Theerapan Songnuy M.D.
Overview Kawasaki disease Standard Treatment Refractory Kawasaki Disease New Treatment : Infliximab- Mechanism- Effica...
Kawasaki Disease Acute febrile illness in children Classical symptoms:- Persistent high fever- Polymorphous rash- Conjun...
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 theimmune response leading to vasculardamage in the coronary arteritis mice model...
Materials & Methods Mice :- Wild-type C57BL/6, TNFRI-/- & TNFRII-/-- From Charles River Lab & The JacksonLab- Housed unde...
Materials & Methods Lactobacillus casei cell wall extract- MRS broth ( Difco, Detroit, MI)- Cytoplasmic membrane disrupte...
Materials & Methods Quantitative real time RT-PCR- Mice 4-5 wk old were injected intra-peritoneallywith 0.5 ml PBS or 1 m...
Materials & Methods Confocal immunomicroscopy- Serial 6-um heart& spleen cryo-section, fixed inacetone- Incubation in PBS...
Materials & Methods Cardiac histology & histological evaluation- Tissue embedded in compound ( Tissue-Tek)snap-frozen in ...
Materials & Methods Treatment of mice with TNF antagonistEtanerept- After disease induced, Etanercept wasinducedIP at 8-1...
Conclusion TNF-alpha plays a key role of coronary artery damage in amurine model After disease induction, TNF-alpha rose...
Standard Treatments-If left untreated, coronary aneurysm 15-25%-IVIG treatment reduced coronary complication to only3-5 %
Refractory Kawasaki Disease Refractoriness to IVIG defined as:- Persisting or re-emerging fever > 38C- Positive fractiona...
Therapy for IVIG-resistanceKawasaki Disease Additional doses of IVIG Intravenous methyl prednisolone Oral corticosteroi...
Infliximab( Tumor Necrotic Factor-alphaAntagonist)
Paper infliximab
Aim To study the efficacy of infliximab forsuppressing the progression ofcoronary artery lesions in cases ofrefractory to...
Materials & Methods Patients aged 2-10 years Fulfilled criteria diagnosis as Kawasakidisease* Primarily treated with IV...
Materials & Methods Refractoriness to IVIG defined as:- Persisting or re-emerging fever > 38C- Positive fractional change...
Materials & Methods Exclusion criteria:- TB lung- Recent therapy with corticosteroids orbiologic response modifiers- Vacc...
Infliximab Administration Dose : 5 mg/kg in 100 ml saline Route : intravenous In case of refractory to infliximab, plas...
Day after infliximabJ Rheumatol 2012;39:864-867
Day after infliximabJ Rheumatol 2012;39:864-867
J Rheumatol 2012;39:864-867
Results One patient showed coronary artery lesion at30 d of follow up but complete regression 1 ylater No adverse reacti...
Aim Efficacy and safety of infliximabcompared to re-treated IVIG for treatingIVIG-resistant Kawasaki diseasepatients
Materials & Methods A two-center retrospective study From Jan 2000-March 2008 Inclusion criteria:- Fever > 4 d & 4 from...
 Exclusion criteria- Initial treatment at other centers- Initial treatment with others than IVIG &aspirin- Re-treatment f...
ResultsPrimaryIVIGMetInclusioncriteriaRe-treatedIVIGRe-treatedInfliximabCenter 1Boston243 41 (17%) 41 0Center 2San Diego39...
J Pediatr 2011; 158: 644-9
(continued)
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...
Thank You VeryMuch
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
Infliximab treatment for refractory kawasaki disease
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Infliximab treatment for refractory kawasaki disease

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Infliximab treatment for refractory kawasaki disease

Presented by Theerapan Songnuy, MD.

April26, 2013

Published in: Health & Medicine
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Infliximab treatment for refractory kawasaki disease

  1. 1. Theerapan Songnuy M.D.
  2. 2. Overview Kawasaki disease Standard Treatment Refractory Kawasaki Disease New Treatment : Infliximab- Mechanism- Efficacy- Side effects Conclusion
  3. 3. 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
  4. 4. Inflammatory Process Inflammatory markers:- TNF-alpha- IL-2R- IL-6- etc.Clin Immunol Immunopathol 1990; 56:29-36
  5. 5. Aim To examine the role of TNF-alpha in theimmune response leading to vasculardamage in the coronary arteritis mice modelof Kawasaki disease
  6. 6. Materials & Methods Mice :- Wild-type C57BL/6, TNFRI-/- & TNFRII-/-- From Charles River Lab & The JacksonLab- Housed under pathogen-free condition atU. of Toronto
  7. 7. 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 cytoplasmicmaterial- 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 inducecoronary arteritis
  8. 8. Materials & Methods Quantitative real time RT-PCR- Mice 4-5 wk old were injected intra-peritoneallywith 0.5 ml PBS or 1 ml of LCWE- After sacrificed, heart & spleen were processedfor RNA isolation- cDNA was synthesized & amplified by real timePCR- Relative quantity of PCR products weredetermined(TNF-alpha) compared to GAPDH- Also can be used for ICAM-1, VCAM-1, E-Selectinet al
  9. 9. Materials & Methods Confocal immunomicroscopy- Serial 6-um heart& spleen cryo-section, fixed inacetone- Incubation in PBS plus 0.1% saponin & 2% BSA- Stained with purified rat antimouse TNF- alphamAb or isotype control- Followed by biotinylated goat anti-rat IgG- Mounted in DAKO anti-fade fluoresent mountingmedium- View under a confocal microscope
  10. 10. 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 ofleft coronary artery- Stained with H&E or elastin van Giesen- Assess arteritis & elastin breakdown
  11. 11. Materials & Methods Treatment of mice with TNF antagonistEtanerept- After disease induced, Etanercept wasinducedIP at 8-10 mg/kg twice weekly- Mice were sacrificed 28 & 42 d later- Cardiac tissue prepared for histology
  12. 12. Conclusion TNF-alpha plays a key role of coronary artery damage in amurine model After disease induction, TNF-alpha rose in the peripheralimmune system & localized at coronary artery Lead to lymphocyte recruitment Lead to elastin degradation, vessel wall damage, coronaryartery aneurysm Blocking TNF-alpha activity ( Etanercept & abolish signalvia TNFRI) result in decrease inflammation & elastinbreakdown
  13. 13. Standard Treatments-If left untreated, coronary aneurysm 15-25%-IVIG treatment reduced coronary complication to only3-5 %
  14. 14. Refractory Kawasaki Disease Refractoriness to IVIG defined as:- Persisting or re-emerging fever > 38C- Positive fractional changes of CRP- Leukocytosis / increased neutrophilsAfter IVIG therapy for 48 hr
  15. 15. Therapy for IVIG-resistanceKawasaki Disease Additional doses of IVIG Intravenous methyl prednisolone Oral corticosteroids Cyclophosphamide Cyclosporin Methotrexate Plasma exchange Infliximab, a tumor necrosis factor-alphablockerPediatrics 2004; 114: 1708-33.
  16. 16. Infliximab( Tumor Necrotic Factor-alphaAntagonist)
  17. 17. Paper infliximab
  18. 18. Aim To study the efficacy of infliximab forsuppressing the progression ofcoronary artery lesions in cases ofrefractory to extensive IVIG therapy
  19. 19. Materials & Methods Patients aged 2-10 years Fulfilled criteria diagnosis as Kawasakidisease* Primarily treated with IVIG 2-4 g/kg
  20. 20. Materials & Methods Refractoriness to IVIG defined as:- Persisting or re-emerging fever > 38C- Positive fractional changes of CRP- Leukocytosis / increased neutrophilsAfter IVIG therapy for 48 hr :Then infliximab would be started within10 days of disease onsetJ Rheumatol 2012;39:864-867
  21. 21. Materials & Methods Exclusion criteria:- TB lung- Recent therapy with corticosteroids orbiologic response modifiers- Vaccination with BCG within 6 mo beforedisease onset- Low cardiac function- Liver/renal dysfunctionJ Rheumatol 2012;39:864-867
  22. 22. Infliximab Administration Dose : 5 mg/kg in 100 ml saline Route : intravenous In case of refractory to infliximab, plasma pheresiswas performed with 5% albumin for 3 consecutive daEvaluation :- At 48 hr. after infliximab (fever & inflammatorymarkers )-At 30 days ( intact coronary artery by echocardio-graphy)J Rheumatol 2012;39:864-867
  23. 23. Day after infliximabJ Rheumatol 2012;39:864-867
  24. 24. Day after infliximabJ Rheumatol 2012;39:864-867
  25. 25. J Rheumatol 2012;39:864-867
  26. 26. Results One patient showed coronary artery lesion at30 d of follow up but complete regression 1 ylater No adverse reactions ( anaphylactoidreaction, heart failure, or severe infectious)
  27. 27. Aim Efficacy and safety of infliximabcompared to re-treated IVIG for treatingIVIG-resistant Kawasaki diseasepatients
  28. 28. 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 forrecurrent or persistent fever > 38 c beyond36 h after completion of initial IVIG ( 2 g/k)
  29. 29.  Exclusion criteria- Initial treatment at other centers- Initial treatment with others than IVIG &aspirin- Re-treatment for coronary arterychangesin the absence of fever- First re-treatment > 10 d after initialIVIGor infliximabMaterials & Methods
  30. 30. ResultsPrimaryIVIGMetInclusioncriteriaRe-treatedIVIGRe-treatedInfliximabCenter 1Boston243 41 (17%) 41 0Center 2San Diego398 65(16%) 45 20
  31. 31. J Pediatr 2011; 158: 644-9
  32. 32. (continued)
  33. 33. J Pediatr 2011; 158: 644-9
  34. 34. 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-resistanceKawasaki disease patients
  35. 35. Thank You VeryMuch
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