A great deal of research into allergic diseases has yielded many new observations that have immediate implications for treatment.1-3 Epidemiologic studies in several countries have indicated that the prevalence of allergies and asthma has been steadily increasing during the past 2 decades.2 At the same time, recent investigations have identified multiple pathogenic entities and several distinct allergic diseases with specific phenotypic characteristics and treatment response profiles, including allergic rhinitis, atopic dermatitis (AD), angioedema, and asthma.2
These findings have all contributed to a game-changing evolution in the treatment of allergic disease that is rapidly moving forward. In 2018, Dagmar Simon, MD, from Bern University Hospital, Switzerland, observed in the first of 2 annual reviews, “With the development of novel therapies, of which some have already been approved, we face a new era of disease management and, with that, probably a modification of the expected course of diseases.” 2
Targeting Immune Mechanisms for Therapy
Many large-scale studies have expanded the understanding of the important role of the immune system in homeostasis and host defense, which has led to the exploration of small molecule and biologic therapies that target immune mechanisms in allergic diseases. 1-3 The pathogenesis of allergies is determined by a complex of overlapping mechanisms that produce different patterns of inflammatory symptoms, as immune cells distributed throughout the body respond to individual and environmental triggers, mediated by lipids, growth factors, chemokines, cytokines, and endothelial barriers.
This multifaceted etiology of allergic diseases, including asthma, makes it difficult to identify a single target for therapy, so novel biological agents are designed to influence particular segments of the pathogenic pathways. Several types of immunologic therapies, including IgE and interleukin-4 (IL-4), IL-13, and IL-5 therapies that target eosinophils and alarmins, have already been approved, based on efficacy in clinical trials against specific subtypes of allergies.
Omalizumab is a monoclonal antibody with a high binding affinity for IgE that has demonstrated good efficacy against asthma and allergic conditions such as AD, reducing the frequency, severity, and chronicity of symptoms by inhibiting the T2 inflammatory action of IgE.3 Omalizumab is considered an appropriate add-on therapy for patients with uncontrolled allergic asthma, as well as those with chronic urticaria.
The IL-4 and IL-13 pathways have been implicated in the production of inflammatory eosinophils in allergic diseases; IL-4 cytokines contribute to IgE mechanisms and hepatic proliferation, whereas IL-13 has effects that are limited mostly to barrier dysfunction and biological disturbances of the skin.3 Dupilumab is a monoclonal antibody that works as a dual inhibitor of IL-4 and IL-13 signaling. It has been approved for the add-on treatment of uncontrolled eosinophilic asthma, AD, and chronic rhinosinusitis with nasal polyps.
Expression of eosinophils has a particularly strong association to asthma by contributing to inflammatory obstruction.4 The protein granules in eosinophils can also cause irritation to the airway structure and trigger bronchial spasm.4 Cytokines such as IL-5 produced by eosinophils may also stimulate new eosinophil formation to promote an ongoing cycle of airway dysfunction.4
Monoclonal antibodies (mAbs) that target the IL-5 pathway, including mepolizumab, reslizumab, and benralizumab, have demonstrated rapid reduction of eosinophil levels in patients with severe, uncontrolled asthma.3,4 All 3 drugs have been shown to reduce asthma exacerbations by about 50%.4 The challenges to IL-5 mAbs are that only about 50% of patients with severe asthma respond to these therapies, and the improvement in exacerbations may not be accompanied by improved lung function and quality of life.3 In addition, the benefits to IL-5 mAbs are lost with discontinuation of therapy, which may even produce rebound eosinophilia.3
Key mediators of homeostasis are cytokines such as thymic stromal lymphopoietin and IL-25 and IL-33, known as alarmins, as they initiate inflammation in response to damage or insult to the body. Tezepelumab is undergoing clinical trials as a first-in-class human mAb designed to block thymic stromal lymphopoietin, whereas antibodies to IL-33 and IL-25 are in the early stages of development. 3
Next Steps for Biologic Therapies
A multitude of dynamic internal and environmental factors have a continuing effect on the status of the immune system, eliminating the possibility of a single therapeutic target for many patients with resistant types of allergic diseases, particularly asthma. And although several biologic therapies have shown great promise, researchers are as-yet unable to identify the patients who are most likely to respond to these interventions. A 2020 review by Agache et al3 reported that “achieving selective immune modulation without altering the healthy immune response and with a long-lasting disease modifying effect is still not reached.” The immediate goals in biologic therapies for allergies and asthma are to develop biomarkers to identify patients who are most likely to respond to these therapies and to monitor disease severity. As experience with biological therapies continues to grow, they are expected move from their current position as add-on therapies for severe allergic disease to play a more prominent role in treatment strategies for many more allergy patients.
1. Simon D. Recent advances in clinical allergy and immunology 2019. Int Arch Allergy Immunol. 2019;180:291-305.
2. Simon D. Recent advances in clinical allergy and immunology. Int Arch Allergy Immunol. 2018;177:324-333.
3. Agache IO, Catalina C, Laculiceanu A, Rogozea L. Critical points on the use of biologicals in allergic diseases and asthma. Allergy Asthma Immunol Res. 2020;12:24-41.
4. Busse W. Biologic treatments for severe asthma: a major advance in asthma care. Allergol Int. 2019;68:158-166.