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Lin SY, Erekosima N, Suarez-Cuervo C, et al. Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Mar. (Comparative Effectiveness Reviews, No. 111.)

Introduction

The Agency for Healthcare Research and Quality (AHRQ) Effective Health Care Program requested a comparative effectiveness review of “Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma.” The topic was selected through the Effective Health Care Program nomination process.

Background

Allergic rhinitis is a common clinical problem affecting as many as 20 to 40 percent of the general population in North America.15 Allergens such as tree, grass, and weed pollens characteristically cause seasonal rhinoconjunctivitis and/or asthma, whereas cat dander, cockroach, or dust mite allergens may induce symptoms year-round and are associated with perennial rhinitis and/or asthma. The prevalence of asthma in the general U.S. population is approximately 9 percent, and approximately 62 percent of individuals with asthma have evidence of atopy (i.e., one or more positive specific IgE).6,7

The medical management of patients with allergic rhinitis and asthma includes allergen avoidance, pharmacotherapy, and immunotherapy.4,5,8 Pharmacotherapies for allergic rhinitis symptoms include topical nasal corticosteroid or cromolyn preparations and/or antihistamines and decongestants. These must be used daily to provide effective control, raising critical issues related to long-term compliance, safety, and cost. Similarly, the long-term use of inhaled steroids for asthma control poses risks, especially if used together with nasal steroids to control seasonal or perennial respiratory conditions. Furthermore, long-acting bronchodilators have the potential to cause cardiovascular complications including arrhythmias and sudden death, and leukotriene antagonists have been associated with neuropsychiatric disturbances.911

Allergen specific immunotherapy (SIT) is typically recommended for patients whose allergic rhinoconjunctivitis and asthma symptoms cannot be controlled by environmental control and pharmacotherapy, those who cannot tolerate their medications, or those who do not comply with chronic medication regimens.12,13 Over the years, allergen specific immunotherapy has proven to be safe.1416 The U.S. Food and Drug Administration (FDA) approved the use of subcutaneous allergen extracts (subcutaneous immunotherapy) for the treatment of seasonal and perennial allergic rhinitis, allergic asthma, and venom sensitivity. The same aqueous materials can also be administered orally (sublingual immunotherapy), although this not an approved use of these materials in the United States and such use would be considered off-label. An increasing number of U.S. physicians are attempting to employ this alternate desensitization approach in the treatment of allergic respiratory conditions based on European and U.S. studies and the European Medicines Agency approval of certain oral products; however due to differing standardization of potency in the Europe and United States, doses have been extremely hard to translate between countries.

Subcutaneous immunotherapy, as a treatment for allergic diseases, was first introduced by Noon and Freeman in 1911 as a means of treating grass-induced allergic symptomatology.17 In the United States, a patient with allergies receives increasing doses of an allergen-containing extract, comprised of the relevant allergens to which the patient is sensitive, to suppress or eliminate allergic symptomatology. With continued administration, it is expected that the treatment regimen will make the patient tolerant to the offending allergen and suppress future untoward responses to the allergen(s) through modulation of the patient’s immune system.1821

Chemical modifications of allergens have been attempted to enhance efficacy, improve safety, and foster compliance with immunotherapy. Many of these approaches have been unsuccessful as the allergenicity (potential to cause an untoward allergic reaction) and immunogenicity (potential to induce a beneficial clinical effect) have changed in parallel, with little change in the risk-benefit ratio. However, recent approaches with modified and recombinant allergens, immunostimulatory adjuvants, T-cell tolerizing constructs, and improved oral approaches have shown promise for treatment of allergic respiratory disease.2125

Oral immunotherapy was first proposed as a treatment for allergic disease in the early 1900s. In 1996, a task force assembled by the World Allergy Organization on Immunotherapy cited the emerging clinical data on oral immunotherapy and its potential as a viable alternative to subcutaneous therapy; this encouraged continued clinical investigation to characterize optimal techniques.26 In this context, oral immunotherapy has been administered as an oral aqueous immunotherapy where the allergen is mixed with a diluent and swallowed; as an oral-sublingual immunotherapy where the allergen is placed under the tongue as an aqueous solution or as a dissolvable tablet for local absorption; and as an oral-encapsulated immunotherapy where the allergen is placed in a liposome, or polymer, or microencapsulated carrier and swallowed with pH-dependent release of the allergen to the gut lymphoid tissue.

Interest has also increased considerably related to using sublingual immunotherapy as an alternative to subcutaneous therapy based on its perceived improved safety margin (reduced risk of anaphylaxis), simple and convenient oral dosing regimen (avoiding the discomfort of injections and the inconvenience of office visits for allergy shots), and possibly shorter time to achieve effect.27,28 Over the past decade, sublingual forms of immunotherapy have gained favor in Europe; sublingual tablet immunotherapy has been approved by the European regulatory authorities but is not available in the United States

Rationale for Comparative Effectiveness Review

Although subcutaneous immunotherapy is used worldwide and sublingual immunotherapies are used broadly in Europe, Latin America, and Asia, sublingual immunotherapy has not been approved by the FDA for use in the United States. Based on U.S. manufacturer package inserts, allergen extracts are sold for skin testing and for preparation of immunotherapy solutions for parenteral administration. Thus, use of these allergenic extracts as sublingual treatment agents is “off-label” in the United States and third-party payers have generally not paid for sublingual immunotherapy. In addition, there is no standardized information on how to prepare an oral extract with licensed allergenic extracts or information on the effective dose. No sublingual allergen tablets are sold in the United States. This comparative effectiveness review addresses the comparative efficacy, effectiveness, and safety of the subcutaneous therapies, presently available for use by clinicians and patients in the United States, as well as the “off-label use” for possible sublingual applications.

Conceptual Model

Our conceptual model for the systematic review is presented in Figure 1. This figure depicts the Key Questions (KQs) addressed in this review. The figure illustrates how SIT administered to patients with respiratory allergies may result in intermediate outcomes including changes in immunologic parameters and long-term outcomes such as improvement of symptoms and quality of life and reduction of health care costs. However, adverse events may occur at any point after treatment is administered. We approached the synthesis of this body of literature by addressing the KQs described below, separately, for the studies evaluating sublingual immunotherapy, for the studies evaluating subcutaneous immunotherapy, and for the studies that compared sublingual immunotherapy with subcutaneous immunotherapy.

Figure 1 is the analytic framework, which depicts the impact of treatment of allergic rhinitis and asthma. It shows the Key Questions within the context of the inclusion criteria described in the following sections. It depicts how allergen-specific immunotherapy in this specific population (Key Question 3) may improve clinical outcomes (Key Question 1) and functional tests or chemical biomarkers. The potential harms (Key Question 2) of specific immunotherapy are shown on this framework as well.

Figure 1

Analytic framework for allergen-specific immunotherapy in the treatment of allergic rhinoconjunctivitis and/or asthma. KQ = Key Question; PFT-FEV = pulmonary function test-forced expiratory volume; SIT = allergen-specific immunotherapy

The analytic framework (Figure 1) depicts the impact of treatment for allergic rhinitis and/or asthma. It depicts the KQs within the context of the inclusion criteria described in the following sections. The framework represents how allergen-specific immunotherapy in these specific populations (KQ3) may improve clinical outcomes (KQ1) and/or be reflected in changes in functional tests or chemical biomarkers. Finally, the potential for harms (KQ2) of specific immunotherapy are illustrated in the framework.

Key Questions

This review includes our evaluation of the efficacy, effectiveness, and safety of both sublingual immunotherapy, subcutaneous immunotherapy and the comparison of both. The KQs to be explored are as follows:

Key Question 1.

What is the evidence for the efficacy and effectiveness of SIT in the treatment of allergic rhinoconjunctivitis and/or asthma?

Key Question 2.

What is the evidence for safety of SIT in patients with allergic rhinoconjunctivitis and/or asthma?

Key Question 3.

Is the safety and effectiveness of SIT different in distinct subpopulations with allergic rhinoconjunctivitis and/or asthma? Specifically:

  • Children
  • Adults
  • The elderly
  • Pregnant women
  • Minorities
  • Inner-city and rural residents
  • Monosensitized individuals
  • Patients with severe asthma
Cover of Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review
Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review [Internet].
Comparative Effectiveness Reviews, No. 111.
Lin SY, Erekosima N, Suarez-Cuervo C, et al.

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