Cryopyrin-associated periodic syndrome

Overview

Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, inherited autoinflammatory disorders caused by mutations in the NLRP3 gene. CAPS is characterized by recurrent episodes of systemic inflammation without infection, involving fever, rash, joint pain, and fatigue. CAPS encompasses a spectrum of conditions with varying severity, including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous and articular (CINCA) syndrome. Although rare, early recognition and treatment are crucial to prevent long-term damage, especially to hearing, vision, and the central nervous system.

Causes

CAPS is caused by mutations in the NLRP3 gene (also known as CIAS1), which plays a key role in regulating inflammation through the inflammasome complex. Mutations in this gene lead to overproduction of interleukin-1 beta (IL-1β), a potent pro-inflammatory cytokine. The condition is inherited in an autosomal dominant pattern, meaning a single mutated copy of the gene is sufficient to cause the disorder. However, some cases arise from new (de novo) mutations with no prior family history.

Symptoms

Symptoms of CAPS vary depending on the severity and subtype. Common features across the CAPS spectrum include:

• Recurrent fevers: Often daily or triggered by cold or stress

• Urticarial-like rash: Non-itchy, red rash resembling hives

• Fatigue and malaise

• Joint and muscle pain: Arthralgia and myalgia, sometimes with arthritis

• Conjunctivitis or eye irritation

• Headaches

Symptoms specific to each CAPS subtype:

• FCAS: Cold-triggered episodes with fever, rash, and joint pain lasting < 24 hours

• MWS: Chronic inflammation with progressive hearing loss, amyloidosis (in some cases), and longer flares

• NOMID/CINCA: Most severe form with neonatal onset, persistent rash, joint deformities, chronic meningitis, intellectual disability, and vision/hearing loss

Diagnosis

Diagnosis of CAPS is based on clinical symptoms, family history, laboratory markers of inflammation, and genetic testing. Diagnostic steps include:

• Clinical evaluation: Observation of recurrent fever, rash, joint issues, and neurologic symptoms

• Inflammatory markers: Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)

• Serum amyloid A (SAA): May be elevated, especially in MWS and NOMID

• Genetic testing: Identification of NLRP3 gene mutation confirms diagnosis

• Imaging and CSF analysis: In severe cases (NOMID), MRI of the brain and cerebrospinal fluid studies may show chronic inflammation

Treatment

The primary goal of CAPS treatment is to control inflammation, relieve symptoms, and prevent organ damage. IL-1 blockers are the mainstay of therapy. Treatment options include:

• Anakinra: A daily IL-1 receptor antagonist, effective in most CAPS forms

• Canakinumab: A long-acting monoclonal antibody against IL-1β, typically given every 4 to 8 weeks

• Rilonacept: A fusion protein that traps IL-1, used for FCAS and MWS

• Supportive care: Pain management, physical therapy, and monitoring for complications

• Treatment of complications: Management of hearing loss, vision changes, or amyloidosis as needed

Prognosis

With appropriate treatment, especially early initiation of IL-1 blockade, most individuals with CAPS can achieve significant symptom relief and improved quality of life. Untreated CAPS, particularly NOMID and MWS, can lead to serious complications such as sensorineural hearing loss, vision impairment, joint damage, and systemic amyloidosis, which can be life-threatening. Lifelong therapy and regular monitoring are essential to manage inflammation and prevent long-term damage.