Cryopyrin-Associated Periodic Syndromes (CAPS) are rare, inherited disorders characterized by uncontrolled, systemic inflammation. They are classified as autoinflammatory diseases, meaning the innate immune system is inappropriately activated, causing inflammation without an external trigger. This differs from autoimmune diseases, where the adaptive immune system mistakenly attacks healthy tissues. CAPS results in recurrent, debilitating symptoms that often affect multiple organ systems from birth or early childhood.
The Underlying Cause Genetics and Inflammation
The root cause of CAPS is a genetic mutation in the $NLRP3$ gene, which codes for the protein cryopyrin. This mutation is typically a “gain-of-function” change, meaning the resulting protein is overly active. This hyperactive cryopyrin is a component of the inflammasome, which coordinates the innate immune response.
When functioning normally, the inflammasome is activated by danger signals, leading to the release of inflammatory molecules. However, the CAPS mutation causes the inflammasome to be permanently active. This constant activation leads to the excessive production of the inflammatory signaling molecule, Interleukin-1 beta (IL-1ß). The uncontrolled release of IL-1ß drives the systemic inflammation and symptoms seen across all forms of CAPS.
The Spectrum of Cryopyrin-Associated Periodic Syndromes
CAPS is a spectrum of three clinically recognized conditions that vary significantly in severity and long-term outcomes. All three syndromes are caused by mutations in the $NLRP3$ gene, forming a continuum of a single autoinflammatory disorder. The mildest form is Familial Cold Autoinflammatory Syndrome (FCAS), formerly known as familial cold urticaria.
FCAS is characterized by episodes of fever, rash, and joint pain typically triggered by exposure to cold temperatures or cool air conditioning. Symptoms usually begin shortly after cold exposure and resolve within 24 to 48 hours. Progression to severe complications like amyloidosis is uncommon, resulting in a good long-term prognosis.
Muckle-Wells Syndrome (MWS) is the intermediate phenotype, featuring symptoms that are more persistent and less reliably linked to cold exposure. Patients frequently experience recurrent fevers, eye inflammation, and joint pain. MWS is distinguished by progressive sensorineural hearing loss and carries a higher risk of developing reactive amyloidosis, which can damage organs like the kidneys.
Neonatal Onset Multisystem Inflammatory Disease (NOMID), also known as Chronic Infantile Neurological Cutaneous and Articular (CINCA) Syndrome, is the most severe form of CAPS. This condition typically begins in infancy, involving continuous, intense inflammation across multiple organ systems. It is distinguished by central nervous system (CNS) inflammation, which can lead to chronic aseptic meningitis, severe headaches, and progressive cognitive and neurosensorial deficits.
Recognizable Signs and Systemic Impacts
The various forms of CAPS share a collection of symptoms that manifest during recurrent inflammatory episodes, known as flares. The most common and often earliest sign is a characteristic urticarial-like skin rash, resembling hives. This rash is typically non-itchy, distinguishing it from allergic hives, and it can be migratory, appearing in different locations on the body.
Patients often experience recurrent, unprovoked fevers not caused by infection, sometimes accompanied by malaise and fatigue. Musculoskeletal involvement is widespread, presenting as joint pain (arthralgia) or true arthritis in severe cases. Eye inflammation is a frequent finding, usually presenting as conjunctivitis or redness, though more serious inflammation, such as uveitis, can occur.
The long-term effects of uncontrolled inflammation can be severe, particularly in MWS and NOMID/CINCA. Persistent systemic inflammation can lead to AA amyloidosis, where serum amyloid A protein deposits in vital organs like the kidneys, potentially causing organ failure. The severe inflammation in NOMID/CINCA can also cause long-term neurological damage, including chronic inflammation around the brain and spinal cord, leading to hearing and vision impairment.
Diagnosis and Modern Management Strategies
Diagnosing CAPS often begins with clinical suspicion based on the characteristic triad of recurrent fever, urticarial-like rash, and systemic inflammation, especially when symptoms begin early in life. Laboratory tests typically reveal elevated markers of inflammation, such as C-reactive protein (CRP) and Erythrocyte Sedimentation Rate (ESR), during flares. The definitive diagnosis is confirmed through genetic testing for the gain-of-function mutation in the $NLRP3$ gene.
Modern management of CAPS centers around a targeted therapeutic strategy that directly addresses the underlying cause of the disease. Since symptoms are driven by the excessive activity of Interleukin-1 beta (IL-1ß), treatment involves IL-1 inhibitors, a class of biologic drugs. These medications work by neutralizing the IL-1ß protein or blocking its ability to bind to its receptor on cells, suppressing the inflammatory cascade.
Targeted IL-1 blockade has transformed the prognosis for CAPS patients, often leading to a rapid reduction in systemic inflammation and symptoms. Medications such as anakinra, rilonacept, and canakinumab are commonly used, each inhibiting IL-1ß slightly differently. Continued monitoring of inflammatory markers, hearing function, and organ health is necessary to ensure treatment effectiveness and prevent long-term damage like amyloidosis and neurological complications.