DR Gill allergen immunotherapy apr 2nd, 2014

Allergen
Immunotherapy:
An Update for
Primary-care Physicians

Faculty/Presenter Disclosure
Faculty/Presenter: [Dr. Shavinder Gill]
Relationships with commercial interests:
Grants/research support: [None]
Speaker’s bureau/honoraria: Merck, Pfizer, Takeda, Novartis]
Consulting fees: [None]
Other: [None]

Declaration of conflict of interest as
per Canada Health.
• I do not directly owe shares of any of the
pharmaceutical company.
• I have given lectures/talks for pharmaceutical
companies in the last several years but have
donated that money to non-profitable
organizations.

Learning Objectives
After completing this program,
participants will be able to:
• Discuss the epidemiology and pathophysiology of
allergic rhinitis.
• Understand practice guidelines for the treatment of
allergic rhinitis including the role of immunotherapy.
• Compare subcutaneous and sublingual
immunotherapy for allergic rhinitis.
• Describe the process for initiation and administration
of immunotherapy in patients with allergic rhinitis.

Lessons learned at recent ACAAI
meeting.
• What is Epigenetics?
• What is beef-pork syndrome?
• What is cat-pork syndrome?
• What is pollen food allergy syndrome?
• What is allergic eosinophillic oesophagitis?

Immunotherapy (IT) Overview
• Introduction to Allergic Rhinitis (AR)
• Subcutaneous Immunotherapy (SCIT)
• Sublingual Immunotherapy Tablet (SLIT-T)
• Approach in Family Practice

What are the two epidemics of last
few decades.?
• ?

What are the two epidemics of last
few decades?
• Allergic diseases. There was a 10 fold increase
i.e. 1000% increase in allergic diseases in 1960’s
and 1970’s.
• Metabolic syndrome.

Epidemiology of
Allergic Rhinitis (AR)
• Affects 10-20% of population
• Often associated with asthma, atopic dermatitis,
food allergy
• Impacts quality of life, sleep, work
• National and international guidelines available
Small and Kim. AACI Nov 2011.

Pathophysiology of Allergic
Inflammation: Clinical Disease
Early-phase Reaction
Max. at 10-30 Minutes
American Academy of Otolaryngology, 2006.
Adapted from: Naclerio RM. N Engl J Med 1991; 325(12):860-9.
Late-phase Reaction
Max. at 10-12 Hours
Allergens
Sneezing
Rhinorrhea
Congestion
Mast
cell
IgE antibodies
Mediator release
Blood
vessels
Nerves
Glands
Cellular
infiltration
Eosinophils
Basophils
Monocytes
Lymphocytes
Resolution
Complications
Irreversible
disease (?)
Late-phase
reaction
Priming
Hyper-
responsiveness

Allergic Rhinitis (AR)
Seasonal Allergic Rhinitis (SAR)
• Tree, grass and ragweed
pollens
• Triggered by pollen in spring
through fall seasons
Perennial Allergic Rhinitis (PAR)
• Dust mites, cockroaches,
molds and animal dander
• Chronic condition

AR Guidelines
LTRAs: leukotriene receptor antagonsists
*Step up if there is no response or incomplete response to treatment, regardless of class
†LTRAs may be used in class III and IV, but there is less supporting evidence
**Oral steroids may be considered for class II (severe intermittent), but there is little supporting evidence
*
Class I Class II Class III Class IV
Allergen / irritant avoidance
Oral H1 antihistamines
Intranasal corticosteroids
LRTAs†
Oral steroids
Immunotherapy
Surgery
Adapted from: Small P, et al. J Otolaryngol 2007; 36 (Suppl 1):S5-S27.

Which of the following is true?
• Immuno-therapy is affective in reducing the
incidence of asthma i.e prevent new asthma.
• It prevents new sensitization.
• It is more economical than medication.
• It does not work for food allergy.
• It has long term efficacy after discontinuing the
treatment.

• All of the above are true.

• Immuno-therapy is affective in reducing the
incidence of asthma i.e prevent new asthma.
True. It reduces the risk by 50%.
• It prevents new sensitization. True
• It is more economical than medication. True
• It does not work for food allergy. True. Except for
Oral allergy syndrome.
• It has long term efficacy after discontinuing the
treatment. True. Efficacy remains several years
after stopping the vaccine.

Subcutaneous Immunotherapy
• Immunotherapy has been used for 100 years
• Immune mechanisms of immunotherapy now
better defined
• Effective in AR, asthma, atopic dermatitis and
possibly Oral allergy syndrome/Pollen food
allergy syndrome.
• Has disease-modifying benefits
• Drawbacks: time commitment and very small but
significant risk of anaphylaxis.

Long-term Clinical Efficacy of
Grass-pollen IT
• RCT of discontinuation of grass-pollen immunotherapy
(vs. continuation and vs. controls) in patients with history of
severe seasonal AR
• Conclusion: SCIT for 3-4 years for grass-pollen allergy induces
prolonged clinical remission accompanied by a persistent
alteration in immunologic reactivity
Durham SR, et al. N Engl J Med 1999; 341:468-75.

Long-Term Clinical Efficacy of
Grass-Pollen Immunotherapy
Initial Placebo Trial Current Trial
PollenCount
(grains/m3)
Symptom
Score
May June July Aug
.
May June July Aug
.
May June July Aug
.
May June July Aug
.1989 1993 1994 1995
Study group
Immunotherapy
Placebo
Immunotherapy
Maintenance
Discontinuation
None (control)

Long-term Clinical Efficacy of
Grass-pollen IT: Conclusions
• Immunotherapy for grass-pollen allergy for 3-4 years induces
prolonged clinical remission accompanied by a persistent
alteration in immunologic reactivity
Durham SR, et al. N Engl J Med 1999; 341:468-75.

IT With a Standardized
D. pteronyssinus Extract
Specific IT prevents the onset of new sensitizations
in children(< 6 years old, asthma)
Des Roches A, et al. J Allergy Clin Immunol 1997; 99(4):450-3.
New Sensitivities
Initial
sensitivity
Number of
patients None Cat Dog Alt Grass
SIT 22 10 6 4 2 1
Control 22 0 12 8 6 6

Effects of Specific Immunotherapy in
AR Patients With Bronchial
Hyper-responsiveness
Grembiale RD, et al. Am J Respir Crit Care Med 2000; 162(6):2048-52.
PD20FEV1(µmolofmethacholine)
1
0.1
10
Baseline 1st year 2nd year
SIT
p = 0.0008 p = 0.0001
PD20FEV1(µmolofmethacholine)
1
0.1
10
Baseline 1st year 2nd year
Placebo
p = NS p = NS

Children With and Without Asthma 7 Years
After Termination of Specific Immunotherapy
Jacobsen L, et al. Allergy 2007; 62(8):943-8.
Based on patients without asthma before treatment (n = 119),
absolute numbers of children shown above bars
Mean age 21 years at
10-year follow-up
Percentofpatients
90
0
80
70
60
50
100
40
30
20
10
SIT
No asthma
Asthma
Odds-ratio = 2.5
(1.1 – 5.9)
n = 48
n = 16
25%
Control
n = 29
n = 24
45%

(Abramson et al. AARD
1995;151)
Meta-Analysis of Immunotherapy for
Asthma
• Mites
– Smith (n=22)
– Maunsell (n=34)
– Werner (n=51)
– D’Souza (n=91)
– Pauli (n=18)
– Newton (n=14)
– BTA (n=56)
 Other Allergens
– Frankland (n=57)
– Ohman (n=17)
– Sundin (n=39)
– Valovirta (n=27)
• Mites Combined
(n=286)
 Other Allergens
(n=140)
 All Studies (n=426)0.1 1 10 100 1000

Administering Subcutaneous IT (1)

Administering Subcutaneous IT (2)

Vial #0
1:1000
Vial #1
1:100
Vial #2
1:10
Vial #3
1:1
Dose mL Dose mL Dose mL Dose mL
1 0.10 6 0.10 11 0.05 17 0.05
2 0.20 7 0.20 12 0.10 18 0.07
3 0.30 8 0.30 13 0.20 19 0.10
4 0.40 9 0.40 14 0.30 20 0.15
5 0.50 10 0.50 15 0.40 21 0.20
16 0.50 22 0.25
***Hollister-Stier Extract***
Note: Record all injections in the treatment record.
Note: This dosage chart is offered as a suggested schedule. However, the degree of
sensitivity varies in many individuals. In these cases, the size of the dose and intervals
between doses may have to be adjusted and should be regulated by the patient’s
tolerance and reaction. Treatment is normally started with the weakest dilution in the set.
Beginning with dose #1 as listed in the schedule. Doses should be administered at
weekly or twice-weekly (at least two days apart) intervals while working up. The
maintenance level is […]
23 0.30
24 0.35
25 0.40
26 0.45
27 0.50
Gradually increase intervals
to monthly maintenance.
*Please read text to left*
Subcutaneous IT: Sample Dose Chart
Dr.: Patient: Content:
Lot No.: Expiry Date:
This is a suggested dose chart only. Please read the instructions before commencing desensitization.
Observe patients for 30 minutes after each injection.
Check extract dilution and dose: Check the patient for local or systemic reaction(s) to previous injection.

Time to Onset of Systemic Reactions
with Allergen Immunotherapy
Greineder DK. J Allergy Clin Immunol 1996; 98:S330-S334. [Data from Matloff et al. Allergy Proc 1993; 14:347-50.]
Time not recorded
10% 2-24 hours
8%
60-120 minutes
minimum 2%
0-30 minutes
72%
30-60 minutes
8%
Note: based on this, patients should be advised that they must wait
30 minutes in the clinic after receiving subcutaneous immunotherapy

Immunotherapy Overview
• Introduction to Allergic Rhinitis (AR)
• Subcutaneous Immunotherapy (SCIT)
• Sublingual Immunotherapy Tablet (SLIT-T)
• Approach in Family Practice

Sublingual Immunotherapy
Tablet (SLIT-T)
• Novel treatment for AR in Canada
• Available to treat grass allergy
• Effective in children and adults
• Has disease-modifying effects
• At-home therapy with minimal risk of anaphylaxis

Rationale for Treatment with
Grass SLIT-T
Treatment of Allergic Rhinoconjunctivitis:
✓Reduction of symptoms in first pollen season
✓Reduction of need for pharmacologic treatment
✓Safe for self-administration
Sustained Efficacy During Treatment:
✓Maintenance of treatment effect during IT
Long-term Efficacy:
✓Disease-modifying effect post-treatment
✓Prevention of disease progression (e.g., asthma)1
Novembre E, et al. J Allergy Clin Immunol 2004; 114(4):851-7.

Grass Sublingual
Immunotherapy Tablets
• Grastek (Merck-ALK)
– Phleum pratense (timothy grass pollen) 75,000
SQ-T (equivalent to 2,800 BAU) for the
treatment of Timothy and cross-reactive Rye,
Meadow Fescue, Bluegrass,Cocksfoot and
Sweet Vernal grasses.
• Oralair (Stallergenes SA)
– contains 5 grass pollens

SLIT-T With Once-daily
Grass Allergen Tablets
• Multi-center randomized controlled trial (RCT)
• 855 subjects aged 18-65 years
• Grass SLIT-T doses: 2,500, 25,000, 75,000 SQ-T
• 18 weeks mean duration of treatment
• AR score 18% better and medication use 28%
better in the 75,000 SQ-T group (vs. placebo)
• If > 8 weeks before grass season, symptoms 21%
better and medication use 29% better (vs. placebo)
Durham SR, et al. J Allergy Clin Immunol 2006; 117:802-9.

Immunologic Changes After Treatment
With Placebo or Grass Pollen Tablets
Before start
of treatment
Relativeunits(RU)
0.06
0
0.05
0.04
0.03
0.07
Placebo 2,500 SQ-T
0.02
0.01
A) Mean IgG
Post-treatmentAfter
approximately
8 weeks of
treatment
25,000 SQ-T 75,000 SQ-T
Before start
of treatment
kU/L
100
0
80
60
40
120
20
B) Mean IgE
Post-treatmentAfter
approximately
8 weeks of
treatment

Efficacy and Safety of SLIT-T
With Grass Allergen Tablets
• 51 centers
• 634 patients with AR from grass for at least two
years
• Treatment: SLIT-T 75,000 SQ-T at least 16 weeks
pre-season and during season
• Primary endpoint: 30% reduction symptoms and
38% reduction medications
• Side effects generally mild
• Treatment withdrawal 4%
Dahl R, et al. J Allergy Clin Immunol 2006; 118(2):434-40.

Mean Entire-season Rhinoconjunctivitis
Symptom Scores and Medication Scores
Placebo Grass
allergen tablet
Meanscore
2.5
2.0
1.5
0
3.5
3.0
Entire-season Rhinoconjunctivitis
Symptom Score
1.0
0.5
4.0
30% reduction
p < 0.00013.4
2.4
Placebo Grass
allergen tablet
Meanscore
2.5
2.0
1.5
0
3.5
3.0
Entire-season Rhinoconjunctivitis
Medication Score
1.0
0.5
4.0
38% reduction
p < 0.0001
2.4
1.5

Global Evaluation of
Treatment Effect
Treatment group
Grass allergen tablet
N (%)
Placebo
N (%)
No. of subjects 316 318
Overall assessment of 2005 compared with previous seasons
N 278 275
Much better 96 (35) 45 (16)
Better 132 (47) 106 (39)
The same 41 (15) 89 (32)
Worse 7 (3) 25 (9)
Much worse 2(1) 10 (4)
Improved 228 (82) 151 (55)
Not improved 50 (18) 124 (45)

Treatment-emergent Adverse Events
Reported by ≥ 5% of Subjects
Treatment group
Grass allergen tablet
N (%)
Placebo
N (%)
No. of subjects 316 318
Oral pruritus 145 (46) 13 (4)
Nasopharyngitis 47 (15) 60 (19)
Edema mouth 58 (18) 2 (1)
Influenza 23 (7) 24 (8)
Ear pruritus 38 (12) 3 (1)
Throat irritation 30 (9) 3 (1)
Headache 9 (3) 19 (6)

Pollen Counts and Mean
Rhinoconjunctivitis Total Symptom
Scores (RTSS) by Study Arm
Didier A, et al. J Allergy Clin Immunol 2007; 120(6):1338-45.
Days (0 = first day of main pollen period)
MeanRTSS
4
3
0
5
2
1
6
Pollencounts/m3/24h
100
90
80
70
60
50
40
30
20
10
0
50454035302520152050-5-10-15-20-25
Placebo
100-IR
300-IR
500-IR
Pollen count
Daily mean symptom scores are plotted as one curve by treatment group with the corresponding scale on the left vertical axis.
Daily mean grass pollen counts are plotted as shaded area and the corresponding scale is on the right vertical axis.

Is Grass SLIT-T Disease-modifying?
GT-08 Study
• Male and female subjects aged 18-65 years
• Clinical history ≥ 2 years of grass-pollen-induced
rhinoconjunctivitis
• Clinical history of moderate to severe rhinoconjunctivitis symptoms
(interfering with usual daily activities or sleep), despite treatment with
symptomatic medications during the grass pollen season
• Positive Phleum pratense SPT (wheal ≥ 3mm) and specific IgE (≥
class 2)
• FEV1 ≥ 70% predicted
• No symptomatic seasonal allergic rhinoconjunctivitis due to
tree/weed pollen adjacent or overlapping the grass pollen season or
active perennial allergic rhinoconjunctivitis (note that approximately
80% of subjects were multi-sensitized)
Durham SR, et al. J Allergy Clin Immunol 2010; 125(1):131-8.

Sustained Effects of Grass Pollen
SLIT-T: GT-08 Study Design
Follow Up
Follow Up
Grass SLIT-T Treatment
2005 2007 2008 20092006
Placebo Treatment
End of treatment
Durham SR, et al. Allergy 2011; 66 (Suppl 95):50-52.

Year 1
32%
Year 5
31%
Year 4
31%
Year 3
37%
Year 2
44%
Grass Pollen Tablet Long-term Efficacy
Effect sustained 2 years after treatment
Total daily rhinoconjunctivitis symptom score (median values)
Symptomscore(median)
4
0
3
2
1
5
Placebo
Grass SLIT-T
End of treatment

Prior to the First Dose
• Physician must be present with appropriate
resuscitation equipment
• Patients should be counseled that they may feel
itching in the mouth or throat, swelling in and around
the mouth, itching in the ears
– these sensations typically self-resolve over 30
minutes
– over time, the sensations occur less frequently
• Proper oral examination should be completed
– SLIT-T may be contraindicated in patients with
severe inflammatory conditions in the oral cavity

Dose Administration
• Tablet should be placed under the tongue,
where it dissolves
• Instruct the patient not to swallow for 1 minute
• Instruct the patient to avoid eating and drinking for
10 minutes
• Should be administered daily at approximately the
same time each day

Dose Administration (cont’d)
The first dose will be administered in the office with
a 30-minute observation period
• Observation period should be extended if
significant AEs occur
• If further attention is required for the treatment of
an AE and such treatment cannot be provided at
the office/clinic, the patient should be transferred
to an appropriate facility

SCIT vs. SLIT-T: Efficacy
SCIT SLIT-T
Efficacy shown in RCTs +++ +++
Mechanism of action identified +++ ++
Standardized dosing in RCTs ++ +++
Disease-modifying ++ ++

SCIT vs. SLIT-T: Safety
SCIT SLIT-T
Administration at home - +++
Risk anaphylaxis +++ +
Local side effects + ++
Use in pediatrics + ++

Duration of Expected
Adverse Effects
Adverse Effect
Grass SLIT-T
(minutes)
Throat irritation 15-85
Oral pruritus 3-30
Ear pruritus 15-30
Mouth edema 15-75
Onset typically occurs with the first several doses of treatment.
Events typically diminish over time.

When to Refer AR to an Allergist
• Symptoms of AR that are not adequately
responding to medical therapy
• Patient or referring physician would like to identify
allergic triggers for proper allergen avoidance
• Patient is having side effects to medical therapy
or does not wish to take medical therapy
• Consideration by the patient and/or family
physician of immunotherapy to treat AR

Simplified AR Treatment Algorithm
Treatments can be used individually or in any combination
Allergen avoidance
Allergen immunotherapy
Oral antihistamines
Leukotriene receptor antagonists
Intranasal corticosteroids

Questions to ask patient for AR
• Do you have nasal congestion, runniness and/or
sneezing?
• Do you have itchy, red and/or watery eyes?
• Are your symptoms impacting your daily activities
or sleep?
• Do your symptoms change over the year and are
they seasonal?
• Have antihistamines and/or prescription nasal
sprays been effective? Have they been used
consistently and had an adequate trial?

Approach to AR in your Office
• History should suggest AR
• Look for associated issues such as atopic
dermatitis, asthma, family history
• Consider trial of non-sedating antihistamines,
intranasal corticosteroids
• Specific allergen-avoidance suggestions should
be based on proper allergy-testing results
• Consider referral

AR: Key Messages
• AR is linked with asthma and conjunctivitis
• Allergen skin tests are the best diagnostic test to confirm AR
• Intranasal corticosteroids are the mainstay of treatment for
most patients that present to physicians with AR
• Allergen immunotherapy is an effective immune-modulating
treatment that should be recommended if pharmacologic
therapy for AR is not effective or is not tolerated

Immunotherapy Conclusions
• AR is common
• SCIT is effective in the treatment of AR
• SLIT-T is a new, effective treatment option in AR
– demonstrated safety
– suitable for pediatric use
– administered at home

Case Study 1: Patient Presentation
• 45-year-old female works in office as VP of
software company
• SAR for 12 years from spring to fall
– symptoms are most bothersome in June now
• She has some benefit with INS and
antihistamines
• No current medical problems or medications
• She would like to try immunotherapy

Case Study 1: Discussion
• Consider referral to allergist
• Patient likely has grass as her major allergen
• If SLIT-T is being considered, patient should be
seen by allergist in December or earlier to
arrange SLIT-T therapy for January preceding the
next grass pollen season

• 27-year-old male
• Allergies to grass and dust mites
• Last injection one week ago
• Regular build-up dose today (third injection into
the final vial of pollen immunotherapy)
• Within minutes, felt unwell, chest pain, groggy
• Treated in clinic for anaphylaxis

• Management of anaphylaxis in family practice
• After a reaction to immunotherapy, should
immunotherapy be continued?
• How would this patient be managed if he wants to
stop SCIT?
• How would this patient be managed if he wants to
continue SCIT?

• 12-year-old boy
• Two-year history of severe rhinitis and
conjunctivitis from May to July
• Missed 10 days of school
• Not better with INS or antihistamines
• Skin test positive to grass
• Parents would like to start immunotherapy

• If a patient presents to you during the time of
severe symptoms, what are some treatment
options?
• What are the options for further testing?
• When would you refer this patient?

DR Gill allergen immunotherapy apr 2nd, 2014

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