Beruflich Dokumente
Kultur Dokumente
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)
3 DIAGNOSTIC FEATURES OF ATOPIC DERMATITIS SELECTED SUSCEPTIBILITY LOCI AND CANDIDATE GENES
FOR ATOPIC DERMATITIS
Papulosquamous and eczematous dermatoses
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
Allergic
rhinitis,
asthma
Impaired Cytokines,
epidermal barrier chemokines
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
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.
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
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
3
Papulosquamous and eczematous dermatoses
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
CHRONIC DERMATOSES
Papulosquamous and eczematous dermatoses
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
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
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.
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