2. Outline
âȘ Background and basic knowledge
âȘ SLIT in the past
âȘ Whatâs new (2016-2017)
âȘ Practice Parameter 2017
âȘ EAACI SLIT Aeroallergen 2017
âȘ EAACI SLIT Food Allergy 2017
âȘ HDM SLIT in Japan 2017
âȘ Pollen SLIT 2017
âȘ Polyallergen SLIT
3. Background
âȘ The history of modern immunotherapy started after the breakthrough discovery of anaphylaxis
in 1902 by Richet and Portier
âȘ Who first observed severe allergic reactions while studying the toxicity of jellyfish in dogs
âȘ Regimens of repeated allergen exposure, leading to a state of âtoleranceâ or âspecific
desensitization
âȘ With this insight, the field of clinical allergen-specific immunotherapy (SIT) was born. Protocols
to desensitize humans were developed, especially using the subcutaneous route
âȘ The sublingual route has been shown to be the safest and most effective alternative route
Middleton. Ed 8th
4. Therapeutic regimens
âȘ Several large clinical trials have shown SLIT to be clinically effective, improving allergic rhinitis
and asthma symptoms and reducing requirements for rescue medication
âȘ The allergen is held under the tongue for 2 minutes to allow optimal contact with the oral
mucosa before being swallowed.
âȘ SLIT delivers high doses of allergens, at 50- to 100-fold the doses used for subcutaneous
immunotherapy (SCIT)
âȘ Proposed duration of treatment vary across the studies, but overall therapy for more than 12
months seems to be more effective, with 3 years suggested when grass pollen tablets are used
Middleton. Ed 8th
5. Mucosal Tolerance
âȘ In mouse models, oral tolerance can be induced either by a single high dose of antigen or by
repeated administration of lower doses.
âȘ High-dose tolerance appears to involve
âȘ Clonal T cell anergy
âȘ T cell failing to proliferate or to produce interleukin-2 (IL-2)
âȘ Involve deletion of relevant T cells.
âȘ Low-dose exposure is mediated by regulatory T cells (Tregs), which actively control tolerance,
preventing responses to food antigens and bacterial microflora.
âȘTolerance can also be induced by T helper type 3 (Th3) cells
âȘ Use transforming growth factor-ÎČ1 (TGF-ÎČ1) to achieve tolerance
Middleton. Ed 8th
6. Mucosal Tolerance
âȘ Tolerance in humans may be induced by several mechanisms
âȘ Induction of secretory immunoglobulin A (IgA) antibodies, which bind foreign proteins and prevent their
entry into the body without causing local inflammation
âȘ Relevant mechanism is the development of Tregs
âȘ Suppression by direct cell-cell contact or through soluble immunoregulatory cytokines : IL-10, TGF-ÎČ1
âȘ Deplete T cell numbers and induce T cell anergy
âȘ Unlike the intestinal mucosa, which has areas of organized mucosa-associated lymphoid tissue
that serve as inductive sites for the immune response, the oral mucosa has no organized
aggregates of lymphoid cells.
Middleton. Ed 8th
7. Immunological mechanism
âȘ Molecular and cellular mechanisms include
âȘ Increased suppressor capacity of CD4+CD25+ forkhead box P3+ protein (Foxp3+) Tregs
âȘ Enhanced suppressor activity of IL-10âsecreting type 1 Tregs (Tr1)
âȘ Suppression of eosinophils, mast cells, and basophils; and antibody isotype switching from IgE to IgG4
âȘ Current data suggest that
âȘ Regulatory IL-10âproducing Th1 cells are pivotal to the various changes induced by SIT.
âȘ This may be driven by triggering TLRs on DCs, creating the necessary microenvironment for Tr1
induction
8. Immunological mechanism
âȘ Chronic allergen exposure
âȘ Favor expansion of Th1-like Tr1 cells through IL-12 and IL-27 synthesis, delta-4 expression on APCs.
âȘ Recruitment of these cells into areas of inflammation will lead to amplification of local cytokine
responses (IL-12, IL-10, and TGF-ÎČ1)
âȘ The IL-12 will skew any Th2 and Th17 cells toward the Th1 phenotype,
âȘ IL-10 suppresses allergen-specific Th2 and Th17 responses, induces IgG4, and inhibits recruitment of
mast cells, basophils, and eosinophils
11. Practice Parameter 2011
âȘAllergen extracts can be administered through several routes in addition to the subcutaneous
route. Currently, there are no FDA-approved formulations for a noninjection immunotherapy
extract. A
⊠The oral approach has been largely abandoned for inhalant allergens but has been pursued for
treatment of food allergy in children
⊠Immunotherapy for inhalant allergens through the oral route is limited to sublingual administration
(SLIT)
12. Practice Parameter 2011
âȘRandomized controlled clinical trials with dust mite and pollen sublingual immunotherapy have
demonstrated significant improvement in symptoms and medication use in patients with allergic
rhinitis and asthma. A
⊠Several meta-analyses conclude that SLIT is effective in the treatment of allergic rhinitis and allergic
asthmain adults and children
⊠Studies of SLIT have shown that it can reduce new sensitization, methacholine sensitivity, and the onset
of asthma
⊠SLIT improves mild-to-moderate atopic dermatitis caused by house dust mite sensitivity
⊠SLIT increases the tolerance to hazelnuts in allergic subjects, some of whom have had anaphylactic
reactions
13. Practice Parameter 2011
âȘLocal reactions, primarily oral mucosal, are common with sublingual immunotherapy.
âȘSystemic reactions can occur, and a few have been reported in subjects who were unable to
tolerate subcutaneous immunotherapy.
âȘA few reported cases have been of a severity to be categorized as anaphylaxis. A
âȘ Patients receiving grass tablets without build-up,
âȘ oral pruritus reported by 46%
âȘ edema of the mouth 18%
14. Practice Parameter 2011
âȘClinical trials evaluating the safety and efficacy of sublingual immunotherapy for patients with
ragweed- and grass pollenâinduced allergic rhinitis. Currently, there are no FDA-approved
formulations for sublingual immunotherapy. A
18. Oral allergy syndrome
- A trial of liquid SLIT for birch pollen allergy: not show efficacy in OAS
- The result: Mal d 1 is suitable allergen for SLIT treatment birch pollen-related apple allergy
Food allergy
- Several clinical trial (phrase 1,2 in US): SLIT milk, peanut, kiwi, peach
- No described routine clinical experience using liquid SLID for food allergy
Latex allergy
- SCIT and SLIT latex were effective in reducing symptoms
- Clinical trial: inconsistent results and limited research in SLIT
Atopic dermatitis
- RCT SLIT HDM significant improve SCORAD in mild-moderate AD
- Adult AD: SLID HDM improve visual analog score at 12 mo , no evidence SLIT other allergen
VIT
- Limit data SLIT venom
- Not recommend for treatment venom allergy
19. Description of Methods Used to
Formulate the Recommendations
âȘThe FDA had approved 3 sublingual products, all of which are tablet formulations (short
ragweed, Timothy pollen, and 5-grass pollen).
âȘBoth the Timothy grass SLIT tablet and the 5-grass tablet have demonstrated clinical benefits
beginning in the first year of a 3-year treatment
Matthew Greenhawt. Practice parameter.2017
20. Grading System for SLIT Local Reactions
Matthew Greenhawt. Practice parameter.2017
21. Summary Statement
âȘSummary Statement 1:
Only use FDA-approved SLIT products for the treatment of allergic
rhinitis/rhinoconjunctivitis and not for any other related or unrelated condition. (Strength of
Recommendation: Strong; Evidence: A/B)
âȘSummary Statement 2:
The physician should be aware that SLIT may not be suitable in patients with certain
medical conditions, particularly those that may reduce the patientâs ability to survive a systemic
reaction or the resultant treatment of the systemic reaction. (Strength of Recommendation:
Strong; Evidence: D)
Matthew Greenhawt. Practice parameter.2017
22. Summary Statement
âȘSummary Statement 3:
Use FDA-approved SLIT products very cautiously in the pregnant or breastfeeding
patient because there are insufficient data regarding the safety of initiating or continuing SLIT
during either pregnancy or breastfeeding. (Strength of Recommendation: Weak; Evidence: C)
âȘSummary Statement 4:
Do not assume dosing equivalence between SLIT tablets and extracts of the same
allergen. There are no direct comparisons between the same allergen extract administered as a
SLIT tablet vs as an aqueous SLIT extract. Each formulation has to have its own safety profile
established. (Strength of Recommendation: Weak; Evidence: C)
Matthew Greenhawt. Practice parameter.2017
23. Summary Statement
âȘSummary Statement 5:
Administer the patientâs first dose of SLIT in a medical facility under the supervision of a
physician or other health care professional with experience in the diagnosis and treatment of
anaphylaxis. The patient should be observed in the clinic or medical facility for 30 minutes after
the administration of the SLIT dose. (Strength ofRecommendation: Strong; Evidence: D)
âȘSummary Statement 6:
Prescribe epinephrine (either an autoinjector or other form for self-injection) to patients
receiving SLIT tablets. Recommendations for when to withhold the SLIT tablet dose to avoid
potential situations when systemic allergic reactions may be more likely should also be provided.
(Strength of Recommendation: Strong; Evidence: D)
Matthew Greenhawt. Practice parameter.2017
24. Summary Statement
âȘSummary Statement 7:
Reduce a patientâs SLIT dose if they have missed treatment for more than 7 days.
(Strength of Recommendation: Weak; Evidence: D)
âȘSummary Statement 8:
Schedule patients receiving SLIT therapy for regular follow-up care with a specialist
trained in the evaluation of patients with allergic conditions to monitor efficacy and safety and as
a strategy for optimizing adherence. (Strength of Recommendation: Moderate; Evidence: D)
Matthew Greenhawt. Practice parameter.2017
25. Summary Statement
âȘ Summary Statement 9:
Currently, the only FDA-approved products for SLIT in the United States are the 5-grass
(Oralair), Timothy grass (Grastek), and ragweek (Ragwitek) tablets, indicated for the treatment of
allergic rhinitis.
Although alternative regimens and preparations for SLIT have been proposed and may
be used off-label in the United States (eg, use of liquid SCIT extract for sublingual delivery or use
of specific sublingual drops or other sublingual tablets), these products and formulations do not
have FDA approval at present and have not been systematically studied in a rigorous manner in
US populations.(Strength of Recommendation: Strong; Evidence: D)
Matthew Greenhawt. Practice parameter.2017
27. Problem 1: miss dose
- Miss day 1-7 : No dose reduction
- Miss day 8-14 : Restart from dose1, escalate as indicated in the package insert
- Miss day > 14 : Return to physician, administered under supervision
Problem 2: Severe reaction
- Delay epinephrine by patient : patient should be educated to have low threshole for use
epinephrine : (1. symptoms beyond local and mild GI symptoms, 2. > mod tongue+throat swelling,
3. wheezing or respiratory distress 4. generalized urticaria 5. any life threatening symptoms)
- After epinephrine: discontinue SLIT at home, final dicision must be made on a case-by-
case basis
Problem 3: Oral and dental problems
- Resume SLIT after 24 hr a dental cleaning procedure, after a few hours after gum
bleeding, 10-14 days after remove teeth with adequate healing
- Resume SLIT after aphthous, herpes recover (1-2week)
Problem 4: Oral and dental problems
- SLIT in patient with high sIgE: no increase risk anaphylaxis, caution advised for SLIT
patient who had anaphylaxis for SLIT
- Active allergen season: no change schedule is advised
28. Problem 5: Active allergic diseases
- Asthma: not approve in severe, unstable asthma. Patient who have mild to moderate
asthma may have determine about risks and benefits
- Asthma exacerbation: increase risk anaphylaxis, should discontinue SLIT until they have
discussed with their physician
- AR,AC,AD: no increase risk associated with SLIT
Problem 6: Special condition
- Overdose: Withhold SLIT until contact their allergist
- Conjunction with SCIT (different allergen): combine SCIT with SLIT -> not well study
- Multiple allergen SLIT: limited Study, reduced efficacy has been concerned
Problem 7: SLIT and other medications
- Thyroid medication, 1st gen antihistamine, TCA, cardiac glycoside, Diuretic: may not be
suitable for start SLIT (inhibit effect epinephrine if anaphylaxis) *
- MAOI : Increase risk adverse effect of epinephrine *
- Beta blocker: less responsive to epinephrine *
- ACEI: Theoritical risk unresponsive anaphylaxis, no evidence infer inhalant IT. No reason
to stop after SLIT initiate.
- NSAID: not advise to use of NSAID
Problem 8: Premedication
- Antihistamine before SLIT: may reduce risk oral symptoms
29. Question or concerns
Problem 9: Medical condition
- GI infection: Hold SLIT until clinical improve
- History food induced anaphylaxis: no data should be exclude from treatment
- Oral allergy syndrome: the studies are limited *
- After severe allergic reaction to food or drugs: Hold SLIT 72 hr
Matthew Greenhawt. Practice parameter.2017
31. âȘSystemic reaction (1.1%)
âȘ A review of 66 SLIT studies (over 4000 patients who received over a million doses), there was 1 SR for
approximately every 4 years of treatment and only 1 severe SR per 384 treatment years
âȘ Several severe reactions (anaphylaxis)In these cases, SLIT was not administered according to the
standards
âȘPatients should be observed for at least 30 minutes after the first dose (Grade C) and supervised
by staff able to manage anaphylaxis (Grade C).
âȘUncontrolled asthma has been reported to be associated with severe systemic reactions after
SLIT
G. Roberts. EAACI.2017
32. âȘLocal reaction
âȘ Correlates with the dosage and has been reported to be 40-75%, for example, temporary local mucosal
reactions (oral pruritus or dysesthesia, swelling of the oral mucosa, throat irritation) or abdominal pain
(commonly in the first 3 weeks).
âȘ As in SCIT, local adverse reactions may be diminished by the intake of oral antihistamines (Grade A).
âȘ For SLIT, temporary cessation of therapy may be advised in a number of situations to reduce the
potential for adverse effects (Dental extraction)
G. Roberts. EAACI.2017
33.
34.
35.
36. Efficacy HDM Tablet in Asthma
âȘObjectives
âȘ To evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations
during an inhaled corticosteroid (ICS) reduction period
âȘStudy design
âȘ Double-blind, randomized, placebo-controlled trial
âȘ conducted between August 2011 and April 2013 in 109 European trial sites.
âȘ Efficacy was assessed during the last 6 months of the trial when ICS was reduced by 50% for 3 months and
then completely withdrawn for 3 months.
J. Christian Virchow. JAMA.2016
37.
38. Outcome
âȘThe 6SQ-HDMand 12SQ-HDMdoses both significantly reduced the risk of a moderate or severe
asthma exacerbation compared with placebo
âȘ 6SQ-HDM group and placebo: hazard ratio [HR]:0.72 [95%CI,0.52-0.99] for the, P = .045
âȘ 12 SQ-HDM group and placebo: HR: 0.69 [95%CI,0.50-0.96] for the, P = .03
âȘHowever, there was no significant difference for change in asthma control questionnaire or
asthma quality-of-life questionnaire for either dose. Therewere no reports of severe systemic
allergic reactions.
âȘThe most frequent adverse events were
âȘ mild to moderate oral pruritus (13%for the 6SQ-HDMgroup, 20%for the 12SQ-HDMgroup)
âȘ mouth edema, and throat irritation.
J. Christian Virchow. JAMA.2016
39. Conclusion
âȘAmong adults with HDM allergyârelated asthma not well controlled by ICS
âȘThe addition of HDM SLIT to maintenance medications improved time to first moderate or
severe asthma exacerbation during ICS reduction, with an estimated absolute reduction at 6
months of 9 to 10 percentage points
âȘThe reduction was primarily due to an effect on moderate exacerbations.
âȘTreatment-related adverse events were common at both active doses. Further studies are
needed to assess long-term efficacy and safety.
J. Christian Virchow. JAMA.2016
40. Allergen mixtures
âȘBoth mixtures of grass pollen and mixtures of tree pollen are frequently used in AIT and such an
approach is effective
âȘA small study in children demonstrated efficacy using a mixture of grass pollen and HDM SLIT.
âȘSLIT drops
âȘ Monomeric Phleum pretense grass pollen extract was more effective when given alone
âȘ Compared to when given in an equivalent dose as part of a combination with a 9-pollen, multi-allergen,
sublingual extract
41.
42. Co-existing asthma
âȘCo-existing asthma has no impact on the efficacy of AIT for AR and may also lead to
improvement in asthma.
âȘWhen controlled, mild-to-moderate asthma does not seem to be a safety issue with AIT (Grade
A recommendation)
âȘIn 1 large recent asthma SLIT trial, participants with not well-controlled asthma based on an
Asthma Control Questionnaire (ACQ-6) were included safely in the study.
âȘ We await confirmatory evidence and emphasize that efforts should be taken to control asthma before
commencing AIT.
Uncontrolled or severe asthma are definitely considered to be an absolute contraindication to AIT
43. Specific pediatric issues
âȘSimilar to adults, AIT should be considered in pediatric patients with AR with evidence of IgE
sensitization to clinically relevant allergens
âȘThe evidence for the efficacy of AIT for AR is limited in children younger than 5 years of age
âȘSome clinical studies have shown the efficacy and safety of both SCIT and SLIT in preschool
children
âȘIt is recommended that the decision to start the treatment has to be taken on a case-by-case
basis together with the patients and their family (Grade D).
âȘFor SLIT, there are more recent pediatric trial data to support this approach. In general, pre-/co-
seasonal and continuous SLIT is recommended for seasonal AR (Grade A)
âȘBoth tablet and aqueous formulations are recommended (Grade A)
44. Elderly
âȘThere are very few studies specifically evaluating the use of AIT in the elderly (defined here as
>65 years as this is usually exclusion criteria in AIT trials)
âȘ SLIT with grass pollen and HDM has been demonstrated to be effective and safe in 2 studies
âȘAIT can be recommended in otherwise healthy elderly patients with AR whose symptoms
cannot be adequately controlled by pharmacotherapy (Grade A for SLIT, B for SCIT).
45. Pregnancy
âȘThere is 1 prospective study investigating the safety of AIT in pregnancy161 and several
retrospective studies that suggest that there is no greater risk of prematurity, fetal abnormality,
or other adverse pregnancy outcome in women who receive AIT during pregnancy
âȘIt is therefore recommended that AIT is not initiated during pregnancy (Grade D)
âȘif already initiated, AIT may be continued during pregnancy or breastfeeding in agreement with
the patientâs general practitioner (GP) and obstetrician if former AIT treatment has previously
been tolerated well (Grade C).
46. G. Roberts. EAACI.2017
SLIT
- Observe 30 min after initial dosage
- Administered by competent staff with
resuscitation equipment
- Patient need to know what to do if SLIT reaction
47. Adverse reactions
âȘIn a review of 66 SLIT studies (over 4000 patients who received over a million doses), there was
1 SR for approximately every 4 years of treatment and only 1 severe SR per 384 treatment years
âȘAnaphylaxis SLIT
âȘ was not administered according to the standards (nonstandardized extracts, rush protocols, excessive
allergen dose, patients in whom SCIT had previously been interrupted due to severe reactions).
âȘ Patients should be observed for at least 30 minutes after the first dose (Grade C) and supervised by staff
able to manage anaphylaxis (Grade C).
âȘLocal adverse events during SLIT
âȘ correlates with the dosage and has been reported to be 40-75%, for example, temporary local mucosal
reactions (oral pruritus or dysesthesia, swelling of the oral mucosa, throat irritation) or abdominal pain
âȘTemporary cessation of therapy may be advised in a number of situations to reduce the
potential for adverse effects
48. Recommendations
âȘ Pre-/coseasonal or continuous SLIT is recommended for seasonal ARs for short-term benefit (Grade A).
âȘ SLIT with tablets for pollens or HDM can be recommended for AR for short-term benefit (Grade A).
âȘ SLIT aqueous solutions for pollens can be recommended for AR for short-term benefit (Grade B for
adults, A in children).
âȘ SLIT aqueous solutions for HDM cannot be recommended for AR for short-term benefit. Continuous
grass pollen SLIT tablets or SLIT solution is recommended for AR for long-term benefit (Grade A).
âȘ HDM SLIT tablet can be recommended for AR for long-term benefit (Grade B for adults, C for children).
âȘ It is recommended that patients should wait in clinic for at least 30 minutes after an initial SLIT dosage
and staff and equipment should be available to manage any severe local or systemic reaction or
anaphylaxis (Grade C).
âȘ It is recommended that patients receiving SLIT should be informed about how to recognize and manage
adverse reactions, particularly severe ones (Grade D).
51. Duration
âȘMost clinical studies evaluating the efficacy of AIT follow participants for 1 or 2 years on therapy
âȘThese studies demonstrate a sustained benefit for 3 years of SLIT-tablet grass pollen therapy for
2 years off therapy
âȘThere are some data to suggest that HDM SLIT tablets give sustained benefit for at least 1 year
after 1 year of therapy in 1 RCT and also after 3 years of therapy in a SLIT drop RCT
âȘGrass pollen SCIT for 3-4 years has been shown to result in long-term efficacy for 3 years after
discontinuation
âȘchildren randomized to 3 or 5 years HDM SCIT had similar outcomes at 5 years.
âȘin summary, for patients with AR, a minimum of 3 years of AIT is recommended to achieve long-
term efficacy after treatment discontinuation (Grade A)
53. Practice Parameter 2011
âȘSeveral clinical trials with oral and sublingual immunotherapy demonstrate an increased
tolerance to oral food challenge in subjects with food hypersensitivity while receiving therapy.
Oral and sublingual food immunotherapy is investigational. NR
âȘ Clinical trials with SLIT demonstrate an increased tolerance to oral food challenge with kiwi anaphylaxis,
hazelnut, and milk
âȘ Other data discuss about OIT
54. Food Allergy and SLIT
Effectiveness of SLIT
âȘA recent meta-analysis identified four placebo-controlled RCTs and one CCT for the assessment
of efficacy of SLIT while on therapy
âȘSLIT revealed substantial benefits for the patients in regard to desensitization,18 but none of the
studies included in the SR assessed post-discontinuation effectiveness
âȘAn open follow-up of a peanut SLIT trial in children and adults found only 11% of patients
achieving tolerance after 3 years on SLIT and post-discontinuation of the AIT for 4-6 weeks
55. OIT VS SLIT
âȘTwo trials directly compared the efficacy of OIT and SLIT: the first trial focused on CM1 and the
second on peanut allergy2
âȘAs in the CM trial, OIT was far more effective than SLIT for the treatment of peanut allergy as
the increased threshold was significantly greater in the active OIT group
âȘOIT would seem to be a better therapeutic option than zesent, we cannot recommend EPIT or
SCIT for FA-AIT
2. Narisety SD, Frischmeyer-Guerrerio PA, Keet CA, et al. J AllergyClin Immunol. 2015
1. Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, et al. JAllergy Clin Immunol. 2012
56. Summary SLIT for FA
âȘSystemic reaction
âȘ Meta-analysis of 2 SLIT studies11,53 did not show a significantly higher risk of systemic reactions in the
active group (RR of not experiencing a systemic reaction in controls: 0.98, 95% CI 0.85, 1.14).
âȘ The most common adverse events in SLIT trials were mild local reactions in the oropharynx (7%-40% of
patients), which can be observed during both the up-dosing and maintenance phases
âȘIn pediatric patients with FA to CM and peanut, data suggest that OIT is more effective than SLIT
âȘAllergen avoidance while awaiting spontaneous resolution may represent a better option than
FA-AIT
57. SLIT Peanut
âȘObjective:
âȘ This study was conducted to compare the safety, efficacy, and mechanistic correlates of peanut OIT and
SLIT.
âȘMethods:
âȘ In this double-blind study children with PA were randomized to receive active SLIT/placebo OIT or active
OIT/placebo SLIT.
âȘ Doses were escalated to 3.7 mg/d (SLIT) or 2000 mg/d (OIT)
âȘ Subjects were rechallenged after 6 and 12 months of maintenance.
âȘ After unblinding, therapy was modified per protocol to offer an additional 6 months of therapy.
âȘ Subjects who passed challenges at 12 or 18 months were taken off treatment for 4 weeks and
rechallenged.
58.
59. Red lines indicate active SLIT
blue lines indicate active OIT
purple lines represent combined SLIT and OIT after unblinding
Cumulative dose OFC
End point wheal of SPT
- Comparison of the SLIT and OIT groups revealed
similar changes in SPT responses over time, with
the exception of greater changes in the OIT group
with the exception of greater changes in the OIT
group at T4 (P 5 .03)
- Therefore in the final analysis 1 of 10 subjects
originally assigned to SLIT and 3 of 11 subjects
assigned to OIT had sustained unresponsiveness
(P= 0.59).
- Between groups, there were significantly greater
changes in OFC thresholds with OIT compared
with SLIT (P 5 .008 and P 5 .01 after 6 and 12
months of maintenance).
60. Red lines indicate active SLIT
blue lines indicate active OIT
purple lines represent combined SLIT and OIT after unblinding
Peanut IgE
Peanut IgG4
By 6 months, the decrease in peanut IgE levels was
greater in the OIT group, and this difference widened
by 12 months (P 5 .07 and P 5 .007, respectively).
Between groups, there was overall a greater change
from baseline in peanut-specific IgG4 levels over
time in the OIT group compared with the SLIT group
at all time points (end of dose build-up [P 5 .003]
after 6 and 12 months of maintenance [P < .001]).
61. Conclusion
âȘBoth SLIT and OIT induced significant changes
âȘ skin test results, as well as peanut-specific IgE and IgG4 levels.
âȘ OIT did induce somewhat greater changes in each of these parameters
âȘWe found that a lower baseline peanut IgE level was associated with sustained
unresponsiveness, we did not identify any biomarkers that were reliable predictors of any
clinical outcome on an individual basis
âȘOIT appeared far more effective than SLIT for the treatment of PA but was also associated with
significantly more adverse reactions and early study withdrawal.
âȘSustained unresponsiveness after 4 weeks of avoidance was seen in only a small minority of
subjects
63. SLIT HDM
âȘObjective:
âȘ To confirm the efficacy and safety of the SQ HDM SLIT tablet in Japanese patients with moderate-to-severe
HDM-induced allergic rhinitis (AR).
âȘMethods:
âȘ The trial was a randomized, double-blind, placebocontrolled trial
âȘ 946 Japanese adults and adolescents (12-64 y)
âȘ Subjects were randomly assigned to daily treatment with the SQ HDM SLIT tablet at a dose of
âȘ 10,000 Japanese allergy units (JAU) , 20,000 JAU and placebo (1:1:1).
âȘThe primary end point
âȘ Total combined rhinitis score (TCRS), which is composed of AR symptom and medication scores during the
efficacy evaluation period.
âȘ Symptom and medication scores of AR and conjunctivitis, rhinitis quality of life, and symptom-free and
symptom-severe days were evaluated as secondary end points.
Okobu et al. JACI.2017
65. Population
âȘHDM-specific IgE antibody levels in each treatment group (sIgE Dp and Df)
âȘ 1/3 levels of less than 17.5 kU/L
âȘ 1/3 one third as having levels of 17.5 to less than 50 kU/L
âȘ 1/3 and the remaining one third as having levels of 50 kU/L or greater
âȘMonosensitization to HDM
âȘ 24.3% in the 10,000-JAU group
âȘ 18.2% in the 20,000-JAU group
âȘPolysensitized subjects the most common other allergen based on specific IgE antibody levels
was
âȘ Japanese cedar pollen (67%), followed by Japanese cypress pollen (34%), cats (26%), orchard grass
(23%), and dogs (15%).
67. Primary End Point: TCRS
Okobu et al. JACI.2017
Full analysis set
Perprotocol
analysis set
Intention to treat
68. The symptom scores for AR and conjunctivitis
during the primary evaluation period in both
active groups were statistically significantly
lower than those in the placebo group in terms
of all symptoms
69. The differences from the placebo group in
adjusted means in adults and adolescents were
1.21 and 1.11 in the 10,000-JAU group and 1.04
and 0.96 in the 20,000-JAU group (P <.05, post
hoc analysis), showing a similarity between both
age populations
70.
71.
72.
73.
74. Summary SLIT HDM
âȘThe trial revealed a statistically significant reduction in TCRSs for both active doses of the SQ
HDM SLIT tablet compared with placebo: moderate-to-severe HDM-induced AR
âȘThis confirms that the SQHDMSLIT tablet has an early onset of effect and provides a year-round
effect in the Japanese population, which is crucial for treatment of a perennial allergy
âȘThe posttreatment effect of the SQ HDM SLIT tablet has not been investigated in this trial and
remains to be confirmed.
âȘIn conclusion,
âȘ The trial confirmed the efficacy and favorable safety profile of both doses of the SQ HDM SLIT tablet in
Japanese adult and adolescent patients with moderate-to-severe HDM-induced AR.
âȘ These data confirm the previously reported European data and support the robust efficacy and safety
profile of the SQ HDM SLIT table
76. SLIT Pollen
âȘRetrospective, longitudinal German prescription database subanalysis of AR patients receiving
5- or 1-grass pollen SLIT tablets (n = 1,466/1,385), versus patients not using allergy
immunotherapy(AIT) (n = 71,275).
âȘPrimary endpoint:
âȘ change over time in AR symptomatic medication prescriptions after treatment cessation;
âȘSecondary endpoints:
âȘ new asthma onset, and change over time in asthma medication prescriptions during treatment/follow-
up periods
âȘSLIT was administered for â„3 years in 59% and 70% of patients with AR receiving 5- and 1-grass-
pollen SLIT tablets, respectively, in line with the recommended treatment duration of 3 grass
pollen seasons.
Philippe Devillier. Expert Review of Clinical Immunology.2017
77. Reduce AR patient initiate asthma medication
Reduce symptomatic treatment in asthma medication
Reduce AR medication after stop treatment
78. Discussion
âȘFor AR
âȘ Reduction in AR progression of 18.8%
âȘFor Asthma
âȘ significance was only achieved for the on-treatment and full-analysis time periods with the 5- grass-
pollen SLIT tablet
âȘ Decreases in asthma occurrence and progression of 42.5% and 16.7%, respectively, after treatment
cessation
âȘ significant reductions in asthma medication prescriptions were only seen during the on-treatment
period for the 5-grass-pollen SLIT tablet and
âȘ Reduce the follow-up period for the 1-grass-pollen SLIT tablet
79. Conclusion
âȘThe findings from this retrospective long-term database subanalysis demonstrate the benefits of
5- and 1-grass-pollen SLIT tablets
âȘ Slower progression of AR,
âȘ Reduced risk of new asthma onset in the non-asthmatic population
âȘ Slower asthma progression in the asthmatic population in real-world use.
âȘThe study data are in line with the key recommendation from the most-recent EAACI guidelines
on AIT for allergy prevention
âȘ that a 3-year course of SLIT/SCIT can be recommended for children and adolescents with moderate to
severe AR triggered by grass/birch pollen allergy to prevent asthma for up to 2 years post-AIT
âȘ In addition to its sustained effect on AR symptoms and medication
81. Case discussion
âȘA 32-year-old man presents for evaluation of nasal pruritus, sneezing, rhinorrhea, and itchy,
watery eyes.
âȘHe does not have any pets, but his parents have a cat. His symptoms are worse outdoors in the
spring and fall and better indoors.
âȘSPT was done
âȘ 4+ (wheal diameter >15 mm with associated flare) responses to short ragweed (Ambrosia
artemisiifolia), timothy grass (Phleum pratense), pigweed (Amaranthus retroflexus), and dog dander
(Can f1).
âȘCurrent medications include twicedaily intranasal fluticasone and once-daily oral cetirizine
âȘThe patient is started on timothy grass and short ragweed SLIT tablets, beginning each 12 weeks
before the respective pollen seasons for the allergens in the tablet
82. Polysensitization VS Polyallergy
âȘThe prevailing approach in Europe is to treat the most clinically significant allergen(s) by using
extracts that contain 1, or at most 2, allergens
âȘIn addition, studies demonstrate that single allergen immunotherapy is effective in
polysensitized patients
âȘImprovements in rhinoconjunctivitis symptom scores were similar for both polysensitized and
monosensitized children and adults after 1 year of SLIT monotherapy with Oralair
âȘMolecular allergen or component-resolved diagnostics can be used to help determine whether
clinically irrelevant crossreactive allergens are the cause of polysensitization.
84. SLIT to Treat Multiple Allergen
âȘNo consensus in the United States on the safety, efficacy, or mechanism for administering
multiple SLIT products in combination
âȘphase 4, multicenter, open-label trial conducted in the United States and Canada found that
dual administration of Ragwitek and Grastek is well tolerated
âȘThis study suggests that coadministration of both grass and ragweed SLIT tablets is safe, but
further clinical long-term trials are needed to determine whether there is any effect on efficacy.
- In patients sensitized and allergic to both grass and birch pollens, combination SLIT therapy with birch and grass
significantly improved symptom plus medication scores over SLIT monotherapy with birch or grass, indicating that
combination SLIT may be effective for polyallergic patients
- Another study compared SLIT with timothy grass monotherapy to timothy grass in combination with 9 other pollen
allergens and found that timothy-specific IgG4 levels increased significantly only in the monotherapy group.
- The authors concluded that this may indicate decreased efficacy if multiple allergens are combined in SLIT