Mechanisms of DiseasePrevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist
Introduction
Familial cold autoinflammatory syndrome (FCAS), commonly known as familial cold urticaria, is an autosomal dominant inflammatory disease that has recently been included in the group of hereditary periodic-fever disorders. As in the more widely known familial Mediterranean fever and other inherited autoinflammatory syndromes, FCAS is characterised by recurrent bouts of fever, rash, and joint pain. However, in contrast to the other inherited autoinflammatory disorders, acute attacks in FCAS are consistently triggered by general cold exposure. Typically, FCAS patients report the development of general rash, low-grade fever, polyarthralgia, and in some cases conjunctivitis beginning 1–2 h after mild exposures such as air-conditioned rooms or cool breezes. These episodes generally resolve spontaneously within 24 h. Many patients with FCAS also show evidence of chronic inflammation between attacks, particularly a daily pattern of rash developing in the afternoon that can be associated with headaches, myalgia, and fatigue by the evening. The atypical urticarial rash in FCAS does not necessarily occur on exposed areas of skin, unlike the classic urticarial rash in the more common acquired cold urticaria, in which direct contact with cold objects causes pruritic hives at the site of exposure. Although colchicine prevents attacks in familial Mediterranean fever, there has been no known effective treatment for FCAS.1
There have been substantial advances in understanding of the genetic basis of the periodic-fever disorders in the past decade. The gene that causes familial Mediterranean fever was identified in 1997; it encodes a protein called pyrin,2, 3 which interacts with and perhaps inhibits an intracellular adaptor protein called ASC that is involved in release of interleukin 1.4, 5 In 2001, we identified the CIAS1 gene, which is mutated in patients with FCAS. Our group and others also identified CIAS1 mutations in two related inflammatory diseases, Muckle-Wells syndrome6, 7, 8, 9 and neonatal-onset multisystem inflammatory disease (NOMID).10, 11 CIAS1 codes for cryopyrin, which shares a similar N-terminal domain (PYD) with pyrin and ASC proteins.6 Interactions between these domains from different proteins are thought to mediate downstream signalling events.12 Cryopyrin interacts with ASC, leading to activation of caspase 1 and subsequent release of interleukin 1, as well as activation of nuclear factor κB (NF-κB) which results in the release of many proinflammatory cytokines such as interleukin 6 (figure 1).13, 14 Because cryopyrin is positioned at a crucial convergence point in signal transduction, it could have a central role in the pathogenesis of many diseases that involve translocation of NF-κB and release of proinflammatory cytokines. Elucidation of the pathobiology of cryopyrin defects in FCAS might therefore provide clues to the mechanisms of more common diseases.
Anakinra, a recombinant selective interleukin-1 receptor antagonist (IL-1Ra), has shown clinical efficacy in terms of symptoms and radiological progression in patients with rheumatoid arthritis. The proposed function of cryopyrin in the interleukin-1 pathway and the finding that cultured monocytes from a patient with NOMID had constitutively increased interleukin-1 production11 implied a potential therapeutic role for IL 1Ra. Hawkins and colleagues gave IL-1Ra to five patients with Muckle-Wells syndrome over a period of several months; the clinical efficacy was striking.15, 16 In this study, we used a novel cold-challenge model to investigate the inflammatory responses in patients with FCAS and the effectiveness of IL-1Ra at preventing acute inflammation.
Section snippets
Patients
All participants in this study were recruited from a family affected by FCAS that has been reported and previously studied at the University of California at San Diego. Diagnosis of FCAS was confirmed by history and direct sequencing of CIAS1. All participants in this study with FCAS have an L353P mutation, which is the most common CIAS1 mutation in North America and is associated with a founder family that accounts for up to 90% of cases of FCAS worldwide.17 Disease severity was assessed by
Results
Disease severity was similar among the individuals with FCAS. There are no reported cases of renal amyloidosis in this family, and there was no evidence of proteinuria in the affected individuals. There was no significant difference in baseline erythrocyte sedimentation rate or concentrations of C-reactive protein, haptoglobin, or serum amyloid A between FCAS and control participants. One FCAS participant had a high concentration of serum amyloid A (table). There were no significant changes in
Discussion
This study shows how the application of genomics to the study of human disease has led to an increased understanding of the underlying mechanisms and improved treatment for patients with FCAS. The discovery of CIAS1 and its protein product cryopyrin, the subsequent elucidation of interacting proteins and inflammatory pathways involved, and the recent advances in targeted cytokine therapy have resulted in a new therapy for a disorder with substantial morbidity and no previously known effective
Glossary
- Familial Mediterranean fever
- An autosomal recessive inflammatory disease characterised by recurrent episodes of fever, arthralgia, rash, and abdominal and chest pain, that is found more commonly in people of Mediterranean origin
- Autoinflammatory syndromes
- Diseases characterised by recurrent episodes of inflammation in the absence of infection, autoantibodies, or antigen-specific T cells—eg, hereditary periodic-fever disorders and Crohn's disease.
- ASC
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