1. Immunotherapy for Allergic Rhinitis
Ayfer Yukselen, MD.
Baskent Unversity Faculty of Medicine
Division of Pediatric Allergy and Immunology
Istanbul, Turkey

2. Allergic Rhinitis: Points to remember
Allergic rhinitis is a global health problem affecting 5 to 50 % of the population.
Its prevalence is increasing worldwide.
Although it is not usually a severe disease, rhinitis alters social life and affects school performance and work productivity.
AR should be considered as risk factor for asthma along with other known risk factors.

3. Allergic Rhinitis: Treatment
AR generally managed by allergen avoidance, which in reality is rarely feasible, drug treatment, which is mainly based on antihistamines and topical steroids, and immunotherapy

4. Allergen –specific immunotherapy: Definition
Allergen immunotherapy is the administration of gradually increasing quantities of an allergen vaccine to an allergic subject, reaching a dose which is effective in ameliorating the symptoms associated with subsequent exposure to the causative allergen.
WHO Position Paper 1998

5. AIT is indicated for the treatment of :
Mild persistent AR
Moderate-to-severe intermittent AR
Moderate-to-severe persistent symptoms of AR

6. Specific Clinical indications for AIT in AR
Especially in those who do not respond well to pharmacotherapy. OR
who can not use pharmacotherapy because of adverse effects of drugs.
Additionally, AR patients who has concomitant mild or moderate asthma may benefit from AIT (but, asthma should be stabile or should be controlled)
Burks AW, Calderon MA, Casale T, Cox L, Demoly P, Jutel M, et al.. J Allergy Clin Immunol 2013;131: e3.
Malling HJ, Bousquet . Clin Allergy Immunol 2008;21:

7. Efficacy of AIT in AR
The efficacy of treatment depends on the allergen dose; thus, every allergen preparation should be evaluated individually, independent of route of administration .
Standardized extracts should be used in clinical practice because the efficacy and safety of AIT depends strictly
on extract quality Jutel 2015

8. Efficacy of AIT in AR Study Patients Allergen IT route Results
Calderon et al. 2007
51 study
2871 adults
Tree, weed, grass
SCIT
Significant reduction in symptom and medication scores
In 2007, the update of Global European Allergy and Asthma Network declaration:
SCIT was specifically effective to improve symptoms and reduce medication use when treated with grass, birch, Parietaria, mite, and ragweed immunotherapy
Radulovic et al. 2010
49 study, 4589 adults and children
Seasonal and perennial
SLIT
Penagos et al. 2006
10 study, 484 children
(especially, more effective if treatment duration is more than 18 months in pollen AIT
Olaguibel ve Alvarez Puebla 2005
7 study, 232 children
Compalati et al.2009
383 adults and children
House dust mites
Di Bona et al. 2010
2971 children
Grass pollen
Reduction in symptom and medication scores is more prominent in adults and better if preseaqs IT > 12 weeks

9. SCIT & SLIT in AR
The clinical efficacy of both SCIT and SLIT in AR is evaluated by the decrease in symptom scores of rhinitis and in consumption of symptomatic anti-allergic drugs.

10. Objective:
The primary aim of this study was to investigate SLIT and SCIT in terms of their efficacy in children with rhinitis and asthma monosensitized to HDM.
The secondary aim was to determine the immunological effects of
both treatment modes.

11. In order to stabilize asthma and to assess the baseline level of symptom and medication scores, all patients were subjected to a follow-up over 1 year (run-in period) before the immunotherapy start.
The design of the second year or immunotherapy period was
randomized, placebo-controlled, double-blind and double-dummy
This study compared treatment with an active allergen extract versus a placebo.

12. Clinical and laboratory parameters were evaluated in 30 patients.
Allocation to 3 study groups was performed by a computergenerated randomization:
- SCIT group (10 patients) received active SCIT (injections) and placebo sublingual drops.
- SLIT group (10 patients) received active SLIT (drops) and placebo subcutaneous injections.
- Placebo group (10 patients) received placebo sublingual drops and placebo subcutaneous injections.

13. The outcomes of this 1-year, randomized, DBPC, double-dummy study were:
Symptom and medication scores,
Visual analog scores (VAS),
Titrated skin prick tests,
Nasal and bronchial allergen provocation doses,
Serum HDM-sIgE, sIgG4, IL-10 and IFN- levels
Exposure to HDM allergens was assesed by using a semiquantitative test (Acarex) at the beginning and at the end of the study.

14. Immunotherapy Protocol
For specific immunotherapy :
Active treatment involved standardized D.pt. and D.f. (50/50) mite extracts for sublingual use (NovoHelisen Oral, Allergopharma) and
for subcutaneous administration (NovoHelisen Depot, Allergopharma).
The cumulative 1-year dose for SLIT was approximately 173,733 TU (86,866.5 TU of D.pt. and 86,866.5 TU of D.f.).
The cumulative 1-year dose for SCIT was approximately 43,770 TU
(21,885 of TU D.pt. and TU of D.f.).
The ratio of dosages during maintenance therapy for SLIT and SCIT was 4.2

15. Results- Symptom scores
There was a statistically significant difference in symptoms related with rhinitis with both SCIT (p = for both) and SLIT (p = and p =0.012, respectively) in comparison to the baseline year.
Compared with the placebo group, the reduction in symptom scores concerning rhinitis was found significant in the SCIT group (p = 0.03).
Although SLIT reduced rhinitis symptoms significantly in comparison to the baseline year (p = 0.008), this reduction was not found significant when compared with the placebo.

16. Results- Medication scores
The medication scores of rhinitis significantly decreased in SCIT patients when compared with the placebo group and with the baseline year (p = 0.02 and p = 0.005,respectively).
There was also a significant decrease in medication scores regarding rhinitis (p = 0.03) with SLIT in comparison to the baseline year.

17. SCIT & SLIT –Symptom and medication scores
No statistical difference between SCIT and SLIT was observed in terms of the reduction in symptoms of rhinitis (p = 0.28), or in medication scores associated with rhinitis.
We found that 1 year of SCIT (compared to the placebo) was more effective in reducing symptoms and improving VAS related to rhinitis.

18. Skin Prick Tests
When compared with the baseline, the wheal diameter of D.pt . and D.f. extracts decreased significantly in both the SCIT and SLIT groups.

19. Titrated NP HDM doses increased significantly after 1-year of immunotherapy in both the SCIT (p = 0.05) and SLIT (p = 0.01) groups.
Nasal eosinophil increment after NP was significantly decreased in both SCIT (p = 0.004) and SLIT (p = 0.01) groups when compared with baseline (p = 0.01) and the placebo group (p = 0.02)

20. A significant decrease in HDM-sIgE levels was observed in SCIT (p = 0
A significant decrease in HDM-sIgE levels was observed in SCIT (p = 0.01) and SLIT (p = 0.02) patients.
We did not detect a significant decrease in the HDM-sIgE levels of the placebo group
Serum IL- 10 levels increased significantly in patients treated with SCIT (p = 0.01) and SLIT (p = 0.02)
No significant difference was observed in terms of HDM-sIgE and IL-10 levels between SCIT and SLIT groups

21. Serum D.pt .- and D.f .-sIgG4 levels increased significantly only in the SCIT group (p = and p = 0.005, respectively).

22. This study, compared the clinical efficacy in children of both SCIT and SLIT with a placebo, with a
double-blind and double-dummy design which was proposed for effective assessment and accurate results.
We showed that both SCIT and SLIT had more clinical efficacy on the symptoms of rhinitis compared to the baseline year.
In comparison to the placebo arm, only SCIT was found to have a superior effect to the placebo on the reduction of symptoms at the end of 1-year treatment.

23. Second part of the study
First part of the study

24. After the 1 yr DBPC, double-dummy IT codes were broken and placebo-treated subjects were switched to active treatment with SCIT or SLIT.
Immunotherapy was administered for one further year to all subjects.
Therefore, children initially assigned to placebo had SCIT or SLIT for 1 yr whereas those initially assigned to active treatment had SCIT or SLIT for two years.

25. The outcomes of this 2-year study were: Symptom and medication scores,
Asian Pac J Allergy Immunol 2013;31:233-41
The outcomes of this 2-year study were:
Symptom and medication scores,
Visual analog scores (VAS),
Titrated skin prick tests,
Nasal and bronchial allergen provocation doses,
Serum HDM-sIgE, sIgG4, IL-10 and IFN- levels

26. SCIT & SLIT –Symptom scores
The reduction of symptoms related to rhinitis was maintained both in SCIT and SLIT (p =0.005, for both) groups in comparison to the baseline year.
We found that the decrease in symptoms related with rhinitis was more prominent at the end of second year in comparison to the first year with SLIT (p =0.005).
When compared with the baseline data, the median percentage improvement of symptom scores :
SCIT SLIT
First year treatment 31 % 6.6 %
Second year of treatment % 28 %

27. SCIT & SLIT – Medication scores
The reduction in medication scores of rhinitis was maintained at 2 yr of treatment with SCIT (p =0.005).
Although the reduction in medication scores for rhinitis with SLIT was not statistically significant (p = 0.18) at the end of 1 yr, it reached a statistical significance at the end of second year of treatment (p =0.012).

28. Titrated nasal provocation HDM-doses increased significantly after 2 years of IT in both the SCIT (p =0.01) and SLIT groups (p =0.02).
No significant difference was observed between SCIT and SLIT regarding titrated nasal provocation HDM-doses (p =0.53).

29. Serum IL-10 levels increased significantly in patients treated with SCIT ( p =0.005) and SLIT (p =0.005) after 2 years of treatment

30. Serum D.pt. and D.f. sIgG4 levels showed statistically significant increases both in SCIT and SLIT groups after two years of immunotherapy (p = 0.005, for both)

31. The main results of our two studies:
Although both clinical and immunologic improvement with SCIT begins from the first year of immunotherapy, it requires longer treatment with SLIT in mite-sensitized children with rhinitis.
Two years immunotherapy in mite sensitive children leads to more pronounced immunologic effects in patients received SCIT than
those of the received SLIT.
Clinical and some immunologic parameters were down modulated since the first year of SCIT and SLIT, and this effect was consolidated in the second year.

32. AIT: Long-term effects
Long-term efficacy
Prevention of new sensitizations
Prevention of progression from rhinitis to asthma

33. Prevention of new sensitizations
The rate of new sensitizations after 3 years SIT:
55 % in SIT group, 100 % in control group.
Des Roches et al, JACI 1997
25 % in SIT group, 67 % in control grup.
Pajno et al, Clin Exp Allergy 2001
The rate of new sensitizations after 4 years SIT:
23 % in SIT group, 68 % control group Purello D’Ambrosio et al, Clin Exp Allergy 2001

34. 45 patients underwent SIT with adsorbed extracts and
147 children with rhinitis and/or asthma monosensitized to house dust mite were studied;
45 patients underwent SIT with adsorbed extracts and
40 patients underwent SIT with aqueous extracts for 5 years.
The control group was comprised of 62 patients given only drugs.
The new sensitization rate after 5-years of treatment with AIT:
24.7 % in AIT group,
53.3 % in control group
Inal A 2007, J Investig Allergol Clin Immunol

35. Summary Allergen immunotherapy can provide:
Significant improvements in symptoms of allergic rhinitis
Reduce the need for additional pharmacotherapy
Provide long-term clinical benefits,
- including symptomatic disease remission
- prevention of new sensitizations
- reduction in disease progression from rhinitis to asthma.

36. Summary
Both SCIT and SLIT are effective in reducing symptoms and drug usage for allergic rhinitis.
SLIT has some advantages over SCIT such as better safety and no need to be adnministered in a medical setting.
In fact, SLIT efficacy is dose-dependent and sufficient duration is crucial.
The recommended duration of AIT for AR is 3 years both for SCIT and SLIT.
Evidence from long-term studies suggests that a 3-year course of SLIT might not be sufficient for a long-term protection.