Seminar: Sinéad M Langan, Alan D Irvine, Stephan Weidinger

Seminar
Atopic dermatitis
Sinéad M Langan, Alan D Irvine, Stephan Weidinger
Atopic dermatitis is a common inflammatory skin disorder characterised by recurrent eczematous lesions and intense Lancet 2020; 396: 345–60
itch. The disorder affects people of all ages and ethnicities, has a substantial psychosocial impact on patients and Faculty of Epidemiology and
relatives, and is the leading cause of the global burden from skin disease. Atopic dermatitis is associated with increased Population Health, London
School of Hygiene & Tropical
risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders. The
Medicine, London, UK
pathophysiology is complex and involves a strong genetic predisposition, epidermal dysfunction, and T-cell driven (Prof S M Langan PhD); St John’s
inflammation. Although type-2 mechanisms are dominant, there is increasing evidence that the disorder involves Institute of Dermatology,
multiple immune pathways. Currently, there is no cure, but increasing numbers of innovative and targeted therapies Guy’s and St Thomas’ NHS
Foundation Trust, London, UK
hold promise for achieving disease control, including in patients with recalcitrant disease. We summarise and discuss (Prof S M Langan); Health Data
advances in our understanding of the disease and their implications for prevention, management, and future research. Research UK, London, UK
(Prof S M Langan); Department
Introduction essential, common, and associated features,11 are often of Clinical Medicine, Trinity
College Dublin, Dublin, Ireland
Atopic dermatitis, also known as eczema and atopic used in clinical settings. Essential features are eczematous (Prof A D Irvine DSc);
eczema, is one of the most common inflammatory disor lesions, intense pruritus, and a chronic or relapsing Dermatology, Children’s Health
ders, affecting up to 20% of children and 10% of adults in disease course. Eczematous lesions typically show an age- Ireland, Crumlin, Ireland
high-income countries.1,2 Globally, the prevalence of related distribution (figure 1A). Infants often present with (Prof A D Irvine); National
Children’s Research Centre,
atopic dermatitis is increasing, although estimates in acute lesions characterised by poorly defined erythema Dublin, Ireland (Prof A D Irvine);
high-income countries are stabilising. The disorder is with oedema, vesicles, excoriations, and serous exudate, and Department of
characterised by intense itching and recurrent eczematous all of which can be widely distributed but typically involve Dermatology and Allergy,
lesions and has a heterogeneous clinical presentation.3 the face, cheeks, and trunk but not the nappy area. In University Hospital Schleswig-
Holstein, Kiel, Germany
Although atopic dermatitis can occur at any age, the usual childhood (aged 2 years and older), eczema becomes (Prof S Weidinger MD)
age of onset is in early childhood, typically at age 3–6 more localised and chronic than in infancy, with paler Correspondence to:
months. Evidence suggests that atopic dermatitis in erythema, dry skin (xerosis), and poorly defined lesions Prof Sinéad M Langan, Faculty of
adults is common, including both persistent and new- commonly affecting flexor surfaces with thickening Epidemiology and Population
onset forms.4,5 (lichenification) of chronic areas (figure 1). Although Health, London School of
Hygiene & Tropical Medicine,
The causes of atopic dermatitis are complex and adolescents and adults usually have diffuse eczema, they London WC1E 7HT, UK
multifactorial. There is a strong genetic component, with can also have localised lesions typically affecting hands, [email protected]
evidence for multiple mechanisms of genetic risk. Loss- eyelids, and flexures (figure 1). Adults can have chronic
of-function mutations in the gene encoding filaggrin hand eczema only or head-neck dermatitis as well,
(FLG) are the most strongly and consistently reported involving the upper trunk, shoulders, and scalp (figure 1).
genetic variants, supporting a key role for the skin Morphological variants include the follicular type, charac
barrier, as filaggrin is a major structural protein in the terised by closely packed follicular papules, frequently seen
epidermis.6 Although genetics are clearly important in in people of Asian and African descent (appendix p 1), and See Online for appendix
atopic dermatitis, the increasing global prevalence of the the prurigo type, with excoriated papules and indurated
disorder highlights the role of environmental factors. nodules, in patients with long-standing disease.3,12
Individuals with atopic dermatitis are at increased risk of Common features seen in most patients with atopic
having asthma, allergic rhinitis, and food allergy, and dermatitis are generalised skin dryness, early disease
could be at increased risk of a wide range of health and onset (typically in the first 2 years of life), and a personal
psychosocial outcomes.3
In this Seminar, we aim to discuss major developments
in the understanding of atopic dermatitis causes and Search strategy and selection criteria
long-term outcomes and to summarise the rapid expan We searched MEDLINE, the GREAT database, and the Centre
sion of therapeutic options, including targeted therapies. of Evidence-based Dermatology web resource of systematic
reviews, using the terms “atopic eczema”, “atopic dermatitis”,
Clinical signs and “eczema”, in combination with search terms for
Atopic dermatitis is difficult to define because of its great diagnostic criteria, epidemiology, aetiology, immunology,
heterogeneity in terms of clinical features, severity, and quality of life, and treatment. Our search focused on articles
course. Without definitive tests, clinical signs are needed published in English from January, 2015, to April, 2020.
for diagnosis; a clinician’s assessment is considered We also included key relevant papers outside this period,
the gold standard.7 To aid diagnosis, several sets of criteria such as papers in the reference lists of included articles.
have been developed. While the UK Working Party We have cited relevant review articles and book chapters to
criteria9,10 are widely used for epidemiological studies enable readers to access more details and more references
of children, the Hanifin and Rajka criteria8 and an empiri than those included in this Seminar.
cally derived, simplified version, which distinguishes
www.thelancet.com Vol 396 August 1, 2020 345

Seminar
history or family history, or both, of atopic disease

(eg, asthma, allergic rhinitis, atopic dermatitis) or specific
IgE reactivity. Since not all patients with atopic dermatitis
A Typical clinical appearence and location of atopic dermatitis at different ages
show IgE-mediated allergic sensitisations and thus are not
technically atopic, eczema has been suggested as an
i umbrella term for atopic and non-atopic forms of atopic
dermatitis. However, today these terms are often used
synonymously in published work.13,14 Asso ciated non-
specific features include hyperlinearity of palms and soles,
Dennie-Morgan infraorbital folds, and Hertoghe’s sign.15
Panel 1 lists the most important differential diagnoses.
Variability in measures to ascertain severity of atopic
ii dermatitis in different settings has been addressed by the
multistakeholder Harmonizing Out come Measures for
Eczema (HOME) initiative, leading to harmonisation
of assessment tools used worldwide in clinical trials
(appendix p 2).16–21
Epidemiology
Atopic dermatitis affects up to 20% of children and 10%
iii
of adults in high-income countries, based on annual self-
reported prevalence estimates.3,8,22 In 2010, 230 million
people worldwide were estimated to have eczema, with
reports that the condition was the non-fatal skin
disorder with the highest disease burden.23 Data on
disease severity are scant but, in a multinational survey,
10–20% of adult patients with atopic dermatitis reported
B Close-up view of skin severe disease.24 In a population-based study from
the UK of individuals presenting to primary care,
approximately 4% of adults had severe disease.25
i ii
Although the prevalence of atopic dermatitis has
plateaued in many high-income countries, it continues to
increase in low-income and middle-income countries.1 The
striking increase in prevalence over the past 30 years
suggests that environmental factors are important in the
aetiology of atopic dermatitis.26 The so-called hygiene
hypothesis is frequently discussed as a possible expla
nation, supported by an inverse socioeconomic gradient
and an association with number of siblings.3,27,28 Other
iii iv
evidence supporting the importance of environmental
factors in atopic dermatitis includes urban–rural gradients
Figure 1: Appearance of atopic dermatitis

The typical clinical appearance and locations of atopic dermatitis are shown at
different ages (A). In infants (Ai), eczema lesions are often more acute than in
adults and mainly located on the face and the extensor surfaces of the limbs.
The trunk might be affected but the nappy area is typically spared. From age
C Associated atopic stigmata 1–2 years and onwards (Aii), polymorphous manifestations with different types
of skin lesions are seen, particularly in flexural folds. In adolescents and adults
(Aiii), often lichenified and excoriated plaques are found, particularly at flexures,
i ii iii wrists, ankles, and eyelids; in the head-and-neck type, the upper trunk,
shoulders, and scalp are involved. Adults might have only chronic hand eczema
or they might present with prurigo-like lesions. Close-up views of the skin (B)
show non-lesional (Bi), acute (Bii), subacute (Biii), and chronic (Biv) lesions of
atopic dermatitis. Atopic stigmata (C), such as palmar and plantar hyperlinearity
(mostly seen in patients with FLG mutations or ichthyosis vulgaris [Ci]),
Dennie-Morgan infraorbital folds (Cii), and Hertoghe’s sign (thinning of the
lateral part of eyebrow [Ciii]) are more common in patients with atopic
dermatitis than in the general population and can help establish the diagnosis.
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Seminar
in prevalence, the substantial increase in prevalence in the

former East Germany after reunification, and reduced Panel 1: Differential diagnoses of atopic dermatitis
prevalence in farming households.29 US ecological data For each age group, the differential diagnoses are listed
support a low prevalence of atopic dermatitis in areas in order of probability (from highest to lowest).
with high humid ity, temperature, and ultraviolet light
exposure.30 Variations in prevalence of atopic dermatitis by Infants and toddlers (age ~0–24 months)
ethnicity have been reported; US studies report higher • Seborrhoeic dermatitis
prevalence in African-American individuals (17%) than • Ichthyosis vulgaris
in white people (11%), with similar findings for black • Scabies
Caribbean children compared with white children in older • Psoriasis
UK studies.3,31–33 • Phenylketonuria
The substantial variation in diagnostic criteria used to • Ectodermal dysplasia
identify atopic dermatitis leads to challenges in describing • Coeliac disease
the epidemiology of the disorder.11 In epidemiological • IgA deficiency
studies, International Society for Asthma and Allergies in • Di George syndrome (also known as 22q11.2 deletion For more on HOME see
Children (ISAAC) criteria are widely used and have been syndrome) http://www.homeforeczema.org/
validated in different settings. Findings support the • DOCK8 deficiency syndrome

adequacy of these criteria for estimating prevalence at the • Agammaglobulinaemia
population level, although they do less well in countries • Netherton syndrome
with a low prevalence of atopic dermatitis than in coun • Wiskott-Aldrich syndrome
tries with a high prevalence.34,35 Routinely collected health Children and adolescents (age ~2–16 years)
data are increasingly being used to address questions • Tinea manuum or tinea pedis
about epidemiology and long-term outcomes of atopic • Impetigo
dermatitis,36 but approaches to defining this disorder in • Psoriasis
routine data settings are heterogeneous;36 one systematic • Pityriasis rosea
review showed the variation in atopic dermatitis prevalence • Conditions listed for infants and toddlers that might have
was three times greater with some criteria used to identify not been diagnosed early in life
the condition than with others.7
Adults (age ~16 years and older)
Natural history • Allergic contact eczema
Although the incidence of atopic dermatitis peaks during • Psoriasis
infancy, there has been a shift from thinking of atopic • Pityriasis rosea
dermatitis as a resolving early childhood disease to an • Cutaneous T-cell lymphoma
understanding that atopic dermatitis can have hetero • Pityriasis rubra pilaris
geneous trajectories.37,38 Patterns described in published • Asteatotic eczema
work are varied and there is no consensus on optimal • Netherton syndrome
identification of subgroups. Trajectories can range from
early transient disease to relapsing–remitting atopic
dermatitis, chronic persistent atopic dermatitis, or long those with a first-degree relative with atopic dermatitis,
periods of remission followed by recurrence.37,38 The focus asthma, or allergic rhinitis, but this intervention has
on atopic dermatitis in early life is largely because of the failed to show benefits in larger trials, including in a
early onset of the disorder and studies in birth cohorts large, multicentre, pragmatic trial in the UK.45,46
with fairly short follow-up.3,5 Active atopic dermatitis
beyond childhood is common. Instances in adults include Pathophysiology and mechanisms of disease
individuals who have had the disease since childhood in The pathophysiology of atopic dermatitis involves a com
addition to incident disease.39,40 Predictors of persistent plex interplay between a dysfunctional epidermal barrier,
atopic dermatitis activity into adulthood include concur skin microbiome abnormalities, and a predominantly
rent asthma, hayfever, or both, young age of onset, low type-2-skewed immune dysregu lation (figure 2A, B).47,48
socioeconomic status, and non-white ethnicity; it is These mechanistic drivers can promote and interact with
unclear if these predictors are independent of disease others. For example, skin barrier weakness attributable to
severity.4,41 There is a need to better understand the causes a filaggrin deficiency promotes inflammation and T-cell
and outcomes of adult atopic dermatitis.39 infiltration; colonisation or infection with Staphylococcus
Atopic dermatitis is debilitating and common, so aureus damages the skin barrier and induces inflammatory
preventing the disease and associated atopic comorbidities responses; and local Th2 immune responses further
is a major priority. Two pilot trials suggested that daily diminish barrier function, drive itching, and facilitate
emollient applications from birth might prevent atopic dysbiosis in favour of members of the genus Staphylococcus,
dermatitis onset in individuals at high risk,42–44 such as particularly S aureus (figure 2).

Seminar
A
Healthy skin Non-lesional skin Acute lesion Chronic lesion
Staphylococcus
aureus
Reduced microbial diversity
Microbiota
Barrier deficiency Barrier disruption Lichenification
DC IL-33
IL-1β TSLP
IL-33
LC IL-25 LC
TARC IDEC
TSLP
MC
IL-22
IL-17A IFN-γ
IgE IL-13
IL-21 IL-17F TNF
Type 2 inflammation
Th22 IL-22
ILC2
Teff IL-4
Th1
IL-31
IL-13 DC Th17
Th2 Sensory
Th2 neuron
IL-5
IL-4
IL-13 Trm
IL-4 IL-13 IL-22
Th22 Eo
B cell
IgE
Th2 Th22
CLA CCR10 H4R

CCR4 CRTH2
Allergens and
B C irritants D Itch
Affected skin
Brain
Trm
MC DC
MC Th2
DC IL-13
Corneodesmosomes IL-4
IgE
Cornified envelope IL-33 B cell
Intercellular lipids Tryptase ILC2
TSLP
NMF B cell IgE IL-4
KLKs Histamine
T naive IL-31 IL-13
Teff Tem
Tem PAR2
TSLPR
IL-4R
Tight junctions Filaggrin granules IL-33R H1/4R
Teff
IL-31R
Free nerve endings
Figure 2: Pathogenesis, main mechanisms, and pathophysiology of atopic dermatitis

Figure shows stage-based pathogenesis and main mechanisms of atopic dermatitis (A). Clinically unaffected skin has an epidermal barrier dysfunction with a reduced
diversity of the surface microbiome. In lesional skin, Langerhans cells, inflammatory epidermal dendritic cells bearing specific IgE bound to the high affinity receptor for IgE,
and dermal dendritic cells take up allergens and antigens. The type-2 cytokines IL-4, IL-13, and IL-31 directly activate sensory nerves, which promotes pruritus.
With increasing chronicity, there is a progressive increase of keratinocyte-derived and Th-cell-derived cytokines. Itch is induced by various pruritogens (eg, antigens
and molecular mediators such as histamine and other substances) and mediated by cutaneous pruriceptive primary sensory nerves, which transmit the pruritic signal via
afferent fibres to the spinal cord (B–D). CCR=CC chemokine receptor. CLA=cutaneous lymphocyte-associated antigen. CRTH2=chemoattractant receptor-homologous
molecule expressed on Th2 cell. DC=dendritic cell. Eo=eosinophil. H1/4=histamine 1/4. IDEC=inflammatory dendritic epidermal cell. IFN=interferon. IL=interleukin.
ILC=innate lymphoid cell. KLK=kallikrein-related peptidase. LC=lymphoid cell. MC=mast cell. NMF=natural moisturising factor. PAR2=protease-activated receptor 2.
TARC=thymus and activation-regulated chemokine. Teff=effector T cell. Tem=effector memory T cell. Th= T-helper cell. Tnaive=naive T cell. TNF=tumour necrosis factor.
Trm=tissue-resident memory T cell. TSLP=thymic stromal lymphopoietin.

Seminar
Genetic risk factors both, of the two proteins might be affected.71,72 In atopic
A family history of atopic disease, particularly atopic dermatitis, the gap in heritability, after accounting for the
dermatitis, is the strongest identifiable risk factor for 34 loci identified to date, might relate to additional
developing the disorder.49 Atopic dermatitis has strong unidentified loci or heritable epigenetic effects.
heritability (approximately 75% in twin studies), sug
gesting that genetic factors are an important contributor.50 Epidermal barrier dysfunction
Genome-wide association studies have identified 34 loci Epidermal barrier dysfunction is consistently observed in
that cumulatively account for less than 20% of atopic affected and unaffected skin of patients with atopic
dermatitis heritability.51 Functional genetic variants have dermatitis, as shown by elevated transepidermal water
not been definitively identified in most of these loci but loss and pH,73,74 increased permeability, reduced water
these genomic regions contain multiple genes with roles retention,75 and altered lipid composition.74,76–78 Disruption
in immune responses, including type-2 differentiation, of barrier function in atopic dermatitis is multifactorial
T-cell activation, and innate immunity, and the epidermal and includes genetic factors, such as FLG mutations, and
differentiation complex, a locus for skin barrier genes.51–53 physical damage from scratching (figure 2A, B). The
barrier is further damaged by microbial dysbiosis,
Filaggrin including colonisation with S aureus and Malassezia
The strongest genetic risk for atopic dermatitis yet iden yeasts. Type 2 immune activity in the skin causes a
tified is associated with mutations in the skin barrier secondary downregulation of skin barrier genes and
protein filaggrin, encoded by the FLG gene.54,55 FLG stratum corneum lipids, exacerbating the underlying
encodes the pre-protein profilaggrin, which is post- barrier defect.77,79 Keratinocytes in the stressed epidermal
translationally processed to filaggrin monomers. Loss-of- barrier send proinflammatory and pruritogenic signals,
function mutations in FLG cause a 50% decrease in through the epidermal alarmins IL-33 and thymic stromal
protein expression in the heterozygous state and a total lymphopoietin (TSLP), causing further tissue damage,
loss of protein expression in the homozygous or com driving recruitment of type 2 inflammatory cells, and
pound heterozygous states.6,56 Loss-of-function mutations activating type 2 innate lymphoid cells resident in the
in FLG cause the mild, semi-dominant, mendelian dis skin.80,81 These lymphoid cells produce IL-5 and IL-13,
order of keratinisation ichthyosis vulgaris.6,57,58 FLG loss-of- which activate eosinophils and Th2 cells.
function mutations confer a 3–5 times higher risk of
atopic dermatitis in individuals who have them than in The role of the microbiome
individuals who do not, and predispose these individuals Atopic dermatitis is associated with a disordered
to asthma and peanut allergy.55,59–62 Although initial data on microbiome, with S aureus being a dominant coloniser
the population genomics of FLG mutations were gen and pathogen.82 A meta-analysis reported colonisation
erated mainly in European, Japanese, and Han Chinese rates on bacterial cultures on non-lesional skin (39%) and
populations, new rapid-sequencing techniques have lesional skin (70%).83 Genome-based assays have shown a
shown that these mutations are important factors in temporal shift in the atopic dermatitis microbiome; there
atopic dermatitis in people from Bangladesh and African- is a loss of community diversity preceding flares, and the
American individuals as well.63–66 Loss-of-function muta microbiome becomes S aureus dominant with regression
tions in FLG appear to be rare in sub-Saharan Africa. In after treatment and a return to baseline severity.84 The
addition to loss-of-function mutations, FLG has an intra temporal relationship between a disordered microbiome
genic copy number variation, with alleles containing ten, and the development of atopic dermatitis is unclear, but
11, or 12 filaggrin repeats, with the shorter alleles studies suggest that early life colonisation with com
conferring risk of atopic dermatitis.67,68 mensal non-S aureus staphylococcus bacteria reduces risk
of atopic dermatitis,85 whereas early colonisation with
Other genetic loci of relevance S aureus preceded development of atopic dermatitis in
Only 20–40% of patients with atopic dermatitis have FLG later life.85,86 S aureus contributes to atopic dermatitis
loss-of-function mutations, implying that many other pathogenesis in many ways, including barrier disruption
genes are important in the condition. Outside of FLG, the and direct proinflammatory effects such as type 2
best replicated locus is the type 2 cytokine cluster on immune activation.87 Cutaneous yeasts such as Malassezia
chromosome 5q31.1. This locus contains genes for the species could trigger or exacerbate cutaneous inflam
classic type 2 immunity cytokines interleukin (IL)-4 and mation in atopic dermatitis,88–91 although the mechanisms
IL-13, and RAD50, which could be a locus for the control are poorly understood. A subgroup of people with atopic
of cytokine expression.69 A third widely replicated locus dermatitis, particularly those individ uals with more
on chromosome 11q13.5, between two candidate genes, severe dermatitis of the head and neck, display specific
EMSY and LRRC32, is associated with multiple atopic IgE reactivities to Malassezia antigens88,89 and might
phenotypes.70 Although causal genes and variants have benefit from topical or oral antifungal therapy, or both,
not been established, results from fine mapping and although evidence to support these treatments is
functional studies imply that the expression, function, or sparse.90–95

Seminar
Immunological dysregulation and inflammation NK cells might serve as potential counter-regulatory

Cutaneous inflammation is central to the pathogenesis of responses to type 2 skin inflammation.117
atopic dermatitis. A better understanding of the key
drivers of this inflammation is crucial to developing Neuroimmune interactions in atopic dermatitis
targeted therapeutic approaches (figure 2A, B). Lesional The dominant symptom of atopic dermatitis is itch,
skin of patients with atopic dermatitis shows a T-cell contributing to pathogenesis through skin barrier
infiltrate predominantly characterised by CD4 expression. damage, allowing allergens and irritants to permeate,
The inflammatory profile is complex and diverse with and activation of alarm signals that perpetuate the
activation of skin-resident inflammatory dendritic cells, itch–scratch cycle (figure 2B).118 Itch is induced by a
innate lymphoid cells, and Langerhans cells.96 The release complex variety of pruritogens such as type 2 cyto
of alarmins initiated by epidermal barrier disruption kines.119 Histamine is the most studied pruri togen,
activates inflammatory epidermal dendritic cells and type- predominantly released from mast cells and basophils.
2-mediated responses. Activated Th2 cells release IL-4 and Circulating and tissue-released histamine stimulate
IL-13, promoting IgE class switching in B cells and histamine H1 and H4 receptors and TRPV1 (vanilloid
production of antigen-specific IgE via the signal trans receptor 1) chan nels.120 However, there is no robust
ducer and activator of transcription (STAT) pathway.97 An evidence that antihistamines are effective in improving
alarmed skin barrier shows dissolution of stratum signs and symptoms of atopic dermatitis, including
granulosum tight junctions, allowing extension of itch.121 Type 2 cytokines, including IL-4, IL-13, TSLP, and
dendrites beyond this second barrier to sense and present IL-31, contribute to itch and might be more relevant to
antigens.98,99 chronic pruritus in patients with atopic dermatitis
Non-lesional atopic dermatitis skin shows immuno (figure 2B). The discovery of the type 2 IL-4 receptor
histological changes, including spongiosis (abnormal subunit α (IL-4Rα) on afferent neurons reinforces the
accumulation of fluid between cells) and T-cell infiltrations inter-relatedness of the type 2 response and neural itch
similar to those of lesional skin, albeit more subtle.100 control.122 Responsiveness of itch to inhibition of IL-4Rα
Likewise, the cytokine profile of unaffected skin is skewed by dupilumab and downstream Janus kinase (JAK)
towards the type 2 system and over-representation of inhibition supports the clinical relevance of these
innate immunity and angiogenesis markers (figure 2A).62,101 type 2 immune–neural interactions.122,123 Several type 2
Lesional atopic dermatitis skin shows dysregulated immune cells release IL-31, which drives itch through
expression of a wide range of genes, mostly related to direct stimulation of IL-31 receptor subunit α (IL-31Rα)
keratinocyte activity and T-cell infiltration, especially for or TRPV1-expressing or TRPA1-expressing neu rons
Th2-associated (IL-4, IL-10, IL-13) and Th22-associated (figure 2B).124 Pronounced improvement of itch after
(IL-22) genes (figure 2A–D).100–102 An activation of Th1- treatment with the humanised monoclonal anti-IL-31Rα
mediated and Th17-mediated responses has been reported antibody nemolizumab reinforces the key role of IL-31
in chronic skin lesions, in particular in children and people in atopic dermatitis-related pruritus.125,126
of Asian descent,103 but the relative importance of these
pathways in atopic dermatitis is unclear.100 Inhibition of Treatment
Th1-cell or Th17-cell axes does not appear to be an effective Basic management strategies
therapeutic intervention for atopic dermatitis.104,105 The Atopic dermatitis management aims to improve symp
cutaneous T-cell infiltrates in atopic dermatitis are highly toms and establish long-term disease control. Manage
polyclonal, but antigen specificity remains inadequately ment plans should be patient-centred and should include
understood.106 Many patients with severe atopic dermatitis avoidance of individual trigger factors, skin barrier
have increased IgE-mediated reactivity to aeroallergens, restoration using moisturiser, and a step-up and step-down
food proteins, microbial antigens, or keratinocyte-derived approach aimed at reducing inflammation according to
auto-antigens.107–109 Indeed, environmental allergens such severity of the disease.127–131 The choice of anti-inflammatory
as house dust mites, pollens, or animal epithelia allergens therapy is largely based on disease severity; mild atopic
can contribute to atopic dermatitis flares in IgE-sensitised dermatitis can usually be controlled with topical treat
patients.110–112 However, data supporting allergen avoidance ments, whereas more severe disease might require
to improve or prevent atopic dermatitis are sparse.113,114 In phototherapy, systemic immunomodulatory therapy, or
infants with moderate-to-severe atopic dermatitis, food both.132 Education for self-managing atopic dermatitis
allergens also induce flares, but most food allergies resolve improves disease severity and quality of life.133,134
during childhood and there is little evidence supporting Approaches for the delivery of educational interventions
dietary interventions for the prevention of atopic vary, from allowing adequate time for discus sion on
dermatitis.115,116 Reduced natural killer (NK)-cell-mediated treatments in clinics to specialty clinics with inter
immunomodulation has been proposed to be involved in disciplinary treatment teams and nurse-led workshops,
the immune dysregulation in atopic dermatitis. Decreased with the strongest evidence from trials supporting more
concentration and altered composition of peripheral blood formalised and structured group-based educational school
NK cells, and enrichment of lesional skin with activated programmes (so-called eczema schools).135–137

Seminar
Avoidance of trigger factors potency. The formulation of the topical corticosteroid also
Many factors can provoke worsening of atopic dermatitis affects potency. The choice of treatment is based on
in individual patients. These include non-specific factors disease activity, patient age, and anatomical location.
such as irritants (eg, wool fabrics and alkaline deter Milder disease, younger age, and flexural and facial skin
gents), climatic factors, infections, psychological stress, involve ment are reasons to choose less potent topical
and exposure to foods, inhalants, or contact allergens in corticosteroids, except in cases of short-term severe flare
sensitised patients.110,111 There are no evidence-based treatment. Traditionally, twice-daily application on affected
avoidance recommendations; thus, any measures should areas is recommended, but there is little evidence that
be based on definite worsening of the condition after twice-daily is more effective than once-daily application.131,145
exposure and allergy testing when necessary.128 As an acute intervention, topical corticosteroids can be
diluted and applied under wet wrap dressings to enhance
Barrier repair and maintenance therapy penetration and skin hydration.146 Topical calcineurin
A deficient epidermal barrier is a key feature of atopic inhibitors, including tacrolimus and pimecrolimus, have
dermatitis, with xerosis presenting in most patients. reduced clinical efficacy (equal to or less effective than
Although trial evidence is scarce, moisturisers could moderately potent topical corticosteroids, respectively).
improve barrier function; a Cochrane systematic review Symptoms of topical calcineurin inhibitors, such as
reported increased hydration and reduced xerosis, itch, burning and pruritus, commonly experienced during the
and flares, alongside a reduced need for anti-inflammatory first days of use, and their high cost restrict their use.
medication with regular use.138 Available moisturisers These inhibitors cause no skin atrophy and are useful at
contain varying amounts of emollient, occlusive, and susceptible sites, including intertriginous areas or the
humectant components. Some products contain other face.147 Topical corti costeroids and topical calcineurin
excipients, such as ceramides and essential fatty acids, inhibitors can be proactively applied to previously active
but there is no robust evidence of their superiority over sites for 2 days every week to reduce flares, particularly
conventional products.139 Similarly, no evidence supports when flares occur on the same body sites.148,149
use of antiseptic-containing or antimicrobial-containing In 2016, the US Food and Drug Administration approved
preparations. Trial evidence guiding the choice of specific crisaborole ointment, a topical inhibitor of the intracel
formulations is scarce but, in general, use of moisturisers lular enzyme phosphodiesterase 4, for treatment of
with fewer ingredients and without fragrances is recom patients aged 2 years or older with mild-to-moderate
mended to avoid irritants and allergic reactions. Skin atopic dermatitis. In phase 3 randomised trials, 32% of
type, body area, dryness and inflammation, and patients’ patients assigned to crisaborole met the primary endpoint
individual preferences should also be considered when of being clear or almost clear (Investigator Static Global
making these choices.139,140 Moisturisers should be used Assessment [ISGA] score of 0 or 1) with at least a 2-point
liberally, twice or three times daily, including after improvement in ISGA scores (scored from 0 to 4) and
bathing.139 There is consensus that non-soap fragrance- no serious side-effects.150,151 Of note, this finding was
free cleaners with a neutral-to-low pH should replace only slightly higher than patients assigned to vehicle
soaps, bubble baths, and shower gels. A randomised trial (18–25%). None of the outcome assessment instruments
found no evidence for bath additives, including bath oils, recommended by the HOME initiative were reported.
in addition to standard treatment regimens for atopic Consensus on the role of crisaborole in atopic dermatitis
dermatitis.141 management is awaited, but it might offer another topical
non-steroidal option for individuals with mild-to-moderate
Topical anti-inflammatory therapies atopic dermatitis or for anatomically sensitive sites.
Topical corticosteroids are widely endorsed as the first- Topical formulations of inhibitors of the JAK-STAT and
line anti-inflammatory treatment, and their appropriate spleen tyrosine kinase pathways are in the late stages of
intermittent use bears little risk.142 Inappropriate use can development and could represent new treatment options
cause local side-effects, including skin atrophy, purpura, for atopic dermatitis. In a randomised, dose-ranging,
striae, telangiectasias, dyspigmentation, and facial vehicle-controlled, and active-controlled phase 2b study in
acneiform changes.143 Systemic side-effects from topical 307 adult patients with mild-to-moderate atopic dermatitis,
corticosteroids are considered very uncommon but can twice-daily application of ruxolitinib (1·5%) cream, which
include hypothalamic–pituitary–adrenal suppression and inhibits JAK1 and JAK2, was superior to vehicle and
growth retardation.144 triamcinolone (0·1%) cream (a mid-potency topical
In the EU, topical corticosteroids are grouped into four corticosteroid).152 Patients given ruxolitinib cream had
classes, from lowest (I) to highest (IV) potency, whereas mean local Eczema Area and Severity Index (EASI)
the US classification includes seven classes, from reductions of 71·6% versus 15·5% for vehicle and 59·8%
highest (I) to lowest (VII). These classifications are based for triamcinolone at week 4, with mild or moderate adverse
on a vasoconstriction assay, with increased vasoconstric events.152 Phase 3 randomised trials are ongoing.
tion occurring with potent topical corticosteroids, which Likewise, for the pan-JAK inhibitor delgocitinib, superior
provides indirect information on anti-inflammatory efficacy over vehicle was reported from several phase 2 and

Seminar
3 trials. In a phase 3 randomised, double-blind, vehicle- off-label treatments for severe atopic dermatitis, even in
controlled study on 158 Japanese patients aged 16 years or children.159 Both drugs work slowly, with maximum
older with moderate-to-severe atopic dermatitis, mean benefits appearing after 4–8 weeks for azathioprine and
percent changes from baseline in the modified EASI 8–12 weeks for methotrexate. A small placebo-controlled
(mEASI) at week 4 were –44·3% in the delgocitinib 0·5% trial showed a 37% improvement in mean disease activity
group and 1·7% in the vehicle group. 51·9% of the patients with azathioprine compared with 20% for placebo at
in the delgocitinib 0·5% group achieved an mEASI50 week 12.132 In a small randomised trial, eight (40%) of
(reduction of baseline mEASI by 50%) and 26·4% achieved 20 patients in the methotrexate group and ten (45%) of
an mEASI75, versus 11·5% and 5·8%, respectively, in 22 patients in the azathioprine group achieved a reduction
the vehicle group.153 In a 52-week, open-label trial on of at least 50% in the SCORAD (SCORing Atopic
352 Japanese patients aged 16 years or older with mild-to- Dermatitis) severity score by week 12.160 17 patients allo
severe atopic dermatitis, at week 4, 31·5% of patients cated to methotrexate and 18 patients allocated to
treated with delgocitinib 0·5% twice daily had achieved an azathioprine were followed up for 2 years. Of those in the
mEASI50 and 10·9% had achieved an mEASI75.153 At per-protocol analysis, ten patients in the methotrexate
week 24, the improvements were maintained in 42·3% group and six patients in the azathioprine group had
and 22·7% of patients, respectively, and 51·9% and achieved a SCORAD50 response. In the methotrexate
27·5% of patients, respectively, at week 52.153 Delgocitinib group, seven patients discontinued treat ment; reasons
0·5% ointment has recently been approved in Japan for included controlled disease (n=2), insufficient response
the treatment of adults with atopic dermatitis. (n=3), and adverse events (n=2). In the azathioprine group,
ten patients discontinued treatment for reasons including
Phototherapy controlled disease (n=5), insufficient response (n=4), and
If disease control cannot be achieved with topical mea adverse events (n=1).161,162 There is no robust trial evidence
sures, phototherapy (usually 4–8 weeks) can be considered. supporting the use of mycophenolate mofetil in atopic
The most effective settings are narrow-band ultraviolet B dermatitis but it appears to have a favourable safety profile
radiation and medium-dose ultraviolet A1.154 Benefits have and some evidence of efficacy, and thus can be considered
to be weighed against long-term cumulative adverse an alternative treatment option in individual cases. A
effects, including photodamage, skin carcinogenesis, and systematic review and network meta-analysis concluded
melanoma induction, particularly for ultra vio
let A1.155 that dupilumab and ciclosporin were more effective in the
Further limiting factors are access to specialised treatment short term than methotrexate and azathiopine.163 However,
centres and the need for frequent treatments (usually low event rates precluded relative safety assessment. In
3–5 applications a week for a total of 2–3 months). relation to newer drugs discussed in the following sections,
the researchers concluded that, although the results from
Conventional systemic treatments existing small trials are promising, data are scarce, in
If appropriate topical treatments and ultraviolet light particular in relation to assessment of safety.163
therapy have failed or are not feasible, systemic therapy is
needed.132 Systemic corticosteroids should only be used in Targeted monoclonal antibodies
exceptional cases for short-term flare treatment or when Although atopic dermatitis is considered to involve
starting another systemic therapy.128 The most com multiple immune pathways, strong activation of type 2
monly used conventional systemic treatments for atopic immune responses, driven by innate type 2 lymphoid cells
dermatitis are ciclosporin, methotrexate, azathioprine, and and Th2 cells, and their signature cytokines IL-4 and IL-13,
mycophenolate mofetil. However, robust long-term data appears to be a dominant mechanism.101,102 Thus, targeting
on the effects of these drugs in atopic dermatitis are largely type 2 pathways appears to be a reasonable therapeutic
missing, and most trials remain placebo controlled with strategy. Dupilumab is a fully human monoclonal anti
no head-to-head comparisons.128 With the exception of body against IL-4Rα that inhibits both IL-4 and IL-13
ciclosporin, which is approved for the treatment of patients signalling and is the first biologic approved as a first-line
aged 16 years and older in at least 15 European countries, treatment for moderate-to-severe atopic dermatitis in
Australia, and Japan, the use of these repurposed legacy patients aged 6 years and older in the USA and in patients
immunosuppressants in atopic dermatitis is considered aged 12 years and older in the EU (approval for children
off-label.128 Ciclosporin has the most robust efficacy and aged 6–12 years is pending). In two phase 3 monotherapy
safety data from RCTs, with a mean improvement of randomised trials in adults, 51·3% and 44·2% of patients
clinical severity scores of 55% from baseline after who were assigned the licensed dose of dupilumab
6–8 weeks of treatment.156,157 It has a rapid onset of action (300 mg every other week) achieved an EASI75 at
but end-organ toxicity and cumulative risk of malignancy week 16, compared with 14·7% and 25·0% of patients in
restrict long-term use. Therefore, most guidelines recom the placebo groups.164 When combined with topical
mend continuous use for no longer than 1–2 years.128,129,156,158 corticosteroids, the proportion of patients achieving an
Although robust long-term data are scant, azathioprine EASI75 response increased to approximately 65% com
and methotrexate appear to be effective and fairly safe pared with 22% for topical corticosteroids only; response

Seminar
rates were sustained until week 52.165 Response rates were available. In JADE MONO-1,178 387 patients aged 12 years
largely similar in a randomised trial of patients with a and older with moderate-to-severe atopic dermatitis were
history of inadequate responses to or an intolerance of randomly assigned to once-daily oral abrocitinib 200 mg,
ciclosporin.166 Observations from large real-world patient 100 mg, or placebo. At week 12, 23·7% of patients given
populations for dupilumab largely accord with trial abrocitinib 100 mg and 43·8% of patients given abrocitinib
data.166–169 Efficacy and safety of dupilumab in adolescents 200 mg achieved an investigator’s global assessment (IGA)
aged 12–18 years are similar to that in adults.170 The safety response of clear (0) or almost clear (1). 39·7% (100 mg)
profile of dupilumab is favourable, with ocular complaints and 62·7% (200 mg) achieved an EASI75, compared with
(in particular conjunctivitis) being the most frequent side- 17·9% and 11·8% in the placebo group.178 Results from
effect observed, in up to 28% of dupilumab users in clinical JADE MONO-2,179 which included 391 patients, were
trials171 and up to 38·2% in real-world settings.167–169,171 Most similar. 38·1% (200 mg) and 28·4% (100 mg) versus 9·1%
cases of conjunctivitis are transitory and can be managed (placebo) of patients achieved an IGA of 0 or 1, and 61·0%
successfully with topical anti-inflammatory (ocular) agents and 44·5% versus 10·4% had an EASI75 response.179 In
without dupilumab withdrawal.171 On the basis of currently both trials, results were also convincing for multiple
available trial data, there appears to be little need for patient-reported outcomes; in particular, there was a
laboratory monitoring.172 72-week data from an open-label significant difference from placebo in peak pruritus
extension in adults given 300 mg dupilumab weekly improvement within the first 48 h. Over the short
showed sustained efficacy with no additional safety signals; observation period, abrocitinib was well tolerated, with
however, long-term and uncommon side-effects are nausea, headache, and nasopharyngitis being the most
insufficiently assessed in trials to date.172,173 Many other frequently reported adverse events. There were also
biologics for atopic dermatitis are in phase 2 and phase 3 transient dose-related decreases in median platelet count
trials that target different cytokines and signalling and a slightly increased incidence of herpes zoster, which is
pathways (appendix p 3).174 probably an outcome common to all JAK inhibitors, and
herpes simplex.
Oral JAK inhibitors Oral JAK inhibitors under development for atopic
Since immune pathways beyond IL-4 and IL-13 and a dermatitis appear to have a high efficacy and a rapid onset
diversity of cytokines are involved in atopic dermatitis of action with clinically meaningful improvements of itch
inflammatory processes, oral JAK inhibitors are prom within the first 1–2 weeks, and of clinical signs from
ising agents because they can block a range of cytokine, week 2–4. However, to address long-term safety concerns,
growth factor, and hormone receptor signalling path such as the dose-dependent induction of immuno-
ways.175 In two phase 3 monotherapy randomised trials in suppressive effects, and uncertainties about impacts on
adults lasting 16 weeks, the JAK1 and JAK2 inhibitor the haematopoietic system and potential thromboembolic
baricitinib showed superiority over placebo for multiple risks associated with JAK inhibition from studies in high-
clinically important measures, with overall good short- risk patients with rheumatoid arthritis,180 data from long-
term safety. At 4 mg daily, treatment benefits were larger term studies are needed to establish the risk–benefit
(eg, EASI75 24·8% vs 8·8% with placebo for one trial and profile in atopic dermatitis.175
21·1% vs 4·4% with placebo for the other) than were
benefits at 2 mg daily (EASI75 18·7% and 17·9%), as Treatment during pregnancy and lactation
were the number of adverse events, the most common of Although atopic dermatitis has no negative effects on
which were nasopharyngitis, headache, increased blood conception, treating pregnant or lactating women and
creatinine phosphokinase concentration, and upper women trying to conceive is challenging. In severe cases
respiratory tract infections.176 of the disease, the risks of active atopic dermatitis must
For the selective JAK1 inhibitor upadacitinib, currently be weighed against any potential or real risk associated
only phase 2 trials have been completed, although some with specific medications for the disorder. The European
phase 3 data for abrocitinib are available (NCT03349060). Task Force for Atopic Dermatitis position paper on
In a double-blind, placebo-con trolled, parallel-group, management of the disease during preconception, preg
dose-ranging monotherapy trial, upadacitinib reduced all nancy, and the lactation period addressed this issue.181 In
clinical disease measures at 16 weeks, with a clear dose– the paper, there is no advice against the use of emollients,
response relationship. At the highest dose (30 mg once a class II and III topical corticosteroids, topical calcineurin
day), an EASI75 was achieved by 69% of patients inhibitors, and phototherapy with ultra violet A1 and
compared with 10% in the placebo group. Over the narrow-band ultraviolet B. However, systemic treatment
16-week period, upadacitinib was generally well tolerated; should be applied with strict indication. Short-term
acne, creatinine phosphokinase elevation, and naso systemic steroids and ciclo sporin are considered
pharingitis were the most frequently reported adverse relatively safe with close monitoring, but avoidance of
events.177 For the selective JAK1 inhibitor abrocitinib, data azathioprine is recommended, and methotrexate and
from two phase 3 double-blind, randomised, placebo- mycophenolate mofetil are contraindicated in pregnant
controlled monotherapy trials of identical design are and lactating women.

Seminar
Long-term outcomes conjunctivitis in people with atopic dermatitis compared

Health and psychosocial outcomes with healthy people (odds ratio [OR] 4·38, 95% CI
Associations between atopic dermatitis and other so-called 1·39–13·79).209 A systematic review showed increased
atopic diseases are well established, including increased risk of atopic dermatitis in people with eosinophilic
risk of asthma, allergic rhinitis, and food allergies, parti oesophagitis compared with controls (OR 2·85, 95% CI
cularly in those with severe and early-onset atopic 1·87–4·34).210
dermatitis (appendix p 4).23,182–207 Traditionally, the term
atopic march was used to describe the evolution from Bacterial, fungal, and viral complications in atopic
atopic dermatitis to asthma and hayfever. Studies using dermatitis
longitudinal and machine-learning approaches have Atopic dermatitis is frequently complicated by bacterial,
challenged this theory, highlighting that only a few fungal, or viral infections, either alone or in combination.
individuals develop typical atopic disease progression.208 The relation between S aureus and atopic dermatitis is
Allergic eye disease can complicate atopic dermatitis, complex, as is the distinction between colonisation and
including keratoconjunctivitis, keratoconus, and cataract; clinically evident infection.87,211 Although true infection
a survey of US adults reported a striking increase in is less common, S aureus remains the most common
bacterial infection seen in people with atopic dermatitis,
with impetigo-like lesions (ie, painful weeping lesions
Panel 2: Controversies and open questions with golden coloured crusts) being the typical clinical
• Do endotypes of atopic dermatitis exist, including ethnicity-associated subgroups that appearance. Viral infections commonly seen in
have different (dominant) mechanisms warranting different therapeutic strategies? individuals with atopic dermatitis include molluscum
• Do patients ever really outgrow atopic dermatitis and, if yes, how often? contagiosum, herpes simplex virus infections (ranging
• Do intensive emollients and early use of topical corticosteroids, or other treatments from mild to life-threatening forms of eczema
for atopic dermatitis reduce disease severity and course, and improve general health herpeticum), herpes zoster, and cutaneous warts.212 In
outcomes, including food allergy? cohort studies, additional risks of non-cutaneous
• What are the temporal dynamics of microbiome changes in atopic dermatitis, and do infections have been proposed.183
these changes play a key role in the evolution of the disease or are they secondary
events? Will manipulating the microbiome play an important part in the primary Other health and psychosocial outcomes
prevention or treatment of atopic dermatitis? Atopic dermatitis can be associated with psychological
• What is the role of key environmental factors in the onset of atopic dermatitis stress, low self-esteem, and sleep deprivation. These out
and disease flares? comes can be exacerbated by visible disease, stigma,
• Is atopic dermatitis a systemic disease (pertaining to or affecting the body as and itch, all of which can also contribute to adverse
a whole)?227 This stance remains controversial but is given some support by psychosocial and health outcomes (appendix p 3).184,213,214
the increasing evidence of associations with major health outcomes. Associations between childhood atopic dermatitis and the
• In moderate-to-severe atopic dermatitis, what is the appropriate place of dupilumab development of attention-deficit hyperactivity disorder are
and other targeted treatments in the therapeutic armamentarium? What biomarkers incompletely understood.214 Age of onset of atopic derma
will help improve treatment selection for dupilumab and other biological and titis, sleeplessness, and antihistamine use could play a
small-molecule drugs? role.214 Systematic reviews and cohort studies have high
• What are the cost–benefit analyses of targeted biological and small-molecule lighted that atopic dermatitis is associated with depression,
treatments for atopic dermatitis? Head-to-head trials comparing systemic treatments anxiety, and increased risk of suicidal ideation.215–217
are required to identify relative efficacy and compare adverse effects, An increasing number of studies point to associations
cost-effectiveness, and general health economic comparisons. between atopic dermatitis and adverse medical outcomes
• What is the evidence to support treatment of special groups, such as conceiving, beyond atopic diseases, but these associations are poorly
pregnant, or lactating women, patients with atopic multimorbidities (eg, nasal understood and no internationally accepted approach to
polyps, eosinophilic oesophagitis, asthma), individuals with complex atopic eye screening for or preventing associated outcomes exists.
disease, a history of severe herpes virus infections or a history of malignancy, Specific issues reported in cohort studies include
or individuals undergoing vaccination programmes? associations between atopic dermatitis and cardiovascular
• Does methotrexate have a role in treating atopic dermatitis in low-income and outcomes and fractures; results are conflicting and effect
middle-income countries or does the requirement for monitoring and the increased sizes are low, with a systematic review showing a mean
risks of major infectious diseases restrict its use? relative risk increase for cardiovascular outcomes of 1·15
• What are the optimal treatment targets for clinicians, and should we be adopting (95% credibility interval 1·09–1·21) with increasing
treat-to-target approaches after co-production and validation of the targets severity categories.218,219 These associations are largely
(eg, in randomised controlled trials or real-world studies)? confined to or more pronounced in those individuals with
• How long should systemic therapy be used in patients with high disease activity, very severe or very active atopic dermatitis.218 A recent
including in children? Treat, withdraw, and re-treat data approaches might be study from the UK and Denmark did not support an
important but are as yet largely undefined. association between atopic eczema and most cancers; in
• Does any systemic treatment for atopic dermatitis modify disease activity? contrast to previous studies,220 however, there was evidence
of higher lymphoma risk with increasing eczema severity.221

Seminar
Quality of life and costs goals and criteria for assessing treatment success should
The effect of atopic dermatitis on the quality of life of be defined, particularly when systemic drugs are used, and
patients, their families, and caregivers is profound and that multidimensional assessment is important to identify
multifaceted (appendix p 4).222 In the 2013 Global Burden the relevant needs of patients. There is legitimate hope
of Disease Study, atopic dermatitis was identified as the that novel prevention strategies, and therapies targeted
skin disease with the greatest population-level disability specifically against atopic dermatitis disease processes will
among skin diseases.23 Similarly, the 2013 US National decrease the global burden in health-care costs and
Health and Wellness Survey in adults reported that, morbidity.
among skin diseases, atopic dermatitis has the greatest Contributors
detriment on skin-disease-specific (Dermatology Life All authors had the idea for and planned the Seminar, and contributed to
Quality Index) and generic (EuroQol 5-Dimension) the analysis, drafting, revision, and final approval of the manuscript.
quality-of-life scores;185 in a large US population-based Declaration of interests
cross-sectional study, moderate-to-severe atopic derma SML is a co-investigator in the European Union Horizon 2020-funded
BIOMAP Consortium, and is supported by a Wellcome Senior Research
titis was associated with worse outcomes in quality of life Fellowship in Clinical Science (205039/Z/16/Z) and by a grant from
than many common chronic illnesses, including heart Health Data Research UK (LOND1), which is funded by the UK Medical
disease and diabetes (appendix p 4).186 Studies on quality Research Council, Engineering and Physical Sciences Research Council,
of life in children and young adults reported a Economic and Social Research Council, Department of Health and Social
Care (England), Chief Scientist Office of the Scottish Government Health
considerable effect of atopic dermatitis on physical, and Social Care Directorates, Health and Social Care Research and
emotional, and social functioning.222 In a survey of Development Division (Welsh Government), Public Health Agency
chronic childhood disorders, atopic dermatitis ranked (Northern Ireland), British Heart Foundation, and the Wellcome Trust.
second to cerebral palsy with respect to measures of ADI is a co-investigator of the UK National Institute for Health Research-
funded TREAT (ISRCTN15837754) trial and the UK–Irish Atopic Eczema
quality of life.222 Of note, the effects of atopic dermatitis Systemic Therapy Register (A-STAR; ISRCTN11210918), a principal
also include impairments to families’ quality of life.223 investigator in the European Union Horizon 2020-funded BIOMAP
The economic burden of atopic dermatitis includes Consortium, and a co-principal investigator on the A-STAR Registry.
direct costs of treatment and indirect costs, such as loss of ADI has received consulting fees from AbbVie, Genentech, Janssen,
LEO Pharma, Novartis, Regeneron, Sanofi Genzyme, and Pfizer. SW is
productivity of individuals or their families.224 There are coordinator of the BIOMAP Consortium, a project funded by the
large variations in cost estimates of atopic dermatitis in Innovative Medicines Initiative 2 Joint Undertaking under grant
studies from different settings and geographical locations, agreement number 821511, and a co-principal investigator of the German
Atopic Eczema Registry (TREATgermany). SW has received institutional
and with different atopic dermatitis severities. A Dutch
research grants from Sanofi Deutschland, Leo Pharma, and La Roche
single-centre study of adults with moderate-to-severe Posay, has received fees from Sanofi Genzyme, Regeneron, LEO Pharma,
atopic dermatitis estimated that the greatest costs were AbbVie, Pfizer, Eli Lilly, Kymab, and Novartis, lectured at educational
attributable to loss of productivity.225 This observation is events sponsored by Sanofi Genzyme, Regeneron, LEO Pharma, AbbVie,
Novartis, and Galderma, and is involved in clinical trials with many
supported by data from the US National Health and
pharmaceutical industries that manufacture drugs used for the treatment
Wellness Survey, in which higher rates of absenteeism and of psoriasis and atopic eczema. The conclusions in this Seminar are those
presenteeism were seen in those with self-reported atopic of the authors and do not necessarily represent the views of the funders.
dermatitis;187 however, response rates were low (9%). This Acknowledgments
survey also proposed that the total annual direct costs of We thank Donna Davoren (London School of Hygiene & Tropical
atopic dermatitis are higher than those for psoriasis Medicine) for help in formatting the references. SW expresses his
sincere gratitude to Johannes Ring for his continuous mentorship and
(appendix p 4).187 A cost-of-illness study from Singapore his contribution to the atopic dermatitis field. SML thanks
estimated that most of societal perspective costs are related Hywel C Williams for being an outstanding mentor and inspiring her to
to informal caregiving and out-of-pocket expenses (83%).226 pursue research in atopic dermatitis.
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history or family history, or both, of atopic disease

Figure 1: Appearance of atopic dermatitis

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in prevalence, the substantial increase in prevalence in the

validated in different settings. Findings support the • DOCK8 deficiency syndrome

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Barrier deficiency Barrier disruption Lichenification

CLA CCR10 H4R

Figure 2: Pathogenesis, main mechanisms, and pathophysiology of atopic dermatitis

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Immunological dysregulation and inflammation NK cells might serve as potential counter-regulatory

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Long-term outcomes con­junctivitis in people with atopic dermatitis compared

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Long-term outcomes conjunctivitis in people with atopic dermatitis compared