Anti-Cytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis

The recognition that atherosclerosis is a complex chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anti-cytokine therapies targeting specific interleukin signaling pathways could serve as powerful adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease. Cytokines involved in human atherosclerosis can be broadly classified as pro-inflammatory and pro-atherogenic (such as IL-1, IL-6, and TNF) or as anti-inflammatory and anti-atherogenic (such as IL-10 and IL-1rA). The recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has shown that specific targeting of IL-1β can significantly reduce cardiovascular event rates without lipid or blood pressure lowering. In CANTOS, the magnitude of benefit of this cytokine targeted approach to atherosclerosis treatment was associated to the magnitude of reduction of the central signaling cytokine IL-6 and the downstream clinical biomarker high-sensitivity C-reactive protein (hsCRP). By contrast, in the recent Cardiovascular Inflammation Reduction Trial (CIRT), low-dose methotrexate neither reduced IL-1β, IL-6, or hsCRP nor lowered cardiovascular event rates. Taken together, these two contemporary trials provide proof-of-principle that focused cytokine inhibition, not broad spectrum anti-inflammatory therapy, is likely to be crucial for atheroprotection. This review provides an overview of cytokines in atherosclerosis, the potential benefits and risks associated with targeted anti-cytokine therapies, and a look to the future of clinical practices addressing “residual inflammatory risk”.