Elsevier

The Lancet

Volume 364, Issue 9447, 13–19 November 2004, Pages 1779-1785
The Lancet

Mechanisms of Disease
Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist

https://doi.org/10.1016/S0140-6736(04)17401-1Get rights and content

Summary

Background

Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterised by recurrent episodes of rash, arthralgia, and fever after cold exposure. The genetic basis of this disease has been elucidated. Cryopyrin, the protein that is altered in FCAS, is one of the adaptor proteins that activate caspase 1, resulting in release of interleukin 1.

Methods

An experimental cold challenge protocol was developed to study the acute inflammatory mechanisms occurring after a general cold exposure in FCAS patients and to investigate the effects of pretreatment with an antagonist of interleukin 1 receptor (IL-1Ra). ELISA, real-time PCR, and immunohistochemistry were used to measure cytokine responses.

Findings

After cold challenge, untreated patients with FCAS developed rash, fever, and arthralgias within 1–4 h. Significant increases in serum concentrations of interleukin 6 and white-blood-cell counts were seen 4–8 h after cold challenge. Serum concentrations of interleukin 1 and cytokine mRNA in peripheral-blood leucocytes were not raised, but amounts of interleukin 1 protein and mRNA were high in affected skin. IL-1Ra administered before cold challenge blocked symptoms and increases in white-blood-cell counts and serum interleukin 6.

Interpretation

The ability of IL-1Ra to prevent the clinical features and haematological and biochemical changes in patients with FCAS indicates a central role for interleukin 1β in this disorder. Involvement of cryopyrin in activation of caspase 1 and NF-κB signalling suggests that it might have a role in many chronic inflammatory diseases.

Relevance to practice

These findings support a new therapy for a disorder with no previously known acceptable treatment. They also offer insights into the role of interleukin 1β in more common inflammatory diseases.

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

References (26)

  • International FMF Consortium

    Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever

    Cell

    (1997)
  • French FMF Consortium

    A candidate gene for familial Mediterranean fever

    Nat Genet

    (1997)
  • N Richards et al.

    Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis

    J Biol Chem

    (2001)
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