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The Future of Precision Medicine in the Treatment of Atopic Dermatitis

The Future of Precision Medicine in the Treatment of Atopic Dermatitis

Genetic polymorphisms and defects are commonly found in patients with atopic dermatitis. A more personalized therapy that considers individual genetics and pathogenesis may provide a more effective treatment approach.

This article was published in the January 2020 issue of The Dermatologist.

One of the most common inflammatory skin conditions, atopic dermatitis (AD), affects up to 25% of children and 10% of adults in developed countries.1 Genetic polymorphisms and defects in skin barrier function are common in patients with AD, yet standard therapy (topical corticosteroids and calcineurin inhibitors, phototherapy, and systemic immunosuppression) do not take into consideration the genetic variations and individual pathogenesis that determine the phenotype of a patient’s AD.2 A more personalized, precise therapy, which takes into consideration the patient’s specific clinical and immunologic subtypes, is greatly needed in order to provide a better tolerated, effective, and tailored therapeutic approach.1 Identifying patients by their specific phenotype and endotype of AD, along with their individual immunologic biomarkers, and using this information to treat them in a targeted fashion, may not only help more effectively treat patients with AD, but it may potentially help identify risk for this inflammatory disease in susceptible individuals and help avoid the development of AD in the first place.1

Phenotypes, Endotypes, and Immunologic Subtypes
AD can be characterized by various patient characteristics, such as age, phase of the disease (acute flare or chronic), severity, and complications. In order to implement personalized, precise therapy, biomarkers associated with these characteristics need to be identified. For example, the acute phase of an AD flare is associated with a robust T helper (TH) 2 and TH22 response, while the chronic phase was marked by a stronger TH1 response. AD can also be characterized as intrinsic or extrinsic, a distinction based on total serum IgE levels and a presence or absence of personal or family history of atopy, characteristics that are consistent with extrinsic AD. Though skin lesions in both intrinsic and extrinsic AD demonstrate an increase in TH2 cytokines (IL-4, IL-5, IL-13, and IL-31), only intrinsic AD lesions show an increase in interferon gamma. In addition, intrinsic AD shows higher immune activation and heightened expression of genes related to inflammation as compared with extrinsic AD—differences that could surely be targeted by future precision therapy.1 TARC/CCL17, a chemokine involved with skin homing of T cells that express the CC chemokine (or b chemokine) receptor 4, was suggested as a dependable serum biomarker of AD severity in a recent meta-analysis.1,3 The filaggrin (FLG) gene is responsible for the production of FLG, a main structural protein in the stratum corneum. Mutations in the FLG gene, especially homozygous ones, are associated with earlier onset, longer persistence, and increased severity of AD, as well as an increased propensity for skin infections.2

Most of the current research on endotypes are concentrated on severe cases of AD and other allergic diseases; however, endotyping patients with mild disease or even those at risk of developing the disease may provide a unique opportunity to identify early mechanisms of the disease.4 As the disease progresses, the distinction may become blurred due to the possibility of change in the endotype with the change in cellular microenvironment with disease chronicity. Therefore, this is one pathway to prevention.

Conventional and Precision Therapies
Conventional treatments for mild to moderate AD include regular use of emollients, topical anti-inflammatory therapies with corticosteroids and calcineurin inhibitors, topical crisaborole, and topical antimicrobials.5 Although the topical treatments are commonly used, they do not offer long-term relief of symptoms, cure for the disease, or prevention of recurrence. For patients with severe AD or those who do not respond to topical therapy, systemic therapies are the next step in management, which include phototherapy, systemic corticosteroids, and systemic immune modulators (methotrexate, azathioprine, mycophenolate mofetil, cyclosporine A).5 Despite the efficacy of systemic treatments, they are often associated with significant side effects and poor tolerability.6 Therefore, precision medicine aims to facilitate the development of more disease-specific AD treatments that target the underlying disease biology with improved safety and potential long-term benefits.

Currently, the only biologic approved in the United States for the treatment of adults and adolescents with moderate to severe AD is dupilumab (Dupixent), an anti-IL4R monoclonal antibody. Dupilumab has a remarkable safety profile and efficacy comparable to immunosuppressive systemic agents. By blocking the IL-4 receptor, this monoclonal antibody interferes with IL-4 and IL-13 functions and with the downstream production of proinflammatory TH2 cytokines and chemokines.5 Besides upregulation of systemic proinflammatory markers, IL-4 and IL-13 have a direct effect on the epidermis, including keratinocyte proliferation and spongiosis. At 16 weeks, skin biopsies obtained from patients treated with dupilumab demonstrated improvement in AD severity by suppression of inflammatory markers and reversal of epidermal changes induced by the disease.7

Other monoclonal antibodies and small molecule inhibitors that target specific cytokines or their receptors are under investigation, including IL-5, IL-12/IL-23, IL-13, IL-17A, IL-22, IL-31R, janus kinase (JAK) 1/2, thymic stromal lymphopoietin (TSLP), and  phosphodiesterase 4 (PDE4) (Table).

The ongoing clinical trials show promising results; however, efficacy is not consistent across all patients. There is still a need for the development of novel treatments with acceptable risk-benefit profiles and applicability to patients with varying degrees of disease severity.

NEA Feature Table
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