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 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.

Effective Doses in Double-Blind Studies (Major Allergen)

Allergen Extract Major Allergen Effective Doses Less or Ineffective doses

Ragweed Amb a 1 4 to 24 mcg 0.6 & 2 mcg

Timothy Phl p 5 15 to 20 mcg 2 mcg

D pteronyssinus Der p 1 7 & 12 mcg 0.7 mcg

D farinae Der f 1 10 mcg Not determined

Cat Fel d 1 11-17 mcg 0.6 & 3.0 mcg

Dog Can f 1 15 mcg 0.6 & 3.0 mcg

Birch Bet v 1 3.28 & 12 mcg Not determined

Alternaria Alt a 1 1.6 & 8 mcg Not determined

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

Evidence for Effectiveness of Immunotherapy Employing

Multiple AllergensJohnstone 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

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

Evidence for Effectiveness of Immunotherapy Employing

Multiple AllergensJohnstone 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

Effectiveness and Specificity of Ragweed Immunotherapy

1200

800

400

0

19 26 2 9 16 23 30 7 14 21 28* * ** * * *

Aug. Sept. Oct.

treated untreated median mean

1963

To

tal

Sco

re

Lowell & Franklin NEJM 1965

Evidence for Effectiveness of Immunotherapy Employing

Multiple AllergensJohnstone 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

6

4

2

0

1985ASTHMA

ME

AN

SM

S

Grass treatedNon-grass treated

25

20

15

10

0

RHINITISM

EA

N S

MS

Grass treatedNon-grass treated

300

200

100

0

CO

UN

TS

/cm

2

Grass pollen count

APRIL MAY JUNE

MONTHS

5

Response to Grass Subcutaneous I.T.

P < 0.05

P = 0.11

MJ Reid, et al. J Allergy Clin Immunol 1986;78:590-600

N = 9

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

Timothy 1.0 mL

Diluent 9.0 mL

Caramelized Sugar

Placebo Group Amount

Diluent 10 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 Extract

Amount

Timothy 1.0 mL

Maple, Box-Elder 1.0 mL

Ash, White 1.0 mL

Juniper, Western 1.0 mL

Elm, American 1.0 mL

Cottonwood, Common 1.0 mL

Firebush (Kochia) 1.0 mL

Ragweed, Western 1.0 mL

Sagebrush, Common 1.0 mL

Russian Thistle 1.0 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.

14

12

10

8

6

4

2

SY

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M S

CO

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EN

CO

UN

T

2800

2400

2000

1600

1200

800

400

TreatedUntreated

Pollen Count

16 20 24 28 1062 14 18 22 30 426AUGUST SEPTEMBER 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 - 0.42 (p = 0.002) - Medications: - 0.43 (p = 0.00003)

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):CD001936.

SMD -0.73

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 SCITTreatment 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

SLIT vs SCIT Comparative Study First Treatment Season

SCIT SLIT Placebo

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.

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.