A new study by Cedars-Sinai investigators found that blocking a protein called interleukin-1-beta improved cardiac dysfunction and arrythmias in ,聽a rare illness that affects children and causes their blood vessels to swell and become inflamed.
The findings, published聽in聽, suggest that a treatment therapy that inhibits interleukin-1-beta聽might help patients, including the approximately 20% of children who don鈥檛 respond to current therapies.
Moshe Arditi, MD
Kawasaki disease was first described by Japanese pediatrician Tomisaku Kawasaki in 1967, but its cause remains unknown. The condition typically affects children under the age of 5, and patients with the disease usually present with a sudden, high fever; rash; redness of eyes, lips and tongue; and swelling of hands and feet that last for 10 days or longer.
In Japan, Kawasaki disease cases are on the rise after a significant decrease in 2020.
鈥淭he disease is treatable in most children if caught early, but聽some children continue to have fever and become at risk of developing cardiovascular complications, such as coronary artery aneurysms or聽arrhythmias,鈥� said聽, executive vice chair of the Department of Pediatrics for Research at Cedars-Sinai Guerin Children鈥檚, the GUESS?/Fashion Industries Guild Chair in Community Child Health, and a co-senior author of the study.
The standard of care for children with Kawasaki disease is to administer intravenous immunoglobulin and aspirin to reduce inflammation and fever. But recent clinical trials have found that blocking proteins called inflammatory cytokines, such as聽tumor necrosis factor alpha or聽interleukin-1-beta, improves symptoms in children.
Drugs that block聽tumor necrosis factor alpha are already being used in patients. A potential new therapy currently being investigated,聽anakinra,聽suppresses and blocks the function of the interleukin-1 receptor, which binds the inflammatory聽interleukin-1聽cytokines.
Eugenio Cingolani, MD
This study sought to identify which cytokines might be involved in the biologic processes that cause cardiovascular complications in children with Kawasaki disease.
Arditi, who is also director of the Infectious and Immunological Diseases Research Center in the Department of Biomedical Sciences and a professor of Pediatrics, and聽,聽who is director of Cardiogenetics and Preclinical Research at the Smidt Heart Institute at Cedars-Sinai and an associate professor of Cardiology,聽brought their labs together to work聽on the study.
Together, the investigators studied publicly available datasets showing gene expressions in children with Kawasaki disease. They found elevated expression of the genes of cytokines聽interleukin-1-beta and聽tumor necrosis factor alpha in patients with the disease.
鈥淲e sought to identify whether one protein caused more cardiac dysfunction and arrythmias in this mouse model of Kawasaki disease,鈥� Cingolani said.
The team performed several experiments in laboratory mice with a disease model resembling Kawasaki disease in humans. The investigators injectd mice with drugs that block the expression of interleukin-1-beta or聽tumor necrosis factor alpha. They found that drugs that blocked聽interleukin-1-beta signaling but not聽tumor necrosis factor alpha聽signaling prevented abnormal changes in how the heart pumps blood and the heart鈥檚 rhythm.聽
Thassio Ricard Ribeiro Mesquita, PhD
鈥淲e need to test whether聽these observations in an animal disease model remain true in children with Kawasaki disease,鈥� said聽,聽a research scientist with the Smidt Heart Institute, an assistant professor of Cardiology at Cedars-Sinai聽and first author of the study. 鈥淚f so, they would further support the use of therapies that block interleukin-1-beta in patients with Kawasaki disease.鈥�
Based on the experimental studies from the Arditi Laboratory on the role of interleukin-1-beta in Kawasaki disease, anakinra鈥攖he drug that blocks the interleukin-1 receptor鈥攊s now in Phase III clinical trials in children.
Other Cedars-Sinai investigators who worked on the study include Shuang Chen, Youngho Lee, Rodrigo Miguel-dos-Santos, Asli Atici, Magali Noval Rivas and Yen-Nien Lin.
The study was funded by the National Institutes of Health, the American Heart Association, the California Institute for Regenerative Medicine and the Cedars-Sinai Board of Governors.
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