1. Allergy Immunotherapy: A New Role for the Family Physician
9/15/2018
Allergy Immunotherapy: A New Role for the Family Physician
Stephen A. Brunton, MD, FAAFP
Adjunct Clinical Professor
Department of Clinical Pharmacy Practice 
Roseman University
Salt Lake City, Utah
Executive Vice President for Education
Primary Care Education Consortium
Los Angeles, CA

3. 9/15/2018
This program is sponsored by and supported by an educational grant from Stallergenes Greer

4. 9/15/2018
The Primary Care Respiratory Group (PCRG) is a national educational initiative providing comprehensive respiratory disease education. Free Membership at PCRG offers free CME and a host of educational resources. Join at

5. 9/15/2018
Disclosures
Stephen Brunton MD has no real or apparent conflicts of interest to report

6. Free 1.0 AMA PRA Category 1 Credit(s)TM
Visit:

7. 9/15/2018
Learning Objectives
After attending this program, the family physician should be able to:
Compare the mechanisms of sublingual and subcutaneous immunotherapy
Describe the efficacy and impact on the natural history of allergy of sublingual immunotherapy
Compare the safety profiles of sublingual and subcutaneous immunotherapy
Safely initiate sublingual immunotherapy in appropriate patients in family medicine

8. Case Study
9/15/2018
Donna is a 44-year-old woman being seen because hay fever is causing her much discomfort
Symptoms are worse this spring than last spring
Symptoms include rhinitis with watery discharge; itchy, watery eyes; frequent sneezing episodes
As in past years, her symptoms began shortly after the snow disappeared and are much worse when her husband mows the lawn
Last year, an intranasal steroid provided adequate relief
She restarted the intranasal steroid once-daily a month ago

9. ? What would you do? Refer to an allergist
9/15/2018 ?
What would you do?
Refer to an allergist
Verify sensitivity to allergen by positive skin test or in vitro pollen-specific IgE antibodies
Discuss with her initiating sublingual immunotherapy
Verify inhaler technique and discuss allergen avoidance
Correct answer: 2- verify sensitivity to allergen by positive skin test or in vitro pollen-specific IgE antibodies. This needs to be done prior to initiating SLIT (if appropriate). Verifying inhaler technique and discussing allergen avoidance is reasonable to reinforce good practice; disease control last year suggests she uses appropriate inhaler technique.

10. Sample Panel of Respiratory Allergens/Region 4
9/15/2018
Sample Panel of Respiratory Allergens/Region 4
Level
Immunoglobulin E
House dust mites/D. pteronyssinus
Penicillium chrysogenum
Elm
House dust mites/D. farina
Cladosporium
Walnut tree
Cat epithelium
Aspergillus fumigatus
Cottonwood
Dog dander
Alternaria tenuis
Mulberry
Bermuda grass
Olive tree
Short ragweed
Timothy grass
Grey alder
Mugwort
Johnson grass
Mountain cedar
Russian thistle
Cockroach
Oak
Rough pigweed
Allergy blood tests detect and measure the amount of allergen-specific antibodies in a person’s blood.
The blood test is usually ordered for a panel of allergens. The panel includes several related allergens that are common to a geographic region. While they are grouped together, each allergen antibody is tested individually.
Profile includes allergens commonly observed in geographic region. Each allergen is tested individually and reported.

12. Allergic Rhinitis/Rhinoconjunctivitis
Allergic rhinitis (AR)
Affects about 20% of the general population in North America
Seasonal allergens
Tree, grass, and weed pollens
Perennial allergens
cat dander, cockroach, or dust mite
Background: Allergic Rhinitis/Rhinoconjunctivitis and Asthma
Allergic rhinitis is a common clinical problem affecting about 20 percent of the general population in North America. Allergens such as tree, grass, and weed pollens characteristically cause seasonal rhinoconjunctivitis and/or asthma. Allergens such as cat dander, cockroach, or dust mite may induce symptoms year-round and are associated with perennial rhinitis and/or asthma. The prevalence of asthma in the general U.S. population is approximately 9 percent, and approximately 62 percent of individuals with asthma have evidence of atopy (i.e., the genetic predisposition to produce elevated immunoglobulin E [IgE] in response to environmental allergens).
References
Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at
Min YG. The pathophysiology, diagnosis and treatment of allergic rhinitis. Allergy Asthma Immunol Res Apr;2(2): PMID:
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at
Min YG. Allergy Asthma Immunol Res. 2010;2(2):65-76.

13. Management of Allergy Symptoms
Medical management of patients with AR includes:
Allergen avoidance
Pharmacotherapy
Immunotherapy
Daily use of medications for AR symptoms raises issues related to adherence, safety, and cost.
Long-term use of inhaled nasal steroids can have adverse effects.
Background: Management of Allergy Symptoms
The medical management of patients with allergic rhinitis and asthma includes allergen avoidance, pharmacotherapy, and immunotherapy. Pharmacotherapies for allergic rhinitis symptoms include topical nasal corticosteroid or cromolyn preparations and/or antihistamines and decongestants. These must be used daily to provide effective control, raising critical issues related to long-term compliance, safety, and cost. Similarly, the long-term use of inhaled steroids for asthma control poses risks, especially if used together with nasal steroids to control seasonal or perennial respiratory conditions. Furthermore, long-acting bronchodilators have the potential to cause cardiovascular complications including arrhythmias and sudden death, and leukotriene antagonists have been associated with neuropsychiatric disturbances.
Reference
Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at

15. Respiratory Comorbidities of AR
Asthma
URI
Allergic Rhinitis
Sinusitis
OME
Nasal Polyposis
URI=upper respiratory infections
OME=otitis media with effusion
Spector SL. J Allergy Clin Immunol. 1997;99:S773-S780.

16. The nose is that part of the lung that you can reach with your finger

17. A Link Between AR and Asthma?
AR affects ~78% of patients with allergic asthma
Asthma affects up to 38% of patients with AR
Patients who have AR without asthma often have bronchial hyperresponsiveness
Onsets of AR and asthma often coincide
Corren J. J Allergy Clin Immunol. 1997;99:S781-S786.

18. Subcutaneous Immunotherapy for Allergies
Allergen-specific immunotherapy is typically used for patients:
Whose allergic rhinoconjunctivitis (ARC) symptoms cannot be controlled by medication and environmental measures
Who cannot tolerate their medications
Who do not adhere to chronic medications
Historically, a patient with allergies underwent subcutaneous immunotherapy (SCIT) with an extract of the relevant allergen(s) in an attempt to suppress or eliminate allergy-related symptoms.
Background: Subcutaneous Immunotherapy for Allergies
Allergen-specific immunotherapy is typically recommended for patients whose allergic rhinoconjunctivitis and asthma symptoms cannot be controlled by environmental control and pharmacotherapy, those who cannot tolerate their medications, or those who do not comply with chronic medication regimens. Over the years, allergen-specific immunotherapy has proven to be safe. The U.S. Food and Drug Administration approved the use of subcutaneous allergen extracts (subcutaneous immunotherapy) for the treatment of seasonal and perennial allergic rhinitis, allergic asthma, and venom sensitivity. In the United States, a patient with allergies receives increasing doses of an allergen-containing extract (comprised of the relevant allergens to which the patient is sensitive) until a maintenance dose is found to suppress or eliminate allergic symptoms. With continued administration, it is expected that the treatment regimen will make the patient tolerant of the offending allergen and will suppress future untoward responses to the allergen(s) through modulation of the patient’s immune system.
Reference
Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at

19. Mechanisms of Allergen-Specific Immunotherapy
9/15/2018
Mechanisms of Allergen-Specific Immunotherapy
Mechanisms of allergen-specific immunotherapy and the role of regulatory T cells in allergic diseases.
An allergen is taken up by regional dendritic cells leading to the induction of regulatory T cells. These cells suppress allergic responses directly and indirectly by the
following mechanisms. 1. Suppression of mast cells, basophils and eosinophils. 2. Suppression of effector T cells. 3. Suppression of inflammatory cell migration to tissues and tissue inflammation. 4. Suppression of mucus production. 5. Suppression of inflammatory dendritic cells and induction of tolerogenic dendritic cells. 6. Suppression of allergen-specific IgE and induction of IgG4 from B cells.
© Fujita H, et al. Clin Transl Allergy. 2012;2(1):2 without modification under Creative Commons License 4.0.

20. Mechanisms of Allergen-Specific Immunotherapy (cont)
9/15/2018
Mechanisms of Allergen-Specific Immunotherapy (cont)
Jutel M, et al. J Allergy Clin Immunol. 2016;137(2):

21. The Dawn of Sublingual Immunotherapy
9/15/2018
The Dawn of Sublingual Immunotherapy
SCIT
Benefits
Limitations
(injections, frequent office visits, rare anaphylaxis)
(↓ incidence/severity of symptoms; addresses natural history of allergy)
SLIT
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at
Jutel M, et al. J Allergy Clin Immunol. 2015;136(3):

22. AHRQ Comparative Effectiveness Review
142 randomized, controlled studies
Subjects
Adults only 52%
Children only 24%
Adults and children 22%
SLIT studies mainly included patients with allergic rhinitis and/or mild asthma
Allergen
Number of Studies
SCIT
SLIT
SCIT vs. SLIT
Dust mite 21 14 6
Grass 11 15 ‒
Weeds 9 7
Cat 5 2
Dog 1
Mold
Tree 13
Multiple allergens
Included Studies by Type of Allergen for SCIT, SLIT, and SCIT Versus SLIT
This table represents the number of studies included for each type of allergen that was included in analyses of subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and SCIT versus SLIT.
Dust mites could include Dermatophagoides pteronyssinus or D. farinae or unspecified dust mites.
Grass could include Bermuda grass, cocksfoot, meadow fescue, orchard grass, rye (Secale cereale or unspecified), Timothy grass, unspecified grass, or grass mix.
Weeds could include English plantain, Kochia, mugwort, Parietaria, tagweed (short, Western, or unspecified), Russian thistle, or sagebrush.
Mold could include Alternaria, Aspergillus, or Cladosporium.
Tree could include American elm, bald cypress, birch, cottonwood, date sugar palm/wild date palm, Japanese cedar, London plane, maple, mountain cedar, olive, red/green ash, white birch, white oak, or tree mix.
Reference
Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at
SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at

23. 9/15/2018

24. AHRQ CER: SCIT Versus SLIT*: All Outcomes
Primary Outcome
Results
No. of RCTs No. of Patients (n)
Strength of Evidence
Improves asthma symptom score
SCIT may improve asthma symptoms more effectively than SLIT
4 RCTs
(n = 171)
Low
Improves rhinitis/ rhinoconjunctivitis symptoms
SCIT is superior to SLIT for improving allergic nasal and/or eye symptoms
6 RCTs
(n = 412)
Moderate
Decreases use of asthma plus rhinoconjunctivitis medications
There are no consistent differences between SCIT and SLIT
5 RCTs
(n = 219)
Improves asthma plus rhinitis/rhinoconjunctivitis symptom and medication score
SCIT is favored in 1 of 2 studies
2 RCTs
(n = 65)
Subcutaneous Versus Sublingual Immunotherapy: All Outcomes
Four trials of dust mite allergen immunotherapy reported improvement in asthma symptom scores. Two studies reported changes in subcutaneous (SCIT) and sublingual (SLIT) immunotherapy groups when compared with placebo and two when compared with pharmacotherapy. All four studies reported significant changes in asthma symptom scores in the SCIT treatment group. The strength of evidence is low (4 studies, N = 171) to support SCIT over SLIT for allergic asthma symptom control.
Six studies reported rhinitis or rhinoconjunctivitis symptom scores in 412 patients. Three trials demonstrated that both SLIT and SCIT reduced symptoms significantly when compared with placebo or with pharmacotherapy. One of these showed that SCIT resulted in a significantly greater reduction in symptom scores when compared with SLIT. The other two studies showed no significant difference between SLIT and SCIT for reducing rhinitis/rhinoconjunctivitis symptoms. One study reported a significant difference in rhinitis symptoms in participants receiving combined SCIT and SLIT when compared with pharmacotherapy. The strength of evidence is moderate that SCIT is more effective than SLIT in reducing allergic nasal and/or eye symptoms.
Medication scores were reported in 5 studies that included 219 patients. The evidence was inconsistent; consequently, there is low-strength evidence that there may not be a difference between SCIT and SLIT in reducing medication use.
Two studies including 65 patients reported improvement in symptom and medication scores. A dust mite trial reported significant improvement post-treatment when compared with pretreatment in the SCIT group. The SLIT group showed significant improvement during early treatment, but the effect was not sustained at 2 years. Another study in patients allergic to tree pollen reported no significant differences in symptoms and medication scores between the SLIT and SCIT groups. None of the studies reported between-group differences. The evidence is low to support SCIT over SLIT for improving combined medication and symptom scores for patients allergic to dust mite.
Reference
Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at
RCT, randomized controlled trial; SCIT, subcutaneous immunotherapy; SLIT, sublingual immunotherapy
*SLIT using drops or tablets of an allergen extract placed under the tongue
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at

25. No. of RCTs No. of Patients (n)
AHRQ CER: SLIT* Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes
Primary Outcome
Results
No. of RCTs No. of Patients (n)
Strength of Evidence
Rhinitis/
rhinoconjunctivitis symptoms
Significant improvement in 56% of studies vs. controls
36 RCTs (n = 2,658)
Moderate
Conjunctivitis
symptoms
Significant improvement in 46% of studies vs. placebo
13 RCTs (n = 1,074)
Disease-specific
quality of life in patients with rhinitis/ rhinoconjunctivitis
Significant improvement by RQLQ in 75% of studies vs. controls
8 RCTs
(n = 819)
SLIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes
Rhinitis or rhinitis plus conjunctivitis symptom scores were reported in 36 studies that included 2,658 patients. The most common allergen was grass or grass mix, followed by dust mite and tree/tree mix. Comparator groups included placebo and pharmacotherapy. Fifty-six percent of sublingual immunotherapy (SLIT) studies reporting rhinoconjunctivitis symptoms demonstrated significant improvement in allergic rhinoconjunctivitis scores with SLIT. There is moderate-grade evidence that SLIT improves control of rhinitis or rhinoconjunctivitis symptoms, particularly with grass mix allergens.
Conjunctivitis symptoms were reported in 13 studies that included 1,074 patients. Forty-six percent of the studies demonstrated significant improvement in conjunctivitis symptom scores when compared with placebo or to pretreatment symptom levels in the SLIT arm. There is moderate-grade evidence that SLIT reduces conjunctivitis symptoms.
Quality of life was reported in 8 studies involving 819 subjects. The instrument used to assess quality of life was a validated, disease-specific instrument: the Rhinoconjunctivitis Quality of Life Questionnaire (adult, pediatric, adolescent, and Japanese-language versions). Six studies demonstrated improved quality of life in the SLIT groups when compared with placebo or when comparing initial to final quality-of-life scores.
Reference
Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at
RCT, randomized controlled trial; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire
*SLIT using drops or tablets of an allergen extract placed under the tongue
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at

27. No. of RCTs No. of Patients (n)
AHRQ CER: Pediatric Patients—SLIT* Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes
Primary Outcome
Results
No. of RCTs No. of Patients (n)
Strength of Evidence
Rhinitis/ rhinoconjunctivitis symptoms
Significant improvement in 42% of studies vs. controls
12 RCTs
(n = 1,065)
Moderate
Conjunctivitis symptoms
Significant improvement in 40% of studies vs. placebo
5 RCTs
(n = 513)
Pediatric Patients—SLIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes
Rhinitis or combined rhinitis plus conjunctivitis symptom scores were reported in 12 articles involving 1,065 patients. Overall, 5 (42%) of the 12 sublingual immunotherapy (SLIT) studies reporting rhinoconjunctivitis symptoms demonstrated significant improvement in allergic rhinoconjunctivitis scores with SLIT. There is moderate-grade evidence that SLIT improves control of rhinitis or rhinoconjunctivitis symptoms.
Conjunctivitis symptom scores were reported in 5 trials involving 513 patients. The comparator in all studies reporting conjunctivitis scores was placebo. Two studies demonstrated significant improvement in conjunctivitis symptom scores when compared with placebo or to pretreatment symptom levels in the SLIT arm. There is moderate-grade evidence that SLIT reduces conjunctivitis symptoms.
Quality of life was reported in 2 studies involving 461 subjects. The instruments used to assess quality of life in both studies were validated, disease-specific instruments: the pediatric and adolescent versions of the Rhinoconjunctivitis Quality of Life Questionnaires. One study found no improvement in quality of life. The other study found no difference between the SLIT and placebo groups in both children and adolescents after 2 years. There is insufficient evidence that SLIT affects disease-specific quality of life in children and adolescents.
Reference
Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at
RCT, randomized controlled trial; SLIT, sublingual immunotherapy
*SLIT using drops or tablets of an allergen extract placed under the tongue
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at

28. AHRQ CER: Overview of Conclusions
There is sufficient evidence to support the overall effectiveness and safety of both SCIT and SLIT* for treating ARC.
However, there is not enough evidence to determine if either SCIT or SLIT is superior.
SCIT and SLIT are usually safe, although local reactions are commonly reported regardless of the mode of delivery.
Overview of Conclusions (1 of 2)
Evidence is sufficient to support the overall effectiveness and safety of both subcutaneous (SCIT) and sublingual (SLIT) immunotherapy for treating allergic rhinoconjunctivitis and asthma. However, there is not enough evidence to determine which mechanism of delivery is superior. SCIT and SLIT are usually safe, although local reactions are commonly reported regardless of the mode of delivery.
Reference
Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at
*Aqueous allergen extract placed under the tongue as drops or on a tablet
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at

29. Case Study
9/15/2018
Donna is a 44-year-old woman being seen because hay fever is causing her much discomfort
Symptoms are worse this spring than last spring
Symptoms include rhinitis with watery discharge; itchy, watery eyes; frequent sneezing episodes
As in past years, her symptoms began shortly after the snow disappeared and are much worse when her husband mows the lawn
Last year, an intranasal steroid provided adequate relief
She restarted the intranasal steroid once-daily a month ago
Testing confirms sensitivity to grass pollen

30. ? What would you do? Refer to an allergist
9/15/2018 ?
What would you do?
Refer to an allergist
Discuss initiating sublingual immunotherapy
Verify inhaler technique and discuss allergen avoidance
Correct answer: 2- discuss initiating SLIT. Confirmation of allergy to grass pollen indicates she is a candidate for SLIT, which can be done in the primary care setting.

31. SLIT Products Available in the United States
9/15/2018
SLIT Products Available in the United States
TGPAE
(Grastek)
5-GPAE
(Oralair)
SRPAE
(Ragwitek)
HDMAE
(Odactra)
Extract(s)
Timothy grass
Sweet Vernal, Orchard, Perennial Rye, Timothy, Kentucky Blue grasses
Short ragweed
House dust mite
Indication(s)
Grass pollen-induced AR/ARC confirmed by positive skin test/in vitro test for pollen-specific IgE antibodies for Timothy grass or cross-reactive grass pollens
Grass pollen-induced AR/ARC confirmed by positive skin test/in vitro test for any of the 5 grass pollens
Short ragweed pollen-induced AR/ARC confirmed by positive skin test/in vitro test for pollen-specific IgE antibodies for short ragweed pollen
House dust mite-induced AR/ARC confirmed by in vitro testing for IgE antibodies to D. farinae or D. pteronyssinus house dust mites or skin testing to licensed house dust mite allergen extracts
Patient ages
5-65 years
10-65 years
18-65 years
5-GPAE, 5-grass pollen allergen extract; AR, allergic rhinitis; ARC, allergic rhinitis with conjunctivitis; HDMAE, house dust mite allergen extract; SRPAE, short ragweed pollen allergen extract; TGPAE, Timothy grass pollen allergen extract
Grastek [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; September Oralair [package insert]. Lenoir, NC: Greer Laboratories, Inc.; December Ragwitek [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; March Odactra [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; March 2017.

32. 9/15/2018
Once-daily TGPAE for Grass Pollen-Induced Allergic Rhinoconjunctivitis: Efficacy
Treatment started 16 weeks before grass pollen season and continued for 7 weeks during grass pollen season
Permission required
N=438
*P=0.005; †P=0.02; ‡‡P=0.08
DMS, daily medication score; DSS, daily symptom score; RQLS(S), Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities; TCS, total combined score; TGPAE, Timothy grass pollen allergen extract (Grastek)
Nelson HS, et al. J Allergy Clin Immunol. 2011;127:72-80.

33. 9/15/2018
Sustained Use of Once-daily TGPAE for Grass Pollen-Induced Allergic Rhinoconjunctivitis: Study Design
Adults (age y) with ≥2-y history of grass pollen-induced ARC despite treatment
Beginning 4-8 months prior to anticipated start of grass pollen season, patients were randomized to
TGPAE or placebo once daily
Continued for 3 seasons until end of grass pollen season
Followed for 2 additional years without treatment
TGPAE, Timothy grass pollen allergen extract (Grastek)
Durham SR, et al. J Allergy Clin Immunol. 2012;129:

34. 9/15/2018
Sustained Use of Once-daily TGPAE for Grass Pollen-Induced Allergic Rhinoconjunctivitis: Efficacy
Permission required
N=473
*Weighted rhinoconjunctivitis combined symptom and medication score
TGPAE, Timothy grass pollen allergen extract (Grastek)
Durham SR, et al. J Allergy Clin Immunol. 2012;129:

35. 9/15/2018
Once-daily 5-GPAE for Grass Pollen-Induced Allergic Rhinoconjunctivitis: Efficacy
Treatment started 4 months before grass pollen season and continued during grass pollen season ‡ ‡ ‡ ‡ ‡
†P≤0.005; ‡P≤0.001; ¶P≤0.05
5-GPAE, 5-grass pollen allergen extract (Oralair); AdSS, Adjusted Symptom Score; RMS, Rescue Medication Score; RTSS, Rhinoconjunctivitis Total Symptom Score
Cox LS, et al. J Allergy Clin Immunol. 2012;130(6):

36. 9/15/2018
Sustained Use of Once-daily 5-GPAE for Grass Pollen-Induced Allergic Rhinoconjunctivitis: Efficacy
Treatment started either 2 or 4 months before grass pollen season and continued during grass pollen season for 3 consecutive seasons * * * * ‡ * * ‡
N=633
*P≤0.0001; †P≤0.005; ‡P≤0.001; ¶P≤0.05; #P≤0.0005
5-GPAE, 5-grass pollen allergen extract (Oralair); AAdSS, Average adjusted symptom score; ARMS, average rescue medication score; ARTSS, average rhinoconjunctivitis total symptom score
Didier A, et al. J Allergy Clin Immunol. 2011;128(3):

37. 9/15/2018
Once-daily SRPAE for Grass Pollen-Induced Allergic Rhinitis/ Rhinoconjunctivitis: Efficacy
Total Combined Score
Treatment started 12 weeks before ragweed pollen season and continued during ragweed pollen season
N=473
RS, ragweed season; SRPAE, short ragweed pollen allergen extract (Ragwitek)
Note: 6-Amb a 1 units AIT not available in the United States
Nolte H, et al. Ann Allergy Asthma Immunol. 2013;110:

38. 9/15/2018
Once-daily HDMAE for Dust Mite-Induced Allergic Rhinitis/Rhinoconjunctivitis: Efficacy Over 52 weeks
*P<0.001
HDMAE, house dust mite allergen extract (Odactra); Rhinitis DMS, rhinitis daily medication score; Rhinitis DSS, rhinitis daily symptom score; TCRS, total combined rhinitis score; TCS, total combined score
Nolte H, et al. J Allergy Clin Immunol. 2016;138(6):

39. Safety of SLIT Products Available in the United States
9/15/2018
Safety of SLIT Products Available in the United States
5-GPAE
(Oralair)
TGPAE
(Grastek)
SRPAE (Ragwitek)
HDMAE
(Odactra)
Common adverse events
AEs in ≥5%:
Oral pruritus, throat irritation, ear pruritus, mouth edema, tongue pruritus, cough, oropharyngeal pain
Ear pruritus; oral pruritus; tongue pruritus; mouth edema; throat irritation
Throat irritation; oral pruritus; ear pruritus; oral paraesthesia; mouth edema; tongue pruritus
AEs in ≥10%:
Throat irritation/tickle; mouth pruritus; ear pruritus; swelling of uvula/back of mouth; swelling of lips; swelling of tongue; nausea; tongue pain; throat swelling; tongue ulcer/sore; stomach pain; mouth ulcer/sore; taste alteration
Contraindi-cations
Severe, unstable or uncontrolled asthma; history of severe systemic allergic reaction; history of severe local reaction to SLIT; history of eosinophilic esophagitis; hypersensitivity to any ingredient of product
5-GPAE, 5-grass pollen allergen extract; AEs, adverse events; HDMAE, house dust mite allergen extract; SLIT, sublingual immunotherapy; SRPAE, short ragweed pollen allergen extract; TGPAE, Timothy grass pollen allergen extract
Oralair [package insert]. Lenoir, NC: Greer Laboratories, Inc.; December Grastek [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; September Ragwitek [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; March Odactra [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; March 2017.

40. Limitations of SLIT Small number of allergens
9/15/2018
Limitations of SLIT
Small number of allergens
Grass(es), ragweed, dust mite
Limited experience vs SCIT
Cost
5-GPAE: $14/day
TGPAE: $10/day
SRPAE: $10/day
HDMAE: not yet available
However, avoids cost of office visit(s) for SCIT

41. What advice would you provide to the patient?
9/15/2018 ?
What advice would you provide to the patient?
Wear latex gloves when handling medication
Suck on hard candy after medication has dissolved
Report worsening dysphagia and/or heartburn
Discontinue treatment if nausea occurs
Correct answer: 3- report worsening dysphagia and/or heartburn. The rationale for these answers is presented in the next 3 slides.

42. Key Points for Family Physicians
9/15/2018
Key Points for Family Physicians
Verify patient sensitivity to allergen by positive skin test or in vitro pollen-specific IgE antibodies1-4
Transitioning from SCIT to SLIT should be guided by allergist
Efficacy and safety of SLIT are similar in children as adults
Initiate therapy
5-GPAE: ≥16 weeks before expect seasonal onset1
TGPAE: ≥12 weeks before expect seasonal onset2
SRPAE: ≥12 weeks before expect seasonal onset3
HDMAE: at diagnosis4
1. Oralair [package insert]. Lenoir, NC: Greer Laboratories, Inc.; December Grastek [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; September Ragwitek [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; March Odactra [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; March 2017.

43. Key Points for Family Physicians (cont)
9/15/2018
Key Points for Family Physicians (cont)
It is not clear if grass/ragweed products can be initiated during the pollen season  potential risk for systemic allergic reactions1
Dosing once daily with no increase in dose except 2-5
5-GPAE: children y  increase dose over 3 days2
Administer first dose with close medical supervision for at least 30 minutes2-5
Prescribe epinephrine auto-injector for home use; educate patients about symptom(s) of allergic reaction and management
1. Creticos PS, et al. J Allergy Clin Immunol Pract. 2016;4(6): Oralair [package insert]. Lenoir, NC: Greer Laboratories, Inc.; December Grastek [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; September Ragwitek [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; March Odactra [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; March 2017.

44. Key Points for Family Physicians (cont)
9/15/2018
Key Points for Family Physicians (cont)
Advise patient to remove tablet with dry hands and immediately place under tongue; let dissolve1-4
Do not swallow for ≥1 minute; no food/beverage for ≥5 minutes
Wash hands after administration
H1 and H2 blockers useful for
mild/moderate oral AEs
mild abdominal pain and nausea5
Counsel patients to report worsening dysphagia and/or heartburn1-4
Currently no CPT code for billing for SLIT administration
1. Oralair [package insert]. Lenoir, NC: Greer Laboratories, Inc.; December Grastek [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; September Ragwitek [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; March Odactra [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; March Epstein TG, et al. J Allergy Clin Immunol Pract. 2017;5(1):34-40.

45. Case Study
9/15/2018
Donna is a 44-year-old woman being seen because hay fever is causing her much discomfort
Symptoms are worse this spring than last spring
Symptoms include rhinitis with watery discharge; itchy, watery eyes; frequent sneezing episodes
As in past years, her symptoms began shortly after the snow disappeared and are much worse when her husband mows the lawn
Last year, an intranasal steroid provided adequate relief
She restarted the intranasal steroid once-daily a month ago
Testing confirms sensitivity to grass pollen

46. ? What would you do? Refer to an allergist
9/15/2018 ?
What would you do?
Refer to an allergist
Discuss initiating sublingual immunotherapy
Verify inhaler technique and discuss allergen avoidance
This question is asked again to determine if the learner now feels more comfortable initiating SLIT rather than referring the patient to an allergist.

51. Allergy Immunotherapy: A New Role for the Family Physician
9/15/2018
Allergy Immunotherapy: A New Role for the Family Physician
Thank you!

52. 9/15/2018
Back-up Slides

53. No. of RCTs No. of Patients (n)
AHRQ CER: SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes
Primary Outcome
Results
No. of RCTs No. of Patients (n)
Strength of Evidence
Rhinitis/ rhinoconjunctivitis symptoms
Significant improvement in 73% of studies vs. controls
25 RCTs (n = 1,734)
High
Use of rhinitis/ rhinoconjunctivitis medications
Significantly decreased in 70% of studies vs. controls
10 RCTs (n = 564)
Moderate
Combined rhinitis/ rhinoconjunctivitis symptom and medication score
Significant improvement in 83% of studies vs. controls
6 RCTs (n = 400)
Low
SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (1 of 2)
Rhinitis/rhinoconjunctivitis symptom scores were included from studies that enrolled patients with rhinitis/rhinoconjunctivitis with or without asthma. Nineteen studies (73%) reporting rhinitis/rhinoconjunctivitis symptom scores demonstrated statistically significant improvement in rhinitis/rhinoconjunctivitis symptoms with subcutaneous immunotherapy (SCIT). Overall, 25 randomized controlled trials reported rhinitis/rhinoconjunctivitis symptom scores in 1,734 participants. The overall strength of evidence is high to support that SCIT improves rhinitis/rhinoconjunctivitis symptoms.
Ten studies that included 564 patients reported on rhinitis/rhinoconjunctivitis medication scores. They all used some type of numeric scoring scale for medication use but were inconsistent across studies. Rhinitis/rhinoconjunctivitis medications included oral antihistamines and intranasal corticosteroids. Seven trials demonstrated significant improvement with SCIT. In six of these studies the comparator was placebo, and in one study the comparator was pharmacotherapy. The overall strength of evidence is moderate to support that SCIT decreases medication use for rhinitis/rhinoconjunctivitis.
Six studies that included 400 patients reported combined rhinitis/rhinoconjunctivitis symptom and medication scores. In five studies, nasal, ocular, and bronchial symptoms were scored in addition to medication use, specifically beta-agonist, oral and nasal steroid, and antihistamine use. Only nasal and ocular symptoms were reported along with nasal corticosteroids and antihistamines in one study. Five of the six studies reported a significant improvement in combination symptom plus medication score with SCIT. The overall strength of evidence is low to support that SCIT improves combination symptom plus medication scores.
Reference
Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at
RCT, randomized controlled trial; SCIT, subcutaneous immunotherapy
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at

54. No. of RCTs No. of Patients (n)
AHRQ CER: SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (cont)
Primary Outcome
Results
No. of RCTs No. of Patients (n)
Strength of Evidence
Conjunctivitis symptoms
Significant improvement in 43% of studies vs. placebo
14 RCTs (n = 1,104)
High
Combined symptoms (nasal, ocular, and bronchial)
Significant improvement in 67% of studies vs. placebo
6 RCTs
(n = 591)
Disease-specific quality of life in patients with rhinitis/ rhinoconjunctivitis
Significant improvement by RQLQ in 67% of studies vs. placebo
(n = 889)
SCIT Versus Placebo or Standard Therapy: Rhinitis/Rhinoconjunctivitis Outcomes (2 of 2)
Fourteen subcutaneous immunotherapy (SCIT) studies that included 1,104 patients reported conjunctivitis symptom scores and were included in the strength-of-evidence analysis for this outcome. Six studies demonstrated significant improvement in conjunctivitis symptom scores in the immunotherapy group when compared with placebo. The most commonly evaluated allergen was Timothy grass in five studies. The overall strength of evidence is high to support that SCIT improves allergic conjunctivitis symptoms.
Six rhinitis/rhinoconjunctivitis studies that included 591 individuals reported combined scores including nasal, ocular, and bronchial symptom scores and were included in the strength-of-evidence rating analysis for this outcome. The total symptom scores used numeric scales that were not validated and varied between studies. Three studies showed significant improvement in combined symptom scores when compared with placebo and one study in the comparison of post-treatment symptoms to pretreatment symptoms. The strength of evidence is high to support that subcutaneous immunotherapy improves combined (nasal, ocular, and bronchial) symptoms scores.
Six studies with 889 subjects included quality-of-life outcomes. Four of the six studies reported significant improvement in disease-specific quality of life when compared with placebo. The instruments used to assess quality of life were validated, disease-specific instruments: the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ; adult, pediatric, adolescent, and Japanese-language versions) and/or the Short Form (36) Health Survey (SF-36®). The evidence is high to support that SCIT improves disease-specific quality of life among individuals with rhinitis/rhinoconjunctivitis.
Reference
Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review. Comparative Effectiveness Review No. 111 (Prepared by the Johns Hopkins University Evidence-based Practice Center under Contract No I). AHRQ Publication No. 13-EHC061-EF. Rockville, MD: Agency for Healthcare Research and Quality; March Available at
RCT, randomized controlled trial; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; SCIT, subcutaneous immunotherapy
Lin SY, et al. AHRQ Comparative Effectiveness Review No Available at