Anticytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis

Abstract

The recognition that atherosclerosis is a complex chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anticytokine therapies targeting specific IL (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 proinflammatory and proatherogenic (such as IL-1, IL-6, and TNF [tumor necrosis factor]) or as anti-inflammatory and antiatherogenic (such as IL-10 and IL-1rA). The recent CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) 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 CRP (C-reactive protein). By contrast, in the recent CIRT (Cardiovascular Inflammation Reduction Trial), low-dose methotrexate neither reduced IL-1β, IL-6, or high-sensitivity CRP nor lowered cardiovascular event rates. Taken together, these 2 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 anticytokine therapies, and a look to the future of clinical practices addressing residual inflammatory risk.

Keywords: cardiovascular diseases; cytokines; humans; inflammasomes; interleukins.

Figure 1.. Cytokines Implicated in the Atherothrombotic Process.

Data derived from mouse studies (left) and human studies (right) suggest an intricate balance between pro- and anti-inflammatory cytokine signaling pathways in the genesis of atherosclerotic lesions and in the probability of plaque rupture leading to clinical events such as myocardial infarction, stoke, and cardiovascular death. Adapted from Kleeman et al, Cardiovascular Research 2008;79:360–376 and Ait-Oufella H et al, Arterioscler Thromb Vasc Biol 2011;31:969–979.

Figure 2.. Meta-analysis of the Associations of Inflammatory Cytokines and Risks of coronary Disease in Prospective Cohort Studies.

Data are shown for IL-6, IL-18, MMP-9, sCD40L, and TNFa, adjusted for age, gender, smoking status, obesity, blood pressure, and lipid levels. Adapted from Kaptoge et al, Eur Heart J 2014;35:578–589.

Figure 3.. Efficacy of Achieving the “Dual Goals” of LDL and hsCRP Reduction.

Best cardiovascular outcomes are achieved among atherosclerosis patients treated with statin therapy (left, PROVE-IT) or with statin therapy plus ezetimibe (right, IMPROVE-IT) who not only lowered LDLC below 70mg/dL but who also lowered hsCRP below 2mg/L. Data from Ridker et al, N Engl J Med 2005; 352:20–8 and Bohula et al Circulation 2015; 132:1224–33.

Figure 4.. Anti-cytokine Therapy to Reduce Cardiovascular Risk: CANTOS Main Results.

Cumulative incidence of MACE (myocardial infarction, stroke, or cardiovascular death, left) or MACE+ (myocardial infarction, stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death, right) in the CANTOS trial. Data are shown for the placebo group and for those in the canakinumab 150mg and 300mg groups. These doses of canakinumab resulted in 35 to 40 percent reductions in hsCRP and interleukin-6 with no effect on LDL cholesterol. Data from Ridker et al, N Engl J Med 2017;377:1119–1131

Figure 5.. Lower is Better for IL-6 and hsCRP: The CANTOS Trial On-Treatment Findings.

Greater risk reductions were seen in CANTOS with greater hsCRP reductions (left) and greater IL-6 reductions (right). Data are shown for those who achieved hsCRP < 2mg/L or IL-6 levels below the trial median measured three months after a single dose of canakinumab. Adapted from Ridker et al Lancet 2018;391:319–28 and Ridker et al, Eur Heart J 2018:ehy310-ehy310.

Figure 6.. Interleukin-1β Inhibition and Lung Cancer.

Cumulative incidence of lung cancer (left) and fatal lung cancer (right) among CANTOS participants randomly allocated to placebo, canakinumab 50mg, canakinumab 150mg, or canakinumab 300mg. Adapted from Ridker et al, Lancet 2017;390:1833–42.

Figure 7.. Low-Dose Methotrexate Neither Reduces IL-1β, IL-6 or CRP, nor Lowers Cardiovascular Event Rates.

Cumulative incidence of major adverse cardiovascular events plus hospitalization for unstable angina in the Cardiovascular Inflammation Reduction Trial (CIRT). Adapted from Ridker et al, N Engl J Med 2018 (5).

Figure 8.. Combining Aggressive LDL Reduction with Concomitant Anti-Cytokine Therapy.

The simple two-by-two factorial design trial shown could be used to test both the independent and additive effects of lipid-lowering and inflammation inhibition in the treatment of atherosclerosis.