Immunoglobulin Plus Prednisolone for Prevention of Coronary Artery Abnormalities in Severe Kawasaki...

7/25/2019 Immunoglobulin Plus Prednisolone for Prevention of Coronary Artery Abnormalities in Severe Kawasaki Disease

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Effi cacy of immunoglobulin plus prednisolone for

prevention of coronary artery abnormalities in severeKawasaki disease (RAISE study): a randomised, open-label,

blinded-endpoints trial

Tohru Kobayashi, Tsutomu Saji, Tetsuya Otani, Kazuo Takeuchi, Tetsuya Nakamura, Hirokazu Arakawa, Taichi Kato, Toshiro Hara,

Kenji Hamaoka, Shunichi Ogawa, Masaru Miura, Yuichi Nomura, Shigeto Fuse, Fukiko Ichida, Mitsuru Seki, Ryuji Fukazawa, Chitose Ogawa,

Kenji Furuno, Hirohide Tokunaga, Shinichi Takatsuki, Shinya Hara, Akihiro Morikawa, on behalf of the RAISE study group investigators

SummaryBackgroundEvidence indicates that corticosteroid therapy might be beneficial for the primary treatment of severeKawasaki 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.

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

FindingsWe randomly assigned 125 patients to the intravenous immunoglobulin plus prednisolone group and 123 tothe 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 thestudy period (four patients [3%] vs28 patients [23%]; risk difference 020, 95% CI 012028, p


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of Pediatrics, Toyama

University, Toyama, Japan

(Prof F Ichida MD); Department

of Cardiology, Gunma Childrens

Medical Center, Gunma, Japan

(M Seki MD); Department of

Pediatrics, Nippon Medical

School Tama Nagayama

Hospital, Tokyo, Japan

(R Fukazawa); Department of

Pediatrics, St Lukes

International Hospital, Tokyo,

Japan(C Ogawa MD);

Department of Pediatrics,

Fukuoka Higashi Medical

Center, Fukuoka, Japan

(K Furuno MD); Department of

Pediatrics, Nagoya Memorial

Hospital, Nagoya, Japan

(H Tokunaga MD); and

Department of Pediatrics,

Toyota Memorial Hospital,

Toyota, Japan(S Hara MD)

coronary and clinical outcomes in patients at high risk for

no response to primary intravenous immunoglobulin.Thus, the addition of corticosteroids to intravenousimmunoglobulin as primary treatment might offerimportant therapeutic benefits to such patients withKawasaki disease at high risk for non-response to primarytreatment with intravenous immunoglobulin.

We aimed to assess the effi cacy of primary prednisolonetreatment as an addition to conventional treatment withintravenous immunoglobulin.

MethodsStudy design and patientsWe did the Randomized controlled trial to AssessImmunoglobulin plus Steroid Effi cacy for Kawasaki

disease (RAISE study)a multicentre, prospective,randomised, open-label, blinded-endpoints, parallel-group studyat 74 hospitals in Japan betweenSept 29, 2008, and Dec 2, 2010. We diagnosed Kawasakidisease with the Japanese diagnostic guidelines for

Kawasaki disease.16Eligible participants had a risk score17

of five points or higher, which emphasises the positivepredictive value of no response to initial treatment withintravenous immunoglobulin. Scoring and cutoff valuesof the risk score were as follows: two points each forserum sodium concentration of 133 mmol/L or less,4 days or fewer of illness at diagnosis, aspartate amino-transferase concentration of 100 U/L or more, whiteblood cells representing neutrophils of 80% or greater;and one point each for platelet count 3010/L or less,C-reactive protein concentration of 100 mg/L or more,and age 12 months or younger. If laboratory tests weredone more than once before primary treatment, we usedthe highest value for percentage of neutrophils, aspartateaminotransferase, and C-reactive protein, and the lowest

value for platelet count and sodium.We excluded patients with a history of Kawasaki disease,

those diagnosed on or after day 9 of illness (the first illnessday was defined as the day of fever onset), those withcoronary artery abnormalities before enrolment, those whowere afebrile before enrolment, those who had receivedsteroids (oral, intravenous, intramuscular, or subcutaneous)in the 30 days before the study or intravenous immuno-globulin in the previous 180 days, those with concomitantsevere medical disorders (eg, immunodeficiency, chromo-somal anomalies, congenital heart diseases, metabolicdiseases, nephritis, collagen diseases), and those withsuspected infectious disease, including sepsis, septicmeningitis, peritonitis, bacterial pneumonia, varicella, andinfluenza. The study was approved by an independentethics committee or institutional review board at allparticipating institutions and was done in accordance withInternational Conference on Harmonisation guidelines onGood Clinical Practice and the Declaration of Helsinki.Before enrolment, all patients or their guardians providedwritten informed consent.

Randomisation and maskingWe used a randomisation sequence that was computergenerated by the Internet Data and Information Centerfor Medical Research (INDICE) at the University HospitalMedical Information Network. We used a web-based

system to register patients in a database at INDICE inTokyo, Japan, and after validation of eligibility criteria, weused dynamic (minimisation) allocation to randomlyassign patients to either the intravenous immunoglobulinplus prednisolone group or the intravenous immuno-globulin group, in a 1:1 ratio within strata according toage (12 months or 13 months), sex, and institution.Group assignment was immediately communicated byINDICE to the investigator via the web-based registrationsystem. Patients and treating physicians were not maskedto assignment.

ProceduresPatients in the intravenous immunoglobulin groupreceived immunoglobulin 2 g/kg given over 24 h and

2014 patients assessed for eligibility

1547 did not meet inclusion criteria1436 had low risk scores

44 had past history of Kawasaki disease24 had defervescence

16 had suspected infectious disease

12 had presence of coronary arteryabnormality at diagnosis10 had illness 9 days

3 had pre-existing severe disease1 had a history of intravenous

immunoglobulin administration1 had a history of corticosteroid

administration219 declined to participate

248 patients randomly assigned

125 patients assigned tointravenous immunoglobulinplus prednisolone group

123 patients assigned to intravenousimmunoglobulin group

121 patients analysed 121 patients analysed

4 were excluded1 withdrew consent2 had presence of

coronary arteryabnormality atenrolment

1 had a misdiagnosisof Kawasaki disease

2 were excluded1 had presence of

coronary arteryabnormality atenrolment

1 did not receiveintravenousimmunoglobulin

(fever resolvedsoon after allocation)

Figure :Trial profile

Three patients were excluded after randomisation because echocardiograms of the coronary artery at enrolmentwere classified as abnormal in a centralised review of echocardiography data.


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aspirin 30 mg/kg per day until they were afebrile, followed

by aspirin 35 mg/kg per day for at least 28 days afterfever onset. Patients in the intravenous immunoglobulinplus prednisolone group received the same immuno-globulin regimen as the monotherapy group plusprednisolone 2 mg/kg per day in three divided dosesgiven by intravenous injection in 5 days. If fever resolved5 days after prednisolone administration, the drug wasgiven orally. When concentration of C-reactive proteinnormalised (5 mg/L), we tapered the prednisolone doseover 15 days in 5-day steps, from 2 mg/kg per day to1 mg/kg per day to 05 mg/kg per day. We did laboratorytesting two to three times per week until concentration ofC-reactive protein had decreased to 5 mg/L or less.

The maximum dose of prednisolone is 60 mg per day;

thus, we tapered patients weighing more than 30 kg fromprednisolone 60 mg per day to 30 mg per day to 15 mg/day.05 mg/kg per day of H2-blocker famotidine wasgiven during prednisolone administration. We allowedadditional treatment for any patient with fever lastingmore than 24 h (ie, no response to primary treatment) orrecrudescent fever associated with other symptoms ofKawasaki disease after an afebrile period (relapse),according to the guidelines for acute phase therapy forKawasaki disease by the Japanese Society of PaediatricCardiology and Cardiac Surgery.18 The appendix showsdetails of additional rescue treatments. We consideredpatients with an axillary temperature of less than 375Cfor more than 24 h as afebrile. We obtained anechocardiogram and laboratory data at baseline and atweeks 1 (68 days after enrolment), 2 (1216 days afterenrolment), and 4 (2432 days after enrolment).

Two-dimensional echocardiograms were digitally recor-ded at institutes and interpreted at a core laboratory by twopaediatric cardiologists who were masked to patientidentity and group assignment (interobserver reliability 092; intraobserver reliability 095 and 097). Wedefined a coronary artery as abnormal when the luminaldiameter was more than 30 mm in a child aged youngerthan 5 years or more than 40 mm in those aged 5 yearsand older, respectively, when the internal diameter of asegment was 15 times or greater than that of an adjacent

segment, or when the luminal contour was clearlyirregular.19 We estimated Z score of the proximal rightcoronary artery, the left main coronary artery, and theproximal left anterior descending artery,20and the maxi-mum Zscore of coronary arteries at weeks 1, 2, and 4.

We clinically monitored patients for adverse eventsduring administration of study treatment and in thesubsequent 4 weeks. Safety assessments included record-ing of all severe adverse events, undertaking of physicalexaminations (including monitoring of vital signs) andlaboratory assessments (including haematology, urinaly-sis, and serum chemistry screening). The appendixshows definitions of adverse events.

The primary endpoint was incidence of coronaryartery abnormalities during the study period, which we

identified with two-dimensional echocardiography. We

classified patients as having an abnormality if they fulfilledthe criterion for the primary endpoint at any timepointie, at week 1, 2, or 4. Secondary endpoints were incidenceof coronary artery abnormalities at week 4 after enrolment,Z scores of coronary arteries, incidence of need foradditional rescue treatment, duration of fever after enrol-ment, serum concentrations of C-reactive protein at 1 and2 weeks after enrolment, and serious adverse events. Ifconcentration of C-reactive protein was undetectable, weimputed it as 50% of the lower limit of the assay.

Statistical analysesWe calculated the required sample size on the basis of theassumption that intravenous immunoglobulin plus

prednisolone would reduce the percentage of patientswith coronary artery abnormalities from 18% to 8%. Witha two-sided test, an of 005, a power of 80%, and theassumption that 10% of patients would not complete thestudy, a total sample of 392 patients would be needed. Wedid analyses by intention to treat. We planned one interimanalysis to analyse the primary endpoint (p=00034). Weused the Lan-DeMets -spending function21 with theOBrien-Fleming monitoring boundaries to adjust forseveral comparisons.

All reported p values are two-sided. To compare thedistributions of data between the two study groups, we

IVIG+PSL (N=121) IVIG (N=121)

Age (months) 31 (1250) 30 (1347)

6 months 17 (14%) 15 (12%)

Male sex 67 (55%) 68 (56%)

Days of illness at enrolment 4 (45) 4 (35)

White-cell count (10/L) 154 (49; 121) 156 (47; 121)

Neutrophils (%) 820% (712870; 121) 805% (696870; 120)

Haematocrit (%) 337% (30; 121) 340% (29; 121)

Platelet count (10/L) 274 (237346; 121) 289 (243363; 121)

Aspartate aminotransferase (U/L) 90 (42211; 121) 120 (47319; 121)

Sodium (mmol/L) 132 (130133; 121) 133 (130134; 121)

Blood glucose (mmol/L) 62 (13; 110) 63 (13; 107)

Total cholesterol (mmol/L) 36 (07; 113) 36 (08; 109)

C-reactive protein (mg/L) 93 (57130; 121) 88 (57114; 121)

Risk score 6 (57; 121) 6 (57; 121)

Absolute diameter of coronary artery* n=121 n=121

Proximal right coronary artery 194 (037) 194 (033)

Left main coronary artery 235 (038) 235 (037)

Proximal left anterior descending artery 196 (035) 193 (029)

Zscore of coronary artery diameters n=119 n=119

Proximal right coronary artery 139 (089206) 161 (106228)

Left main coronary artery 157 (120197) 170 (130213)

Proximal left anterior descending artery 157 (107215) 167 (120204)

Data are median (IQR), n (%), mean (SD; n), or median (IQR; n), unless otherwise indicated. IVIG=intravenous

immunoglobulin. PSL=prednisolone.

Table :Demographic, laboratory, and echocardiographic characteristics of p atients at enrolment

See Online for appendix

Correspondence to:

Dr Tohru Kobayashi, Department

of Pediatrics, Gunma University

Graduate School of Medicine,

Gunma 371-8511, Japan

[email protected]


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used the ttest for continuous variables if the data were

normally distributed, and the Mann-Whitney U test fordata that were not normally distributed. We used theKolmogorov-Smirnov algorithm to identify whethervariables had a normal distribution. We assessed dura-tion of fever after enrolment with the log-rank test, andassessed categorical variables with Fishers exact test.We did statistical analyses related to the interim analysiswith programs for computing group sequential bound-aries using the Lan-DeMets method (version 2.1). Wedid other analyses with the IBM SPSS statisticalsoftware (version 19.0). This trial is registered with theUniversity Hospital Medical Information Networkclinical trials registry, number UMIN000000940.

Role of funding source

The sponsor of the study had no role in the study design,data collection, data analysis, data interpretation, orwriting of the report. The corresponding author had fullaccess to all study data and had final responsibility forthe decision to submit for publication.

ResultsThe study started on Sept 29, 2008. We did the pre-planned interim analysis after enrolment of the200th patient in June, 2010. The analysis showed asignificant difference in the incidence of coronaryartery abnormalities between the two treatment groups(p


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risk difference 020, 95% CI 012028, number needed

to treat was five). Similarly, the incidence of abnormalitiesat week 4 after enrolment was significantly lower in theintravenous immunoglobulin plus prednisolone groupthan in the intravenous immunoglobulin group (table 2;risk difference 009, 002016, number needed to treatwas ten). Only one patient in the intravenous immuno-globulin group developed a giant coronary aneurysm(maximum diameter 103 mm) in the left descendingartery. Z scores of the proximal right coronary arteries,left main coronary artery, and proximal left anteriordescending arteries were significantly lower in theintravenous immunoglobulin plus prednisolone groupthan in the intravenous immunoglobulin group atweeks 1, 2, and 4 (table 2). Figure 2 shows a boxplot of

maximum Zscores for each coronary artery.Patients in the intravenous immunoglobulin plus

prednisolone group had more rapid fever resolution thandid those in the intravenous immunoglobulin group(table 3). The incidence of additional rescue treatmentswas lower in the intravenous immunoglobulin plusprednisolone group than in the intravenous immuno-globulin group (table 3; risk difference 026, 95% CI016037, number needed to treat was four).Patients inthe intravenous immunoglobulin group needed moreadditional rescue treatment than did those in theintravenous immunoglobulin plus prednisolone group

(table 3). About 60% of patients who received additional

rescue treatments were retreated with intravenousimmunoglobulin (table 3).Children in the intravenous immunoglobulin plus

prednisolone group had higher white-blood cell countsat weeks 1 and 2 and lower counts at week 4; higherpercentage of neutrophils at weeks 1 and 2; higherhaematocrit at weeks 1, 2, and 4; lower platelet count atweek 4; lower aspartate aminotransferase concentra-tions at weeks 2 and 4; higher serum sodium at week 4;higher total cholesterol at weeks 1, 2, and 4; and lower

IVIG+PSL(N=121) IVIG (N=121) p value

Duration of fever after

enrolment (days)

1 (11) 2 (14)


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concentrations of C-reactive protein at weeks 1 and 2

than did those in the intravenous immunoglobulingroup (table 4). Other laboratory measures were similarin the two groups (table 4).

Three (2%) of 121 patients in the intravenousimmunoglobulin plus prednisolone group and two (2%)of 121 in the intravenous immunoglobulin group hadserious adverse events. Events in the intravenousimmunoglobulin plus prednisolone group were hightotal cholesterol in two patients (104 mmol/L and120 mmol/L) and neutropenia in one patient (300/L).Events in the intravenous immunoglobulin group werehigh total cholesterol (118 mmol/L) and a non-occlusivethrombus in the left coronary artery on echocardiography.All adverse events resolved spontaneously.

DiscussionOur findings show that combination treatment withintravenous immunoglobulin plus prednisolone hada significant advantage compared with intravenousimmunoglobulin alone for prevention of coronary arteryabnormalities, reduced need for additional rescue treat-ment, and more rapidly resolved fever and inflammatorymarkers in patients with severe Kawasaki disease (panel).The high incidence of additional rescue treatment in theintravenous immunoglobulin group was because weused the risk score system to select the patients withsevere disease and confirms the positive predictive valueof the risk score in prediction of no response to initialintravenous immunoglobulin.

In the early stage of coronary arerty lesion develop-

ment (79 days after disease onset), an influx of neutrophilsoccurs in an affected coronary artery. This influx isfollowed by rapid transition to large mononuclear cellsand lymphocytes (mostly CD8 T cells) and immuno-globulin-A plasma cells.25,26At this stage, destruction of theinternal elastic lamina occurs, followed by myofibroblastproliferation, which leads to formation of a coronaryaneurysm. These findings underscore the importance ofimmediate treatment of inflammation and vasculitisie, before pathological changes become irreversible.Because patients who do not respond to primary treat-ment with intravenous immunoglobulin are usuallyidentified 2448 h after completion of treatment, rescuetherapies are generally started 23 days after diagnosis of

Kawasaki disease. Such delays in the start of additionaltreatments might allow formation of coronary arteryabnormalities. Our therapeutic strategynamely, riskstratification at diagnosis followed by intensive primarytreatment in high-risk patientsmight effectively sup-press inflammation due to Kawasaki disease and sub-sequent remodelling of the coronary arterial wall.

We previously reported27 that intravenous immuno-globulin plus prednisolone as primary treatment forpatients with this disease rapidly reduced circulatinginflammatory cytokines. In the present study, serumconcentrations of C-reactive protein rapidly recoveredin the intravenous immunoglobulin plus prednisolonegroup, which is consistent with reduced inflammationand improved coronary outcomes. In a 2007 US study,Newburger and colleagues12noted no improvement ineffi cacy of a regimen of corticosteroid treatment com-bined with intravenous immunoglobulin. A reason forthe difference in the findings of the US study and ourstudy is the time that primary treatment was started:median time until start of treatment was 2 days earlierin our study than in the US report .12If the main benefitof corticosteroid treatment for Kawasaki disease isearly suppression of vasculitis that precedes vascularremodelling, a delay in start of treatment could play acrucial part in formation of coronary artery abnor-malities. A second difference between these studies

was the duration of corticosteroid administration.Although the total dose of corticosteroids was similarin the studies, median duration of prednisoloneadministration was 21 days in our study comparedwith one course of 30 mg/kg methylprednisolone inthe US study. The serum half-life of a pulsed dose ofmethylprednisolone is about 3 h;28,29 we administeredprednisolone over 3 weeks. The serum half-life ofintravenous immunoglobulin is 4 weeks.30 AlthoughKawasaki disease is self-limiting, fever caused by thedisease persists for about 23 weeks if untreated.Thus, duration of corticosteroid administration mightbe more important than maximum concentration ofcorticosteroid in suppression of inflammation andvasculitis in this disease.

Panel:Research in context

Systematic review

We searched PubMed and the Cochrane library for articles in English with a combination of

the search terms Kawasaki disease and corticosteroids. We excluded retrospective

studies, and those that investigated corticosteroids as an additional rescue treatment for

patients who do not respond to intravenous immunoglobulin. We identified two US

studies12,22and one Japanese study.13,23Findings from the US studies showed no decrease in

the incidence of coronary artery abnormalities; however, the Japanese study reported a

significant decrease in the incidence of such abnormalities. The effect of corticosteroid

treatment was assessed in a meta-analysis24that included a retrospective study. The

investigators noted that the rates of initial treatment failure were significantly lower inpatients who received corticosteroid treatment in combination with intravenous

immunoglobulin than in those who received intravenous immunoglobulin alone

(odds ratio 050, 95% CI 032079). No significant increase was noted in the incidence of

coronary artery lesions or coronary aneurysms in the corticosteroid group (067, 035128).

Interpretation

Findings from our randomised study show that combination treatment with intravenous

immunoglobulin plus prednisolone is better than that with intravenous immunoglobulin

alone in prevention of coronary artery abnormalities, reducing the need for additional

rescue treatment, and rapid resolution of fever and inflammatory markers in Japanese

patients with severe Kawasaki disease. Although the incidence of severe adverse events

was similar between the two treatment groups, our study had insuffi cient statistical

power to assess the incidence of rare adverse events. Further study of intensified primary

therapy for this disease in a mixed ethnic population is warranted.


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A third explanation for the different outcomes in the

two studies is patient selection. We enrolled patientswho, on the basis of high risk scores, were identifiedas potential non-responders to primary intravenousimmunoglobulin. This method of risk stratificationincreased the statistical power to assess whether intra-venous immunoglobulin plus prednisolone had asignificant advantage in prevention of abnormalities.Finally, the genetic background of the populationsmight have affected the results. The patients in our studywere ethnically homogeneous, unlike those in the USstudy. Additionally, findings from a retrospective study31showed that initial therapy with methylprednisoloneplus intravenous immunoglobulin improved coronaryoutcomes in patients with severe Kawasaki disease, as

defined by another predictive model.Predicted adverse events in our study included

marked leucocytosis, with an increase in neutrophilicleucocytes at weeks 1 and 2, which we noted more often inthe intravenous immunoglobulin plus prednisolone groupthan in the intravenous immunoglobulin group; however,the affected patients recovered by week 4. Concentration ofserum cholesterol was substantially increased in theintravenous immunoglobulin plus prednisolone group.Moreover, we could not assess potential adverse effects ofcorticosteroidssuch as severe bacterial infection, throm-bosis, bone mineral loss, osteonecrosis of the femoralhead, and ophthalmic lesionsbecause of the short follow-up and insuffi cient statistical power to exclude thepossibility of rare adverse events. Therefore, further studyis needed to assess the safety of treatment with intravenousimmunoglobulin plus prednisolone.

Additional limitations of this study should be noted ininterpretation of our results. First, some concern existsabout the generalisability of the risk score. Although thescoring system was validated in a Japanese cohort,32it hadadequate specificity but poor sensitivity for predicting noresponse to primary intravenous immunoglobulin in aNorth American cohort.33Additionally, primary treatmentwith pulsed-dose methylprednisolone plus intravenousimmunoglobulin did not improve coronary outcomes inpatients who were classified as being at high risk for

intravenous immunoglobulin resistance with our scoringsystem. In other regions, new prospective models thatmodify our risk-adapted therapeutic strategy might need tobe developed. Another concern is the accuracy of predictionof no response to primary intravenous immunoglobulinon the basis of risk score. In this study, the positivepredictive value to predict resistance to primary intravenousimmunoglobulin with the risk score was 40%, which isfairly low. We anticipate the development of an accuratepredictive model, which possibly includes other biomarkersor genetic background.

Contributors

TS, TK, YK, CG, and KI organised the study. TS, HA, TK, TH, MM, KF,CO, AM, and DK edited the manuscript. TN, MO, SF, AM, ES, and FM

obtained the data. TO and KT did the statistical analyses. SO, TK, and

MS analysed echocardiographic data. MY edited the images and maskedthe echocardiographic video.

The RAISE study group investigators

Sterling committee Tsutomu Saji (chair), Tohru Kobayashi, Tetsuya Otani,Kazuo Takeuchi, Tetsuya Nakamura, Akihiro Morikawa,Hirokazu Arakawa, Taichi Kato, Toshiro Hara, Shunichi Ogawa,Masaru Miura, Yuichi Nomura, Shigeto Fuse, Fukiko Ichida,Mamoru Ayusawa, Jun Abe, Tomoyoshi Sonobe, Yoshinari Inoue,Yoshihiro Onouchi. RAISE study offi ceTohru Kobayashi (chair),Yasushi Kemmotsu, Chiaki Goto, Kiyoko Inokuma. Data coordinatingcentre Tetsuya Nakamura (chair), Mami Okada, Sayuri Fukushima,Atsushi Matsumoto, Etsuko Saito, Fumie Tokuda. Statistical CentreKazuo Takeuchi (chair), Tetsuya Otani. Echocardiographic core laboratoryShunichi Ogawa, Shigeto Fuse, Mitsuru Seki, Masakazu Yokosaka.Data and safety monitoring board Takeshi Tomomasa. Clinical investigators(Institution [number of patients contributed])Ryuji Fukazawa (NipponMedical School Tama Nagayama Hospital [13]); Chitose Ogawa (St LukesInternational Hospital [12]); Kenji Furuno (Fukuoka Higashi Medical

Center [12]); Hirohide Tokunaga (Nagoya Memorial Hospital [12]);Tsutomu Saji, Shinichi Takatsuki, Yasushi Kemmotsu (Toho UniversityOmori Medical Center [11]); Shinya Hara (Toyota Memorial Hospital [11]);Keiji Tsuchiya (Japan Red Cross Medical Center [10]); Takanari Fujii(Showa University School of Medicine [10]); Masaru Miura,Takuya Tamame (Tokyo Metropolitan Childrens Medical Center [10]);Yoshiaki Okuma (National Center for Global Health and Medicine [9]);Tomio Kobayashi (Gunma Childrens Medical Center [8]);Osamu Shinohara (Handa City Hospital [7]); Makoto Kuwashima(Kiryu Kousei General Hospital [7]); Maiko Tatsuki (Fujioka GeneralHospital [7]); Muneo Yoshibayashi (Nara Hospital Kinki University Facultyof Medicine [6]); Hisashi Takasugi (Kochi Medical School [6]);Kiminori Masuda (Kagoshima Medical Association Hospital [6]);Maya Fujiwara (Tokyo Rinkai Hospital [6]); Shigeto Fuse (NTT EastSapporo Hospital [6]); Noriko Nagai (Okazaki City Hospital [5]);Hiroshi Komatsu (Maizuru Medical Center [5]); Fukiko Ichida,Kazuyoshi Saito (Toyama University [5]); Tamaki Ueno (Ayabe City

Hospital [4]); Asami Maruyama (Saitama Medical Center Jichi MedicalUniversity [4]); Yasuo Sunaga (Gunma Chuo General Hospital [4]);Atsushi Matsui (Maebashi Red Cross Hospital [4]); Tatsuo Tsuboi (DokkyoMedical University [4]); Mika Sasaki (Iwate Medical University Hospital[4]); Tomohiro Usuku (Shakaihoken Kobe Central Hospital [3]);Tsuneo Igarashi (National Hospital Organization Takasaki GeneralMedical Center [3]); Toshiro Hara, Kazuyuki Ikeda (Kyusyu UniversityGraduate School of Medical Sciences [3]); Mamoru Ayusawa,Naokata Sumitomo (Nihon University [3]); Masashi Morooka (FujitaHealth University [2]); Shinya Shimoyama (Saiseikai Maebashi Hospital[2]); Hideko Nishimura (Tone Central Hospital [2]); Koichi Kataoka(Kochi Health Sciences Center [2]); Kazuetsu Mori (Seirei Sakura CitizenHospital [2]); Motohiro Shibata (Social Insurance Chukyo Hospital [2]);Hiroyuki Ishida (Matsushita Memorial Hospital [2]); Hiroyuki Yamagishi(Keio University [1]); Tamotsu Matsunaga (Toda Chuo General Hospital[1]); Masahiro Yasui (Nakatsugawa Municipal General Hospital [1]);Syozo Maeda (Isesaki Municipal Hospital [1]); Akihito Sasaki (Tokyo

Medical and Dental University [1]); Kazuyo Fukuda (Fukaya Red CrossHospital [1]); Toshihiro Tanaka (JA Shizuoka Kosei Hospital [1]);Satoru Tanaka (Kagoshima Prefectural Kanoya Hospital [1]); Jun Furui(JA Hiroshima General Hospital [1]); Keiji Haseyama (Kushiro CityGeneral Hopital [1]); Hiroshi Arakawa (Saitama Medical Center [1]);Tomoko Takano (Osaka General Medical Center [1]); Kunio Ohta(Kanazawa University Hospital [1]); Mami Nakayashiro. (OkinawaPrefectural Nanbu Medical Center and Childrens Medical Center [1]).Design and maintenance of websiteTohru Itoi, Hiromi Konno,Sanae Ashimura. Advisers to steering committeeMitsuru Asai (KawasakiDisease Parents Association), Tomisaku Kawasaki (Japan KawasakiDisease Research Center).

Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgments

This study was supported by Japanese Ministry of Health, Labour and

Welfare, Health and Labour Sciences Research Grants for the


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Comprehensive Research on Practical Application of MedicalTechnology: Randomized controlled trial to Assess Immunoglobulin

plus Steroid Effi cacy for Kawasaki disease (RAISE study). We thank allour patients, their families, and the site investigators, and David Kiplerfor editing of the article.

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