Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial

Summary

Background

Evidence indicates that corticosteroid therapy might be beneficial for the primary treatment of severe Kawasaki disease. We assessed whether addition of prednisolone to intravenous immunoglobulin with aspirin would reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease.

Methods

We did a multicentre, prospective, randomised, open-label, blinded-endpoints trial at 74 hospitals in Japan between Sept 29, 2008, and Dec 2, 2010. Patients with severe Kawasaki disease were randomly assigned by a minimisation method to receive either intravenous immunoglobulin (2 g/kg for 24 h and aspirin 30 mg/kg per day) or intravenous immunoglobulin plus prednisolone (the same intravenous immunoglobulin regimen as the intravenous immunoglobulin group plus prednisolone 2 mg/kg per day given over 15 days after concentrations of C-reactive protein normalised). Patients and treating physicians were unmasked to group allocation. The primary endpoint was incidence of coronary artery abnormalities during the study period. Analysis was by intention to treat. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000000940.

Findings

We randomly assigned 125 patients to the intravenous immunoglobulin plus prednisolone group and 123 to the intravenous immunoglobulin group. Incidence of coronary artery abnormalities was significantly lower in the intravenous immunoglobulin plus prednisolone group than in the intravenous immunoglobulin group during the study period (four patients [3%] vs 28 patients [23%]; risk difference 0·20, 95% CI 0·12–0·28, p<0·0001). Serious adverse events were similar between both groups: two patients had high total cholesterol and one neutropenia in the intravenous immunoglobulin plus prednisolone group, and one had high total cholesterol and another non-occlusive thrombus in the intravenous immunoglobulin group.

Interpretation

Addition of prednisolone to the standard regimen of intravenous immunoglobulin improves coronary artery outcomes in patients with severe Kawasaki disease in Japan. Further study of intensified primary treatment for this disease in a mixed ethnic population is warranted.

Funding

Japanese Ministry of Health, Labour and Welfare.

Introduction

Kawasaki disease is an acute systemic vasculitis of unknown cause that affects mainly infants and children and is a major cause of acquired heart disease in developed countries.¹ Treatment with high-dose intravenous immunoglobulin plus aspirin resolves inflammation and reduces the occurrence of coronary artery abnormalities.2, 3, 4 However, about 20% of patients have persistent or recurrent fever after completion of intravenous immunoglobulin⁵ and these patients have a particularly high risk of developing coronary artery abnormalities.6, 7, 8

Although corticosteroids are a useful treatment option for various forms of vasculitis, many physicians have hesitated to use them because a report⁹ showed a high incidence of coronary artery abnormalities in patients who received a prolonged course of oral prednisolone alone. However, findings from a subsequent retrospective study¹⁰ of the effects of corticosteroids in Kawasaki disease showed possible benefits. In a meta-analysis,¹¹ inclusion of corticosteroids in regimens containing aspirin for primary treatment of Kawasaki disease reduced the incidence of coronary artery abnormalities. In 2007, findings from a randomised, placebo-controlled trial¹² of the efficacy of a single dose of pulsed intravenous methylprednisolone added to conventional therapy showed that pulsed corticosteroid treatment did not improve coronary artery outcomes. In a randomised, open-label, non-blinded trial,¹³ intravenous immunoglobulin plus prednisolone decreased the incidence of coronary artery abnormalities and treatment failure; however, the trial had potential methodological flaws.¹⁴ We subsequently noted in a retrospective analysis¹⁵ that primary treatment with intravenous immunoglobulin plus prednisolone improved coronary and clinical outcomes in patients at high risk for no response to primary intravenous immunoglobulin. Thus, the addition of corticosteroids to intravenous immunoglobulin as primary treatment might offer important therapeutic benefits to such patients with Kawasaki disease at high risk for non-response to primary treatment with intravenous immunoglobulin.

We aimed to assess the efficacy of primary prednisolone treatment as an addition to conventional treatment with intravenous immunoglobulin.