Cryopyrin-Associated Autoinflammatory Syndromes

grandmother and grandson

Fast Facts

  • The major symptoms include fever; hive-like rash; joint pain and swelling; red eyes; and symptoms of the nervous system, including headaches and deafness.
  • CAPS are not contagious.
  • Treatments that block interleukin-1, an important molecule involved in the inflammatory process, are very effective.
  • To prevent permanent damage, treatment needs to be started early in life.

Cryopyrin-Associated Autoinflammatory Syndromes (CAPS) consist of three very rare diseases related to a defect in the same protein: cryopyrin. These diseases differ in the systems involved and in the severity of the disease. All the CAPS are very rare, found in about one in 360,000 to 1,000,000 people. Familial cold autoinflammatory syndrome is more common in the Unites States, and Muckle-Wells syndrome is more common in Europe. NOMID, the least common disease, is present around the world, and usually starts shortly after birth. Familial cold autoinflammatory syndrome usually starts in the first year of life. Muckle-Wells syndrome may start later. Males and females are both affected, and all ethnic groups can be affected.

What are CAPS?

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), called in Europe Chronic Inflammatory Neurological Cutaneous Articular Syndrome (CINCA)
  • Muckle-Wells syndrome
  • Familial cold autoinflammatory syndrome

Neonatal Onset Multisystem Inflammatory Disease is the most severe and least common of the CAPS and causes fever with inflammation in multiple organs. Newborn babies can have signs that appear like an infection (e.g., fever, rash) but no infection is found. The rash resembles hives, but is not itchy. 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. After 1 year of age, 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, patients develop episodic fever, chills, rash, red eyes, joint pain, and severe headaches with vomiting. Episodes last from one - three days. Deafness or partial hearing loss often develops by teenage years.

In familial cold autoinflammatory syndrome, exposure to cold (including air-conditioning) and - perhaps - other environmental triggers causes a hive-like rash. 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. 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, 65 - 75% in patients with Muckle-Wells syndrome and in nearly all patients with familial cold auto inflammatory syndrome. Genetic defects may be found in more patients by new, more sophisticated gene testing techniques. The gene mutation causes a defect in a protein called cryopyrin, which has an important role in controlling inflammation.

How is it diagnosed?

CAPS is suspected by the symptoms and signs found by the physician on physical examination. The diagnosis may be confirmed by a genetic test, although occasionally the genetic test may be normal. Other tests may include skin biopsy (examining a small sample of the skin) of the rash, 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).

How is CAPS treated?

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 hearing. 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.

Living with the disease

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.

For additional information

The American College of Rheumatology compiled this list to give you a starting point for your own additional research. The ACR does not endorse or maintain these websites, and is not responsible for any information or claims provided on them. It is always best to talk with your rheumatologist for more information and before making any decisions about your care.

Muckle-Wells syndrome
Neonatal onset multisystem inflammatory disease
Familial cold autoinflammatory syndrome

Updated March 2017 by Philip Hashkes, MD, MSc and reviewed by the American College of Rheumatology Committee on Communications and Marketing.

This information is provided for general education only. Individuals should consult a qualified health care provider for professional medical advice, diagnosis and treatment of a medical or health condition.