Atopic Dermatitis: Diagnosis, Clinical Features & Pathogenesis

Chapter 22 :: Atopic Dermatitis
PART 3
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Part 3 :: Dermatitis
DERMATITIS
Chapter 22
Atopic Dermatitis
Eric L. Simpson, Donald Y. M. Leung, Lawrence F. Eichenfield & Mark Boguniewicz
AT-A-GLANCE
• Atopic dermatitis (AD) has a prevalence peak of 15% to 20% in early childhood in
industrialized countries.
• AD has variable rates of remission, with many patients continuing or recurring with
symptoms into adulthood.
• AD is a chronic or chronically relapsing disorder with major features of:
– Pruritus
– Eczematous dermatitis (acute, subacute, or chronic) with typical morphology and
age-specific patterns
– Facial and extensor involvement in infancy
– Flexural eczema or lichenification in children and adults
• Commonly associated with:
– Personal or family history of atopy (allergic rhinitis, asthma, atopic dermatitis)
– Xerosis or skin barrier dysfunction
– Immunoglobulin E reactivity
• Pathogenesis driven by skin barrier defects (most importantly in the FLG gene),
environmental effects and alterations in immunologic responses in T cells, antigen
processing, inflammatory cytokines, host defense proteins, allergen sensitivity, and
infection.
INTRODUCTION
Atopic dermatitis (atopic eczema, AD) is a chronic inflammatory skin disease primarily beginning
in childhood with a variable natural course. Itch is the hallmark symptom of the disease, often
unrelenting in severe cases, and leads to sleep disturbance and excoriated, infection-prone skin.
Patients with AD often additionally have atopic comorbidities such as allergic asthma and allergic
rhinitis and experience a significantly impaired quality of life.
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DEFINITIONS AND HISTORICAL PERSPECTIVE
Nomenclature
The term atopic dermatitis was first coined in 1933 by Sulzberger and Wise and replaced early
terms corresponding to probable AD such as tinea muquese, porrigo larvalis, and Hebra’s prurigo.
The term atopy was first introduced by Coca and Cooke in 1923 to describe the tendency toward
developing allergic hypersensitivity manifested by asthma and hayfever.¹ The term atopi is
derived from the Greek word atopos meaning “without place,” reflecting the mysterious
pathogenic underpinnings of allergic hypersensitivity disease. Wise and Sulzberger coined the
term atopic dermatitis in 1933 to describe recurring eczematous skin disease found in patients
with a family history of atopic disease.²
Importantly, they noted that patients with AD may not have a personal history of other atopic
disease. Since this seminal paper, several groups attempted to rename the disease primarily to
differentiate AD that has concomitant immunoglobulin E (IgE) sensitization from AD without
sensitization, such as atopiform dermatitis and nonatopic eczema. A recent systematic review
reveals atopic dermatitis to be the most commonly used name for the disease and proposed the
universal use of this term for AD.³ The authors of that paper discourage the use of less specific
terms such as eczema, which is a morphological term and includes contact and other eczematous
conditions.
Diagnostic Criteria
Significant advancement of our understanding of the disease could not be made without a proper
disease definition. Early work by luminaries in AD, such as Rajka, Lobitz, and Hanifin, paved the
way for the first comprehensive diagnostic criteria for AD — the Hanifin-Rajka criteria.⁴ The
major criteria have been validated and remain the gold standard for AD diagnosis. Similar to AD
nomenclature, numerous attempts have been made to refine and shorten the original criteria to
make them more useful in clinical practice. The UK Working Party Criteria were developed using
modern statistical methods and represent a distilled set of the original criteria useful for
population-based epidemiologic study.⁵ The American Academy of Dermatology consensus
diagnostic criteria for pediatric AD are a useful and clinician-friendly guide to AD diagnosis,
although no formal validation studies have been published.⁶
EPIDEMIOLOGY
Since the 1960s, there has been a more than threefold increase in the prevalence of AD.² AD is a
major public health problem worldwide, with a prevalence in children of 10% to 20% in the
United States, Northern and Western Europe, urban Africa, Japan, Australia, and other
industrialized countries.³ The Global Disease Burden project ranks “dermatitis,” which includes
AD, as the highest ranking skin disease in regards to total global disability burden.⁷ The
prevalence of AD in adults is less clear, but recent studies estimate the prevalence to be between
3% to 7% in the United States, Germany, and Japan.⁸⁻¹⁰ The International Study of Asthma and
Allergies in Childhood (ISAAC) Phase Three study confirmed that AD is a disease with high
prevalence worldwide, affecting patients in both developed and developing countries.⁴ There is
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also an observed female preponderance for AD, with an overall female-to-male ratio of 1.3 to 1.0.
Racial and ethnic differences in prevalence also exist with African Americans having a higher
prevalence of the disease in the United States.¹¹
Wide variations in prevalence have been observed within countries inhabited by similar ethnic
groups, suggesting that environmental factors are critical in determining disease expression.
Several studies reveal lower prevalence rates in rural settings compared with urban centers
within the same country.¹² Other risk factors reported to be associated with AD include exposure
to airborne pollution, use of hard water, increased income and education both in whites and
blacks, obesity, and increased use of antibiotics.¹³⁻¹⁷ Climate may also play a role in disease
expression with lower humidity and lower ultraviolet (UV) areas displaying higher prevalence
rates.¹⁸ Climatic factors and pollution levels may also influence symptoms and flares of the
disease.¹⁹
CLINICAL FEATURES
Cutaneous Findings
Acute eczematous lesions are characterized by erythematous papulovesicles, often with pinpoint
crusting or frank weeping. More subacute to chronic lesions often display scale, excoriation, and
lichenification. Patients with AD may present with only one stage of eczematous lesions, but most
often patients have a mixture of both acute and chronic lesions in multiple areas of the body
simultaneously or even in the same lesion. Individual eczematous lesions of AD cannot be readily
distinguished clinically or histologically from lesions found in other eczematous conditions such
as allergic contact dermatitis or nummular dermatitis. Patients with darker skin tones often
present with follicular accentuation, flat-topped papules in lichenified areas, and a tendency
toward hyperpigmentation in inflamed areas, which can be very distressing for patients. Rarely,
patients may also experience a vitiligo-like depigmentation in involved areas that is difficult to
distinguish from topical steroid-induced pigment loss.
The distribution of eczematous lesions varies according to the patient’s age (Fig. 22-1) and
disease activity. During infancy, AD is generally more acute and primarily involves the face (Fig.
22-2), the scalp, and the extensor surfaces of the extremities (Fig. 22-3).²⁰ The diaper area is
usually spared. In older children and in those who have long-standing skin disease, the patient
develops the chronic form of AD with lichenification and localization of the rash to the flexural
folds of the extremities (Fig. 22-4). AD may subside as the patient grows older, leaving an adult
with skin that is prone to itching and inflammation when exposed to exogenous irritants. Chronic
hand eczema may be the primary manifestation of AD in many adults (Fig. 22-5). At least one
third of patients will have clinical features of filaggrin deficiency such as ichthyosis vulgaris,
keratosis pilaris, and hyperlinear palms. These clinical features are associated with genetic
defects encoding the filaggrin protein and can identify patients who have a more severe disease
course and allergic comorbidities.²¹ Other less specific but common associated features of AD are
listed in Table 22-1. Other specific skin conditions associated with AD include vitiligo and alopecia
areata.²²
Figure 22-1 Atopic dermatitis progression and distribution: infancy, older childhood, and adulthood.
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Figure 22-2 Edematous, erythematous eyelids with lichenification and hyperpigmentation in an adolescent with
atopic dermatitis. Note the infraocular (Dennie-Morgan) folds.
Figure 22-3 Itching infant with atopic dermatitis.
Figure 22-4 Childhood atopic dermatitis with lichenification of antecubital fossae and generalized severely
pruritic eczematous plaques.
Figure 22-5 Typical papules, vesicles, and erosions seen in atopic hand dermatitis.
TABLE 22-1 Features of Atopic Dermatitis
Major Features
Pruritus
Rash on face, extensors, or both in infants and young children
Lichenification in flexural areas in older children
Tendency toward chronic or chronically relapsing dermatitis
Personal or family history of atopic disease: asthma, allergic rhinitis, atopic dermatitis
Other Common Findings
Dryness
Dennie-Morgan folds (accentuated lines or grooves below the margin of the lower eyelid)
Allergic shiners (darkening beneath the eyes)
Facial pallor
Pityriasis alba
Keratosis pilaris
Ichthyosis vulgaris
Hyperlinearity of palms and soles
White dermatographism (white line appears on skin within 1 minute of being stroked with a blunt
instrument)
Conjunctivitis
Keratoconus
Anterior subcapsular cataracts
Elevated serum immunoglobulin E
Immediate skin test reactivity
Noncutaneous Findings
Atopic Comorbidities
There is growing recognition that patients with AD carry a large burden of comorbid conditions.
Patients with AD often show signs of T helper 2 (Th2) immune activation, including high levels of
total and specific serum IgE, eosinophilia, and a predisposition toward allergic comorbidities.
Large population-based studies reveal patients with AD have a higher prevalence of food allergy,
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asthma, and allergic rhinitis. The severity of the skin disease correlates with both the risk and
severity of the comorbidity.²³ AD is often the first atopic disease to develop, but the diseases can
occur in any order and in any combination.²⁴ For example, allergic sensitization may occur before
or after AD development²⁵ but does develop in up to 80% of patients. Large collaborative efforts
to integrate clinical cohort and “omics” data are underway and suggest Th2-driven
pathobiological pathways underlie the multimorbidity seen in AD.²⁶ There are no studies as of
yet demonstrating treatment of the skin alone has a positive impact on allergic comorbidities or
whether prevention of AD can halt the development of other atopic diseases (“atopic march”).
Psychosocial Impact
Numerous studies in pediatric populations and adults reveal AD, especially moderate to severe
disease, profoundly impacts the emotional and psychological well-being of a patient. Children
with AD display more emotional and behavioral problems compared with normal control
participants.²⁷ Population-based studies also find a higher prevalence of attention-deficit
hyperactivity disorder (ADHD), anxiety, conduct disorder, and autism in children with AD
compared with children without AD.²⁸ Children with more severe disease appear to be
particularly at risk. The risk of ADHD in both children and adults appears to be mediated by sleep
disturbance, a common consequence of pruritus in AD.²⁹
Anxiety and depression are commonly found comorbidities in adult patients with AD. Between
43% and 57% of patients met thresholds on the Hospital Anxiety and Depression Scale for
probable anxiety or depression in phase 3 clinical trials for AD.³⁰ Effective antiinflammatory
therapy appeared to alleviate both anxiety and depression symptoms in a significant proportion
of adults during these trials.
COMPLICATIONS
Bacterial Infection
Superficial Staphylococcus aureus infections are by far the most common infection found in AD. S.
aureus colonizes skin lesions in more than 70% of patients with AD with more severe AD having
higher rates of colonization.³¹˒³² Studies conflict regarding the prevalence of methicillin-resistant
S. aureus (MRSA) in this population but does not appear to be higher than background
colonization rates. Few studies address the rate of true infection from S. aureus, in contrast to
colonization. One study from Japan found almost a twofold increase in impetigo in children with
AD compared with non-AD control participants.³³ The rate of serious infections from S. aureus is
also not well characterized in patients with AD, but there are reports in the literature of
endocarditis, osteomyelitis, and septicemia.³⁴
Both skin barrier and immune deficits found in AD may explain the propensity to colonization
and infection. Inflamed skin increases the expression of fibronectin and fibrinogen, which are S.
aureus binding sites.³⁵ The elevated pH and disrupted barrier from excoriation seen in AD skin
promotes S. aureus growth. Antimicrobial peptide expression is also blunted in these patients,
thought to be secondary to the inhibitory effect of type 2 cytokines.³⁶˒³⁷ Type 2 cytokines also
augment the killing effect of S. aureus toxins on keratinocytes.³⁸ Blockade of type 2 cytokines in
AD appears to reduce skin infections in AD.³⁹
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S. aureus colonization likely contributes to skin inflammation; S. aureus toxins activate antigen
presenting cells and increase T-cell cutaneous lymphocyte antigen (CLA) expression. Flares of AD
correspond to shifts in the microbiome toward larger proportions of S. aureus representation.⁴⁰
Antibiotic treatment of clinically uninfected skin, however, has not been found to reduce AD
severity.⁴¹ The use of dilute sodium hypochlorite baths (bleach baths) appears to improve AD
severity, but it is uncertain if this is through antiinflammatory and barrier effects rather than
antimicrobial ones.⁴²
The decision to treat a S. aureus infection is not straightforward. It is often difficult to distinguish
acute crusted AD or excoriation from S. aureus impetiginization, and culturing of lesions does not
help in distinguishing between colonization and infection. Culturing is recommended, however,
to help guide antibiotic therapy and identify MRSA strains. MRSA has become an increasingly
important pathogen in patients with AD.⁴³ Erosive plaques, honey-colored crusting, folliculitis,
and persistent or multiple tender pustules are indicators of clinically relevant secondary bacterial
skin infection in which antibiotic use would be indicated. Interestingly, topical steroids alone
reduce S. aureus counts illustrating the role inflammation plays in S. aureus susceptibility.
Viral Infection
Patients with AD display an increased susceptibility to common warts and exaggerated clinical
presentations to other viral infections such as molluscum contagiosum. The most serious virally
mediated complication is eczema herpeticum (EH). After an incubation period of 5 to 12 days,
multiple itchy, vesiculopustular lesions erupt in a disseminated pattern; vesicular lesions are
umbilicated, tend to cluster, and often become hemorrhagic and crusted (Fig. 22-6). Punched-out
and extremely painful erosions result. These lesions may coalesce to large, denuded, and bleeding
areas that can extend over the entire body and be fatal in some cases. Defects in interferon
pathways may explain why some patients develop this potentially devastating complication.⁴⁴
Figure 22-6 Eczema herpeticum. Typical vesicles and crusting in a patient with disseminated disease.
Although smallpox infections have been eradicated worldwide since the late 1970s, threats of
bioterrorism (with smallpox and other infectious agents) have forced nations to reconsider their
policies toward initiating vaccination programs. In AD patients, smallpox vaccination (or even
exposure to vaccinated individuals) (see Chap. 166) may cause a severe widespread eruption
(eczema vaccinatum) that appears very similar to EH. Thus, in patients with AD, vaccination is
contraindicated unless there is a clear risk of smallpox. In addition, decisions regarding
vaccination of family members should take into consideration the potential of eczema vaccinatum
in household contacts.
Exaggerated responses to coxsackie virus have also been reported in patients with AD that may
resemble EH and has been termed eczema coxsackium.⁴⁵ Children present with hand and foot
vesicles or papules that resemble typical hand, foot, and mouth disease, but lesions tend to be
more severe and hemorrhagic and involve additional areas involved with eczema. Despite the
sometimes dramatic presentation, the skin rash resolves with no negative sequelae.
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Fungal Infection
It is unclear whether superficial fungal infections are more common in atopic individuals. There
has been particular interest in the role of Malassezia sympodialis (Pityrosporum ovale or
Pityrosporum orbiculare) in AD. M. sympodialis is a lipophilic yeast (see Chaps. 160 and 161)
commonly present in the seborrheic areas of the skin. IgE antibodies against Malassezia furfur are
commonly found in AD patients and most frequently in patients with head and neck dermatitis.⁴⁶
Although there are some case reports of improvement of head and neck AD with antifungal
therapy, controlled trials are needed to determine the efficacy of targeting fungi in AD in this
subset of patients.
Ocular Problems
Eye complications associated with severe AD can lead to significant morbidity. Eyelid dermatitis
and chronic blepharitis are commonly associated with AD and may result in visual impairment
from corneal scarring. Atopic keratoconjunctivitis is usually bilateral and can have disabling
symptoms that include itching, burning, tearing, and copious mucoid discharge. Vernal
conjunctivitis is a severe bilateral recurrent chronic inflammatory process associated with
papillary hypertrophy or cobblestoning of the upper eyelid conjunctiva. It usually occurs in
younger patients and has a marked seasonal incidence, often in the spring. The associated intense
pruritus is exacerbated by exposure to irritants, light, or sweating. Keratoconus is a conical
deformity of the cornea believed to result from chronic rubbing of the eyes in patients with AD
and allergic rhinoconjunctivitis. Cataracts were reported in the early literature to occur in up to
21% of patients with severe AD. However, it is unclear whether this was a primary manifestation
of AD or the result of the extensive use of systemic and topical glucocorticoids, particularly
around the eyes. Indeed, more recent studies suggest that routine screening for cataracts in
patients with AD may not be productive unless there is concern about potential side effects from
steroid therapy.
Hand Dermatitis
Patients with AD often develop nonspecific, irritant hand dermatitis. It is frequently aggravated
by repeated wetting and by washing of the hands with harsh soaps, detergents, and disinfectants.
Atopic individuals with occupations involving wet work are prone to develop an intractable hand
dermatitis in the occupational setting, which is a common cause of occupational disability. Less
frequently, patients with AD may also develop a recurring chronic palmar or palmoplantar
vesicular dermatitis.
Exfoliative Dermatitis
Patients with extensive skin involvement may develop exfoliative dermatitis (see Chap. 21). This
is associated with generalized redness, scaling, weeping, crusting, systemic toxicity,
lymphadenopathy, and fever. Although this complication is rare, it is potentially life threatening.
It is usually caused by superinfection, for example, with toxin-producing S. aureus or herpes
simplex infection, continued irritation of the skin, or inappropriate therapy. In some cases, the
withdrawal of topical or systemic glucocorticoids used to control severe AD may be a
precipitating factor for exfoliative erythroderma.
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ETIOLOGY AND PATHOGENESIS
Overview
Atopic dermatitis is a complex familial transmitted skin disease caused by interactions among
genetic, immune, and environmental risk factors.⁴⁷ The interindividual variation of these factors
compound the heterogeneity of mechanisms leading to AD. AD often occurs in association with
asthma, allergic rhinitis, and food allergy. As such, AD may be considered part of a systemic
disorder. Genetic and mechanistic studies suggest that two major biologic pathways are
responsible for AD: epidermal dysfunction and altered innate or adaptive immune responses to
microbes, allergens, stress, and irritants. Discovery of key pathogenic pathways and their
associated biomarkers represents an active area of investigation required for the discovery of
novel drugs or biologics that will effectively treat severe AD unresponsive to standard
medications.
Decreased Skin Barrier Function
Atopic dermatitis is associated with decreased skin barrier function caused by the
downregulation of cornified envelope genes (e.g., keratin, filaggrin, and loricrin), reduced
ceramide levels, increased endogenous proteolytic enzyme activity, and enhanced
transepidermal water loss.⁴⁸ Addition of soap and detergents to the skin raises its pH, thereby
increasing activity of endogenous proteases, leading to further breakdown of epidermal barrier
function. The epidermal barrier may also be damaged by scratching, exposure to exogenous
proteases from house dust mites, and S. aureus. This is worsened by the lack of certain
endogenous protease inhibitors in atopic skin. These epidermal changes likely contribute to
increased allergen absorption into the skin and microbial colonization. Because epicutaneous
sensitization to allergen results in higher level allergic immune responses, decreased skin barrier
function could act as a site for allergen sensitization and predispose such children to the
development of food allergy and respiratory allergy.
Genetics
More than 80 genes have been associated with AD.⁴³˒⁴⁹ Of these genes, loss-of-function mutations
involving the epidermal barrier protein filaggrin have been most consistently replicated to be a
major predisposing factor for AD in European whites and Asians. Of note, the filaggrin gene is
found on chromosome 1q21, which contains genes (including involucrin, loricrin, and S100
calcium binding proteins) in the epidermal differentiation complex (EDC), known to be expressed
during terminal differentiation of the epidermis. Gene profiling studies have demonstrated
downregulation of genes encoding proteins involved in epidermal differentiation, including
multiple skin barrier proteins and antimicrobial peptides required for host defense in AD.⁵⁰
Candidate gene approaches have also implicated variants in the SPINK5 gene, which is expressed
in the uppermost epidermis, where its product, LEKT1, inhibits two serine proteases involved in
desquamation and inflammation (stratum corneum tryptic enzyme and stratum corneum
chymotryptic enzyme). Stratum corneum tryptic enzyme and stratum corneum chymotryptic
enzyme expression is increased in AD, suggesting that an imbalance of protease versus protease
inhibitor activity may contribute to atopic skin inflammation. Other skin barrier genes that have
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been implicated in AD include LAMA3, TMEM79, filaggrin-2 (FLG2), Late Cornified Envelope-like
Proline-rich 1 (LELP1), and claudin-1 (CLDN1). The relative importance of different skin barrier
genes and immune responses may vary by race.⁵¹ It is interesting, for example, that FLG
mutations have currently not been consistently found in African populations; however, loss-offunction mutations in FLG2 are associated with increased risk in African Americans.⁴⁹
These observations establish a key role for impaired skin barrier function in the pathogenesis of
AD because impaired skin barrier formation allows increased transepidermal water loss, and
importantly, increased attachment and entry of allergens and chemicals from the environment,
resulting in skin inflammatory responses.⁴⁷ It is important to note that filaggrin mutations and
likely other mutations affecting the skin barrier can occur in normal healthy individuals, patients
with ichthyosis vulgaris who do not have significant skin inflammation, and only a minority of
individuals with AD have filaggrin gene mutations. This suggests that factors other than skin
barrier gene mutations are also required for the development of AD.
Atopic dermatitis has also been associated with variation of genes involved in innate and adaptive
immunity, interleukin-1 (IL-1) family signaling, regulatory T cells, vitamin D pathway, and nerve
growth factor pathway.⁴³ Thus, a combination of various genetic factors may influence the
development of different AD phenotypes. Patients with filaggrin null mutations often have early
onset of AD, severe eczema, and high-level allergen sensitization and develop asthma later in
childhood (i.e., the so-called atopic march).⁴⁸˒⁴⁹ In patients with AD susceptible to EH (ADEH+),
filaggrin mutations occur in combination with transcriptomic signatures in peripheral blood
mononuclear cells (PBMCs) that are distinct from AD without a history of EH (ADEH−). In a recent
report, it was demonstrated that unstimulated ADEH+ and ADEH− PBMC had similar
transcriptomes.⁵² However, after stimulation with herpes simplex virus (HSV), PBMCs from
ADEH+ had distinct transcriptomic profiles compared with ADEH−, with striking downregulation
of antiviral cytokines, including both type I and type III IFNs. These results are indicative of
defective innate immune responses in ADEH+ subjects.
Atopic dermatitis is a complex trait that involves interactions between multiple gene products
requiring environmental factors and the immune response, leading to a final clinical phenotype.
Chromosome 5q31-33 contains a clustered family of functionally related cytokine genes — IL-3,
IL-4, IL-5, IL-13, and granulocyte macrophage colony-stimulating factor — involved in generation
of IgE, eosinophilia, and allergic inflammation. Gain-of-function mutations in the alpha subunit of
the IL-4 receptor, IL-4, and IL-13 have been significantly associated with AD, providing a rationale
for the use of biologicals that interfere with the IL-4 receptor signaling pathway.³⁰ A significant
association has also been observed between TSLP gene polymorphisms and AD, supporting
further evidence for the importance of Th2 polarization in this disease.⁵³
IMMUNOPATHOLOGY OF ATOPIC DERMATITIS
Based on clinical appearance and duration of illness, AD skin can be characterized as nonlesional
AD, acute AD lesions (3 or fewer days after onset), and chronic skin lesions (>3 days’ duration).
Nonlesional AD skin may not be normal but characterized by mild epidermal hyperplasia and a
sparse perivascular T-cell infiltrate. Dendritic antigen-presenting cells (e.g., Langerhans cells
[LCs], inflammatory dendritic epidermal cells [IDECs], macrophages) in lesional and, to a lesser
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extent, in nonlesional skin of AD exhibit surface-bound immunoglobulin E molecules. In acute
lesions, there is epidermal spongiosis with an increased infiltration of activated memory T cells
bearing the skin-homing CLA. Eosinophils, basophils, and neutrophils are rare. Mast cells are in
various stages of degranulation.
Chronic lichenified lesions are characterized by a hyperplastic epidermis with elongation of the
rete ridges, prominent hyperkeratosis, and minimal spongiosis. There is an increased number of
IgE-bearing LCs in the epidermis, and macrophages dominate the dermal mononuclear cell
infiltrate. Mast cells are increased in number but are fully granulated. Neutrophils are absent in
AD skin lesions even in the setting of increased S. aureus colonization and infection. Increased
numbers of eosinophils are observed in chronic AD skin lesions. Eosinophils are thought to
contribute to allergic inflammation by the secretion of cytokines and mediators that augment
allergic inflammation and induce tissue injury in AD through the production of reactive oxygen
intermediates and release of toxic granule proteins.
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