Cytokines and stroke: worst enemies or best friends?

Inflammation

Inflammation plays a central and complex role in the pathogenesis of cerebrovascular diseases. Indeed, at early stages of the post-ischemic molecular cascade, activated intravascular leucocytes and proinflammatory mediators from endothelium and microglia contribute to brain damage, and, later on, they are pivotal for brain repair ¹. In the clinical setting, a growing body of evidence suggests that systemic inflammation, including blood levels of circulating pro-inflammatory cytokines, is associated to higher risk of cerebrovascular diseases and worse clinical outcomes after in acute ischemic stroke (AIS) ². Over the years, several cytokines, including interleukin (IL) 1-beta, IL-6, IL-10, IL-17, and IL-8 have been identified as peripheral blood prognostic markers, and have been associated to worse long-term functional and cognitive outcomes after an AIS ^3,4.

Cardiology

In cardiology, the CANTOS trials provided the first evidence on antibody targeting interleukin-1β (canakinumab) for secondary prevention after myocardial infarction ⁵. Results showed a significantly lower risk of recurrent ischemic cardiovascular events in the interventional arm compared to placebo, however, canakinumab was associated with higher risk of fatal infections. The recent randomised controlled trial (RCT) on colchicine (COLCOT) found a significantly lower risk of ischemic cardiovascular events than placebo in patients with a recent myocardial infarction⁶. Results of COLCOT were confirmed by another RCT (LoDoCo2), and a following meta-analysis showed that the risk of stroke almost halves in patients with coronary artery disease (CAD) treated with colchicine^7,8. Accordingly, new 2021 European Society of Cardiology (ESC) guidelines recommend low-dose of colchicine (0.5 mg daily) for secondary prevention of cardiovascular diseases, particularly if other risk factors are insufficiently controlled or if recurrent cardiovascular disease events occur under optimal therapy (Class IIb, Level A) ⁹.

Stroke Medicine

In the field of stroke medicine, many RCTs were conducted on patients with AIS to prove the benefit of anti-inflammatory and immunomodulatory drugs on functional outcome. Recently, SCIL-STROKE trial tested subcutaneous IL-1 receptor antagonist (IL-1Ra) in patients with AIS and found that IL-1Ra was safe but without benefit on 3-months clinical outcome ¹⁰. ACTION II trial evaluated the effect of 2 doses of natalizumab on functional outcomes in patients with AIS but patients receiving natalizumab had worse outcomes ¹¹. A double-blind, placebo-controlled, randomised, phase Ib/IIa clinical ongoing study is evaluating ApTOLL, a Toll-like receptor 4 (TLR4) antagonist in patients with large vessel occlusions (NCT04734548).

Secondary Prevention

Regarding secondary prevention, different RCTs are ongoing. The CONVINCE study (NCT02898610), is currently investigating the efficacy of low-dose colchicine on reducing stroke recurrence or death after AIS or transient ischemic attacks of non-cardioembolic origin and the CIAFS-1 study (NCT02282098) is testing colchicine in patients with atrial fibrillation. Finally, the ZEUS trial is studying Ziltivekimab (a human monoclonal antibody against IL-6) in patients with cardiovascular and chronic kidney disease (NCT05021835).

The post-stroke inflammatory response still represents a potential target for improving acute and secondary prevention strategies. Stroke treatments are always a matter of time: despite the negative results of previous RCTs on immunomodulatory drugs in the acute phase, there are reasons to be optimistic for the future. Challenging the identification of an inflammatory “window” will probably allow a more accurate and personalised patients’ selection, both imaging- and biologically based.