Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised,

open-label, blinded-endpoints trial

Introduction

Kawasaki disease is an acute systemic vasculitis.

Major cause of acquired heart disease in developed countries Tx: high dose IVIG + aspirin reduces coronary a. abnormalities But 20% received IVIG have fever and have high risk of developing coronary a. abnormalities.

Although corticosteroids are useful, report showed high incidence of coronary a. abnormalities in patients received prolonged course of oral prednisolone alone.

However, findings from a subsequent retrospective study of the effects of corticosteroids in Kawasaki disease showed possible benefits. Therefore, we aimed to assess the efficacy of primary prednisolone treatment as an addition to conventional treatment with IVIG.

Methods

74 hospitals in Japan Sept 29, 2008 Dec 2, 2010 Japanese diagnostic guidelines

Randomisation and masking

Internet Data and Information Center for Medical Research (INDICE) Patients and treating physicians were not masked to assignment

Procedures

IVIG group: immunoglobulin 2g/kg given over 24 h + aspirin 30mg/kg per day until afebrile, followed by aspirin 35mg/kg per day for at least 28 days after fever onset IVIG + prednisolone: above + IV prednisolone 2 mg/kg per day in three divided doses for 5 days If fever resolved 5 days after prednisolone administration, the drug was given orally When CRP normalised (5 mg/L), we tapered the prednisolone dose over 15 days in 5-day steps, from 2 mg/kg per day to 1 mg/kg per day to 05 mg/kg per day

Echocardiograms

interpreted by two pediatric cardiologists who were masked to patient identity and group assignment abnormal coronary artery definition

<5y/o: luminal diameter >3mm > = 5y/o: luminal diameter >4mm internal diameter of a segment > = 15 times that of an adjacent segment luminal contour was clearly irregular

Results

Discussion

Key Point 1

Combination treatment with IVIG + prednisolone had a significant advantage compared with IVIG alone for:

prevention of coronary artery abnormalities reduced need for additional rescue treatment more rapidly resolved fever and inflammatory markers

The high incidence of additional rescue treatment in the IVIG group was because we used the risk score system to select the patients with severe disease and confirms the positive predictive value of the risk score in prediction of no response to initial intravenous immunoglobulin.

Key Point 2

coronary artery lesion development

influx of neutrophils rapid transition to large mononuclear cells and lymphocytes (mostly CD8 T cells) and immunoglobulin-A plasma cells. destruction of the internal elastic lamina followed by myofibroblast proliferation formation of a coronary aneurysm

These findings underscore the importance of immediate treatment of inflammation and vasculitis, before pathological changes become irreversible.

Because patients who do not respond to primary treatment with intravenous immunoglobulin are usually identified 2448 h after completion of treatment, rescue therapies are generally started 2 3 days after diagnosis of Kawasaki disease. Such delays in the start of additional treatments might allow formation of coronary artery abnormalities. Our therapeutic strategynamely, risk stratification at diagnosis followed by intensive primary treatment in high-risk patientsmight effectively suppress inflammation due to Kawasaki disease and subsequent remodelling of the coronary arterial wall.

Key Point 3

In this study, CRP rapidly recovered in the IVIG + PSL group, which is consistent with reduced inflammation and improved coronary outcomes VS 2007 US study, Newburger and colleagues noted no improvement in efficacy of a regimen of corticosteroid treatment combined with IVIG

What are the possible reasons for the difference?

median time until start of treatment was 2 days earlier in our study than in the US report. If the main benefit of corticosteroid treatment for Kawasaki disease is early suppression of vasculitis that precedes vascular remodelling, a delay in start of treatment could play a crucial part in formation of coronary artery abnormalities.

duration of corticosteroid administration. Although the total dose of corticosteroids was similar in the studies, median duration of prednisolone administration was 21 days in our study compared VS one course of 30 mg/kg methylprednisolone in the US study. Kawasaki disease is self-limiting, but fever caused by the disease persists for about 23 weeks if untreated. Thus, duration of corticosteroid administration might be more important than maximum concentration of corticosteroid in suppression of inflammation and vasculitis in this disease.

patient selection We enrolled patients with high risk scores, they were identified as potential non-responders to primary intravenous immunoglobulin. This method of risk stratification increased the statistical power to assess whether intravenous immunoglobulin plus prednisolone had a significant advantage in prevention of abnormalities.

Key Point 4

Safety of treatment: we could not assess potential adverse effects of corticosteroids (severe bacterial infection, thrombosis, bone mineral loss, osteonecrosis of the femoral head, and ophthalmic lesions) because of the short f/u. Different ethnics group: Although the scoring system was validated in a Japanese cohort, it had poor sensitivity for predicting no response to primary IVIG in a North American cohort. The positive predictive value to predict resistance to primary IVIG with the risk score was 40%, which is fairly low. We anticipate the development of an accurate predictive model, which possibly includes other biomarkers or genetic background.

Thank you