Infliximab Treatment of Intravenous Immunoglobulin–Resistant Kawasaki Disease

Abstract

Objective-To test the safety, tolerability, and pharmacokinetics of the anti-TNF-α monoclonal antibody, infliximab, in subjects with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD).Study design-We conducted a multicenter, randomized, prospective trial of second IVIG infusion (2 g/kg) versus infliximab (5 mg/kg) in 24 children with acute KD and fever following initial treatment with IVIG. Primary outcome measures were infliximab safety, tolerability, and pharmacokinetics. Secondary outcome measures were duration of fever and changes in markers of inflammation.Results-Study drug infusions were associated with cessation of fever within 24 hours in 11 of 12 subjects treated with infliximab and 8 of 12 subjects retreated with IVIG. No infusion reactions or serious adverse events were attributed to either study drug. No significant differences were © 2008 Mosby, Inc. All rights reserved.Corresponding author: Jane C. Burns, M.D. Dept of Pediatrics 9500 Gilman Dr. La Jolla, CA 92093-0830 Tel. 619-543-5326 FAX 619-543-3546 jcburns@ucsd.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. observed between treatment groups in the change from baseline for laboratory variables, fever, or echocardiographic assessment of coronary arteries. NIH Public AccessConclusion-Both infliximab and a second IVIG infusion were safe and well-tolerated in subjects with KD who were resistant to standard IVIG treatment. The optimal management of patients resistant to IVIG remains to be determined. KeywordsTNF-α; cytokine; monoclonal antibody; coronary artery aneurysm; infliximab; Kawasaki disease Kawasaki disease (KD) is a self-limited illness that results in coronary artery aneurysms in up to 25% of untreated children. Administration of high-dose intravenous immunoglobulin (IVIG) in combination with aspirin (ASA) results in dramatic clinical improvement and reduced incidence of coronary artery aneurysms in the majority of patients with KD (1). However, a subset of patients has persistence or recrudescence of fever following IVIG treatment (2). Common practice is to administer a second dose of IVIG (2 g/kg) to patients who fail to become afebrile within 24 to 48 hours after completion of the first infusion, even though the benefits of this approach have never been formally evaluated (3). Fever persists in approximately half of the patients treated with a second dose of IVIG (2 g/kg) (2). Because KD is a self-limited illness from which most children eventually recover with no specific therapy, it is unclear whether retreated patients become afebrile as a result of the addition...

Infliximab for intensification of primary therapy for Kawasaki disease: a phase 3 randomised, double-blind, placebo-controlled trial

“…33 12 of these 48 patients had received infl iximab as part of a phase 1 multicentre, randomised, prospective trial of second intravenous immunoglobulin versus infl iximab for intravenous immunoglobulin-resistant Kawasaki disease. 8 This study showed that infl iximab was safe and well tolerated. Subsequently, a two-centre retrospective review of intravenous immunoglobulin-resistant patients treated with either a second intravenous immunoglobulin (n=86) or infl iximab (n=20) indicated that patients treated with infl iximab had fewer days of fever (median 8 vs 10 days, p=0·028) and shorter lengths of hospital syay (median 5·5 vs 6 days, p=0·04) than those given a second intravenous immunoglobulin.…”

“…7,[28][29][30][31][32][33] A phase 1 trial of second intravenous immunoglobulin versus infl iximab for intravenous immunoglobulin-resistant Kawasaki disease showed that infl iximab was safe and well tolerated. 8 Subsequently, a retrospective review of intravenous immunoglobulin-resistant patients treated with either a second intravenous immunoglobulin or infl iximab showed that patients treated with infl iximab had fewer days of fever (median 8 vs 10 days, p=0·028) and shorter lengths of hospitalisation (median 5·5 vs 6 days, p=0·04) than those treated with a second intravenous immunoglobulin. 9 Interpretation Although the addition of infl iximab to primary treatment in acute Kawasaki disease did not reduce treatment resistance in this randomised clinical trial, infl iximab was shown to be safe and well tolerated, achieved a greater reduction in the left anterior descending coronary artery Z score, and reduced the number of days of fever, laboratory markers of infl ammation, and intravenous immunoglobulin reaction rates.…”

“…7 A phase 1, randomised, multicentre clinical trial in children with Kawasaki disease and persistent or recrudescent fever after standard therapy reported no infusion reactions or serious adverse events attributable to infl iximab. 8 In a subsequent two-centre retrospective study of intravenous immunoglobulin-resistant disease, retreatment with infl iximab resulted in faster resolution of fever and fewer days of hospitalisation than did a second intravenous immunoglobulin infusion. 9 These data suggest that infl iximab is safe and eff ective in reducing infl ammation in acute Kawasaki disease.…”

Kawasaki Disease: The Coronary Affection Perspective

“…In the future, by identifying a genetic signature for this group, more aggressive therapies, such as anticytokine therapy, plasmapheresis, or cyclosporin A, may be used to reduce the risk of coronary complications [70,86].…”

Susceptibility genes for Kawasaki disease: toward implementation of personalized medicine

“…74,75 In accordance with this hypothesis, the usage of infliximab, the monoclonal antibody against TNF-a, has recently been found to be effective as a novel therapy for IVIG-resistant KD. [76][77][78] Thus, genes for cytokines including TNF-a could be candidates for KD susceptibility. However, consistent results have not been obtained.…”