Knowledge on rare diseases and orphan drugs

The prevalence in France is estimated to be 1/360,000. Males and females are equally affected.

CAPS comprises 3 disorders on a continuum of severity: FCAS which usually has an early-onset after birth (< 20 years), and is characterized by recurrent episodes of urticarial rash triggered by exposure to cold, low-grade fever (malaise), conjunctivitis, abdominal discomfort, and arthromyalgia; MWS which usually presents at birth or later in childhood, with recurrent urticarial rash, fever, abdominal pain, arthralgia/arthritis, myalgias, secondary amyloidosis and/or premature deafness; and CINCA syndrome characterized by the triad of arthropathy, chronic urticarial rash (neonatal onset), and central nervous system (CNS) involvement (ranging from hearing loss to chronic aseptic meningitis and intellectual disability). Non-pruriginous urticarial rash (diffuse, erythematous, edematous plaques on a background of generalized, faintly erythematous patches) is a key feature of CAPS and is generally present with marked intensification during acute episodes. These disorders were previously thought to be distinct conditions but represent now three grades of severity in which FCAS and CINCA syndrome are the extremes in a single spectrum of clinical manifestations.

CAPS is due to mutations in the NLRP3 (1q44; gene encoding cryopyrin), which result in a gain of function of cryopyrin, leading to increased secretion of interleukin (IL)-1 beta and and dysregulated inflammation. Patients with identical amino acid substitution may present distinct clinical subtypes, suggesting the role of additional genetic and/or environmental factors in disease expression. Somatic NLRP3 mosaicism could explain 30-60% of these patients. Some patients with MWS, FCAS or CINCA syndrome may not have mutations in NLRP3.

Diagnosis is based on clinical manifestations and on laboratory findings revealing generalized leukocytosis and neurophilia along with others elevated acute phase reactants (C reactive protein and serum amyloid A). Progressive secondary amyloidosis manifests as proteinuria and is observed in the most severe cases (25% of cases). In CINCA syndrome, an increase in cytokine or neopterin levels in the cerebrospinal fluid may be detected. Histologic examination of affected skin shows a characteristic neutrophilic dermal infiltration in the reticular dermis. Diagnosis is confirmed by genetic screening of the NLRP3 gene.

Differential diagnosis includes systemic-onset juvenile idiopathic arthritis, rheumatoid arthritis, systemic lupus erythematosus, familial mediterranean fever, Schnitzler syndrome, PLCG2-associated antibody deficiency and immune dysregulation, mevalonate kinase deficiency, TRAPS syndrome, acquired cold and common allergic urticaria and serum sickness-like reaction.

CAPS can occur sporadically or be inherited as an autosomal dominant trait. In the latter case, genetic counseling may be proposed.

The only effective treatment for CAPS is IL-1 blockade using anakinra, riloncept, or canakinumab. Supportive treatment is essential to manage the global burden of the disease including learning and cognitive impairment, growth and pubertal retardation, psychological /psychiatric distress, consequences of visual and hearing impairments.

CAPS is a life-long disease, and early diagnosis and early treatment may improve prognosis. With optimal treatment adjustments, progression of hearing loss and vision loss can be halted in most patients.

Last update: July 2014 - Expert reviewer(s): Pr Isabelle KONE-PAUT