Anda di halaman 1dari 15

PAPULOSQUAMOUS AND ECZEMATOUS DERMATOSES SECTION 3

Atopic Dermatitis
Thomas Bieber and Caroline Bussmann
12
Working Partys Diagnostic Criteria for AD, which were validated for
Synonym: Atopic eczema the purpose of clinical studies; these criteria were modified slightly by
Williams in 2005 (Table 12.2)2.
According to the current consensus nomenclature by the World
Allergy Organization (WAO)8, the term atopy is tightly linked to the
presence of allergen-specific IgE antibodies in the serum, as docu-
Key features mented by positive fluorescence enzyme immunoassays (previously
radioallergosorbent [RAST] tests) or skin prick tests. Thus, an IgE-
Common inflammatory skin condition that typically begins during associated or allergic form of dermatitis corresponds to AD in the strict
infancy or early childhood and is often associated with other sense (formerly known as extrinsic AD). The remaining 2030% of
atopic disorders such as asthma and allergic rhinoconjunctivitis patients with the clinical phenotype of AD who have no evidence of
Complex genetic disease with environmental influences IgE-sensitization are categorized as having a non-IgE-associated or non-
Characterized by intense pruritus and a chronic or chronically allergic form of dermatitis (formerly known as intrinsic AD). However,
relapsing course IgE-associated/allergic true AD and non-IgE-associated/non-allergic
Acute inflammation and involvement of the cheeks, scalp and dermatitis have substantial overlap and cannot be considered as two
extensor aspects of the extremities predominates in infants, separate diseases; for example, the latter often represents an early tran-
shifting to chronic inflammation with lichenification and a sitional form of IgE-associated AD.
predilection for flexural sites in children and adults
A proactive approach to management is recommended, including
avoidance of trigger factors, daily use of emollients, and anti-
EPIDEMIOLOGY
inflammatory therapy to control subclinical inflammation as well The current prevalence of AD in most high-income and some low-
as overt flares income countries is approximately 1030% in children and 210% in
adults, representing a two- to threefold increase over the past several
decades1. In general, the prevalence of AD in rural areas and low-
income countries is significantly lower than in their urban and high-
income counterparts, illustrating the importance of lifestyle and
environment in the pathogenesis of atopic disease. This observation
INTRODUCTION supports the controversial hygiene hypothesis, which postulates that
Atopic dermatitis (AD) is the most common chronic inflammatory skin decreased exposure to infectious agents in early childhood increases
disease, and its increasing prevalence presents a major public health susceptibility to allergic diseases.
problem worldwide1. Characteristic features of AD include pruritus and Three subsets of AD based on age of onset have emerged from epi-
a chronic or chronically relapsing course, usually beginning during demiologic studies:
infancy (early onset) but occasionally first developing in adulthood (late early-onset type: defined as AD beginning in the first 2 years of
onset)2. AD is a paradigmatic complex genetic disease and is often life. This is the most common type of AD, which develops during
accompanied by other atopic disorders such as allergic rhinoconjuncti- the first 6 months of life in 45% of affected individuals, during the
vitis and asthma. These conditions may appear simultaneously or first year of life in 60%, and before 5 years of age in 85%.
develop in succession. AD has a predilection for infants and young Approximately half of children with disease onset during the first
children, while asthma favors older children and pollen allergy pre- 2 years of life develop allergen-specific IgE antibodies by 2 years of
dominates in adolescents. This characteristic age-dependent sequence
is referred to as the atopic march3,4 (Fig. 12.1). Considering that the
atopic disease progression starts with AD, management should not be
concentrated solely on the treatment of acute flares, but also be directed THE ATOPIC MARCH
towards improving the underlying genetically determined epidermal
barrier dysfunction and preventing active dermatitis (e.g. via mainte-
100
nance therapy). Such an approach could potentially block the sensitiza-
tions and ongoing inflammation that drive the atopic march forward5.
Eczema
Food allergy
Incidence (% of peak)

HISTORY AND DEFINITIONS Asthma


Rhinitis
Since its description during the nineteenth century, the clinical pheno- 50
type of AD has been given multiple different names, including
Besniers prurigo and disseminated neurodermatitis. The associa-
tion of AD with allergic rhinitis and asthma was recognized by Besnier
in 1892. The term atopy (originating from the Greek word atopos,
meaning strange or unusual) was first applied to this triad in the 1920s,
including the use of atopic eczema. A decade later, Hill and Sulzberger
proposed the name atopic dermatitis. The list of characteristic fea- 0 5 10 15
tures proposed by Hanifin and Rajka6 in 1980 (Table 12.1) helped to Age (years)
establish unity in the clinical concept of AD. In 1994, Williams and 203
co-workers7 simplified Hanifin and Rajkas criteria to establish the UK Fig. 12.1 The atopic march.
SECTION

3 DIAGNOSTIC FEATURES OF ATOPIC DERMATITIS SELECTED SUSCEPTIBILITY LOCI AND CANDIDATE GENES
FOR ATOPIC DERMATITIS
Papulosquamous and eczematous dermatoses

MAJOR FEATURES (3 OF 4 PRESENT)


Chromosomal Candidate Defective protein(s)
Pruritus
location gene(s)
Typical morphology and distribution of skin lesions
Chronic or chronically relapsing dermatitis GENES ENCODING EPIDERMAL PROTEINS
Personal or family history of atopy 1q21 (epidermal FLG Filaggrin (loss-of-function variants; see
MINOR FEATURES (3 OF 23 PRESENT) differentiation text)
complex)
Xerosis
Ichthyosis/palmar hyperlinearity/keratosis pilaris 5q31q32 SPINK5 Serine protease inhibitor LETKI
Immediate (type I) skin test reactivity 11q13.5 (rs7927894 SNP) ? (synergistic interaction with FLG null
Elevated serum IgE mutations)
Early age of onset
Tendency toward cutaneous infections/impaired cell-mediated immunity 19q13 KLK7/SCCE Kallikrein-related peptidase 7/stratum
Tendency toward nonspecific hand or foot dermatitis corneum chymotryptic enzyme
Nipple eczema GENES ENCODING IMMUNOLOGIC PROTEINS
Cheilitis
1q23 FCER1A High-affinity IgE receptor, chain
Recurrent conjunctivitis
DennieMorgan infraorbital fold 4q32 TLR2 Toll-like receptor-2
Keratoconus 4q34 IRF2 Interferon regulatory factor 2
Anterior subcapsular cataract
Orbital darkening 5q31 IL4 Interleukin-4
Facial pallor/erythema IL5 Interleukin-5
Pityriasis alba IL12B Interleukin-12B
Anterior neck folds IL13 Interleukin-13
Pruritus when sweating GM-CSF Granulocytemacrophage colony-
Intolerance to wool and lipid solvents stimulating factor
Perifollicular accentuation CD14 Monocyte differentiation antigen CD14
Food intolerance 8p23 DEFB1 -defensin 1
Course influenced by environmental/emotional factors
11q13 GSTP1 Glutathione S-transferase P1
White dermographism/delayed blanch
11q22 IL18 Interleukin-18
Table 12.1 Diagnostic features of atopic dermatitis6.
14q11 CMA1 Mast cell chymase
16p12 IL4R Interleukin-4 receptor, subunit
(gain-of-function polymorphisms)
DIAGNOSTIC GUIDELINES FOR ATOPIC DERMATITIS 17q11 CCL5/RANTES Chemokine (C-C motif ) ligand 5/RANTES
(gain-of-function polymorphisms in the
Must have: promoter region)
An itchy skin condition (or parental report of scratching or rubbing in a child)
Plus three or more of the following:
Table 12.3 Selected susceptibility loci and candidate genes for atopic
History of involvement of the skin creases such as folds of elbows, behind the dermatitis1018. Genome-wide association studies have identified other
knees, fronts of ankles, the neck and around the eyes* susceptibility loci, including 3q21, 3p26, 16q, 17q25 and 20p. FCER1A,
A personal history of asthma or hayfever (or history of atopic disease in a Fc fragment of IgE high-affinity receptor I alpha polypeptide; LETKI,
first-degree relative in children under 4 years of age) lymphoepithelial Kazal-type-related inhibitor; RANTES, regulated on activation,
A history of generally dry skin in the last year normally T-cell expressed and secreted; SNP, single nucleotide polymorphism;
Visible flexural eczema (or eczema involving the cheeks/forehead and extensor
SPINK5, serine peptidase inhibitor Kazal type 5.
limbs in children under 4 years of age)
Onset under 2 years of age (not used if child is under 4 years of age)
*Original 1994 guidelines also included the cheeks in young children. rhinitis, suggesting the existence of genes specific to AD10. AD is a
complex genetic disease, and both genegene and geneenvironment
Table 12.2 Diagnostic guidelines for atopic dermatitis2,7.
interactions have pathogenic roles (Fig. 12.2). Two major sets of genes
have been implicated in AD: (1) genes encoding epidermal proteins;
and (2) genes encoding proteins with immunologic functions that are
age. About 60% of infants and young children with AD go into not specific to the skin. Selected chromosomal loci and candidate genes
remission by 12 years of age, but in others disease activity persists in these two groups that have been identified to date are listed in Table
into adolescence and adulthood 12.3. In addition to classic genetic changes, epigenetic alterations may
late-onset type: defined as AD that starts after puberty. There are
have a role in the development of AD.
few recent epidemiological studies on AD with onset in adulthood. Mutations in the filaggrin gene (FLG), which encodes a protein that
Approximately 30% of AD patients overall are in the non-IgE- aggregates keratin filaments during terminal differentiation of the epi-
associated category, and among adults, the vast majority of such dermis, are responsible for ichthyosis vulgaris (see Table 12.5 and Ch.
patients are women 57) and represent a major predisposing factor for AD13. A number of
senile-onset type: an unusual subset of AD that begins after 60
studies have shown that the same loss-of-function filaggrin variants
years of age has been identified more recently9. that cause ichthyosis vulgaris have a prevalence of 2050% in European
children and adults with AD (compared to 10% of the general popula-
tion)14, and different loss-of-function filaggrin variants have been iden-
PATHOGENESIS tified in similar proportions of Asian patients with AD ( ichthyosis
vulgaris). With an overall odds ratio of 4, these filaggrin variants rep-
Genetics resent one of the strongest known genetic factors for a complex disease,
The concordance rate for AD is higher among monozygotic twins (77%) with penetrances of ~60% for one variant allele and ~90% for two
compared to dizygotic twins (15%), supporting the importance of variant alleles. The presence of the filaggrin variants is correlated with
genetic factors in its pathogenesis. Although the entities in the atopic early-onset, relatively severe, extrinsic (specific IgE-associated) AD
204 triad cluster together in families, a parental history of AD is a stronger that tends to persist into adulthood; affected individuals have an
risk factor for the development of AD than either asthma or allergic increased risk of eczema herpeticum and peanut allergies as well as a
CHAPTER

12
Fig. 12.2 Genetic and environmental factors in the
GENETIC AND ENVIRONMENTAL FACTORS IN THE DEVELOPMENT development and exacerbation of atopic dermatitis
AND EXACERBATION OF ATOPIC DERMATITIS TLR, Toll-like receptor. Adapted with permission from

Atopic Dermatitis
ref. 5.
Environment
Scratching/irritants

Staphylococcus aureus Allergens


Sensitization Autoallergic
to self atopic
proteins dermatitis

Non-IgE Sensitization IgE-associated


Epigenetic modifications

associated to allergens atopic dermatitis


dermatitis

Allergic
rhinitis,
asthma

Impaired Cytokines,
epidermal barrier chemokines

Genes encoding Genes encoding


epidermal proteins immunologic proteins
(e.g. filaggrin, serine protease (e.g. cytokines,TLRs)
inhibitor LEKTI)
Genes

propensity to later develop asthma14,14a. However, in general, there is AD and are characterized by edematous, erythematous papules and
no correlation between the filaggrin variants and asthma without prior plaques that may exhibit vesiculation, oozing and serous crusting.
AD, supporting a role for epicutaneous sensitization and inflammation Subacute eczematous lesions display erythema, scaling and variable
in the skin (related to the disrupted epidermal barrier) in the subse- crusting. Chronic lesions, which typify adolescent/adult AD, present as
quent development of asthma. thickened plaques with lichenification as well as scale; prurigo nodule-
like lesions can also develop (see below). Perifollicular accentuation and
Epidermal Barrier Dysfunction small, flat-topped papules (papular eczema) are particularly common in
AD is characterized by dry, scaly skin (xerosis) in lesional and non- individuals with darkly pigmented skin. In any stage of AD, the most
lesional areas, which is the consequence of epidermal barrier dysfunc- severely affected individuals may evolve to a generalized exfoliative
tion and an altered stratum corneum leading to increased transepidermal erythroderma (see Ch. 10). All types of AD lesions can leave postin-
water loss19. Factors that contribute to the impaired cutaneous barrier flammatory hyper-, hypo- or (in more severe cases) depigmentation
of AD are summarized in Table 12.4. upon resolution (Fig. 12.3).
Infantile AD (age <2 years) typically develops after the second month
of life, often initially appearing as edematous papules and papulo
Immunopathology vesicles on the cheeks (often sparing the central face), which may evolve
Immunologic mechanisms involved in the pathogenesis of AD are to form large plaques with oozing and crusting (Fig. 12.4). Involvement
presented in Table 12.4. of the scalp, neck, extensor aspects of the extremities, and trunk (Fig.
12.5) can also occur, usually with sparing of the diaper area. In the first
Pruritus 6 months of life, the face and the neck are affected in over 90% of
AD is characterized by persistent, severe pruritus, which significantly patients with AD44. Young infants may attempt to relieve itch through
impacts the quality of life in affected individuals. The mechanisms of rubbing movements against their bedding, whereas older infants are
pruritus have just started to be understood. Since classic antihistamines better able to directly scratch affected areas.
are ineffective in AD, it is assumed that this mediator does not have a In childhood AD (age 2 to 12 years), the lesions are less exudative
crucial role in AD-related pruritus. In contrast, neuropeptides, pro- and tend to become lichenified. The classic sites of predilection are the
teases, kinins, and cytokines such as interleukin (IL)-31 are known to antecubital and popliteal fossae (flexural eczema) (Fig. 12.6). In addi-
induce itch. IL-31 is strongly pruritogenic and exerts its biologic activity tion, the head (especially periorificial regions), neck, wrists, hands,
through a heterodimeric receptor composed of the IL-31 receptor A and ankles and feet are often affected (Fig. 12.7). Xerosis typically becomes
oncostatin M receptor protein, both of which are overexpressed in pronounced and widespread.
lesional skin of AD4143. These findings imply that IL-31 has an impor- Adult/adolescent AD (age >12 years) also features subacute to
tant role in the pruritus of AD. chronic, lichenified lesions, and involvement of the flexural folds
typically continues. However, the clinical picture may also change.
Adults with AD frequently present with chronic hand dermatitis
CLINICAL FEATURES that has both endogenous and exogenous components (Fig. 12.8),
while others have primarily facial dermatitis (Fig. 12.9), often with
severe eyelid involvement (see below). Additional sites of predilec-
Disease Course tion include the retroauricular region, neck and chest. Patients who
AD is characterized by a broad clinical spectrum that varies depending have suffered from continuous AD since childhood are more likely
upon the age of the patient, and it is divided into infantile, childhood to have extensive or even erythrodermic disease that is resistant
and adolescent/adult stages. In each stage, patients may develop acute, to treatment. Such individuals may also have severe excoriations
subacute and chronic eczematous lesions, all of which are intensely and chronic papular skin lesions (Fig. 12.10) as a result of habitual 205
pruritic and often excoriated. Acute lesions predominate in infantile scratching and rubbing.
SECTION

3 EPIDERMAL DEFECTS AND IMMUNOLOGIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF ATOPIC DERMATITIS
Papulosquamous and eczematous dermatoses

IMPAIRMENT OF THE EPIDERMAL BARRIER


Changes in the balance between proteolytic enzymes (e.g. kallikrein-related peptidase 7/stratum corneum chymotryptic enzyme) and their antiprotease counterparts
(e.g. the serine protease inhibitor LETKI) lead to a net increase in protease activity that accelerates degradation of corneodesmosomes and lipid-processing enzymes;
one result is a failure to generate ceramides15,20
Deficiency of filaggrin, which normally contributes to the assembly of the cornified envelope and (via its breakdown products) increases the water-binding capacity of
the stratum corneum; of note, Th2-type inflammation can decrease the expression of filaggrin21
Disturbed maturation of lamellar bodies, potentially due to variations in the pH of the stratum corneum as well as alterations in epidermal lipid metabolism
Other alterations in epidermal differentiation, including changes in cornified envelope proteins (e.g. involucrin, loricrin) and lipid composition
As a result of the defective epidermal barrier, there is increased penetration of environmental irritants and allergens into the skin, triggering inflammation and
sensitization22
MECHANISMS OF INFLAMMATION IN THE ABSENCE OF IgE-MEDIATED SENSITIZATION*
Increased epidermal protease activity may initiate an inflammatory cascade16
Neuropeptides, irritants and scratching can stimulate the release of proinflammatory cytokines by keratinocytes
T-cell-mediated (but IgE-independent) reactions to epicutaneous (through the disrupted epidermal barrier) allergen exposure, as demonstrated by atopy patch testing23
EPICUTANEOUS SENSITIZATION
Animal models have shown that epicutaneous sensitization can induce both a localized AD-like dermatitis and bronchial hyperreactivity to aerosolized allergens24
Allergens have increased cutaneous penetration due to the impaired epidermal barrier
Keratinocytes in AD patients produce high levels of thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine that drives dendritic cells to induce Th2 polarization25
Pollen-associated prostaglandin-like bioactive lipids and water-soluble mediators also modulate dendritic cell function and promote Th2 polarization26
Proinflammatory mechanisms may be amplified by increased epidermal protease activity16
Chronic cutaneous inflammation in AD patients has systemic consequences (e.g. functional changes in circulating monocytes27); the skin may therefore represent the
point of entry for atopic sensitization and deliver systemic signals promoting sensitization upon allergen exposure in the lungs or gut
ROLE OF DENDRITIC CELLS (DCS)
Key roles that link innate and adaptive immunity28
Plasmacytoid DCs (responsible for antiviral defense) are almost absent in AD lesional skin29
Two distinct populations of myeloid DCs are present: Langerhans cells (LCs) and inflammatory dendritic epidermal cells (IDECs; only found in inflamed skin)30
Both express the high-affinity receptor for IgE (FcRI) only in IgE-associated (extrinsic) AD; inflammatory signals can lead to upregulation of FcRI expression31
Participate in the sensitization phase (see above)
Central roles in the uptake and presentation of allergens to Th1/Th2 cells and possibly Tregs32
LCs promote Th2 polarization and have a limited capacity to produce proinflammatory cytokines
IDECs promote Th1 polarization and produce proinflammatory cytokines; in acute AD, IDECs are actively recruited and large numbers invade the epidermis after 4872
hours33
T-CELL RESPONSES, CYTOKINES AND CHEMOKINES
Th2 cytokines (e.g. IL-4, IL-5, IL-13) predominate in acute AD lesions and in the systemic immunologic background of IgE-associated (extrinsic) AD
Th1 cytokines (e.g. IFN-, IL-12) predominate in chronic AD lesions
IDECs and eosinophils produce IL-12 and may be instrumental in the Th2 to Th1/Th0 switch
An orchestra of cytokines and chemokines produced by keratinocytes and endothelial cells contributes to inflammatory cell recruitment and evolution of the
inflammatory reaction over time34
TSLP (see above) stimulates DCs to: (1) release CCL17 and CCL22; and (2) expand T cells that produce IFN- as well as those that produce IL-5 and IL-13
CCL1, CCL27 (CTACK) and CCL18 attract CCR4+ Th2 cells
IL-22-producing CD4+ or CD8+ T cells that do not produce IL-17 have been described in AD patients
The role of CD25+/Foxp3+ Tregs in AD is not yet fully understood
Circulating CLA+, CCR6+ Tregs are increased in AD patients
Lesional AD skin is devoid of functional Tregs35
ROLE OF MICROBIAL COLONIZATION
Epidermal keratinocytes express a variety of pattern recognition receptors (e.g. Toll-like receptors [TLRs]) that bind to specific microbial structures, which induces an
inflammatory response and the release of antimicrobial peptides such as defensins and cathelicidins (see Ch. 4); however, production of the latter peptides is down-
regulated in the skin of patients with AD
S. aureus colonization of the skin occurs in >90% of AD patients due to factors such as decreased levels of antimicrobial peptides and increased bacterial adherence to
eczematous/excoriated skin
S. aureus contributes to sensitization and inflammation in AD via several mechanisms
TLR-2 recognition of S. aureus cell wall components (e.g. lipoteichoic acid, peptidoglycan) stimulates an inflammatory response
Staphylococcal superantigens amplify inflammatory reactions via multiple pathways36 and may contribute to corticosteroid resistance by inducing the competing
isoform of the glucocorticoid receptor
Staphylococcal enterotoxins AD (SEA-D) can provoke IgE-mediated sensitization, which correlates with disease severity37
Staphylococcal toxins also augment inflammation by subverting the function of Tregs
ROLE OF AUTOIMMUNITY
Some patients with AD have circulating IgE antibodies directed against self-proteins expressed by keratinocytes and endothelial cells38
The presence of these antibodies correlates with disease severity
Prevalence of ~25% in adult patients; have also been detected in infants39
Predisposing factors include early-onset AD, severe pruritus, recurrent bacterial skin infections and high serum IgE levels
Structural similarities between exogenous allergens and human proteins are thought to have a role in the development of IgE autoantibodies; this likely occurs in the
context of cutaneous inflammation and scratching/cellular damage that leads to exposure of the autoantigens (see Fig. 12.2)
Some autoallergens induce Th1 responses40
These observations suggest that AD exists at the frontier between allergy and autoimmunity
*Commonly occurs in early-onset as well as intrinsic forms of AD.

Table 12.4 Epidermal defects and immunologic mechanisms involved in the pathogenesis of atopic dermatitis (AD). CCL or CXCL, chemokine (C-C or C-X-C
motif ) ligand; CCR or CXCR, chemokine (C-C or C-X-C motif ) receptor; CLA, cutaneous lymphocyte antigen; CTACK, cutaneous T-cell-attracting chemokine;
206 IL, interleukin; Tregs, regulatory T cells.
CHAPTER

12
Fig. 12.3 Post
inflammatory
pigmentary alteration

Atopic Dermatitis
in atopic dermatitis.
A Ill-defined
hypopigmented patches
with variable residual
erythema and scale on
the shoulder and upper
arm. B Postinflammatory
depigmentation in a
patient with widespread,
severe disease and
multiple lesions of
prurigo nodularis.
B, Courtesy, Jean L Bolognia, MD.

Fig. 12.4 Atopic dermatitis on the face of an infant. Acute lesions with
oozing and serous crusting are common in this age group. Courtesy, Julie V
Schaffer, MD.

A Fig. 12.5 Atopic


dermatitis on the
extensor surface of an
infants arm.
Involvement of the
extensor aspects of the
extremities is common in
this age group. Note the
follicular prominence on
the trunk.

Senile AD (age >60 years) is characterized by marked xerosis. Most


of these patients do not have the lichenified flexural lesions typical of
AD in children and younger adults.
AD has a profound adverse impact on the quality of life of affected
children and adults, with intense pruritus and stigmatization the earlobe and in the retroauricular area, sometimes in association
often resulting in sleep disturbances, psychological distress, social with bacterial superinfection. Eyelid eczema can represent the only
isolation, disrupted family dynamics and impaired functioning at manifestation of AD, especially in adults. In contrast to eyelid eczema
school or work. due to other causes, it is characterized by lichenification of the perior-
bital skin.
Regional Variants of Atopic Dermatitis Head and neck dermatitis represents a variant of AD that typi-
Several regional variants of AD can occur in isolation or together with cally occurs after puberty and primarily involves the face, scalp and
the classic age-related patterns of involvement described above. The neck. When older children and teenagers present with this form of AD,
face is a frequent location for site-specific manifestations. Eczema of it usually persists into adulthood. It is postulated that lipophilic Malas-
the lips, referred to as cheilitis sicca, is common in AD patients, espe- sezia yeasts, members of the normal skin flora that colonize the head
cially during the winter. It is characterized by dryness (chapping) of and neck area, represent an aggravating factor for this condition. Serum
the vermilion lips, sometimes with peeling and fissuring, and may be levels of M. furfur-specific IgE have been shown to correlate with the
associated with angular cheilitis. Patients try to moisten their lips by severity of head and neck dermatitis45, and improvement with systemic
licking, which in turn may irritate the skin around the mouth, resulting antifungal treatment has been observed in some patients. Sweating,
in so-called lip-lickers eczema. Another common feature of childhood heat, dryness, sun exposure and emotional stress can also aggravate 207
AD is ear eczema, presenting as erythema, scaling and fissures under this form of AD.
SECTION

3
Fig. 12.6 Atopic Fig. 12.8 Severe chronic
dermatitis extending hand dermatitis in an
from the antecubital adult with atopic
fossae to the wrists and dermatitis.
Papulosquamous and eczematous dermatoses

hands. Note the


excoriations and
lichenification.

Fig. 12.9 Severe atopic


dermatitis with facial
involvement in an adult.

A
Fig. 12.10 Chronic
papular lesions in an
adult with atopic
dermatitis. This resulted
from habitual scratching
and rubbing in the
setting of longstanding
disease.

Fig. 12.7 Lichenified atopic dermatitis on the wrists and hands of children.
208 A Pink plaques with excoriation and hemorrhagic crusting as well as
lichenification. B Thick lichenified plaques. Courtesy, Julie V Schaffer, MD.
CHAPTER
household or occupational settings. Atopic hand eczema typically
involves the volar wrists and dorsum of the hands. The palms and sides 12
of the fingers may develop the deep-seated vesicles of dyshidrotic

Atopic Dermatitis
eczema (see Ch. 13).
The prurigo form of AD favors the extensor aspects of the extremi-
ties and is characterized by firm, dome-shaped papules and nodules
with central scale-crust, similar to prurigo nodularis lesions in non-
atopic patients. Nummular lesions also tend to develop on the extremi-
ties in children and adults with AD, appearing as coin-shaped
eczematous plaques, usually 1 to 3cm in diameter and often with
prominent oozing and crusting (similar in appearance to the lesions
that characterize nummular dermatitis occurring outside the setting of
atopy; see Ch. 13). Colonization with Staphylococcus aureus is thought
to represent a trigger for this type of eczema. Intense pruritus is a
feature of both prurigo and nummular lesions. Frictional lichenoid
eruption has a predilection for atopic children (especially boys) and
presents as multiple small, flat-topped, pink to skin-colored papules on
the elbows and (less often) knees and dorsal hands. It classically occurs
in the spring or summer, pruritus is variable, and the histologic findings
Fig. 12.11 Nipple eczema in an adolescent with atopic dermatitis. Courtesy,
Julie V Schaffer, MD. are nonspecific. Lastly, chronic nipple eczema can develop in children
and adults with AD (Fig. 12.11).

Eczema variants also occur in acral sites. Juvenile plantar dermato- Associated Features
sis presents with glazed erythema, scale and fissuring on the balls of
the feet and plantar aspect of the toes in children with AD, especially Pruritus
during the winter (see Ch. 13). Atopic hand eczema (see Fig. 12.8) Intense pruritus is a hallmark of AD. The itch is often worse in the
affects approximately 60% of adult patients with AD and may be the evening and may be exacerbated by exogenous factors such as sweating
only manifestation of the condition. It often occurs in atopic individu- or wool clothing. Rubbing and scratching in response to pruritus can
als whose hands are frequently exposed to water and other irritants in initiate flares or exacerbate existing dermatitis, explaining why AD

ASSOCIATED FEATURES OF ATOPIC DERMATITIS (ATOPIC STIGMATA)

Xerosis Important feature that is present in most patients with AD


Often most prominent on the lower legs; may be generalized
Dry skin with fine scale in areas without clinically apparent inflammation
Typically worse during the winter
Impaired epidermal barrier function from decreased water content in the stratum corneum leads to easier entry of irritants,
which can promote pruritus and initiate an inflammatory response
Ichthyosis vulgaris Autosomal semidominant disorder with incomplete penetrance caused by mutations in the filaggrin gene (FLG; see text and
Ch. 57)
~15% of patients with AD have moderate to severe ichthyosis vulgaris; conversely, >50% of patients with ichthyosis vulgaris
have AD
Excessive fine, whitish to brown scaling that favors the lower legs (especially the shins) and spares the flexures
Keratosis pilaris Common condition that affects >40% of patients with AD and ~75% of those with ichthyosis vulgaris
Onset typically in childhood; may improve after puberty (especially facial involvement)
Affects the lateral aspect of the upper arms, thighs and (especially in children) lateral cheeks > trunk and extensor aspects of
the distal extremities
Keratotic follicular papules, often with a rim of erythema (see Fig. 12.12A) or (especially on the cheeks) a background of
patchy erythema
The keratosis pilaris rubra (KPR) variant features numerous tiny, grain-like follicular papules superimposed on prominent
confluent erythema (see Fig. 12.12B&C); often widespread (face & ears > trunk & proximal extremities) and tends to persist
after puberty; presence of erythema rather than hyperpigmentation differentiates KPR from erythromelanosis follicularis
faciei et colli, and a lack of atrophy in KPR differentiates it from keratosis pilaris atrophicans (see Ch. 38)
Keratolytic agents and topical retinoids are sometimes used to decrease the hyperkeratotic component, but the benefit is
limited and these agents can be irritating, especially in AD patients; treatment with vascular lasers (e.g. the pulsed dye laser)
can improve associated erythema
Palmar and plantar hyperlinearity Increased prominence of the palmar and, less often, plantar creases (see Fig. 12.13)
Associated with ichthyosis vulgaris and FLG mutations
DennieMorgan lines Symmetric, prominent horizontal fold(s) (single or double) just beneath the margin of the lower lid, originating at or near the
inner canthus and extending one-half to two-thirds the width of the lid (see Fig. 12.14)
Periorbital darkening (allergic shiners) Skin around the eyes appears gray to violetbrown, while the rest of the facial skin is rather pale
Periorbital edema and lichenification may also be seen
Anterior neck folds Horizontal folds across the middle of the anterior neck
Hertoghe sign Absence or thinning of the lateral eyebrows
White dermographism Stroking the skin leads to a white streak that reflects excessive vasoconstriction
Most apparent on the forehead
Mid-facial pallor (see Fig. 12.14) and a delayed blanch response represent additional manifestations of aberrant vascular
reactivity in patients with atopic dermatitis
Follicular prominence Goose bump-like appearance of the skin, most often on the trunk (see Fig. 12.5)
More commonly observed in children with darkly pigmented skin
209
Table 12.5 Associated features of atopic dermatitis (atopic stigmata). AD, atopic dermatitis.
SECTION

3
Papulosquamous and eczematous dermatoses

Fig. 12.12 Keratosis


pilaris. A Discrete
Fig. 12.13 Exaggerated palmar creases. This patient had both atopic
perifollicular papules
dermatitis and ichthyosis vulgaris. Courtesy, Jean L Bolognia, MD.
with central keratotic
cores on the extensor
surface of the upper arm.
Each papule has a rim of
erythema. B, C Keratosis
Fig. 12.14 Infant with
pilaris rubra on the
atopic dermatitis of the
lateral face. This variant is
face with central facial
characterized by tiny,
sparing. Note the
grain-like follicular
DennieMorgan lines
papules superimposed
and central facial pallor.
on confluent erythema.
B, C, Courtesy, Julie V Schaffer,
MD.

B Fig. 12.15 Pityriasis


alba. Note the slight
scale associated with
the hypopigmented
macules and patches
on the cheeks. Courtesy,
Anthony J Mancini, MD.

Atopic stigmata
Physical findings other than dermatitis that are frequently observed in
patients with AD are presented in Table 12.5 (see Figs 12.1212.15).

Pityriasis alba
Pityriasis alba frequently affects children and adolescents with AD. It
is characterized by multiple ill-defined hypopigmented macules and
C patches (usually 0.5 to 2cm in diameter) with fine scaling, which are
typically located on the face (especially the cheeks; Fig. 12.15) but
occasionally appear on the shoulders and arms. These lesions are most
obvious in individuals with darkly pigmented skin and/or following
is known as the itch that rashes. Excoriations (linear or punctate) sun exposure. Pityriasis alba is thought to result from a low-grade
are frequently present, providing evidence of scratching (see Figs 12.6 eczematous dermatitis that disrupts the transfer of melanosomes from
& 12.7A). With repeated rubbing and scratching, the skin becomes melanocytes to keratinocytes. Similar hypopigmented lesions can
210 thickened and leathery with exaggerated skin markings (see Figs 12.6 appear upon resolution of more overtly inflamed, erythematous lesions
& 12.7). of AD (see Fig. 12.3A). The differential diagnosis of pityriasis alba also
CHAPTER
malaise and lymphadenopathy, and complications may include super-
infection with S. aureus or S. pyogenes as well as herpetic keratocon- 12
junctivitis and meningoencephalitis46. Patients with mutations in t

Atopic Dermatitis
he filaggrin gene and those who have both severe AD and asthma
have an increased risk for eczema herpeticum, and decreased produc-
tion of antimicrobial peptides may have a pathogenic role. Patients
with AD are also predisposed to the development of widespread mol-
luscum contagiosum, sometimes with several hundred lesions (see
Ch. 81).

Ocular complications
Besides development of acute conjunctivitis as a component of allergic
rhinoconjunctivitis, the spectrum of atopic eye disease also includes
chronic manifestations such as atopic keratoconjunctivitis (typically in
adults) and vernal keratoconjunctivitis (favors children living in warm
climates)47. Symptoms include ocular itching, burning, tearing and
mucus discharge, often in association with conjunctival injection and
(especially in atopic keratoconjunctivitis) blepharitis that manifests as
Fig. 12.16 Infected hand dermatitis in a patient with atopic dermatitis. swelling and scaling of the eyelids. Vernal keratoconjunctivitis features
There is impetigo-like crusting as well as pustules. Courtesy, Louis A Fragola, Jr, MD. large, cobblestone-like papillae on the upper palpebral conjunctiva, and
atopic keratoconjunctivitis is more prone to scarring. Additional infre-
quent ocular complications of AD include subcapsular cataracts (ante-
rior more specific to AD, posterior more common)48, keratoconus and
retinal detachment.
Fig. 12.17 Eczema
herpeticum. Note the
monomorphic erosions
and hemorrhagic crusts.
Courtesy, Julie V Schaffer, MD. DIAGNOSTIC CRITERIA
Several authors and groups have suggested guidelines to assist in estab-
lishing the clinical diagnosis of AD. Major features in these sets of
criteria include pruritus, eczematous skin lesions in typical age-specific
distribution patterns, a chronic or chronically relapsing course, early
age at onset, and a personal and/or family history of atopy. Atopic
stigmata (see Table 12.5), especially xerosis, are also recognized as sup-
porting features. The Diepgen score represents another validated set of
diagnostic criteria, which is separated into objective, subjective and
laboratory features49. Validated scores to assess the severity of AD
include the EASI (Eczema Area Scoring Index), SCORAD (SCORing
Atopic Dermatitis) and POEM (Patient-Oriented Eczema Measure)50.
IgE-associated and non-IgE-associated AD are distinguished based on
the evaluation of total serum IgE levels (elevated in the former; normal
<150IU/ml) and the presence or absence of specific IgE. Although
includes postinflammatory hypopigmentation secondary to other der- recognition of the latter can support the diagnosis of an atopic state,
matoses (e.g. psoriasis or pityriasis lichenoides chronica; usually also exposures to the allergens identified are not necessarily relevant to
extrafacial involvement), pityriasis versicolor (typically more sharply aggravation of AD (see below).
demarcated, small lesions that may coalesce centrally), vitiligo (sharply
demarcated and depigmented rather than hypopigmented) and (occa-
sionally if extrafacial involvement) hypopigmented mycosis fungoides.
Regular use of sunscreens and other forms of photoprotection may PATHOLOGY
minimize the appearance of pityriasis alba. The histologic features of AD depend upon the stage of the lesion
sampled. Acute, exudative eczema is characterized by marked spongi-
Complications osis, with intraepidermal fluid collection leading to the formation of
vesicles (micro and macro) or even bullae. Some dermal edema may
Infections also be present, together with perivascular lymphocytes that extend into
Patients with AD are predisposed to the development of skin infec- the epidermis and a variable number of eosinophils (Fig.12.18A). In
tions because of factors including an impaired skin barrier and modi- subacute lesions, vesiculation is absent whereas acanthosis, hyperkera-
fied immune milieu (see Table 12.4). Bacterial and viral infections tosis and parakeratosis become evident (Fig. 12.18B). In chronic,
represent the most common complications of AD. Considering that S. lichenified eczema, epidermal thickening is more pronounced in a
aureus colonizes the skin of the vast majority of patients with AD, it pattern that may be either irregular or regular (psoriasiform). Changes
is not surprising that impetiginization (which can also occur due to in the granular layer vary from thickening secondary to rubbing (as in
Streptococcus pyogenes) occurs quite frequently (Fig. 12.16). Bacterial lichen simplex chronicus) to thinning when there is a psoriasiform
infections may also exacerbate AD by stimulating the inflammatory pattern (seen in some nummular lesions). Spongiosis and inflamma-
cascade, e.g. via S. aureus exotoxins that act as superantigens (see tion are less conspicuous, but there may be an increased number of
Table 12.4). mast cells and dermal fibrosis.
Eczema herpeticum represents rapid dissemination of a herpes These features are not specific, as similar findings are observed in
simplex viral infection over the eczematous skin of AD patients46. other eczematous dermatoses such as allergic contact dermatitis.
It initially develops as an eruption of vesicles, but affected individuals There are occasionally histologic clues to the etiology, such as
more often present with numerous monomorphic, punched-out ero- individually necrotic keratinocytes that suggest an irritant contact
sions with hemorrhagic crusting (Fig. 12.17). Eczema herpeticum dermatitis. However, a skin biopsy is usually more helpful in exclud-
is frequently widespread and may occur at any site, with a predilec- ing other entities that can mimic AD clinically, such as mycosis 211
tion for the head, neck and trunk. It is often associated with fever, fungoides.
SECTION

3 DIFFERENTIAL DIAGNOSIS OF ATOPIC DERMATITIS

CHRONIC DERMATOSES
Papulosquamous and eczematous dermatoses

C>A Seborrheic dermatitis Common


B Contact dermatitis (allergic* or irritant) Common
B Psoriasis (especially palmoplantar) Common
A>C Nummular dermatitis Uncommon (although
nummular lesions can be
seen in AD, nummular
eczema outside this setting is
uncommon)
A Asteatotic eczema Common
A>C Lichen simplex chronicus (secondary to Common
pruritus of variable etiology)
INFECTIONS AND INFESTATIONS
B Scabies Common
A B Dermatophytosis* Common
B HIV-associated dermatoses Variable
C HTLV-1-associated infective dermatitis Variable
C Chronic mucocutaneous candidiasis Rare
C Neonatal mucocutaneous candidiasis Variable
B Impetigo Variable (nummular lesions of
AD most commonly mimic
impetigo)
C Congenital syphilis Variable
PRIMARY IMMUNODEFICIENCIES
C WiskottAldrich syndrome Rare
C Hyperimmunoglobulin E syndrome Rare
C Severe combined immunodeficiency Rare
C DiGeorge syndrome (congenital thymic Rare
aplasia)
C Immunoglobulin deficiencies: X-linked Variable
hypogammaglobulinemia, common variable
immunodeficiency, IgA deficiency
C Ataxia telangiectasia Rare
MALIGNANCIES
A>C Mycosis fungoides and Szary syndrome Uncommon
B
C Langerhans cell histiocytosis Rare
Fig. 12.18 Histologic features of acute and subacute atopic dermatitis. METABOLIC AND GENETIC DISORDERS
A Acute lesion showing spongiosis, intraepidermal vesicles and exocytosis of C Netherton syndrome Rare
lymphocytes. B Subacute lesion with parakeratosis and less spongiosis.
A, Courtesy, Ronald P Rapini, MD. C Ectodermal dysplasias Rare
B Keratosis pilaris Common
C Hartnup disease Rare
DIFFERENTIAL DIAGNOSIS C Phenylketonuria Rare
The differential diagnosis of AD is broad and includes other chronic B Acrodermatitis enteropathica, glucagonoma Rare
dermatoses, infections, infestations and malignancies as well as meta- syndrome, pellagra, riboflavin deficiency
bolic, genetic (e.g. primary immunodeficiencies) and autoimmune dis- C>A Other causes of nutritional dermatitis, e.g. Rare
orders (Table 12.6). Depending upon the age of the patient and the biotin deficiency, essential fatty acid
clinical presentation, such entities may be considered prior to diagnos- deficiency, organic acidurias, cystic fibrosis
ing AD, especially when the history, morphology and/or distribution of AUTOIMMUNE DISORDERS
the skin lesions are atypical. A>C Dermatitis herpetiformis Uncommon
In infants, AD is often preceded and/or accompanied by seborrheic A>C Pemphigus foliaceus Uncommon
dermatitis, which commonly presents during the first month of life as B Dermatomyositis Uncommon (but often
yellowish-white, adherent scale-crusts on the scalp. Infantile seborrheic misdiagnosed as AD in
dermatitis also has a predilection for skin folds (where lesions may be children)
oozing and lack scale) and the forehead, in contrast to the typical dis- A>C Lupus erythematosus Uncommon
tribution of infantile AD on the extensor surfaces of the extremities OTHER
and cheeks as well as the scalp. Scabies in infants often has generalized
B Drug eruptions Uncommon (although drug
involvement and can mimic AD; in addition to the presence of burrows eruptions are common, those
or identification of the mite or eggs (e.g. via dermoscopy or skin scrap- resembling atopic dermatitis
ings), scabies can usually be distinguished by the predominance of are uncommon)
discrete small crusted papules, involvement of the axillae and diaper A>C Photoallergic contact dermatitis Uncommon
area, and the presence of acral vesiculopustules. Other less common A Chronic actinic dermatitis Uncommon
conditions that occasionally represent a diagnostic consideration in
B Graft-versus-host disease Uncommon
infants, such as primary immunodeficiencies, are listed in Table 12.6.
*More common causes of disseminated eczema (id reaction), which is especially frequent in the setting
Adolescents and adults without a personal or family history of atopy of stasis dermatitis + allergic contact dermatitis.
who present with an eczematous eruption should have a thorough
212 history and (when indicated) patch testing to assess for the possibility Table 12.6 Differential diagnosis of atopic dermatitis. A, adults; B, both; C,
of allergic contact dermatitis. This diagnosis should also be considered children/infants.
CHAPTER
in children and adults with established AD who fail to respond as
expected to treatment or develop lesions in an atypical distribution
peanuts, soy and wheat. Reactivity to peanuts (as well as tree nuts, fish
and shellfish) tends to persist, but children usually outgrow sensitivi- 12
pattern. Components of emollients or topical corticosteroid prepara- ties to other foods54. The clinical history and (in selected instances)

Atopic Dermatitis
tions represent potential allergens in these individuals. Protein contact provocation tests should be used to determine the relevance of positive
dermatitis can also present as a chronic eczematous dermatitis and is laboratory and skin prick tests, since results of the latter tests do not
more common in atopic individuals. Common causes include a variety necessarily identify allergies that are exacerbating the patients AD. For
of foods and animal products (Table 12.7; see Ch. 16), and it is diag- example, double-blind food challenges may be useful in young children
nosed by prick testing or observation of an urticarial reaction within with a history of food-induced paroxysms of pruritus. Although avoid-
30 minutes of patch testing on previously affected skin. ance of food allergen triggers can help to prevent flares in a subset of
Mycosis fungoides (MF) should be considered in adolescents and patients with the IgE-associated form of AD (especially infants with
adults with chronic dermatitis poorly responsive to topical corticoster- severe, refractory disease), this must be balanced with the potential for
oid treatment. Because the histologic findings of early MF may be
difficult to distinguish from those of AD, multiple biopsies are recom-
mended, preferably from untreated areas of skin since corticosteroids
can eliminate epidermotropic T cells that point to the diagnosis of MF. CAUSES OF PROTEIN CONTACT DERMATITIS
Longitudinal evaluation of such individuals is required, especially when
Fruits (banana, fig, kiwi, lemon, pineapple)
the clinical and/or histologic features are not classic for AD, with addi-
Grains (barley, rye and wheat flours)
tional biopsies as indicated. Latex
Meats (fish, seafood, beef, pork, poultry)
Mites and insects (rice flour beetle, dust mite, storage mite)
TREATMENT Nuts (almond, hazelnut, peanut)
Spices (caraway, curry, dill, garlic, paprika, parsley)
Because AD is a chronic relapsing disease, the classic approach to
Vegetables (carrot, cauliflower, celery, cucumber, lettuce, mushroom, onion,
therapy is targeting acute flares with short-term treatment regimens, parsnip, potato)
i.e. reactive management. Based on recent insights into the underlying Animal dander, hair, saliva or urine (cow, deer, goat, dog, cat, rodents,
skin barrier defect and its relationship to inflammatory processes in hedgehog, rabbit, giraffe)
the skin and other organs, a proactive approach that includes long-term
Table 12.7 Causes of protein contact dermatitis.
maintenance therapy is now recommended51. Currently, management
of AD includes the following components:
avoidance of trigger factors, including irritants, relevant allergens
and microbial agents THERAPEUTIC LADDER FOR ATOPIC DERMATITIS
skin care that aims to compensate for the genetically determined
impaired epidermal barrier function Evidence
anti-inflammatory therapy to control subclinical inflammation as
Emollients (basic therapy) 1
well as overt flares
in selected cases, adjunctive or complementary modalities. Topical corticosteroids 1

As a rule, management should be adapted to the severity of the disease. Topical calcineurin inhibitors 1
While mild cases can typically be controlled by continuous use of emol- UVB (narrowband>broadband), UVA-UVB, UVA1 or oral PUVA 1
lients and intermittent use of a low-potency topical corticosteroid for Systemic corticosteroids (short term for severe acute flares; 2
flares, moderate AD may also require proactive maintenance with anti- rebound exacerbations often occur upon discontinuation)
inflammatory agents. In more severe and refractory cases, the use of
Cyclosporine (short/intermediate term) 1
phototherapy and systemic drugs may be necessary to control the
disease (Table 12.8). An appropriate educational program for patients Azathioprine 1
and parents is another essential component of the management of AD. Mycophenolate mofetil/enteric-coated mycophenolate sodium 1*/2
Methotrexate 1*/2
Avoidance of Trigger Factors Interferon- **
Multiple environmental and psychological factors can trigger AD,
IVIg 2
including allergens (e.g. pollen, dust mites, animal dander), sweating,
harsh soaps, wool or other rough fabrics, cigarette smoke and emotional Omalizumab 2
stress. These vary depending upon the patient and may be identified Rituximab 2
(and subsequently avoided) by a careful history and (when indicated) Other (crude coal tar, hydroxychloroquine, extracorporeal 23
allergy testing. Fluorescence enzyme immunoassays (which have largely photochemotherapy)
replaced RAST tests) can be performed on serum samples to quantify
ADJUNCTIVE THERAPIES
specific IgE antibodies against suspected allergens; skin prick testing
represents another option to assess for immediate hypersensitivity. The Wet wraps, open wet dressings or soaks (combined with topical corticosteroids
atopy patch test can provoke an eczematous reaction through the epi- for acute flares)
cutaneous application of aeroallergens (for which the test has been Dilute sodium hypochlorite (bleach) baths
standardized) or food allergens, with readings at 48 and 72 hours to Treatment of associated bacterial, viral or fungal infections
Oral antihistamines for antipruritic and sedative effects
detect delayed hypersensitivity52. It holds promise as a relatively specific
Leukotriene antagonists
tool to evaluate children with AD for clinically significant allergies. Sodium cromoglycate (topical or oral)
Allergen-specific immunotherapy, which can abrogate allergic sensi- Probiotics (may have efficacy in primary prevention)
tizations, represents a strategy to block trigger factors in selected
*In recent randomized controlled trials in adults with severe AD, enteric-coated
patients with AD. For example, in some randomized controlled studies, mycophenolate sodium was found to have similar efficacy to cyclosporine as
sublingual or subcutaneous immunotherapy led to improvement of maintenance therapy, and methotrexate was found to have similar efficacy to
skin disease in AD patients with specific sensitizations against house azathioprine (see text).
dust mites53. Modest improvement in this subset of AD patients has **Although found to be effective in one randomized controlled trial, results of other
studies have been inconsistent (see Ch. 128).
also been observed after reducing dust mites in the home (especially
No significant benefit was found in a small controlled trial.
the bedroom) through methods such as utilization of mattress and
Inconsistent demonstration of efficacy in controlled trials.
pillow covers, high-filtration vacuum cleaning and miticide sprays.
Food hypersensitivity affects about 1030% of infants and children Table 12.8 Therapeutic ladder for atopic dermatitis (AD). Key to evidence-
with AD, and ~90% of reactions in this patient population are caused based support: (1) prospective controlled trial; (2) retrospective trial or large 213
by five allergens: eggs (most often linked to AD exacerbations), milk, case series; (3) small series or individual case reports.
SECTION

3 adverse sequelae from unnecessarily restrictive diets (e.g. kwashiorkor


due to rice milk diets). Modified diets should be supervised by a
decreased systemic bioavailability and a favorable therapeutic index
(e.g. prednicarbate, hydrocortisone butyrate, fluticasone propionate,
pediatric dietician to ensure that they are nutritionally adequate. mometasone furoate) may be preferable, especially for infants and
Papulosquamous and eczematous dermatoses

Because S. aureus, which densely colonizes the skin in most AD young children with widespread involvement.
patients, is known to amplify the cutaneous inflammation that under- Considerations in selecting the potency and vehicle of the topical
lies AD (see Table 12.4), reduction of bacterial load can play a role in corticosteroid include the location, type (e.g. acute versus chronic),
the management of AD. In a recent randomized controlled study, thickness and extent of the AD lesions as well as the age of the patient.
0.005% sodium hypochlorite baths (0.5 cup of household bleach [6% The corticosteroid should have an appropriate potency to quickly gain
sodium hypochlorite] added to a full 40-gallon bathtub) twice weekly control of the flare, and continuation of daily therapy until the active
together with intermittent use of intranasal mupirocin ointment over dermatitis is completely clear minimizes the likelihood of a rebound.
a 1- to 3-month period led to greater improvement of moderate to Long-term daily use of an inadequately potent topical corticosteroid can
severe, superinfected AD than did placebo (with both groups initially result in a greater risk of side effects (as well as less control of the
receiving a 2-week course of oral cephalexin)55. Cleansers and emol- eczema) than relatively brief use of a more potent agent. After clinical
lients containing antiseptics such as triclosan or clioquinol represent resolution of longstanding or severe lesions, tapering to every-other-day
additional options. In general, the use of topical and systemic antibiot- treatment may be considered prior to decreasing to maintenance
ics should be restricted to short-term treatment of superinfections in therapy. For children and adults with moderate to severe AD, rand-
order to prevent the development of bacterial resistance. There is some omized controlled trials have demonstrated that the risk of relapse can
evidence that the S. aureus strains that colonize and superinfect patients be significantly reduced by proactive maintenance with twice-weekly
with AD are more likely to be susceptible to first-generation cepha- application of a mid-potency topical corticosteroid to the usual areas of
losporins (e.g. cephalexin) than are those that cause other S. aureus involvement (in conjunction with emollient use), with no evidence of
skin infections in the same communities55,56. cutaneous atrophy after up to a year of treatment5961.
For the face and body folds, high-potency corticosteroids (particularly
long-term use) should be avoided if possible due to risk of cutaneous
Basic Therapy (Skin Care) atrophy. Potent corticosteroids (e.g. class 12) are often needed for thick
Recent findings highlighting the critical role of an impaired skin barrier or lichenified plaques, nummular or prurigo-like lesions, and eczema
in the pathogenesis of AD underscore the importance of a continuous on the palms and soles. Flurandrenolide tape represents another option
basic therapy with emollients, even in periods and sites in which the for prurigo-like lesions, since it physically blocks scratching and rubbing
AD is not active. The formulation of the emollient should be chosen of the affected area. Corticosteroid ointments (which minimize burning/
based upon the degree of dryness of the skin, the sites of application, stinging) and creams are generally preferred considering the dryness of
acceptance by the patient and the season. Ointments (e.g. petrolatum) the skin in AD patients and the emollient effects of these vehicles.
and water-in-oil creams are more occlusive and tend to cause less Application immediately after bathing improves cutaneous penetration
burning and stinging than oil-in-water creams and lotions. However, and also decreases burning. Corticosteroid solutions, foams or (espe-
the greasiness of an ointment is not acceptable to all patients. Poten- cially for children and individuals of African descent) oils represent
tially allergy-provoking ingredients such as perfumes, lanolin and choices for AD on the scalp.
herbal extracts should be avoided. The addition of moisturizing factors Two topical calcineurin inhibitors (TCIs) have been approved by the
that are able to bind water (e.g. glycerol, urea) leads to increased hydra- US Food and Drug Administration (FDA) for the treatment of AD:
tion of the epidermis57. However, emollient products with higher con- tacrolimus 0.03% and 0.1% ointment (for moderate to severe disease)
centrations of urea or - and -hydroxy acids, which can decrease and pimecrolimus 1% cream (for mild to moderate disease) (see
scaling as well as dryness, tend to sting when used in children and on Ch. 128). These agents suppress T-cell activation and modulate the
acutely inflamed or excoriated skin. Emollients containing particular secretion of cytokines and other proinflammatory mediators. Their
combinations of lipids that are normally present in the stratum efficacy in the treatment of AD has been proven in clinical trials in
corneum (e.g. cholesterol, fatty acids, ceramides) may optimize barrier adults and children at least 2 years of age (and, for pimecrolimus,
repair58. Emollients should be applied twice daily to the entire cutane- infants ages 323 months, although it is not approved for this group)62,63.
ous surface. The major side effect of both medications is burning at the site of
AD patients should use mild, non-alkaline cleansers (e.g. syndet application; they are not associated with cutaneous atrophy.
bars; see Ch. 153) as needed (e.g. focusing on soiled and apocrine- There has been no short-term or intermediate-term (>10 years)
containing areas). Bubble baths and scented salts or oils should be evidence of systemic immunosuppression or an increased risk
avoided. Although allowing moisture to fully evaporate from the skin for malignancy in clinical studies or post-marketing surveillance of
following bathing can worsen xerosis, application of an emollient to topical tacrolimus and pimecrolimus, and long-term data collection is
the skin within 3 minutes of exiting a daily lukewarm bath or ongoing64,65. However, in 2006 the FDA introduced black box warnings
shower increases skin hydration and barrier function. If treatment with for both drugs concerning a theoretical cancer risk; this was based on
a topical corticosteroid is indicated, it should be applied immediately the occurrence of lymphomas in mice exposed to systemic levels 3050-
after bathing, prior to the emollient. For acute flares of AD, 10- to fold greater than the highest recorded blood levels in human patients.
20-minute soaks in lukewarm bathwater or tap water compresses fol- Pharmacokinetic studies in children and adults with AD have demon-
lowed directly with corticosteroid application (soak and smear) or strated minimal systemic absorption of TCIs, with transient detectable
placement of wet wraps after topical corticosteroid application can (but low) blood levels occasionally observed in patients with severe AD
soothe oozing or crusted lesions and result in rapid improvement. Scalp involving a large portion of the body surface area.
care should include a bland shampoo. Shampoos, lotions and creams TCIs are particularly suitable for AD affecting the face and inter
containing tar (510% liquor carbonis detergens) are helpful in some triginous areas, sites where corticosteroid-induced skin atrophy is of
patients but may be irritating in children and when used on acutely increased concern and TCI therapy is especially effective. TCIs are also
inflamed skin. beneficial in patients with frequently flaring or persistent AD that
would otherwise require almost continual use of topical corticosteroids.
Recent randomized controlled studies have shown that the proactive
Topical Anti-inflammatory Therapy application of tacrolimus ointment (e.g. twice weekly as maintenance)
Topical corticosteroids are the mainstay of pharmacologic therapy for can prevent flares of AD without increasing the overall amount of
AD, and topical calcineurin inhibitors (TCIs) also play an important medication used66,67.
role. For the treatment of acute flares of AD, topical corticosteroids
represent the first-line therapy because of their potent anti-inflammatory
effects. These agents suppress production of several transcription Phototherapy
factors, which leads not only to reduced expression of proinflammatory AD patients can benefit from treatment with ultraviolet (UV) light.
cytokines, but also to inhibition of cell growth and decreased synthesis UVA1, UVA combined with UVB, and narrowband UVB have each been
214 of collagen and other structural proteins (explaining side effects such shown to improve both the eczema and associated pruritus. The immu-
as skin atrophy; see Ch. 125). Topical corticosteroids designed to have nomodulatory effects of phototherapy occur via induction of T-cell
CHAPTER
apoptosis, reduction of dendritic cells, and modified cytokine expres-
sion (e.g. decreased IL-5, IL-13 and IL-31 after treatment of AD with
bedtime, especially in patients with pruritus that disrupts sleep or who
scratch excessively during the night. Non-sedating antihistamines are 12
UVA1)68 (see Ch. 134). In addition, treatment with UVB has been occasionally helpful, but the most benefit is usually obtained at higher

Atopic Dermatitis
shown to reduce S. aureus colonization of the skin in AD patients69. doses, that are sedating. In controlled trials, adjunctive therapy with
Narrowband UVB and high-dose UVA1 can both be helpful for chronic antihistamines and other medications, including leukotriene inhibitors
AD, and UVA1 may also be useful in the treatment of acute flares. and antimicrobial agents aimed at reducing colonization (see above),
Phototherapy can be combined with topical corticosteroids, particularly has not consistently demonstrated efficacy (see Table 12.8).
in the initial phase of treatment. The side-effect profile of phototherapy
is favorable compared to systemic immunosuppressive agents, with
potential risks of sunburn and, with long-term treatment, photoaging Alternative/Complementary Therapy
and possibly induction of cutaneous malignancies. The time and effort Dietary lipid supplements (e.g. evening primrose and borage oils) have
required to travel several times a week to a phototherapy center may been studied as a treatment for AD but showed no advantage over
be problematic for some patients (e.g. disrupting school and work), and placebo. Chinese herbal therapy for AD has been evaluated in control-
a home UV unit may be an option for those receiving chronic treat- led trials; although benefit was reported in some of these studies, other
ment. In younger children, phototherapy may be difficult for practical investigators have not been able to replicate the results. In one report,
reasons (e.g. lack of cooperation), and some centers limit its routine analysis of herbal creams noted by parents in the UK to improve their
use to patients 12 years of age. childrens AD revealed that 80% contained a corticosteroid, more than
half of which represented clobetasol propionate74.
Patients with AD and parents of affected children often seek and tend
Systemic Anti-inflammatory Therapy to be receptive to alternative treatment methods such as biofeedback
Systemic anti-inflammatory treatment should be restricted to severe, and hypnotherapy. Although beneficial effects of such modalities have
refractory cases of AD that do not respond adequately to intensive been reported, efficacy has not been established in controlled studies,
topical therapy. The riskbenefit profile should be carefully considered and placebo groups in controlled trials of AD treatments often have
before starting an immunosuppressive agent, and patients receiving high response rates.
these medications require close monitoring for side effects. Of note, no
systemic medications besides corticosteroids have been FDA-approved
for treatment of AD. However, in general, treatment of AD with sys- Targeted Molecular Therapy (Biologics)
temic corticosteroids should be avoided due to a propensity for signifi- The anti-IgE monoclonal antibody omalizumab, which inhibits the
cant rebound flares upon their discontinuation69a and the unacceptable binding of IgE to its high-affinity receptor (FcRI), is FDA-approved for
side effects of long-term use (see Ch. 125). In the occasional exception the treatment of asthma in patients 12 years of age with sensitization
of a severe, generalized acute flare (e.g. with a specific trigger) resistant to aeroallergens and a total IgE level up to 700IU/ml (with dosing based
to aggressive topical management, treatment with a systemic cortico on the IgE level). It is administered every 24 weeks via subcutaneous
steroid should be limited to a short course, with transition to a topical injection, which must be performed in-office due to the risk of anaphy-
regimen, phototherapy and/or an alternative systemic agent. laxis. Improvement of AD upon treatment with omalizumab has been
Administration of oral cyclosporine typically leads to rapid improve- described in several uncontrolled series. However, in a small ran
ment of skin disease and associated pruritus in patients with AD, and domized controlled trial in adults with AD, a clinical response was not
its efficacy has been established in randomized controlled trials. noted despite depletion of IgE and decreased responses to allergens in
However, the use of oral cyclosporine to treat AD is limited by potential immediate- and delayed-type skin tests75. Whether a subgroup of AD
side effects such as nephrotoxicity (which can develop after as little as patients (e.g. with acute disease) may respond better than others
36 months of therapy) and increased blood pressure, which seem to remains to be determined.
be dose-dependent. Treatment is frequently started with a dose of 5mg/ The anti-CD20 monoclonal antibody rituximab (administered via
kg/day, which should be gradually reduced to the minimal effective two intravenous infusions separated by 2 weeks), which inhibits mature
maintenance dose (usually ~2mg/kg/day). Of note, cyclosporine is B cells but does not affect plasma cells or IgE levels, has been shown
often not sufficient as monotherapy, requiring combination with topical in an open-label trial to substantially improve severe AD in adults76.
corticosteroids to reach an almost complete remission. The monoclonal antibody mepolizumab inhibits IL-5, a crucial factor
Azathioprine can be an effective treatment for moderate to severe AD for growth and differentiation of eosinophils. Although mepolizumab
in children and adults70, with modest benefit documented in a rand- can decrease the eosinophil count in patients with AD, it failed to lead
omized controlled trial. Because individuals with genetically deter- to a significant clinical improvement in a controlled trial77.
mined low activity of the enzyme thiopurine methyltransferase (TPMT)
have increased susceptibility to azathioprine-induced myelotoxicity, the Emerging Therapies
risk of this complication can be decreased by determining TPMT activ-
Additional targeted molecular therapies are currently under develop-
ity and/or genotyping for TPMT polymorphisms prior to initiating
ment for the treatment of asthma and AD, with goals of blocking
therapy and adjusting the dose accordingly (23.5mg/kg/day if normal,
factors such as cytokines involved in the regulation of IgE synthesis
0.51mg/kg/day if low)71. The results of several uncontrolled studies
(e.g. IL-4) or chemoattractant receptor-homologous molecule expressed
suggest that mycophenolate mofetil (12.5g/day; 2550mg/kg/day in
on Th2 cells (CRTH2). Other potential targets are involved in the
children) is also an effective and safe treatment for moderate to severe
migration of inflammatory cells, such as the chemokine receptor CCR3
AD72. A recent randomized controlled trial found that enteric-coated
and phosphodiesterase 4. Since AD patients are deficient in antimicro-
mycophenolate sodium and cyclosporine (3 mg/kg daily) overall had
bial peptides, the development of similar synthetic antimicrobial agents
similar effectiveness for long-term maintenance treatment (following 6
could improve control of microbial, fungal and viral infections. Design-
weeks of cyclosporine 5 mg/kg daily) of severe AD in adults, although
ing better agents to repair the skin barrier represents another area of
patients receiving mycophenolate had more flares early in maintenance
investigation.
and those receiving cyclosporine had shorter remissions following dis-
continuation of therapy72a. In AD patients treated with either azathio-
prine or mycophenolate mofetil, initial responses are often delayed a Educational Programs
month or more, and full benefit typically occurs after 23 months of Education of patients and their parents about skin care and the natural
therapy. Methotrexate (7.525mg/week) has shown promising results history, triggers and rationale for proactive management of AD is
in small series of adults with AD and had similar efficacy to azathio- very important. Parents often seek an eradicable cause for their childs
prine in a recent randomized controlled trial73. AD and have difficulty accepting control rather than a cure of the
condition78. The majority of patients and parents are particularly
anxious about corticosteroid use, which often leads to delayed and
Adjunctive Pharmacologic Therapy inadequate treatment79. Addressing their specific concerns and acknowl-
Sedating antihistamines (e.g. hydroxyzine, diphenhydramine, doxepin) edging the stresses associated with this chronic disease (also noting the 215
can be useful in breaking the itchscratch cycle in AD when given at improvement in pruritus and sleep disturbances likely to result from
SECTION

3 treatment) make it easier for families to deal with AD and facilitate


doctorpatient/parent communication. Interdisciplinary educational
46 months of life or feeding with formulas based on hydrolyzed milk
products rather than intact cows milk protein can protect against the
programs involving psychologists and dieticians as well as dermatolo- development of AD (no benefit from soy milk)81,82. In these high-risk
Papulosquamous and eczematous dermatoses

gists have been shown to improve both the severity of the eczema and infants, some studies have also shown a modest benefit with a low-
quality of life80. Patients and families can also receive information allergen maternal diet during breastfeeding, but manipulated maternal
and support from groups such as the National Eczema Association diets during pregnancy have been associated with preterm labor and
(www.nationaleczema.org). lower birthweights. In several randomized placebo-controlled studies,
administration of probiotics (e.g. lactobacilli) or prebiotics (non-
digestible oligosaccharides that promote the growth of desirable bacte-
ria) to pregnant mothers and infants has been associated with
Primary Prevention significantly decreased frequencies of AD at 1 to 4 years of age (approxi-
Although the therapeutic armamentarium available for AD can suc- mately half of the frequencies in placebo groups)83,84. There is no sub-
cessfully control the disease in most patients, primary prevention of stantial evidence for effects of dietary interventions beyond 46 months
AD represents a highly desirable goal. For infants with a family history of age (including delayed introduction of allergenic foods such as eggs)
of atopy, there is evidence that exclusive breastfeeding during the first on the development of AD81.

REFERENCES
1. Asher MI, Montefort S, Bjorksten B, et al. Worldwide time 20. Hansson L, Backman A, Ny A, et al. Epidermal dermatitis skin. J Allergy Clin Immunol.
trends in the prevalence of symptoms of asthma, allergic overexpression of stratum corneum chymotryptic 2006;117:17683.
rhinoconjunctivitis, and eczema in childhood: ISAAC enzyme in mice: a model for chronic itchy dermatitis. 36. Cardona ID, Cho SH, Leung DY. Role of bacterial
Phases One and Three repeat multicountry cross- J Invest Dermatol. 2002;118:4449. superantigens in atopic dermatitis: implications for
sectional surveys. Lancet. 2006;368:73343. 21. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of future therapeutic strategies. Am J Clin Dermatol.
2. Williams HC. Clinical practice. Atopic dermatitis. N Engl J atopic dermatitis filaggrin skin expression. J Allergy Clin 2006;7:2739.
Med. 2005;352:231424. Immunol. 2009;124:R712. 37. Bunikowski R, Mielke M, Skarabis H, et al. Prevalence and
3. Barnetson RC, Gawkrodger D. Atopic dermatitis. In: 22. Cork MJ, Robinson DA, Vasilopoulos Y, et al. New role of serum IgE antibodies to the Staphylococcus
Holgate ST, Church MK (eds). Allergy. London: Gower perspectives on epidermal barrier dysfunction in atopic aureus-derived superantigens SEA and SEB in children
Medical, 1993:28. dermatitis: gene-environment interactions. J Allergy Clin with atopic dermatitis. J Allergy Clin Immunol.
4. Spergel JM, Paller AS. Atopic dermatitis and the atopic Immunol. 2006;118:321. 1999;103:11924.
march. J Allergy Clin Immunol. 2003;112:S11827. 23. Ingordo V, DAndria G, DAndria C, et al. Results of atopy 38. Mittermann I, Aichberger KJ, Bunder R, et al.
5. Bieber T. Atopic dermatitis. N Engl J Med. patch tests with house dust mites in adults with Autoimmunity and atopic dermatitis. Curr Opin Allergy
2008;358:148394. intrinsic and extrinsic atopic dermatitis. J Eur Acad Clin Immunol. 2004;4:36771.
6. Hanifin JM, Rajka G. Diagnostic features of atopic Dermatol Venereol. 2002;16:4504. 39. Mothes N, Niggemann B, Jenneck C, et al. The cradle of
eczema. Acta Derm Venereol Suppl (Stockh). 24. Spergel JM, Mizoguchi E, Brewer JP, et al. Epicutaneous IgE autoreactivity in atopic eczema lies in early infancy.
1980;92:447. sensitization with protein antigen induces localized J Allergy Clin Immunol. 2005;116:7069.
7. Williams HC, Burney PG, Pembroke AC, Hay RJ. The U.K. allergic dermatitis and hyperresponsiveness to 40. Aichberger KJ, Mittermann I, Reininger R, et al. Hom s 4,
Working Partys Diagnostic Criteria for Atopic Dermatitis. methacholine after single exposure to aerosolized an IgE-reactive autoantigen belonging to a new
III. Derivation of a minimum set of discriminators for antigen in mice. J Clin Invest. 1998;101: subfamily of calcium-binding proteins, can induce Th
atopic dermatitis. Br J Dermatol. 1994;131:40616. 161422. cell type 1-mediated autoreactivity. J Immunol.
8. Johansson SG, Bieber T, Dahl R, et al. Revised 25. Soumelis V, Reche PA, Kanzler H, et al. Human epithelial 2005;175:128694.
nomenclature for allergy for global use: report of the cells trigger dendritic cell mediated allergic 41. Sonkoly E, Muller A, Lauerma AI, et al. IL-31: a new link
Nomenclature Review Committee of the World Allergy inflammation by producing TSLP. Nat Immunol. between T cells and pruritus in atopic skin inflammation.
Organization, October 2003. J Allergy Clin Immunol. 2002;3:67380. J Allergy Clin Immunol. 2006;117:41117.
2004;113:8326. 26. Traidl-Hoffmann C, Mariani V, Hochrein H, et al. 42. Paus R, Schmelz M, Biro T, et al. Frontiers in pruritus
9. Tanei R. Atopic dermatitis in the elderly. Inflamm Allergy Pollen-associated phytoprostanes inhibit dendritic cell research: scratching the brain for more effective itch
Drug Targets. 2009;8:398404. interleukin-12 production and augment T helper type 2 therapy. J Clin Invest. 2006;116:117486.
10. Barnes KC. An update on the genetics of atopic cell polarization. J Exp Med. 2005;201:62736. 43. Neis MM, Peters B, Dreuw A, et al. Enhanced expression
dermatitis: scratching the surface in 2009. J Allergy Clin 27. von Bubnoff D, Scheler M, Hinz T, et al. Comparative levels of IL-31 correlate with IL-4 and IL-13 in atopic and
Immunol. 2010;125:1629.e111; quiz 301. immunophenotyping of monocytes from symptomatic allergic contact dermatitis. J Allergy Clin Immunol.
11. Cookson W. The immunogenetics of asthma and and asymptomatic atopic individuals. Allergy. 2006;118:9307.
eczema: a new focus on the epithelium. Nat Rev 2004;59:9339. 44. Eller E, Kjaer HF, Host A, et al. Development of atopic
Immunol. 2004;4:97888. 28. Novak N, Koch S, Allam JP, et al. Dendritic cells: bridging dermatitis in the DARC birth cohort. Pediatr Allergy
12. Bowcock AM, Cookson WO. The genetics of psoriasis, innate and adaptive immunity in atopic dermatitis. Immunol. 2010;21:30714.
psoriatic arthritis and atopic dermatitis. Hum Mol Genet. J Allergy Clin Immunol. 2010;125:509. 45. Bayrou O, Pecquet C, Flahault A, et al. Head and neck
2004;13 Spec No 1:R4355. 29. Wollenberg A, Wagner M, Gunther S, et al. Plasmacytoid atopic dermatitis and Malassezia-furfur-specific IgE
13. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. dendritic cells: a new cutaneous dendritic cell subset antibodies. Dermatology. 2005;211:10713.
Common loss-of-function variants of the epidermal with distinct role in inflammatory skin diseases. J Invest 46. Wollenberg A, Wetzel S, Burgdorf WH, et al. Viral
barrier protein filaggrin are a major predisposing factor Dermatol. 2002;119:1096102. infections in atopic dermatitis: pathogenic aspects and
for atopic dermatitis. Nat Genet. 2006;38:4416. 30. Wollenberg A, Kraft S, Hanau D, et al. clinical management. J Allergy Clin Immunol.
14. Rodriguez E, Baurecht H, Herberich E, et al. Meta-analysis Immunomorphological and ultrastructural 2003;112:66774.
of filaggrin polymorphisms in eczema and asthma: characterization of Langerhans cells and a novel, 47. Ono SJ, Abelson MB. Allergic conjunctivitis: update on
robust risk factors in atopic disease. J Allergy Clin inflammatory dendritic epidermal cell (IDEC) population pathophysiology and prospects for future treatment.
Immunol. 2009;123:136170.e7. in lesional skin of atopic eczema. J Invest Dermatol. J Allergy Clin Immunol. 2005;115:11822.
14a. Irvine AD, McLean WH, Leung DY. Filaggrin mutations 1996;106:44653. 48. Bair B, Dodd J, Heidelberg K, et al. Cataracts in atopic
associated with skin and allergic diseases. N Engl J Med. 31. Novak N, Valenta R, Bohle B, et al. FcepsilonRI dermatitis: a case presentation and review of the
2011;365:131527. engagement of Langerhans cell-like dendritic cells and literature. Arch Dermatol. 2011 E-PUB AHEAD OF PRINT.
15. Vasilopoulos Y, Cork MJ, Murphy R, et al. Genetic inflammatory dendritic epidermal cell-like dendritic cells 49. Diepgen TL, Sauerbrei W, Fartasch M. Development and
association between an AACC insertion in the 3UTR of induces chemotactic signals and different T-cell validation of diagnostic scores for atopic dermatitis
the stratum corneum chymotryptic enzyme gene and phenotypes in vitro. J Allergy Clin Immunol. incorporating criteria of data quality and practical
atopic dermatitis. J Invest Dermatol. 2004;123:626. 2004;113:94957. usefulness. J Clin Epidemiol. 1996;49:10318.
16. Briot A, Deraison C, Lacroix M, et al. Kallikrein 5 induces 32. Bieber T. The pro- and anti-inflammatory properties of 50. Ricci G, Dondi A, Patrizi A. Useful tools for the
atopic dermatitis-like lesions through PAR2-mediated human antigen-presenting cells expressing the high management of atopic dermatitis. Am J Clin Dermatol.
thymic stromal lymphopoietin expression in Netherton affinity receptor for IgE (FcepsilonRI). Immunobiology. 2009;10:287300.
syndrome. J Exp Med. 2009;206:113547. 2007;212:499503. 51. Wollenberg A, Bieber T. Proactive therapy of atopic
17. ORegan GM, Campbell LE, Cordell HJ, et al. 33. Gros E, Bussmann C, Bieber T, et al. Expression of dermatitis an emerging concept. Allergy.
Chromosome 11q13.5 variant associated with childhood chemokines and chemokine receptors in lesional and 2009;64:2768.
eczema: an effect supplementary to filaggrin mutations. nonlesional upper skin of patients with atopic 52. Lipozencic J, Wolf R. The diagnostic value of atopy patch
J Allergy Clin Immunol. 2010;125:1704.e12. dermatitis. J Allergy Clin Immunol. 2009;124: testing and prick testing in atopic dermatitis: facts and
18. Weidinger S, Gieger C, Rodriguez E, et al. Genome-wide 75360.e1. controversies. Clin Dermatol. 2010;28:3844.
scan on total serum IgE levels identifies FCER1A as novel 34. Homey B, Steinhoff M, Ruzicka T, et al. Cytokines and 53. Werfel T, Breuer K, Rueff F, et al. Usefulness of specific
susceptibility locus. PLoS Genet. 2008;4:e1000166. chemokines orchestrate atopic skin inflammation. immunotherapy in patients with atopic dermatitis and
19. Elias PM, Schmuth M. Abnormal skin barrier in the J Allergy Clin Immunol. 2006;118:17889. allergic sensitization to house dust mites: a multi-centre,
216 etiopathogenesis of atopic dermatitis. Curr Opin Allergy 35. Verhagen J, Akdis M, Traidl-Hoffmann C, et al. Absence randomized, dose-response study. Allergy.
Clin Immunol. 2009;9:26592. of T-regulatory cell expression and function in atopic 2006;61:2025.
CHAPTER

12
54. Hon KL, Leung TF, Kam WY, et al. Dietary restriction and 65. Darsow U, Wollenberg A, Simon D, et al. ETFAD/EADV 75. Heil PM, Maurer D, Klein B, et al. Omalizumab therapy in
supplementation in children with atopic eczema. Clin eczema task force 2009 position paper on diagnosis and atopic dermatitis: depletion of IgE does not improve the
Exp Dermatol. 2006;31:18791. treatment of atopic dermatitis. J Eur Acad Dermatol clinical course a randomized, placebo-controlled and
55. Huang JT, Abrams M, Tlougan B, et al. Treatment of Venereol. 2010;24:31728. double blind pilot study. J Dtsch Dermatol Ges.

Atopic Dermatitis
Staphylococcus aureus colonization in atopic dermatitis 66. Wollenberg A, Reitamo S, Girolomoni G, et al. Proactive 2010;8:9908.
decreases disease severity. Pediatrics. 2009;123: treatment of atopic dermatitis in adults with 0.1% 76. Simon D, Hosli S, Kostylina G, et al. Anti-CD20
e80814. tacrolimus ointment. Allergy. 2008;63:74250. (rituximab) treatment improves atopic eczema. J Allergy
56. Niebuhr M, Mai U, Kapp A, et al. Antibiotic treatment of 67. Thaci D, Reitamo S, Gonzalez Ensenat MA, et al. Clin Immunol. 2008;121:1228.
cutaneous infections with Staphylococcus aureus in Proactive disease management with 0.03% tacrolimus 77. Oldhoff JM, Darsow U, Werfel T, et al. Anti-IL-5
patients with atopic dermatitis: current antimicrobial ointment for children with atopic dermatitis: results of recombinant humanized monoclonal antibody
resistances and susceptibilities. Exp Dermatol. a randomized, multicentre, comparative study. Br J (mepolizumab) for the treatment of atopic dermatitis.
2008;17:9537. Dermatol. 2008;159:134856. Allergy. 2005;60:6936.
57. Loden M. The clinical benefit of moisturizers. J Eur Acad 68. Gambichler T, Kreuter A, Tomi NS, et al. Gene expression 78. Smith SD, Hong E, Fearns S, et al. Corticosteroid phobia
Dermatol Venereol. 2005;19:67288. of cytokines in atopic eczema before and after and other confounders in the treatment of childhood
58. Katoh N. Future perspectives in the treatment of atopic ultraviolet A1 phototherapy. Br J Dermatol. atopic dermatitis explored using parent focus groups.
dermatitis. J Dermatol. 2009;36:36776. 2008;158:111720. Australas J Dermatol. 2010;51:16874.
59. Peserico A, Stadtler G, Sebastian M, et al. Reduction of 69. Dotterud LK, Wilsgaard T, Vorland LH, et al. The effect of 79. Zuberbier T, Orlow SJ, Paller AS, et al. Patient
relapses of atopic dermatitis with methylprednisolone UVB radiation on skin microbiota in patients with atopic perspectives on the management of atopic dermatitis.
aceponate cream twice weekly in addition to dermatitis and healthy controls. Int J Circumpolar J Allergy Clin Immunol. 2006;118:22632.
maintenance treatment with emollient: a multicentre, Health. 2008;67:25460. 80. Staab D, Diepgen TL, Fartasch M, et al. Age related,
randomized, double-blind, controlled study. Br J 69a. Schmitt J, Schkel K, Flster-Holst R, et al. Prednisolone structured educational programmes for the
Dermatol. 2008;158:8017. vs. ciclosporin for severe adult eczema. An investigator- management of atopic dermatitis in children and
60. Berth-Jones J, Damstra RJ, Golsch S, et al. Twice weekly initiated double-blind placebo-controlled multicentre adolescents: multicentre, randomised controlled trial.
fluticasone propionate added to emollient maintenance trial. Br J Dermatol. 2010;162:6618. BMJ. 2006;332:9338.
treatment to reduce risk of relapse in atopic dermatitis: 70. Hon KL, Ching GK, Leung TF, et al. Efficacy and 81. Greer FR, Sicherer SH, Burks AW, et al. American
randomised, double blind, parallel group study. BMJ. tolerability at 3 and 6 months following use of Academy of Pediatrics Committee on Nutrition,
2003;326:1367. azathioprine for recalcitrant atopic dermatitis in children American Academy of Pediatrics Section on Allergy and
61. Schmitt J, von Kobyletzki L, Svensson A, et al. Efficacy and young adults. J Dermatolog Treat. 2009;20:1415. Immunology. Effects of early nutritional interventions on
and tolerability of proactive treatment with topical 71. Weinshilboum R. Inheritance and drug response. N Engl the development of atopic disease in infants and
corticosteroids and calcineurin inhibitors for atopic J Med. 2003;348:52937. children: the role of maternal dietary restriction,
eczema: systematic review and meta-analysis of 72. Heller M, Shin HT, Orlow SJ, et al. Mycophenolate mofetil breastfeeding, timing of introduction of complementary
randomized controlled trials. Br J Dermatol. for severe childhood atopic dermatitis: experience in 14 foods, and hydrolyzed formulas. Pediatrics.
2011;164:41528. patients. Br J Dermatol. 2007;157:12732. 2008;121;18391.
62. Ruzicka T, Bieber T, Schopf E, et al. A short-term trial of 72a. Haeck IM, Knol MJ, Ten Berge O, et al. Enteric-coated 82. von Berg A, Koletzko S, Grubl A, et al. The effect of
tacrolimus ointment for atopic dermatitis. European mycophenolate sodium versus cyclosporin A as hydrolyzed cows milk formula for allergy prevention in
Tacrolimus Multicenter Atopic Dermatitis Study Group. long-term treatment in adult patients with severe atopic the first year of life: the German Infant Nutritional
N Engl J Med. 1997;337:81621. dermatitis: a randomized controlled trial. J Am Acad Intervention Study, a randomized double-blind trial.
63. Reitamo S, Wollenberg A, Schopf E, et al. Safety and Dermatol. 2011;64:107484. J Allergy Clin Immunol. 2003;111:53340.
efficacy of 1 year of tacrolimus ointment monotherapy 73. Schram ME, Roekevisch E, Leeflang MM, et al. A 83. Lee J, Seto D, Bielory L. Meta-analysis of clinical trials of
in adults with atopic dermatitis. The European randomized trial of methotrexate versus azathioprine for probiotics for prevention and treatment of pediatric
Tacrolimus Ointment Study Group. Arch Dermatol. severe atopic eczema. J Allergy Clin Immunol. 2011;128: atopic dermatitis. J Allergy Clin Immunol.
2000;136:9991006. 3539. 2008;121:11621.
64. Arellano FM, Wentworth CE, Arana A, et al. Risk of 74. Ramsay HM, Goddard W, Gill S, Moss C. Herbal creams 84. Grber C, van Stuijvenberg M, Mosca F, et al. Reduced
lymphoma following exposure to calcineurin inhibitors used for atopic eczema in Birmingham, UK illegally occurrence of early atopic dermatitis because of
and topical steroids in patients with atopic dermatitis. contain potent corticosteroids. Arch Dis Child. immunoactive prebiotics among low-atopy-risk infants.
J Invest Dermatol. 2007;127:80816. 2003;88:10567. J Allergy Clin Immunol. 2010;126:7917.

217