IL-4 and IL-13 Inhibition in Atopic Dermatitis
August 2016 | Volume 15 | Issue 8 | Original Article | 925 | Copyright © August 2016
Matthew C. Matsunaga MDa and Paul S. Yamauchi MD PhDb
aUniversity of Minnesota Medical School, Minneapolis, MN
bDermatology Institute and Skin Care Center, Santa Monica, CA; David Geffen School of School of Medicine at UCLA, Los Angeles, CA
Atopic dermatitis (AD) is a chronic, prevalent, multi-factorial condition that affects infants, children, and adults. Beyond topical therapy, a variety of systemic agents such as steroids, methotrexate, cyclosporine, azathioprine, mycophenoloic acid, and other agents are utilized to treat moderate to severe AD. However, these agents are associated with potential long term adverse events and organ toxicity. There is an unmet need for a safer, long-term systemic agent to adequately control moderate to severe AD. The role of the Th2 cytokines, IL-4 and IL-13, in AD has led to the development of biologic agents to treat AD. The aim of this article is to review the role of IL-4 and IL-13 in the pathogenesis of AD and discuss some of the clinical trial data that target and inhibit IL-4 and IL-13 in positively altering the course and outcome of AD. J Drugs Dermatol
Atopic dermatitis (AD) is a common, chronic, relapsing inflammatory skin disease characterized by erythema, pruritis, xerosis, excoriations, seepage, crusting, and lichenification. Its prevalence in the United States is 10.7%1 but rates range from 0.3-20.5%.2 It is especially common in the pediatric population under the age of 5.3,4 The majority of cases clear by age 16, however, some cases persist into adulthood. Symptoms of AD can also begin to appear after the age of 18 in a smaller percentage of individuals.5
Although AD’s pathogenesis is complex, with contributions from genetic (family history of Type I allergies, asthma, and allergic rhinitis), environmental, barrier defects, and immunologic factors, one avenue of research is being directed toward the immunologic causative factors.6 Such investigations are corroborating the subset of CD4+, Th2-cells as the principal players that Such investigations are corroborating the subset of CD4+, Th2-cells as the principal players that influence the disease process.
For those patients whose disease has been suboptimally controlled with topical therapy and/or phototherapy, the available systemic treatments such as azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, and interferon gamma all have variable responses and potential long term side effects and risks. Currently there are several biologic agents approved or in development for the treatment of moderate to several psoriasis. There is currently an unmet need for a targeted therapy for AD with biologic agents similar to psoriasis. Recent advances in the treatment of AD that target the Th2 cytokines, IL-4 and IL-13 have proven to be efficacious. This article seeks to review the current literature on IL-4 and IL-13 inhibition in the pathogenesis of AD and how the blockade of these cytokines can be used to treat AD.
Searches were conducted via PubMed and PubMed MeSH between 1980-2015. Titles were reviewed and abstracts were read if they were deemed potentially relevant. Search terms included: “’Interleukin-4/antagonists and inhibitors’(Mesh)”, “’Receptors, Interleukin-4/antagonists and inhibitors’(Mesh)”, “interleukin 4 ‘atopic dermatitis”, and “interleukin 13 ‘atopic dermatitis’”. A total of 1398 titles were reviewed, which led to 181 abstracts, and 65 papers being used.
Effect of IL-4 and IL-13 in AD
IL-4 was first described by Howard and Paul in 1982.8 These interleukins function to produce increased levels of IgE and eosinophils in the peripheral blood and tissue. IL-13 was discovered in 1993 as a unique Th2 related cytokine that affects B-cells and monocytes thereby regulating inflammatory and immune responses.9,10 The IL-4 and IL-13 genes are located on chromosome 5q31 and are closely linked to one another.11,12 IL-4 and IL-13 have been implicated as important players in the pathogenesis of atopic diseases including asthma, allergic rhinitis, and AD. Both cytokines exert their effects via IL-4Rα, which is expressed on T cells, B cells, and macrophages, among others.13-15 Activation leads to Th2 differentiation and IgE class switching in B-cells and increased mast cells. Thus IL-4’s association with Th2 cell differentiation plays an important role in subsequent inflammation.16,17
Increased levels in IL-4 were found to cause AD symptoms in mouse and human models. Studies on a transgenic mouse that overexpressed IL-4 in the epidermis exhibited symptoms of xerosis, inflammatory skin lesions, scratching behavior, skin infections, and elevated IgE.18-20 The pathway by which IL-4 and IL-13 exert their effects and lead to the symptoms of AD are shown in Figure 1. These mice also exhibited early increases