Physicians' Academy for Cardiovascular Education

Residual inflammatory risk associated with IL-6 and IL-18 after IL-1β inhibition

Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis

Literature - Ridker PM, MacFadyen JG, Thuren T et al., on behalf of the CANTOS Group - Eur Heart J. 2019. ehz542,

Introduction and methods

The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) showed that targeting inflammation with interleukin-1β (IL-1β) inhibition with canakinumab lowered CV event rates, without affecting blood pressure and cholesterol [1]. The CANTOS trial thereby established the importance of inflammation in human atherosclerosis. It also provided proof-of-principle of targeting pro-inflammatory cytokine pathways, with the magnitude of inflammation inhibition being related to the magnitude of clinical benefit [2,3]. CANTOS participants treated with high-intensity statins and canakinumab remain, however, at considerable risk for recurrent CV events.

It has been suggested that IL-18 may play a role in the residual inflammatory risk [4-6]. No data is available, however, to date that addresses whether IL-18 levels remain a significant predictor of residual risk after therapy with aggressive IL-1β inhibition. This would be relevant in light of development of NLRP-3 inflammasome inhibitors, which would inhibit active forms of IL-1β as well as IL-18.

This study therefore tested the hypothesis in CANTOS data that plasma IL-18 levels associate with future vascular risk both before and after treatment with canakinumab. The relation of IL-6 with future risk was also assessed, as IL-6 signaling has been linked to plaque progression and rupture [7-9]. Plasma levels of IL-18 and IL-6 were measured at randomization and after three months of therapy in 4848 CANTOS participants. Individuals in this analysis were mostly enrolled in Western Europe, the USA and Canada. Any effect of canakinumab on the median percent change in IL-18 and IL-6 between the two measurements was assessed. Assuming regression to the mean for the change in IL-18 and Il-6 in the placebo group over the 3 months period, analyses for the canakinumab therapy were placebo-subtracted. Relative hazards for major adverse CV events (MACE), consisting of myocardial infarction, stroke, or CV death, and other composite CV endpoints were calculated.

Main results


These randomized data show that IL-1β inhibition with canakinumab lowers plasma IL-6 but not IL-18 levels, and baseline and on-treatment levels of IL-6 or IL-18 predict risk of recurrent CV events. IL-6 showed a greater association with residual inflammatory risk after IL-1β inhibition than IL-18. These data are informative for the development of therapies targeting cytokines other than IL-1β.


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Find this article online at Eur Heart J.

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