Immunotherapy in allergic rhinitis

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Immunotherapy in Allergic Rhinitis: What is the evidence? Prof DR Dr Ariyanto Harsono SpA(K)

Transcript of Immunotherapy in allergic rhinitis

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Immunotherapy in Allergic Rhinitis: What is the evidence?

Prof DR Dr Ariyanto Harsono SpA(K)

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Introduction

Epidemiologic data shows a high and increasing prevalence of allergic rhinitis (AR) worldwide. AR is particularly frequent in children, in whom the atopic disease usually starts with atopic dermatitis and then develops into AR and asthma by the picture of the so-called “allergic march”. AR is generally managed by allergen avoidance, which in reality is rarely feasible, drug treatment, which is mainly based on antihistamines and topical corticosteroids, and allergen-specific immunotherapy (AIT)

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In 1987, the sublingual route was proposed for AIT , and in the ensuing years it emerged as the best option for immunotherapy, by demonstrating a comparable efficacy and better safety when compared to the classical subcutaneous route of administration. Today, a high number of studies showing the efficacy of sublingual immunotherapy (SLIT) have made the use of this treatment more frequent than subcutaneous IT (SCIT) in several European countries, and recent studies are paving the way for the introduction of SLIT also in the USA

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The World Health Organization and various allergy, asthma, and immunology societies throughout the world met on January 27 through 29, 1997, in Geneva, Switzerland to write guidelines for allergen immunotherapy. Over the ensuing year, the editors and panel members reached a consensus about the information to include in the WHO position paper “Allergen immunotherapy: Therapeutic vaccines for allergic diseases.”

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The goal of this review is to analyze up to date the role of SLIT in the treatment of AR through the evidence which demonstrates its efficacy and safety, while highlighting the pharmacoeconomic issue.

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LeukotrieN C4

Prostaglandin D2

Tryptase

HISTAMINE

CYTOKINEIL-1IL-3IL-4IL-5IL-6IL-13TNF-

ChemokineIL-8EotaxinRANTES

Adhesion MoleculesP-selectinICAM

Early onset Response

• Sneezing• Itchy nose, • Watery eyes • Rhinorhoe• Stuffy nose

Rapid Type Response of inflammation

Overview: Allergic Rhinitis

Early Onset Mediator Rapid Reaction interaction with target cells

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Allergic Rhinitis and co-morbid conditions

Allergic rhinitis

Nasal polyps

Sleep disturbance, including sleep-disordered breathing

Rhinosinusitis (acute and chronic)

Asthma with AR

CongestionInflammation

CongestionInflammation

Common cold

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ARIA = Allergic Rhinitis and its Impact on Asthma.Bousquet et al. J Allergy Clin Immunol. 2001;108 (5 suppl):S147.

ARIA Guidelines: Recommendations for Management of Allergic Rhinitis

Mildintermittent

Moderatesevere

intermittent

Mildpersistent

Moderatesevere

persistent

Immunotherapy Allergen and irritant avoidance

Intranasal decongestant (<10 days) or oral decongestant

Second-generation nonsedating H1 antihistamine

Leukotriene receptor antagonists

Local cromone

Intra-nasal steroid

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EFFICACY OF SUBLINGUALIMMUNOTHERAPY

The clinical efficacy of SLIT in AR, similarly to AIT in general, is evaluated by the decrease in symptom scores of rhinitis and in the consumption of symptomatic anti-allergic drugs. Currently, more than 60 double-blind, placebo-controlled studies are available, and provided the material for numerous meta-analyses on SLIT.

The first meta-analysis was published in 2005, 22 controlled trials were available, showing a significantly higher efficacy of SLIT versus placebo, with a standardized mean difference (SMD) corresponding to -0.42 for symptom scores (p = 0.002) and to -0.43 for medication scores (p = 0.00003) [12]. In 2011, the same group updated meta-analysis: 60 controlled trials were retrieved from the literature and 49 were suitable for pooling in meta-analysis. A significant reduction was found in symptoms (SMD -0.49, p < 0.00001) and in medication use (SMD -0.32, p< 0.00001) compared to the placebo. Therefore, the authors concluded that the updated review reinforced the statement of the previous meta-analysis that SLIT is effective for AR.

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However, a subsequent meta-analysis on SLIT in children, concerning only the efficacy on AR, showed positive outcomes, with a significant reduction of symptoms (SMD -0.56, p = 0.02) and medication scores (SMD -0.76, p = 0.03)

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Compalati et al. considered 8 controlled studies for house dust mite-induced AR, including 194 adults and children, and found a significant reduction in symptoms of AR (SMD -0.95; p = 0.02) and in antiallergic medication use (SMD -1.88; p = 0.04) in SLIT treated patients when compared to the placebo

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In a study on SLIT performed by a dust mite extract, 137 patients were divided in 2 groups, 67 receiving the treatment for 2 years and 70 receiving the treatment for 3 years; all patients were followed-up for 3 years after stopping SLIT, and a greater improvement of symptoms was found in patients treated for 3 years. In a prospective open controlled study, patients monosensitized to mites were divided in 4 groups, 1 receiving only drug treatment and the other 3 receiving SLIT for 3, 4, or 5 years. The observation period was extended to 15 years, and the clinical scores showed that the clinical benefit continued for 7 years in patients treated for 3 years, while it continued for 8 years in those treated for 4-5 years.

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SAFETY AND TOLERABILITY OF SUBLINGUAL IMMUNOTHERAPY

The first observations on safety and tolerability of SLIT were reported in the meta-analyses on efficacy, and showed that the most common adverse events were local reactions in the mouth followed by gastrointestinal reactions (including vomiting and diarrhea), that systemic reactions such as asthma, rhinitis, or urticaria were quite rare, and that no anaphylactic reaction was described in controlled trials. However, reviews specifically addressing SLIT safety are also available, concerning only children or patients of any age.

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Of interest, differently from SCIT, a dose-dependence of safety was not apparent, since the rate of systemic reactions was comparable in studies using low doses and in studies using high doses. The local reactions are generally estimated to affect 20-40% of patients, but they can be easily managed and generally do not require to withdraw the treatment

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We found significant reductions in symptoms (SMD -0.49; 95%CI (-0.64 to -0.34, P < 0.00001)) and medication requirements (SMD -0.32; 95%CI (-0.43 to -0.21, P < 0.00001)) compared with placebo. None of the trials reported severe systemic reactions, anaphylaxis or use of Adrenaline. This updated review reinforces the conclusion of the original 2003 Cochrane Review that sublingual immunotherapy is effective for allergic rhinitis and appears a safe route of administrationAllergy, 2011;66:740-52

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SCIT

The weighted mean RCI of SCIT on TNSSs (-34.7% ± 6.8%) was higher than those of mometasone (-31.7% ± 16.7%, P < .00001) and montelukast (-6.3% ± 3.0%, P < .00001). The weighted mean RCI of SCIT on TSSs (-32.9% ± 12.7%) was higher than that of desloratadine (-12.0% ± 5.1%, P < .00001). The overall ES of SCIT in terms of TNSSs (SMD, -0.94; 95% CI, -1.45 to -0.43) was similar to that of mometasone (SMD, -0.47; 95% CI, -0.63 to -0.32; P > .05) and higher than that of montelukast (SMD, -0.24; 95% CI, -0.33 to -0.16; P < .05). The overall ES of SCIT in terms of TSSs (SMD, -0.86; 95% CI, -1.17 to -0.55) was comparable with that of desloratadine (SMD, -1.00; 95% CI, -1.68 to -0.32; P > .05).

J Allergy Clin Immunol 2011 Oct;128(4):791-799

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Subcutaneous immunotherapy and pharmacotherapy in seasonal allergic rhinitis: a comparison based on meta-analyses

The weighted mean RCI of SCIT on TNSSs (-34.7% ± 6.8%) was higher than those of mometasone (-31.7% ± 16.7%, P < .00001) and montelukast (-6.3% ± 3.0%, P < .00001). The weighted mean RCI of SCIT on TSSs (-32.9% ± 12.7%) was higher than that of desloratadine (-12.0% ± 5.1%, P < .00001). The overall ES of SCIT in terms of TNSSs (SMD, -0.94; 95% CI, -1.45 to -0.43) was similar to that of mometasone (SMD, -0.47; 95% CI, -0.63 to -0.32; P > .05) and higher than that of montelukast (SMD, -0.24; 95% CI, -0.33 to -0.16; P < .05). The overall ES of SCIT in terms of TSSs (SMD, -0.86; 95% CI, -1.17 to -0.55) was comparable with that of desloratadine (SMD, -1.00; 95% CI, -1.68 to -0.32; P > .05).

J Allergy Clin Immunol. 2011 Oct;128(4):791-799.

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We retrieved 1111 publications of which 51 satisfied our inclusion criteria. In total there were 2871 participants (1645 active, 1226 placebo), each receiving on average 18 injections. Duration of immunotherapy varied from three days to three years. Symptom score data from 15 trials were suitable for meta-analysis and showed an overall reduction in the immunotherapy group (SMD -0.73 (95% CI -0.97 to -0.50, P < 0.00001)). Medication score data from 13 trials showed an overall reduction in the immunotherapy group (SMD of -0.57 (95% CI -0.82 to -0.33, p<0.00001)). Clinical interpretation of the effect size is difficult. Adrenaline was given in 0.13% (19 of 14085 injections) of those on active treatment and in 0.01% (1 of 8278 injections) of the placebo group for treatment of adverse events. There were no fatalities.

This review has shown that specific allergen injection immunotherapy in suitably selected patients with seasonalallergic rhinitis results in a significant reduction in symptom scores and medication use. Injection immunotherapy has a known and relatively low risk of severe adverse events. We found no long-term consequences from adverse events.

Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001936

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SCIT versus SLIT

Specific immunotherapy (SIT) is the only diseases-modifying treatment option for allergies. Meta-analysis reveals standardized mean differences in allergic rhinitis symptom scores of -0.73 for subcutaneous immunotherapy (SCIT) and -0.49 for sublingual immunotherapy (SLIT); the corresponding mean differences in medication scores are -0.57 and -0.32, respectively. The treatment should be carried out for at least three years. It is indicated when the symptoms are severe and allergen avoidance is not a realistic option. The efficacy of treatment depends on the allergen dose; thus, every allergen preparation should be evaluated individually, independent of route of administration. SCIT can cause systemic adverse effects, including anaphylaxis. SLIT is safer but often causes allergic symptoms of the oral mucosa at the beginning of treatment.

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• Subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: The overall effect size of SCIT for symptom score (SMD, -0.92; 95%CI, -1.26 to -0.58) was significantly higher than SLIT, both administered via drops (SMD, -0.25; 95% CI, -0.45 to -0.05) and tablets (SMD, -0.40; 95%CI, -0.54 to -0.27). Similar results were reported for medication score (SCIT: SMD, -0.58; 95% CI, -0.86 to -0.30. SLIT drops: SMD, -0.37; 95% CI, -0.74 to -0.00. SLIT tablets SMD, -0.30; 95% CI, -0.44 to -0.16).

• Our results provide indirect but solid evidence that SCIT is more effective than SLIT in controlling symptoms and in reducing the use of anti-allergic medications in seasonal allergic rhino-conjuntivitis to grass pollen.

J Allergy Clin Immunol 130, 1097-1107.e2, 2012

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PHARMACOECONOMIC ASPECTS

The significant reduction in the use of symptomatic drugs showed by all meta-analyses on SLIT highlights the cost-effectiveness of this treatment. In fact, a number of studies addressed the pharmaco-economics of AIT. The review of such studies in 2008 led to the conclusion that there was clear data that substantiated the capacity of both SCIT and SLIT to be very beneficial to the healthcare system. The major advantage of AIT takes place when the treatment, usually after 3 years, is stopped, because the effectiveness of AIT persists over time

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Such persistence is related to the immunologic changes induced by AIT, especially regarding the T lymphocytes and their cytokine profile and the production of IgG blocking antibodies [38] and the consequent modification of the natural history of respiratory allergy

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Recent studies expanded the concept of economic advantage of AIT even before its termination. In a study performed in US, children with AR treated with AIT had significantly lower 18-month median total health care costs ($ 3247 vs $ 4872), outpatients costs of AIT-related care ($1107 vs $ 2626), and pharmacy costs ($1108 vs $ 1316) compared with matched controls (p < 0.001 for all comparisons)

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This data has led the authors to conclude that “This study demonstrates the potential Sublingual immunotherapy in allergic rhinitis 175 for early and significant cost savings in children with AR treated with immunotherapy. Greater use of this treatment in children could significantly reduce AR related morbidity and its economic burden”

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Of interest, the direct comparison of costs between SCIT and SLIT was in favour of the latter, as expected because of the lack of the necessity for hospital visits for the injections. In France, the reported savings compared with drug treatment over a 6-year period were € 393 for dust mite and € 1327 for pollen allergy with SCIT, but they were € 3158 for dust mite and € 1708 for pollen allergy with SLIT. In the Czech Republic, the sum of direct and indirect costs recorded, over a 3-year treatment, € 684 for SLIT and € 1004 for SCIT.

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CONCLUSION

SLIT has achieved sound evidence of efficacy and safety and currently in some European countries is more frequently used than the classical SCIT, due to better safety. Other advantages over SCIT concern the cost as well as the compliance , because SLIT does not need to be administered in a medical setting. Still, it is important to note that such outcomes take place only if SLIT meets its needs, that is, the administration of high doses is continued on a regular basis for at least 3 consecutive years. In fact, SLIT efficacy is dose-dependent and a sufficient duration is crucial to elicit the immunologic changes underlying its clinical effectiveness.

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