Cryopyrin-Associated Periodic Syndrome (CAPS): A Comprehensive Overview

By SWA

Cryopyrin-Associated Periodic Syndrome (CAPS) is a rare, inherited autoinflammatory disorder caused by mutations in the NLRP3 gene. This gene encodes cryopyrin, a key component of the inflammasome—a protein complex essential to innate immune defense. CAPS is not a single disease but a spectrum of related conditions that vary in severity:

  • Familial Cold Autoinflammatory Syndrome (FCAS)

  • Muckle-Wells Syndrome (MWS)

  • Neonatal-Onset Multisystem Inflammatory Disease (NOMID), also known as Chronic Infantile Neurologic Cutaneous Articular (CINCA) Syndrome

Causes and Pathophysiology

CAPS results from gain-of-function mutations in the NLRP3 gene (formerly CIAS1). These mutations cause inappropriate activation of the inflammasome, leading to excess production of interleukin-1 beta (IL-1β)—a potent inflammatory cytokine.

This unregulated inflammation underlies the characteristic recurrent fevers, skin rash, joint pain, and systemic symptoms seen in CAPS patients.

 Learn more from the NIH Genetics Home Reference

CAPS Subtypes

1. Familial Cold Autoinflammatory Syndrome (FCAS)

  • Symptoms: Fever, urticaria-like rash, arthralgia, conjunctivitis

  • Trigger: Cold exposure

  • Onset: Infancy or early childhood

  • Flare Duration: Less than 24 hours

  • Severity: Mildest CAPS variant

2. Muckle-Wells Syndrome (MWS)

  • Symptoms: Recurrent fever, rash, joint pain, fatigue, progressive hearing loss

  • Complication: AA amyloidosis, especially affecting the kidneys

  • Onset: Childhood or adolescence

  • Severity: Intermediate

3. Neonatal-Onset Multisystem Inflammatory Disease (NOMID / CINCA)

  • Symptoms: Persistent rash, CNS involvement (aseptic meningitis), joint deformities, vision and hearing loss, developmental delays

  • Onset: Shortly after birth

  • Severity: Most severe form

 See the NIH CAPS Fact Sheet

Diagnosis

Diagnosis involves a combination of clinical assessment and confirmatory genetic testing.

Diagnostic Tools

  • Genetic testing for NLRP3 mutations

  • Inflammatory markers: Elevated ESR, CRP, and serum amyloid A

  • Family and symptom history evaluation

 Detailed in GeneReviews – CAPS

Treatment

Targeted IL-1 Inhibition

The cornerstone of CAPS treatment is interleukin-1 inhibition, which neutralizes the overactive inflammation.

Available Therapies

These biologics have dramatically improved outcomes, preventing long-term damage and enhancing quality of life.

Long-Term Risks and Complications

If untreated or inadequately managed, CAPS may lead to:

  • Sensorineural hearing loss

  • Amyloidosis (mainly in MWS)

  • Joint damage and deformity

  • Neurologic impairments (especially in NOMID)

🩺 Early IL-1 therapy is essential to prevent irreversible damage.

Diet and Lifestyle Considerations

While not causative, diet and lifestyle can modulate inflammation.

Foods to Avoid

  • Processed foods

  • Refined sugars

  • Saturated and trans fats

  • Cold beverages (especially for FCAS)

  • Alcohol

Foods to Embrace (Anti-Inflammatory Diet)

  • Omega-3 rich foods (salmon, flaxseed)

  • Berries, leafy greens

  • Whole grains

  • Turmeric and ginger

  • Healthy fats (olive oil, avocado)

 See Harvard Health – Anti-inflammatory Diet

Living with CAPS

CAPS requires lifelong multidisciplinary care:

  • Routine monitoring by rheumatologists and immunologists

  • Hearing and vision screenings

  • Surveillance for amyloidosis

  • Genetic counseling for affected families

  • Connection to patient support networks

Find resources at NORD – CAPS

Related Conditions: A Broader View

1. Illnesses Linked to NLRP3 Mutations

  • CAPS spectrum: FCAS, MWS, NOMID/CINCA

  • Other associated diseases:

    • Systemic-onset juvenile idiopathic arthritis (sJIA)

    • Adult-onset Still’s disease (IL-1 driven)

2. TPMT Deficiency – Drug-Induced Complications

TPMT (thiopurine S-methyltransferase) is an enzyme involved in thiopurine metabolism. Deficiency can lead to severe side effects from:

  • Azathioprine

  • 6-mercaptopurine (6-MP)

  • Thioguanine

Used to treat:

  • Leukemias

  • Inflammatory bowel disease (Crohn’s, ulcerative colitis)

  • Lupus and rheumatoid arthritis

  • Organ transplant rejection

Risks of TPMT Deficiency

  • Myelosuppression (life-threatening bone marrow failure)

  • Requires genetic testing or enzyme assay before drug initiation

Summary Table

Gene/EnzymeAssociated Conditions
NLRP3 (Cryopyrin)    CAPS (FCAS, MWS, NOMID/CINCA), sJIA, Still’s disease
TPMT    Drug-induced toxicity (not a disease itself) from thiopurines                 

Conclusion

CAPS is a serious, yet increasingly manageable genetic autoinflammatory syndrome. With advancements in genetic testing, targeted IL-1 inhibitors, and comprehensive care, patients can achieve significantly improved outcomes. Early diagnosis and consistent management are key to reducing complications and ensuring a better quality of life.

 

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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