To examine the synthesis, processing, and secretion of interleukin‐1β (IL‐1β), as well as the clinical and biologic effects of IL‐1 blockade, in patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome and Muckle‐Wells syndrome (MWS), in an effort to understand the molecular mechanisms linking mutations of the CIAS1 gene and IL‐1β hypersecretion, and the underlying response to IL‐1 receptor antagonist (IL‐1Ra).

Six patients with CINCA syndrome or MWS were treated with IL‐1Ra and followed up longitudinally. Monocytes obtained from the patients and from 24 healthy donors were activated with lipopolysaccharide (LPS) for 3 hours, and intracellular and secreted IL‐1β levels were determined by Western blotting and enzyme‐linked immunosorbent assay before and after exposure to exogenous ATP.

LPS‐induced IL‐1β secretion was markedly increased in monocytes from patients with CIAS1 mutations. However, unlike in healthy subjects, secretion of IL‐1β was not induced by exogenous ATP. Treatment with IL‐1Ra resulted in a dramatic clinical improvement, which was paralleled by an early and strong down‐regulation of LPS‐induced IL‐1β secretion by the patients' cells in vitro.

Our results showed that the requirements of ATP stimulation for IL‐1β release observed in healthy individuals are bypassed in patients bearing CIAS1 mutations. This indicates that cryopyrin is the direct target of ATP and that the mutations release the protein from the requirement of ATP for activation. In addition, the dramatic amelioration induced by IL‐1Ra treatment is at least partly due to the strong decrease in IL‐1β secretion that follows the first injections of the antagonist. These findings may have implications for other chronic inflammatory conditions characterized by increased IL‐1β.