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

Abstract

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 1beta in this disorder. Involvement of cryopyrin in activation of caspase 1 and NF-kappaB 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 1beta in more common inflammatory diseases.

Figure 1. Proposed mechanism of cryopyrin function

Cryopyrin interacts with ASC resulting in activation of caspase 1 or NF-κB, leading to the release of proinflammatory cytokines. Pyrin inhibits the interaction between cryopyrin and ASC. IL-1Ra competes with interleukin 1, for its receptor. Activation of interleukin-1 receptor also leads to NF-κB activation. Interleukin 6 is released into the blood, leading to fever and arthralgia.

Figure 2. Mean oral temperature before, during, and after cold challenge

Figure 3. Appearance of skin (upper arm) of a patient with FCAS after cold challenge

Figure 4. Mean white-blood-cell counts before and after cold challenge

Figure 5. Mean change from baseline in serum concentrations of interleukin 6 after cold challenge

Error bars=SD.

Figure 6. Mean cytokine gene expression in skin tissue before and after cold challenge

Cytokine mRNA concentrations in skin tissue are normalised to those of mRNA for glyceraldehyde-3-phosphate dehydrogenase and expressed as relative expression units (REU). Error bars=SD.

Figure 7. Histopathology and cytokine immunohistochemistry of FCAS skin

A: haematoxylin and eosin staining of skin from affected area (×10 magnification) showing dermal oedema and prominent leucocyte infiltrate. B: high-power (×40 magnification) showing predominant neutrophilic infiltrate concentrated in the perivascular and sweat gland areas. C: staining of unaffected skin for interleukin 6 before cold challenge. D: staining of affected skin for interleukin 6 after cold challenge; there is intracellular (red) staining of infiltrating leucocytes and resident spindle-shaped cells. E: staining of unaffected skin for interleukin 1β before cold challenge. F: staining of affected skin for interleukin 1β after cold challenge showing staining (red) of infiltrating leucocytes and resident cells. G: staining of unaffected skin for interleukin 8 before cold challenge. H: staining of affected skin for interleukin 8 after cold challenge showing staining (red) of infiltrating leucocytes.