1. Monotherapy for the polysensitized patient Noel Rodriguez-Perez, MD Professor of pediatrics State University of Tamaulipas, Mexico

2. Monotherapy for the polysensitized patient  Objectives  To review the evidence for efficacy of immunotherapy with the more prevalent single allergen.  To highlight the importance of dosing and optimal concentration for efficacy.

3. 33 % 41.2 % 41.4% 28.8 % 22.6 % 36.4 % 29.7 % 39.6 % 45.4 % 37.2 % 49.1 % 21.4 % 51.9 % Prevalence of sensitization by testing 9 allergens Bousquet PJ. Clin Exp Allergy. 2007 37: 780-7. Whole population: 35.6% /11 355 subjects were sensitized

4. Arbes SJ. J Allergy Clin Immunol 2005; 116: 377-383 Prevalences of positive SPT to 10 allergens in the US National Health and Nutrition Examination Surveys III NHANES III  10,508 subjects tested to 10 allergens between 1988-1994  54.3% + SPT to 1 or more allergens  15.5% + SPT to a single allergen  38.8% + SPT to 2 or more allergens Mean 3.5, median 3  HDM (28%), Perennial rye (27%), Short ragweed (26%), Cockroach (26%), Bermuda grass (18%) Percentage (%) Number of sensitizations No sensitized Monosensitized 2 or more sensitizations

5.  Retrospective analysis of all sIgE tests in children 0–18 yrs  9044 children tested. The ImmunoCap. sIgE ≥0.35 kU/l.  60.1% were not sensitized  39.9% were sensitized to 1 or more allergens: 31.1% + sIgE to a single allergen 47.4% + sIgE to 2 to 4 allergens 21.5% + sIgE to 5 or more allergens de Jong AB. Pediatr Allergy Immunol 2011; 22: 166-71 % within age group Age (years) Sensitization patterns to allergens in Childhood No sensitized Monosensitized 2 or more sensitizations

6. Clinical characteristics of polysensitized patients Characteristics of polysensitized patients wit AR. The POLISMAIL study (Italy)  418 subjects, age 3.5–65 years  52.6% had AR and 47.4 had AR and asthma.  90% of patients were polysensitized (3.6 allergns)  Polysensitized patients had more severe symptoms Ciprandi G. Eur Ann Allergy Clin Immunol 2008; 40: 77-83. Aeroallergen sensitization in asthmatics  SPT to 1338 subjects 12-65 YoA. with asthma  95% were sensitized to 1 or more allergens 14% + sIgE to a single allergen 81% + sIgE to 3 or more allergens Average of +SPT 5 allergens Craig TJ. J Allergy Clin Immunol 2008; 121: 671-7 Mean number of positive skin tests Number of cases of AR or AR + Asthma Number of sensitizations Age group

7. The average allergic patient is polysensitized

8. Canonica GW. WAO Journal 2009; 2: 233-281.

9. Is specific immunotherapy with single allergen effective in polysensitized patients?

10. Sublingual immunotherapy

11. Response to sublingual immunotherapy with grass pollen extract: Monotherapy versus combination in a multiallergen extract  Methods  Single-center, randomized, double-blind, placebo-controlled trial with SLIT.  After an observational grass season, SLIT was administered for 10 months to 54 patients randomized to 1 of 3 arms:  Placebo  Timothy extract (19 μg Phl p 5/day) as monotherapy  Same dose of Timothy extract plus 9 additional pollen extracts.  Outcomes included: Symptom and medication scores, titrated nasal challenges, titrated skin prick tests, sIgE, IgG4 and INF-g. Amar SM. J Allergy Clin Immunol 2009; 124: 150-156

12. Response to sublingual immunotherapy with grass pollen extract: Monotherapy versus combination in a multiallergen extract Titrated nasal challenge t Skin Prick Tests ** * *  Log 10 Dose (BAU/mL) Monotherapy TimothyMultiallergen ITPlacebo

13. Amar SM. J Allergy Clin Immunol 2009; 124: 150-156 Response to sublingual immunotherapy with grass pollen extract: Monotherapy versus combination in a multiallergen extract Timothy specific IgG 4 *  Log 10 IgG 4 (µcg/mL) Monotherapy TimothyMultiallergen ITPlacebo

14. Lee JE. Ann Allergy Asthma Immunol 2011; 107: 79–84. Efficacy of sublingual immunotherapy with house dust mite extract in polyallergen sensitized patients with allergic rhinitis  Objective  To compare the efficacy of SLIT with standardized HDM extract in monosensitized and polysensitized patients with allergic rhinitis.  Methods  This study was a prospective case series conducted at a tertiary referral center.  Patients with allergic rhinitis sensitized only to HDM were compared with patients sensitized to HDM and other unrelated allergens after 1 year of SLIT with house dust mite extract.  Medication scores (AMS) and total nasal symptoms score (TNSS), including rhinorrhea, sneezing, nasal obstruction, and itchy nose, were evaluated before and 1 year after SLIT.

15. Lee JE. Ann Allergy Asthma Immunol 2011; 107: 79–84. Efficacy of sublingual immunotherapy with house dust mite extract in polyallergen sensitized patients with allergic rhinitis Allergic symptoms in the monosensitized group Allergic symptoms in the polysensitized group p < 0.001 Symptoms scores Pre-treatment Post-treatment

16. Lee JE. Ann Allergy Asthma Immunol 2011; 107: 79–84. Efficacy of sublingual immunotherapy with house dust mite extract in polyallergen sensitized patients with allergic rhinitis Comparison of changes symptoms score and medication score between the 2 groups. Total nasal symptom score (TNSS)Antiallergic medication score (AMS) Pre-treatment Post-treatment

17. Ciprandi G. J Investig Allergol Clin Immunol 2010; 20: 274-9. Sublingual immunotherapy in polysensitized patients: effect on quality of life  Methods  167 polysensitized patients with allergic rhinitis were prospectively evaluated  QOL was measured in all cases with the Rhinoconjunctivitis Quality of Life Questionnaire at baseline and after 1 year of SLIT  The mean number of sensitizations per patient was 3.65  SLIT using one extract was given to 123 patients (73.6%), with 2 extracts to 31 patients (18.6%), and with more than 2 extracts to 13 patients (7.8%)

18. Ciprandi G. J Investig Allergol Clin Immunol 2010; 20: 274-9. Sublingual immunotherapy in polysensitized patients: effect on quality of life Changes in health-related quality of life scores before and after sublingual immunotherapy Mean Scores * ** * * * *

19. Radulovic S. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD002893. Sensitized to 2 or more allergens ArianoBowen PanznerDrachenberg Di RienzoLa Rosa PajnoDurham Dahl 2006 aBufe HordijkRoder NelsonPradalier Dahl 2006 bVourdas OttBufe ValovirtaLima AndreAmar WahnHirsh Didier Monosensitized Passalacqua 2006Guez Passalacqua 1998Marcucci FelizianiTroise CasanovasPassalacqua 1999 D’AmbrosioBahceciler CaffarelliVoltolini No data available CaoDubakiene Taride Blay PfaarPeter TonnelRolinck-Werninghaus Palma CarlosSmith WessnerVervloet

20. Didier A. J Allergy Clin Immunol 2007; 120: 1338-45. Optimal dose, efficacy, and safety of once-daily SLIT with a 5 –grass pollen tablet for seasonal allergic rhinitis Placebo100 IR300 IR500 IR Randomized156157155160 ITT148142136143 PP136132123133 Age (y)29.1 ± 7.6029.3 ± 6.9028.7 ± 7.3430.4 ± 7.45 Sex (% male)59.551.454.462.2 Body mass index (kg/m 2 )23.7 ± 3.5423.8 ± 3.5924.5 ± 4.1324.0 ± 3.91 Polysensitized patients (%)57.454.951.554.5 Patients with asthma (%)8.89.911.010.5  Randomized, double-blind, placebo-controlled study  628 adults with grass pollen ARC received 1 of 3 doses of a standardized 5–grass pollen extract, or placebo, administered sublingually using a once-daily tablet formulation  The treatment was initiated 4 months before the estimated pollen season and continued throughout the season  Outcomes: ARC Total Symptom Score,(6 most common symptoms), rescue medication use, quality of life, and safety

21. Durham SR. J Allergy Clin Immunol 2010;125:131-38. Long-term clinical efficacy in grass pollen–induced RC after treatment with SQ-standardized grass allergy immunotherapy tablet Active groupPlacebo group Year 3Year 4Year 3Year 4 SubjectsNo. (%)170 (100)157 (100)138 (100)126 (100) SexMale, no. (%)109 (64)101 (64)86 (62)81 (64) Women, N (%)61 (36)56 (36)52 (38)45 (36) Age at inclusionMean (SD)35.7 (9.87)36.4 (9.89)36.4 (9.86)36.8 (9.86) Median35.036.035.036.0 SensitizationsGrass155 (100)139 (100)126 (100)114 (100) Birch60 (39)57 (41)50 (40)45 (39) Weed34 (22)31 (22)27 (21)23 (20) Cat37 (24)32 (23)33 (26)26 (23) Dog56 (36)69 (50)58 (46)66 (58) Horse9 (6)6 (4)14 (11)8 (7) Der pt26 (17)24 (17)25 (20)24 (21) Der fa17 (11)17 (12)15 (12)16 (14) Alternaria21 (14)21 (15)12 (10)7 (6)  A randomized, double-blind, placebo-controlled, phase III trial  257 Adults with a history of moderate-to-severe grass pollen induced rhinoconjunctivitis inadequately controlled by symptomatic medications were included.  Efficacy end points were rhinoconjunctivitis symptom and medication scores, quality of life, and percentages of symptom and medication free days.

22. Injective immunotherapy

23. Roberts G. J Allergy Clin Immunol 2006;117:263-8. Grass pollen immunotherapy as an effective therapy for childhood seasonal allergic asthma  A randomized, double-blind, placebo-controlled study assessing the efficacy of grass pollen SIT over 2 pollen seasons was performed.  Children (3-16 years) with a history of seasonal allergic asthma sensitized to grass pollen (P pratense) and requiring at least 200 μg of inhaled beclomethasone equivalent per day were enrolled.  The primary outcome measure was a combined asthma symptom-medication score during the second pollen season.  Secondary outcome measures included end- point titration skin prick testing and conjunctival and bronchial provocation testing to allergen, sputum eosinophilia, exhaled nitric oxide, and adverse events. Active groupPlacebo group All subjects18 (100.0%)17 (100.0%) Female subjects5 (27.8%)5 (29.4%) Ethnic origin White/English/Scottish/Welsh12 (66.7%)13 (76.5%) Black African/Caribbean/Other2 (11.1%)1 (5.9%) Indian subcontinent4 (22.2%)1 (11.8%) White other0 (0.0%)1 (5.9%) Mean age (SD)9.2 (4.4)10.6 (2.9) Mean weight (SD)37.3 (22.0)39.3 (12.1) Mean height (SD)134 (27.2)139 (17.8) Summer asthma Mild symptoms0 (0.0%) Moderate symptoms15 (83.3%)15 (88.2%) Severe symptoms3 (16.7%)2 (11.8%) Summer rhinoconjunctivitis Mild symptoms3 (16.7%)0 (.0.0%) Moderate symptoms15 (83.3%)14 (82.4%) Severe symptoms0 (0.0%)3 (17.6%) Atopic dermatitis9 (50.0%)5 (29.4%) Symptoms on exposure to tree pollen2 (11.1%)0 (0.0%) Symptoms on exposure to house dust mite5 (27.8%)2 (11.8%) Symptoms on exposure to animal hair and dander 8 (44.4%)6 (35.3%) Median (IQR) daily inhaled beclomethasone400 (400-400)400 (200-400) Mild symptoms had only a minimal effect on daily life, moderate symptoms were defined as having a significant effect on at least 50% of days, and severe symptoms have a major effect on life with daily symptoms. Subjects only had mild symptoms on exposure to tree pollen or house dust mite. Details of subjects

24. Roberts G. J Allergy Clin Immunol 2006;117:263-8. Grass pollen immunotherapy as an effective therapy for childhood seasonal allergic asthma First seasonSecond season Active groupPlacebo grouppActive groupPlacebo groupp No. of subjects1817–1817– Median symptom scores (IQR) 0.9 (0.4-1.8)1.5 (0.5-2.3).520.5 (0.1-0.8)0.8 (0.4-2.1).07 Median medication scores (IQR) 0.6 (0.0-1.5)1.4 (0.5-1.9).210.5 (0.0-1.7)1.2 (0.0-3.2).56 Median symptom- medication scores (IQR) 1.0 (0.7-1.8)1.5 (0.4-2.2).350.5 (0.1-0.9)1.0 (0.4-2.0).04 Grass pollen counts and symptom-medication scores for the second summer Asthma symptom-medication scores Change in cutaneous allergen reactivity Change in conjunctival allergen reactivity Change in bronchial allergen reactivity

25. Frew A. J Allergy Clin Immunol 2006; 117: 319-25. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis  Double-blind, randomized, placebo-controlled trial  410 subjects with seasonal ARC were randomized: 203 to 100,000 SQ-U (20mcg Phl p5) 104 to 10,000 SQ-U (2mcg Phl p5) 103 to placebo  347(85%) completed treatment. Grains/m3 Score Pollen Symptoms week Peak season  276 / 347 (78%) subjects were polysensitized  The polysensitized group showed a similar degree of improvement in symptoms, medication use, RQLQ, and VAS scores compared with the whole study group.  Both active doses were effective, but 100,000 SQ-U was more effective than 10,000 SQ-U

26. Shamji MH. Allergy 2011; DOI: 10.1111/j.1398-9995.2011.02745.x. Functional rather than immunoreactive levels of IgG(4) correlate closely with clinical response to grass pollen immunotherapy Combined symptom and medication scores during the pollen season  This is an 8-month dose-response randomized double-blind placebo- controlled study  221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100,000 SQ-U, 10,000 SQ-U or placebo injections.  Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study.  Allergen-specific IgG(4) titres and IgG-associated inhibitory activity were evaluated. Adjusted mean (SE) Difference vs Placebo (95% CI) 100 000 SQ-U vs 10 000 SQ-U (95% CI) Combined symptom and medication scores whole season Alutard 100 000 SQ-U (n = 112) 5.84 (0.57) −2.80 (−4.44, −1.15) P = 0.001 −1.21 (−2.86, 0.44) P = 0.15 Alutard 10 000 SQ-U (n = 54) 7.05 (0.76) −1.58 (−3.50, 0.34) P = 0.11 Placebo (n = 55) 8.63 (0.77) Combined symptom and medication scores peak season Alutard 100 000 SQ-U (n = 112) 7.94 (0.76) −4.57 (−6.79, −2.35) P < 0.0001 −2.62 (−4.84, −0.40) P = 0.021 Alutard 10 000 SQ-U (n = 54) 10.6 (1.02) −1.95 (−4.53, 0.63) P = 0.14 Placebo (n = 55) 12.5 (1.03)

27. Shamji MH. Allergy 2011; DOI: 10.1111/j.1398-9995.2011.02745.x. Functional rather than immunoreactive levels of IgG(4) correlate closely with clinical response to grass pollen immunotherapy Subcutaneous allergen immunotherapy is associated with increases in Phleum pratense- specific IgE antibodies and blunting of seasonal increases in IgE antibodies. Time course and dose dependency of SC grass pollen immunotherapy–induced changes in allergen-specific IgG 4 antibodies and serum inhibitory activities. Phleum pratense-specific IgG 4 antibody levels were measured by enzyme-linked immunosorbent assay. Serum inhibitory activity was measured by (B) IgE-FAB assay ADVIA Centaur automated analyser measurement of IgE levels that included a ‘no-wash’ step to measure IgE-blocking factor.

28. Calderon MA, Boyle RJ, Penagos M, Sheik A. Immunol Allergy Clin North Am. 2011;31(2):159- 73, vii. Immunotherapy: The Meta-Analyses. What have we Learned?

29. Th 2 Th 1 i T reg Th 9 Th 17

30. Monotherapy for the polysensitized patient  CONCLUSIONS  The majority of AR and asthma patients are polysensitized  SIT (SCIT and SLIT) with single allergen is effective in polysensitized patients  Further head-to-head comparisons of the efficacy of SIT in polysensitized vs. monosensitized patients are required in the context of RCTs.  “Decision must be based on the allergen which causes:”*  The longest duration of symptoms per year  The most severe symptoms  A major impact on quality of life  Which is more difficult to avoid * Allergy 2010; 65: 1525–1530.