In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes

The investigation of interleukin 1 beta (IL-1 beta) 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-1 beta antibody canakinumab (ACZ885) to humans, the resulting formation of IL-1 beta-antibody complexes allowed the detection of in vivo-produced IL-1 beta. A two-compartment mathematical model was generated that predicted a constitutive production rate of 6 ng/d IL-1 beta 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-1. to normal levels within 8 wk of treatment, suggesting that IL-1. production in these patients was mainly IL-1. driven. The model further indicated that IL-1. 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-1. in man. It also indicated that CAPS is entirely mediated by IL-1. and that canakinumab treatment restores physiological IL-1. production.