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Cryopyrin-associated periodic syndrome (CAPS)


Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Cryopyrin-associated periodic syndrome (CAPS) is a rare autosomal dominantly-inherited autoinflammatory disease characterized by urticarial rashes, conjunctivitis, fever, fatigue, articular involvement, and inflammation, which may be triggered by cold exposure in some patients. It encompasses a spectrum of mild-to-severe conditions including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Left untreated, patients with severe involvement may develop sensorineural hearing loss, visual loss, chronic meningitis, and amyloidosis. CAPS is caused by gain-of-function mutations in the NLRP3 gene , which lead to inappropriate NLRP3 inflammasome activation and overproduction of interleukin-1β (IL-1β). New nomenclature for CAPS was recently proposed to incorporate FCAS, MWS, and NOMID under one name, NLRP3 -associated autoinflammatory disease ( NLRP3 -AID), with mild, moderate, and severe phenotypic subtypes.

Management Strategy

Early diagnosis and aggressive treatment of CAPS are essential to prevent organ damage, and early symptoms may be reversible if treatment is commenced expediently. Symptoms may be present from birth or may not become apparent until childhood or early adulthood. Diagnosis is complicated by the fact that, even if molecular genetic analysis of NLRP3 is performed, mutations cannot always be demonstrated. However, high-throughput sequencing has identified somatic mosaic NLRP3 mutations in some ‘mutation-negative’ patients, including adults with late-onset CAPS symptoms. Evidence-based criteria were proposed in 2019 for the classification of CAPS based on clinical symptoms with or without genetic analysis ( Table 48.1 ).

Table 48.1
Criteria for CAPS classification
With genetic analysis With unknown genetics
Confirmatory NLRP3 mutation plus at least one symptom: ∗ or Non-confirmatory NLRP3 mutation plus at least two symptoms: ∗ At least two of five symptoms: ∗

  • Urticarial rash

  • Urticarial rash

  • Red eye (conjunctivitis, episcleritis, uveitis)

  • Cold/stress-triggered episodes

  • Sensorineural hearing loss

  • Sensorineural hearing loss

  • Chronic aseptic meningitis

  • Skeletal abnormalities (epiphysial overgrowth/frontal bossing)

∗ Must have recurrent disease symptoms (≥6 months), elevated acute phase reactants (C-reactive protein [CRP]/serum amyloid A [SAA]) during at least one flare, and exclusion of confounding disease (i.e., infection, neoplasm, autoimmune condition, inborn errors of immunity).

CAPS is ideally managed by a multidisciplinary team with expertise in autoinflammatory disease. Patients should have access to genetic counseling, psychosocial support, hearing aids, orthotic aids, and physiotherapy. The mainstay of medical management is pharmacologic blockade of IL-1.

Three IL-1 blockers are currently used to treat CAPS: anakinra, canakinumab, and rilonacept . All are administered as subcutaneous injections. Anakinra is a recombinant IL-1 receptor antagonist; canakinumab is a human monoclonal antibody targeting IL-1β and has a much longer half-life than anakinra; and rilonacept is a fusion protein consisting of the binding domains of the IL-1 receptor and its accessory protein linked to the Fc portion of human IgG1. All three drugs currently have US Food and Drug Administration (FDA) approval for use in CAPS, whereas only anakinra and canakinumab are approved by the European Medicines Agency (EMA).

Side effects associated with IL-1 blockers include injection-site reactions and increased risk of infection. Most injection-site reactions occur within the first 6 months of treatment and are generally mild and resolve over a period of weeks without requiring discontinuation of treatment. Headaches and arthralgia may also occur. Live vaccines are not recommended during IL-1 blockade.

The primary treatment target is complete remission, and the dosing of IL-1 blockers should be individually adjusted using a treat-to-target strategy. Anakinra is given at a starting dose of 1–2 mg/kg/day in adults and children but can be escalated based on phenotypic severity and clinical response. Doses as high as 5–8 mg/kg/day have been required in some children. Anakinra is currently FDA approved for patients of all ages with NOMID.

Canakinumab dosing is also weight-based but given every 8 weeks, starting at 150 mg (> 40 kg) or 2 mg/kg (15–40 kg); some patients require dose escalation up to 8 mg/kg every 8 weeks. Canakinumab is currently FDA approved for patients 4 years and older with MWS and FCAS.

Rilonacept is initiated with a loading dose of 320 mg (adults) or 4.4 mg/kg (children), followed by weekly injections of 160 mg (adults) or 2.2 mg/kg (children). It is FDA approved for patients 12 years and older with MWS and FCAS.

During symptomatic flares, short courses of non-steroidal antiinflammatory drugs (NSAIDs) or oral corticosteroids may be used as adjunct therapy in association with IL-1 blockers. However, monotherapy with NSAIDs or oral corticosteroids is not recommended due to the potential disease-modifying effect of IL-1 blockers. Treatment with tocilizumab, a monoclonal antibody targeting the IL-6 receptor, has led to symptomatic improvement in isolated CAPS patients as monotherapy (initiated prior to CAPS diagnosis) or when used as adjunct therapy with IL-1 blockers. Evidence supporting the efficacy of tocilizumab for CAPS is currently lacking.

Specific Investigations

  • Skin biopsy of urticarial rash will show characteristic scattered dermal neutrophilic infiltrate without vasculitis

  • C-reactive protein (CRP) and serum amyloid A (SAA) to determine systemic inflammatory activity

  • Genetic testing for NRLP3 mutation to confirm diagnosis (mutation may not be apparent by Sanger sequencing in some patients due to mosaicism) Autoinflammatory disease panels are available from multiple genetic testing labs

Monitoring

  • Full physical examination, urine testing for proteinuria, audiogram, and ophthalmologic examination

In severe disease consider:

  • Cognitive testing

  • Radiologic imaging (brain, inner ear, skeletal)

  • Lumbar puncture

Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study

Ben-Chetrit, E, Gattorno M, Gul A, et al. Ann Rheum Dis 2018; 77: 1558–65.

Revision of autoinflammatory diseases nomenclature by an international expert committee after systematic literature review. The proposed name for CAPS is NLRP3 -associated autoinflammatory disease.

Classification criteria for autoinflammatory recurrent fevers

Gattorno M, Hofer M, Federici S, et al. Ann Rheum Dis 2019; 78: 1025–32.

Consensus report of evidence-based criteria for classifying hereditary recurrent fever syndromes, including CAPS. Criteria were developed by an international consensus committee after systematic literature review, statistical analyses, and cross-sectional validation on 1018 patients randomly selected from the Eurofever Registry.

Consensus protocols for the diagnosis and management of the hereditary autoinflammatory syndromes CAPS, TRAPS, and MKD/HIDS: a German PRO-KIND initiative

Hansmann S, Lainka E, Horneff G, et al. Pediatr Rheumatol 2020; 18: 17.

Consensus evidence-based treat-to-target therapeutic guidelines for autoinflammatory diseases, including CAPS, developed by an expert committee.

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