BackgroundInterleukin-1 (IL-1) is a key mediator of ischaemic brain injury induced by stroke and subarachnoid haemorrhage (SAH). IL-1 receptor antagonist (IL-1Ra) limits brain injury in experimental stroke and reduces plasma inflammatory mediators associated with poor outcome in ischaemic stroke patients. Intravenous (IV) IL-1Ra crosses the blood–brain barrier (BBB) in patients with SAH, to achieve cerebrospinal fluid (CSF) concentrations that are neuroprotective in rats.MethodsA small phase II, double-blind, randomised controlled study was carried out across two UK neurosurgical centres with the aim of recruiting 32 patients. Adult patients with aneurysmal SAH, requiring external ventricular drainage (EVD) within 72 hours of ictus, were eligible. Patients were randomised to receive IL-1Ra (500 mg bolus, then a 10 mg/kg/hr infusion for 24 hours) or placebo. Serial samples of CSF and plasma were taken and analysed for inflammatory mediators, with change in CSF IL-6 between 6 and 24 hours as the primary outcome measure.ResultsSix patients received IL-1Ra and seven received placebo. Concentrations of IL-6 in CSF and plasma were reduced by one standard deviation in the IL-1Ra group compared to the placebo group, between 6 and 24 hours, as predicted by the power calculation. This did not reach statistical significance (P = 0.08 and P = 0.06, respectively), since recruitment did not reach the target figure of 32. No adverse or serious adverse events reported were attributable to IL-1Ra.ConclusionsIL-1Ra appears safe in SAH patients. The concentration of IL-6 was lowered to the degree expected, in both CSF and plasma for patients treated with IL-1Ra.

Summary:Stroke has enormous clinical, social, and economic implications, and demands a significant effort from both basic and clinical science in the search for successful therapies. Atherosclerosis, the pathologic process underlying most coronary artery disease and the majority of ischemic stroke in humans, is an inflammatory process. Complex interactions occur between the classic risk factors for atherosclerosis and its clinical consequences. These interactions appear to involve inflammatory mechanisms both in the periphery and in the CNS. Central nervous system inflammation is important in the pathophysiologic processes occurring after the onset of cerebral ischemia in ischemic stroke, subarachnoid hemorrhage, and head injury. In addition, inflammation in the CNS or in the periphery may be a risk factor for the initial development of cerebral ischemia. Peripheral infection and inflammatory processes are likely to be important in this respect. Thus, it appears that inflammation may be important both before, in predisposing to a stroke, and afterwards, where it is important in the mechanisms of cerebral injury and repair. Inflammation is mediated by both molecular components, including cytokines, and cellular components, such as leukocytes and microglia, many of which possess pro-and/or antiinflammatory properties, with harmful or beneficial effects. Classic acute-phase reactants and body temperature are also modified in stroke, and may be useful in the prediction of events, outcome, and as therapeutic targets. New imaging techniques are important clinically because they facilitate in vivo dynamic evaluation of tissue damage in relation to outcome. Inflammatory conditions such as giant cell arteritis and systemic lupus erythematosus predispose to stroke, as do a range of acute and chronic infections, principally respiratory. Diverse mechanisms have been proposed to account for inflammation and infection-associated stroke, ranging from classic risk factors to disturbances of the immune and coagulation systems. Considerable opportunities therefore exist for the development of novel therapies. It seems likely that drugs currently used in the treatment of stroke, such as aspirin, statins, and modulators of the renin-angiotensin-aldosterone system, act at least partly via antiinflammatory mechanisms. Newer approaches have included antimicrobial and antileukocyte strategies. One of the most promising avenues may be the use of cytokine antagonism, for example, interleukin-1 receptor antagonist.

F o r S t r o k Background and PurposeThe pro-inflammatory cytokine interleukin-1 (IL-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6 (IL-6), which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous (SC) IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke. MethodsSCIL-STROKE was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of SC IL-1Ra (100mg administered twice daily for three days) in patients presenting within 5h of ischemic stroke onset. Randomization was stratified for baseline NIHSS score and thrombolysis. Measurement of plasma IL-6 and other peripheral inflammatory markers was undertaken at five time points. The primary outcome was difference in concentration of log(IL-6) as area under the curve to Day 3. Secondary outcomes included exploratory effect of IL-1Ra on three month outcome with the modified Rankin Scale (mRS). ResultsWe recruited 80 patients (mean age 72, median NIHSS 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma and plasma C-reactive protein (p<0.001). IL-1Ra was well-tolerated with no safety concerns.Allocation to IL-1Ra was not associated with a favorable outcome on mRS: OR (95% CI) = 0.67 (0.29 to 1.52); p=0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit. ConclusionsIL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. SC IL-1Ra is safe and well-tolerated. Further 3