What blood tests can be ordered before genetic testing for a patient suspected of having cryopyrin-associated periodic syndrome (CAPS)?

Blood Tests to Order Before Genetic Testing for Suspected CAPS

Before ordering genetic testing for cryopyrin-associated periodic syndrome (CAPS), you should obtain C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and complete blood count (CBC) with differential; if available, also measure serum amyloid A (SAA) and S100 proteins. 1

Essential Inflammatory Markers

The 2021 EULAR/American College of Rheumatology guidelines explicitly state that the clinical workup of systemic inflammation should include the following blood tests 1:

• CRP (C-reactive protein) - Essential marker of systemic inflammation 1
• ESR (erythrocyte sedimentation rate) - Core inflammatory marker 1
• CBC with differential - Evaluates for leukocytosis and other hematologic abnormalities 1

Additional Markers When Available

If your laboratory offers these tests, they provide additional diagnostic value 1:

• Serum amyloid A (SAA) - More sensitive marker for CAPS-related inflammation 1
• S100 proteins - Can help assess inflammatory activity 1

Clinical Context for Testing

Elevated inflammatory markers (CRP and ESR) are a prerequisite for considering CAPS diagnosis. The overarching principles from EULAR/ACR state that patients presenting with chronic or episodic flares of unexplained systemic inflammation (including elevations of CRP and ESR) should receive a prompt diagnostic workup comprising genetic testing 1, 2.

When to Suspect CAPS Clinically

Order these blood tests when patients present with at least three of the following features 3, 4:

• Recurrent episodes of symptoms
• Age at disease onset <20 years
• Urticaria-like rash (neutrophilic, not true urticaria) 1, 5, 4
• Cold or stress-triggered episodes 1, 5, 4
• Sensorineural hearing loss 1, 5, 4
• Chronic aseptic meningitis 1, 5, 4
• Skeletal abnormalities 1, 5, 4

Diagnostic Algorithm

The validated diagnostic model for CAPS requires: 4

1. Raised inflammatory markers (CRP/SAA) PLUS
2. At least two of six CAPS-typical symptoms:
   • Urticaria-like rash
   • Cold-triggered episodes
   • Sensorineural hearing loss
   • Musculoskeletal symptoms
   • Chronic aseptic meningitis
   • Skeletal abnormalities

This model has 81% sensitivity and 94% specificity for CAPS diagnosis 4.

Important Caveats

Markers of systemic inflammation correlate with disease symptoms and risk of organ damage. 1 Most CAPS patients (except those with the mildest form, FCAS) have evidence of chronic subclinical inflammation even between episodes 1.

Patients with longstanding untreated systemic inflammation need screening for amyloidosis, as 25% of Muckle-Wells syndrome patients develop this serious complication 1, 6. This screening should be performed if inflammatory markers have been persistently elevated 1.

Relationship to Genetic Testing

Genetic testing should proceed even if inflammatory markers are normal during evaluation, as CAPS can have episodic presentations with periods of lower inflammation 1. However, the presence of elevated CRP/ESR significantly strengthens the clinical suspicion and justifies the genetic workup 3, 4.

The genetic diagnosis is required to facilitate initiation of targeted IL-1 inhibitor treatments, provide genetic counseling, and inform prognosis 1.