An drug licensed for treating rheumatoid arthritis and given to patients in the early stages of a stroke has been shown by researchers at The University of Manchester and Salford Royal NHS Foundation Trust to reduce harmful inflammation.
The drug, Kineret©, licensed for treating rheumatoid arthritis, was given as a small injection just under the skin without giving the patients any identifiable adverse reactions. It is one of biologic agents transforming treatment in a range of illnesses.
The protein Interleukin-1 (IL-1) is part of the body's defences and naturally produced to combat a range of illnesses. However, scientists at the University of Manchester have previously shown IL-1 increases inflammation and brain injury following a stroke. Kineret works by blocking the actions of IL-1 which is released into the body following injury caused by a stroke.
The researchers cannot say for sure at this stage how the reduction in inflammation will impact on clinical outcomes.
The study, funded by the Stroke Association, follows earlier research that shows the drug given as an intravenous therapy reduces inflammation in stroke and sub arachnoid haemorrhage patients.
A stroke occurs when poor blood flow to the brain results in cell death. There are two main types of stroke: ischemic, caused by lack of blood flow, and haemorrhagic, caused by bleeding in the brain. Stroke is the most common cause of disability in adults and a leading cause of death worldwide.
The Manchester study – a double blind trial where Kineret was tested against placebo – looked at ischaemic strokes only. The 80 participants in the study – carried out at Salford's Greater Manchester Stroke Centre at Salford Royal – were given 6 doses of the drug or placebo over three days. The first dose was given within 6 hours after the onset of the stroke symptoms.
Inflammatory markers were measured in the blood before treatment began and during study treatment.
Professor Craig Smith from The University of Manchester is also a stroke physician at Salford Royal. He said: "Though strokes affect different people in different ways, for many people they have a devastating effect on their long-term health and wellbeing. Excessive inflammation after a stroke is known to be harmful and predicts a worse outcome in patients. We have shown that Kineret injections, started within six hours of stroke onset significantly reduces levels of inflammation in patients."
Hilary Reynolds, executive director of strategy & research at the Stroke Association said: "This study builds on evidence that IL-1Ra (Kineret) helps to reduce inflammation and brain damage in a wide range of stroke patients soon after a stroke. The drug can be given quickly, via injection or via a drip. This means that it can be used in different settings, for example, it could potentially be given in ambulances on the way to hospital. The brain loses around 2 million brain cells every minute during a stroke, so this could provide a major step forward in fast and effective treatment of stroke.
"The research has not yet proven that this drug can reduce patient disability after stroke. However, if further trials are successful, we hope it could vastly improve outcomes and quality of life for people who have had a stroke."
Further research is needed to see whether Kineret is an effective treatment for ischemic stroke and whether it can be given alongside current treatments such as clot-busting drugs (thrombolysis).
The same research team have shown that Kineret reduces inflammation and is safe in patients with bleeding around the brain, a condition known as subarachnoid haemorrhage.
To definitively test if Kineret improves patient outcomes in subarachnoid haemorrhage, a national trial of Kineret in 1000 patients, funded by the Medical Research Council and National Institute for Health Research, will start in 2018.
And another trial in 80 patients with stroke caused bleeding in the brain, known as intracerebral haemorrhage, will also start in 2018. It is funded by the National Institute for Health Research.
That trial will test if markers of inflammation are reduced by Kineret and test safety in intracerebral haemorrhage.
Background and Purpose: The proinflammatory cytokine IL-1 (interleukin-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, which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke.
Methods: SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke) was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of subcutaneous IL-1Ra (100 mg administered twice daily for 3 days) in patients presenting within 5 hours of ischemic stroke onset. Randomization was stratified for baseline National Institutes of Health Stroke Scale score and thrombolysis. Measurement of plasma interleukin-6 and other peripheral inflammatory markers was undertaken at 5 time points. The primary outcome was difference in concentration of log(interleukin-6) as area under the curve to day 3. Secondary outcomes included exploratory effect of IL-1Ra on 3-month outcome with the modified Rankin Scale.
Results: We recruited 80 patients (mean age, 72 years; median National Institutes of Health Stroke Scale, 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma interleukin-6 (P<0.001) 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 modified Rankin Scale: odds ratio (95% confidence interval)=0.67 (0.29–1.52), 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.
Conclusions: IL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. Subcutaneous IL-1Ra is safe and well tolerated. Further experimental studies are required to investigate efficacy and possible interactions of IL-1Ra with thrombolysis.
Craig J Smith, Sharon Hulme, Andy Vail, Calvin Heal, Adrian R Parry-Jones, Sylvia Scarth, Karen Hopkins, Margaret Hoadley, Stuart M Allan, Nancy J Rothwell, Stephen J Hopkins, Pippa J Tyrrell