Elsevier

Cytokine

Volume 73, Issue 2, June 2015, Pages 311-318
Cytokine

New pathogenic and therapeutic paradigms in atopic dermatitis

https://doi.org/10.1016/j.cyto.2014.11.023Get rights and content

Highlights

  • Atopic Dermatitis (AD) is an increasingly prevalent inflammatory skin disease.

  • Atopic dermatitis is a Th2- and Th22-polarized disease.

  • There is a large, unmet need for effective therapeutics for AD.

  • Translational research is leading pathogenic and therapeutic transformations in AD.

  • Targeted immune antagonists show promise in ameliorating the disease in severe AD.

Abstract

Atopic Dermatitis (AD) is a common inflammatory skin disease with increasing prevalence in industrialized countries. Up to one-third of adults with AD have moderate-to-severe disease, leading to a large, unmet need for effective treatments. While current therapeutics focus mainly on symptom control, major advances have been made in translational research, with the goal of developing drugs to eradicate disease.

A translational revolution is now occurring in AD, similar to the one that has occurred in psoriasis over the past decade. Research has focused on elucidating immune pathways responsible for AD, including Th2, Th22, and Th17 pathways, with testing of immune antagonists specific to these axes. An IL-4R antagonist, dupilumab, is the first drug that shows great promise in phase II trials. By studying clinical and molecular responses following treatment with specific immune antagonists, our understanding of and ability to treat AD will expand.

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.

References (181)

  • J.W. Holloway et al.

    Using genetics to predict the natural history of asthma?

    J Allergy Clin Immunol

    (2010)
  • S.J. Brown

    Intragenic copy number variation within filaggrin contributes to the risk of atopic dermatitis with a dose-dependent effect

    J Invest Dermatol

    (2012)
  • D.Y. Leung

    Our evolving understanding of the functional role of filaggrin in atopic dermatitis

    J Allergy Clin Immunol

    (2009)
  • G.M. O’Regan

    Filaggrin in atopic dermatitis

    J Allergy Clin Immunol

    (2009)
  • M.K. Oyoshi

    Cellular and molecular mechanisms in atopic dermatitis

    Adv Immunol

    (2009)
  • P.M. Elias et al.

    Basis for the barrier abnormality in atopic dermatitis: outside–inside–outside pathogenic mechanisms

    J Allergy Clin Immunol

    (2008)
  • M.J. Cork

    Epidermal barrier dysfunction in atopic dermatitis

    J Invest Dermatol

    (2009)
  • D.J. Margolis

    The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort

    J Allergy Clin Immunol

    (2012)
  • M. Bohme

    Filaggrin mutations increase the risk for persistent dry skin and eczema independent of sensitization

    J Allergy Clin Immunol

    (2012)
  • S.P. Saunders

    Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects

    J Allergy Clin Immunol

    (2013)
  • I.H. Kuo

    The cutaneous innate immune response in patients with atopic dermatitis

    J Allergy Clin Immunol

    (2013)
  • I.H. Kuo

    Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair

    J Invest Dermatol

    (2013)
  • T. Muller

    Increased T-helper 2 cytokines in bile from patients with IgG4-related cholangitis disrupt the tight junction-associated biliary epithelial cell barrier

    Gastroenterology

    (2013)
  • P.M. Schlievert

    Secreted virulence factor comparison between methicillin-resistant and methicillin-sensitive Staphylococcus aureus, and its relevance to atopic dermatitis

    J Allergy Clin Immunol

    (2010)
  • Y. Lai

    Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections

    J Invest Dermatol

    (2010)
  • M.D. Howell

    Cathelicidin deficiency predisposes to eczema herpeticum

    J Allergy Clin Immunol

    (2006)
  • B.E. Kim

    IL-25 enhances HSV-1 replication by inhibiting filaggrin expression, and acts synergistically with Th2 cytokines to enhance HSV-1 replication

    J Invest Dermatol

    (2013)
  • S.H. Cho

    Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin

    J Allergy Clin Immunol

    (2001)
  • S.H. Cho

    Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model

    J Invest Dermatol

    (2001)
  • T. Jung et al.

    Atopic dermatitis: therapeutic concepts evolving from new pathophysiologic insights

    J Allergy Clin Immunol

    (2008)
  • J.M. Jensen

    Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis

    J Allergy Clin Immunol

    (2009)
  • T. Czarnowicki et al.

    Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications

    J Allergy Clin Immunol Pract

    (2014)
  • D.Y. Leung et al.

    Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches

    J Allergy Clin Immunol

    (2014)
  • M.A. McAleer et al.

    The multifunctional role of filaggrin in allergic skin disease

    J Allergy Clin Immunol

    (2013)
  • J.K. Gittler

    Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis

    J Allergy Clin Immunol

    (2012)
  • M.D. Howell

    Cytokine modulation of atopic dermatitis filaggrin skin expression

    J Allergy Clin Immunol

    (2009)
  • B.E. Kim

    Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6

    Clin Immunol

    (2008)
  • S. Khattri

    Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology

    J Allergy Clin Immunol

    (2014)
  • B. Homey

    Cytokines and chemokines orchestrate atopic skin inflammation

    J Allergy Clin Immunol

    (2006)
  • D.Y. Leung

    Characterization of the mononuclear cell infiltrate in atopic dermatitis using monoclonal antibodies

    J Allergy Clin Immunol

    (1983)
  • M.D. Howell

    Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation

    J Invest Dermatol

    (2008)
  • A. Rebane

    Mechanisms of IFN-gamma-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis

    J Allergy Clin Immunol

    (2012)
  • C. Koga

    Possible pathogenic role of Th17 cells for atopic dermatitis

    J Invest Dermatol

    (2008)
  • M. Toda

    Polarized in vivo expression of IL-11 and IL-17 between acute and chronic skin lesions

    J Allergy Clin Immunol

    (2003)
  • M.D. Howell

    Mechanism of HBD-3 deficiency in atopic dermatitis

    Clin Immunol

    (2006)
  • G.J. de Jongh

    High expression levels of keratinocyte antimicrobial proteins in psoriasis compared with atopic dermatitis

    J Invest Dermatol

    (2005)
  • S. Nakajima

    IL-17A as an inducer for Th2 immune responses in murine atopic dermatitis models

    J Invest Dermatol

    (2014)
  • S. Eyerich

    IL-17 and IL-22: siblings, not twins

    Trends Immunol

    (2010)
  • N. Novak

    Dendritic cells: bridging innate and adaptive immunity in atopic dermatitis

    J Allergy Clin Immunol

    (2010)
  • J.A. Odhiambo

    Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three

    J Allergy Clin Immunol

    (2009)
  • Cited by (96)

    • Diversity of atopic dermatitis and selection of immune targets

      2024, Annals of Allergy, Asthma and Immunology
    • American Academy of Dermatology Guidelines: Awareness of comorbidities associated with atopic dermatitis in adults

      2022, Journal of the American Academy of Dermatology
      Citation 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 Dermatology
      Citation 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

    View all citing articles on Scopus
    View full text