New pathogenic and therapeutic paradigms in atopic dermatitis
Introduction
Atopic Dermatitis (AD) is the most common inflammatory skin disease, with rising prevalence in industrialized nations [1], [2]. It is present in up to 25% of children in the U.S., and while only one-third of cases persist into adulthood, the vast majority of these children will go on to develop asthma or allergic rhinitis later in life [3], [4]. This pattern of onset has been termed the atopic March, and atopic dermatitis represents the earliest possible point of intervention in this series of related diseases.
The lifetime prevalence of AD in adults is 2–10%, but remains lower in rural and non-industrialized countries [5]. This observation has led to controversy surrounding the “hygiene hypothesis”, in which lack of exposure to antigens in early life creates immune imbalances favoring a pro-allergic Th2 response, leading to a predilection for atopic disease [6], [7], [8]. Of all adults with AD, one-third are classified as having moderate to severe disease, representing a large and unmet need for safe, effective and reliable treatments [9].
Molecular medicine is radically changing the AD pathogenic and therapeutic landscape, similar to the process in psoriasis over the past decade [10], [11]. Translational research accelerates therapeutic development by identification of pathogenic pathways that foster development of drugs to target specific components of these pathways. Efficacy can then be proven if suppression of the pathway is associated with improvement of clinical and tissue pathology.
However, several criteria are required for this translational approach to succeed in AD. First, investigators must have a well-defined cellular and molecular disease phenotype and a comprehensive understanding of immune circuits, although testing with targeted inhibitors can certainly contribute to this understanding. Additionally, well-established biomarkers of disease activity are vital to quantifying response to treatment, especially in a disease known to have high rates of clinical improvement in placebo cohorts [12] and diverse clinical phenotypes. Lastly, in order to test an immune-based hypothesis, researchers require access to drugs that will selectively target components of the immune system. The first example of the successful translational model in AD has been recently shown with the IL-4R antagonist, dupilumab [12], [13]. This landmark trial marks an important turning point in the study and treatment of AD, demonstrating reversal of epidermal pathology with a specific immune antagonist targeting the Th2 pathway. Additional targeted therapies are currently being studied in the clinic, with the hope of shifting the paradigm of AD management from symptom control to disease eradication.
Section snippets
Clinical characteristics/clinical phenotypes
A diagnosis of AD is generally made on clinical criteria alone [14]. The disease is characterized by pruritic, eczematous, erythematous, often excoriated plaques with serous exudate and crusts (Fig. 1). The lesions are poorly demarcated, often involve the face and flexor surfaces, and are prone to development of cutaneous bacterial and viral infections [15]. The appearance of AD varies according to disease phase; the acute stage manifests as bright red, oozing lesions that transform into dull,
Genetics
AD has a strong familial component. One recent twin study showed that 82% of AD risk is determined by genetic factors, and only 18% by environmental factors [25]. Genes that have been associated with AD encode factors in the innate and adaptive immune systems as well as proteins that regulate the terminal differentiation of keratinocytes [26], [27], [28]. Adaptive immune response genes associated with AD include known Th2 cytokines and chemokines (IL4, IL4RA, IL13, TSLP, CCR5), while several
Epithelial skin barrier dysfunction in AD: “outside-in”
The association of FLG mutations with atopic dermatitis has prompted further support of the “outside-in” hypothesis, or the idea that functional disruption of the epidermal barrier is the primary pathogenic process in AD [30], [33], [34], [35]. In mice, FLG mutations result in flaky skin on the tails, with a barrier abnormality that predisposes them to penetration of irritants and allergens, and resulting increased inflammatory processes in the skin [36]. However, the precise cellular
Immune-mediated abnormalities in AD: “inside-out”
Despite the evidence supporting the fixed genetic barrier abnormalities in AD, growing evidence exists for the “inside-out” model [66], [67], in which activation of specific cytokine pathways causes defective keratinocyte differentiation, ultimately resulting in barrier defects.
Several arguments exist in favor of immune abnormalities as the primary pathogenic process in AD. While the filaggrin mutation has provided an important piece of the pathogenic puzzle, the mutation is absent in most AD
Emerging therapeutics
The treatment of psoriasis has undergone a revolution in the past decade, resulting in specific immune antagonists that are safer, more effective, and less toxic than broad immunomodulatory agents [11], [123], [124]. These translational developments in psoriasis have helped promote targeted therapeutics for AD.
Clinical trials with specific cytokine antagonists may help elucidate their individual contributions to the AD phenotype. To monitor responses to various interventions, it is vital to
Looking forward
Atopic dermatitis is currently undergoing a pathogenic and therapeutic transformation. At the forefront of the paradigm shift is recently published work showing efficacy of a targeted inhibitor of the Th2 pathway in establishing clinical and mechanistic responses [12], [13]. The exact contributions of Th17, Th22, and Th2 will be elucidated through trials of targeted immune antagonists coupled with molecular correlates.
Funding
D.M. was supported by the American Dermatological Association’s Medical Student Fellowship.
Disclosures
E.G.Y. received research grants from Regeneron, Bristol Meyers Squibb, Janssen, Celgene, Dermira and Leo Pharmaceuticals. E.G.Y. is a consultant for and/or on the advisory board of Regeneron, Sanofi Aventis, GlaxoSmithKline/Steifel, Dermira, Celsus, Bristol Meyers Squibb, Celgene, Anacor, Leo Pharma, and Galderma.
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2022, Journal of the American Academy of DermatologyCitation Excerpt :More recently, studies examined links between AD and autoimmune,9 metabolic,10,11 cardiovascular12 and mental health conditions.13 This section of the guidelines reviews the evidence for potential comorbidities of AD in adults (Table III).14-168 For select comorbidities with supporting evidence, we evaluate whether the association is modified by the severity of AD.
Difamilast ointment in adult patients with atopic dermatitis: A phase 3 randomized, double-blind, vehicle-controlled trial
2022, Journal of the American Academy of DermatologyCitation Excerpt :Elevated PDE4 activity is associated with the production of inflammatory cytokines by degradation of adenosine 3′,5′-cyclic monophosphate.7,8 Therefore, PDE4 inhibition can decrease the inflammatory process of AD and is a potential therapeutic target for AD.9,10 The first marketed PDE4 inhibitor indicated to treat AD, crisaborole, was approved by the US Food and Drug Administration (2016) and, more recently, by the European Medicines Agency (2020).11