Methods. Patients' disease manifestations and cytokine measurements were recorded before anakinra treatment was started, during 14 months of therapy, and after discontinuation of anakinra treatment.Results. Spontaneous secretion of IL-1 by patients' PBMCs was found to be dramatically increased (80-175 fold) compared to healthy controls. Consistent with these findings, anakinra initially led to a marked clinical improvement and to a rapid near-normalization of IL-1 secretion. However, a progressive clinical relapse occurred secondarily, associated with an increase in TNF␣ secretion, persistent elevated levels of IL-1Ra and IL-6, and a reactivation of IL-1 secretion. Anakinra was discontinued after 14 months of therapy.Conclusion. Our findings provide in vivo evidence of the crucial role of IL-1 in the pathophysiology of NLRP12AD. This is the first time anakinra has been used to treat this disorder. This study provides new insights into the mechanisms underlying resistance to anti-IL-1 therapy observed in a few patients with autoinflammatory syndromes. Our data also point to the potential of ex vivo cytokine measurements as predictors of response to treatment.Recurrent fever syndromes are autoinflammatory disorders characterized by recurrent episodes of fever, systemic inflammation, sterile peritonitis, arthritis, and/or cutaneous manifestations. Among them, cryopyrin-associated periodic syndromes have been associated with mutations in NLRP3, a gene of myelomonocytic expression. Peripheral blood mononuclear cells (PBMCs) from patients carrying NLRP3 mutations secrete excessive amounts of interleukin-1 (IL-1) (e.g., refs. 1 and 2), a crucial cytokine in systemic inflammation. IL-1 acts on multiple organs and amplifies inflammation by inducing the expression of proinflammatory cytokines (including IL-1 itself) and numerous genes involved in inflammatory processes. In patients with cryopyrin-associated periodic syndromes, there is constitutive activation of a multiprotein complex, called the NLRP3 inflammasome, which triggers the cleavage of procaspase 1 into caspase 1 and leads to the conversion of proIL-1 to mature IL-1. Once