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

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.

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

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

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

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;131:1288-96.e3. Malling HJ, Bousquet . Clin Allergy Immunol 2008;21:343-58.

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

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

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.

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.

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.

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.

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.

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 21885 TU of D.f.). The ratio of dosages during maintenance therapy for SLIT and SCIT was 4.2

Results- Symptom scores There was a statistically significant difference in symptoms related with rhinitis with both SCIT (p = 0.005 for both) and SLIT (p = 0.008 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.

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.

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.

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.

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)

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

Serum D.pt .- and D.f .-sIgG4 levels increased significantly only in the SCIT group (p = 0.007 and p = 0.005, respectively).

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.

Second part of the study First part of the study

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.

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

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 64.5 % 28 %

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).

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).

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

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)

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.

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

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

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

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.

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.