Kawasaki Disease: Blocking Protein Improves Cardiac Effects, Investigators Report
A new study by Cedars-Sinai investigators found that blocking a protein called interleukin-1-beta improved cardiac dysfunction and arrythmias in Kawasaki disease, a rare illness that affects children and causes their blood vessels to swell and become inflamed.
The findings, published in Arteriosclerosis, Thrombosis, and Vascular Biology, suggest that a treatment therapy that inhibits interleukin-1-beta might help patients, including the approximately 20% of children who don’t respond to current therapies.
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.
“The disease is treatable in most children if caught early, but some children continue to have fever and become at risk of developing cardiovascular complications, such as coronary artery aneurysms or arrhythmias,” said Moshe Arditi, MD, executive vice chair of the Department of Pediatrics for Research at Cedars-Sinai Guerin Children’s, 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 tumor necrosis factor alpha or interleukin-1-beta, improves symptoms in children.
Drugs that block tumor necrosis factor alpha are already being used in patients. A potential new therapy currently being investigated, anakinra, suppresses and blocks the function of the interleukin-1 receptor, which binds the inflammatory interleukin-1 cytokines.
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 Eugenio Cingolani, MD, who is director of Cardiogenetics and Preclinical Research at the Smidt Heart Institute at Cedars-Sinai and an associate professor of Cardiology, brought their labs together to work 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 interleukin-1-beta and tumor necrosis factor alpha in patients with the disease.
“We sought to identify whether one protein caused more cardiac dysfunction and arrythmias in this mouse model of Kawasaki disease,” Cingolani said.
The team performed several experiments in laboratory mice with a disease model resembling Kawasaki disease in humans. The investigators injected 
mice with drugs that block the expression of interleukin-1-beta or tumor necrosis factor alpha. They found that drugs that blocked interleukin-1-beta signaling but not tumor necrosis factor alpha signaling prevented abnormal changes in how the heart pumps blood and the heart’s rhythm.
“We need to test whether these observations in an animal disease model remain true in children with Kawasaki disease,” said Thassio Ricard Ribeiro Mesquita, PhD, a research scientist with the Smidt Heart Institute, an assistant professor of Cardiology at Cedars-Sinai and first author of the study. “If so, they would further support the use of therapies that block interleukin-1-beta in patients with Kawasaki disease.”
Based on the experimental studies from the Arditi Laboratory on the role of interleukin-1-beta in Kawasaki disease, anakinra—the drug that blocks the interleukin-1 receptor—is 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.
Follow Cedars-Sinai Academic Medicine on X for more on the latest basic science and clinical research from Cedars-Sinai.