Cryopyrin-Associated Periodic Syndromes (CAPS) are a group of rare, inherited autoinflammatory disorders affecting multiple body systems. The condition is characterized by chronic, recurrent episodes of inflammation and fever not caused by infection. This inflammation results from a malfunction in the innate immune system, which triggers an inflammatory response without an external threat. Symptoms typically begin in infancy or early childhood, and the severity of the condition exists on a spectrum. CAPS often involves the skin, joints, and central nervous system, requiring a targeted approach to diagnosis and treatment.
The Spectrum of CAPS Subtypes
CAPS encompasses three main recognized forms that share a common underlying genetic cause. Familial Cold Autoinflammatory Syndrome (FCAS) is the mildest form, often triggered by cold temperatures. FCAS symptoms typically last less than 24 hours and include fever, joint pain, and a hive-like rash. Long-term organ damage is uncommon in FCAS.
Muckle-Wells Syndrome (MWS) is the intermediate form of CAPS, with symptoms that are generally more persistent. Patients experience recurrent fevers, a generalized skin rash, and joint discomfort. MWS carries a significant risk of long-term complications, including the progressive development of sensorineural hearing loss, which can begin in childhood or early adulthood.
Neonatal-Onset Multisystem Inflammatory Disease (NOMID), also known as Chronic Infantile Neurologic Cutaneous Articular (CINCA) syndrome, is the most severe and rarest form. NOMID has the earliest onset, often presenting with a rash at birth or shortly thereafter, and involves persistent inflammation across multiple organs. This form is associated with chronic inflammation of the membranes surrounding the brain and spinal cord, which can lead to severe neurological damage, vision issues, and intellectual disability.
Understanding the Underlying Cause
The cause of Cryopyrin-Associated Periodic Syndromes is a mutation in the NLRP3 gene, which provides instructions for making the protein cryopyrin. This gene is inherited in an autosomal dominant pattern, meaning inheriting one copy of the altered gene is sufficient to cause the disorder. The mutation is a “gain-of-function” change, causing the cryopyrin protein to be hyperactive.
Cryopyrin is a component of the inflammasome, which acts as a sensor and regulator for inflammation. When functioning normally, the inflammasome is activated only in response to a genuine threat. The hyperactive cryopyrin protein in CAPS patients causes the inflammasome to spontaneously assemble and activate itself, even in the absence of a threat.
This inappropriate activation leads to the excessive release of the inflammatory messenger Interleukin-1 beta (IL-1\(\beta\)). IL-1\(\beta\) is a driver of the body’s inflammatory response, and its constant overproduction causes the fevers, rash, and systemic inflammation seen across the CAPS spectrum.
Recognizable Symptoms and Complications
The most recognizable sign of CAPS is a characteristic skin rash, which appears as a migratory, non-itchy, hive-like eruption (urticarial). This rash is usually the first symptom to appear, often presenting in early infancy, and is common across all three CAPS subtypes. Recurrent fevers are another hallmark, accompanied by generalized symptoms like fatigue, muscle aches, and joint pain (arthralgia). Eye involvement is also frequent, presenting as conjunctivitis or inflammation of the uvea.
The more severe forms of CAPS carry a significant risk of long-term complications due to persistent, uncontrolled inflammation. Patients with Muckle-Wells syndrome and NOMID are susceptible to progressive sensorineural hearing loss, which develops from chronic inflammation within the inner ear.
The most life-threatening complication is systemic secondary amyloidosis, which can occur in up to 25% of MWS patients. Amyloidosis involves the abnormal buildup of Amyloid A protein in various organs, most commonly the kidneys, which can lead to kidney failure. In the most severe cases of NOMID, chronic inflammation of the central nervous system can cause headaches, cognitive impairment, and hydrocephalus (a buildup of fluid in the brain).
Diagnosis and Management Strategies
Diagnosis of Cryopyrin-Associated Periodic Syndromes begins with a clinical evaluation of the patient’s symptoms, focusing on the classic triad of recurrent fever, urticarial rash, and joint pain. Blood tests measure inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), which are usually elevated during flares. Sustained elevation of these markers without an infectious cause suggests a chronic autoinflammatory condition.
Definitive confirmation requires genetic testing, which involves sequencing the NLRP3 gene to identify a disease-causing mutation. Genetic testing is important because it distinguishes CAPS from other periodic fever syndromes and allows for risk stratification. While a positive genetic test confirms the diagnosis, a negative result does not completely rule out CAPS, as some mutations may not be detected by conventional sequencing.
Management focuses on neutralizing the inflammatory cytokine that drives the disease. Since the issue is the overproduction of Interleukin-1 beta (IL-1\(\beta\)), the standard of care uses targeted biological medications called IL-1 inhibitors. Medications such as anakinra, canakinumab, and rilonacept work by blocking the IL-1 receptor or binding to the IL-1\(\beta\) molecule, preventing it from triggering inflammation. These inhibitors lead to a rapid reduction in symptoms and normalize inflammatory markers, which prevents long-term organ damage.