Elsevier

The Lancet

Volume 387, Issue 10023, 12–18 March 2016, Pages 1109-1122
The Lancet

Seminar
Atopic dermatitis

https://doi.org/10.1016/S0140-6736(15)00149-XGet rights and content

Summary

Atopic dermatitis (also known as atopic eczema) is a chronic inflammatory skin disease that is characterised by intense itching and recurrent eczematous lesions. Although it most often starts in infancy and affects two of ten children, it is also highly prevalent in adults. It is the leading non-fatal health burden attributable to skin diseases, inflicts a substantial psychosocial burden on patients and their relatives, and increases the risk of food allergy, asthma, allergic rhinitis, other immune-mediated inflammatory diseases, and mental health disorders. Originally regarded as a childhood disorder mediated by an imbalance towards a T-helper-2 response and exaggerated IgE responses to allergens, it is now recognised as a lifelong disposition with variable clinical manifestations and expressivity, in which defects of the epidermal barrier are central. Present prevention and treatment focus on restoration of epidermal barrier function, which is best achieved through the use of emollients. Topical corticosteroids are still the first-line therapy for acute flares, but they are also used proactively along with topical calcineurin inhibitors to maintain remission. Non-specific immunosuppressive drugs are used in severe refractory cases, but targeted disease-modifying drugs are being developed. We need to improve understanding of the heterogeneity of the disease and its subtypes, the role of atopy and autoimmunity, the mechanisms behind disease-associated itch, and the comparative effectiveness and safety of therapies.

Introduction

The description of atopic dermatitis (also known as atopic eczema) in ancient times already noted its clinical hallmarks—namely, intense itch and inflammatory eczematous lesions.1 Nowadays, atopic dermatitis is one of the most common chronic diseases and affects up to a fifth of the population in developed countries. For many years, it was thought to be the first manifestation of atopy (the familial propensity to become IgE-sensitised to environmental allergens) and the initial step in the so-called atopic march that ultimately leads to asthma and allergic rhinitis. As such, research into pathogenesis, prevention, and treatment focused on systemic abnormalities of humoral and T-cell-mediated immune responses. However, findings from epidemiology and molecular research have questioned a primary role of allergic mechanisms and, although not detracting the importance of immune mechanisms, they have placed the epidermis and its barrier functions at the forefront of research and management efforts.2, 3

Section snippets

Prevalence

Lifetime prevalence has shown a worldwide increase in the past 30 years. In developed countries, it seems to plateau now at 10–20%, whereas it is lower but continues to increase in many developing countries.4, 5 In roughly 60% of cases, the disease manifests during the first year of life (ie, early onset), but it can start at any age.6, 7 The earliest clinical signs are skin dryness and roughness, but eczematous lesions usually do not occur before the second month of life. The course can be

Clinical features and diagnosis

No specific laboratory or histological findings have been reported, and thus the diagnosis relies exclusively on clinical features. Several sets of diagnostic criteria have been developed12—eg, the Hanifin and Rajka criteria, and an empirically derived, simplified version distinguishing essential, common, and associated features (appendix), which are useful in the clinical setting. Essential features are pruritus and eczematous lesions that can be acute, subacute, or chronic (figure 1). The

Frequent complications

The skin of patients with atopic dermatitis is prone to secondary infections, which tend to generalise. S aureus is a leading cause of skin and soft-tissue infections. It is present transiently on healthy skin,22 but permanently colonises patients' skin and frequently provokes an impetiginisation of lesions (figure 3A).23 The progression to infection is often associated with a worsening of the disease. Eczema herpeticum (figure 3B) is a severe widespread skin infection with herpes simplex virus

Effects on patients

Itch, sleep deprivation, and social embarrassment due to visible lesions have substantial effects on the psychosocial wellbeing of patients and their relatives. In children, the effect of atopic dermatitis on health-related quality of life is similar to that of other major childhood disorders such as asthma and diabetes.28 Children and adolescents with atopic dermatitis are also at a roughly 1·5-times increased risk for attention-deficit hyperactivity disorder, which might be driven by sleeping

Effects on society

In the WHO 2010 Global Burden of Disease survey, atopic dermatitis ranked first among common skin diseases with respect to disability-adjusted life-years38 and years lived with a disease.39 These findings show that the disease has an important health effect at a population level, albeit the true burden was probably underestimated because psychosocial effects and comorbidities were not considered. The economic effects have been investigated only in a few studies, which are not readily comparable

Causes and risk factors

The strongest risk factor is a positive family history for atopic diseases, particularly for atopic dermatitis.43 Twin studies suggested a heritability of more than 80%,44 although this percentage might be an overestimation, since gene–gene interaction effects were not considered. Until now, 32 susceptibility loci have been identified through gene-mapping studies, but they explain less than 20% of the estimated heritability.45, 46, 47, 48, 49, 50 The strongest known genetic risk factor is null

Main mechanisms of disease

The two major and converging pathophysiological peculiarities are abnormalities of epidermal structure and function, and cutaneous inflammation due to inappropriate immune responses to antigens encountered in the skin. The primary events and key drivers of the disease are topics of continuing debate;3 however, clearly, skin barrier biology and immune mechanisms closely interact.

The skin is an efficient physicochemical, microbial, and immunological barrier that exerts several protective

Management

Atopic dermatitis cannot be cured at present; thus, the aim of management is to improve symptoms and achieve long-term disease control with a multistep approach, as outlined in national and international guidelines (appendix). The main principles are continuous epidermal barrier repair with emollients, avoidance of individual trigger factors, and anti-inflammatory therapy with topical corticosteroids or calcineurin inhibitors. In severely affected cases, phototherapy or systemic

Prevention

No primary prevention strategy has been established at present. Most interventions tested so far focused on allergen avoidance or immunomodulation,152 but an overview of systematic reviews153 did not report clear evidence for effectiveness of measures such as maternal dietary antigen avoidance during pregnancy and breastfeeding, long-term breastfeeding, hydrolysed protein formulas, soy formulas, omega-3 or omega-6 fatty acid supplementation, and interventions with prebiotics or probiotics.

Unresolved questions

Despite much progress (panel), a synthesis of research findings for atopic dermatitis has proved difficult. Our understanding of the natural history of childhood disease and the factors determining its remission and persistence is incomplete, as is the knowledge on epidemiology and clinical features in adults. Ironically, pathophysiological investigations were mostly done in tissue from (few) adult patients, and the generalisability of these results is unclear. Epidermal dysfunction is

Search strategy and selection criteria

We searched MEDLINE and the Cochrane Library for reports in English from Jan 1, 2010, to March 31, 2015. We used the search terms “atopic dermatitis”, “atopic eczema”, “childhood eczema”, “infantile eczema”, and “endogenous eczema”. Relevant articles were reviewed, and the most recent ones were preferably cited. Additional reports were identified from the reference lists of selected articles. In general, we gave priority to studies in man for basic scientific research, and to randomised

References (157)

  • FJ Dalgard et al.

    The psychological burden of skin diseases: a cross-sectional multicenter study among dermatological out-patients in 13 European countries

    J Invest Dermatol

    (2015)
  • AE van der Hulst et al.

    Risk of developing asthma in young children with atopic eczema: a systematic review

    J Allergy Clin Immunol

    (2007)
  • M Pinart et al.

    Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: a population-based cohort study

    Lancet Respir Med

    (2014)
  • CJ Murray et al.

    Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

    Lancet

    (2012)
  • T Vos et al.

    years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

    Lancet

    (2012)
  • G Ricci et al.

    Atopic dermatitis in Italian children: evaluation of its economic impact

    J Pediatr Health Care

    (2006)
  • J Ishikawa et al.

    Changes in the ceramide profile of atopic dermatitis patients

    J Invest Dermatol

    (2010)
  • M Janssens et al.

    Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients

    J Lipid Res

    (2012)
  • L Samuelov et al.

    Peeling off the genetics of atopic dermatitis-like congenital disorders

    J Allergy Clin Immunol

    (2014)
  • JP Thyssen et al.

    Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis

    J Allergy Clin Immunol

    (2014)
  • V Pendaries et al.

    Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation

    J Invest Dermatol

    (2014)
  • R Gruber et al.

    Filaggrin genotype in ichthyosis vulgaris predicts abnormalities in epidermal structure and function

    Am J Pathol

    (2011)
  • K Vávrová et al.

    Filaggrin deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin construct

    J Invest Dermatol

    (2014)
  • M Mildner et al.

    Knockdown of filaggrin impairs diffusion barrier function and increases UV sensitivity in a human skin model

    J Invest Dermatol

    (2010)
  • JK Gittler et al.

    Progressive activation of TH2/TH22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis

    J Allergy Clin Immunol

    (2012)
  • SF Ziegler

    Thymic stromal lymphopoietin and allergic disease

    J Allergy Clin Immunol

    (2012)
  • S Khattri et al.

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

    J Allergy Clin Immunol

    (2014)
  • N Novak

    An update on the role of human dendritic cells in patients with atopic dermatitis

    J Allergy Clin Immunol

    (2012)
  • B Homey et al.

    Cytokines and chemokines orchestrate atopic skin inflammation

    J Allergy Clin Immunol

    (2006)
  • M Hvid et al.

    IL-25 in atopic dermatitis: a possible link between inflammation and skin barrier dysfunction?

    J Invest Dermatol

    (2011)
  • T Savinko et al.

    IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors

    J Invest Dermatol

    (2012)
  • Y Hirasawa et al.

    Staphylococcus aureus extracellular protease causes epidermal barrier dysfunction

    J Invest Dermatol

    (2010)
  • O Takeuchi et al.

    Pattern recognition receptors and inflammation

    Cell

    (2010)
  • D Wallach et al.

    Atopic dermatitis/atopic eczema

    Chem Immunol Allergy

    (2014)
  • IA Deckers et al.

    Investigating international time trends in the incidence and prevalence of atopic eczema 1990–2010: a systematic review of epidemiological studies

    PLoS One

    (2012)
  • H Williams et al.

    Is eczema really on the increase worldwide?

    J Allergy Clin Immunol

    (2008)
  • D Garmhausen et al.

    Characterization of different courses of atopic dermatitis in adolescent and adult patients

    Allergy

    (2013)
  • N Ballardini et al.

    Eczema severity in preadolescent children and its relation to sex, filaggrin mutations, asthma, rhinitis, aggravating factors and topical treatment: a report from the BAMSE birth cohort

    Br J Dermatol

    (2013)
  • AS Peters et al.

    Prediction of the incidence, recurrence, and persistence of atopic dermatitis in adolescence: a prospective cohort study

    J Allergy Clin Immunol

    (2010)
  • JS Margolis et al.

    Persistence of mild to moderate atopic dermatitis

    JAMA Dermatol

    (2014)
  • EE Brenninkmeijer et al.

    Diagnostic criteria for atopic dermatitis: a systematic review

    Br J Dermatol

    (2008)
  • FM de Benedictis et al.

    The allergic sensitization in infants with atopic eczema from different countries

    Allergy

    (2009)
  • E Eller et al.

    Food allergy and food sensitization in early childhood: results from the DARC cohort

    Allergy

    (2009)
  • M Worm et al.

    Frequency of atopic dermatitis and relevance of food allergy in adults in Germany

    Acta Derm Venereol

    (2006)
  • PE Martin et al.

    Which infants with eczema are at risk of food allergy? Results from a population-based cohort

    Clin Exp Allergy

    (2015)
  • JA Wisniewski et al.

    Sensitization to food and inhalant allergens in relation to age and wheeze among children with atopic dermatitis

    Clin Exp Allergy

    (2013)
  • A Sonesson et al.

    Sensitization to skin-associated microorganisms in adult patients with atopic dermatitis is of importance for disease severity

    Acta Derm Venereol

    (2013)
  • J Oh et al.

    Shifts in human skin and nares microbiota of healthy children and adults

    Genome Med

    (2012)
  • HH Kong et al.

    Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis

    Genome Res

    (2012)
  • LA Beck et al.

    Phenotype of atopic dermatitis subjects with a history of eczema herpeticum

    J Allergy Clin Immunol

    (2009)
  • Cited by (0)

    View full text