Are You Confident of the Diagnosis?

Cryopyrin associated periodic syndrome (CAPS) is the new preferred name for urticarial familial syndrome with systemic features of inflammation. Previously, the following three unrelated syndromes had been described in the literature: familial cold urticaria (FCU), also called familial cold autoinflammatory syndrome [FCAS]), Muckle Wells syndrome (MWS), and neonatal onset multisystem inflammatory disorder (NOMID), also called chronic infantile neurologic cutaneous and articular syndrome [CINCA]). A common genetic basis for these syndromes has been elucidated in the past 10 years and they are now thought of as one disease with a spectrum of severity that ranges from FCU (mildest), through MWS (moderately severe), to NOMID (most severe).

What you should be alert for in the history

There is a universal history of a “hive”-like rash that differs from standard urticaria in that it tends to have minimal or no itch. Most patients will experience a rash on a daily basis, although it may fluctuate in severity. The vast majority of patients have a history of the rash beginning in the neonatal period and lasting throughout life. Some patients notice worsening of the rash with cold exposure or when they are stressed. Most patients notice diurnal variation in the rash with little or no rash in the morning and symptoms worsening throughout the day. Patients may describe a sensation of tightness in the skin or a burning sensation associated with the rash.

Other associated symptoms include swelling of joints (particularly the knees and ankles), with wrists, elbows, and the small joints of the hands less frequently affected. Commonly, patients report headache, fever, rigors, and lethargy. As CAPS is an autosomal dominantly inherited condition, there is frequently (50% of the time) a concomitant family history of similar symptoms. Due to the rarity of the condition, there is frequently a very long delay in diagnosis, so many patients are diagnosed as adults.

Characteristic findings on physical examination

Examination of the skin reveals an urticarial-like eruption (Figure 1). Pink, evanescent macules appear on the trunk, limbs, and (less frequently) the face. Often, these are morphologically figurate and can be subtle. The rash is typically more prominent later in the day, and then can appear indistinguishable from severe acute urticaria. Other physical findings include conjunctivitis and synovitis affecting the joints as described above.

Figure 1.

Typical CAPS rash seen in an infant: Pink figurate macules.

CAPS patients affected on the most severe end of the spectrum (NOMID) can have severe deforming arthropathy resulting from cartilage overgrowth, most commonly seen affecting the knees. About 50% of patients will have some degree of sensorineural hearing impairment, which may require the use of hearing aids.

Expected results of diagnostic studies

The diagnostic tool of choice is genetic testing, looking for a mutation in the NLRP3 gene, which is also known as CIAS-1. This test can be ordered from a commercial genetics laboratory; however, only 50% of patients affected by CAPS have a positive mutation, so a diagnosis may be rendered based on the patient’s clinical features, other test results, and response to treatment.

Skin biopsies are helpful and will show features of a neutrophilic urticaria with predominant perivascular and perieccrine inflammation. Inflammatory markers such as C-reactive protein (CRP) and (where available) serum amyloid A (SAA) will be markedly elevated. A complete blood count (CBC) may reveal a mild normocytic anemia and a slightly elevated neutrophil count.

Who is at Risk for Developing this Disease?

Since it is an autosomal-dominant disease, children of affected individuals have a 50% chance of inheriting the mutated gene and therefore the clinical phenotype.

What is the Cause of the Disease?
Etiology

CAPS is an autosomal-dominantly inherited condition. Patients have mutations in a gene called NLRP3 (also called CIAS-1). The protein coded by the NLRP3 gene is called cryopyrin. Mutations in NLRP3 lead to a gain of function of cryopyrin.

Pathophysiology

Cryopyrin proteins aggregrate to form a multimeric structure, called an inflammasome, in response to pathogens (or danger signals). This process is a key part of the innate immune system and leads to downstream activation of Interleukin 1-beta (IL-1β), which is a proinflammatory cytokine. In CAPS, the inflammasome is permanently activated, leading to excessive production of IL-1β. This cytokine appears to mediate all the symptoms and signs of the disease.

Systemic Implications and Complications

Systemic Amyloidosis: Patients with untreated CAPS have a 25% chance of developing Systemic AA Amyloidosis. If this complication develops, patients frequently get renal amyloid deposition. This results in nephrotic syndrome and ultimately end-stage renal failure. Frequent monitoring of renal function is recommended, including 24-hour creatinine clearance, blood urea nitrogen (BUN) and creatinine, and urine dipstick analysis for protein.

Treated patients whose inflammatory markers have normalized (i.e. normal CRP and SAA), do not appear to be at risk of systemic amyloidosis. In NOMID, central nervous system involvement may present as chronic meningitis, bilateral papilledema, sensorineural deafness, learning disabilities, and/or cerebral atrophy.

Treatment Options

CAPS patients respond to drugs that block Interleukin 1. There are no randomized controlled trials that compare the three treatments available, although all are reported to be remarkably effective. There have been reports of increased incidence of serious infections and neutropenia in patients who were coadministered tumor necrosis factor blockers. Prior to starting any patient on IL-1 blockade, rule out underlying serious infections, including tuberculosis (TB), Hepatitis B, Hepatitis C, and HIV.

Canakinumab (fully human monoclonal antibody directed against IL-1β):

Subcutaneous administration every 8 weeks (licensed for CAPS in adult and pediatric patients over 4 years of age)

Adult dosing: Initially 150mg, but can be titrated up to 600mg if response is suboptimal

Pediatric dosing: Initially 2mg/kg, but can be titrated up to 8mg/kg if response is suboptimal

The side effect profile is fairly good, although only short-term data are available. There appears to be an increased risk of infections (mainly upper respiratory tract infections (URTI), some of which have been serious) and vertigo. Live vaccinations should be avoided when patients are receiving concurrent canakinumab.

Rilonacept (IL-1 Trap fusion protein):

Subcutaneous administration once weekly (licensed for CAPS in adults and children 12 and older. Not studied in severe phenotype patients)

Adult dosing: Loading dose is 320mg. Continue dosing once weekly with 160mg.

Pediatric dosing: For ages 12-17, the loading dose is 4.4mg/kg up to a maximum of 320mg. Continue dosing once weekly with 2.2mg/kg, up to a maximum of 160mg.

Side effects include injection site reactions and increased urinary frequency or URTI. In the main clinical trial, six serious adverse reactions were reported: mycobacteria intracellulare, gastrointestinal bleeding, colitis, sinusitis, bronchitis, and Streptococcus pneumoniae meningitis. Live vaccinations should be avoided when patients are receiving concurrent rilonacept.

Anakinra (IL-1 receptor antagonist):

Subcutaneous administration daily (licensed for adults with rheumatoid arthritis). Please note that the use of anakinra in CAPS is off-label.

Adult dosing: 100mg, once daily

Pediatric dosing: 1-2mg/kg, once daily.

Side effects include injection site reactions (relatively frequent). These normally settle down after a few weeks of administration of anakinra. Neutropenia has been seen, as well as increased risk of serious infections. Regular CBC monitoring is required (every 3 months).

CAPS patients should have their levels of acute phase reactants (i.e. CRP), CBC, BUN, and creatinine) measured every 3 months, and should have a urinalysis performed, to monitor adequacy of therapeutic response.

Optimal Therapeutic Approach for this Disease

All treatments previously listed have been reported to offer patients complete clinical remission, including resolution of all symptoms of inflammation such as rash, arthralgia, headache, etc. Furthermore, prolonged IL-1 blocking therapy has reduced and cleared systemic amyloidosis in patients with this complication. Unfortunately, sensorinueural deafness tends to persist, despite adequate treatment.

The first-line choice of therapy would probably be canakinumab or rilonacept, as these are licensed for CAPS and may be more easily obtained through medical insurance. Patients may also prefer canakinumab because it is dosed every 8 weeks (as opposed to rilonacept, which is dosed weekly). Also, canakinumab is licensed for children over 4 years of age, and has been studied in patients with more severe symptoms, whereas rilonacept is licensed for children over 12 years of age and has been studied in moderate/mild CAPS phenotypes.

Anakinra is useful for cases in which there is diagnostic uncertainty, because patients with CAPS respond dramatically to this therapy within hours. If there is no response, it is very unlikely that the patient has CAPS.

All of these treatments appear to be well tolerated and have reasonable side effect profiles. Patients using anakinra frequently get injection site reactions that tend to settle down with prolonged therapy. It is unknown whether prolonged inhibition of IL-1 will have any long-term sequelae, as all of the treatments for this condition have been in use for less than 10 years at the time of writing.

Patient Management

After initiation of therapy, patients should be seen relatively frequently (every 2 weeks) to monitor symptoms and markers of systemic inflammation such as CRP. After clinical remission is obtained, visits every 3 months are appropriate. Routine laboratory studies to be checked are CRP, CBC, and renal function; a urinalysis should be performed every 3 months.If other organ systems are involved, patients should be referred for follow up with appropriate specialists (e.g. rheumatology, neurology, audiology, and ophthalmology).

Unusual Clinical Scenarios to Consider in Patient Management

There can be many overlapping features among the three originally described diseases. Of particular note is that the severity phenotype does not predict who will develop systemic amyloidosis. Even patients with relatively mild symptoms (FCAS-like) can develop systemic amyloidosis. There is one case report of a CAPS patients with myelodysplasia and a cerebrovascular accident.

What is the Evidence?

Witherspoon, FG, White, CB. “Familial urticaria due to cold”. Arch Derm Syphilol. vol. 58. 1948. pp. 52-5. (Original family with FCAS)

Muckle, TJ, Wells, M. “Urticaria, deafness, and amyloidosis: a new heredo-familial syndrome”. Q J Med. vol. 31. 1962. pp. 235-48. (Original report linking urticarial rash with deafness and systemic amyloidosis)

Prieur, AM. “A chronic, infantile, neurological, cutaneous, and articular (CINCA) syndrome. A specific entity analysed in 30 patients”. Scand J Rheumatol Suppl. vol. 66. 1987. pp. 57-68. (Severe phenotype described [also known as NOMID])

Leslie, KS. “Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations”. Arch Dermatol. vol. 142. 2006. pp. 1591-7. (Large case series reporting sustained response to treatment with anakinra [IL-1 blockade])

Goldbach-Mansky, R. “Neonatal onset multisystem inflammatory disease responsive to interleukin-1beta inhibition”. N Engl J Med. vol. 355. 2006. pp. 581-92. (Prospective study confirming efficacy of anakinra in patients with severe phenotype disease)

Lachmann, HJ. “Use of canakinumab in the cryopyrin-associated periodic syndrome”. N Engl J Med. vol. 360. pp. 2416-25. (Prospective study confirming efficacy of canakinumab for CAPS)

Hoffman, HM. “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. (Prospective study confirming efficacy of rilonacept for CAPS)

Madan, V. “Muckle Wells Syndrome/neonatal-onset multisystem inflammatory disease overlap associated with myelodysplasia and cerebrovascular accident”. Clin Exp Dermatol. vol. 35. 2010. pp. 752-5. (Case report of a CAPS patient with myelodysplasia and cerebrovascular accident)