Etanercept With IVIg for Acute Kawasaki Disease: A Randomized Controlled Trial

Abstract

Objectives: Patients with Kawasaki disease can develop life-altering coronary arterial abnormalities, particularly in those resistant to intravenous immunoglobulin (IVIg) therapy. We tested the tumor necrosis factor α receptor antagonist etanercept for reducing both IVIg resistance and coronary artery (CA) disease progression.

Methods: In a double-blind multicenter trial, patients with Kawasaki disease received either etanercept (0.8 mg/kg; n = 100) or placebo (n = 101) subcutaneously starting immediately after IVIg infusion. IVIg resistance was the primary outcome with prespecified subgroup analyses according to age, sex, and race. Secondary outcomes included echocardiographic CA measures within subgroups defined by coronary dilation (z score >2.5) at baseline. We used generalized estimating equations to analyze z score change and a prespecified algorithm for change in absolute diameters.

Results: IVIg resistance occurred in 22% (placebo) and 13% (etanercept) of patients (P = .10). Etanercept reduced IVIg resistance in patients >1 year of age (P = .03). In the entire population, 46 (23%) had a coronary z score >2.5 at baseline. Etanercept reduced coronary z score change in those with and without baseline dilation (P = .04 and P = .001); no improvement occurred in the analogous placebo groups. Etanercept (n = 22) reduced dilation progression compared with placebo (n = 24) by algorithm in those with baseline dilation (P = .03). No difference in the safety profile occurred between etanercept and placebo.

Conclusions: Etanercept showed no significant benefit in IVIg resistance in the entire population. However, preplanned analyses showed benefit in patients >1 year. Importantly, etanercept appeared to ameliorate CA dilation, particularly in patients with baseline abnormalities.

Conflict of interest statement

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Copyright © 2019 by the American Academy of Pediatrics.

Figures

FIGURE 1

Approach, consent, randomization, and follow-up of participants. Four randomly assigned patients withdrew before dosing. A total of 201 patients received study medication; 4 received at least an initial dose but did not receive a second or third dose. They were included in the mITT analyses. Patients received “drug” either etanercept or placebo. a One subject was randomly assigned to etanercept but received the placebo. b In the etanercept arm, 1 subject was determined to have measles and not KD, and the parents of the other refused to attend the final follow-up visit. In the placebo arm, 2 subjects’ parents refused further dosing.

FIGURE 2

Primary end point ORs and 95% CIs for IVIg resistance in prespecified ethnic subgroups. A favorable and significant response to etanercept is shown for AAs.

FIGURE 3

A, Trajectories of the average (mean) of all 3 CA zscores over time in spaghetti diagram format. The center panel indicates more variability in response in placebo subjects with baseline CA dilation (etanercept baseline dilated, n = 24; placebo baseline dilated, n = 22; etanercept baseline nondilated, n = 73; placebo baseline nondilated,n = 76). The z scores from individual coronaries were included in the GEE model, and averages are shown for descriptive purposes. B, Box plots revealing the 3 CA averagez scores overall and within dilation subgroups over time. These data are provided for descriptive purposes.

FIGURE 4

GEE model results for change in z scores over time including all 3 CAs. Etanercept revealed significant reductions inz scores from baseline; the entire 95% CI lies below 0 for patients without and patients with baseline CA dilation. For placebo, there was a numerical reduction among patients with no dilation and a numerical increase among patients with dilation, but neither reached significance. ** P = .001, * P = .04.

FIGURE 5

Algorithm design for evaluating change in absolute CA dimensions, used to determine primary echocardiographic end point. Absolute echocardiographic measurements (diameter in millimeters) were used to determine this echocardiographic end point. Scores provided for worsened, improved, or no change were submitted for logistic regression. V5, visit 5.