Rheumatology

Cryopyrin-associated periodic syndrome (CAPS)

Does this patient have a cryopyrin-associated periodic syndrome (CAPS)?

History and symptoms

The CAPS family of diseases are due to autosomal dominant gain of function mutations in NLRP3 (also known as NALP3, CIAS1 or PYPAR1) encoding the protein cryopyrin. Cryopyrin mutations lead to increased activity of the caspase-1 activating inflammasome, which results in the cleavage of pro-IL-1ß to its active form, IL-1ß. As such, these disorders are marked by a dramatic therapeutic response to IL-1 blocking therapies.

There are three members of this family: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous and arthritis (CINCA) syndrome. These disorders present early in life and represent a spectrum of disease severity, with FCAS at the mildest end and NOMID at the most severe end.

In FCAS, flares are triggered by the exposure to cold. Clinical manifestations include an urticaria-like rash, conjunctivitis, fevers, joint pain and elevation of acute phase reactants (APRs). Patients may describe eye redness and pain in association with conjunctivitis. A typical flare lasts from 12-48 hours and resolves without sequelae. Flares in MWS and NOMID are not clearly triggered by the cold but rather infections, surgery and other conditions or stress and may be continuous in nature without adequate treatment.

Patients present at birth with the clinical manifestations of FCAS but also can develop episcleritis and optic disk edema as well as sensorineural hearing loss due to cochlear inflammation. Hearing loss typically occurs in the second or third decade of life but may occur earlier.

In NOMID, patients also develop central nervous system (CNS) inflammation with a neutrophilic aseptic meningitis and elevated intracranial pressure, which can lead to cognitive impairment, hydrocephalus, brain atrophy and, if not well controlled, loss of vision. Patients may experience severe headaches. In addition vision loss with blindness may occur in severe cases as consequences of anterior and posterior uveitis and subcorneal infiltration, leading to retinal scarring, corneal opacification and visual field loss in NOMID.

While arthralgia is common in all patients with CAPS, arthritis is not common. However, bony changes may occur in NOMID with 50-70% of patients developing a classic bony overgrowth of the long bone epiphyses, which is not seen in FCAS or MWS. The most commonly affected bones are the distal femur and proximal tibia leading to joint contractures and deformities.

In contrast to other NOMID manifestations, bone lesions continue to progress despite adequate IL-1 blockade. Patients with uncontrolled systemic inflammation may also experience severe growth and weight retardation, which can be reversible if the growth plates are not fused when inflammation is adequately controlled. Patients respond dramatically to IL-1 inhibition and a lack of a response is a clue for an alternate diagnosis.

Epidemiology

CAPS are rare diseases with an estimated prevalence of 1-2 patients per 1,000,000 in Europe and the United States. There is no known ethnic predominance for disease. FCAS and MWS may be familial, however, NOMID is due to sporadic mutations.

Physical exam

FCAS, MWS and NOMID

Fever is a hallmark of disease and may be present on vital signs. Conjunctivitis marked by conjunctival injection may be present. Patients may have joint tenderness on exam, however, joint swelling is rare. An urticaria-like rash marked by migratory non-pruritic raised erythematous wheals with well-defined borders and a smooth surface may be present. The rash does not typically scar.

MWS and NOMID

Episcleritis and/or optic nerve edema may also be present. This can be best evaluated on ophthalmoscopy or slit lamp examination. Hearing loss may be detected on clinical exam or on audiologic testing in more subtle cases.

NOMID

Growth and weight may be abnormally low. Decreased cognition may be observed on clinical exam or by formal cognitive testing. Neck stiffness may be present. Visual acuity and field may be reduced. A slit lamp exam versus ophthalmoscopy may reveal papilledema, uveitis, and/or subcorneal infiltrates. Bony overgrowth of the knees may be present.

Differential diagnosis

Patients with FCAS are often incorrectly diagnosed with an allergic reaction or acquired cold induced urticaria. In the neonate, NOMID may be confused with sepsis or a congenital TORCH infection, given the acute inflammatory response and multi-organ involvement. Other differential diagnoses include systemic-onset juvenile idiopathic arthritis (SoJIA) and adult onset Still's disease (AOSD). While fever, joint pain, rashes and elevation of acute phase reactants are common to these diseases, SoJIA and AOSD do not present at birth.

Diagnostic criteria

No formal diagnostic criteria exist for FCAS, MWS or NOMID. A clinical diagnosis is made based on a constellation of classic symptoms and usually confirmed with a genetic diagnosis on the basis of at least one mutation in NLRP3.

What tests to perform?

Laboratories

CAPS are marked by excessive IL-1ß production with laboratory abnormalities being a consequence of IL-1 production and resultant inflammation. Acute phase reactants (APRs) including the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum amyloid A (SAA) are elevated. Notably, SAA is not commercially available, however, may be measured in a research setting.

In FCAS, inflammatory markers may be normal in between attacks. Peripheral white blood cell (WBC) counts may be elevated with a neutrophilic predominance and ferritin may also be increased as markers of acute inflammation. In NOMID, cerebral spinal fluid (CSF) may reveal aseptic meningitis with elevated WBC counts with a neutrophilic predominance. CSF opening pressure, protein and albumin may also be elevated.

Serum laboratories should be monitored on a regular basis as elevations of APRs may warrant an increase in therapy. CSF is typically surveyed with annual lumbar punctures, as aseptic meningitis may be present in the setting of normal serum APRs. This would also warrant an increase in therapy. In the setting of ongoing CSF inflammation and given the known risks for developing hydrocephalus, brain atrophy, cognitive impairment, hearing impairment and vision loss, more frequent lumbar punctures may be required until inflammation is controlled.

Genetic testing

Genetic testing for mutations in NLRP3 mutations are commercially available and may be covered by insurance companies. The presence of a single mutation confirms the genetic diagnosis as these disorders are autosomally dominant. No clear genotype-phenotype correlations have been observed. The majority of NOMID patients with negative genetic testing and classical symptoms will have somatic mutations which can be detected in the research setting.

Imaging

Brain MRI

Brain MRI with fluid attenuated inversion recovery (FLAIR) sequences is a sensitive tool for detecting inflammatory lesions. In NOMID, thin cuts through the cochlea can reveal enhancement indicative of cochlear inflammation, which is predictive of ongoing hearing loss. The presence of cochlear enhancement is used as a criterion for IL-1 blockade increases by some investigators. Leptomeningeal enhancement can be present and may represent meningeal inflammation. However, this technique is not sensitive enough to detect all cases of aseptic meningitis and LPs are still necessary for adequate monitoring of CNS inflammation.

Joint radiographs

In NOMID, joint radiographs may reveal a classic bony overgrowth of the epiphyses of the long bones in the distal femur and proximal tibia. They are also useful in monitoring the limb length discrepancy that may occur when lesions affect the growth plates. Bone MRI is a better modality for measuring the volume of bony lesions and can be helpful as these lesions continue to grow despite adequate therapy.

Optical coherence tomography (OCT)

OCT is a technique performed by ophthalmologists to measure optic nerve thickness. An optic nerve thickness less than 80 microns is correlated with ongoing vision loss and is a useful prognostic factor in patients with NOMID.

Biopsy

A skin biopsy may be helpful in distinguishing the skin lesions of CAPS from those of other forms of urticaria. Lesions are characterized by a perivascular neutrophilic inflammatory infiltrate in the superficial dermis and mid-dermis. Vascular wall destruction is not seen and the number of mast cells is normal. The epidermis is usually unaffected. This contrasts with classic urticarial biopsies where lymphocytic and eosinophilic infiltrates are more common.

How should patients with cryopyrin-associated periodic syndrome (CAPS) be managed?

Treatment

Patients with CAPS universally respond to IL-1 blocking therapies. Three IL-1 blocking therapies exist:

  1. Anakinra (Kineret®), the recombinant IL-1 receptor antagonist.

  2. Canakinumab (Ilaris®), a long acting IL-1ß blocking antibody.

  3. Rilonacept (Arcalyst™) or IL-1 Trap, an IL-1 receptor fused to the Fc portion of IgG1.

Canakinumab and rilonacept were both FDA approved in 2008 under orphan drug status for the treatment of FCAS and MWS. The initial choice of therapy may depend on the patient's insurance coverage as these medications are quite costly.

The goal of therapy is to achieve disease remission, both in the serum and at the organ level. Anakinra is the most well studied IL-1 blocking medication in severe disease. The initial daily dose is 1 mg/kg subcutaneously, with rapid dose escalation in the event of elevated APRs or any evidence of ongoing organ inflammation including aseptic meningitis on LP, leptomeningeal or cochlear enhancement on MRI, and eye inflammation on exam.

Doses necessary to achieve disease remission in NOMID are typically much higher than doses studied for the treatment of RA. Doses as high as 10 mg/kg/day have been necessary in some tertiary referral centers.

Canakinumab is FDA approved at a dose of 150 mg subcutaneously every 8 weeks. In children older than 4 years of age and less than 40 kg, the dose is adjusted to 2 mg/kg subcutaneously every 8 weeks with the option to escalate to 3 mg/kg subcutaneously every 8 weeks in the event of an incomplete response.

Rilonacept is FDA approved at a dose of 320 mg subcutaneously as an initial dose followed by 160 mg subcutaneously weekly. In children 12 years of age and older, the loading dose is adjusted to 4.4 mg/kg (maximum 320 mg) with subsequent weekly doses of 2.2 mg/kg (maximum 160mg).

It has not been adequately studied whether higher doses of canakinumab or rilonacept are more efficacious in severe disease. Patients with NOMID may benefit from referral to a tertiary care center with experience in the treatment of this disorder, given the rarity of this disease and the potential serious complications of inadequate IL-1 blockade dose escalation.

What happens to patients with cryopyrin-associated periodic syndrome (CAPS)?

Natural history

The natural history of disease is variable depending on the severity of disease and access to therapy. Patients with FCAS have relapsing and remitting symptoms but rarely develop organ damage. In contrast, patients with MWS can develop hearing and vision loss if inflammation is not well controlled.

In NOMID, ongoing inflammation can cause chronically elevated intracranial pressure leading to hydrocephalus, brain atrophy, cognitive decline and papilledema with vision loss; subcorneal infiltrates can cause scarring and blindness; cochlear inflammation may cause hearing loss; chronic systemic inflammation leads to growth and weight retardation; bony lesions may lead to leg length discrepancies and contracture.

Prevention of organ damage

In MWS and NOMID, organ damage can be prevented with adequate IL-1 blocking therapy. Therapy should be targeted to control both serum and organ based inflammation. Control of serum inflammation alone is insufficient to prevent organ damage. With adequate IL-1 blocking therapies, further cognitive, vision and hearing loss can be prevented. Doses required to control inflammation are much higher than those used in other rheumatic conditions.

How to utilize team care?

Specialty consultations

A multidisciplinary team is essential for managing patients with severe disease given the variety of organ manifestations.

Rheumatology

Patients should be under the care of a rheumatologist who is responsible for monitoring serum inflammation and organ damage as well as for guiding therapeutic dose escalations. Given the rarity of disease and potentially severe manifestations, referral to a tertiary care center with experience in the care of patients with CAPS may be indicated.

Ophthalmology

A thorough ophthalmologic evaluation is needed to monitor for papilledema, subcorneal infiltrates, uveitis, and optic nerve pallor or atrophy. This requires a full fundoscopic exam. Visual acuity and visual field should be monitored.

Audiology

Audiology testing is indicated on a periodic basis to monitor for the presence and progression of hearing loss.

Nurses

CAPS are chronic conditions and the involvement of clinic nurses knowledgeable in this condition and with the individual patient is crucial for patient education and optimal care.

Pharmacists

Pharmacists can be helpful in evaluating for multiple drug interactions and in guiding changes in therapeutic doses when indicated due to renal insufficiency or other co-morbidities. They may also be helpful in guiding dose escalation decisions in the event of an inadequate response to IL-1 blockade.

Therapists

Patients with leg length discrepancies or contractures will benefit from a physical therapy evaluation and treatment plan to improve physical limitations. Shoe inserts, braces, stretching and exercise therapy may all be helpful in improving patient function. Occupational therapists can assist in improving function in patients with physical or cognitive impairments.

Are there clinical practice guidelines to inform decision making?

No clear clinical practice guidelines exist to inform decision making. The mainstay of therapy is colchicine with further treatment and work-up based on expert opinion in patients with resistant or atypical disease.

Other considerations

DRG codes

  • 240 Connective tissue disorders with complications, comorbidities.

  • 241 Connective tissue disorders without complications, comorbidities.

  • 256 Other musculoskeletal and connective tissue diagnosis.

Typical lengths of stay

Patients with CAPS are managed in the outpatient setting with inpatient admissions required only in the event of complications. Notably, inpatient admissions may be frequent in patients with complications from severe disease.

What is the evidence?

Masters, SL, Simon, A, Aksentijevich, I, Kastner, DL. "Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease". Annu Rev Immunol. vol. 27. 2009. pp. 621-68..

Dinarello, CA. "A clinical perspective of IL-1beta as the gatekeeper of inflammation". Eur J Immunol. vol. 41. 2011. pp. 1203-17..

Sanchez, GA, de Jesus, AA, Goldbach-Mansky, R. "Monogenic autoinflammatory diseases: disorders of amplified danger sensing and cytokine dysregulation". Rheum Dis Clin North Am. vol. 39. 2013. pp. 701-34..

Sibley, CH, Plass, N, Snow, J, Wiggs, E, Brewer, C, King, K. "Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease (NOMID) treated with anakinra". Arthritis Rheum. 2012.

Neven, B, Marvillet, I, Terrada, C, Ferster, A, Boddaert, N, Couloignier, V. "Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome". Arthritis Rheum. vol. 62. 2010. pp. 258-67..

Lachmann, HJ, Kone-Paut, I, Kuemmerle-Deschner, JB, Leslie, KS, Hachulla, E, Quartier, P. "Use of canakinumab in the cryopyrin-associated periodic syndrome". N Engl J Med. vol. 360. 2009. pp. 2416-25..

Hoffman, HM, Throne, ML, Amar, NJ, Sebai, M, Kivitz, AJ, Kavanaugh, A. "Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies". Arthritis Rheum. vol. 58. 2008. pp. 2443-52..

Goldbach-Mansky, R, Dailey, NJ, Canna, SW, Gelabert, A, Jones, J, Rubin, BI. "Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition". N Engl J Med. vol. 355. 2006. pp. 581-92..

Hawkins, PN, Lachmann, HJ, Aganna, E, McDermott, MF. "Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra". Arthritis Rheum. vol. 50. 2004. pp. 607-12..

Aksentijevich, I, Nowak, M, Mallah, M, Chae, JJ, Watford, WT, Hofmann, SR. "De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases". Arthritis Rheum. vol. 46. 2002. pp. 3340-8..

Hoffman, HM, Mueller, JL, Broide, DH, Wanderer, AA, Kolodner, RD. "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome". Nat Genet. vol. 29. 2001. pp. 301-5..

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