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


RESULTS
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.


CONCLUSIONS
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.


CONCLUSIONS
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.
Hoffman
Hal M
HM
Division of Rheumatology, Allergy, and Immunology, University of California at San Diego School of Medicine, La Jolla, CA 92093-0635, USA. hahoffman@ucsd.edu
Rosengren
Sanna
S
Boyle
David L
DL
Cho
Jae Y
JY
Nayar
Jyothi
J
Mueller
James L
JL
Anderson
Justin P
JP
Wanderer
Alan A
AA
Firestein
Gary S
GS
D000208:Acute Disease; D000368:Aged; D018771:Arthralgia; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D003080:Cold Temperature / Q000009:adverse effects*; D016207:Cytokines / Q000378:metabolism; D005076:Exanthema; D005260:Female; D005334:Fever; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000627:therapeutic use*; D012867:Skin / Q000378:metabolism; D013577:Syndrome; D014581:Urticaria / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control
D002352:Carrier Proteins; D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins