Epicutaneous immunotherapy Boonthorn 4 december 2009
outline <ul><li>Specific immunotherapy and meta-analysis </li></ul><ul><li>Immunological mechanism of SIT </li></ul><ul><l...
Meta-analysis <ul><li>Data Sources:  </li></ul><ul><ul><li>Electronic databases searched up to April 30, 2008, for meta-an...
Specific immunotherapy: current meta-analysis   (Sc IT) Enrico C.  et al., Ann Allergy Asthma Immunol.  2009;102:22–28 Sou...
Meta-analysis ( SL IT ) Enrico C.  et al., Ann Allergy Asthma Immunol.  2009;102:22–28 Source Patients Characteristics Out...
Efficacy of specific immunotherapy (SIT). Summary of meta-analysis results expressed as effect size on symptoms.  ( SMD, s...
Immunological mechanism Nat Rev Immunol 2006;6:761-71
Mechanisms of allergic reactions Nat Rev Immunol 2006;6:761-71
Effects of allergen-specific immunotherapy on clinical and experimental  i mmune parameters Nat Rev Immunol 2006;6:761-71
Proposed role of regulatory T cells and cytokines in allergen-specific immunotherapy Nat Rev Immunol 2006;6:761-71
<ul><li>Epicutaneous immunotherapy in animal model </li></ul>
Epicutaneous is as efficient as subcutaneous desensitization in a mouse model of allergy <ul><li>Method </li></ul><ul><ul>...
Epicutaneous is as efficient as subcutaneous desensitization in a mouse model of allergy <ul><li>Result (index of provocat...
Epicutaneous is as efficient as subcutaneous desensitization in a mouse model of allergy <ul><li>Result </li></ul><ul><ul>...
EPIT for HDM allergy using VIASKIN R  technology : a preclinical study <ul><li>Method </li></ul><ul><ul><li>4 Group BALB/c...
EPIT for HDM allergy using VIASKIN R  technology : a preclinical study <ul><li>Results  </li></ul>JACI .2008;123:S177 Sc E...
EPIT for HDM allergy using VIASKIN R  technology : a preclinical study <ul><ul><li>Result </li></ul></ul><ul><ul><ul><li>s...
EPIT:proof of concept with various Ag in sensitized mouse <ul><li>Methods </li></ul><ul><ul><li>Sensitized mice (sc) to Ov...
EPIT:proof of concept with various Ag in sensitized mouse <ul><li>results </li></ul>Doi:10.1016/j.clim.2009.03.254 No sign...
EPIT:proof of concept with various Ag in sensitized mouse <ul><li>results </li></ul>Doi:10.1016/j.clim.2009.03.254 Penh va...
Repeated applications of Peanut protein extracts during EPIT induce a change of cytokine response from Th2 to mixed Th2/Th...
Repeated applications of Peanut protein extracts during EPIT induce a change of cytokine response from Th2 to mixed Th2/Th...
Repeated applications of Peanut protein extracts during EPIT induce a change of cytokine response from Th2 to mixed Th2/Th...
<ul><li>Epicutaneous immunotherapy in human </li></ul>
Epicutaneous Immunotherapy In Severe Cow Milk Allergy: A Double Blind Pilot Trial <ul><li>RATIONALE </li></ul><ul><ul><li>...
Epicutaneous Immunotherapy In Severe Cow Milk Allergy: A Double Blind Pilot Trial <ul><li>METHODS </li></ul><ul><ul><li>pa...
Epicutaneous Immunotherapy In Severe Cow Milk Allergy: A Double Blind Pilot Trial <ul><li>RESULTS : At day 90 </li></ul><u...
Epicutaneous Immunotherapy In Severe Cow Milk Allergy: A Double Blind Pilot Trial <ul><li>results </li></ul><ul><li>SPT : ...
Epicutaneous allergen administration as a novel method of allergen-specific immunotherapy <ul><li>METHODS </li></ul><ul><u...
<ul><li>Inclusion criteria </li></ul><ul><ul><li>age 18 to 65 years </li></ul></ul><ul><ul><li>Hx  of summer hay fever  > ...
<ul><li>Study design </li></ul><ul><ul><li>monocentric </li></ul></ul><ul><ul><li>phase I/II randomized, placebo-controlle...
<ul><li>Clinical endpoints  </li></ul><ul><li>main objective  :  assess safety and efficacy of epicutaneous allergen immun...
Test drug <ul><li>The patch consisted of a 3  *  5 cm polyethylene pouch that was filled with grass pollen extract in Vase...
Statistical analysis <ul><li>detect changes in symptom scores of NPTs </li></ul><ul><ul><li>from baseline ( intragroup ) <...
Results J Allergy Clin Immunol 2009;124:997-1002
Safety and tolerability 10  pts .  used topical corticosteroids for total duration of 13  +/-  20 days J Allergy Clin Immu...
Nasal provocation  <ul><li>differences between 2 groups not reach statistical significance September 2006, P  =  .66; Apri...
Subjective symptom scores J Allergy Clin Immunol 2009;124:997-1002
Use of rescue medication <ul><li>similar in 2 test groups </li></ul><ul><li>symptoms were significantly better controlled ...
Discussion <ul><li>in 1950s, Blamoutier performed allergen-specific immunotherapy by needle scarification of the volar for...
Discussion  <ul><li>scratching enhances allergen penetration into epidermis and activates keratinocytes  ( allergen-pulsed...
Limitation of study <ul><li>Most patches  applied at home, quality control of correct application difficult. </li></ul><ul...
Limitation of study <ul><li>grass pollen patches induced eczema  contrast with placebo, one may argue that blinding of  st...
Discussion  <ul><li>expect symptom amelioration to last longer than the 1½ years of observation time in this study, but lo...
Conclusion  <ul><li>meta-analysis => useful both Sc and SL IT </li></ul><ul><li>Immunological mechanism  </li></ul><ul><ul...
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epicutaneous immunotherapy

  1. 1. Epicutaneous immunotherapy Boonthorn 4 december 2009
  2. 2. outline <ul><li>Specific immunotherapy and meta-analysis </li></ul><ul><li>Immunological mechanism of SIT </li></ul><ul><li>Epicutaneous immunotherapy in animal model </li></ul><ul><li>Epicutaneous immunotherapy in human </li></ul>
  3. 3. Meta-analysis <ul><li>Data Sources: </li></ul><ul><ul><li>Electronic databases searched up to April 30, 2008, for meta-analyses of randomized, placebo-controlled trials assessing specific IT in respiratory allergy. We looked for studies that evaluated effects on symptom scores and use of rescue medication </li></ul></ul><ul><li>Results: </li></ul><ul><ul><li>7 of 13 meta-analyses met the inclusion criteria </li></ul></ul><ul><ul><li>5 evaluating sublingual IT and 2 evaluating subcutaneous IT </li></ul></ul><ul><ul><li>7 meta-analyses reported reduction in symptom and medication scores </li></ul></ul><ul><ul><li>Sublingual IT meta-analysis not find significant size effect, probably because of the inclusion criteria. </li></ul></ul>Enrico C. et al., Ann Allergy Asthma Immunol. 2009;102:22–28
  4. 4. Specific immunotherapy: current meta-analysis (Sc IT) Enrico C. et al., Ann Allergy Asthma Immunol. 2009;102:22–28 Source Patients Characteristics Outcomes Abramson et al 2003 1,064 adults and children Meta-analysis of RCT of asthma Double-blind, single-blind, and open studies 75 studies for outcomes (36 with HDM , 20 pollen, 10 animal dander, 2 Cladosporium mould allergy, 1 latex, and 6 multiple allergens) significant improvements in asthma symptom scores Calderon et al, 2007 1,063 adults Meta-analysis of randomized DBPC studies of rhinitis 15 studies for outcomes (a variety of allergens were administered: ragweed, mixed grass, timothy, Parietaria , birch, orchard, cedar, Bermuda grass, Juniperus ashei , and Cocos Symptom scores , Medication scores were reduced in the immunotherapy
  5. 5. Meta-analysis ( SL IT ) Enrico C. et al., Ann Allergy Asthma Immunol. 2009;102:22–28 Source Patients Characteristics Outcomes Calamita et al 2006 303 adults and children Meta-analysis of randomized placebo-controlled,open and blinded studies of asthma 9 studies (5 with pollen and 4 with mites) no significant reduction in asthma symptoms Penagos et al 2008 441 children Meta-analysis of randomized DBPC studies of asthma 9 studies for the outcomes (6 with mites and 3 with pollens) Overall, there was a significant reduction in symptoms Olaguibel et al 2005 256 children Meta-analysis of randomized DBPC clinical trials of respiratory asthma or allergic rhinitis 7 studies for the outcomes Decreased symptom and m edication scor e Penagos et al 2006 484 children Meta-analysis of randomized DBPC studies of AR 10 studies for the outcomes (6 with pollens and 4 with HDM ) There were significant reductions in symptom scores Wilson et al 2005 959 adults and children Meta-analysis of randomized DBPC studies of AR 22 studies for the outcomes (6 with HDM , 5 grass pollen, 5 Parietaria , 2 olive, and 1 ambrosia, cat, and cupressaceous Overall there were significant reductions in symptoms
  6. 6. Efficacy of specific immunotherapy (SIT). Summary of meta-analysis results expressed as effect size on symptoms. ( SMD, standardized mean difference ) Enrico C. et al., Ann Allergy Asthma Immunol. 2009;102:22–28
  7. 7. Immunological mechanism Nat Rev Immunol 2006;6:761-71
  8. 8. Mechanisms of allergic reactions Nat Rev Immunol 2006;6:761-71
  9. 9. Effects of allergen-specific immunotherapy on clinical and experimental i mmune parameters Nat Rev Immunol 2006;6:761-71
  10. 10. Proposed role of regulatory T cells and cytokines in allergen-specific immunotherapy Nat Rev Immunol 2006;6:761-71
  11. 11. <ul><li>Epicutaneous immunotherapy in animal model </li></ul>
  12. 12. Epicutaneous is as efficient as subcutaneous desensitization in a mouse model of allergy <ul><li>Method </li></ul><ul><ul><li>48 BALB/c mice were Sc sensitized,nasally boosted to pollen or ovalbumin </li></ul></ul><ul><ul><li>Desensitized during 8,16 wks by EC or Sc </li></ul></ul><ul><ul><li>Compared sensitized,nontreated and naïve </li></ul></ul><ul><ul><li>Plethysmography ( index of bronchochonstriction) </li></ul></ul><ul><ul><li>Serum specific Ab ( IgE,IgG1,IgG2a ) </li></ul></ul>JACI .2008;121:793
  13. 13. Epicutaneous is as efficient as subcutaneous desensitization in a mouse model of allergy <ul><li>Result (index of provocation, % of control) </li></ul>JACI .2008;121:793 nontreated EC Sc 8wk 16wk 8wk 16wk 8wk 16wk pollen 174% 139% 67% P<0.001 76% P<0.01 90% P<0.05 57% P<0.01 ovalbumin 291% 171% 79% P<0.01 112% P<0.01 154% P<0.05 86% P<0.05
  14. 14. Epicutaneous is as efficient as subcutaneous desensitization in a mouse model of allergy <ul><li>Result </li></ul><ul><ul><li>desensitization ( for pollen ) </li></ul></ul><ul><ul><ul><li>Specific IgG2a increase 2.3 times (EC,P<0,05) </li></ul></ul></ul><ul><ul><ul><li>Increase 1.9 times ( Sc,p<0.05 ) </li></ul></ul></ul><ul><ul><li>For ovalbumin </li></ul></ul><ul><ul><ul><li>10 times both SC,EC ( p<0.05 ) </li></ul></ul></ul><ul><ul><li>NT and control unchange </li></ul></ul><ul><li>Conclusion </li></ul><ul><ul><li>In animal model ,EPIT seem as efficient as subcutaneous route </li></ul></ul>JACI .2008;121:793
  15. 15. EPIT for HDM allergy using VIASKIN R technology : a preclinical study <ul><li>Method </li></ul><ul><ul><li>4 Group BALB/c mice(C,n=10),(NT,n=9),(EP,n=9),(Sc,n=9) </li></ul></ul><ul><ul><li>IT once a week,8weeks (EP 48hrs. HDM extract , Sc) </li></ul></ul><ul><ul><li>Monitor </li></ul></ul><ul><ul><ul><li>IgE,IgG1,IgG2a </li></ul></ul></ul><ul><ul><ul><li>Penh ( measure bronchial hyper-reactivity) </li></ul></ul></ul><ul><ul><ul><li>BAL cell </li></ul></ul></ul>JACI .2008;123:S177
  16. 16. EPIT for HDM allergy using VIASKIN R technology : a preclinical study <ul><li>Results </li></ul>JACI .2008;123:S177 Sc EP NT P value sIgG2a Der.f/Der p baseline 0.009/0.075 0.097/0.061 <0.01 After IT 2.009/0.726 2.463/0.468 BAL ( Eo,L) baseline 4.1*10 4 1.0*10 5 1.9*10 5 <0.001 After IT 3.3*10 4 6.9*10 4 2.9*10 5
  17. 17. EPIT for HDM allergy using VIASKIN R technology : a preclinical study <ul><ul><li>Result </li></ul></ul><ul><ul><ul><li>sIgE and sIgG1 not vary </li></ul></ul></ul><ul><ul><ul><li>BAL neutrophil and macrophage not vary </li></ul></ul></ul><ul><ul><ul><li>Penh lower in treated group ( 158% of C in EP,141%in Sc,185% in NT,p<0.05) </li></ul></ul></ul><ul><ul><li>Conclusion </li></ul></ul><ul><ul><ul><li>In HDM sensitized mice,EPIT seems as efficient as SCIT </li></ul></ul></ul>JACI .2008;123:S177
  18. 18. EPIT:proof of concept with various Ag in sensitized mouse <ul><li>Methods </li></ul><ul><ul><li>Sensitized mice (sc) to Ova (n=18),pollen(n=18),HDM (n=24) </li></ul></ul><ul><ul><li>Oral to peanut (n=18) </li></ul></ul><ul><ul><li>Allocated into 3 group (EP,Sc,NT)and control </li></ul></ul><ul><ul><li>Monitor sIgE,sIgG1,sIgG2a </li></ul></ul><ul><ul><li>Plethysmography after provocation (Penh) </li></ul></ul>
  19. 19. EPIT:proof of concept with various Ag in sensitized mouse <ul><li>results </li></ul>Doi:10.1016/j.clim.2009.03.254 No significant diff. between EP and sc IgG2a pollen OVA HDM peanuts P value EP ( μ g/ml) 0.97 0.39 2.5 18 <0.05 NT ( μ g/ml) 0.42 0.15 0.5 5.5
  20. 20. EPIT:proof of concept with various Ag in sensitized mouse <ul><li>results </li></ul>Doi:10.1016/j.clim.2009.03.254 Penh value not significant diff. in EP , sc and control Conclusion : in sensitized mice ,with 4 tested allergens, EPIT as efficient as SCIT Penh value pollen OVA HDM peanuts EP 7.2 4.8 7.6 4.6 NT 12.8 9.7 9.6 7.1
  21. 21. Repeated applications of Peanut protein extracts during EPIT induce a change of cytokine response from Th2 to mixed Th2/Th1 in sensitized mice <ul><li>Methods </li></ul><ul><ul><li>BABL/c mice sensitized by PPE </li></ul></ul><ul><ul><li>EPIT perform during 8wks by 24 or 48 hrs.,application of PPE on VIASKIN R </li></ul></ul><ul><ul><li>Skin was harvested after D42,91 for cytokine measurement and histology </li></ul></ul>Doi:10.1016/j.clim.2009.03.251
  22. 22. Repeated applications of Peanut protein extracts during EPIT induce a change of cytokine response from Th2 to mixed Th2/Th1 in sensitized mice <ul><li>Results </li></ul><ul><ul><li>Increase IgG2a,decrease IgG1/IgG2a ratio </li></ul></ul><ul><ul><li>Thickening of epidermis,langerhan cell network perturbation ,migration of dendritic epidermal T cell,massive recruitement of CD11b+ inflammatory cell </li></ul></ul><ul><ul><li>After 24 hrs. </li></ul></ul><ul><ul><ul><li>Th2 cytokine (IL-1 β ,IL-4) increase compared control at D42,91 </li></ul></ul></ul>Doi:10.1016/j.clim.2009.03.251
  23. 23. Repeated applications of Peanut protein extracts during EPIT induce a change of cytokine response from Th2 to mixed Th2/Th1 in sensitized mice <ul><li>Results </li></ul><ul><ul><ul><li>Treg ,Th1 cytokines,TNF α not diff. from control at D42,but significant increase at D91 </li></ul></ul></ul><ul><ul><li>During 48 hrs, </li></ul></ul><ul><ul><ul><li>D42 , Th2 cytokine decrease dramatically </li></ul></ul></ul><ul><ul><ul><li>D91, cytokine response was attenuated </li></ul></ul></ul><ul><li>Conclusion </li></ul><ul><ul><li>In animal model , EPIT with VIASKIN R induced reorientation from only Th2 to diversified and mixed response </li></ul></ul>Doi:10.1016/j.clim.2009.03.251
  24. 24. <ul><li>Epicutaneous immunotherapy in human </li></ul>
  25. 25. Epicutaneous Immunotherapy In Severe Cow Milk Allergy: A Double Blind Pilot Trial <ul><li>RATIONALE </li></ul><ul><ul><li>Immunotherapy has promising results in food hypersensitivity but significant side effects with oral route </li></ul></ul><ul><li>METHODS </li></ul><ul><ul><li>DBPC study investigated safety and efficacy of new method, EPIT </li></ul></ul><ul><ul><li>Using patch (Viaskin, DBV Technologies) </li></ul></ul><ul><ul><li>in children with severe cow’s milk allergy (CMA). </li></ul></ul><ul><ul><li>In 19 children, 8 m-6y (med 3y), with IgE-mediated CMA </li></ul></ul><ul><ul><li>in 2 French pediatric centers </li></ul></ul>JACI .vol.123 ,No.2:s183
  26. 26. Epicutaneous Immunotherapy In Severe Cow Milk Allergy: A Double Blind Pilot Trial <ul><li>METHODS </li></ul><ul><ul><li>patch coated with 1 mg cow milk powder was applied every other day, during 3 months, on the children’s back (treated group, n = 10, drop out 1; placebo group, n = 9, drop out 2) </li></ul></ul><ul><ul><li>cumulated tolerated dose of milk (CTD),measured during an open challenge at days 0 and 90, allowed to calculate a tolerance index (CTD90 - CTD0)/CTD0 </li></ul></ul><ul><ul><li>SPTs, milk sIgE and sIgG were assayed monthly. From days 90 to 180, all patients could receive active treatment. </li></ul></ul>JACI .vol.123 ,No.2:s183
  27. 27. Epicutaneous Immunotherapy In Severe Cow Milk Allergy: A Double Blind Pilot Trial <ul><li>RESULTS : At day 90 </li></ul><ul><ul><li>in treated group, CTD was x10 in 5 and x3 in 1, unchanged in 3 </li></ul></ul><ul><ul><li>With the placebo, it was x2 in 4 and unchanged in 3 </li></ul></ul><ul><ul><li>tolerance index was 101 in treated group and 0.68 with placebo (p =0.13) </li></ul></ul><ul><ul><li>The additional 3-month treatment (n = 11) significantly increased the CTD (p 0.02) </li></ul></ul><ul><ul><li>SPTs, sIgE and IgG subclasses levels exhibited individual variations, with no detectable common profile </li></ul></ul><ul><ul><li>Adverse events were similar in 2 groups except for GI symptoms, diarrhea (2) and vomiting (1) reported only in the active group. </li></ul></ul>JACI .vol.123 ,No.2:s183
  28. 28. Epicutaneous Immunotherapy In Severe Cow Milk Allergy: A Double Blind Pilot Trial <ul><li>results </li></ul><ul><li>SPT : substantial reduction in wheal diameter,little change in placebo </li></ul><ul><li>CONCLUSIONS </li></ul><ul><ul><li>This pilot study shows the EPIT feasibility. These promising results need confirmation (larger studies, additional allergens) </li></ul></ul>JACI .vol.123 ,No.2:s183 Active Rx placebo P value Mean maximum tolerated dose at baseline 2.1mL (SD 2.6 ) 4.4 mL (SD 5.9) Mean maximum tolerated dose at 3 mo. 21 ( SD 24.3 ) 5.4 ( SD 5.9 ) P=0.37 Median change from baseline 5.6 mL 0.17 mL P=0.02
  29. 29. Epicutaneous allergen administration as a novel method of allergen-specific immunotherapy <ul><li>METHODS </li></ul><ul><ul><li>Study population </li></ul></ul><ul><ul><ul><li>Inclusion criteria </li></ul></ul></ul><ul><ul><ul><li>Exclusion criteria </li></ul></ul></ul>J Allergy Clin Immunol 2009;124:997-1002
  30. 30. <ul><li>Inclusion criteria </li></ul><ul><ul><li>age 18 to 65 years </li></ul></ul><ul><ul><li>Hx of summer hay fever > 2 seasons </li></ul></ul><ul><ul><li>positive reactions to grass pollen allergen extract in nasal provocation </li></ul></ul><ul><ul><li>Positive skin prick tests (Phleum pratense) </li></ul></ul><ul><li>Exclusion criteria </li></ul><ul><ul><li>atopic eczema , perennial allergic rhinitis , moderate to severe asthma </li></ul></ul><ul><ul><li>infection of upper airways within last 2 wks </li></ul></ul><ul><ul><li>surgical intervention within last 30 days </li></ul></ul><ul><ul><li>Hx of HIV/AIDS , malignancy , mastocytosis , uncontrolled high BP </li></ul></ul><ul><ul><li>pregnancy or lactation </li></ul></ul><ul><ul><li>presence or Hx of significant cardiovascular, renal, pulmonary, liver, infectious , hematologic, autoimmune, neurologic, and psychiatric disease </li></ul></ul><ul><ul><li>intake of antihistamines within last 2 wks or systemic or topic steroids within last 5 d </li></ul></ul><ul><ul><li>intake of contraindicated medicaments for specific IT eg. b-blockers or ACEI, ARB within last week </li></ul></ul><ul><ul><li>participation in another clinical trial within last 60 d </li></ul></ul>J Allergy Clin Immunol 2009;124:997-1002
  31. 31. <ul><li>Study design </li></ul><ul><ul><li>monocentric </li></ul></ul><ul><ul><li>phase I/II randomized, placebo-controlled, double-blind trial </li></ul></ul><ul><ul><li>evaluate the safety and clinical efficacy </li></ul></ul>J Allergy Clin Immunol 2009;124:997-1002
  32. 32. <ul><li>Clinical endpoints </li></ul><ul><li>main objective : assess safety and efficacy of epicutaneous allergen immunotherapy </li></ul><ul><li>primary outcome </li></ul><ul><ul><li>change in allergic response assessed by NPTs </li></ul></ul><ul><li>Secondary outcome </li></ul><ul><ul><li>hay fever symptoms by visual analog scale </li></ul></ul><ul><ul><li>use of medication </li></ul></ul><ul><ul><li>occurrence of local reactions and adverse events </li></ul></ul>J Allergy Clin Immunol 2009;124:997-1002
  33. 33. Test drug <ul><li>The patch consisted of a 3 * 5 cm polyethylene pouch that was filled with grass pollen extract in Vaseline. The side of the pouch that faced the skin was perforated. The pouch was held onto the skin by a self-adhesive tape. </li></ul>J Allergy Clin Immunol 2009;124:997-1002
  34. 34. Statistical analysis <ul><li>detect changes in symptom scores of NPTs </li></ul><ul><ul><li>from baseline ( intragroup ) </li></ul></ul><ul><ul><li>between allergen and placebo group </li></ul></ul><ul><li>Efficacy </li></ul><ul><ul><li>increase of threshold dose in NPTs of > 0.8 (log 10) from the baseline ranks and a difference of 0.9 (log 10) between allergen treatment and placebo </li></ul></ul><ul><li>2-tailedWilcoxon signed-rank test for related samples or with the exact Mann-Whitney U test for independent samples. </li></ul>J Allergy Clin Immunol 2009;124:997-1002
  35. 35. Results J Allergy Clin Immunol 2009;124:997-1002
  36. 36. Safety and tolerability 10 pts . used topical corticosteroids for total duration of 13 +/- 20 days J Allergy Clin Immunol 2009;124:997-1002
  37. 37. Nasal provocation <ul><li>differences between 2 groups not reach statistical significance September 2006, P = .66; April 2007, P = .55; October-December 2007, P = .15 </li></ul>J Allergy Clin Immunol 2009;124:997-1002
  38. 38. Subjective symptom scores J Allergy Clin Immunol 2009;124:997-1002
  39. 39. Use of rescue medication <ul><li>similar in 2 test groups </li></ul><ul><li>symptoms were significantly better controlled in verum group </li></ul><ul><li>Patients receiving verum used significantly more topical corticosteroids to treat eczema under the patch than the placebo group (P = .04) </li></ul><ul><li>none of placebo-treated patients used topical steroids, </li></ul><ul><li>10 patients from allergen-treated group (47.6%) applied topical steroids. </li></ul>J Allergy Clin Immunol 2009;124:997-1002
  40. 40. Discussion <ul><li>in 1950s, Blamoutier performed allergen-specific immunotherapy by needle scarification of the volar forearm in an area 4 * 4 c m 1 </li></ul><ul><li>Blamoutier observed formation of wheal-like plate, and majority of treated patients experienced improvement or complete relief from hay fever for 3 days - 3 weeks 2 </li></ul>1. Presse Med 1959;67:2299-301 2. Acta Allergologica 1965;XXI:261-7.
  41. 41. Discussion <ul><li>scratching enhances allergen penetration into epidermis and activates keratinocytes ( allergen-pulsed Langerhans cells ) leave epidermis and migrate into regional LN for stimulation of l Ø </li></ul><ul><li>In this study, replaced scarification with adhesive tape stripping method </li></ul><ul><li>Tape stripping induces bystander effect mediated by keratinocyte-derived proinflammatory cytokines </li></ul><ul><li>inducing secretion of IL-1, IL-6, IL-8, andTNF-a </li></ul><ul><li>induce production of IL-12 and IFN-g in skin </li></ul><ul><li>increase expression of MHC class II, CD86, CD40,CD54, and CD11c on Langerhans cells </li></ul><ul><li>enhanced expression of TLR 9 in keratinocytes, producing an environment favoring induction of allergy-protective immune responses mediated by Langerhans cells </li></ul>J Allergy Clin Immunol 2009;124:997-1002
  42. 42. Limitation of study <ul><li>Most patches applied at home, quality control of correct application difficult. </li></ul><ul><li>8 patches applied during pollen season, clear distinction between hay fever symptoms and systemic allergic reactions more difficult than first 4 patches applied before pollen season. </li></ul><ul><li>score improvements of actual symptoms compared with those of previous pollen seasons may contain recall bias, same for both placebo and verum patients. </li></ul><ul><li>grass pollen patches induced eczema contrast with placebo, one may argue that blinding of study was limited. Occurrence of eczema, however, had no influence on study outcome, because those verum patients with eczema at application site showed no significantly better improvement (48% +/- 20%) than those verum patients without eczema (57% +/- 23%). </li></ul><ul><li>At visit 3, a sample size of 35 required to yield statistically significant result with power of 80% . Although sample size at visit 3 was only 1 patient fewer than required—that is,34, patient numbers at visits 4 and 5 were only 26 and 30, respectively. </li></ul>J Allergy Clin Immunol 2009;124:997-1002
  43. 43. Limitation of study <ul><li>grass pollen patches induced eczema contrast with placebo, one may argue that blinding of study was limited. </li></ul><ul><li>Occurrence of eczema no influence on study outcome, because verum pts . with eczema at application site showed no significantly better improvement (48% +/- 20%) than verum pts . without eczema (57% +/- 23%). </li></ul><ul><li>At visit 3, sample size of 35 required to yield statistically significant result with power of 80% . Although sample size at visit 3 —that is,34, at visits 4 and 5 were only 26 and 30, respectively. </li></ul>J Allergy Clin Immunol 2009;124:997-1002
  44. 44. Discussion <ul><li>expect symptom amelioration to last longer than the 1½ years of observation time in this study, but longer studies will be necessary to evaluate longevity of the treatment effect. </li></ul><ul><li>In conclusion, </li></ul><ul><ul><li>first trial in human beings suggested that epicutaneous allergen immunotherapy was safe, well tolerated, and significantly stronger symptom amelioration than placebo. </li></ul></ul><ul><ul><li>epicutaneous immunotherapy could also be used to treat other IgE-mediated allergies. </li></ul></ul><ul><ul><li>Because needle-free and can be applied at home, epicutaneous allergen administration may represent promising alternative to other methods of immunotherapy. </li></ul></ul>J Allergy Clin Immunol 2009;124:997-1002
  45. 45. Conclusion <ul><li>meta-analysis => useful both Sc and SL IT </li></ul><ul><li>Immunological mechanism </li></ul><ul><ul><li>Regulatory T cell </li></ul></ul><ul><ul><li>IgG blocking Ab </li></ul></ul><ul><li>Epicutaneous immunotherapy </li></ul><ul><ul><li>Novel and interest </li></ul></ul><ul><ul><li>may be effective and causative treatment against IgE-mediated allergies that is safe and encourages patient compliance </li></ul></ul>

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