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

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Presentation transcript:

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.  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.

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.

SCIT versus SLIT Advantages 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.

Effective Doses in Double-Blind Studies (Major Allergen) Allergen ExtractMajor AllergenEffective DosesLess or Ineffective doses RagweedAmb a 14 to 24 mcg0.6 & 2 mcg TimothyPhl p 515 to 20 mcg2 mcg D pteronyssinusDer p 17 & 12 mcg0.7 mcg D farinaeDer f 110 mcgNot determined CatFel d mcg0.6 & 3.0 mcg DogCan f 115 mcg0.6 & 3.0 mcg BirchBet v & 12 mcgNot determined AlternariaAlt a 11.6 & 8 mcgNot determined

Studies of the Use of ≥ 2 Allergens in Immunotherapy Reviewed English & non-English literature :  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

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: 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:

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:

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: 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:

Effectiveness and Specificity of Ragweed Immunotherapy ******* Aug.Sept.Oct. treateduntreatedmedianmean 1963 Total Score Lowell & Franklin NEJM 1965

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: 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:

ASTHMA MEAN SMS Grass treated Non-grass treated RHINITIS MEAN SMS Grass treated Non-grass treated COUNTS/cm 2 Grass pollen count APRILMAYJUNE MONTHS 5 Response to Grass Subcutaneous I.T. P < 0.05 P = 0.11 MJ Reid, et al. J Allergy Clin Immunol 1986;78: N = 9

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:

 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

TM Group, Allergen Extract Amount Timothy1.0 mL Diluent9.0 mL Caramelized Sugar Placebo GroupAmount Diluent10 mL Caramelized Sugar *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 MAT Group, Allergen ExtractAmount Timothy1.0 mL Maple, Box-Elder1.0 mL Ash, White1.0 mL Juniper, Western1.0 mL Elm, American1.0 mL Cottonwood, Common1.0 mL Firebush (Kochia)1.0 mL Ragweed, Western1.0 mL Sagebrush, Common1.0 mL Russian Thistle1.0 mL

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.

p=0.03

p=0.001 p=0.04

p=0.005

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.

SYMPTOM SCORE POLLEN COUNT Treated Untreated Pollen Count AUGUSTSEPTEMBER OCTOBER 1971 Norman & Lichtenstein JACI 1978;61:370 Pre-seasonal Immunotherapy

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

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

Symptom scores Cochrane Database Syst Rev 2007; (1):CD SMD Allergen Injection Immunotherapy for Seasonal Allergic Rhinitis Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S

Clinical Efficacy of Sublingual and Subcutaneous Birch Pollen Allergen-Specific Immunotherapy: A Randomized, Placebo-Controlled,Double-Blind, Double-Dummy Study  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 MS Khinchi, et al. Allergy 2004;59:45-53

SLIT versus SCIT Treatment SymptomsMedication* Placebo SLIT SCIT-.75No 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

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

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.