same gene. The three diseases differ in the organs involved and in the severity of the disease. They include:
Neonatal Onset Multisystem Inflammatory Disease (NOMID) is the most severe and least common of the CAPS. It causes fever with inflammation in multiple organs starting shortly after birth. Infants present with symptoms of infection (e.g., fever, rash) but no infection is found. The rash resembles hives. Patients can have chronic meningitis (inflammation of the membranes surrounding the brain) resulting in headache, blindness, hearing loss, or other neurologic problems. 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. There can be growth delay; children with NOMID are often very short. Not all children have all of these symptoms.
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. Deafness or partial hearing loss often develops by teenage years, and, if untreated, it may lead to amyloidosis.
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. There are no known long-term secondary consequences.
CAPS are genetic diseases. CAPS are inherited as an autosomal dominant disease (in which a mutation in only one copy of the gene inherited from one parent is sufficient to cause disease). That means that one of the parents may be ill with CAPS, or that the gene mutation developed in the sick child. A genetic defect is found by traditional methods in only 50 - 60% of patients with NOMID, in 65 - 75% of patients with Muckle-Wells syndrome, and in nearly all patients with familial cold auto inflammatory syndrome. The gene mutation causes a defect in a protein called cryopyrin or NLRP3, which has an important role in controlling inflammation.
CAPS is suspected by the patient’s history, as well as by symptoms and signs found by the physician on physical examination during a fever episode. Bloodwork may reveal high levels of inflammation during flares. The diagnosis may be confirmed by a genetic test, although occasionally the genetic test may be normal. Other tests to support the diagnosis may include skin biopsy (examining a small sample of the skin), an eye examination, hearing tests, lumbar puncture (obtaining fluid from the spine) and imaging of the brain and inner ears by magnetic resonance imaging (MRI).
Medications that target interleukin-1 are very effective in treating CAPS. These medications, given by injection, include anakinra (Kineret), rilonacept (Arcalyst) and canakinumab (Ilaris). Treatment must continue throughout life, as there is no known cure. It is important to diagnose early and start treatment quickly since there is usually no repair to damage that has occurred to brain, eyes, bones, and ears. Higher doses and more frequent injections are often needed to treat patients with brain involvement and severe headaches.
Other treatments include physical therapy, splints and other aids to treat joint deformities if they occur. Surgery is occasionally needed. Hearing aids are needed for children with deafness.
Untreated patients suffer from frequent episodes, decreasing the quality of life. Families experience emotional and financial stress taking care of a chronically ill child, and patients can miss a lot of school. Prior to the discovery of effective treatment, patients with familial cold autoinflammatory syndrome usually needed to live in a place with mild weather, a place that is not too cold but also not so hot that there is a constant need for air-conditioning.
The outcome of NOMID used to be such that many patients developed severe joint deformities and neurologic damage, mainly to the ears and eyes. There also were cases of death from brain damage. New treatments may allow children to lead near-normal lives.
Untreated patients may develop a complication of inflammation called amyloidosis. Amyloid is a protein that deposits in certain organs in children with chronic inflammatory disease. The most common organ involved is the kidney, but amyloid can deposit in the intestines, skin and heart. Eventually, amyloid causes a loss of function, especially of the kidneys. This is another reason to continue life-long treatment, even when the child is feeling better.
Fortunately, effective treatments are available for most patients, allowing them to live rich lives while avoiding disease complications.
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Neonatal onset multisystem inflammatory disease
Familial cold autoinflammatory syndrome
Updated December 2021 by the American College of Rheumatology Committee on Communications and Marketing.
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