Allergen Immunotherapy: The Evidence Supporting the Efficacy and Safety of Subcutaneous Immunotherapy and Sublingual Forms of Immunotherapy for Allergic Rhinitis/Conjunctivitis and Asthma.

Allergen immunotherapy (AIT) is a recognized key therapeutic modality for the treatment of allergic respiratory disease. Definitive studies have provided evidence-based data to demonstrate its effectiveness in allergic rhinitis and asthma due to the inhalation of proteinaceous allergic substances from specific seasonal pollens, dust mites, animal allergens, and certain mold spores. Over the ensuing decades, laboratory investigations have provided objective evidence to demonstrate immunologic changes, including production of protective IgG antibody, suppression of IgE antibody, upregulation of regulatory T cells, and induction of a state of immune tolerance to the offending allergen(s). Tangential to this work were carefully designed clinical studies that defined allergen dose and duration of treatment, established the importance of preparing extracts with standardized allergens (or well-defined extracts) based on major protein moieties, and used allergen provocation models to demonstrate efficacy superior to placebo. In the United States, the use of subcutaneous immunotherapy extracts for AIT was grandfathered in by the Food and Drug Administration based on expert literature review. In contrast, sublingual tablet immunotherapy underwent formal clinical development programs (phase I-III clinical trials) that provided the necessary clinical evidence for safety and efficacy that led to regulatory agency approvals for the treatment of allergic rhinitis in properly characterized patients with allergy. The allergy specialist's treatment options currently include traditional subcutaneous AIT and specific sublingual tablets approved for grass, ragweed, house dust mites, trees belonging to the birch-homologous group, and Japanese cedar. Tangential to this are sublingual drops that are increasingly being used off-label (albeit not approved by the Food and Drug Administration) in the United States. This article will review the evidence-based literature supporting the use of these forms of AIT, as well as focus on several current controversies and gaps in our knowledge base that have relevance for the appropriate selection of patients for treatment with specific AIT.

Subcutaneous allergen immunotherapy in the treatment of allergic respiratory disease.

Subcutaneous immunotherapy is recognized as a cornerstone in the management of allergic respiratory disease in patients who are properly characterized with allergy and with allergic rhinoconjunctivis and/or well-controlled asthma, and who are willing to adhere to the rigorous treatment program. A key tenet is that it affords the opportunity to effect long-term clinical remission through its disease-modifying properties. Furthermore, it has the potential to prevent the progression of allergic rhinitis to asthma, prevent new allergen sensitivities, and improve a patient's quality of life.

New insights in mite immunotherapy - sublingual tablets.

PURPOSE OF REVIEW: Sublingual tablet immunotherapy has been demonstrated to be effective for allergies induced by exposure to grass, ragweed, specific trees (Japanese Cedar; birch homologous tree mix), and house dust mites (HDM). This review provides both an overview of the evidence-based clinical studies that address the use of the HDM SLIT-tablet for the treatment of HDM-induced allergic rhinitis/conjunctivitis and its appropriate use in carefully selected asthmatic patients and provides the clinician with practical management considerations. RECENT FINDINGS: Solid evidence-based clinical studies have shown that the HDM SLIT-tablet is both well tolerated in patients with mild-to-moderate asthma and has demonstrated a meaningful improvement in exacerbations, need for rescue medication, quality of life, and asthma control. SUMMARY: The HDM SLIT-tablet provides the allergy specialist with a well-tolerated treatment that has established superior safety to subcutaneous injection therapy, which can be administered easily as a sublingual dissolvable tablet, and which provides the opportunity to address one of the more difficult aspects in the management of an inducer of perennial allergic disease - that of persistent airway inflammation and allergic asthma.

Ragweed sublingual tablet immunotherapy: part II - practical considerations and pertinent issues.

Sublingual allergen immunotherapy (SLIT) has been demonstrated to be both efficacious and safe for the treatment of respiratory allergies such as allergic rhinoconjunctivitis or allergic asthma. Based on the clinical documentation of SLIT ragweed tablets, they have gained marketing authorization in the USA by the US FDA in 2014 for adult patients. Following clinical data from (pivotal) multicenter Phase II and III trials as performed in the USA and Canada and real life experience after registration in 2014, SLIT ragweed tablets can be recommended as efficacious and safe treatment option with disease modifying potential when adequately indicated and performed. Therefore, several practical issues should be considered for treating ragweed allergic patients with these tablets. This second part of a thorough review on ragweed SLIT tablets addresses important clinical questions which should be taken into account by the subscribing practitioner before initiation and during the treatment.

Ragweed sublingual tablet immunotherapy: part I - evidence-based clinical efficacy and safety.

Sublingual tablet immunotherapy provides an attractive alternative approach to allergen immunotherapy, as the allergen is administered as a rapidly dissolving sublingual tablet. Part I of this two-part series on the ragweed sublingual tablet describes the dose-ranging clinical work, the safety studies and the clinical outcomes from the pivotal trials which provide clear evidence for statistically significant and clinically meaningful benefit in the treatment of patients suffering from ragweed-induced seasonal allergic rhinitis-conjunctivitis with or without milder asthma. The robust results observed in the clinical trials performed with the ragweed sublingual tablet are defined by the quality of their study design, their use of a standardized allergen extract, their consistent reproducibility in demonstrating therapeutic efficacy and their properly quantified and graded safety data.

International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis.

BACKGROUND: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). METHODS: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. CONCLUSION: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding.

Allergen Immunotherapy: Vaccine Modification.

There is a need for newer therapeutic agents that improve the safety of allergen immunotherapy, provide ease of delivery to patients that fosters compliance and allows access to a greater proportion of the allergic population who could benefit from this disease-modifying treatment, and achieve an acceptable therapeutic benefit for patients committing to the treatment. The advances in sublingual allergen immunotherapy are encouraging, as this offers patients a noninjectable form of treatment of inhalant allergies. The continued research and development of the novel therapeutic constructs discussed in this article holds the promise of accomplishing the aforementioned goals in the future.

Advances in synthetic peptide immuno-regulatory epitopes.

Synthetic peptide immuno-regulatory epitopes (SPIRE) represent a new class of therapeutics for allergen immunotherapy that offer the potential to suppress the IgE-mediated allergic disease process through induction of T-cell tolerance. These synthetic T-cell-tolerizing peptides have been designed to induce immunologic tolerance via binding to MHC class II molecules on antigen presenting cells, with subsequent upregulation of regulatory T-cells.

Cat peptide antigen desensitisation for treating cat allergic rhinoconjunctivitis.

INTRODUCTION: Allergic rhinoconjunctivitis is an increasingly common source of morbidity with sensitivity to cats accounting for 10-15% of the disease burden. Allergy to cats is a major risk factor for the development of asthma. AREAS COVERED: Within the present manuscript, the current data on a novel therapeutic approach to treat cat allergy is reviewed. Cat Peptide Antigen Desensitisation (Cat-PAD) is a mixture of seven small peptides developed for the treatment of cat allergy. It is designed to induce immunological tolerance via binding to MHC class II on antigen presenting cells and interacting with regulatory T cells without triggering the cross-linking of IgE on mast cells and basophils. The peptide sequences are derived from the major cat allergen Fel d 1. The peptides have been selected to ensure a similar T cell response to that generated to whole cat dander in ex-vivo PBMC derived from cat allergic individuals. The size of the peptides is insufficient to induce cross-linking of IgE. Clinical data from a series of studies shows that Cat-PAD is able to significantly reduce allergic rhinoconjunctivitis symptoms after a short course of four injections over 12 weeks, and that the treatment effect is persistent lasting 2 years after the start of treatment. EXPERT OPINION: Taken together Cat-PAD is a novel, well tolerated and promising therapeutic approach to treat cat allergic patients. Data from the current international Phase III study will unravel whether the concept is also efficient and tolerable under daily life circumstances.

New approaches in immunotherapy: allergen vaccination with immunostimulatory DNA.

Despite its success, conventional immunotherapy is saddled with a number of encumbrances. An allergenic vaccine that could reduce allergenicity, maintain immunogenicity, and be given in a few doses would have important therapeutic implications, as millions of patients with poorly controlled allergic rhinitis and asthma would be candidates for such a form of immunomodulation. This article addresses a specific adjuvant approach to immunotherapy in which highly active immunostimulatory phosphorothioate oligodeoxyribonucleotide moieties are linked to the principal allergenic moiety of a relevant aeroallergen.