INFLIXIMAB TREATMENT FOR

REFRACTORY KAWASAKI DISEASE

Theerapan Songnuy M.D.

Overview

Kawasaki disease Standard Treatment Refractory Kawasaki Disease New Treatment : Infliximab - Mechanism - Efficacy - Side effects Conclusion

Kawasaki Disease

Acute febrile illness in children Classical symptoms: - Persistent high fever - Polymorphous rash - Conjunctival congestion - Lip cracking/ strawberry tongue - Cervical lymphadenopathy - Indurative edema of extremities

Inflammatory Process

Inflammatory markers: - TNF-alpha - IL-2R - IL-6 - etc.

Clin Immunol Immunopathol 1990; 56:29-36

Aim

To examine the role of TNF-alpha in the immune response leading to vascular damage in the coronary arteritis mice model of Kawasaki disease

Materials & Methods

Mice : - Wild-type C57BL/6, TNFRI-/- &

TNFRII-/- - From Charles River Lab & The

Jackson Lab - Housed under pathogen-free

condition at U. of Toronto

Materials & Methods Lactobacillus casei cell wall extract - MRS broth ( Difco, Detroit, MI) - Cytoplasmic membrane disrupted by detergent lysis with 4%

sodium dodecyl sulfate for 1night at room temp.

- Washing cell wall-associated materials - Incubated with DNase, RNase, trypsin to remove cytoplasmic

material - Cell wall-materials were sonicated 2 hr by W-375 sonicator &

cooling by a dry ice-ethanol bath

- Centrifuged for 1 hr at 20,000 /min - Suspended in phosphase buffed saline before use to induce coronary arteritis

Materials & Methods Quantitative real time RT-PCR - Mice 4-5 wk old were injected intra-peritoneally with 0.5 ml PBS or 1 ml of LCWE - After sacrificed, heart & spleen were processed for RNA isolation - cDNA was synthesized & amplified by real time PCR - Relative quantity of PCR products were determined (TNF-alpha) compared to GAPDH - Also can be used for ICAM-1, VCAM-1, E-Selectin et

al

Materials & Methods Confocal immunomicroscopy - Serial 6-um heart& spleen cryo-section, fixed in acetone - Incubation in PBS plus 0.1% saponin & 2% BSA - Stained with purified rat antimouse TNF- alpha mAb or isotype control - Followed by biotinylated goat anti-rat IgG - Mounted in DAKO anti-fade fluoresent mounting medium - View under a confocal microscope

Materials & Methods

Cardiac histology & histological evaluation

- Tissue embedded in compound ( Tissue- Tek)

snap-frozen in liquid nitrogen, stored at -80 c

- Coronary artery: 6-um-thick serial section of

left coronary artery - Stained with H&E or elastin van Giesen - Assess arteritis & elastin breakdown

Materials & Methods

Treatment of mice with TNF antagonist Etanerept

- After disease induced, Etanercept was induced

IP at 8-10 mg/kg twice weekly - Mice were sacrificed 28 & 42 d later - Cardiac tissue prepared for histology

Conclusion TNF-alpha plays a key role of coronary artery damage

in a murine model After disease induction, TNF-alpha rose in the

peripheral immune system & localized at coronary artery

Lead to lymphocyte recruitment Lead to elastin degradation, vessel wall damage,

coronary artery aneurysm

Blocking TNF-alpha activity ( Etanercept & abolish signal via TNFRI) result in decrease inflammation & elastin breakdown

Standard Treatments

-If left untreated, coronary aneurysm 15-25%-IVIG treatment reduced coronary complication to only 3-5 %

Refractory Kawasaki Disease

Refractoriness to IVIG defined as: - Persisting or re-emerging fever

> 38 C - Positive fractional changes of

CRP - Leukocytosis / increased

neutrophils After IVIG therapy for 48 hr

Therapy for IVIG-resistance Kawasaki Disease

Additional doses of IVIG Intravenous methyl prednisolone Oral corticosteroids Cyclophosphamide Cyclosporin Methotrexate Plasma exchange Infliximab, a tumor necrosis factor-

alpha blocker Pediatrics 2004; 114: 1708-33.

Infliximab ( Tumor Necrotic Factor-alpha

Antagonist)

Paper infliximab

Aim

To study the efficacy of infliximab for suppressing the progression of coronary artery lesions in cases of refractory to extensive IVIG therapy

Materials & Methods

Patients aged 2-10 years Fulfilled criteria diagnosis as

Kawasaki disease* Primarily treated with IVIG 2-4 g/kg

Materials & Methods Refractoriness to IVIG defined as: - Persisting or re-emerging fever > 38

C - Positive fractional changes of CRP - Leukocytosis / increased neutrophilsAfter IVIG therapy for 48 hr : Then infliximab would be started within

10 days of disease onset

J Rheumatol 2012;39:864-867

Materials & Methods Exclusion criteria: - TB lung - Recent therapy with corticosteroids or biologic response modifiers - Vaccination with BCG within 6 mo before disease onset - Low cardiac function - Liver/renal dysfunction J Rheumatol 2012;39:864-867

Infliximab Administration Dose : 5 mg/kg in 100 ml saline Route : intravenous In case of refractory to infliximab, plasma pheresis was performed with 5% albumin for 3 consecutive

days Evaluation : - At 48 hr. after infliximab (fever & inflammatory markers ) -At 30 days ( intact coronary artery by echocardio- graphy) J Rheumatol 2012;39:864-867

Day after infliximab

J Rheumatol 2012;39:864-867

Day after infliximab

J Rheumatol 2012;39:864-867

J Rheumatol 2012;39:864-867

Results

One patient showed coronary artery lesion at

30 d of follow up but complete regression 1 y later

No adverse reactions ( anaphylactoid reaction, heart failure, or severe infectious)

Aim

Efficacy and safety of infliximab compared to re-treated IVIG for treating IVIG-resistant Kawasaki disease patients

Materials & Methods A two-center retrospective study From Jan 2000-March 2008 Inclusion criteria: - Fever > 4 d & 4 from 5 principal symptoms - Fever > 4 d & < 4 from 5 principal

symptoms & coronary artery abnormality - Received at least one re-treatment for recurrent or persistent fever > 38 c beyond 36 h after completion of initial IVIG ( 2 g/k)

Exclusion criteria - Initial treatment at other centers - Initial treatment with others than IVIG

& aspirin - Re-treatment for coronary artery

changes in the absence of fever - First re-treatment > 10 d after initial

IVIG or infliximab

Materials & Methods

Results

Primary IVIG

Met Inclusion criteria

Re-treated IVIG

Re-treatedInfliximab

Center 1Boston

243 41 (17%)

41 0

Center 2San Diego

398 65(16%) 45 20

J Pediatr 2011; 158: 644-9

(continued)

J Pediatr 2011; 158: 644-9

J Pediatr 2011; 158: 644-9

J Pediatr 2011; 158: 644-9

Conclusion

Infliximab as the first re-treatment : - Fewer days of fever - Fewer length of stay - Not improve coronary artery outcomes - No adverse effects were noted Need a prospective trials for IVIG-

resistance Kawasaki disease patients

Thank You Very Much