1. Etanercept in Kawaski
Disease
Ada Kong
IDS presentation
May 2009

2. Etanercept in Kawasaki Disease
• Overview of Kawasaki Disease
• Current therapy of Kawasaki Disease
• TNF in Kawasaki Disease
• Study Design & Methods
• Case studies

3. Kawasaki Disease - Overview
• Acute, febrile, systemic,
vasculitis syndrome of early
childhood
• Etiology unknown –
immunologic, infectious,
genetic Coronary aneurysm
in KD
• Major complications:
Coronary artery aneurysm
leading to MI, sudden death
or ischemic heart disease

4. Typical symptoms of KD
4.) Conjunctivitis
1.) Redness, swelling,
peeling in palms &
soles
3.) Mucositis, “strawberry tongue”
AHA/AAP Diagnostic
criteria: FEVER at least 5
days with no known
2.) Swelling of
cause plus at least 4 out 5.) Rash
lymph nodes of 5 features

5. Current therapy for KD
• Standard of care = IVIG (2g/kg) plus ASA
(80-100 mg/kg q6h until afebrile then
3-5mg/kg/day)
• ~10-15% patients are resistant/refractory
to IVIG + ASA treatment
• At Children’s, 23% require retreatment
and 8% may develop coronary aneurysm
Wallace et al. Pediatrics 2000;105(6)
• Refractoriness/resistance increases risk of
CA aneurysms, hospitalization & costs

6. Tumor necrosis factor-α in KD
• KD patients demonstrate marked elevation
in serum soluble TNF-α despite IVIG
therapy
• Animal models show TNF-α antagonism
abolishes coronary artery inflammation
• Etanercept: soluble human TNF receptor
attached to Fc portion of human IgG1
• Etanercept inexpensive relative to cost of
IVIG (e.g. 10kg patient: IVIG 2g/kg =
$1200 vs. Enbrel 0.8mg/kg = $510)
*calculations do not consider hospitalization, #doses, IV
infusion etc…

7. Open Label Etanercept Pilot Study
• Open label, nonrandomized pilot study in patients
6 mos to 5 years
• To determine safety & pharmacokinetics
• 12 patients enrolled. First 5 patients received
0.4mg/kg SC, 0.8mg/kg SC given to all others
Results:
• 1 serious AE occurred but unrelated to etanercept
• Only 1 patient received 2nd dose IVIG
• 10 patients showed CRP normalization by day 7
• No patients developed new coronary artery
dilation or aneurysm after etanercept

8. Etanercept in Kawasaki:
Study Objectives and Endpoints
Primary Objective
• To determine effectiveness of etanercept
vs. placebo in reducing IVIG refractory
rate and re-treatment rate
Secondary Objective(s)
• To determine safety profile of etanercept
• To determine if etanercept alters rate of
CAD at 2 & 6 weeks of treatment
• To determine pharmacokinetics of
etanercept in KD

9. Study Design and Methods
• Placebo-controlled, randomized, double-
blinded, multi-center study
• Inclusion: age 2 months to 20 years with
acute KD, begun IVIG infusion within 10
days of onset
• Exclusion: any lab toxicities, females
>12years, severe comorbidities, prior
treatment with TNF-α antagonists/steroid,
active severe infections, live vaccines,
immunosuppressives in last 3 mos.

10. Study Design & Methods
• Dosing:
Etanercept 0.8mg/kg (max 50mg) S.C.
injection or placebo once a week for 3
weeks (days 0, 7, 14)
• First dose of study drug within 48 hours of
initializing IVIG
• Concomitant therapy with IVIG and ASA is
permitted

11. Study Design & Methods
• Pharmacy is unblinded and will randomize
subject to a treatment arm
• Subject will be inpatient for first dose
• Investigator will enter orders in CIS
• Serum blood draw, echo, EKG performed
at first dose
• Parents are to record daily temperature for
2 weeks after discharge

12. Etanercept: Drug Info
• Drug stored in IDS refrigerator
• Requires reconstitution with 1mL of
bacteriostatic water for injection
• Swirl gently to avoid foaming (may take
5-10 minutes to go into solution)
• Draw up dose, attach safety needle (no
larger than 27gauge)
• Prepared doses should be refrigerated &
used within 24 hours

13. Patient #1
• AR: 11y.o. boy with 1 week history of sore throat,
neck pain, intermittent fever, spreading
erythematous rash and bilateral nonexudative
conjunctivitis.
• 5/18: Presented at ED hypotensive, transferred to
PICU with concern for sepsis. Dermatology, ID,
Cardiology, Opthalmology consults followed.
• 5/20: Echocardiogram performed.
• 5/21: Initiated IVIG plus ASA. Patient consented
to study. Withdrawn from study due to suspected
viremia (HSV/adenovirus/EBV/CMV). No doses
of study drug given.
• 5/24: 2nd dose IVIG per Rheumatology, continued
monitoring of CRP & magnesium
Principle Diagnosis: Kawasaki disease

14. Patient #2
• JG: 6 y.o. boy admitted 5/19 with right neck
pain/swelling x 2wks, fever~5d, bilateral
conjunctivitis, cracked lips, fine rash on chest.
• 5/20: Echocardiogram showed dilatation of right
coronary artery
• Cardiology & ID consults
• 5/21: 1 dose of IVIG given, ASA initiated. Patient
consented to study.
• 5/22: Patient withdrawn from study due to unusual
clinical presentation. No study drug given.
• 5/23: Patient discharged afebrile x36h.
Transitioned to PO ASA
Principle Diagnosis: Kawasaki Disease

15. REFERENCES
• Treatment of Refractory Kawasaki Disease.
UpToDate Online 17.1. Accessed May 26, 2009
• Wallace et al. Initial Intravenous
Gammaglobulin Treatment Failure in Kawasaki
Disease. Pediatrics 2000;105(6):e78.
• Freeman A, Stanford S. Kawasaki Disease:
Summary of the American Heart Association
Guidelines. Am Family Physician 2006;74:1141-
1148.
• Etanercept in Kawasaki Disease. IDS Pharmacy
Binder.