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Steroids benefited high-risk Kawasaki disease patients in Japan
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NEW YORK — Patients with Kawasaki disease at high risk for coronary artery abnormalities in Japan appear to have better outcomes when steroids are added to their primary therapy of intravenous immunoglobulin, according to a speaker at the 25th Annual Infectious Diseases in Children symposium.
“High, single-dose IVIG plus high-dose aspirin started within 10 days of the onset of illness is the mainstay of therapy. Steroids are controversial. It seems to be that steroids are useful in refractory cases of Kawasaki disease, and their role in primary therapy is evolving right now,” said Stanford T. Shulman, MD, chief of the division of infectious diseases at the Ann & Robert H. Lurie Children’s Hospital of Chicago, and an Infectious Diseases in Children Editorial Board member.
Stanford T. Shulman
Noting that steroids as adjunctive primary therapy has had a “tortured history” because of what Shulman said was a “not well-randomized” paper published in 1979 suggesting treating Kawasaki disease patients with steroids “probably” worsened coronary artery outcomes.
RAISE trial
Now, data from a recent Japanese, randomly controlled trial — Assess Immunoglobulin plus Steroid Efficacy for Kawasaki disease (RAISE) — indicate there is up to an 80% reduced risk for coronary lesions in high-risk patients given steroid as an adjuvant to IVIG plus aspirin therapy.
“This is an elegant, large trial to evaluate the role of steroids,” Shulman said. High-risk patients in the RAISE study were identified using the Kobayashi score, which uses a combination of clinical and lab features. The high-risk patients were randomly assigned to standard IVIG therapy plus aspirin, with or without IV steroids for 5 days, with another 2 weeks or more of oral prednisone. “The study demonstrated that that there was a marked reduction in the coronary artery aneurysm rates in the patients that received steroids,” Shulman said.
He said the Kobayashi scoring system has not been demonstrated to be useful for identifying high-risk patients in multi-ethnic populations such as the United States, although the reason for this is yet unknown. Kawasaki disease, with an annual 19 to 21 cases of the disease per 100,000 children aged younger than 5 years in the United States, is the leading cause of acquired pediatric heart disease in the United States.
“Our challenge is how to identify the subset of patients we believe to be at high risk. We do know that infants under 6 months, and maybe under 12 months, are at high risk for developing coronary artery abnormalities in our society and in Japanese society. The problem is knowing how much steroids to give them and for how long,” Shulman said.
Infliximab as adjunctive therapy
Shulman also reported new data from a three-hospital study of patients with Kawasaki disease treated with the monoclonal antibody infliximab (Remicade, Centocor) combined with IVIG and aspirin vs. those treated with IVIG and aspirin alone. “It was a disappointing result,” Shulman said. “Eleven percent in each group required additional therapy so that there was no difference in the rate of refractory patients, and there were no significant differences in coronary artery outcomes.”
Shulman said there are so few data on refractory cases of Kawasaki disease that “there is no consensus on how best to treat them,” and up to 4% of all patients with Kawasaki disease fail to respond to two doses of IVIG plus aspirin. The current standard options in these cases, he added, have been a third dose of IVIG; IV steroids, sometimes with adjunctive oral prednisone; or infliximab. Up to 60% of patients given the third dose of IVIG will respond.
Recommendations for refractory cases
Shulman said although there is no standard protocol for treatment of refractory Kawasaki disease, he generally prefers a third dose of IVIG as the first-line therapy because, “I am going to know within 24 more hours whether it worked, or if we will need to on from there.”
Afterward, Shulman said pulse therapy with 30 mg/kg/day for 3 days of methylprednisolone sodium succinate (Solu-Medrol, Pharmacia and Upjohn), with a possible additional oral dose of prednisone or one dose of 5 mg/kg infliximab, in that order, were his preferred lines of treatment. Newer, incompletely assessed alternatives include low-dose (10 mg/m²) methotrexate and a 2- to 3-week course of cyclosporine.
For more information:
Shulman ST. Kawasaki disease. Presented at: 25th Annual Infectious Diseases in Children Symposium; Nov. 17-18; New York.
Disclosure: Shulman reports no relevant financial disclosures.