Immunotherapy SCIT/SLIT John Oppenheimer MD Rutgers Univ. School of Med

Learning Objectives The participant will be able to: use current guidelines to improve the safety and effectiveness of SCIT and SLIT

Potential Conflicts Consultant/Clinical Research: AZ/BI/Glaxo/Merck/Novartis/Genetech/Meda Associate Editor: Annals of Allergy, Allergy Watch, Current Allergy and Asthma Reports Board of Directors: ABAI

Practice Parameters for IT Initially published in Ann Allergy 2003;90(1) Defined extracts as diagnostic Defined “maintence concentrate” as a vaccine Estimated effective doses Standardized labeling Second Update in JACI. 2007; 120(3) Instead of vaccines now called immunotherapy extracts Effective doses further defined Cross-reactivity patterns refined Compatibility refined Patient vials rather than off the board Standardized forms for skin testing, IT prescriptions and delivery

Practice Parameters for IT Third update Update published in 2011 New requirements for extract preparation USP 797 New indications for immunotherapy Further defined responses to reactions to immunotherapy Medications and immunotherapy reviewed Expanded discussion of SLIT

General Rule for Success Ideally use patient-specific vials Individualized to each patient with identifiers Avoid Multi-patient vials Off the board Include an effective dose of each component Avoid inclusion of cross-reacting antigens Avoid mixing incompatible extracts protease Esch JACI 2008;122:659-660

It works!

18 ANTIGEN E Placebo Aqueous Extract Pollen Count 3500 16 3000 14 2500 12 10 2000 Symptom Index Pollen Count 8 1500 6 1000 4 500 2 15 20 25 30 1 4 5 14 19 24 29 AUGUST SEPTEMBER 1964 Norman J. A. 1968;42:93

3833 16 14 12 10 8 6 4 2 3000 2500 2000 1500 1000 500 AUGUST SEPTEMBER 1965 Symptom Index Pollen Count OCTOBER 18 22 26 30 1 20 24 28 ANTIGEN E Placebo Aqueous Extract Pollen Count

Journal of Allergy and Clinical Immunology 5 SYMPTOM INDEX 15 14 12 10 8 6 4 2 500 1000 1500 2000 2500 3000 AUGUST SEPTEMBER OCTOBER POLLEN COUNT 1967 Antigen E Placebo Aqueous Extract Pollen Count 15 20 25 30 1 5 10 15 20 25 30 8

16 14 ANTIGEN E Placebo Aqueous Extract Pollen Count 2500 12 10 2000 8 Symptom Index 1500 6 Pollen Count 1000 4 2 500 16 20 24 28 2 6 10 14 18 22 26 30 4 8 AUGUST SEPTEMBER OCTOBER Norman JACI 1971;47:273 1968

Usefulness of Immunotherapy in Patients with Severe Summer Hay Fever Uncontrolled by Anti-allergic Drugs 40 adults with severe grass pollen allergy uncontrolled by standard anti-allergic drugs. Two month immunotherapy build-up during April and May, then monthly maintenance. Alum adsorbed extract Varney VA, Gaga M, Frew AJ, Aber VR, Kay AB, Durham SR. BMJ 1991;302:265

Reduction in Rhinitis Symptoms and Medication Use from Immunotherapy 100 Grass Pollen Count 80 Symptoms 150 Drugs IT Treatment IT Treatment 70 Placebo 80 120 Placebo 60 Counts/m 60 50 Median Score 90 Median Score 40 40 60 30 20 20 30 10 24 April 8 22 May 5 19 June 3 17 31 July 14 28 August 11 25 September Varney et al. BMJ. 1991;302:265-269.

Immunotherapy (immunomodulatory) Immunoglobulins Specific IgE decreases Specific IgG increases Cells TH2 to TH1 phenotype switch Mediators IL4 and IL-5 to IL-2 and IFN gamma Local changes Target organ reactivity decreases

Intracellular Expression of IL-10 by CD4+CD25+ Lymphocytes After Immunotherapy PBMCs from IT patients stimulated with P. pratense CD4+CD25+ expression by allergen-stimulated cells Francis JN, et al. J. Allergy Clin. Immunol. 2003;111:1255-61.

Pick the correct dose!

AJ Frew et al. J Allergy Clin Immunol 2006;117:319-25 Efficacy and Safety of Specific Immunotherapy with SQ Allergen Extract in Treatment-resistant Seasonal allergic Rhinoconjunctivitis 347 adults with grass-pollen induced SAR inadequately controlled in previous year by antihistamines, topical steroids and eye drops Randomized to pre-seasonal immunotherapy with timothy grass extract high dose (20 mcg Phl p 5), low dose (2 mcg Phl p 5) or placebo AJ Frew et al. J Allergy Clin Immunol 2006;117:319-25

Efficacy and Safety of Specific Immunotherapy with SQ Allergen Extract in Treatment-resistant Seasonal allergic Rhinoconjunctivitis (Results compared to placebo during peak pollen period) Symptoms Medication High-dose timothy - 32% (p < .0001) - 41% (p < .0001) Low-dose timothy - 19% (p = .014) - 14% (p = .16 NS) Systemic reactions Early (urt or asthma) late (urt, AE, or asthma) (< 1 hour) (1-24 hours) High-dose timothy 9 (4.4%) 39 (16%) Low-dose timothy 0 4 (4%) Placebo 0 2 (2%) AJ Frew et al. J Allergy Clin Immunol 2006;117:319-25

AJ Frew et al. J Allergy Clin Immunol 2006;117:319-25

AJ Frew et al. J Allergy Clin Immunol 2006;117:319-25

Potency of currently available manufacturer’s extracts Extract Potency Cat hair and pelt 5000 and 10,000 BAU/mL Dust mite 3000, 5000, 10,000, and 30,000 AU/mL Bermuda grass 10,000 AU/mL Short ragweed 1:10-1:20 wt/vol or 100,000 AU/mL Other grasses* 10,000 and 100,000 BAU/mL Other pollen 1:10 to 1:40 (wt/vol) or 10,000 PNU/mL Molds 1:10 to 1:40 (wt/vol) or 20,000 to 100,000 PNU/mL AU, Allergy unit; BAU, bioequivalent allergy unit; PNU, protein nitrogen unit. *Perennial rye, Kentucky blue/June, timothy, sweet vernal, redtop, orchard, and meadow.

Probable effective dose range for allergen extracts: US units Antigen Labeled potency or concentration Probable effective dose range Dust mites: (D farinae and D pteronyssinus) 3000, 5000, 10,000, and 30,000 AU/mL 500-2000 AU Cat 5000-10,000 BAU/mL 1000-4000 BAU Grass, standardized 10,000-100,000 BAU/mL 1000-4000 BAU Short ragweed 1:10 to 1:20 wt/vol 100,000 AU/mL 6-12 mg of Amb a 1 (Concentration of Amb a 1 is on the label of wt/vol extracts) 1000-4000 AU Nonstandardized extracts Dog 1:10 to 1:100 wt/vol 15 mcg of Can f 1 Other extracts 1:10 to 1:40 wt/vol or 2.5 to 10mg 10,000-40,000 PNU/mL Highest tolerated dose 22

Median Dosing Recommendations by Board Certified Allergists for Immunotherapy Allergen Mean 25-75 % Effective Timothy 18.6 mcg 7.4 - 35.2 mcg 15.0 mcg Ragweed 26.8 mcg 13.4 - 26.8 mcg 12.0 mcg Dp 4.3 mcg 2.6 - 8.6 mcg 7.0 mcg Df 1.0 mcg 0.6 - 2.0 mcg 10.0 mcg Cat 1.6 mcg 1.0 - 3.0 mcg 11.0 mcg Nelson, HS. JACI 2000;106:41

Prolonged protection!

Subcutaneous Immunotherapy: Effect on Serum Specific IgE Initiation of immunotherapy 70 60 August 50 November Anti - ragweed IgE (ng/ml) 40 30 20 10 baseline year 1 year 2 year 6 year 7 year 8 Peng et al. J Allergy Clin Immunol 1992;89:519

Long-Term Clinical Efficacy of Grass-Pollen Immunotherapy Methods: Randomized, double-blind, placebo-controlled trial of the discontinuation of immunotherapy for grass-pollen allergy in patients in whom three to four years of this treatment had previously been shown to be effective. 921 continued immunotherapy 504 discontinued immunotherapy During the three years of this trial, primary outcome measures were scores for seasonal symptoms and the use of rescue medication. Objective measures included the immediate conjunctival response and the immediate and late skin responses to allergen challenge. A matched group of patients with hay fever who had not received immunotherapy was followed as a control for the natural course of the disease. Durham et al. N Eng J Med 1999;341:468

Long-Term Efficacy of Subcutaneous Immunotherapy 80 Immunotherapy continued 60 40 20 May June July Aug. 1993 Symptom score 1994 1995 Placebo Immunotherapy 80 60 40 20 May June July Aug. Symptom score 1989 Immunotherapy discontinued Durham et al. N Eng J Med 1999;341:468

Long-term benefits of SCIT 6-yr follow-up study of grass pollen IT Symptoms and medication use remained lower in the SCIT group 23% in active IT v. 70% in control group experienced asthma sxs Skin test reactivity remained lower 61% in active IT v. 100% in control developed new sensitizations 6-yr follow-up of tree pollen IT Sxs remained improved at “the same level” in 86% of AR patients Skin test reactivity remained unchanged as at the end of IT Specific IgE remained at the same level as at the end of IT Jacobsen L et al. Allergy 1997; 52:914-20. Eng PA et al. Allergy 2012;57:306-12

Break Even Point For Cost Effectiveness of SCIT v Break Even Point For Cost Effectiveness of SCIT v. Nasal Corticosteroids Design: To determine the timing at which initiation of specific IT becomes more cost-effective than continued nasal steroid therapy in the treatment of allergic rhinitis using a decision- making model. Results: For patients with seasonal allergic rhinitis requiring NS 3 months and 4 months per year, the age at which initiation of IT provides long- term direct cost advantage is less than 41 years and 50 years, respectively. For patients with perennial rhinitis symptoms requiring year-round NS, the cut-off age for IT raises to 65 years. *Kennedy, J, L Borish, D Robinson, J Christophel, and S Payne S Annals of Allergy, Asthma & Immunology 2011;107:A35.

Could IT Prevent New Sensitization or Prevent Asthma?

Prevention of New Sensitizations in Asthmatic Children Monosenstized to HDM by Specific IT. A Six year F/U Methods 134 children (5-8 yo) with intermittent asthma +/- AR monosensitized to HDM Parents of 75 children accepted IT Parents of 63 declined IT IT x 3yrs with f/u for 3 further yrs Maintenance dose was ½ usual adult dose Pajno GB Clin Exp All 2001;31:1392-7

Prevention of New Sensitizations in Asthmatic Children Monosenstized to HDM by Specific IT. A Six year F/U Results At the end of 6 yrs, new sensitizations occurred in: IT 17/69 (24.5%) No IT 36/54 (66.7%) Pajno GB Clin Exp All 2001;31:1392-7

Back to our rules for Success

Significant Cross-Allergenicity Among Trees Birch family: birch, elder, hazelnut, hornbeam Olive family: European olive, ash, privet, Russian olive (botanically unrelated) Conifer family: cedar, cypress, juniper, arbor vitae. Fagaceae family: beech, oak Carya genus: pecan, hickory Populus genus: poplar, cottonwood, aspen Use major local species for each group

Botonical Relationships Among the Grasses Festucoideae: Northern pasture grasses (timothy, orchard, June, red top, rye, etc) Eragrostoideae: Bermuda, grama, and several Western prairie grasses. Pancoideae: Bahia and Johnson grass Use timothy +/- other NPGs (but reduce amount of each. Use Bermuda/Bahia/Johnson if locally important

Botanical Relationships Among the Weeds AMBROSIA: ragweeds,cocklebur, burweed marsh elder ARTEMESIA: sages, wormwood, mugworts AMARANTHS: pigweed, western water hemp, Palmer’s amaranth Use locally important species CHENOPHODS: Russian thistle, kochia, lambs quarters, atriplex species Treat both RT and Kochia if locally important

Protease Content of Various Extracts Trypsin Equivalent Pollens < 1 g Cat & dog dander < 1g House dust mites (US) < 5 g Alternaria alternata 29 g American cockroach 168 g Aspergillus fumigatus 212 g Penicillium notatum 242 g Robert Esch PhD, Greer Laboratories

Fig 1. Combinations producing low (X), moderate or risky (Ø), and favorable (+) compatibilities when allergenic extracts are mixed with protease-containing insect, fungal, and mite extracts are shown. Esch JACI 2008;122:659-660 38

IT and Asthma Cochrane Analysis 75 trials involving 3,506 subjects 3188 with asthma Conclusions: IT: significantly reduces SX significantly reduces Rx required No consistent effect on lung function Less likely to develop BHR Modest improvement in nonspecific BHR Significantly reduces allergen specific BHR Abramson MJ Cochrane Database 2006

Allergen IT versus placebo, Asthma symptom scores Abramson MJ Cochrane Database 2006

Injection allergen immunotherapy for asthma. Objectives The objective of this review was to assess the effects of allergen specific immunotherapy for asthma. Search methods The authors searched the Cochrane Airways Group Trials Register up to 2005, Dissertation Abstracts and Current Contents. Selection criteria Randomized controlled trials using various forms of allergen specific immunotherapy to treat asthma and reporting at least one clinical outcome. Data collection and analysis Three authors independently assessed eligibility of studies for inclusion. Two authors independently performed quality assessment of studies. Abramson Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD001186.

Injection allergen immunotherapy for asthma. Main results Eighty-eight trials were included. There were 42 trials of immunotherapy for house mite allergy; 27 pollen allergy trials; 10 animal dander allergy trials; two Cladosporium mold allergy, two latex six trials looking at multiple allergens. Concealment of allocation was assessed as clearly adequate in only 16 of these trials. Significant heterogeneity was present in a number of comparisons. Abramson Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD001186.

Injection allergen immunotherapy for asthma. Main results Overall, there was a significant reduction in asthma symptoms and medication, and improvement in bronchial hyper-reactivity following immunotherapy. There was a significant improvement in asthma symptom scores (standardized mean difference -0.59, 95% confidence interval -0.83 to -0.35) and it would have been necessary to treat three patients (95% CI 3 to 5) with immunotherapy to avoid one deterioration in asthma symptoms. Allergen immunotherapy significantly reduced allergen specific BHR, with some reduction in non-specific BHR as well. There was no consistent effect on lung function. If 16 patients were treated with immunotherapy, one would be expected to develop a local adverse reaction. If nine patients were treated with immunotherapy, one would be expected to develop a systemic reaction (of any severity). Abramson Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD001186.

Injection allergen immunotherapy for asthma. Authors’ conclusions Immunotherapy reduces asthma symptoms and use of asthma medications and improves bronchial hyper-reactivity. One trial found that the size of the benefit is possibly comparable to inhaled steroids. The possibility of local or systemic adverse effects (such as anaphylaxis) must be considered. Abramson Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD001186.

Safety of Immunotherapy Fatalities occur at a rate of 1 per 2.5 million injections (3.4/yr in the US/Canada) Vast majority occur in asthmatics Fatalities associated with: Poorly controlled asthma Delayed administration of epinephrine / resuscitation efforts SCIT must be administered in a setting where prompt recognition and treatment of anaphylaxis is assured Epi 0.3-0.5 cc 1:1000 IM Patients must remain in the physician’s office at least 20 mins (AR) - 30 mins (asthmatics) after an injection Bernstein DI et al. J Allergy Clin Immunol 2004;113:1129-36

SLIT

SLIT Approved Doses PI Oralair ORALAIR® (Sweet Vernal, Orchard, Perennial Rye, Timothy, and Kentucky BlueGrass Mixed Pollens Allergen Extract) PI Oralair

SLIT Approved Doses Grastek=Timothy grass 2800BAUs SL tablet 5-65 yrs 1 Tab QD Ragwitek=Short RW 12 Amb a 1 unit SL tab 18-65 yrs 1 Tab QD Medical Letter 2014;56:47

Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: The importance of allergen-specific serum IgE Objectives: We sought to evaluate the efficacy and safety of 300 index of reactivity (IR) 5- grass pollen sublingual tablet in US adults. Methods: Adults with grass pollen allergy and Rhinoconjunctivitis Total Symptom Scores of 12 or greater(scale,0-18) during the previous grass pollen season were randomized in a double-blind, placebo-controlled study to receive 300IR 5- grass pollen sublingual tablet or placebo starting 4 months before and continuing through the pollen season. The primary efficacy end point was the daily Combined Score (CS; scale, 0-3), which integrates symptoms and rescue medication use. Cox JACI 2012;130:1327-34

Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: The importance of allergen-specific serum IgE Results: Four hundred seventy-three participants were randomized. The mean daily CS over the pollen period was significantly lower in the active treatment group versus the placebo group (least-squares mean difference: -0.13; 95% CI, -0.19 to -0.06; P=.0003; relative reduction: 28.2%; 95% CI, 13.0% to 43.4%). In placebo-treated participants, the daily CS least-squares mean was 0.32 in the subgroup with baseline timothy grass–specific serum IgE of less than 0.1 kU/L (n=23) and 0.46 in those with baseline timothy grass–specific serum IgE of 0.1 kU/L or greater (n=204). The most frequent reported adverse events were oral pruritus, throat irritation, and nasopharyngitis. There were no reports of anaphylaxis, and no actively treated participant received epinephrine Cox JACI 2012;130:1327-34

Fig 3. Mean daily CS and pollen count Overall Δ P=0.0003 Cox JACI 2012;130:1327-34

FIG 4. RQLQ scores: change from baseline to the expected middle of the grass pollen period (FAS). Vertical bars are 95% CIs. Overall P=.0042 Cox JACI 2012;130:1327-34

Randomized controlled trial of ragweed allergy immunotherapy tablet efficacy and safety in North American adults Methods Adults with ragweed pollen–induced AR/C were randomized 1:1:1 to daily ragweed AIT (6 or 12 Amb a 1 units) or placebo before, throughout, and after ragweed season Patients could use predefined allergy rescue medications in season. Efficacy end points included peak and entire season total combined score (TCS) and its components daily symptom score (DSS), and daily medication score (DMS). Safety assessments included adverse events.

Randomized controlled trial of ragweed allergy immunotherapy tablet efficacy and safety in North American adults Results A total of 565 patients were randomized. During peak season, the 6– and 12–Amb a 1 unit ragweed AIT doses showed 21% (−1.76 score) and 27% (−2.24 score) improvement in TCS vs placebo ( P < .05). The 6– and 12–Amb a 1 unit AIT doses significantly improved DSS and DMS vs placebo ( P < .05). Peak and entire season efficacy were comparable. The 12–Amb a 1 unit AIT dose reduced peak-season TCS vs placebo by 21% and 25% in subgroups with and without local application-site reactions, respectively. Most treatment-related adverse events were mild, oral reactions; no systemic allergic reactions were reported. One patient in the 6–Amb a 1 unit group received epinephrine at an emergency facility for sensation of localized pharyngeal edema.

Ragweed Slit in North American Adults Total combined score plotted against pollen count Nolte, H., et al. Annals Allergy, Asthma, Immunol. 2013;110:450-8

Ragweed Slit in North American Adults Total combined score during the peak and entire ragweed season (RS) % of patients reporting rescue medication use during peak ragweed season *RS=ragweed season Nolte, H., et al. Annals Allergy, Asthma, Immunol. 2013;110:450-8

Safety and tolerability of a short ragweed sublingual immunotherapy tablet Methods: Data from 4 randomized, double-blinded, placebo-controlled trials of MK-3641 (2 28-day and 2 52-week trials) were evaluated. Pooled analyses examined short-term safety over 28 days from all 4 trials and long-term safety from the 52-week trials. Results: Across studies,757,198,454,and1,058subjects were randomized to placebo or 1.5,6,or12Amba1-U ofMK-3641,respectively. Treatment-related adverse events were more frequent in the 6-and12-Amba1-UMK-3641 groups than in the placebo group and were primarily local application-site reactions occurring in the first few days of treatment. There was no treatment-associated loss of asthma control or worsening of asthma associated with treatment. No swellings led to airway obstruction or respiratory compromise. No treatment-related anaphylactic shock, life-threatening, or serious treatment-related adverse events were reported for any MK- 3641 dose. Of the 1,707 MK-3641-treated subjects,1 systemic (anaphylactic) reaction was reported (0.06%). The 52-week long-term assessment was generally similar to the safety profile based on the 28-day assessment Nolte Ann Allergy Asthma Immunol 2014;113:93-100

Table 4: Adverse event summary (all treated subjects) for pooled analyses Nolte Ann Allergy Asthma Immunol 2014;113:93-100

Table 5 All treatment-related AE occurring in at least 5% of subjects in any treatment group in the pooled analyses Nolte Ann Allergy Asthma Immunol 2014;113:93-100

Long-lasting effects of sublingual immunotherapy according to its duration: A 15-year prospective study Methods: In this prospective open controlled study we followed up patients with respiratory allergy who were monosensitized to mites for 15 years. The subjects were divided in 4 groups receiving drug therapy alone or SLIT for 3, 4, or 5 years. Clinical scores, skin sensitizations, methacholine reactivity, and nasal eosinophil counts were evaluated every year during the winter months. The clinical effect was considered to persist until clinical scores remained at less than 50% of the baseline value, and then patients underwent another course of SLIT. Marogna JACI 2010;126:969-75

Long-lasting effects of sublingual immunotherapy according to its duration: A 15-year prospective study Results: Seventy-eight patients were enrolled, and 59 completed the study. In the 12 control subjects no relevant change in clinical scores was seen throughout the study. In the patients receiving SLIT for 3 years, the clinical benefit persisted for 7 years. In those receiving immunotherapy for 4 or 5 years, the clinical benefit persisted for 8 years. New sensitizations occurred in all the control subjects over 15 years and in less than a quarter of the patients receiving SLIT (21%, 12%, and 11%, respectively). The second course of vaccination induced a benefit more rapidly than the first course. Marogna JACI 2010;126:969-75

FIG 2. Mean monthly SMSs (means and SDs) throughout the 15 years of the study in patients in the SLIT3 (A), SLIT4 (B), and SLIT5 (C) groups. Marogna JACI 2010;126:969-75

FIG 4. Percentage of patients with at least 1 new skin sensitization in the SLIT3 (blue line), SLIT4 (red line), SLIT5 (green line), and control (black line) groups. The asterisk indicates the significant difference versus the control group. Marogna JACI 2010;126:969-75

Anaphylaxis to SLIT Allergen Build-Up or Maintenance Symptoms Reference Multiple Build-Up Pruritus, wheezing, dizziness Allergy 2006;61:1235 Maintenance Urticaria, asthma, “anaphylactic shock” Allergy 2007;62:567 HDM Maintenance (3 yrs) Urticaria, wheezing, hypotension, syncope Allergy 2008;63:374 Grass (2) 1st Dose Hypotension Allergy 2009;64:963-4 No fatal or near-fatal reactions have been reported FDA requires epipen

Lin et al. AHRQ

Relative to a control group: Evidence for the Efficacy and Effectiveness of Subcutaneous Immunotherapy in the Treatment of Rhinitis and Rhinoconjunctivitis Key Points Relative to a control group: High grade evidence supports that subcutaneous immunotherapy improves rhinoconjunctivitis symptoms, based on 26 randomized controlled trials with 1764 subjects. High grade evidence supports that subcutaneous immunotherapy improves conjunctivitis symptoms, based on 14 randomized controlled trials with 1104 subjects. High grade evidence supports that subcutaneous immunotherapy improves control of combined nasal, ocular, and bronchial symptoms, based on six randomized controlled trials with 591 subjects. Lin et al. AHRQ

Evidence for the Efficacy and Effectiveness of Subcutaneous Immunotherapy in the Treatment of Rhinitis and Rhinoconjunctivitis Key Points. Moderate grade evidence supports that subcutaneous immunotherapy decreases rhinoconjunctivitis medication use, based on ten randomized controlled trials with 564 subjects High grade evidence supports that subcutaneous immunotherapy decreases combined medication use (rhinitis/rhinoconjunctivitis plus asthma medication use), based on 11 randomized controlled trials with 768 subjects. Low grade evidence supports that subcutaneous immunotherapy improves rhinoconjunctivitis (with or without asthma) combined symptom-medication scores, based on six randomized controlled trials with 400 subjects. High grade evidence supports that subcutaneous immunotherapy improves disease specific quality of life, based on six randomized controlled trials with 889 subjects. Lin et al. AHRQ

Effectiveness of sublingual immunotherapy in the treatment of allergic rhinitis/rhinoconjunctivitis and/or asthma Key Points • High grade evidence supports that sublingual immunotherapy improves asthma symptoms based on 13 randomized controlled trials with 625 subjects. • Moderate grade evidence supports that sublingual immunotherapy improves asthma or rhinitis/rhinoconjunctivitis (asthma combined scores) symptom control based on 5 randomized controlled trials with 308 subjects. • Moderate grade evidence supports that sublingual immunotherapy improves rhinitis/rhinoconjunctivitis symptoms based on 35 randomized controlled trials with 2658 subjects.

Effectiveness of sublingual immunotherapy in the treatment of allergic rhinitis/rhinoconjunctivitis and/or asthma Key Points Moderate grade evidence supports that sublingual immunotherapy improves control of conjunctivitis symptoms based on 13 randomized controlled trials with 1074 subjects. • Moderate grade evidence supports that sublingual immunotherapy decreases medication use based on 38 randomized controlled trials with 2724 subjects. • Moderate grade evidence supports that sublingual immunotherapy improves allergy symptoms or decreases medication use based on 19 randomized controlled trials with 1462 subjects. • Moderate grade evidence supports that sublingual immunotherapy improves disease specific quality of life based on eight randomized controlled trials with 819 subjects.

Evidence for the safety of sublingual immunotherapy in patients with allergic rhinitis/rhinoconjunctivitis and/or asthma Key Points • Local reactions (occurring at the site of allergen administration) were common across trials • Systemic reactions were uncommon • No life threatening systemic reactions or anaphylaxis were reported in these trials • No deaths were reported Lin et al. AHRQ

Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy Objective: To assess levels and predictors of compliance and persistence among grass pollen, tree pollen, and house dust mite immunotherapy users in real life and to estimate the costs of premature discontinuation. Methods: performed a retrospective analysis of a community pharmacy database from The Netherlands containing data from 6486 patients starting immunotherapy for1 or more of the allergens of interest between 1994 and 2009. Two thousand seven hundred ninety-six patients received SCIT,and 3690 received SLIT. Time to treatment discontinuation was analyzed and included Cox proportional hazard models with time-dependent covariates, where appropriate. Kiel JACI 2013;132:353-60

Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy Results: Overall, only 18% of users reached the minimally required duration of treatment of 3 years (SCIT, 23%; SLIT, 7%). Median durations for SCIT and SLIT users were 1.7 and 0.6 years, respectively (P < .001). Other independent predictors of premature discontinuation were prescriber, with patients of general practitioners demonstrating longer persistence than those of allergologists and other medical specialists; single allergen immunotherapy, lower socioeconomic status; and younger age. Of the persistent patients, 56% were never late in picking up their medication from the pharmacy. Direct medication costs per non-persistent patient discontinuing in the third year of treatment were €3800, an amount that was largely misspent. Kiel JACI 2013;132:353-60

Fig 2: Kaplan-Meier curse of time to treatment discontinuation by route of administration of allergen Kiel JACI 2013;132:353-60

Studies Directly Comparing SLIT and SCIT Adherencea

Improved Adherence = Communicate and Educate When the physician’s goal for AIT does not match the patient’s goal, adherence is likely to be poor Differences in goals and patient expectations must be discussed and resolved before the treatment plan is finalized Shared decision-making is a communication strategy to increase concordance about treatment choices and goals and leads to higher adherence in patients with asthma Bender B, Oppenheimer J, J Allergy Clin: In Practice 2014;2:152-5.

Questions that still remain Efficacy of SCIT vs. SLIT Long term safety studies in SLIT Will we need to prescribe AIE in the future Multiple allergen sensitivity and SLIT Other forms of IT Intralymphatic IT