ALLERGEN SPECIFIC IMMUNOTHERAPY: EFFICACY & NEW DEVELOPMENTS Prof. Dr. Nerin N Bahçeciler Önder Near East University Hospital Division of Pediatric Allergy & Immunology, Nicosia, Cyprus Montenegro, 2017

Flow Efficacy – META-ANALYSES /PP / GUIDELINES Immunological mechanism Long-term efficacy SCIT or SLIT? Clinical studies Tablet /drop / injection ?? IT in polysensitized patient New developments Conclusions

META-ANALYSES: Asthma / AR Seasonal / Perreniel CLINICALLY EFFICIENT

SCIT: Long-term Efficacy PAT (Preventive Allergy Treatment) Aim: Does SCIT prevent development of ASTHMA in children with AR sensitized to pollens? Duration:: 3 yrs SIT astım gelişimini engelliyebilir mi? 7-13 yasında çocuklar ,Avusturya,Danımarka,Fınlan,Almanya ve Isvec den 205 çocuk 6-14 yas arası.. 3 yıl IT sonrası kontrol grupta anlamlı derecede fazla astım hastası bulundu. IT öncesi hastaların %20 sinde astım zaten vardı. Astımlı olmayan hastalar arasında SIT alanlarda 3 yıl sonra daha az astım semptomu vardı. Method: randomized 208 AR children -92 Controls -97 SCIT Moller et al. JACI, 2002

PREVENTED DEVELOPMENT OF ASTHMA

IMPROVEMENT IN ARC SYMPTOMS

Prospective open controlled J Allergy Clin Immunol 2010:126:969. Drug ANNUALLY SMS Prick test PC20 Nasal Eo HDM+ AR/Asthma Adults f/up 15 years 3 y SLIT 4 y 5 y J Allergy Clin Immunol 2010:126:969.

Symptom-Medication Scores long-term efficay with > 4 yrs treament

% of patients with ≤1 new sensitization prevents new sensitizations in long-term

Durham RS et al. J Allergy Clin Immunol 2012:129:717.

SMS during pollen season

Persistence of immunological tolerance Long-term efficacy of SLIT Tablets Clinical parameters Immunological tolerance

SCIT or SLIT? Head-to-head comparison Few studies comparing Efficacy? Adult / children Safety Long-term efficacy? Immunological mechanisms?

Comparable efficacy

Keles S,Bahceciler NN. J Allergy Clin Immunol 2011;128(4):808.

Steroid sparing & asthma attacks Keles S,Bahceciler NN. J Allergy Clin Immunol 2011;128(4):808.

SCIT vs SLIT: Differences in immunulogic mechanism INCREASE IN SLIT : IL-10, TGF-b SCIT : IL-10, TGF-b, IgG4 Keles S,Bahceciler NN. J Allergy Clin Immunol 2011;128(4):808.

Improvement in SMS with 2 yrs SLIT & SCIT

Improvement in nasal provocation

Comparison of Il-10 & specific IgG4 responses Both increase IL-10 Increase in IgG4 less and later in SLIT

ASTMA / AR SMS SCIT comparable SLIT

SCIT specific IgG4 response SCIT SLIT SCIT SLIT IgG4 response in long-term SCIT

SCIT compared to SLIT Clinical efficacy Earler in SCIT Comparable after 1 yr T cell response IL-10, TGF-B comarable Antibody responses More IgG4 response in SCIT IgA in SLIT?

SLIT OR SCIT? PATIENT-DOCTOR COOPERATION PATIENT-BASED DON’T GENERELİZE

POLISENSITIZATION Sensitization status in allergy patients %25-75 of PATIENTS POLISENSITIZED

NOMENCLATURE - DIAGNOSTIC TECHNIQUE protein allergenic molecule Modificato da Aalberse et al. Allergy, 2001 epitope “allerjen” ALLERGEN SOURCE ALLERGEN SPT MOLECULE SP-IgE B-CELL EPITOPE COMPONENT MOLECULAR Dg (CMD) POLYALLERGIC / POLYSENSITIZED / CO-SENSITIZATION

POLYALLERGIC / POLYSENSITIZED / CO-SENSITIZATION SHARED MOLECULAR STRUCTURE PSODO POLYSENSITIZED SHARED STRUCTURE DIFFERENT STRUCTURE DIFFERENT MOLECULAR STRUCTURE REAL POLYSENSITIZED Bianchi A, et Al. Rivista di Immunologia e Allergologia Pediatrica 01/2011 • 12-19

Grass Birch Mugwort SHARED MOLECULAR ST. PSODO POLYSENSITIZED PATIENT 1 Grass Birch profilin CBP Phl p 2 Phl p 1 Phl p 4 Phl p 5 Phl p 6 polcalcin profilin CMD histamine grass birch mugwort ctr negative Prik test Mugwort profilin CBP PRIK: POLYSENSITIZED CMD: MONOALLERGIC

DIFFERENT MOLECULAR St. REAL POLYSENSITIZED HASTA 2 Grass Birch Phl p 2 Phl p 1 Bet v 1 Phl p 5 Phl p 4 Phl p 6 Phl p 7 Bet v 4 Phl p 12 Bet v 2 Mugwort histamine grass birch mugwort ctr negative SPT Art v 5 Art v 4 CMD SPT: Polisensitized CMD: Poliallergic Art v 1

IT PRESCRIPTION CHANGED IN %56.8 OF PATIENTS AFTER CMD IT PRESCRIPTION CHANGED IN %56.8 OF PATIENTS PRİK CMD

APPROACH TO POLY-ALLERGIC PATIENT AR AND / OR MILD-MODERATE ASTHMA Q 1- SENSITIZATION STATUS? [SPT, sIgE, CRD, Hx] 1 ALLERGEN 2≤ ALLERGENS MONOSENSİTİZED POLİSENSİTİZED Q 2- NUMBER OF ALLERGENS CLINICALLY IMPORTANT? Test results and clinical correlation] MONOALLERGIC POLYALLERGIC

ALGORYTHM FOR IT IN POLYALLERGIC PATIENT 2 OR MORE= POLYALLERGIC Q 1- NUMBER OF ALLERGENS RESPONSIBLE FOR SYMPTOMS WHICH MODE OF IT? PATIENT-PHYSICIAN COOPERATION ONE 2 OR MORE SIT WITH 1 ALLERGEN MULTI IT Q 2- ARE ALLERGENS HOMOLOGOUS? START WITH MOST CLINICALLY RELEVANT ALLERGEN YES NO 2 SEPERATE AIT or 1 HOMOLOGOUS MIXTURE 2 SEPERATE AIT or MIXTURE IN SPECIAL CASES*

ALLERGEN SELECTION IN POLY-ALLERGIC PATIENT (Homologous) BIRCH or FAGALES OLEACEAE CUPRESSACEAE GRASSES AND CEREAL WEED POLLEN MITES (≠ SOURCES) VENOM DANDERS MOULDS 1 AIT 2 AIT &/or mixtures 2 AIT Then when AIT is with 2 allergens sources indicated? When 2 allergens are necessary we must evaluate if a mix or parallel AIT will be used. Here the 3 key parameters to take into account. Please note that from a practical point of view when mix is used there is no justification to change the dose. It means that for two allergens the mixture should be ½+ ½ Demoly P et al. Allergy Asthma Clin Immunol 2016

Novel Approaches:Expectations Improved Efficacy and Safety?? UNMET NEED CONFIRMATION BY PHASE 3 STUDIES

CONCLUSIONS SCIT /SLIT efficient in AR and ASTHMA in ADULT / CHILDREN SCIT earlier clinical efficacy side effects more SLIT later clinical efficacy negligible side effects SLIT SCIT long-term efficacy SCIT vs SLIT slight differences in immunological responses Tablet /drop /SC effiicient - PATIENT BASED CHOICE Novel Developments: CRD in differentiation of Pollyallegy/monoallergy New therapeutic approaches to improve efficacy and safety