2417Elevated interleukin-6 and interleukin-18 concentrations predict residual inflammatory risk both before and after interleukin-1beta inhibition with canakinumab

Abstract

Abstract Background The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1b (IL-1b) inhibition can significantly reduce cardiovascular event rates in the absence of beneficial effects on cholesterol. Yet, CANTOS participants treated with both statins and canakinumab remain at considerable risk. Both interleukin-6 (IL-6, a central signaling cytokine) or interleukin-18 (IL-18, which like IL-1b requires the NLRP3 inflammasome for activation) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis. Purpose To assess the impact of canakinumab therapy on plasma levels of IL-6 and IL-18, and to assess the potential contributions of IL-6 and IL-18 to residual inflammatory risk both before and after treatment with canakinumab. Methods Plasma samples from 3,381 stable post-myocardial infarction patients assigned to active IL-1b inhibition within CANTOS underwent measurement of IL-6 and IL-18 both before and after initiation of canakinumab. All participants were followed over a 3.7 year period for major adverse cardiovascular events (MACE) and all-cause mortality. Results When compared to placebo, canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8, 36.3, and 43.2 percent for the 50mg, 150mg, and 300mg doses, respectively (all p-values <0.001). In marked contrast, no dose of canakinumab significantly altered IL-18 levels measured at 3 months (all effects less than 1 percent, all p-values >0.05). Yet, despite these differential plasma effects, both baseline and on-treatment levels of IL-6 and IL-18 associated with rates of future cardiovascular events and with all-cause mortality. For example, for MACE, each tertile increase in IL-6 measured 3 months after canakinumab initiation associated with a 42 percent increase in risk (95% CI 26–59%, P<0.0001) while each tertile increase in IL-18 measured 3 months after canakinumab initiation associated with a 15 percent increase in risk (95% CI 3–29% P=0.015). Similar effects were observed for MACE-plus, cardiovascular death, and all-cause mortality. Conclusions These randomized trial biomarker analyses from CANTOS demonstrate that interleukin-1b inhibition with canakinumab significantly reduces plasma levels of IL-6 but not IL-18, yet that there remains substantial residual inflammatory risk related to both IL-6 and IL-18. As such, our data support further pharmacologic development of potential anti-cytokine therapies for atherothrombosis that simultaneously inhibit IL-1b and IL-18 (such as NLRP3 inhibitors) as well as agents that directly target IL-6 signaling. Acknowledgement/Funding Novartis