Immunotherapy SCIT/SLIT

1
Immunotherapy SCIT/SLIT

• John Oppenheimer MD
• Rutgers Univ. School of Med

2
Learning Objectives

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

3
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

4
Practice Parameters for IT

• Initially published in Ann Allergy 200390(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

5
Practice Parameters for ITThird 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

6
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 2008122659-660
7
It works!
8
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
0
0
15
20
25
30
1
4
5
14
19
24
29
AUGUST
SEPTEMBER
1964
Norman J. A. 19684293
9
3833
ANTIGEN E Placebo Aqueous Extract Pollen Count
10
Journal of Allergy and Clinical Immunology
Antigen E
Placebo
Aqueous Extract
Pollen Count
15
20
25
30
1
5
15
10
20
25
30
8
11
16
14
ANTIGEN E Placebo Aqueous Extract Pollen Count
2500
12
10
2000
8
Symptom Index
1500
6
Pollen Count
1000
4
2
500
0
0
6
14
4
20
24
28
2
10
22
18
26
30
8
16
AUGUST
OCTOBER
SEPTEMBER
Norman JACI 197147273
1968
12
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 1991302265
13
Reduction in Rhinitis Symptoms and Medication
Use from Immunotherapy
150
Drugs
100
Symptoms
80
Grass Pollen Count
IT Treatment
IT Treatment
70
Placebo
Placebo
120
80
60
50
Median Score
90
60
Counts/m
Median Score
40
60
40
30
20
30
20
10
0
0
0
24 April
8 22 May
5 19 June
3 17 31 July
14 28 August
11 25 September
Varney et al. BMJ. 1991302265-269.
14
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

15
Intracellular Expression of IL-10 by CD4CD25
Lymphocytes After Immunotherapy
Francis JN, et al. J. Allergy Clin. Immunol.
20031111255-61.
16
Pick the correct dose!
17
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
2006117319-25
18
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 MedicationHigh-dose timothy -
  32 (p lt .0001) - 41 (p lt .0001)Low-dose
  timothy - 19 (p .014) - 14 (p .16 NS)
• Systemic reactions Early (urt or asthma) late
  (urt, AE, or asthma) (lt 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
2006117319-25
19
AJ Frew et al. J Allergy Clin Immunol
2006117319-25
20
AJ Frew et al. J Allergy Clin Immunol
2006117319-25
21
Potency of currently availablemanufacturers
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 110-120 wt/vol or 100,000 AU/mL
• Other grasses 10,000 and 100,000 BAU/mL
• Other pollen 110 to 140 (wt/vol) or 10,000
  PNU/mL
• Molds 110 to 140 (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.

22
Probable effective dose range for allergen
extracts US units

• Antigen Labeled potency or concentration
  Probable effective dose range
• Dust mites (D farinaeand 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 110 to 120 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 110 to 1100 wt/vol 15 mcg of Can f 1
• Other extracts 110 to 140 wt/vol or 2.5 to 10mg
  
• 10,000-40,000 PNU/mL Highest tolerated dose

23
Median Dosing Recommendations by Board Certified
Allergists for Immunotherapy

• Allergen Mean 25-75 EffectiveTimothy 18
  .6 mcg 7.4 - 35.2 mcg 15.0 mcgRagweed 26.8
  mcg 13.4 - 26.8 mcg 12.0 mcgDp 4.3 mcg 2.6
  - 8.6 mcg 7.0 mcgDf 1.0 mcg 0.6 - 2.0
  mcg 10.0 mcgCat 1.6 mcg 1.0 - 3.0 mcg 11.0
  mcg

Nelson, HS. JACI 200010641
24
Prolonged protection!
25
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 7
year 8
year 6
Peng et al. J Allergy Clin Immunol 199289519
26
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 1999341468
27
Long-Term Efficacy of Subcutaneous Immunotherapy
Durham et al. N Eng J Med 1999341468
28
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 52914-20. Eng PA
et al. Allergy 201257306-12
29
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 2011107A35.
30
Could IT Prevent New Sensitization or Prevent
Asthma?
31
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 2001311392-7
32
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 2001311392-7
33
Back to our rules for Success
34
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

35
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 grassUse timothy
  /- other NPGs (but reduce amount of each.Use
  Bermuda/Bahia/Johnson if locally important

36
Botanical Relationships Among the Weeds

• AMBROSIA ragweeds,cocklebur, burweed marsh elder
• ARTEMESIA sages, wormwood, mugworts
• AMARANTHS pigweed, western water hemp, Palmers
  amaranth
• Use locally important species
• CHENOPHODS Russian thistle, kochia, lambs
  quarters, atriplex speciesTreat both RT and
  Kochia if locally important

37
Protease Content of Various Extracts

• Trypsin Equivalent
• Pollens lt 1 ?g
• Cat dog dander lt 1?g
• House dust mites (US) lt 5 ?g
• Alternaria alternata 29 ?g
• American cockroach 168 ?g
• Aspergillus fumigatus 212 ?g
• Penicillium notatum 242 ?g

Robert Esch PhD, Greer Laboratories
38
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 2008122659-660
39
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
40
Allergen IT versus placebo, Asthma symptom scores
Abramson MJ Cochrane Database 2006
41
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.
42
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.
43
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.
44
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.
45
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 11000 IM
• Patients must remain in the physicians office at
  least 20 mins (AR) - 30 mins (asthmatics) after
  an injection

Bernstein DI et al. J Allergy Clin Immunol
20041131129-36
46
SLIT
47
SLIT Approved Doses

• ORALAIR
• (Sweet Vernal, Orchard, Perennial Rye, Timothy,
  and Kentucky BlueGrass Mixed Pollens Allergen
  Extract)

PI Oralair
48
SLIT Approved Doses

• GrastekTimothy grass 2800BAUs SL tablet
  5-65 yrs 1 Tab QD
• RagwitekShort RW 12 Amb a 1 unit SL tab 18-65
  yrs 1 Tab QD

Medical Letter 20145647
49
Clinical efficacy of 300IR 5-grass pollen
sublingual tablet ina 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 20121301327-34
50
Clinical efficacy of 300IR 5-grass pollen
sublingual tablet ina 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 grassspecific serum IgE of less
  than 0.1 kU/L (n23) and 0.46 in those with
  baseline timothy grassspecific serum IgE of 0.1
  kU/L or greater (n204).
• 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 20121301327-34
51
Fig 3. Mean daily CS and pollen count
Overall ? P0.0003
Cox JACI 20121301327-34
52
FIG 4. RQLQ scores change from baseline to the
expected middle of thegrass pollen period (FAS).
Vertical bars are 95 CIs.
Overall P.0042
Cox JACI 20121301327-34
53
Randomized controlled trial of ragweed allergy
immunotherapy tablet efficacy and safety in North
American adults

• Methods
• Adults with ragweed polleninduced AR/C were
  randomized 111 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.

54
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 12Amb a 1 unit
  ragweed AIT doses showed 21 (-1.76 score) and
  27 (-2.24 score) improvement in TCS vs placebo (
  P lt .05).
• The 6 and 12Amb a 1 unit AIT doses
  significantly improved DSS and DMS vs placebo ( P
  lt .05).
• Peak and entire season efficacy were comparable.
  The 12Amb 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 6Amb a 1 unit group received
  epinephrine at an emergency facility for
  sensation of localized pharyngeal edema.

55
Ragweed Slit in North American Adults
Total combined score plotted against pollen count
Nolte, H., et al. Annals Allergy, Asthma,
Immunol. 2013110450-8
56
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
RSragweed season
Nolte, H., et al. Annals Allergy, Asthma,
Immunol. 2013110450-8
57
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 201411393-100
58
Table 4 Adverse event summary (all treated
subjects) for pooled analyses
Nolte Ann Allergy Asthma Immunol 201411393-100
59
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 201411393-100
60
Long-lasting effects of sublingual
immunotherapyaccording 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 2010126969-75
61
Long-lasting effects of sublingual
immunotherapyaccording 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 2010126969-75
62
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 2010126969-75
63
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 2010126969-75
64
Anaphylaxis to SLIT
Allergen Build-Up or Maintenance Symptoms Reference
Multiple Build-Up Pruritus, wheezing, dizziness Allergy 2006611235
Multiple Maintenance Urticaria, asthma, anaphylactic shock Allergy 200762567
HDM Maintenance (3 yrs) Urticaria, wheezing, hypotension, syncope Allergy 200863374
Grass (2) 1st Dose Hypotension Allergy 200964963-4
No fatal or near-fatal reactions have been
reported FDA requires epipen
65
Lin et al. AHRQ
66
Evidence for the Efficacy and Effectiveness of
SubcutaneousImmunotherapy 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
67
Evidence for the Efficacy and Effectiveness of
SubcutaneousImmunotherapy 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
68
Effectiveness of sublingual immunotherapy in the
treatment of allergicrhinitis/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.

69
Effectiveness of sublingual immunotherapy in the
treatment of allergicrhinitis/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.

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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
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Real-life compliance and persistence among users
ofsubcutaneous 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 2013132353-60
72
Real-life compliance and persistence among users
ofsubcutaneous 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 lt .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 2013132353-60
73
Fig 2 Kaplan-Meier curse of time to treatment
discontinuation by route of administration of
allergen
Kiel JACI 2013132353-60
74
Studies Directly Comparing SLIT and SCIT
Adherencea
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Improved Adherence Communicate and Educate

• When the physicians goal for AIT does not match
  the patients 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 20142152-5.
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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

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