sublingual immunotherapy

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Sublingual immunotherapy Presented by Theerapan Songnuy, MD. Sep14, 2012

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  • 1. Sublingual ImmunotherapyMechanism and Applicationson Food AllergyTheerapan Songnuy M.D.

2. Sublingual Immunotherapy ( SLIT) Definition Mechanism Clinical application Future trend 3. Definition Allergen specific immunotherapy :- administering gradually increasingdoses of the specific allergen to reducethe clinical reaction - the only treatment focusing the causesof hypersensitivityMarseglia G L, Incorvaia C, Rosa M L, Frati F & Marcucci F. Sublingual immunotherapy in children : facts and needs. Italian Journal of Pediatrics 2009, 35:31 4. Definition Subcutaneous immunotherapy ( SCIT) - traditional route but risk for systemic reaction Sublingual immunotherapy ( SLIT)- non injection route for specific immuno-therapyMarseglia G L, Incorvaia C, Rosa M L, Frati F & Marcucci F. Sublingual immunotherapy in children : facts and needs. Italian Journal of Pediatrics 2009, 35:31 5. Why SLIT ? SCIT : not widely accepted due to - Possible severe symptoms - Inconvenience of injection - Frequent office visits Less than 5% of all allergic patients receiveimmunotherapy Compliance is even poorer : more than 2/3 ofpatients dropped out within a year of initiationMorris MS., Lowery A., Theodoropoulos DS., Duquette RD. & Morris DL.Quality of Life Improvement with Sublingual Immunotherapy : A Prospective Study of Efficacy. Journal of Allergy. 2012, Article ID 253879, 6 pages doi: 10.1155/2012/253879.Brown D., Hankin C., Scott D. et al. Characteristic Association with Premature Discontinuation of Allergen Immunotherapy among Children and Adults: Finding from a large, Single Specialty Allergy Practice . Journal of Allergy and Clinical Immunology 6. Mechanism of SLITScadding G, MRCPa,b,*, Durham SR, Immunol Allergy Clin N Am 31 (2011) 7. Mechanism of SLIT oral mucosa has a degree of immune privilege & potentiallytolerogenic antigen-presenting cells & T cells Intraoral environment is protected from inflammatoryresponses by high levels of secretory IgA, antimicrobialpeptides in saliva, and commensal bacteria All factors may be important in facilitating tolerogenicresponses to SLITNovak N, Haberstok J, Bieber T, et al. The immune privilege of the oral mucosa.Trends Mol Med 2008;14(5):1918 . 8. Immune Changes Associated withSLIT Allergen specific immunotherapy reducesimmediate and late-phase allergen-induced symptoms Processing by humoral and cellularmechanism Immune mechanism leads to clinicaltoleranceScadding G & Durham S. Mechanism of Sublingual Immunotherapy. Journal of Asthma. 2009.46;4:332-334 9. Immune Changes Associated withSLIT Antibody Responses- After SLIT initiation, decreasing serial IgElevels & prevent seasonal sIgE rising- Eliciting IgG1, IgG4 blocking Ab bycompeting with IgE for allergen binding- SLIT also down regulate mast cell & B cellactivationScadding G & Durham S. Mechanism of Sublingual Immunotherapy. Journal of Asthma. 2009.46;4:332-334 10. Immune Changes Associated with SLITPro-inflammatory Cells : - Reduced recruitment & activation of inflammatory cells inskin, nose, eye & mucosaT-Cell Responses : - Shifting from Th2 >>> Th1 with the stimulation of IFNgamma producing T lymphocyte - Inducing Treg ( inhibit effector mechanism) - Treg1 : produce IL-10 & TGF-beta - IL-10 : decrease IgE production, inhibit Th2 cytokines - TGF-beta : enhance IgG4 & IgA production, inhibit Th2cytokinesScadding G & Durham S. Mechanism of Sublingual Immunotherapy. Journal of Asthma. 2009.46;4:332-334 11. SLIT applying on Food Allergy Sublingual Immunotherapy for Peanut Allergy:Clinical and Immunologic Evidence ofDesensitization - Peanut is one of the most common and severe food allergy* - Less than 20% will outgrow the allergy naturally - Current standard of care is strict avoidance*Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA, Burks W, Wood RA. The . natural history of peanut allergy. J Allergy Clin Immunol 2001;107:367-74 12. Sublingual Immunotherapy for PeanutAllergy: Clinical and Immunologic Evidenceof Desensitization SCIT is used successfully in allergic rhinitis & asthma But for food allergy, unacceptable due to systemic reaction* Oral immunotherapy ( OIT) The first study using SLIT in treatment of peanut allergy Inchildren Double-blind, placebo-controlled trial Aim to evaluate safety & efficacy of peanut SLIT after 12months of therapy and observe immunologic changes*Nelson HS, Lahr J, Rule R, Bock A, Leung D. Treatment of anaphylactic sensitivity to peanuts byimmunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol 1997; 124: 292-300,e1-97. 13. MethodsPrimary end point : reaction threshold to peanut ingestion after 12 months oftherapySecondary end point : frequency, severity, ofside effect to dosing, immunologicchanging(sIgE, IgG4 level, basophilactivation, skin test,cytokines level,interferon gamma, Treg cells)Kim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1 14. MethodsInclusion criteria - Participants aged 1-11 y - physician- documented clinical history ofreaction to peanut within 60 min of ingestion- CAP-FEIA peanut sIgE > 7 kU/LExclusion criteria- severe anaphylaxis to peanut or need ICU careKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1 15. Methods- Peanut and placebo sublingual drops from Greer Lab. Treatment gr. : crude peanut extract (1:20w/v)dissolved in 0.2% phenol & 50%-55%glycerinated saline ( conc. 5000 ug/ml)Ara h2 protein conc. 6 % Placebo gr. : glycerinated saline & phenol withcaramel coloringKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1 16. SLIT PROTOCOL- Strict peanut-free diet- Carry on epinephrine autoinjector- Restrict eating 15 min before & 30 min after dosing- Drug was administered sublingually held 2min. then swallowedKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640- 646.e1 17. SLIT PROTOCOL Escalation phase- initial dose is 0.25 ug of peanut protein, 2-hr observation time- return for 13 biweekly visits- dose were increased 25-100% until max. of 2,000 ug of peanut protein- after each visit, continuing the same dose at home for 2 wkKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1 18. Sublingual Immunotherapy for Peanut Allergy: Clinical and Immunologic Evidence of Desensitization Maintenance phase - the 2000-ug dose was used based on pilot study - continue daily dose at home for 6 monthsDouble-blind placebo-controlled food challenge - 9 increasing dose peanut protein mixed with vehicle food - doses were given q 20 min until 2500 gm( cumulative dose) - placebo portion using oat flour mixed in vehicle food - the outcome was defined as a cumulative dose ingestedbefore symptom occursKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1 19. Results Participants in peanut SLIT gr. increasereaction threshold after ingesting amedian cumulative dose of 1710 gm ofpeanut protein Clinically significant to protect fromaccidental ingestion of peanut ( 100 gm) Association between DBPCFC with alower peanut sIgE levelKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1 20. Results Decreased mast cell and basophil reactivity Peanut-sIgE decrease Peanut-sIgG increase Down-regulation of Th 2 response ( decreaseIL-5 production) Side effect ; oropharyngeal itching ( 9.3% ofdoses ) Epinephrine not requiredKim EH et al.Journal of Allergy and Clinical Immunology. 2011.127;3: 640-646.e1 21. The Safety and Efficacy of Sublingual andOral Immunotherapy for Milk Allergy To compare- safety and efficacy of OIT and SLITfor treatment of cows milk allergy- effect of withdrawal therapy after 1 and 6 wk- mechanistic changes associated with therapy ( sIgE,sIgG4, skin test response, basophil function & intracellularsignaling- Double-blind, placebo-controlled trialKeet CA et al. J Allergy Clin Immunol 2012;129:448-55. 22. The Safety and Efficacy of Sublingual andOral Immunotherapy for Milk Allergy Methods- Open-label randomized study- primary end point : ability to tolerate at least10-fold more milk protein compared withbaseline ( duration 15 months)- secondary end point:-desensitization maintains after 1, 6 wk off treatment- clinical response rate- serious adverse events- changes in biological markersKeet CA et al. J Allergy Clin Immunol 2012;129:448-55. 23. The Safety and Efficacy of Sublingual andOral Immunotherapy for Milk Allergy Participants - aged 6-21 y from pediatric allergy clinic, Johns Hopkins Hospital & Duke U Medical Centre- Inclusion criteria: documented history CMA,sIgE to CM> 0.35 Ku/l , SPT, DBPCFC-Exclusion criteria: severe persistent asthma, pt. on fluticasone, non-allergic medical problem severe anaphylaxis to CM etc.Keet CA et al. J Allergy Clin Immunol 2012;129:448-55 24. SLIT Dosing Initial dosing - low-dose SLIT - continue at home, daily home diary Continued escalation - patient returns q 1-2 wk for dose increase - At 4-weekly SLIT, randomized to 3 gr.1. OITA target dose 2 gm2. OITB target dose 1 gm3. SLIT goal dose of 7 mgKeet CA et al. J Allergy Clin Immunol 2012;129:448-55 25. Keet CA et al. J Allergy Clin Immunol 2012;129:448-55 26. Keet CA et al. J Allergy Clin Immunol 2012;129:448-55 27. Keet CA et al. J Allergy Clin Immunol 2012;129:448-55 28. Keet CA et al. J Allergy Clin Immunol 2012;129:448-55 29. Results Challenge threshold after therapy - increased at least 10 times compared tobaseline, more common in OIT gr.Keet CA et al. J Allergy Clin Immunol 2012;129:448-55 30. Results1. Desensitization vs tolerance - tolerance found in all group, no difference2. Symptoms with dosing -Significant difference in rate of respiratory, GI, & multisystem symptom between SLITand OIT - No difference reaction between OITA andOITBKeet CA et al. J Allergy Clin Immunol 2012;129:448-55 31

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