sublingual immunotherapy: what's new

Sublingual Immunotherapy:What’s new

ATHIPAT ATHIPONGARPORN

DEPARTMENT OF ALLERGY AND IMMUNOLOGY

KING CHULA MEMORIAL HOSPITAL

Outline▪ Background and basic knowledge

▪ SLIT in the past

▪ What’s new (2016-2017)▪ Practice Parameter 2017

▪ EAACI SLIT Aeroallergen 2017

▪ EAACI SLIT Food Allergy 2017

▪ HDM SLIT in Japan 2017

▪ Pollen SLIT 2017

▪ Polyallergen SLIT

Background▪ The history of modern immunotherapy started after the breakthrough discovery of anaphylaxis in 1902 by Richet and Portier▪ Who first observed severe allergic reactions while studying the toxicity of jellyfish in dogs

▪ Regimens of repeated allergen exposure, leading to a state of “tolerance” or “specific desensitization

▪ With this insight, the field of clinical allergen-specific immunotherapy (SIT) was born. Protocols to desensitize humans were developed, especially using the subcutaneous route

▪ The sublingual route has been shown to be the safest and most effective alternative route

Middleton. Ed 8th

Therapeutic regimens▪ Several large clinical trials have shown SLIT to be clinically effective, improving allergic rhinitis and asthma symptoms and reducing requirements for rescue medication

▪ The allergen is held under the tongue for 2 minutes to allow optimal contact with the oral mucosa before being swallowed.

▪ SLIT delivers high doses of allergens, at 50- to 100-fold the doses used for subcutaneous immunotherapy (SCIT)

▪ 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

Mucosal Tolerance▪ In mouse models, oral tolerance can be induced either by a single high dose of antigen or by repeated administration of lower doses.

▪ High-dose tolerance appears to involve ▪ Clonal T cell anergy

▪ T cell failing to proliferate or to produce interleukin-2 (IL-2)

▪ Involve deletion of relevant T cells.

▪ Low-dose exposure is mediated by regulatory T cells (Tregs), which actively control tolerance, preventing responses to food antigens and bacterial microflora.

▪Tolerance can also be induced by T helper type 3 (Th3) cells▪ Use transforming growth factor-β1 (TGF-β1) to achieve tolerance

Middleton. Ed 8th

Mucosal Tolerance▪ Tolerance in humans may be induced by several mechanisms▪ Induction of secretory immunoglobulin A (IgA) antibodies, which bind foreign proteins and prevent their

entry into the body without causing local inflammation

▪ Relevant mechanism is the development of Tregs▪ Suppression by direct cell-cell contact or through soluble immunoregulatory cytokines : IL-10, TGF-β1

▪ Deplete T cell numbers and induce T cell anergy

▪ 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

Immunological mechanism▪ Molecular and cellular mechanisms include ▪ Increased suppressor capacity of CD4+CD25+ forkhead box P3+ protein (Foxp3+) Tregs

▪ Enhanced suppressor activity of IL-10–secreting type 1 Tregs (Tr1)

▪ Suppression of eosinophils, mast cells, and basophils; and antibody isotype switching from IgE to IgG4

▪ Current data suggest that ▪ Regulatory IL-10–producing Th1 cells are pivotal to the various changes induced by SIT.

▪ This may be driven by triggering TLRs on DCs, creating the necessary microenvironment for Tr1 induction

Immunological mechanism▪ Chronic allergen exposure ▪ Favor expansion of Th1-like Tr1 cells through IL-12 and IL-27 synthesis, delta-4 expression on APCs.

▪ Recruitment of these cells into areas of inflammation will lead to amplification of local cytokine responses (IL-12, IL-10, and TGF-β1)

▪ The IL-12 will skew any Th2 and Th17 cells toward the Th1 phenotype,

▪ IL-10 suppresses allergen-specific Th2 and Th17 responses, induces IgG4, and inhibits recruitment of mast cells, basophils, and eosinophils

Middleton. Ed 8th

Sublingual Immunotherapy:Practice Parameter 2011

Practice Parameter 2011▪Allergen 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)

Practice Parameter 2011▪Randomized 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

Practice Parameter 2011▪Local reactions, primarily oral mucosal, are common with sublingual immunotherapy.

▪Systemic reactions can occur, and a few have been reported in subjects who were unable to tolerate subcutaneous immunotherapy.

▪A few reported cases have been of a severity to be categorized as anaphylaxis. A▪ Patients receiving grass tablets without build-up,

▪ oral pruritus reported by 46%

▪ edema of the mouth 18%

Practice Parameter 2011▪Clinical trials evaluating the safety and efficacy of sublingual immunotherapy for patients with ragweed- and grass pollen–induced allergic rhinitis. Currently, there are no FDA-approved formulations for sublingual immunotherapy. A

Sublingual Immunotherapy:Practice Parameter 2017

Sublingual Immunotherapy in 2017

SLIT in update practice parameter Efficacy of HDM SLIT

SLIT in ARC SLIT in Food Allergy

Matthew Greenhawt. Practice parameter.2017

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

Description of Methods Used to Formulate the Recommendations▪The FDA had approved 3 sublingual products, all of which are tablet formulations (short ragweed, Timothy pollen, and 5-grass pollen).

▪Both the Timothy grass SLIT tablet and the 5-grass tablet have demonstrated clinical benefits beginning in the first year of a 3-year treatment


Grading System for SLIT Local Reactions


Summary Statement▪Summary 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)

▪Summary 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 patient’s ability to survive a systemic reaction or the resultant treatment of the systemic reaction. (Strength of Recommendation: Strong; Evidence: D)



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)


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)



Administer the patient’s 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)


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)



Reduce a patient’s SLIT dose if they have missed treatment for more than 7 days. (Strength of Recommendation: Weak; Evidence: D)


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)


Summary Statement▪ 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)


Grass pollenORALAIR® (Sweet Vernal, Perennial Rye, Orchard, Timothy, and Kentucky Blue Grass Mixed Pollens Allergen Extract)

Ragweed (Ragwitek) Timothy grass (Grastek)

Sweet Vernal Perennial Rye Orchard Timothy Kentucky Blue Grass

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

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

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


Sublingual Immunotherapy:in AR/ARC 2017

▪Systemic reaction (1.1%)▪ 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

▪ Several severe reactions (anaphylaxis)In these cases, SLIT was not administered according to the standards

▪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).

▪Uncontrolled asthma has been reported to be associated with severe systemic reactions after SLIT

G. Roberts. EAACI.2017

▪Local reaction▪ 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).

▪ As in SCIT, local adverse reactions may be diminished by the intake of oral antihistamines (Grade A).

▪ For SLIT, temporary cessation of therapy may be advised in a number of situations to reduce the potential for adverse effects (Dental extraction)


Efficacy HDM Tablet in Asthma

▪Objectives▪ To evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations

during an inhaled corticosteroid (ICS) reduction period

▪Study design▪ Double-blind, randomized, placebo-controlled trial ▪ conducted between August 2011 and April 2013 in 109 European trial sites. ▪ 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

Outcome▪The 6SQ-HDMand 12SQ-HDMdoses both significantly reduced the risk of a moderate or severe asthma exacerbation compared with placebo ▪ 6SQ-HDM group and placebo: hazard ratio [HR]:0.72 [95%CI,0.52-0.99] for the, P = .045

▪ 12 SQ-HDM group and placebo: HR: 0.69 [95%CI,0.50-0.96] for the, P = .03

▪However, 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.

▪The most frequent adverse events were ▪ mild to moderate oral pruritus (13%for the 6SQ-HDMgroup, 20%for the 12SQ-HDMgroup)

▪ mouth edema, and throat irritation.


Conclusion▪Among adults with HDM allergy–related asthma not well controlled by ICS

▪The 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

▪The reduction was primarily due to an effect on moderate exacerbations.

▪Treatment-related adverse events were common at both active doses. Further studies are needed to assess long-term efficacy and safety.


Allergen mixtures▪Both mixtures of grass pollen and mixtures of tree pollen are frequently used in AIT and such an approach is effective

▪A small study in children demonstrated efficacy using a mixture of grass pollen and HDM SLIT.

▪SLIT drops ▪ Monomeric Phleum pretense grass pollen extract was more effective when given alone

▪ Compared to when given in an equivalent dose as part of a combination with a 9-pollen, multi-allergen, sublingual extract

Co-existing asthma▪Co-existing asthma has no impact on the efficacy of AIT for AR and may also lead to improvement in asthma.

▪When controlled, mild-to-moderate asthma does not seem to be a safety issue with AIT (Grade A recommendation)

▪In 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. ▪ 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

Specific pediatric issues▪Similar to adults, AIT should be considered in pediatric patients with AR with evidence of IgEsensitization to clinically relevant allergens

▪The evidence for the efficacy of AIT for AR is limited in children younger than 5 years of age

▪Some clinical studies have shown the efficacy and safety of both SCIT and SLIT in preschool children

▪It 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).

▪For 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)

▪Both tablet and aqueous formulations are recommended (Grade A)

Elderly▪There 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)▪ SLIT with grass pollen and HDM has been demonstrated to be effective and safe in 2 studies

▪AIT 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).

Pregnancy▪There 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

▪It is therefore recommended that AIT is not initiated during pregnancy (Grade D)

▪if already initiated, AIT may be continued during pregnancy or breastfeeding in agreement with the patient’s general practitioner (GP) and obstetrician if former AIT treatment has previously been tolerated well (Grade C).


SLIT- Observe 30 min after initial dosage- Administered by competent staff with

resuscitation equipment- Patient need to know what to do if SLIT reaction

Adverse reactions▪In 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

▪Anaphylaxis SLIT ▪ 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).

▪ 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).

▪Local adverse events during SLIT ▪ 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

▪Temporary cessation of therapy may be advised in a number of situations to reduce the potential for adverse effects

Recommendations▪ Pre-/coseasonal or continuous SLIT is recommended for seasonal ARs for short-term benefit (Grade A).

▪ SLIT with tablets for pollens or HDM can be recommended for AR for short-term benefit (Grade A).

▪ SLIT aqueous solutions for pollens can be recommended for AR for short-term benefit (Grade B for adults, A in children).

▪ 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).

▪ HDM SLIT tablet can be recommended for AR for long-term benefit (Grade B for adults, C for children).

▪ 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).

▪ It is recommended that patients receiving SLIT should be informed about how to recognize and manage adverse reactions, particularly severe ones (Grade D).

Duration▪Most clinical studies evaluating the efficacy of AIT follow participants for 1 or 2 years on therapy

▪These studies demonstrate a sustained benefit for 3 years of SLIT-tablet grass pollen therapy for 2 years off therapy

▪There 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

▪Grass pollen SCIT for 3-4 years has been shown to result in long-term efficacy for 3 years after discontinuation

▪children randomized to 3 or 5 years HDM SCIT had similar outcomes at 5 years.

▪in summary, for patients with AR, a minimum of 3 years of AIT is recommended to achieve long-term efficacy after treatment discontinuation (Grade A)

Sublingual Immunotherapy:EAACI Food Allergy 2017

Practice Parameter 2011▪Several 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▪ Clinical trials with SLIT demonstrate an increased tolerance to oral food challenge with kiwi anaphylaxis,

hazelnut, and milk

▪ Other data discuss about OIT

Food Allergy and SLIT

Effectiveness of SLIT

▪A recent meta-analysis identified four placebo-controlled RCTs and one CCT for the assessment of efficacy of SLIT while on therapy

▪SLIT revealed substantial benefits for the patients in regard to desensitization,18 but none of the studies included in the SR assessed post-discontinuation effectiveness

▪An 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

OIT VS SLIT▪Two trials directly compared the efficacy of OIT and SLIT: the first trial focused on CM1 and the second on peanut allergy2

▪As 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

▪OIT 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. 20151. Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, et al. JAllergy Clin Immunol. 2012

Summary SLIT for FA▪Systemic reaction▪ 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).

▪ 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

▪In pediatric patients with FA to CM and peanut, data suggest that OIT is more effective than SLIT

▪Allergen avoidance while awaiting spontaneous resolution may represent a better option than FA-AIT

SLIT Peanut▪Objective: ▪ This study was conducted to compare the safety, efficacy, and mechanistic correlates of peanut OIT and

SLIT.

▪Methods: ▪ In this double-blind study children with PA were randomized to receive active SLIT/placebo OIT or active

OIT/placebo SLIT.

▪ Doses were escalated to 3.7 mg/d (SLIT) or 2000 mg/d (OIT)

▪ Subjects were rechallenged after 6 and 12 months of maintenance.

▪ After unblinding, therapy was modified per protocol to offer an additional 6 months of therapy.

▪ Subjects who passed challenges at 12 or 18 months were taken off treatment for 4 weeks and rechallenged.

Red lines indicate active SLITblue lines indicate active OITpurple 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 groupwith 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 greaterchanges in OFC thresholds with OIT compared with SLIT (P 5 .008 and P 5 .01 after 6 and 12 months of maintenance).

Red lines indicate active SLITblue lines indicate active OITpurple lines represent combined SLIT and OIT after unblinding

Peanut IgE

Peanut IgG4

By 6 months, the decrease in peanut IgE levels wasgreater 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 changefrom 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]).

Conclusion▪Both SLIT and OIT induced significant changes ▪ skin test results, as well as peanut-specific IgE and IgG4 levels.

▪ OIT did induce somewhat greater changes in each of these parameters

▪We 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

▪OIT appeared far more effective than SLIT for the treatment of PA but was also associated with significantly more adverse reactions and early study withdrawal.

▪Sustained unresponsiveness after 4 weeks of avoidance was seen in only a small minority of subjects

Sublingual Immunotherapy:Efficacy of HDM SLIT 2017

SLIT HDM▪Objective: ▪ To confirm the efficacy and safety of the SQ HDM SLIT tablet in Japanese patients with moderate-to-severe

HDM-induced allergic rhinitis (AR).

▪Methods: ▪ The trial was a randomized, double-blind, placebocontrolled trial

▪ 946 Japanese adults and adolescents (12-64 y)

▪ Subjects were randomly assigned to daily treatment with the SQ HDM SLIT tablet at a dose of ▪ 10,000 Japanese allergy units (JAU) , 20,000 JAU and placebo (1:1:1).

▪The primary end point ▪ Total combined rhinitis score (TCRS), which is composed of AR symptom and medication scores during the

efficacy evaluation period.

▪ 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

SLIT HDM


Population▪HDM-specific IgE antibody levels in each treatment group (sIgE Dp and Df)▪ 1/3 levels of less than 17.5 kU/L

▪ 1/3 one third as having levels of 17.5 to less than 50 kU/L

▪ 1/3 and the remaining one third as having levels of 50 kU/L or greater

▪Monosensitization to HDM ▪ 24.3% in the 10,000-JAU group

▪ 18.2% in the 20,000-JAU group

▪Polysensitized subjects the most common other allergen based on specific IgE antibody levels was ▪ Japanese cedar pollen (67%), followed by Japanese cypress pollen (34%), cats (26%), orchard grass

(23%), and dogs (15%).

Primary End Point: TCRS


Full analysis set

Perprotocolanalysis set

Intention to treat

The symptom scores for AR and conjunctivitis during the primary evaluation period in both active groups were statistically significantlylower than those in the placebo group in terms of all symptoms

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

Summary SLIT HDM▪The 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

▪This 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

▪The posttreatment effect of the SQ HDM SLIT tablet has not been investigated in this trial and remains to be confirmed.

▪In conclusion, ▪ 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.

▪ These data confirm the previously reported European data and support the robust efficacy and safety profile of the SQ HDM SLIT table

Sublingual Immunotherapy:Pollen Tablet SLIT 2017

SLIT Pollen

▪Retrospective, 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).

▪Primary endpoint: ▪ change over time in AR symptomatic medication prescriptions after treatment cessation;

▪Secondary endpoints: ▪ new asthma onset, and change over time in asthma medication prescriptions during treatment/follow-

up periods

▪SLIT was administered for ≥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

Reduce AR patient initiate asthma medication

Reduce symptomatic treatment in asthma medication

Reduce AR medication after stop treatment

Discussion▪For AR▪ Reduction in AR progression of 18.8%

▪For Asthma▪ significance was only achieved for the on-treatment and full-analysis time periods with the 5- grass-

pollen SLIT tablet

▪ Decreases in asthma occurrence and progression of 42.5% and 16.7%, respectively, after treatment cessation

▪ significant reductions in asthma medication prescriptions were only seen during the on-treatment period for the 5-grass-pollen SLIT tablet and

▪ Reduce the follow-up period for the 1-grass-pollen SLIT tablet

Conclusion▪The findings from this retrospective long-term database subanalysis demonstrate the benefits of 5- and 1-grass-pollen SLIT tablets ▪ Slower progression of AR,

▪ Reduced risk of new asthma onset in the non-asthmatic population

▪ Slower asthma progression in the asthmatic population in real-world use.

▪The study data are in line with the key recommendation from the most-recent EAACI guidelines on AIT for allergy prevention▪ 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

▪ In addition to its sustained effect on AR symptoms and medication

Sublingual Immunotherapy:Pollyallergen

Case discussion▪A 32-year-old man presents for evaluation of nasal pruritus, sneezing, rhinorrhea, and itchy, watery eyes.

▪He does not have any pets, but his parents have a cat. His symptoms are worse outdoors in the spring and fall and better indoors.

▪SPT was done ▪ 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).

▪Current medications include twicedaily intranasal fluticasone and once-daily oral cetirizine

▪The 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

Polysensitization VS Polyallergy▪The prevailing approach in Europe is to treat the most clinically significant allergen(s) by using extracts that contain 1, or at most 2, allergens

▪In addition, studies demonstrate that single allergen immunotherapy is effective in polysensitized patients

▪Improvements in rhinoconjunctivitis symptom scores were similar for both polysensitized and monosensitized children and adults after 1 year of SLIT monotherapy with Oralair

▪Molecular allergen or component-resolved diagnostics can be used to help determine whether clinically irrelevant crossreactive allergens are the cause of polysensitization.

SLIT pollyallergen

SLIT to Treat Multiple Allergen▪No consensus in the United States on the safety, efficacy, or mechanism for administering multiple SLIT products in combination

▪phase 4, multicenter, open-label trial conducted in the United States and Canada found that dual administration of Ragwitek and Grastek is well tolerated

▪This 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

Thank You

sublingual immunotherapy: what's new

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