SUBLINGUAL IMMUNOTHERAPY Giovanni Passalacqua Allergy & Respiratory Diseases Dept.Internal Medicine- University of Genoa ITALY.

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SUBLINGUAL IMMUNOTHERAPY Giovanni Passalacqua Allergy & Respiratory Diseases Dept.Internal Medicine- University of Genoa ITALY

THE LITERATURE 66 RDBPC TRIALS 8 RANDOMIZED OPEN TRIALS 6 COMPARATIVE (SLIT vs SCIT) 6 TRIALS IN OTHER DISEASES

10 20 grass HDM parietaria cypress cat ragweed birch other 67%

Less or equal 6 months: 23 studies Less or equal 12 months: 15 studies More than 12 months: 20 studies TREATMENT DURATION < 20 : 4 studies < 50 : 21 studies < 100 : 16 studies PATIENTS ENROLLED < 150 : 11 studies > 150 : 8 studies

10 STUDIES WITH SAMPLE SIZE CALCULATION Durham 2006De Blay, 2007 Dahl 2006Pfaar 2008 Pham Ti 2007Wahn 2009 Roder 2006Ott 2009 Didier 2007Bufe 2009 Skoner 2010Cortellini 2010

Sublingual immunotherapy with once-daily grass allergen tablets: A randomized controlled trial in seasonal allergic rhinoconjunctivitis Durham SR, JACI 2006

Prolonged preseasonal treatment with Grazax improves the clinical efficacy Calderon M et al, Allergy 2007

Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. Dahl et al, JACI 2006 VERSUS PLACEBO: SYMPTOM REDUCTION - 30% MEDICATION REDUCTION - 38% 634 PATIENTS !!!

VS PLACEBO Symptoms -28% (-39%) Medications - 24% (-48%) Efficacy and safety of 5- grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis Wahn 2009

VS PLACEBO Symptoms -34% to –44%

VS PLACEBO Symptoms -24% Medications - 34%

Sublingual immunotherapy for allergic rhinitis. Allergy, Wilson D., Torres Lima I, Durham S. 21 trials

Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients: Meta-analysis of randomized controlled trials. Martin Penagos, Enrico Compalati, Francesco Tarantini, Rodrigo Baena Cagnani, Jose Huerta Lopez, Giovanni Passalacqua and Giorgio Walter Canonica 2006

Meta-analysis of the efficacy of sublingual immunotherapy in allergic asthma in pediatric patients, 3 to 18 years of age. M Penagos, G Passalacqua, E Compalati, C Baena-Cagnani, S Orozco, A Pedroza GW Canonica

SCITSLIT Clinical efficacy: RhinitisIa Clinical Efficacy: AsthmaIa Clinical efficacy: Children (rhinitis) Children (asthma) Ib Ia Prevention of new sensitizationsIbIIa Longterm effectIbIIa Prevention of asthmaIIb ARIA Update on immunotherapy SR Durham and G.Passalacqua JACI 2007 in press

Abramson 2003 AsthmaA-Cp< 0.01 Calamita 2006AsthmaA-CP= 0.07 Penagos 2008AsthmaCP= 0.02 Olaguibel 2005 Asthma /Rhinitis CP= 0.01 Calderon 2007RhinitisAp< 0.01 Penagos 2006RhinitisCp= 0.02 Wilson 2005RhinitisA-Cp= A = adults C = children Specific immunotherapy for respiratory allergy: state of the art according to current meta- analyses. Compalati E et al, Ann Allergy Asthma Immunol 2009 Meta analisi: sintomi SCIT SLIT

49 (OUT OF 60) RDBPC TRIALS SUITABLE FOR POOLING: 2333 SLIT 2256 PLACEBO

SYMPTOM SCORE

MEDICATION SCORE

Symptom Score Rhintis

JACI 2010

No fatal event reported since 1986 SLIT

Author, year Sex (age) Allergen (producer) PhaseOnsetDescription Epineph rine De Groot, 2009 M (13)Grass (Grazax, ALK-Abellò) First dose15 minGeneralized urticaria, swelling of tongue NO De Groot, 2009 F (27)Grass (Grazax, ALK-Abellò) First dose5 minAbdominal cramps, asthma, generalized itching, hypotension YES Blazowski, 2008 F (16)HDM (Staloral, Stallergenes) Maintenance overdose (60 drops) 10 minHypotension- collapse, flushing, urticaria YES Eifan, 2008 F (11)dust mite + grass pollen mix (Stallergenes) Maintenance. 3 minAbdominal pain, chest pain, fever, nausea Not specified Dunski, 2006 F (31)Alternaria, cat, dog grass, ragweed, (Greer) 2 nd day of updosing 5 minAngioedema, dizziness, dyspnea, generalized itching NO Antico, 2006 F (36)LatexEnd of rush buildup 10 minAsthma, generalized urticaria Not specified Anaphylaxis with SLIT

Cox L, Linneman D, Nolte H, Weldon D, Finegold I, Nelson HS. Sublingual immunotherapy: A comprehensive review. J Allergy Clin Immunol 2006; 117: In 41 studies with information on the total number of AEs, 1047 adverse reactions in a total of 386,149 doses were identified (2.7 reactions/1,000 doses). In 49 studies with information on the number of patients, the AEs were 529 per 4378 patients (12%). In the trials that specified the severity of reaction, the occurrence of severe AE was 0.56 per 1,000 doses. Overall, 14 serious AEs probably related to the treatment were found.

AuthorN patsAge rangeFollow- up AE % of patients AE/1,000 doses Di Rienzo years3 years3 %0.1/1,000 Lombardi198> 14 years3 years7.5 %0.5/1,000 Pajno years36 months6 %0.15/1,000 Agostinis363-5 years2 years5 %0.07/1,000 Di Rienzo years2 years5. 6%0.2/1,000 SLIT: POST MARKETING SURVEYS

THE SAFETY OF SUBLINGUAL IMMUNOTHERAPY WITH ONE OR MORE ALLERGENS IN CHILDREN Fabio Agostinis, Marcello Cottini, Carlo Lombardi, Giorgio Walter Canonica, Giovanni Passalacqua, Allergy 2008 in press SINGLE ALLERGEN n (%)MULTI ALLERGENS n (%) Grass140 (82)Grass + pariet6 (2) Parietaria4 (3)Grass+ olive18 (7) Birch14 (9)Grass + birch +alder+hazelnut 220 (87) Ragweed4 (3)Grass + ragweed9 (4) Olive-Grass + mugwort Birch+hazelnut +alder TOTAL172 (100) 253 (100) 415 children, 3-18 years, 272 male

Coseasonal SLIT reduces the development of asthma in children with allergic rhinitis. Novembre E. et al, JACI 2004 SLITNO SLIT NO ASTHMA ASTHMA 79 children Allergic rhinitis only Follow-up: 3 yrs

PREVENTIVE EFFECTS OF SUBLINGUAL IMMUNOTHERAPY IN CHILDHOOD. AN OPEN RANDOMIZED CONTROLLED STUDY MAURIZIO MAROGNA MD 1, D.TOMASSETTI 1, A. BERNASCONI 1, F.COLOMBO 1, ALESSANDRO MASSOLO BS 2, A. DI RIENZO BUSINCO 4, GIORGIO W CANONICA MD 3, GIOVANNI PASSALACQUA MD 3 AND SALVATORE TRIPODI MD 4 1 Pneumology Unit, Cuasso al Monte, Macchi Hospital Foundation, Varese 2 Department of Animal Biology, University of Pavia, Pavia 3 Allergy & Respiratory Diseases,Department of Internal Medicine, Genoa University 4 Pediatric Allergy Unit, S. Pertini Hospital, Rome AAAI 2008, 101: 261

Diary card Visit Skin test MCh challenge 144 SLIT 72 CONTROLS 14 dropout 6 dropout 1 year BASELINE RANDOMIZED PHASE Year 1 PATIENTS 216 Year 2Year 3 * ****** * * * * * 130 SLIT 66 CONT

CONTROLS NS *** baseline3rd year PERSISTENT ASTHMA % PATIENTS SLIT *** baseline3rd year MONOSENSITIZED PATIENTS % PATIENTS