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 ObjectivesAfter 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.

What is the prevalence?

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 AllergicInflammation: Clinical DiseaseEarly-phase ReactionMax. at 10-30 Minutes

American Academy of Otolaryngology, 2006.Adapted from: Naclerio RM. N Engl J Med 1991; 325(12):860-9.

Late-phase ReactionMax. at 10-12 Hours

Allergens

SneezingRhinorrheaCongestion

Mast cell

IgE antibodies

Mediator release

Blood vessels

Nerves

Glands

Cellular infiltration

EosinophilsBasophilsMonocytesLymphocytes

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.

Immunotherapy (IT) Overview• Introduction to Allergic Rhinitis (AR)

• Subcutaneous Immunotherapy (SCIT)• Sublingual Immunotherapy Tablet (SLIT-T)• Approach in Family Practice

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.

Which of the following is true?• All of the above are true.

Which of the following is 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

Polle

n Co

unt

(gra

ins/

m3 )

Sym

ptom

Scor

e

May June July Aug.

May June July Aug.

May June July Aug.

May June July Aug.1989 1993 1994 1995

Study groupImmunotherapyPlacebo

ImmunotherapyMaintenanceDiscontinuationNone (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 ExtractSpecific 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.

PD

20F

EV

1 (

µm

ol o

f m

etha

cho

line)

1

0.1

10

Baseline 1st year 2nd year

SIT

p = 0.0008 p = 0.0001

PD

20F

EV

1 (

µm

ol o

f m

etha

cho

line)

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-upP

erce

nt

of p

atie

nts

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 #01:1000

Vial #11:100

Vial #21:10

Vial #31:1

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 ChartDr.: 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 recorded10% 2-24 hours

8%60-120 minutesminimum 2%

0-30 minutes72%

30-60 minutes8%

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-TTreatment 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 startof treatment

Rel

ativ

e u

nits

(R

U)

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 startof treatment

kU/L

100

0

80

60

40

120

20

B) Mean IgE

Post-treatmentAfter approximately

8 weeks of treatment

Durham SR, et al. J Allergy Clin Immunol 2006; 117:802-9.

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

Dahl R, et al. J Allergy Clin Immunol 2006; 118(2):434-40.

Placebo Grass allergen tablet

Mea

n sc

ore 2.5

2.0

1.5

0

3.5

3.0

Entire-season Rhinoconjunctivitis Symptom Score

1.0

0.5

4.0

30% reductionp < 0.00013.4

2.4

Placebo Grass allergen tablet

Mea

n sc

ore 2.5

2.0

1.5

0

3.5

3.0

Entire-season Rhinoconjunctivitis Medication Score

1.0

0.5

4.0

38% reductionp < 0.0001

2.4

1.5

Global Evaluation of Treatment Effect

 Treatment group

Grass allergen tablet N (%)

PlaceboN (%)

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)

Dahl R, et al. J Allergy Clin Immunol 2006; 118(2):434-40.

Treatment-emergent Adverse Events Reported by ≥ 5% of Subjects

 Treatment group

Grass allergen tablet N (%)

PlaceboN (%)

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)

Dahl R, et al. J Allergy Clin Immunol 2006; 118(2):434-40.

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)

Mea

n R

TS

S 4

3

0

5

2

1

6

Pol

len

cou

nts/

m3/2

4h

100

90

80

70

60

50

40

30

20

10

050454035302520152050-5-10-15-20-25

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 EfficacyEffect sustained 2 years after treatment

Durham SR, et al. J Allergy Clin Immunol 2010; 125:231-8.

Total daily rhinoconjunctivitis symptom score (median values)

Sym

pto

m s

core

(m

edi

an)

4

0

3

2

1

5

PlaceboGrass 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 EffectGrass 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.

Immunotherapy Overview• Introduction to Allergic Rhinitis (AR)

• Subcutaneous Immunotherapy (SCIT)• Sublingual Immunotherapy Tablet (SLIT-T)• Approach in Family Practice

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

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.

Simplified AR Treatment Algorithm

Small and Kim. AACI Nov 2011.

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

Small and Kim. AACI Nov 2011.

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

Case Study 2: Patient Presentation • 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

Case Study 2: Discussion• 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?

Case Study 3: Patient Presentation• 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

Case Study 3: Discussion• 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?