Abstract
The cryopyrin-associated periodic syndromes (CAPS) are usually caused by heterozygous NLRP3 gene variants, resulting in excessive inflammasome activation with subsequent overproduction of interleukin (IL)-1β. The CAPS spectrum includes mild, moderate, and severe phenotypes. The mild phenotype is called familial cold autoinflammatory syndrome (FCAS), the moderate phenotype is also known as Muckle–Wells syndrome (MWS), and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) describes the severe phenotype. The CAPS phenotypes display unspecific and unique clinical signs. Dermatologic, musculoskeletal, ocular, otologic, and neurologic disease symptoms combined with chronic systemic inflammation are characteristic. Nevertheless, making the CAPS diagnosis is challenging as several patients show a heterogeneous multi-system clinical presentation and the spectrum of genetic variants is growing. Somatic mosaicisms and low-penetrance variants lead to atypical clinical symptoms and disease courses. To avoid morbidity and to reduce mortality, early diagnosis is crucial, and a targeted anti-IL-1 therapy should be started as soon as possible. Furthermore, continuous and precise monitoring of disease activity, organ damage, and health-related quality of life is important. This review summarizes the current evidence in diagnosis and management of patients with CAPS.
Highlights
Autoinflammatory diseases (AID) are rare, often severe illnesses caused by genetic variants in innate immunity genes resulting in a constitutive overproduction of proinflammatory cytokines [1,2]
The mild phenotype is called familial cold autoinflammatory syndrome (FCAS, OMIM 120100), the moderate phenotype is known as Muckle–Wells syndrome (MWS, OMIM 191900), and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) (OMIM 607115) describes the severe phenotype
We summarize what we know today, nearly 20 years after NLRP3 gene discovery, give an overview of the current evidence in making the diagnosis, and give an update regarding the current management recommendations for patients with cryopyrin-associated periodic syndromes (CAPS)
Summary
Autoinflammatory diseases (AID) are rare, often severe illnesses caused by genetic variants in innate immunity genes resulting in a constitutive overproduction of proinflammatory cytokines [1,2]. In 2001/2002, the NLRP3 gene ( known as CIAS1 or NALP3 gene) was discovered, coding for the protein cryopyrin or synonymously called NLRP3/NALP3 protein [9,10,11] Variants of this gene usually cause the cryopyrin-associated periodic syndromes (CAPS), a clinical spectrum of different autoinflammatory phenotypes with varying disease activity and phenotype-related risk for morbidity and mortality [12]. The different levels of phenotypic severity of the same disease should be reflected by using the adjectives: mild, moderate, and severe [13] It seems that this new taxonomy has yet failed to receive broad recognition, the, up until now, more prevalent term CAPS is used in this paper. We summarize what we know today, nearly 20 years after NLRP3 gene discovery, give an overview of the current evidence in making the diagnosis, and give an update regarding the current management recommendations for patients with CAPS
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