Most studies showed that LPS alone was sufficient to overactivate IL-1b secretion in SS, suggesting an abnormal activation of the intracellular processes leading to production and secretion of inflammatory cytokines, perhaps through inflammasome-dependent mechanisms. Conversely, one study suggested that in some SS patients LPS could not increase the inflammatory cytokines production. Our study adds some line of evidence that LPS does induce an abnormal release of proinflammatory cytokines IL-1b, IL-6 and TNF-a by PBMCs in SS, with different kinetic patterns and magnitude according to the patients. In patient 1, all the 3 cytokines were produced at a high level after 6 hours of LPS stimulation. In patient 2, cytokines production after 16 hours of LPS was higher than after 6 hours and was very high for IL-6. These interindividual variations in cytokine responses observed in our patients had to be expected and may be explained by polymorphisms as well as gender and age differences. The high production of IL-6 after LPS stimulation is of particular interest since a recent study reported a complete remission after anti-IL-6 treatment in 3 patients who failed anti-IL-1b treatment. We observed that stimulation of the patients PBMCs with their own plasmas induced a negligible secretion of cytokines. This argues against the eDNA techniques could be used to form cost-efficient multi-species inventory and monitoring programs for sensitive species existence of a stimulatory factor in the plasma in SS. Although the spontaneous production of IL-1b and IL-6 by unstimulated PBMCs of SS patients was very low and not different from healthy subjects, we show that spontaneous IL-1b but not IL6 gene expression was markedly increased in unstimulated PBMCs of SS patient when compared to healthy subjects. This spontaneous high gene expression of IL-1b in unstimulated PBMCs in SS could explain why LPS alone can trigger an efficient release of cytokine. Indeed, these findings suggest that PBMCs in SS patients have already undergone a first priming from extrinsic or intrinsic origin that allows substantial IL-1 b release in the absence of the ��second hit�� usually required to trigger efficient release. The fact that the spontaneous gene expression of IL-6 in PBMCs was similar in SS patient and healthy subjects while IL-6 production after LPS stimulation was much higher than in healthy controls suggests that IL-6 production could be dependent on IL-1 b stimulation, by an amplification loop process. We report here for the first time the effects on LPS-induced cytokines release of anakinra both in vitro and after 1 month of subcutaneous in vivo administration in two SS patients. The direct and rapid in vitro effect of anakinra on IL-1b suggests that there is an inhibition of the known autostimulatory loop of IL-1b production. In keeping with this hypothesis, we show that the spontaneous gene expression of IL-1b in PBMC after 1 month of anakinra was normalized in SS patient 2. IL-1 trap has also been shown to reduce IL-1b, IL-6 and TNF-a production by LPS-stimulated PBMCs in SS. These in vitro results suggest that inhibiting the IL-1 autostimulatory loop by blocking IL-1 receptors, can also inhibit TNF-a production in SS. Patterns of response differed between the 2 patients for IL-6 as its production was markedly decreased after in vitro anakinra in patient 2 and less impressively in patient 1. After 1 month of anakinra treatment, we observed a dramatic decrease in IL-1b production.