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