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Which Patients for Subcutaneous Immunotherapy?

Which Patients for Subcutaneous Immunotherapy?. Harold S. Nelson. MD Professor of Medicine National Jewish Heath University of Colorado Denver School of Medicine Denver, Colorado, USA. Which Patients for Immunotherapy?. Appropriate clinical manifestations.

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Which Patients for Subcutaneous Immunotherapy?

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  1. Which Patients for Subcutaneous Immunotherapy? Harold S. Nelson. MD Professor of Medicine National Jewish Heath University of Colorado Denver School of Medicine Denver, Colorado, USA

  2. Which Patients for Immunotherapy? • Appropriate clinical manifestations. • Demonstrated IgE-mediated sensitivity to relevant aeroallergen(s) • Significant exposure to the relevant allergen(s) • Availability of high quality extract for the relevant allergen(s). • Asthma, if present, adequately controlled.

  3. Present Status of Immunotherapy with Inhalant Allergens: • Common to SCIT & SLIT • Effective in allergic rhinitis, allergic asthma and selected patients with atopic dermatitis • Defined mechanisms • Demonstrated prevention of:- New sensitization in monosensitized subjects- Progression from rhinitis to asthma • Established duration required for:Persistence of efficacy after stopping • Therefore should not be limited to those failing symptomatic treatment.

  4. SCIT versus SLITAdvantages of Each • Favoring SLIT:- Relative safety in subjects with allergic rhinitis and controlled asthma. - Home administration • Favoring SCIT:- Optimal dosing has been determined for many allergens - Efficacy of treatment with mixes of multiple unrelated allergens verified.- Efficacy, at least in the first year, may be greater.

  5. Effective Doses in Double-Blind Studies (Major Allergen)

  6. Studies of the Use of ≥ 2 Allergens in Immunotherapy Reviewed English & non-English literature 1961-2007: • 4 studies with 2-allergen mixes (SCIT & SLIT):Results > placebo and = to single allergen when reported. • 6 studies with > 2 allergen mixes (all SCIT):4 showed clinical efficacy (2 asthma, 2 rhinitis.2 failed to show clinical efficacy. HS Nelson. J Allergy Clin Immunol 2009;123:763-0

  7. Evidence for Effectiveness of Immunotherapy Employing Multiple Allergens Johnstone included all allergens to which the child was skin test positive. He demonstrated a dose dependent improvement in asthma. Pediatrics 1968;l42:793-802 Lowell & Franklin removed or reduced only ragweed in patients’ multi-allergen mixture and demonstrated increased symptoms during the ragweed pollen season.N. Engl J Med1965;273:675-9;JAMA 1967;201:915-7 Reid added only grass or placebo to multiple allergen mixes and showed significant reduction in asthma symptoms during the grass pollen season.J Allergy Clin Immunol 1986;78:590-600

  8. The Value of Hyposensitization Therapy for Bronchial Asthma in Children - A 14-year Study • “Free of Asthma” After 4 years- placebo and lowest dose 18%- 1/5,000 w/v 58%- 1/250 w/v 81% • “Free of Asthma” at end of study (age 16 yr)- placebo and lowest dose 22%- 1/5,000 w/v 66%- 1/250 w/v 78% DE Johnstone, A Dutton Pediatrics 1968l42:793-802

  9. Evidence for Effectiveness of Immunotherapy Employing Multiple Allergens Johnstone included all allergens to which the child was skin test positive. He demonstrated a dose dependent improvement in asthma. Pediatrics 1968;l42:793-802 Lowell & Franklin removed or reduced only ragweed in patients’ multi-allergen mixture and demonstrated increased symptoms during the ragweed pollen season.N. Engl J Med1965;273:675-9; JAMA 1967;201:915-7 Reid added only grass or placebo to multiple allergen mixes and showed significant reduction in asthma symptoms during the grass pollen season.J Allergy Clin Immunol 1986;78:590-600

  10. Effectiveness and Specificity of Ragweed Immunotherapy 1200 800 Total Score 400 0 * * * * * * * 19 26 2 9 16 23 30 7 14 21 28 1963 Aug. Sept. Oct. treated untreated median mean Lowell & Franklin NEJM 1965

  11. Evidence for Effectiveness of Immunotherapy Employing Multiple Allergens Johnstone included all allergens to which the child was skin test positive. He demonstrated a dose dependent improvement in asthma. Pediatrics 1968;l42:793-802 Lowell & Franklin removed or reduced only ragweed in patients’ multi-allergen mixture and demonstrated increased symptoms during the ragweed pollen season.N. Engl J Med1965;273:675-9;JAMA 1967;201:915-7 Reid added only grass or placebo to multiple allergen mixes and showed significant reduction in asthma symptoms during the grass pollen season.J Allergy Clin Immunol 1986;78:590-600

  12. Response to Grass Subcutaneous I.T. 1985 ASTHMA 8 Grass treated Non-grass treated N = 9 P < 0.05 6 MEAN SMS 4 2 0 25 RHINITIS Grass treated Non-grass treated 20 N = 9 P = 0.11 15 MEAN SMS 10 5 0 300 Grass pollen count 200 COUNTS/cm2 100 0 APRIL MAY JUNE MONTHS MJ Reid, et al. J Allergy Clin Immunol 1986;78:590-600

  13. Sheila M. Amar, MD, Ronald J. Harbeck, PhD, Michael Sills, BS, Lori J. Silveira, MS, Holly O’Brien, RN, Harold S. Nelson, MD National Jewish Health, J Allergy Clin Immunol 2009;121:

  14. Single-center, randomized, double-blind, placebo-controlled SLIT for 10 months, 56 subjects randomized to 3 arms - SLIT with timothy pollen extract alone (17 mcg Phl p 5 daily) - SLIT with same dose of timothy extract + 9 additional pollen extracts - SLIT placebo

  15. *Amount added to 10 ml vial for 1 month of treatment *CMD : Timothy approximately 30x SCIT dose (17 mcg Phl p 5 qday), other allergens 15-20x SCIT dose

  16. Multi-allergen Sublingual Immunotherapy:Results • Only 3 “ of rain fell in Denver the first 6 months of 2008 • Accordingly there was little grass pollen, few symptoms and no difference in symptom scores or medication use among the three treatment groups. • There were, however, significant differences in several clinically relevant outcomes.

  17. p=0.03

  18. p=0.001 p=0.04

  19. p=0.005

  20. Evidence for Effectiveness of Immunotherapy Employing Multiple Allergens: Conclusions • Four studies support the clinical effectiveness of subcutaneous immunotherapy employing multiple allergens. • The only study of multiple allergen sublingual immunotherapy raises questions regarding its effectiveness.

  21. 2800 14 Treated Untreated Pollen Count 12 2400 2000 10 8 1600 SYMPTOM SCORE POLLEN COUNT 6 1200 800 4 400 2 26 16 20 24 28 2 6 10 14 18 22 30 4 AUGUST SEPTEMBER OCTOBER 1971 Norman & Lichtenstein JACI 1978;61:370 Pre-seasonal Immunotherapy

  22. Sublingual Immunotherapy for allergic Rhinitis: Systematic Review and Meta-Analysis DR Wilson, M Torres Lima, SR Durham Allergy 2005;60:4-12 • 21 trials involving 959 patients were included, all were DBPC parallel design. • Overall standard mean reduction in- Symptoms - 0.42 (p = 0.002) - Medications: - 0.43 (p = 0.00003) • Insufficient data to analyze for dose.

  23. SMD -0.43 Sublingual immunotherapy for allergic rhinitis: systematic review and meta- analysis. DR Wilson, M Torres Lima, SR Durham. Allergy 2005:60:4-12.

  24. SMD -0.73 Allergen Injection Immunotherapy for Seasonal Allergic RhinitisCalderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S Symptom scores Cochrane Database Syst Rev 2007; (1):CD001936.

  25. Clinical Efficacy of Sublingual and Subcutaneous Birch Pollen Allergen-Specific Immunotherapy: A Randomized, Placebo-Controlled,Double-Blind, Double-Dummy Study MS Khinchi, et al. Allergy 2004;59:45-53 • Subcutaneous maintenance dose contained 3.28 mg Bet v 1 once monthly. • Sublingual maintenance dose contained 49.2 mg Bet v 1 every other day (cumulative dose 225 times SC). • 5 cases of grade 3 or 4 systemic reactions in the s.c. group, two treated with adrenalin. No grade 3 or 4 reactions with SLIC

  26. SLIT versus SCIT Treatment Symptoms Medication* Placebo + .02 + 1.35 SLIT - .36 + .29 SCIT - .75 No change SLIT & SCIT significantly better than placebo, no difference between active treatments. * Pollen counts higher second year MS Khinchi, et al. Allergy 2004;59:45-53

  27. SCIT SLIT Placebo SLIT vs SCIT Comparative Study First Treatment Season Mean Weekly Rhinoconjunctivitis Symptom and Medication Scores Symptom Scores Medication Scores The hatched areas indicate the daily birch pollen count. The rectangles indicate the defined pollen season. Khinchi MS, et al. Allergy. 2004;59:45-53.

  28. Considerations Favoring the Use of Subcutaneous Rather Than Sublingual Immunotherapy • Well-defined effective and ineffective doses have been determined for more allergens. • Multiple-allergen mixes have been shown to be effective in multiple studies. • Where comparisons are available, they suggest greater efficacy for SCIT, at least in the first year.

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