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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