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J Exp Med ; 206(5): 1029-36, 2009 May 11.
Article in English | MEDLINE | ID: mdl-19364880

ABSTRACT

The investigation of interleukin 1beta (IL-1beta) in human inflammatory diseases is hampered by the fact that it is virtually undetectable in human plasma. We demonstrate that by administering the anti-human IL-1beta antibody canakinumab (ACZ885) to humans, the resulting formation of IL-1beta-antibody complexes allowed the detection of in vivo-produced IL-1beta. A two-compartment mathematical model was generated that predicted a constitutive production rate of 6 ng/d IL-1beta in healthy subjects. In contrast, patients with cryopyrin-associated periodic syndromes (CAPS), a rare monogenetic disease driven by uncontrolled caspase-1 activity and IL-1 production, produced a mean of 31 ng/d. Treatment with canakinumab not only induced long-lasting complete clinical response but also reduced the production rate of IL-1beta to normal levels within 8 wk of treatment, suggesting that IL-1beta production in these patients was mainly IL-1beta driven. The model further indicated that IL-1beta is the only cytokine driving disease severity and duration of response to canakinumab. A correction for natural IL-1 antagonists was not required to fit the data. Together, the study allowed new insights into the production and regulation of IL-1beta in man. It also indicated that CAPS is entirely mediated by IL-1beta and that canakinumab treatment restores physiological IL-1beta production.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Autoimmune Diseases/genetics , Carrier Proteins/genetics , Familial Mediterranean Fever/genetics , Interleukin-1beta/immunology , Urticaria/genetics , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , C-Reactive Protein/metabolism , Familial Mediterranean Fever/blood , Familial Mediterranean Fever/drug therapy , Familial Mediterranean Fever/immunology , Homeostasis , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-6/blood , NLR Family, Pyrin Domain-Containing 3 Protein , Receptors, Interleukin-1/blood , Serum Amyloid A Protein/metabolism , Urticaria/blood , Urticaria/drug therapy , Urticaria/immunology
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