The Future of Precision Medicine in the Treatment of Atopic Dermatitis

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

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 (T_H) 2 and T_H22 response, while the chronic phase was marked by a stronger T_H1 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 T_H2 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 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 T_H2 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.

Biomarkers are best described as biologic indicators that link disease endotype with a phenotype. AD-specific biomarkers provide insights into pathogenesis of disease, help to stratify severity of disease, and can be used as targets to develop pathway-specific treatments.⁴ Despite the predominance of AD in childhood, current research primarily aims to identify biomarkers in adults. It is well known that pediatric and adult AD have different clinical profiles, including distribution of the affected skin areas, expression of T_H22/T_H17, and the fact that a significant percent of childhood AD does not continue into adulthood.⁸ This heterogeneity of AD and variations in immune profiles may be detected using biomarkers to separate the disease into different clinically relevant subtypes. In a recent study, noninvasive sampling with tape-stripping of the stratum corneum was performed and biomarkers, both previously reported and novel, were identified.⁸ The authors recommended further studies of these biomarkers, especially in early AD, as potential targets of predicting disease severity or comorbidities. Less invasive, cost-effective, simple, less time-consuming, and age-specific biomarkers are the most desirable.

Defects in proteins making up the epidermal skin, such as FLG, triglycerides, keratins, and loricrin, can lead to defects in the skin barrier, which can subsequently lead to increased exposure to allergens, sensitization, and finally a systemic allergic response. Transepidermal water loss (TEWL) is currently the most useful noninvasive marker of skin barrier function; patients with AD have an increased TEWL, which indicates a loss of integrity of their epidermal barrier. FLG deficiency in patients with AD contributes to the breakdown of the skin barrier, as the inflammatory threshold for irritants and haptens is reduced. TEWL can be a marker of current skin barrier disruption but also a predictive measure: TEWL at 2 days of age and 2 years of age foretold the development of AD at 1 year of age.⁹ Moisturizers, the cornerstone of daily management of AD, may also be preventive, as moisturizers have been shown to reduce the rates of AD development by decreasing rate of TEWL and maintaining a more intact epidermal barrier in susceptible individuals.⁹ By using simple, noninvasive measures such as TEWL and serum biomarkers to identify those individuals at risk for developing atopy, personalized medicine has the potential to become a prophylactic tool, helping to avoid the development of AD altogether.

The improved understanding of the pathophysiology of AD, development of biomarkers, and emergence of targeted therapies promises potential breakthroughs in the management and prevention of AD.

Inclusion criteria for trials investigating AD are based on disease severity rather than AD endotypes. To utilize precision medicine and optimize the response to targeted therapies, molecular, clinical, genetic, and epigenetic factors will need to be taken into consideration in future research trials. With the emergence of novel therapies from current clinical trials, dermatologists will be able to implement them into their clinical practice and switch from a generalized “one-drug-fits-all” approach to more personalized “patient-endotype-specific” management.

Dr Balogh is a research fellow at the Wake Forest School of Medicine, department of dermatology, Center for Dermatology Research, in Winston-Salem, NC. Ms Muradova is a medical student at University of South Florida, Morsani College of Medicine, in Tampa, FL. Dr Strowd is an assistant professor at the Wake Forest School of Medicine, department of dermatology.

Disclosure: Dr Strowd has received research, speaking, and/or consulting support from Galderma, Pfizer, Regeneron, Sanofi, and Actelion. The remaining authors report no relevant financial relationships.