efficacy of immunoglobulin plus prednisolone for prevention of

8/13/2019 Efficacy of Immunoglobulin Plus Prednisolone for Prevention Of

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Efficacy of immunoglobulin plus

prednisolone for prevention ofcoronary artery abnormalities insevere Kawasaki disease (RAISEstudy): a randomised, open-label,

blinded-endpoints trial


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Introduction


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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.


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Although corticosteroids are useful, report

showed high incidence of coronary a.abnormalities in patients received prolonged

course of oral prednisolone alone.


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However, findings from a subsequent

retrospective study of the effects ofcorticosteroids in Kawasaki disease showed

possible benefits.

Therefore, we aimed to assess the efficacy of

primary prednisolone treatment as anaddition to conventional treatment with IVIG.


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74 hospitals in Japan

Sept 29, 2008Dec 2, 2010

Japanese diagnostic guidelines


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Randomisation and masking

Internet Data and Information Center for MedicalResearch (INDICE)

Patients and treating physicians were not masked

to assignment


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Procedures IVIG group: immunoglobulin 2g/kg given over 24 h + aspirin

30mg/kg per day until afebrile, followed by aspirin 35mg/kgper day for at least 28 days after fever onset

IVIG + prednisolone: above + IV prednisolone 2 mg/kg perday 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 theprednisolone dose over 15 days in 5-day steps, from 2mg/kg per day to 1 mg/kg per day to 05 mg/kg per day


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Echocardiograms

interpreted by two pediatric cardiologists who weremasked to patient identity and group assignment

abnormal coronary artery definition

3mm

> = 5y/o: luminal diameter >4mm internal diameter of a segment > = 15 times that of an

adjacent segment

luminal contour was clearly irregular


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Results


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Discussion


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Key Point 1

Combination treatment with IVIG + prednisolone hada 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 inthe IVIG group was because we used the risk score

system to select the patients with severe diseaseand confirms the positive predictive value of the riskscore in prediction of no response to initialintravenous immunoglobulin.


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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 ofimmediate treatment of inflammation and vasculitis,before pathological changes become irreversible.


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Because patients who do not respond to primarytreatment with intravenous immunoglobulin are

usually identified 2448 h after completion oftreatment, rescue therapies are generally started 23 days after diagnosis of Kawasaki disease. Suchdelays in the start of additional treatments mightallow formation of coronary artery abnormalities.

Our therapeutic strategynamely, risk stratificationat diagnosis followed by intensive primary treatmentin high-risk patientsmight effectively suppressinflammation due to Kawasaki disease andsubsequent remodelling of the coronary arterial wall.


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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?


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1

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.


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2

duration of corticosteroid administration.

Although the total dose of corticosteroids was similar in the

studies, median duration of prednisolone administration was 21days in our study compared VS one course of 30 mg/kgmethylprednisolone in the US study.

Kawasaki disease is self-limiting, but fever caused by thedisease persists for about 23 weeks if untreated.

Thus, duration of corticosteroid administration might be more

important than maximum concentration of corticosteroidinsuppression of inflammation and vasculitis in this disease.


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3

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 significantadvantage in prevention of abnormalities.


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Key Point 4

Safety of treatment: we could not assess potential adverseeffects 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 forpredicting no response to primary IVIG in a North Americancohort.

The positive predictive value to predict resistance to primary

IVIG with the risk score was 40%, which is fairly low. Weanticipate the development of an accurate predictive model,which possibly includes other biomarkers or geneticbackground.


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Thank you

efficacy of immunoglobulin plus prednisolone for prevention of

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