Cryopyrin-associated periodic syndrome and autoinflammation

Department of Dermatology, University of California, San Francisco, CA, USA.
Clinical and Experimental Dermatology (Impact Factor: 1.09). 02/2008; 33(1):1-9. DOI: 10.1111/j.1365-2230.2007.02540.x
Source: PubMed


Autoinflammatory syndromes are a distinct class of inherited diseases of cytokine dysregulation with important cutaneous features. Several disorders, including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome and neonatal onset multisystem inflammatory disorder (NOMID), are associated with mutations in a common gene, CIAS-1. These disorders are now believed to represent related conditions along a spectrum of disease severity, in which FCAS is the mildest and NOMID is the most severe phenotype. Patients typically present with lifelong atypical urticaria with systemic symptoms, with potential for developing end-organ damage due to chronic inflammation. Advances in the understanding of the genetic basis of these syndromes have also revealed cytokine signalling molecules that are critical to normal regulation of inflammatory pathways. The dramatic response of these syndromes to anakinra, an interleukin (IL)-1 antagonist, highlights the important role of IL-1 cytokine signalling in the pathogenesis of this rare but fascinating class of diseases.

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    • "CAPS comprise the mild familial cold-induced autoinflammatory syndrome (FCAS), the moderate MWS, and the severe neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome [1-3]. Most CAPS patients carry mutations in the NLRP3 gene encoding the protein cryopyrin/NALP3 [4,5] which is essential for the activation of intracellular caspase 1 and the processing of interleukin-1β (IL-1β) [6-11]. Macrophages from MWS patients show a constitutive increase of IL-1β [2,10,12,13]. "
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    ABSTRACT: Objectives Muckle-Wells syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1β monoclonal antibody, can abolish excess IL-1β. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies. Methods Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed. Results The study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumab-treated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles. Conclusions IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.
    Full-text · Article · May 2013 · Arthritis research & therapy
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    • "Regardless the putative role of propolis in NLRC4 inflammasome, our data clearly demonstrate that Brazilian green propolis extract acts in regulating the IL-1β secretion by NLRP3 inflammasomes. This is a remarkable finding, since it was demonstrated that mutations in inflammasome-related genes, such as NLRP3 and NLRP1, are associated with autoimmune and autoinflammatory disorders [72]. Therefore, the use of natural products such as Brazilian propolis may open promising therapeutic strategies for the treatment of these severe chronic autoinflammatory diseases. "
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    ABSTRACT: Propolis extracts have gained the attention of consumers and researchers due to their unique chemical compositions and functional properties such as its anti-inflammatory activity. Recently, it was described a complex that is also important in inflammatory processes, named inflammasome. The inflammasomes are a large molecular platform formed in the cell cytosol in response to stress signals, toxins, and microbial infections. Once activated, the inflammasome induces caspase-1, which in turn induces the processing of inflammatory cytokines such as IL-1 β and IL-18. So, to understand inflammasomes regulation becomes crucial to treat several disorders including autoinflammatory diseases. Since green propolis extracts are able to regulate inflammatory pathways, this work purpose was to investigate if this extract could also act on inflammasomes regulation. First, the extract was characterized and it demonstrated the presence of important compounds, especially Artepillin C. This extract was effective in reducing the IL-1 β secretion in mouse macrophages and this reduction was correlated with a decrease in activation of the protease caspase-1. Furthermore, we found that the extract at a concentration of 30 μ g/mL was not toxic to the cells even after a 18-hour treatment. Altogether, these data indicate that Brazilian green propolis (EPP-AF) extract has a role in regulating the inflammasomes.
    Full-text · Article · Apr 2013 · Evidence-based Complementary and Alternative Medicine
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    • "Histologic examination of affected skin can assist in confirming an early diagnosis of CAPS. A common characteristic feature is neutrophilic dermal infiltrate in the reticular dermis [9]. The infiltrate tends to be perivascular and also may be peri-eccrine. "
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    ABSTRACT: Cryopyrin-associated periodic syndrome (CAPS) is a rare hereditary inflammatory disorder encompassing a continuum of three phenotypes: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease. Distinguishing features include cutaneous, neurological, ophthalmologic, and rheumatologic manifestations. CAPS results from a gain-of-function mutation of the NLRP3 gene coding for cryopyrin, which forms intracellular protein complexes known as inflammasomes. Defects of the inflammasomes lead to overproduction of interleukin-1, resulting in inflammatory symptoms seen in CAPS. Diagnosis is often delayed and requires a thorough review of clinical symptoms. Remarkable advances in our understanding of the genetics and the molecular pathway that is responsible for the clinical phenotype of CAPS has led to the development of effective treatments. It also has become clear that the NLRP3 inflammasome plays a critical role in innate immune defense and therefore has wider implications for other inflammatory disease states.
    Preview · Article · Feb 2011 · Current Allergy and Asthma Reports
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