Corticosteroids of No Benefit in Kawasaki Disease

February 15, 2007

February 15, 2007

(Boston, MA) - A new multicenter, randomized, double-blind, placebo-controlled trial has failed to shown any benefit of methylprednisolone when added to usual treatment for acute Kawasaki disease [ 1]. Dr Jane W Newburger (Children's Hospital and Harvard Medical School, Boston, MA) and colleagues report their findings in the February 15, 2007 issue of the New England Journal of Medicine.

"We were disappointed," Newburger told heart wire . "We had hoped we could make things better for everybody with Kawasaki disease by adding steroids to primary treatment."

The team did, however, show a benefit of steroid treatment in a very small subgroup of patients in a post hoc analysis, but Newburger says this finding would need to be confirmed in a prospective study.

Steroids will not be the cornerstone of treatment for KD

Kawasaki disease—an acute self-limiting vasculitis of unknown cause that occurs in childhood—is most common in Japan, although it affects children of all ethnic backgrounds. Coronary artery aneurysms develop in 15% to 25% of untreated children and can lead, over time, to ischemic heart disease, MI, and, in rare cases, death. Intravenous immune globulin therapy plus aspirin has been shown to blunt the acute inflammation and reduce the risk of coronary artery damage, with routine treatment cutting the rate of coronary artery aneurysms detectable on echo to around 5%.

In their paper, Newburger and colleagues explain that the trial data so far on the use of corticosteroids in the primary treatment of Kawasaki disease have been inconclusive, despite the fact that steroids are generally of benefit in other chronic vasculitides.

So they set out to determine whether the addition of a single pulsed dose of 30 mg/kg of methylprednisolone (or placebo) to conventional IV immune globulin therapy (2g/kg) plus aspirin would reduce the risk of coronary artery abnormalities.

But at weeks 1 and 5 after randomization, patients in the two study groups had similar coronary outcomes. Those in the methylprednisolone group (n=101) did have a shorter initial period of hospitalization (p=0.05) and, at week 1, a lower erythrocyte sedimentation rate (p=0.02), but the two groups had similar numbers of days spent in the hospital, numbers of days of fever, rates of re-treatment with immune globulin, and numbers of adverse events.

"Our data do not provide support for the addition of a single dose of pulsed intravenous methylprednisolone to conventional therapy in the routine primary treatment of Kawasaki disease," they state.

In an accompanying Perspective [ 2], Dr Jane C Burns (University of California, San Diego, La Jolla) says: "The failure of corticosteroids to benefit these patients underscores the difference between Kawasaki disease and other chronic vasculitides, for which corticosteroids are the foundation of most treatment strategies."

Better understanding of disease needed for better therapies

Newburger told heart wire she believes that one of the reasons that the steroids failed to show a benefit in the overall trial was that the children generally did very well in the study, so it was hard to improve upon the already-good outcomes.

There has been one previous single-center study using the same steroid regimen as her group used, which was positive in the sense that it improved inflammation, "but it was not powered for coronary outcomes," she noted.

And a recent Japanese study that used high-dose steroids to begin with, followed by an IV regimen and then a long oral course of steroid therapy, did show some differences in coronary outcomes within the first month of therapy, but beyond one month this difference was no longer significant, she said. The study suffered from lack of blinding with regard to assignment of steroids or placebo and interpretation of echoes, she noted.

Newburger said her group decided to do their post hoc analysis at the suggestion of one of the New England Journal of Medicine reviewers. When they looked at those children requiring re-treatment with immune globulin due to persistent fever—12 of the original methylprednisolone group and 15 from the placebo arm—they found that those assigned to the steroid did better, with fewer coronary abnormalities.

"But this needs to be studied prospectively," she said, adding that there are logistic issues when looking at small subsets of what is already a rare disease.

"What is ultimately required for improved treatments for Kawasaki disease is a better understanding of the basic science and etiology of the condition," she concluded.

Kawasaki disease: The leading cause of acquired heart disease in the US

Kawasaki disease primarily affects those under five and begins with an abrupt onset of fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy appearing over the course of several days. These clinical signs are accompanied by an acute-phase response with an elevated white-cell count, anemia, an elevated erythrocyte sedimentation rate, elevated C-reactive protein, and thrombocytosis.

About 4000 cases of Kawasaki disease occur in the US each year, and the incidence is on the rise; it has replaced acute rheumatic fever as the leading cause of acquired heart disease in children in the US and Japan.

It remains unknown to what extent Kawasaki disease in childhood contributes to coronary artery disease in adulthood, but the current recommendations of the American Heart Association advise that long-term follow-up be tailored to the degree of coronary involvement [ 3].

Newburger told heart wire that her institution would generally see a patient who has developed giant aneurysms once every six months, performing myocardial-perfusion studies and stress testing once a year. A patient who has never had any coronary involvement is likely to be discharged from care after one year; after that a doctor will see them around once every five years.

  1. Newburger JW, Sleeper LA, McCrindle BW, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. New Engl J Med 2007; 356:663-675.

  2. Burns JC. The riddle of Kawasaki disease. New Engl J Med 2007; 356:659-661.

  3. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 2004; 110:2747-2771.

The complete contents of Heart wire , a professional news service of WebMD, can be found at, a Web site for cardiovascular healthcare professionals.


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