Asthma and Atopic Dermatitis: A Review of Targeted Inhibition of Interleukin-4 and Interleukin-13 As Therapy for Atopic Disease

February 2016 | Volume 15 | Issue 2 | Original Article | 165 | Copyright © February 2016

Catherine D. Buzney MA,a Alice B. Gottlieb MD PhD,a,b David Rosmarin MDa,b

aTufts University School of Medicine, Boston, MA
bDepartment of Dermatology, Tufts Medical Center, Boston, MA

Abstract
Type 2 helper T cell (Th2)-mediated inflammation plays a critical role in the pathogenesis of allergic asthma and atopic dermatitis (AD). Recent research focusing on the suppression of the Th2 axis with targeted inhibitors in atopic disease is showing promising early results. In particular, the simultaneous blockage of interleukin (IL)-4 and IL-13 has successfully mitigated symptoms of allergic asthma and AD in preliminary clinical trials. Given the current therapeutic challenges of treating these chronic and severe diseases, this review brings to light new data demonstrating that agents targeting IL-4 and IL-13 are relatively safe and effective medications in blocking the inflammatory cascade responsible for allergic asthma and atopic dermatitis.

J Drugs Dermatol. 2016;15(2):165-171.

INTRODUCTION

Allergic asthma and atopic dermatitis are dependent upon cutaneous inflammation driven by type 2 helper T cell (Th2)-mediated immunological responses. Allergic asthma, a chronic inflammatory lung disease, involves recurrent episodes of wheezing, labored breathing, coughing, and thick mucous secondary to airway inflammation, bronchial hyperresponsivity, and structural remodeling.1,2 It is often accompanied by elevated eosinophils and CD4+ Th2 cytokines. Atopic dermatitis (AD), the most common inflammatory skin disorder, is chronic and relapsing and characterized by pruritus, dryness, erythema, weeping, and lichenification. The disturbed skin barrier function leads to transepidermal water loss (TEWL) and a Th2-mediated immunological response.3,4 Given their similar pathogenesis, asthma and AD are clinically associated, with AD frequently preceding the development of allergy and asthma.3
Successful treatment of asthma and AD presents therapeutic challenges, and there is significant need for improved management strategies.5 Mainstays of treatment for moderate-to-severe asthma include bronchodilators such as long-acting beta agonists, muscarinic antagonists, anti-immunoglobulin E (IgE) therapy, and anti-inflammatory drugs including corticosteroids, leukotriene modifiers, and theophylline.1 However, these therapies are often inadequate, leaving patients with uncontrolled disease and high risk of exacerbation, reduced quality of life, and in the case of long-term steroids, undesirable side effects.1,6
Treatment of AD involves symptomatic management with chronic use of emollients, topical glucocorticosteroids, and calcineurin inhibitors. Thirty three percent of patients with moderate-to-severe AD, however, require systemic treatments such as oral steroids, cyclosporine, mycophenolate, methotrexate, azathioprine, UVA1/NB-UVB phototherapy, and other immunosuppressants.7 Developed tolerance to these drugs, unsatisfactory clinical effects, toxicities limiting long-term use, and inconvenience with these regimens underscore the need to develop more efficacious yet safe and well-tolerated treatments. Management with biologic agents such as anti-tumor necrosis factor (TNF) and anti-IgE drugs has been largely ineffective.8
Given the importance of the Th2 pathway in atopic diseases, there is considerable focus on targeted antagonists as treatments. Several recent studies report the success of new drugs targeting cytokines interleukin (IL)-4 and IL-13 in asthma and atopic dermatitis. This article reviews the role of IL-4 and IL-13 in these Th2-polarized disorders and evaluates the benefits of the simultaneous targeting of IL-4 and IL-13 in optimizing therapeutic efficacy.

Asthma Pathophysiology

Asthma triggered by allergens causes recurrent episodes of wheezing, labored breathing, and coughing. Severe and chronic asthma sufferers can have fatal or near-fatal exacerbations.1 There is usually detectable allergen-specific serum IgE. Inflammatory processes associated with Th2 immunity are present in approximately half the population suffering from asthma.9
At the center of the allergic asthma immune response lies the handling and presentation of allergen by antigen-presenting