Epidemiology, clinical manifestations, and diagnosis of

atopic dermatitis (eczema)

INTRODUCTION  — Atopic dermatitis is a chronic inflammatory skin condition that

appears to involve a genetic defect in the proteins supporting the epidermal barrier.
Atopy, referring to "out of place", describes a group of disorders that include
eczema, asthma, and allergic rhinitis [ 1 ]. However such a link between atopic
dermatitis and asthma and hay fever has been called into question and is now
controversial [ 2-4 ]. (See "Risk factors for asthma", section on 'Atopy' .)

The terms "dermatitis" and "eczema" are frequently used interchangeably. When
the term "eczema" is used alone, it usually refers to atopic dermatitis (atopic
eczema). "Eczematous" also connotes some crusting, serous oozing, or blister
formation as opposed to mere erythema and scale.

EPIDEMIOLOGY  — Atopic dermatitis affects approximately 5 to 20 percent of

children worldwide [ 5 ]. The prevalence of atopic dermatitis in the United States is
around 11 percent [ 6 ].

The incidence of atopic dermatitis appears to be increasing. It may occur in any

race or geographic location, although there appears to be a higher incidence in
urban areas and developed countries, especially western societies [ 6,7 ].

The vast majority of atopic dermatitis has an onset before age five years, and
prevalence data in children show a slight female to male preponderance (1.3 to 1)
[ 8 ].

PATHOGENESIS  — Two major models currently exist to explain the pathogenesis

of atopic dermatitis. The predominant model describes atopic dermatitis as a result
of impaired epidermal barrier function due to intrinsic structural and functional
abnormalities in the skin. In this model, the disease evolves from the outside in,
with an abnormal epidermal barrier as the primary defect [ 9 ]. The second and
traditional model views atopic dermatitis as primarily an immune function disorder
in which Langerhans cells, T-cells, and immune effector cells modulate an
inflammatory response to environmental factors. While widely accepted for years,
there is now little support that atopic dermatitis is the result of allergies [ 2-4 ].

Epidermal permeability barrier  — The epidermis is the first line of defense

between the body and the environment. An intact epidermis keeps environmental
irritants, allergens, and microbes from entering the body [ 10 ]. Permeability of the
epidermis is determined by complex interactions of differentiated keratinocytes on
the surface of the skin called corneocytes and groups of structural proteins, such as
filaggrin, regulatory enzymes, and lipids [ 11 ]. Any disruption of these components
through inherited defects, trauma, decreased humidity, alteration of pH, and
infection can interfere with the ability of the epidermis to function as an effective
barrier. Disruption allows antigenic and irritant agents to penetrate the barrier and
come into contact with immune cells, leading to the release of proinflammatory
mediators [ 11 ]. This can then produce the clinical and pathologic findings of
dermatitis.
Epidermal hydration  — Hydration of the epidermis is a key factor in maintaining
an intact barrier, and the stratum corneum layer of the epidermis plays a key role
in the retention of water in the skin. Water absorption into the stratum corneum
occurs as a function of stratum corneum natural moisturizing factor, which consists
of a variety of molecules that promote water absorption, including amino acids
derived from the proteolysis of epidermal filaggrin, urea, lactate and electrolytes
[ 12,13 ]. The stratum corneum also prevents epidermal water loss through the
presence of an extracellular lipid barrier composed of ceramides, cholesterol, and
free fatty acids.

Defects that affect filaggrin, epidermal lipids, or other key components of the
stratum corneum can result in the creation of an inadequate epidermal barrier,
leading to decreased water content in the epidermis. Increased rates of
transepidermal water loss (TEWL) have been detected in skin of patients with atopic
dermatitis [ 10,14 ], and an association between this finding and mutations in the
gene for filaggrin have been reported [ 15 ]. In addition, decreased levels of
ceramides in the stratum corneum due to upregulation of sphingomyelin deacylase
may contribute to increase TEWL in atopic dermatitis [ 11 ].

Abnormalities in the skin barrier that result in increased water loss likely contribute
to the clinical findings in atopic dermatitis. Higher levels of transepidermal water
loss in patients with atopic dermatitis have been associated with greater disease
severity [ 14,16 ]. In patients with atopic dermatitis, dry skin (xerosis) secondary
to decreased epidermal water content may contribute to pruritus and scratching.
Resultant cutaneous trauma from scratching can promote the release of
proinflammatory mediators and inflammation, thereby worsening pruritus [ 17 ].
This “itch-scratch” cycle may play a role in the persistence of symptoms.

Filaggrin  — Filaggrin is encoded by the FLG gene on the 1q21 epidermal

differentiation complex. Filaggrin is a protein produced by differentiating
keratinocytes that functions to aggregate keratin filaments into a cytoskeleton that,
in combination with other components, comprise the cornified cell envelope [ 11 ].

Filaggrin loss of function mutations (R501X and 2282del4) cause ichthyosis

vulgaris, the most common inherited disorder of keratinization [ 18 ]. The same
mutations also are associated with atopic dermatitis and other skin and allergic
conditions including atopic dermatitis, irritant contact dermatitis, asthma, and food
allergy [ 18-20 ]. (See "Irritant contact dermatitis in adults" and "Genetics of
asthma" and "Peanut, tree nut, and seed allergy: Clinical features" .)

Spink 5  — Spink 5 is a serine protease inhibitor (Kazal-type 5 serine protease

inhibitor) that is deficient in Netherton's syndrome (a rare autosomal recessive
disorder characterized by severe atopic dermatitis). Spink 5 inhibits a well
characterized protease stratum corneum chymotryptic enzyme (SCCE) that is
involved in cleaving the intercellular attachments between corneocytes in normal
desquamation process. Decreased Spink 5 results in upregulated SCCE function and
increased cleavage of intercellular attachments and reduced corneocyte cohesion
and compromised barrier function [ 11 ].  

Epicutaneous sensitization  — Immune responses to allergens, irritants, and

microbes that enter the skin through a defective skin barrier may contribute to the
development of local inflammatory responses and the cutaneous findings of atopic
dermatitis. Antigen presenting cells in the skin, in particular IgE bearing Langerhans
cells, can interact with environmental allergens, leading to the local Th2-mediated
inflammatory responses that have been detected in the skin of patients with atopic
dermatitis [ 21 ].

Immune hypersensitivity  — Another theory explaining the pathogenesis of

atopic dermatitis proposes that the immune system is responsible for atopic
disorders [ 22 ]. Atopic dermatitis in this view may represent a cutaneous sign of a
systemic disorder that is characterized by food allergy, asthma, and allergic rhinitis
[ 1 ].

The discovery that defects in the filaggrin protein lead to a dysfunctional epidermal
barrier and are the primary cause of atopic dermatitis has made this theory less
plausible. Emphasis is now placed on the study of the epidermal barrier dysfunction
as it relates to the abnormal epidermal architecture and how the immune system
responds to the barrier failure [ 23 ].

Serum IgE levels vary among patients with atopic dermatitis. Patients with mild to
moderate atopic dermatitis typically have much lower (or normal) serum IgE levels
compared to patients with severe atopic dermatitis [ 11,24 ]. This finding suggests
that the systemic Th2 driven axis of the immune system detected in atopic
dermatitis may be related to epidermal barrier dysfunction and the introduction of
environmental antigens, rather than intrinsic immune hypersensitivity.

Genetics  — Most experts believe that atopic dermatitis has a genetic basis. A

genetic basis is suggested by twin studies that have found concordance rates of 80
percent for monozygotic twins compared to 20 percent for dizygotic twins [ 25-27 ].

Other genes  — In addition to filaggrin, many other genes have been proposed as
potential contributors to atopic dermatitis, including genes involved in the creation
of the skin barrier or immune regulation [ 28,29 ]. Linkage on chromosomes 3q21,
1q21, 17q25, and 20p, all of which correspond closely with known psoriasis loci,
have been reported [ 30,31 ]. (See 'Filaggrin' above.)

In 2009, the first genome-wide association study of atopic dermatitis detected a

strong association between atopic dermatitis and an allele on chromosome 11q13.5
[ 32 ]. The risk of atopic dermatitis was approximately 1.5 times greater in patients
who were homozygous for the risk allele than in noncarriers (OR 1.47, 95% CI
1.29-1.68). The results of this genome-wide association study were supported by a
subsequent case-control study of 511 children with atopic dermatitis and 1000
controls [ 33 ]. The case-control study implicated the same susceptibility locus as a
potential contributor to atopic dermatitis, and found that the effect of the risk allele
was independent of and supplementary to filaggrin mutations. A subsequent
genome-wide study performed in the Chinese Han population found two new
susceptibility loci for atopic dermatitis at 5q22.1 and 20q13.33 [ 34 ]. However,
fine mapping and functional studies of the candidate genes are required to
determine their role in the pathogenesis of atopic dermatitis.  

Staphylococcus aureus  — Staphylococcus aureus colonization is common in

patients with atopic dermatitis and may play a role in the exacerbation of this
disorder via locally acting staphylococcal superantigens. In normal skin,
endogenous antimicrobial peptide (cathelicidin and others) production is
upregulated by two cytokines, IL-17 and IL-22, secreted by Th17 T cells. In atopic
skin, this effect is abrogated by the presence of Th2 cytokines, resulting in lower
levels of antimicrobial peptides, which could be a possible mechanism of
staphylococcal superinfection [ 35 ]. (See "Treatment of atopic dermatitis
(eczema)", section on 'Staphylococcus aureus' .)

CLINICAL MANIFESTATIONS  — Atopic dermatitis occurs in the first year of life

in 60 percent of cases, and by the age of 5 years in nearly 85 percent of cases.
Atopic dermatitis will clear in nearly 40 percent of patients by adulthood [ 36-38 ].
There are three age-group stages of atopic dermatitis: infantile (from infancy to 2
years old), childhood (from 2 years old to 12 years old) and the adult stage for
those older than 12 years [ 36 ]. Virtually all patients report dry skin [ 37-39 ].
Pruritus is characteristic, and secondary changes in the skin due to chronic rubbing
or scratching are frequently present.

The infantile stage may present with pruritic, red, scaly, and crusted lesions on the
extensor surfaces and cheeks or scalp ( picture 1A-C ). There is usually sparing of
the diaper area ( picture 2 ) [ 36 ]. Acute lesions can include vesicles and there can
be serous exudates and crusting in severe cases.

The childhood stage is characterized by less exudation and often demonstrates

lichenified plaques in a flexural distribution, especially of the antecubital and
popliteal fossae, volar aspect of the wrists, ankles, and neck ( picture 3A-D ) [ 36 ].

The adult stage of atopic dermatitis is considerably more localized and lichenified
and has a similar distribution to the childhood stage, or may be primarily located on
the hands and feet [ 36 ]. Adults who no longer have dermatitis in areas present
when they were younger are at increased risk for developing hand eczema,
especially when the hands are exposed to "wet-work" environments. Adult atopic
dermatitis is characterized by thickened skin, increased skin markings
(lichenification), and excoriated and fibrotic papules ( picture 4A-B ). In adults, the
flexural areas (neck, antecubital fossae, and popliteal fossae) are most commonly
involved ( picture 5 ); other common sites include the face, wrists, and forearms.

In severe cases, any area of the body can be involved, although it is uncommon to
see lesions in the axillary, gluteal, or groin area; lesions in these locations should
prompt consideration of other diagnoses such as psoriasis. The presence of pustules
within areas of dermatitis suggests secondary infection with Staphylococcus aureus.

DIAGNOSIS  — Atopic dermatitis is diagnosed by observing its representative

clinical features. The United Kingdom working group on atopic dermatitis published
criteria for diagnosing atopic dermatitis that include the following [ 37 ]:

 Evidence of pruritic skin, including the report by a parent of a child rubbing

or scratching.

In addition to itchy skin, three or more of the following are needed to make the
diagnosis:

 History of skin creases being involved. These include: antecubital fossae,

popliteal fossae, neck, areas around eyes, fronts of ankles.
 The presence of generally dry skin within the past year.
  Symptoms beginning in a child before the age of two years. This criterion is
not used to make the diagnosis in a child who is under four years old.
 Visible evidence of dermatitis involving flexural surfaces. For children under
four years old, this criterion is met by dermatitis affecting the cheeks or
forehead and outer aspects of the extremities.

The UK working group's analysis excluded allergy criteria as originally proposed by

Hanifin and Rajka. The UK working group data have been validated by investigators
from the Netherlands [ 39 ].

Laboratory testing, including IgE levels, are not used routinely in the evaluation of
patients with suspected atopic dermatitis, and are not currently recommended.

When the diagnosis is uncertain, we suggest that patients be referred to a specialist

(eg, dermatologist, allergist).

DIFFERENTIAL DIAGNOSIS  — The differential diagnosis of atopic dermatitis

includes other eczematous disorders such as contact dermatitis ( picture 6 ),
seborrheic dermatitis ( picture 7 ), and drug reactions ( picture 8 ). (See "Overview
of dermatitis" .)

In infants, considerations include psoriasis ( picture 9 ), scabies ( picture 10 ),

Wiskott-Aldrich syndrome, hyperimmunoglobulin E syndrome ( picture 11 ),
nutritional deficiencies, acrodermatitis enteropathica ( picture 12 ) and Netherton's
syndrome. (See "Epidemiology, clinical manifestations, and diagnosis of
psoriasis" and "Scabies" and "Wiskott-Aldrich
syndrome" and "Hyperimmunoglobulin E syndrome" and "Zinc deficiency and
supplementation in children and adolescents" .)

INFORMATION FOR PATIENTS  — UpToDate offers two types of patient

education materials, “The Basics” and “Beyond the Basics.” The Basics patient
education pieces are written in plain language, at the 5 th to 6 th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who
prefer short, easy-to-read materials. Beyond the Basics patient education pieces
are longer, more sophisticated, and more detailed. These articles are written at the
10 th to 12 th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage
you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on “patient info” and the
keyword(s) of interest.)

 Basics topics (see "Patient information: Eczema (atopic dermatitis) (The

Basics)" )
 Beyond the Basics topics (see "Patient information: Atopic dermatitis
(eczema) (Beyond the Basics)" )

SUMMARY AND RECOMMENDATIONS  — Atopic dermatitis is a chronic

inflammatory skin condition that appears to involve genetic defects in the proteins
and lipids supporting the epidermal barrier. Disruption of the barrier results in
inflammation of the skin. (See 'Introduction' above.)
The diagnosis of atopic dermatitis is generally based on its typical clinical
presentation (see 'Clinical manifestations' above):

 Most patients have manifestations of atopic dermatitis by age five to seven

years.
 In children, acute skin lesions that appear as intensely pruritic erythematous
patches with papules and some crusting can be seen on the face, scalp,
extremities, or trunk; diaper areas are usually spared.
 The skin lesions in older individuals with more chronic disease are
characterized by thickened skin, increased skin markings (lichenification),
and excoriated and fibrotic papules. In adults, the flexural areas (neck,
antecubital fossae, and popliteal fossae) are most commonly involved.
 We suggest not performing routine laboratory testing in patients felt
clinically to have atopic dermatitis. When the diagnosis is uncertain, we
suggest that patients be referred to a specialist (eg, dermatologist,
allergist). (See 'Diagnosis' above.)
 The differential diagnosis of atopic dermatitis includes other eczematous
disorders such as contact dermatitis, seborrheic dermatitis, and drug
reactions. (See 'Differential diagnosis' above.)

REFERENCES
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 38. Williams HC, Strachan DP. The natural history of childhood eczema:
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Treatment of atopic dermatitis (eczema)

View in Chinese
Authors:
William L Weston, MD
William Howe, MD
Section Editors:
Robert P Dellavalle, MD, PhD, MSPH
Moise L Levy, MD
Joseph Fowler, MD
Deputy Editor:
Rosamaria Corona, MD, DSc
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2021. | This topic last updated: Apr 15, 2021.

INTRODUCTION Atopic dermatitis is a chronic, pruritic, inflammatory

skin disease that occurs most frequently in children but also affects many adults
[1]. Clinical features of atopic dermatitis include skin dryness, erythema, oozing
and crusting, and lichenification. Pruritus is a hallmark of the condition and is
responsible for much of the disease burden for patients and their families.
The goals of treatment are to reduce symptoms (pruritus and dermatitis),
prevent exacerbations, and minimize therapeutic risks. Standard treatment
modalities for the management of these patients are centered around the use of
topical anti-inflammatory preparations and moisturization of the skin, but
patients with severe disease may require phototherapy or systemic treatment
[2,3].

Conventional therapy for atopic dermatitis is reviewed here. The management

of severe, refractory atopic dermatitis in children and adults and the
epidemiology, pathogenesis, clinical manifestations, and diagnosis of atopic
dermatitis are discussed separately.

●(See "Management of severe atopic dermatitis (eczema) in

children".)
●(See "Evaluation and management of severe refractory atopic
dermatitis (eczema) in adults".)
●(See "Atopic dermatitis (eczema): Pathogenesis, clinical
manifestations, and diagnosis".)
 ASSESSMENT OF SEVERITY For the management of the

individual patient, it is important that clinicians evaluate the extent and

characteristics of the rash (eg, presence of erythema, excoriations, oozing,
lichenification, clinical signs of bacterial superinfection) and ask general
questions about itch, sleep, impact on daily activities, and persistence of
disease [4]. Several disease severity scales (eg, the Scoring of Atopic
Dermatitis [SCORAD] index, the Eczema Area and Severity Index [EASI], and
the Patient-Oriented Eczema Measure [POEM]) and patient quality-of-life
measurement scales have been tested and validated for use in clinical trials, but
they are not commonly used in clinical practice [4]. However, POEM, which
asks about the frequency of seven symptoms (itch, sleep disturbance, dryness,
flaking, weeping or oozing, bleeding, and cracking) in the previous seven days,
typically takes less than two minutes to complete and is available from
the Centre of Evidence Based Dermatology [5].
A practical guide to visual assessment of eczema severity that also includes the
evaluation of disease impact on quality of life and psychosocial well-being has
been proposed by the United Kingdom National Institute for Health and Care
Excellence:
●Mild – Areas of dry skin, infrequent itching (with or without small
areas of redness); little impact on everyday activities, sleep, and
psychosocial well-being
●Moderate – Areas of dry skin, frequent itching, redness (with or
without excoriation and localized skin thickening); moderate impact
on everyday activities and psychosocial well-being, frequently
disturbed sleep
●Severe – Widespread areas of dry skin, incessant itching, redness
(with or without excoriation, extensive skin thickening, bleeding,
oozing, cracking, and alteration of pigmentation); severe limitation
of everyday activities and psychosocial functioning, nightly loss of
sleep

GENERAL APPROACH The optimal management of atopic

dermatitis requires a multipronged approach that involves the elimination of

exacerbating factors, restoration of the skin barrier function and hydration of the
skin, patient education, and pharmacologic treatment of skin inflammation
(algorithm 1) [6].
Patient education — Patient education is an important component of the
management of atopic dermatitis. A systematic review of nine randomized
trials (2003 participants) of educational interventions for atopic
dermatitis suggests that children and their parents or caregivers may benefit
from structured education provided by nurses or multidisciplinary teams [7]. In
the largest of these trials including 992 children and adolescents with atopic
dermatitis and their families, a six-week education program was compared with
no intervention [8]. The program consisted of two-hour weekly sessions
covering medical, nutritional, and psychologic issues and were carried out by a
multiprofessional team of dermatologists or pediatricians, psychologists, and
dietitians. After one year, the decrease in the total severity of the Scoring of
Atopic Dermatitis (SCORAD) score was greater in the intervention group than in
the control group. There was also a significant improvement in subjective
assessment of severity, itching behavior, and emotional coping.
Elimination of exacerbating factors — Exacerbating factors in atopic
dermatitis that disrupt an already abnormal epidermal barrier include excessive
bathing without subsequent moisturization, low-humidity environments,
emotional stress, xerosis (dry skin), overheating of skin, and exposure to
solvents and detergents [9,10]. Avoiding these situations is helpful for acute
flares as well as for long-term management. Since atopic individuals tend to
respond more readily to pruritic stimuli, anything that tends to induce itch in an
individual should be avoided.
Adjunctive measures that can be useful in all patients with dermatitis include
[11]:
●Avoid trigger factors such as heat and low humidity
●Treat skin infections such as Staphylococcus aureus and herpes
simplex (see 'Management of infection' below)
●Use antihistamines for sedation and control of itching
(see 'Controlling pruritus' below)
●Manage stress and anxiety
Aeroallergens and food allergens — There is controversy regarding whether
environmental or food allergies are exacerbating factors in patients with atopic
dermatitis. (See "Role of allergy in atopic dermatitis (eczema)".)
Hypersensitivity to house dust mites (eg, Dermatophagoides
pteronyssinus, Dermatophagoides farinae), animal danders, molds, and pollens
is thought to be associated with flares of atopic dermatitis [12,13]. However,
although many atopic dermatitis patients are sensitized to house dust mites,
reduction of house dust mite antigens in the atopic dermatitis patient's
environment does not seem to be useful for disease control [14,15].
There is a lack of evidence that dietary interventions are helpful in reducing the
severity or preventing flares of atopic dermatitis in unselected patients. Although
approximately 50 percent of children with atopic dermatitis may have positive
skin prick tests or specific immunoglobulin E (IgE) to one or more food allergens
(in particular, cow's milk, egg, wheat, and peanut), food sensitization is clinically
irrelevant in most cases [16]. A systematic review of nine randomized trials
including 421 children and adults with atopic eczema indicates that either milk
and egg exclusion, a few-foods diet, or an elemental diet are not beneficial in
unselected patients with atopic dermatitis [17]. Moreover, food restriction in
toddlers may result in lower Z-scores of weight, height, head circumference,
and body mass index for age [18]. One trial suggests that an egg-free diet may
be helpful for infants with proven sensitivity to eggs [19].
Contact allergens — Atopic individuals are at an increased risk for developing
allergic contact dermatitis (ACD) to nickel as well as to many components of
topical treatments (eg, fragrances, preservatives, neomycin) [20,21]. ACD
should be suspected when patients do not respond to appropriate topical
therapy or when affected areas continue to spread beyond the usual flexural
locations.
Maintaining skin hydration
Emollients and moisturizers — Skin hydration is a key component of the
overall management of patients with atopic dermatitis. To maintain skin
hydration, emollients should be applied at least two times per day and
immediately after bathing or hand washing.

Thick creams, which have a low water content, or ointments (eg, petroleum
jelly), which have zero water content, are generally preferred, as they better
protect against xerosis, but some patients may complain that they are greasy.
Lotions, although less effective than thick creams and ointments, can be an
alternative for these patients.

Since atopic skin is deficient in stratum corneum lipids (especially ceramide)

and "natural moisturizing factor" (a mixture of hygroscopic amino acids resulting
from filaggrin breakdown), moisturizers that contain those ingredients may be
beneficial. There are a number of topical moisturizers available in the United
States by prescription. These agents contain a variety of components intended
to improve skin barrier function but are expensive. There are few data
demonstrating their efficacy, but one randomized trial suggests that they are no
more effective than over-the-counter emollients [22].
A 2017 systematic review of 77 studies including 6603 participants (mean age
19 years) with mostly mild to moderate eczema evaluated the efficacy of
emollients and moisturizers in reducing the signs and symptoms of eczema and
the frequency of flares [23,24]:
●Based on both physician and patient assessment, the use of any
moisturizers reduced eczema severity and itch compared with no
use, resulted in fewer flares, and reduced the need for topical
corticosteroids.
●In three studies, patients found that a moisturizer containing
glycyrrhetinic acid (a natural anti-inflammatory agent) was four
times more effective than vehicle in reducing eczema severity.
●In four studies, patients using a cream containing urea (a
humectant agent) reported improvement more often than those
using a control cream without urea.
●Three studies assessed a moisturizer containing glycerol (a
humectant agent) versus control. More patients in the glycerol
group experienced skin improvement, both by physician and patient
assessment.
●Four studies examined oat-containing moisturizers versus no
treatment or control. No significant difference in skin improvement
was noted between groups, although patients using oat
moisturizers tended to have fewer flares and reduced need for
topical corticosteroids.

Emollients are best applied immediately after bathing, when the skin is well
hydrated.

Bathing practices
Frequency of bathing — Warm soaking baths or showers using mild or soap-
free cleansers should be part of the routine skin care for patients with atopic
dermatitis. Some controversy exists concerning the frequency of bathing and
whether showering or bathing is preferable in patients with atopic dermatitis [25-
27]. Most experts recommend a hydrating bath followed by immediate emollient
application, but others recommend a shower of short duration. No well-designed
studies have been published to address this controversy. We feel that either
option is reasonable but suggest daily bathing to most patients. Whether bath or
shower is preferred, rapid application of emollients and/or prescribed topical
preparations immediately after is important.
A small, randomized, single-blind, crossover trial examined the effect of
frequent versus infrequent bathing on atopic dermatitis. In this study, 42
children (median age 3.9 years, range 6 months to 11.5 years) with moderate to
severe atopic dermatitis were randomized to two groups. Group 1 was assigned
to twice-weekly, soak-and-seal baths for 10 minutes or less for two weeks
(infrequent bathing) followed by twice-daily, soak-and-seal baths for 15 to 20
minutes for two weeks (frequent bathing); group 2 did the inverse [28]. Frequent
bathing was associated with a greater decrease of SCORAD score from
baseline compared with infrequent bathing (mean difference in SCORAD 21.2
[95% CI 4.9-27.6]).
Bath additives — We do not support the use of bath additives for atopic
dermatitis. However, despite a lack of high-quality studies providing evidence of
benefit, bath emollient additives (eg, liquid paraffin, oils with or without
emulsifiers, colloidal oatmeal) are widely used to improve skin hydration in
children and adults with atopic dermatitis, especially in Europe, where their use
is supported by national and international guidelines [29,30]. In the United
States, while the American Academy of Allergy, Asthma, and Immunology's
practice parameter for atopic dermatitis supports the use of bath additives, the
American Academy of Dermatology guidelines recommend against them [2,31].
A large, well-designed, pragmatic, randomized trial demonstrated that emollient
bath additives provide no additional benefits beyond standard care in the
management of atopic dermatitis [32,33]. In this study, 463 children aged 1 to
11 years with mild to moderate atopic dermatitis were assigned to use bath
emollient additives or no bath additives in addition to standard care (ie, leave-on
emollients and topical corticosteroids as needed) for 52 weeks. The primary
outcome was eczema severity assessed weekly by the Patient-Oriented
Eczema Measure (POEM) over 16 weeks. At 16 weeks, there was no significant
difference between the mean POEM score in the bath additives group and that
in the no bath additives group (7.5 versus 8.4). After adjusting for potential
confounders (eg, baseline severity, use of topical corticosteroids, use of soap
substitutes), the POEM score in the no bath additives group was 0.41 (95% CI -
0.27 to 1.10) points higher than in the bath additives group, which is markedly
lower than the accepted minimal clinically important difference of three points
[34,35]. Similar results were obtained at 52 weeks.

CONTROLLING PRURITUS The management of atopic pruritus

requires a multipronged approach that addresses the multiple factors involved

in its pathogenesis [36-41]. These include:
●Skin barrier disruption
●Aberrant type 2 immune response, with increased IgE production,
eosinophilia, mast cell activation, and overexpression of Th2
cytokines
 ●Itch mediators, such as histamine, nerve growth factor (NGF),
substance P (SP), proteases, and cytokines/chemokines (eg,
thymic stromal lymphopoietin [TSLP], interleukin [IL] 2, IL-4, IL-13,
and IL-31)
●Hyperinnervation of skin and central sensitization of itch
Nonpharmacologic interventions — Optimal skin hydration and
moisturization and treatment with topical anti-inflammatory therapy are the
cornerstone of atopic itch management.
Tepid baths to hydrate and cool the skin, followed by application of emollients,
can relieve itching. In more severe cases, the use of wet dressings (wet wraps)
helps soothe the skin, reduce pruritus, and interrupts the itch-scratch cycle by
limiting access to the skin. Emollients are applied to the skin, and dampened
cotton garments are worn over the affected area and covered with a dry
garment [42]. The wet layer should not be allowed to dry out. The patient may
use these dressings overnight if tolerated or change them every few hours
during the day. Antipruritic ingredients, such as phenol, menthol, and camphor,
are found in some moisturizers.
Psychologic interventions, including habit reversal training, relaxation training,
and cognitive behavioral therapy, have been reported as beneficial in patients
with chronic pruritus [43-45].
Topical treatments — Topical anti-inflammatory therapy with topical
corticosteroids or topical calcineurin inhibitors is effective in controlling pruritus.
In a meta-analysis of 22 randomized trials including 481 adult
patients, pimecrolimus 1% cream or tacrolimus 0.03 to 0.1% ointment were
more effective than vehicle in reducing pruritus (odds ratio [OR] 0.64, 95% CI
0.61-0.68) [46].
Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor approved for the
treatment of mild to moderate atopic dermatitis in patients aged ≥3 months,
appears to be effective in reducing pruritus [47]. Inhibition of PDE4 results in an
increase in intracellular cyclic adenosine monophosphate, which causes a
decrease in the production of pruritogenic cytokines [48].
Topical doxepin, a tricyclic antidepressant with potent H1- and H2-blocking
properties, may be used as a second-line treatment if others fail [49]. However,
allergic contact dermatitis to this agent is common [50].
Phototherapy — In patients with diffuse pruritus that is not controlled with
topical therapy alone, narrowband ultraviolet B (NBUVB) or ultraviolet A1
(UVA1) phototherapy are therapeutic options [36,51,52]. The mechanism of
action involves a reduced production of histamine from mast cells and
basophils. Moreover, as ultraviolet A (UVA) light penetrates deeper into the
skin, compared with ultraviolet B (UVB), it may also cause damage to Schwann
and perineural cells, resulting in decreased sensitivity to pruritus.
Both NBUVB and medium-dose UVA1 have been shown to be equally effective
in reducing atopic pruritus [53]. However, high-dose UVA1 may be more
effective in reducing pruritus and other symptoms of atopic dermatitis in
individuals with darker skin types [51].
Oral antihistamines — Oral H1 antihistamines are widely used as a
therapeutic adjunct in patients with atopic dermatitis to alleviate pruritus [54].
The evidence supporting their use is relatively weak since no large,
randomized, placebo-controlled trials with definitive conclusions have been
performed. Nevertheless, first-generation, sedating antihistamines
(eg, diphenhydramine, hydroxyzine, and cyproheptadine) may be beneficial for
patients with disturbed sleep secondary to itch, although optimal doses and
length of treatment have not been determined [3].
The efficacy of second-generation, less-sedating H1 antihistamines, such
as fexofenadine, cetirizine, or loratadine, as an adjunct to topical treatment in
adults and children with atopic dermatitis remains uncertain, and their use
should be limited to patients with concurrent symptoms of urticaria or allergic
rhinitis. A 2019 systematic review of 25 randomized trials, most of which were of
low methodologic quality, did not find evidence that these agents are effective in
improving the symptoms of atopic dermatitis [55]. In one of the trials including
795 children aged one to two years with eczema, cetirizine 0.5 mg/kg per day
for 18 months was no more effective than placebo in reducing the Scoring of
Atopic Dermatitis (SCORAD) score (from 24.9 to 15.2 in the cetirizine group and
from 25.1 to 15.7 in the placebo group) [56]. Another study including 400 adult
patients with atopic dermatitis found that fexofenadine 120 mg daily for one
week reduced patient-assessed pruritus more than placebo, although the
reduction was probably not clinically significant (mean change -0.75 in the
fexofenadine group versus -0.5 in the placebo group on a pruritus scale of 0 to
8) [57].
Cyclosporine — The efficacy of oral cyclosporine in improving pruritus and
other symptoms of atopic dermatitis has been demonstrated in several
randomized trials [58,59]. Cyclosporine may be especially useful for the rapid
control of pruritus associated with atopic dermatitis. However, recurrence is
common upon discontinuation of treatment.
Dupilumab — Dupilumab, a fully human monoclonal antibody inhibiting IL-4
and IL-13, has been shown to rapidly and substantially improve atopic pruritus,
even in patients with an unsatisfactory cutaneous response. In an analysis of
patients from two randomized trials who were not clear or almost clear
(Investigator's Global Assessment >1) after 16 weeks of treatment with
dupilumab or placebo [60], dupilumab was more effective than placebo in
improving secondary outcome measures, including pruritus (numerical rating
scale -35 versus -9 percent) [61]. (See 'Dupilumab' below.)
An analysis of data from 1505 adult and adolescent patients from four
randomized trials showed that the least squares mean percent change from
baseline of daily Peak Pruritus Numerical Rating Scale scores was
approximately -48 to -57 percent in the dupilumab groups compared with -19 to
-31 percent in the placebo groups. The improvement in the dupilumab groups
occurred by day 2 in adults and day 5 in adolescents and was sustained
through the end of treatment [62].

PATIENTS WITH MILD TO MODERATE DISEASE

Initial treatment — Topically applied corticosteroids and emollients are the

mainstay of therapy for atopic dermatitis (algorithm 1) [2]. The choice of the
corticosteroid potency should be based upon the patient's age, body area
involved, and degree of skin inflammation. Topical calcineurin inhibitors may be
an alternative to topical corticosteroids, in particular for the treatment of the
face, including the eyelids, neck, and skin folds.
Topical corticosteroids — For patients with mild atopic dermatitis, we suggest
a low-potency (groups 5 and 6 (table 1)) corticosteroid cream or ointment
(eg, desonide 0.05%, hydrocortisone 2.5%) (algorithm 1). Topical
corticosteroids are applied one or two times per day for two to four weeks.
Emollients should be liberally used multiple times per day in conjunction with
topical corticosteroids. Emollients can be applied before or after topical
corticosteroids [63]. (See 'Emollients and moisturizers' above.)
For patients with moderate disease, we suggest medium- to high-potency
(groups 3 and 4 (table 1)) corticosteroids
(eg, fluocinolone 0.025%, triamcinolone 0.1%, betamethasone dipropionate
0.05%). In patients with acute flares, super high- or high-potency topical
corticosteroids (groups 1 to 3 (table 1)) can be used for up to two weeks and
then replaced with lower-potency preparations until the lesions resolve.
The face and skin folds are areas that are at high risk for atrophy with
corticosteroids. Initial therapy in these areas should start with a low-potency
steroid (group 6 (table 1)), such as desonide 0.05% ointment. High-potency
topical corticosteroids are generally avoided in skin folds and on the face.
However, limited, brief use (five to seven days) of potent corticosteroids may
produce a rapid response, after which patients can be switched to lower-
potency preparations.
Topical corticosteroid-based ophthalmic solutions can be used for the treatment
of atopic dermatitis involving the ear canal. (See "External otitis: Treatment".)
Maintenance therapy that includes intermittent use of a topical corticosteroid or
a topical calcineurin inhibitor may help prevent relapse. (See 'Maintenance and
prevention of relapses' below.)
Efficacy and adverse effects — A systematic review of randomized trials
identified 83 studies of topical corticosteroids for atopic dermatitis [64]. Although
studies were of poor methodologic quality and short duration (<4 weeks), all
indicated a large therapeutic efficacy of topical corticosteroids compared with
placebo. No clear benefit has been demonstrated with more than once-daily
application [65-67].
Long-term use of topical corticosteroids, especially high- or super high-potency
preparations, on large body areas may lead to adrenal suppression. Other
adverse effects include skin thinning, telangiectasias, folliculitis, and contact
dermatitis. (See "Topical corticosteroids: Use and adverse effects", section on
'Adverse effects'.)
Topical calcineurin inhibitors — Topical calcineurin inhibitors are
nonsteroidal immunomodulating agents that, unlike topical corticosteroids, do
not cause skin atrophy or other corticosteroid adverse effects. They can be
used as an alternative to topical corticosteroids for the treatment of mild to
moderate atopic dermatitis involving the face, including the eyelids, neck, and
skin folds [68,69].
Tacrolimus ointment and pimecrolimus cream are applied twice a day.
Tacrolimus comes in two strengths. The 0.1% formulation is appropriate initial
therapy for adults (and those >15 years old), and the 0.03% formulation is
appropriate for children and for adults who do not tolerate the higher dose. In
patients who do not tolerate tacrolimus because of burning or stinging,
pimecrolimus may be better tolerated.
Both tacrolimus and pimecrolimus topical preparations are approved by the US
Food and Drug Administration (FDA) for use in children over the age of two
years. However, concerns have been raised by the FDA about a possible link to
cancers, in particular lymphoma and skin cancer [70,71]. (See 'Long-term safety
concerns' below.)
Efficacy and minor side effects — Topical tacrolimus is generally recognized
as being equal in strength to medium-potency (groups 4 and 5 (table 1)) topical
steroids and should be considered a second-line therapy [72]. In addition to its
inhibitory effect on cytokine production, topical tacrolimus causes alterations in
epidermal antigen-presenting dendritic cells that may result in decreased
immunologic response to antigens [73]. Pimecrolimus 1% cream is a calcineurin
inhibitor, like tacrolimus, that was developed specifically to treat inflammatory
skin conditions. Although less effective than topical tacrolimus, pimecrolimus
has a mechanism of action similar to topical tacrolimus and does not appear to
have systemic immune effects [74]. Transient burning, erythema, and pruritus
are the most common adverse effects [75].
The efficacy of tacrolimus has been demonstrated in several randomized trials
and systematic reviews [68,76,77]. Tacrolimus ointment, particularly the 0.1%
preparation, may be more effective than pimecrolimus cream, although it may
also cause greater local irritation:
●A meta-analysis of 25 randomized trials including 6897 patients
showed that tacrolimus 0.1% was more effective than vehicle for
the treatment of patients with moderate to severe atopic dermatitis
(44 percent of patients in the tacrolimus group improved by >90
percent versus 20 percent in the vehicle group) [68]. Tacrolimus
was more effective than hydrocortisone acetate and comparable in
efficacy to hydrocortisone butyrate. Pimecrolimus was more
effective than vehicle in the treatment of mild to moderate atopic
dermatitis (33 percent of patients were clear or almost clear at
three weeks versus 10 percent of those who used the vehicle) and
in preventing flares. Pimecrolimus was less effective
than betamethasone valerate, but its potency compared with
hydrocortisone was not evaluated in any of the included trials.
●A subsequent meta-analysis of four randomized trials
comparing tacrolimus with pimecrolimus for the treatment of atopic
dermatitis including more than 1800 patients found that tacrolimus
0.1% ointment was more effective than pimecrolimus 1% cream
after six weeks of therapy in adult patients (relative risk 0.58, 95%
CI 0.46-0.72) [77]. In pediatric patients with moderate to severe
eczema, tacrolimus 0.03% was superior to pimecrolimus 1%
(relative risk 0.65, 95% CI 0.57-0.75). However, in the group of
pediatric patients with mild to moderate eczema, there was no
significant difference between tacrolimus 0.03% and 1%
pimecrolimus.
●In a systematic review of 31 randomized trials, pimecrolimus was
significantly better than vehicle in preventing flares at six months
[78]. However, pimecrolimus was less effective than medium-
potency topical corticosteroids (triamcinolone acetonide 0.1%
and betamethasone valerate 0.1%) and tacrolimus 0.1%.
Long-term safety concerns — Although the topical calcineurin inhibitors in
controlled trials have appeared to be safe in adults and children [75,79-82], in
2005, based upon case reports, animal studies, and the known risks with
systemic calcineurin inhibitors, the FDA issued warnings about a possible link
between the topical calcineurin inhibitors and cancer [83] and, in 2006, placed a
boxed warning on the prescribing information for these medications [84].

Issues of concern include:

●Animal studies in mice, rats, and monkeys have found an

increased risk of lymphoma and skin cancers with topical or oral
exposure to calcineurin inhibitors.
●As of December 2004, the FDA had received 29 reports of
cancers in adults and children treated with topical calcineurin
inhibitors. Approximately half the cases were lymphomas, and the
other half were cutaneous tumors.
●Between January 2004 and January 2009, the FDA received 46
reports of new cancer cases among children 0 to 16 years old who
used topical pimecrolimus and/or topical tacrolimus (30
lymphomas/leukemias, 8 skin cancers, and 8 other cancers).
However, no definite causal relationship has been established [85], and two
case-control studies did not detect an increased risk of lymphoma among
patients treated with topical calcineurin inhibitors [86,87]. The results of
subsequent studies are summarized below:
●The Pediatric Eczema Elective Registry (PEER) is an industry-
sponsored, ongoing cohort study established in 2004, as part of the
postmarketing commitments for the approval of pimecrolimus, to
evaluate the risk of malignancy in children. Among 7500 children
enrolled between 2004 and 2014, five malignancies (two
leukemias, one osteosarcoma, and two lymphomas) were reported
[88]. The standardized incidence ratio, based upon the age-
standardized Surveillance, Epidemiology, and End Results
Program population, was 1.2 (95% CI 0.5-2.8) for all malignancies,
2.9 (95% CI 0.7-11.7) for lymphoma, and 2.0 (95% CI 0.5-8.2) for
leukemia. Although the excess risk of lymphoma and leukemia is
not statistically significant, the authors acknowledge that the small
sample size and the resulting wide confidence interval may not
allow the exclusion of all risk.
●A 2015 meta-analysis did not find a statistically significant
association between the use of topical calcineurin inhibitors and
risk of lymphoma [89], although an included cohort study reported a
fivefold increased risk of T cell lymphoma in patients exposed to
topical tacrolimus (relative risk 5.44, 95% CI 2.51-11.79) [90].
●A European, multicenter, cohort study that included over 147,000
adults and children initiating tacrolimus or pimecrolimus, nearly
600,000 users of topical corticosteroids, and 257,000 untreated
subjects found an increased risk of lymphoma, of borderline
statistical significance, associated with tacrolimus compared with
topical corticosteroids in children but not in adults (incidence rate
ratio [IRR] 3.74, 95% CI 1.00-14.06 and IRR 1.76, 95% CI 0.81-
3.79, respectively) [91].
●A subsequent, international, cohort study of nearly 8000 children
(mean age at enrollment 7.1 years) with atopic dermatitis exposed
to tacrolimus ointment before the age of 16 years did not
 demonstrate an increased incidence of any cancers among
tacrolimus users compared with the general population
(standardized incidence ratio 1, 95% CI 0.37-2.20) [92].
●The risk of keratinocyte carcinoma associated with topical
calcineurin inhibitors was evaluated in a 2020, United States,
cohort study that included over 93,000 patients (mean age at
cohort entry 58.5 years) diagnosed with atopic dermatitis from 2002
to 2013 who received at least two prescriptions for topical
calcineurin inhibitors (n = 7033) or topical corticosteroids (n =
73,674) [93]. A multivariate analysis, adjusted for demographic
variables, immunosuppression, exposure to systemic treatment for
atopic dermatitis, ultraviolet (UV) treatment, and radiation
treatment, did not show an increased risk of either squamous cell
carcinoma or basal cell carcinoma among patients exposed to
topical calcineurin inhibitors compared with those exposed to
topical corticosteroids and unexposed patients (hazard ratio [HR]
1.02, 95% CI 0.93-1.13 and HR 1.03, 95% CI 0.92-1.14,
respectively).
Although most cohort studies do not indicate an increased risk of lymphoma or
other cancers with topical calcineurin inhibitors, the following FDA
recommendations seem reasonable precautions [94,95]:
●Use these agents only as second-line therapy in patients
unresponsive to or intolerant of other treatments.
●Avoid the use of these agents in children <2 years of age.
●Continuous, long-term use of topical calcineurin inhibitors in any
age group should be avoided, and application should be limited to
areas of involvement with atopic dermatitis.
●Avoid the use of these agents in patients with compromised
immune systems.
Providers and patients will need to weigh the risks and benefits of topical
calcineurin inhibitors in comparison with those of other therapies. In particular,
calcineurin inhibitors may continue to have an important role in the
management of atopic dermatitis in areas at high risk for skin atrophy when
treated with corticosteroids (eg, face) [96].
Off-label use in infants — Topical calcineurin inhibitors have been approved in
the United States as second-line therapies for the short and intermittent
treatment of mild to moderate atopic dermatitis in adults and children aged ≥2
years. However, they have been used off-label in children as first-line treatment
for atopic dermatitis and in children <2 years, in the absence of long-term
studies evaluating their efficacy and safety compared with low- or mid-potency
topical corticosteroids [97].
A five-year, industry-sponsored, randomized trial evaluated the safety and long-
term efficacy of pimecrolimus 1% cream compared with low-potency
(1% hydrocortisone) or medium-potency (0.1% hydrocortisone butyrate) topical
corticosteroids in over 2400 infants 3 to 12 months of age with mild to moderate
atopic dermatitis [98]. After five years, overall treatment success, measured by
an investigator global assessment score, was achieved in approximately 89
percent of children in the pimecrolimus group and 92 percent in the topical
corticosteroid group. Vaccine responsiveness, growth, immune function, and
cancer rates were similar in the two groups. The overall rates of adverse events
were also similar in the two groups, although episodes of bronchitis, infected
eczema, impetigo, and nasopharyngitis were slightly more frequent in the
pimecrolimus group than in the topical corticosteroid group.
Since the rates of cutaneous adverse events (eg, skin irritation, atrophy,
telangiectasias) were not reported in this trial, the advantage of
using pimecrolimus rather than low- to mid-potency topical corticosteroids for
infants with mild to moderate atopic dermatitis remains unclear.
Crisaborole — Crisaborole is a boron-based, small molecule, topical
phosphodiesterase 4 (PDE4) inhibitor approved by the FDA for the treatment of
mild to moderate atopic dermatitis in adults and children three months of age
and older [99]. Preliminary studies in adolescents and adults indicated that
crisaborole 2% ointment may improve the clinical signs of atopic dermatitis,
including erythema, excoriation, exudation, lichenification, and, in particular,
pruritus [47,100-102]. Adverse effects of topical crisaborole were mild and
mainly limited to application site reactions (pain, paresthesia). Systemic
exposure to crisaborole has been shown to be limited even after maximal use (3
mg/cm2) [102].
Two subsequent, phase III, multicenter, randomized trials (AD-301 and AD-302)
were performed to assess the efficacy and safety of topical crisaborole in
patients with mild to moderate atopic dermatitis [48]. In these trials, a total of
1522 patients ≥2 years of age were randomized to receive crisaborole 2%
ointment twice daily for 28 days. The primary efficacy endpoint (success) was
defined as an investigator's static global assessment (ISGA) score of 0 (clear)
or 1 (almost clear) with a two-grade or more improvement from baseline. At day
29, more patients in the crisaborole groups than in the vehicle groups achieved
success (32.8 versus 25.4 percent in AD-301 and 31.4 versus 18 percent in AD-
302). Improvement was noted in pruritus, skin inflammation, excoriation, and
lichenification. Crisaborole-related adverse events occurred in 4.4 percent of
patients, were mild, and were limited to burning or stinging at the site of
application.
The long-term safety of crisaborole was evaluated in a 48-week, open-label,
extension study including 517 patients (60 percent children) who had completed
the AD-301 and AD-302 trials without experiencing adverse effects [103].
Patients with an ISGA score ≥2 initiated crisaborole treatment twice daily for 28
days. Participants underwent an average of six treatment periods and used an
average of 133 g of crisaborole ointment per month. Adverse events, of which
86 percent were mild or moderate, occurred in 10 percent of patients. The most
frequently reported adverse events were exacerbation of atopic dermatitis,
burning or stinging in the application site, and application site infection. Diarrhea
or vomiting, side effects observed with oral PDE4 inhibitors, were reported by
approximately 1 to 2 percent of patients throughout the study. Rescue therapy
with topical corticosteroids or topical calcineurin inhibitors was needed by 22
and 26 percent of children and adolescents, respectively, and 13 percent of
adults.
Although crisaborole seems to be generally safe for long-term use, its efficacy
remains uncertain due to the strong placebo effect noted in trials [48,104].
Head-to-head studies comparing crisaborole with established therapies for
atopic dermatitis are needed to better define its role in the management of mild
to moderate atopic dermatitis.
Assessing adherence to topical treatment — Poor adherence to prescribed
topical therapies is a major cause of exacerbation of atopic dermatitis.
Assessing the patient's adherence to topical therapy is thus critical when
evaluating the response to initial treatment and need for additional therapy.
While "steroid phobia" resulting in insufficient use of prescribed topical
corticosteroids is a common cause of treatment failure, the use of inadequate
amounts of emollients needs consideration as an additional obstacle to
treatment success [105-108].
In a Scottish, population-based study that included 844 patients with moderate
to severe atopic dermatitis who failed treatment in a primary care setting, the
analysis of nearly 30,000 verified prescriptions of relevant topical medications
showed significant underuse. The median daily amount of emollients used was
9.6 g in adults and 17.5 g in children, and the median monthly amount of topical
corticosteroids used was 47 g for male patients and 30 g for female patients,
roughly corresponding to an average daily use of 0.5 to 2 g [106].
Maintenance and prevention of relapses — We suggest proactive therapy to
prevent relapse in adolescents and adults with moderate to severe atopic
dermatitis (picture 1A-B) that responds to continuous therapy with topical
corticosteroids or calcineurin inhibitors (algorithm 1). After induction of
remission, we suggest intermittent therapy with moderate- to high-potency
topical corticosteroids (groups 3 to 5) (table 1). The steroid should be applied
once daily to previously affected skin areas for two consecutive days per week
(eg, weekends) and may be continued for up to 16 weeks. Emollients can be
liberally used multiple times per day.
Flares of atopic dermatitis that occur during intermittent treatment may be
treated by resuming continuous use of topical corticosteroids or calcineurin
inhibitors that have been effective for the patient in the past. Similar strategies
for proactive therapy are recommended in multiple national and international
guidelines for the management of atopic dermatitis [2,31,109-111].
In infants and young children with moderate to severe atopic dermatitis (picture
2) who have frequent flares, proactive, intermittent therapy with low-potency
topical corticosteroids (groups 6 and 7 (table 1)) may be beneficial in preventing
relapse [112]. The steroid should be applied once daily to previously affected
skin areas for two consecutive days per week (eg, weekends) and may be
continued for up to 16 weeks. Flares of atopic dermatitis that occur during
intermittent treatment may be treated by resuming continuous use of topical
corticosteroids that have been effective for the patient in the past.
In meta-analyses of randomized trials, proactive, intermittent therapy with
moderate- to high-potency corticosteroids or tacrolimus, after achieving disease
control with continuous use of these agents, was effective in reducing the risk of
subsequent flares [113]. However, there were fewer adverse effects with
corticosteroids, as illustrated below:
●In a meta-analysis of four randomized trials,
topical fluticasone propionate (once daily for two consecutive days
per week for 16 weeks) reduced the risk of a subsequent flare by
54 percent (relative risk 0.46, 95% CI 0.38-0.55) [113]. No serious
adverse events were reported.
●In a meta-analysis of three randomized trials,
topical tacrolimus (once daily two to three days per week for 10 to
12 months) reduced the risk of a subsequent flare by 22 percent
 (relative risk 0.78, 95% CI 0.60-0.78) [113]. Adverse effects
included pruritus, burning sensation, skin infections, and
bronchopneumonia. In addition, four patients developed a cancer.
(See 'Long-term safety concerns' above.)
Treatment of acute exacerbations — In adolescents and adults, an acute
exacerbation of chronic atopic dermatitis can sometimes be aborted by a short
course of systemic glucocorticoids (eg, prednisone 40 to 60 mg/day for three to
four days, then 20 to 30 mg/day for three to four days). To avoid rebound flare,
topical therapy should be resumed while tapering systemic glucocorticoids. This
strategy is not recommended for infants and young children. (See "Major side
effects of systemic glucocorticoids" and "Management of severe atopic
dermatitis (eczema) in children", section on 'Systemic corticosteroids'.)

PATIENTS WITH MODERATE TO SEVERE

DISEASE Patients with persistent, moderate to severe disease despite

optimal topical therapy may require phototherapy or systemic

immunomodulatory therapy to achieve adequate disease control [3,58,114].
(See 'Phototherapy' below and 'Systemic therapies' below.)
Evidence on the efficacy and safety of phototherapy and systemic therapies for
young children is limited. These treatments should be used only when other
management options have failed and the disease has a significant impact on
the quality of life [115]. (See "Management of severe atopic dermatitis (eczema)
in children".)
Phototherapy — Narrowband ultraviolet B (NBUVB), broadband ultraviolet B
(UVB), ultraviolet A1 (UVA1), or psoralens plus ultraviolet A (PUVA) radiation
phototherapy are treatment options for moderate to severe atopic dermatitis
[3,116,117]. (See "UVB therapy (broadband and narrowband)" and "UVA1
phototherapy" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)
We suggest NBUVB phototherapy rather than other forms of phototherapy as
first-line therapy for adult patients with moderate to severe atopic dermatitis that
is not controlled with topical therapy (algorithm 1). Phototherapy is usually
administered two to three times per week. Topical corticosteroids can be
continued as needed during phototherapy. Additional emollients may be
necessary since phototherapy may increase skin dryness.
Phototherapy is not suitable for infants and young children. In older children
and adolescents with atopic dermatitis not controlled with topical therapies,
NBUVB phototherapy may be a therapeutic option, if available. However, the
benefits of phototherapy must be weighed against potential adverse effects.
(See "Management of severe atopic dermatitis (eczema) in children", section on
'Phototherapy'.)
Phototherapy for the treatment of moderate to severe atopic dermatitis has
been evaluated in a limited number of randomized trials and systematic
reviews. In a 2013 systematic review of 19 randomized trials including 905
patients, medium-dose UVA1 (30 to 60 J/cm2) and NBUVB were more effective
than other phototherapy modalities in reducing the clinical signs and symptoms
of atopic dermatitis as measured with several clinical scores [51].
Disadvantages of phototherapy include cost and need for multiple office visits
per week. Moreover, prolonged treatment may lead to an increased risk of
melanoma and nonmelanoma skin cancer [118-120].
Systemic therapies — Several systematic reviews and meta-analyses have
evaluated the efficacy of systemic therapies for atopic dermatitis [121-123]:
●A network meta-analysis of 74 randomized trials with over 8000
participants indicated, with a high degree of certainty, dupilumab as
the most effective treatment in achieving a 75 percent reduction in
the Eczema Area and Severity Index (EASI-75) score and
improving the Patient-Oriented Eczema Measure (POEM) score
during short-term follow-up when compared with placebo (risk ratio
[RR] 3.04, 95% CI 2.51-3.69 and mean difference 7.3, 95% CI
6.61-8.00, respectively) [121]. Dupilumab was also ranked first
among other investigational and noninvestigational biologics in
terms of achieving EASI-75 and improving POEM scores during
short-term follow-up. However, due to the lack of comparative data,
the ranking of conventional immunosuppressive treatments for
efficacy, compared with dupilumab and other biologic agents,
remained uncertain.
●Another network meta-analysis of 39 randomized trials (6360
patients) indicated that higher-dose cyclosporine (3 to 5 mg/kg per
day) and dupilumab (600 mg as first dose, then 300 mg every two
weeks) were similarly effective compared with placebo in clearing
the clinical signs of atopic dermatitis and may be superior
to methotrexate and azathioprine [122].
Impact of COVID-19 pandemic — The coronavirus disease 2019 (COVID-19)
pandemic has led medical professional organizations, including the American
Academy of Dermatology, to issue provisional guidelines regarding the use of
systemic immunomodulatory drugs and biologic agents during the pandemic
[124-126]. General information on the use of systemic immunomodulatory
therapies during the COVID-19 pandemic is provided elsewhere. (See "COVID-
19: Management in hospitalized adults", section on 'Immunomodulatory
agents'.)
Dupilumab — We suggest dupilumab, rather than conventional
immunosuppressant agents, for patients with moderate to severe disease
unresponsive to topical therapy alone for whom phototherapy is not feasible or
acceptable. Dupilumab is also an option for patients who are not candidates for
or failed previous treatment with conventional immunosuppressive agents, such
as cyclosporine, methotrexate, mycophenolate mofetil, or azathioprine.
Compared with conventional immunosuppressive agents, dupilumab has a
favorable safety profile and may be used for long-term treatment of atopic
dermatitis [127,128]. However, cost may be a major consideration with
dupilumab.
Dupilumab is administered as subcutaneous injections two weeks apart. In
adults, an initial dose of 600 mg is followed by a maintenance dose of 300 mg
every other week. In children ≥6 years and in adolescents, dosing is based on
body weight. For patients <60 kg, the initial dose is 400 mg, followed by a
maintenance dose of 200 mg every other week; for patients ≥60 kg, the initial
dose is 600 mg, followed by a maintenance dose of 300 mg every other week.
Topical corticosteroids are usually continued as needed during treatment
with dupilumab.
Efficacy and adverse effects — Dupilumab is a fully human monoclonal
antibody that binds to the alpha subunit of the interleukin (IL) 4 receptor and
inhibits downstream signaling of IL-4 and IL-13, cytokines of type 2 helper T
lymphocytes (Th2) that are believed to play a key role in atopic diseases,
including asthma and atopic dermatitis. Multiple randomized trials in adults and
children have documented its efficacy in the treatment of moderate to severe
atopic dermatitis.
Studies in adults — The efficacy of dupilumab for the treatment of atopic
dermatitis in adults has been evaluated in several randomized trials,
prospective cohort studies, and meta-analyses:
●Dupilumab 300 mg or placebo given by subcutaneous injection
weekly or every other week was evaluated in two phase III trials of
identical design, SOLO1 and SOLO2, which included 671 and 708
adult patients with long-standing, moderate to severe atopic
dermatitis not controlled by topical treatments, respectively [60]. At
16 weeks, more patients in the dupilumab groups than in the
placebo groups achieved the primary endpoint of an Investigator's
Global Assessment (IGA) score of clear or almost clear
(approximately 40 versus 10 percent). There were no differences
between trials and between weekly or biweekly dupilumab
regimens. An EASI-75 score was achieved by 44 to 52 percent of
patients receiving dupilumab versus 12 to 15 percent of those
receiving placebo. Rescue treatment was required in approximately
50 percent of patients receiving placebo and 15 to 20 percent of
those receiving dupilumab. Serious adverse events were rare in all
groups; however, injection site reactions and conjunctivitis occurred
more frequently in the dupilumab groups than in the placebo group.
Exacerbation of atopic dermatitis was reported overall in three
patients receiving dupilumab and in eight patients receiving
placebo.
●Of note, in an analysis of patients from the two trials described
above who were not clear or almost clear (IGA >1) at week 16
[60], dupilumab, compared with placebo, induced a greater
improvement in secondary outcome measures, including
pruritus (numerical rating scale -35 versus -9 percent) and quality
of life (Dermatology Life Quality Index [DLQI] score ≥4-point
improvement 59 versus 24 percent) [61].
●The long-term efficacy and safety of dupilumab was subsequently
evaluated in a randomized, double-blind, multicenter trial (LIBERTY
AD CHRONOS) [127]. In this study, 740 patients were treated with
dupilumab 300 mg once weekly, dupilumab 300 mg every two
weeks, or placebo for 52 weeks. All patients received concurrent
treatment with topical corticosteroids (or topical calcineurin
inhibitors, if indicated) and were allowed to receive rescue
treatments (topical or systemic medications or phototherapy) after
two weeks of dupilumab. The two coprimary endpoints were the
 proportion of patients with both an IGA score of 0/1 (clear/almost
clear), or a two-point or higher reduction from baseline at week 52,
and the proportion of patients achieving EASI-75 from baseline to
week 52. At week 52, more patients in the dupilumab plus topical
corticosteroids groups achieved the IGA endpoint and EASI-75
compared with those receiving placebo plus topical corticosteroids
(approximately 40 versus 13 percent, and 65 versus 22 percent,
respectively). The rates of adverse events were similar in the three
groups (83 to 88 percent); however, patients in the dupilumab
groups experienced an approximately twofold higher frequency of
eye disorders and noninfectious conjunctivitis.
●An open-label, extension study including patients enrolled in
previous randomized trials who continued treatment
with dupilumab 300 mg weekly confirmed a sustained efficacy of
dupilumab over time, with more than 60 percent of patients
achieving a 90 percent reduction in the Eczema Area and Severity
Index (EASI-90) score at 56 and 76 weeks [128]. Approximately 50
percent of patients received additional treatment with topical
corticosteroids (44 percent) and topical calcineurin inhibitors (13
percent). Four percent of patients required rescue systemic
therapy.
●In a study evaluating the efficacy of dupilumab in 138 consecutive
adult patients with difficult-to-treat atopic dermatitis in a real-life
setting, treatment with dupilumab for 16 weeks induced a mean
reduction of the EASI score of 73 percent [129]. A 50 percent
reduction in the Eczema Area and Severity Index (EASI-50) score,
EASI-75, and EASI-90 were achieved by 86, 62, and 24 percent of
patients, respectively. Improvement also occurred in patient-
reported outcomes, including POEM score, pruritus, and quality of
life. The most frequent adverse effects were conjunctivitis and eye
irritation in 34 and 25 percent of patients, respectively.
Studies in children and adolescents — Studies of dupilumab in children and
adolescents with atopic dermatitis are limited [130-132]:
●In a phase III, randomized trial, 251 adolescents aged 12 to 18
years with moderate to severe atopic dermatitis were treated
with dupilumab 200 or 300 mg every two weeks, dupilumab 300 mg
every four weeks, or placebo for 16 weeks [130]. Most participants
had associated comorbidities, including allergic rhinitis (66
percent), asthma (54 percent), and food allergy (61 percent), The
coprimary endpoints (proportion of patients with ≥75 percent
improvement from baseline in the EASI and an IGA score of 0/1
[clear or almost clear]) were achieved by a higher proportion of
patients in both the every-two-weeks and every-four-weeks groups
compared with the placebo group (EASI-75: 42, 38, and 8 percent,
respectively; IGA 0/1: 24, 18, and 2 percent, respectively). The
most common adverse events were atopic dermatitis, skin
infection, upper respiratory infection, and conjunctivitis. The last
was more frequent in the dupilumab groups than in the placebo
group (10 to 11 versus 5 percent).
 ●A 16-week, phase III, randomized trial examined the efficacy and
safety of dupilumab plus topical corticosteroids in children [132]. In
this study, 367 children aged 6 to 11 years with severe atopic
dermatitis inadequately controlled with topical medications were
treated with dupilumab 300 mg every four weeks, a weight-based
regimen of 100 to 200 mg every two weeks, or placebo, in
combination with a medium-potency topical corticosteroid. More
patients in the dupilumab 300 mg and 100 or 200 mg groups than
in the placebo group achieved the coprimary endpoints (IGA score
of 0 to 1 or EASI-75) at week 16 (33, 30, and 11 percent; and 67,
70, and 27 percent, respectively). Adverse events occurred in 73
percent of patients in the placebo group and 65 to 67 percent in the
dupilumab groups. Injection site reactions and conjunctivitis were
more common with dupilumab; severe reactions leading to
treatment discontinuation occurred in two patients in the placebo
group (asthma and exacerbation of atopic dermatitis) and in two
patients in the dupilumab groups (food allergy and urinary tract
infection).
Dupilumab facial redness — Exacerbation or new onset of head and neck
dermatitis ("dupilumab facial redness") has been reported in approximately 4 to
10 percent of adult patients treated with dupilumab after a median time of 65
days after initiating dupilumab [133-135]. This reaction has also been reported
in children and adolescents treated with dupilumab [136,137].
The pathogenesis of the dupilumab-induced head and neck dermatitis is
unclear. It may represent a hypersensitivity reaction, a site-specific treatment
failure, a seborrheic dermatitis-like or rosacea-like reaction, or an allergic
contact dermatitis [135].
Topical corticosteroids, topical calcineurin inhibitors, and topical and systemic
antifungals have been used in a few patients with dupilumab facial redness with
variable results [134,135,138]. No worsening or progression to a generalized
reaction has been noted upon continuation of dupilumab therapy.
Cyclosporine — Oral cyclosporine is a short-term treatment option for patients
with moderate to severe atopic dermatitis (algorithm 1) [58,114]. Cyclosporine is
typically given at a dose of 3 to 5 mg/kg per day in two divided doses for four to
eight weeks or longer, until improvement is noted. The dose is then lowered to
the minimum effective dose and maintained until stable improvement is
achieved. After cyclosporine withdrawal, treatment with topical corticosteroids
and emollients can be continued. (See 'Initial treatment' above
and 'Maintenance and prevention of relapses' above.)
Oral cyclosporine is not recommended in infants and young children with atopic
dermatitis. In older children and adolescents, the use of cyclosporine should be
reserved for the most severe cases that failed to respond to optimal topical
treatment and where there is a significant, negative impact on quality of life.
(See "Management of severe atopic dermatitis (eczema) in children", section on
'Cyclosporine'.)
Efficacy and adverse effects — The efficacy of oral cyclosporine for the
treatment of atopic dermatitis has been evaluated in randomized trials and
systematic reviews. In a 2013 systematic review of 34 randomized trials
including 1653 patients with moderate to severe atopic dermatitis, cyclosporine
was more effective than placebo in five trials, with a mean improvement of 50 to
95 percent in different clinical severity scores after short-term treatment (10
days to 8 weeks) [58]. In head-to-head trials, cyclosporine was more effective
than prednisolone, intravenous immunoglobulins, and phototherapy with
ultraviolet A (UVA)/UVB. Higher doses (5 mg/kg per day) lead to a more rapid
response than lower doses (2.5 to 3 mg/kg).
Side effects of cyclosporine include nephrotoxicity, hypertension, hypertrichosis,
gum hyperplasia, and increased susceptibility to serious infections. Monitoring
of patients receiving cyclosporine includes measuring blood pressure and
serum creatinine every two weeks for three months, followed by monthly
monitoring. Significant elevations of either are an indication to lower the dose or
stop treatment. (See "Pharmacology of cyclosporine and tacrolimus".)
Methotrexate — Methotrexate is a treatment option for the long-term control of
moderate to severe atopic dermatitis in adults and, less frequently, in
adolescents and children [139]. In adults and adolescents, methotrexate is
usually administered in a single weekly dose of 7.5 to 25 mg in combination with
daily supplementation with folic acid 1 mg to reduce the risk of several common
methotrexate toxicities. Methotrexate has a slow onset of action, and benefit
may not be noted in the first few months of treatment.
The use and dosing of methotrexate in children with severe atopic dermatitis is
discussed separately. (See "Management of severe atopic dermatitis (eczema)
in children", section on 'Methotrexate'.)
Efficacy and adverse effects — There is limited, high-quality evidence for the
use of methotrexate for the treatment of atopic dermatitis [139-142].
In an open-label, follow-up study that included 35 of 43 adult participants of a
randomized trial comparing methotrexate and azathioprine for the treatment of
moderate to severe atopic dermatitis, both agents were equally effective in
reducing the Scoring of Atopic Dermatitis (SCORAD) score at five years [141].
Viral respiratory infections were the most common adverse events in both
treatment groups. Serious adverse events requiring hospitalization occurred in 7
of 14 patients in the methotrexate group and 1 of 11 patients in the azathioprine
group and included pneumonia, myocardial infarction, surgical wound abscess,
bladder carcinoma, and exacerbation of atopic dermatitis.
In a randomized trial comparing oral methotrexate 15 mg per week
with cyclosporine 2.5 mg/kg per day in 97 adult patients with moderate to
severe atopic dermatitis, more patients in the cyclosporine group than in the
methotrexate group achieved the primary endpoint of a 50 percent reduction of
SCORAD at eight weeks (42 versus 8 percent, respectively) [140].
Common adverse effects of methotrexate include nausea and stomach upset,
increased liver enzyme levels, headache, fatigue, and malaise. Periodic routine
laboratory testing, including complete blood count and liver function, is required
to monitor hematologic toxicity and hepatotoxicity. (See "Major side effects of
low-dose methotrexate".)
Other immunosuppressive agents — Second-line systemic
immunosuppressive agents for the long-term treatment of atopic dermatitis
include azathioprine and mycophenolate mofetil. Their use in children and
adults with severe atopic dermatitis is discussed in detail separately.
(See "Management of severe atopic dermatitis (eczema) in
children" and "Evaluation and management of severe refractory atopic
dermatitis (eczema) in adults".)
 PATIENTS WITH SEVERE REFRACTORY DISEASE The

management of severe refractory atopic dermatitis in children and adults is

discussed separately. (See "Management of severe atopic dermatitis (eczema)
in children" and "Evaluation and management of severe refractory atopic
dermatitis (eczema) in adults".)

PREGNANT WOMEN The management of atopic dermatitis during

pregnancy is discussed separately [143]. (See "Recognition and management

of allergic disease during pregnancy" and "Recognition and management of
allergic disease during pregnancy", section on 'Atopic
dermatitis' and "Dermatoses of pregnancy", section on 'Atopic eruption of
pregnancy'.)

MANAGEMENT OF INFECTION Patients with atopic dermatitis

are at increased risk for cutaneous bacterial, viral, and fungal infections. Clinical
signs of bacterial superinfection, most often from S. aureus, include weeping,
pustules (picture 3), honey-colored crusting (picture 4), worsening of dermatitis,
or failure to respond to therapy. The presence of vesicles and punched-out
erosions may be a sign of eczema herpeticum.
Staphylococcus aureus — S. aureus is a frequent skin colonizer in patients
with atopic dermatitis. A meta-analysis of 95 observational studies found that 70
percent of patients with atopic dermatitis carried S. aureus on lesional skin
(95% CI 66-74) and 39 percent on nonlesional skin (95% CI 31-47) [144].
However, in patients without frank clinical infection, the role of staphylococcal
colonization in driving the disease severity is still unclear, although multiple lines
of evidence indicate that a relationship between heavy colonization and eczema
severity does exist [145]. An analysis of data from studies including patients
with mild or severe atopic dermatitis found a pooled colonization rate of 43
percent (95% CI 31-57) in patients with mild atopic dermatitis compared with 83
percent (95% CI 74-89) in those with severe atopic dermatitis [144].
Clinically infected skin — Because of the universal skin colonization with S.
aureus in patients with atopic dermatitis, routine skin swabs for bacteriologic
culture are not recommended. However, skin and nasal swabs may be useful
for recurrent infection, for infection that does not respond to treatment, or if
there is concern about antimicrobial resistance or clinical suspicion of unusual
organisms [146].
For patients with localized clinical infection, we suggest topical mupirocin.
Mupirocin 2% cream is applied twice a day for one to two weeks. A prolonged
use of topical antibiotics should be avoided because of the risk of inducing
bacterial resistance. For patients with more extensive infection, we suggest oral
antibiotic therapy with cephalosporins or penicillinase-resistant penicillins [109].
Oral antibiotics are given for two weeks. (See "Impetigo", section on
'Treatment'.)
Clinically uninfected skin — Multiple observations indicate that in patients
with atopic dermatitis without frank clinical infection there is a relationship
between the epidermal density of S. aureus and eczema severity or flare
frequency [147-149]. Since sodium hypochlorite 6% solution (liquid chlorine
bleach) has activity against S. aureus, including methicillin-
resistant Staphylococcus aureus (MRSA), diluted bleach baths (obtained by
adding 0.5 cup or 120 mL of 6% bleach in a full bathtub [40 gallons or 150 L] of
lukewarm water, or one-half of a teaspoon of bleach in one gallon or four liters
of lukewarm water) have been suggested as an adjunct to topical treatment
between episodes of clinical infection to reduce the cutaneous load of S.
aureus and improve symptoms [150].
However, studies evaluating the efficacy of bleach baths for atopic dermatitis
have been scarce and inconsistent [151-153]. A meta-analysis of four small,
randomized trials (116 participants) found that bleach baths were not more
effective than plain water baths at four weeks in decreasing the severity of
atopic dermatitis as assessed by the Eczema Area and Severity Index (EASI)
and by the body surface area involved [154]. Emollients and topical
corticosteroids were permitted in all studies. Three of the four included studies
also found a decrease in S. aureus density after both bleach and normal baths,
without a significant difference between groups. Moreover, one of the included
trials found that the addition of bleach baths to topical corticosteroids was not
more effective than corticosteroids alone in reducing the skin colonization in
children with moderate to severe atopic dermatitis [155].
The results of this meta-analysis indicate that bathing per se (with or without
bleach) may be effective in reducing the skin colonization from S. aureus and
improving symptoms. However, since bleach baths are inexpensive, well
tolerated, and devoid of adverse effects, we continue to suggest their use in
patients with atopic dermatitis and frequent flares of clinically infected eczema.
The efficacy of other topical antiseptics or oral or topical antibiotics in improving
the severity of dermatitis is uncertain. A systematic review found insufficient
evidence to recommend the use of oral antibiotics for the treatment of atopic
dermatitis in the absence of clinical infection [156,157]. The same review found
that topical antibiotics or antiseptics reduced colonization with S. aureus in
patients with atopic dermatitis but could not conclude that treatment with these
agents in combination with topical corticosteroids induced greater clinical
improvement than topical corticosteroids alone. However, the systematic review
was primarily based on poor-quality studies and cannot definitively discount
antimicrobial therapies for patients without overt infection.
Viral infections — Atopic dermatitis patients with lesions that are infected with
herpes simplex (called eczema herpeticum or Kaposi's varicelliform eruption)
should be treated immediately with oral antiviral therapy. Examination reveals
skin with punched-out erosions, hemorrhagic crusts, and/or vesicles (picture
5A-C). Involved skin may be pruritic or painful, and lesions may be widespread.
The diagnosis should be considered in patients who fail to respond to oral
antibiotics [158]. Cases of life-threatening dissemination have been reported,
and intravenous antiviral therapy may be necessary in severe cases [158].
(See "Treatment and prevention of herpes simplex virus type 1 in
immunocompetent adolescents and adults".)
Patients with atopic dermatitis may also develop widespread molluscum
contagiosum infections (picture 6). (See "Molluscum contagiosum".)
Fungal infections — Dermatophyte infections are more common in patients
with atopic dermatitis and can be treated with standard regimens of topical or
oral antifungals. (See "Dermatophyte (tinea) infections".)
In addition, the Malassezia furfur yeast (a normal component of skin flora) may
be an exacerbating factor in patients with head/neck atopic dermatitis [159].
Elevated Malassezia-specific IgE levels have been reported in these patients
[159]. Treatment may result in improvement. (See "Role of allergy in atopic
dermatitis (eczema)", section on 'Malassezia'.)

IMMUNOTHERAPY Allergen-specific immunotherapy (SIT) with dust

mite extract in sensitized patients with atopic dermatitis has been studied using
both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy
(SLIT) administration with conflicting results [160-163]. A meta-analysis of eight
randomized trials including 385 patients that compared SIT (mostly using house
dust mite allergens) with placebo found that patients in the SIT group were
more likely to experience treatment success, as assessed by patients or
investigators, than those in the placebo group (odds ratio [OR] 5.35, 95% CI
1.61-17.77) [164]. However, there was considerable heterogeneity among
studies regarding types, doses, and pharmaceutical preparations of allergens;
treatment schedules and duration; patients' age and disease severity; and
assessment of outcome. Although this meta-analysis suggests that SIT
improves the course of atopic eczema, it is unclear which patients may benefit
from this form of treatment. SIT may be a treatment option for patients with
proven sensitization to house dust mites (eg, positive allergen-specific test,
exacerbation upon natural exposure to the allergen) and severe eczema that is
not controlled with conventional therapies [165]. (See "Subcutaneous
immunotherapy (SCIT) for allergic disease: Indications and efficacy".)

EXPERIMENTAL AGENTS

JAK inhibitors — Tofacitinib and baricitinib are oral small-molecule Janus

kinase (JAK) inhibitors approved for the treatment of rheumatoid arthritis that
block multiple cytokine signaling, including interleukin (IL) 4, IL-5, and IL-13,
involved in immune response and inflammation. Tofacitinib, baricitinib, and
other JAK inhibitors are being investigated for the treatment of atopic dermatitis:
●Topical tofacitinib − The efficacy of topical tofacitinib for the
treatment of atopic dermatitis has been evaluated in a phase IIa,
randomized trial [166]. In this study, 69 adult patients with clinically
stable, mild to moderate atopic dermatitis were treated with
tofacitinib 2% ointment or placebo twice daily for four weeks. The
primary endpoint was the percentage change from baseline in the
Eczema Area and Severity Index (EASI). At week 4, the mean
percentage change from baseline in the EASI score was
significantly greater in patients treated with topical tofacitinib than in
those treated with placebo (-82 and -30 percent, respectively).
Moreover, the proportion of patients with a physician general
assessment score of clear or almost clear was higher in the
tofacitinib group than in the placebo group (73 versus 22 percent).
Adverse effects, including infection, increased blood creatine
phosphokinase, and contact dermatitis, were mild and occurred in
31 percent of patients treated with tofacitinib and 60 percent of
those treated with placebo.
●Abrocitinib − Abrocitinib, an oral JAK-1 selective inhibitor, has
been investigated for the treatment of atopic dermatitis in adults
and adolescents [167,168]:
•In a phase III, randomized trial, 387 patients aged 12 years or
older with moderate to severe atopic dermatitis received oral
abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily
for 12 weeks [167]. At 12 weeks, more patients in the
abrocitinib 100 and 200 mg groups than in the placebo group
achieved the Investigator's Global Assessment (IGA) of clear
or almost clear (24, 44, and 8 percent, respectively) and a 75
percent reduction in the Eczema Area and Severity Index
(EASI-75) response (40, 63, and 12 percent, respectively).
Adverse events, including exacerbation of atopic dermatitis,
nasopharyngitis, nausea, and headache, were reported in 69
and 78 percent of patients in the 100 and 200 mg abrocitinib
groups, respectively, and in 57 percent of patients in the
placebo group.
•In a 12-week, phase III, randomized trial, 838 adult patients
with atopic dermatitis unresponsive to topical treatments were
randomized to receive abrocitinib 200 mg daily, abrocitinib 100
mg daily, dupilumab 300 mg subcutaneously every other week
(after a loading dose of 600 mg), or placebo [169]. All patients
also received topical therapy. An IGA response of clear or
almost clear at week 12 was observed in 48, 37, 37, and 14
percent of participants in the 200 mg abrocitinib group, 100 mg
abrocitinib group, dupilumab group, and placebo group,
respectively. An EASI-75 response at week 12 was observed
in 70, 59, 58, and 27 percent of participants, respectively. The
overall rate of adverse events was higher in the 200 mg
abrocitinib group than in the other groups; the most frequent
were nausea, acne, and conjunctivitis.
●Baricitinib – In a 16-week, phase II, randomized trial that included
124 adults with moderate to severe atopic dermatitis, more patients
treated with baricitinib 4 mg per day plus topical corticosteroids
achieved a 50 percent reduction in the Eczema Area and Severity
Index (EASI-50) score from baseline compared with placebo (61
versus 37 percent) [170]. Baricitinib also improved pruritus and
sleep. Adverse events related to baricitinib included headache,
increased blood levels or creatine phosphokinase, decrease in the
neutrophil count, and nasopharyngitis.
In two subsequent, 16-week, phase III trials (BREEZE-AD1 and
BREEZE-AD2) including a total of 1239 adults with moderate to
severe atopic dermatitis, more patients treated with baricitinib 2 mg
and 4 mg per day monotherapy achieved a validated IGA score of
0/1 (clear or almost clear) compared with placebo (11.4, 16.8, and
 4.8 percent for baricitinib 2 mg, baricitinib 4 mg, and placebo,
respectively, in BREEZE-AD1; 10.6, 13.8, and 4.5 percent for
baricitinib 2 mg, baricitinib 4 mg, and placebo, respectively, in
BREEZE-AD2) [171]. Adverse events occurred in approximately 60
percent of patients in all groups; the most frequent adverse events
reported in the baricitinib groups were nasopharyngitis and
headache.  
●Upadacitinib − A 16-week, randomized trial evaluated the
efficacy of the selective JAK-1 inhibitor upadacitinib given orally at
the dose of 7.5, 15, or 30 mg or placebo in 167 patients with
moderate to severe atopic dermatitis [172]. The percentage
improvement of EASI from baseline was 39, 62, and 74 percent for
the upadacitinib 7.5, 15, and 30 mg groups, respectively, versus 23
percent for the placebo group. Adverse events occurred in 71 to 79
percent of patients in the upadacitinib groups and 63 percent in the
placebo group and included respiratory infections, worsening of
atopic dermatitis, and acne.

Although topical and oral JAK inhibitors seem to be promising treatments for
atopic dermatitis, larger studies of longer durations are needed to evaluate their
long-term efficacy and safety.

Anti-IL-31 antibodies (nemolizumab) — Nemolizumab is a humanized

monoclonal antibody against the receptor A of IL-31, a newly discovered
cytokine associated with chronic skin inflammation and pruritus [173]. Several
studies indicated that nemolizumab may be effective in controlling pruritus
associated with atopic dermatitis [174-176]:
●A phase II, 12-week, randomized trial evaluated the efficacy of
nemolizumab for the treatment of adult patients with moderate to
severe atopic dermatitis not controlled by topical corticosteroids or
topical calcineurin inhibitors [175]. In this study, 264 patients
received subcutaneous nemolizumab at a dose of 0.1, 0.5, or 2 mg
per kilogram of body weight or placebo every four weeks or
nemolizumab at a dose of 2 mg per kilogram every eight weeks
with placebo given at week 4. The primary outcome was the
percentage improvement from baseline in the score on the pruritus
visual analogue scale. At 12 weeks, pruritus was reduced by 44,
60, and 63 percent in the 0.1, 0.5, and 2 mg groups, respectively,
versus 21 percent in the placebo group. The body surface area
affected by atopic dermatitis decreased by 8, 20, and 19 percent in
the 0.1, 0.5, and 2 mg groups, respectively, compared with 16
percent in the placebo group. Adverse events occurred in
approximately 70 percent of patients in all study groups and were
generally mild, with the most frequent being exacerbation of atopic
dermatitis and respiratory tract infections.
●The efficacy of nemolizumab in reducing pruritus associated with
atopic dermatitis was confirmed in a subsequent Japanese
randomized trial that included 215 patients aged 13 years or older
with atopic dermatitis and moderate to severe pruritus [176].
Patients received subcutaneous nemolizumab 60 mg or placebo
every four weeks for 16 weeks, plus topical therapy for atopic
 dermatitis (eg, medium-potency topical glucocorticoids, topical
calcineurin inhibitors). At week 16, the least squares mean of the
pruritus visual analogue scale score (primary endpoint) was
reduced by 43 percent in the nemolizumab group compared with 21
percent in the placebo group. Adverse events occurred in 71
percent of patients in both groups and were generally mild. In the
nemolizumab group, four treatment-related adverse events
occurred in three patients (atopic dermatitis exacerbation,
Meniere's disease, alopecia, and peripheral edema).

Although nemolizumab appears to be a promising agent for the treatment of

pruritus associated with atopic dermatitis and the interruption of the itch-scratch
cycle, larger studies of longer durations are needed to evaluate its long-term
efficacy and safety.

Anti-IL-13 antibodies — Lebrikizumab is a monoclonal antibody that binds

specifically to soluble IL-13, a pleiotropic T helper 2 cytokine that is likely to play
a role in the pathogenesis of barrier dysfunction and inflammation in atopic
dermatitis, asthma, and pulmonary fibrosis [177]. Lebrikizumab has been
investigated for the treatment of asthma with inconsistent results [178-180].
In a proof-of-concept, phase II, multicenter, randomized trial, 209 patients with
moderate to severe atopic dermatitis received subcutaneous injections of
lebrikizumab 125 or 250 mg (single dose), or 125 mg or placebo every four
weeks as an add-on to topical corticosteroid treatment [181]. At 12 weeks, more
patients in the lebrikizumab 125 mg every four weeks group achieved the
primary endpoint (EASI-50) compared with the placebo group (82 versus 62
percent). Lebrikizumab was generally well tolerated; nonsevere infection was
the most common adverse event and occurred with similar frequency in all
groups.
In a phase II, randomized trial, 280 adult patients with moderate to severe
atopic dermatitis were treated with lebrikizumab 125 mg every four weeks, 250
mg every four weeks, 250 mg every two weeks, or placebo every two weeks for
16 weeks [182]. Rescue therapy with topical corticosteroids was allowed.
Compared with placebo, all lebrikizumab groups showed a dose-dependent,
statistically significant reduction in the EASI score at week 16. Common
adverse effects in the lebrikizumab groups included upper respiratory tract
infection, nasopharyngitis, headache, injection site pain, and fatigue.

The results of these studies indicate that lebrikizumab in combination with

topical corticosteroids may provide some additional benefit compared with
topical corticosteroids alone; however, its efficacy as long-term monotherapy for
atopic dermatitis needs further confirmation.

Anti-IL-22 antibodies — A small, phase II, randomized trial evaluated the

efficacy and safety of intravenous fezakinumab, an IL-22 antagonist, for the
treatment of atopic dermatitis [183]. Sixty adult patients with at least a six-month
history of moderate to severe atopic dermatitis received fezakinumab (a loading
dose of 600 mg at baseline, followed by 300 mg every two weeks) or placebo
for 12 weeks and were followed for 8 additional weeks. At 12 and 20 weeks, the
mean Scoring of Atopic Dermatitis (SCORAD) score decrease from baseline
was greater in the fezakinumab group than in the placebo group (13.8 and 18.8
points, respectively, in the fezakinumab group versus 8 and 11.7 points,
respectively, in the placebo group). Adverse events occurred with similar
frequency in the active treatment and placebo groups and were considered mild
to moderate.

UNPROVEN THERAPIES

Complementary and alternative therapies

Probiotics — Probiotic therapy with Lactobacillus and other organisms has
been studied for the treatment of atopic dermatitis in infants and children but
has proven to be of limited benefit [184-188]. In a 2009 meta-analysis of 12
randomized trials including 781 participants, probiotics were not more effective
than placebo in reducing eczema symptoms and sleep disturbance [187]. In
addition, the use of probiotics did not reduce the need for other treatments,
such as topical corticosteroids. A subsequent meta-analysis of 25 randomized
trials including 1600 participants found that probiotics were associated with a
modest, clinically insignificant reduction of the baseline Scoring of Atopic
Dermatitis (SCORAD) score (-4.5, 95% CI -6.8 to -2.2) [189].
A 2018 systematic review of 39 randomized trials (2599 participants) evaluated
the efficacy of oral live probiotics or placebo for the treatment of adults and
children with mild to severe eczema [190]. The probiotics used were bacteria of
the Lactobacillus and Bifidobacteria species taken alone or in combination with
other probiotics for a period of four weeks to six months. A pooled analysis did
not show a difference between probiotics and placebo in participant- or parent-
rated severity of atopic dermatitis (mean difference in SCORAD part C [pruritus
plus sleep loss] score at the end of treatment -0.44, 95% CI -1.22 to 0.33) or
quality of life. Similarly, no difference between treatments was noted when
using clinician-rated disease severity (mean difference in SCORAD part A/B
[eczema extent and intensity] -2.24, 95% CI -4.69 to 0.20). An analysis using
the total SCORAD score suggested only a modest reduction in eczema severity
of uncertain clinical significance (mean difference -3.91, 95% CI -5.86 to -1.96)
in patients taking probiotics compared with placebo. (See "Prebiotics and
probiotics for treatment of allergic disease".)
Dietary supplements — Dietary supplements, including vitamins, fish oil, and
plant-derived essential fatty acids, do not appear to be beneficial for the
treatment of atopic dermatitis [191-193]. Evening primrose oil and borage oil,
which are rich in the essential fatty acid gamma-linolenic acid, have been widely
used for the treatment of atopic dermatitis as a complementary and alternative
medicine remedy [194,195]. However, studies of supplementation of gamma-
linolenic acid for eczema have provided conflicting results [196]. A meta-
analysis of 19 randomized trials of evening primrose oil for the treatment of
eczema in children and adults did not find a significant difference in global
eczema symptoms (assessed by both the participants and clinicians) between
the active treatment and the placebo groups [193].
Melatonin — Melatonin is a hormone produced in the pineal gland involved in
the regulation of sleep and circadian rhythms (see "Physiology and available
preparations of melatonin"). It has also been suggested that melatonin has
antioxidant, anti-inflammatory, and immunomodulating properties [197,198]. In
children and adults with atopic dermatitis, abnormal melatonin levels have been
correlated with disease severity and degree of sleep disturbance [199-201].
In two small, randomized trials, melatonin supplementation reduced disease
severity and improved sleep in children and adolescents with atopic dermatitis
[202,203]:
●In a crossover trial, 48 children with atopic dermatitis involving >5
percent of the body surface area and a history of sleep disturbance
interfering with daytime activities more than three days per week in
the previous three months were treated with oral melatonin 3 mg
per day or placebo at bedtime for four weeks and then, after a
washout period of two weeks, were switched to the alternate
treatment for an additional four weeks [202]. Compared with
placebo, melatonin was associated with a greater decrease from
the baseline in the total SCORAD score (-9.9 versus -0.7 points)
and a greater decrease of the sleep-onset latency time (-23 versus
-1.2 minutes). No adverse effects were reported.
●Similar results were provided by another randomized trial including
70 children of 6 to 12 years of age with atopic dermatitis who
received oral melatonin 6 mg or placebo an hour before bedtime for
six weeks, while continuing their usual treatment with topical
corticosteroids and emollients [203]. At the end of the study,
children in the melatonin supplementation group compared with
those in the placebo group had a greater improvement in the total
SCORAD score from baseline (-6.6 versus -2.6 points) and in the
total Children's Sleep Habits Questionnaire (CSHQ) score (-5.5
versus -2.7 points) but not in the pruritus score. A decrease in the
total IgE level and an increase in the total sleep time per night were
also noted in the melatonin group but not in the placebo group. No
adverse effects associated with treatment were reported.

Larger studies with longer follow-up are needed to establish the role and safety
of long-term melatonin supplementation in the management of atopic dermatitis
in children and adolescents.

Chinese herbal medicine — Chinese herbal medications for atopic dermatitis

have been used for many years, but their efficacy and safety have not been
adequately evaluated in clinical trials [204,205]. A systematic review found three
small, randomized trials and one open-label trial of a commercial preparation of
10 traditional Chinese herbs (Zemaphyte, no longer available) [206]. Two trials
showed a reduction in erythema and skin surface damage and improvement in
sleep in the active treatment group but not in the placebo group. Another trial
did not find any significant difference between the active treatment and placebo
groups. However, all studies were small (less than 50 patients) and had
methodologic flaws. (See "Chinese herbal medicine for the treatment of allergic
diseases", section on 'Therapy for atopic dermatitis'.)
Leukotriene receptor antagonists — Montelukast, an oral leukotriene
receptor antagonist approved for the treatment of asthma and allergic rhinitis in
children and adults, has been evaluated for the treatment of atopic dermatitis in
a few randomized trials with conflicting results.
A systematic review of five randomized trials including 202 adults and children
older than six years with moderate to severe atopic dermatitis evaluated the
efficacy of oral montelukast (10 mg/day in adults and 5 mg/day in children aged
6 to 14 years) given for four to eight weeks compared with placebo (three
studies) or conventional treatment with oral antihistamines and topical
corticosteroids (two studies) [207]. The main outcome measure was a reduction
in disease severity assessed by using validated score systems (ie, SCORAD;
Eczema Area and Severity Index [EASI]; six area, six sign atopic dermatitis
[SASSAD]). The pooled analysis of three studies did not show a difference
between montelukast and placebo in improving disease severity (standardized
mean difference 0.29, 95% CI -0.23 to 0.81) and pruritus and in reducing the
need for topical corticosteroids. In the two studies comparing montelukast with
conventional treatment, participants using montelukast experienced
improvement in disease severity in one study but no effect in the other study
[208,209]. All trials were of low quality with a significant risk of bias.

Because of the limited and low-quality available evidence, the role of

leukotriene receptor antagonists in the management of atopic dermatitis
remains uncertain. While waiting for larger and well-designed studies, we do not
support the use of this class of agents for adults or children with atopic
dermatitis.

REFERRAL Many patients with atopic dermatitis can initially be

treated by a nonspecialist. We suggest that patients be referred to a specialist

(eg, dermatologist, allergist) in the following circumstances:
●When the diagnosis is uncertain
●When patients have failed to respond to appropriate therapy
●If treatment of atopic dermatitis of the face or skin folds with high-
potency topical corticosteroids is being contemplated
●If treatment with systemic immunosuppressive agents is being
considered

PREVENTION

Skin barrier enhancement — Epidermal barrier dysfunction is recognized as a

key factor in the initiation and progression of atopic dermatitis. (See "Atopic
dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis",
section on 'Epidermal barrier dysfunction'.)
Two small, randomized trials, one performed in Japan and the other in the
United States and United Kingdom, found that the enhancement of a defective
skin barrier with daily application of emollients in the first months of life reduces
the incidence of atopic dermatitis in infants at increased risk (ie, those with a
parent or sibling with atopic dermatitis) [210,211]. In a cost-effectiveness
analysis, petrolatum was the most cost-effective emollient [212].
However, several subsequent, randomized trials, including the large United
Kingdom BEEP multicenter trial and the Norwegian PreventADALL trial, did not
confirm these findings [213-216]. A 2021 meta-analysis that used individual
participant data from 10 randomized trials or parallel group studies (5154
participants), most of which were at low risk of bias, concluded that skin
moisturizing in the early weeks of life is not effective in the prevention of
eczema and food allergy at age one to three years [217,218]:
●For the primary outcome of eczema diagnosis at one to two years,
the analysis of pooled individual patient data from 3075 participants
in seven studies showed no effect of emollients on the risk of atopic
dermatitis (relative risk [RR] 1.03, 95% CI 0.81-1.31, moderate
quality of evidence).
●Subgroup analysis showed that family history of allergic
disease, FLG mutation, type of emollient, and duration of emollient
use did not have an impact on the risk of developing eczema.
●For the coprimary outcome of IgE-mediated food allergy by age
one to two years, confirmed by oral food challenge at two years of
age, data were available for 996 participants in one study and
favored standard care (RR 2.53, 95% CI 0.99-6.47). The quality of
evidence was considered very low, due to missing data and
imprecision due to the small number of events from a single study
and wide confidence interval.
●For adverse events, skin infections occurred more frequently in
children in the emollient group than in those in the standard care
group (RR 1.34, 95% CI 1.02-1.77, pooled data from 2728
participants in six studies).

Based on the results of this meta-analysis, daily skin moisturization in the first
months of life probably does not influence the risk of developing atopic
dermatitis and may be associated with an increased risk of skin infections.
However, sensible skin care, which may include emollient use, should be
continued for newborns at high risk of atopic dermatitis, especially in dry and
cold climate conditions. Caregivers should adopt appropriate hygiene measures
when applying emollients to the skin of infants to avoid local skin infections (eg,
washing hands, using emollients in tubes rather than jars, which can be more
easily contaminated).

Probiotics and dietary supplements — Probiotic supplementation in pregnant

mothers and infants at risk for atopic dermatitis may prevent the development of
the disease in children younger than three years [219]. A 2014 meta-analysis of
16 randomized trials including approximately 3500 participants found that
probiotics given in the prenatal and postnatal period reduced the risk of atopic
dermatitis in the first years of life in both children at high risk of atopic dermatitis
and in those from the general population (pooled odds ratio [OR] 0.56, 95% CI
0.52-0.60) [220].
However, two subsequent, randomized trials did not confirm this finding
[221,222]. In one study, a multispecies probiotic preparation or placebo was
given to 454 unselected women at 36 weeks gestation and their infants to age
six months [221]. At two years, the cumulative frequency of eczema was similar
in the probiotic and placebo groups (34 versus 32 percent; OR 1.07, 95% CI
0.7-1.6). In another randomized trial including 184 children at high risk for
allergic disease, probiotic supplementation with Lactobacillus rhamnosus GG
during the first six months of life did not decrease the cumulative incidence of
eczema at two years of age compared with placebo (29 versus 31 percent;
hazard ratio [HR] 0.95, 95% CI 0.59-1.53) [222]. The cumulative incidences of
asthma at five years were also not significantly different in the two groups (10
versus 17 percent; HR 0.88, 95% CI 0.41-1.87). (See "Prebiotics and probiotics
for prevention of allergic disease".)
A few small, randomized trials have evaluated the role of vitamin D
supplementation in the prevention of winter-related exacerbation of atopic
dermatitis [223-225]. In the largest study, 107 children with a history of atopic
dermatitis worsening during winter were treated with 1000 international units
daily of vitamin D or placebo for one month [223]. The primary outcome was a
reduction in the clinician-measured Eczema Area and Severity Index (EASI). At
the end of the study, the mean decrease in the EASI score was 6.5 in the
vitamin D group and 3.3 in the placebo group.

Although the results of these trials suggest that winter supplementation of

vitamin D may be beneficial for patients with atopic dermatitis, larger, well-
designed studies are needed to clarify the role of vitamin D in the prevention
and treatment of atopic dermatitis.

Nutritional interventions — Previous international guidelines recommended

the use of hydrolyzed formula for the prevention of allergic diseases in high-risk
infants who cannot be exclusively breastfed [226,227]. However, the results of a
2016 systematic review and meta-analysis of 37 randomized trials evaluating
the effect of hydrolyzed formula in infancy on the risk of childhood eczema,
wheezing, allergic rhinitis, or food allergy do not support this recommendation
[228]. This meta-analysis did not find a significant difference between
hydrolyzed formula and standard cow's milk formula in the risk of eczema at
age 0 to 4 years (OR 0.84, 95% CI 0.67-1.07) or 5 to 14 years (OR 0.86, 95%
CI 0.72-1.02). (See "Introducing formula to infants at risk for allergic disease".)

SOCIETY GUIDELINE LINKS Links to society and government-

sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Atopic dermatitis".)

INFORMATION FOR PATIENTS UpToDate offers two types of

patient education materials, "The Basics" and "Beyond the Basics." The Basics
patient education pieces are written in plain language, at the 5 th to 6th grade
reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10 th to 12th grade reading level and are
best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)
 ●Basics topics (see "Patient education: Eczema (atopic dermatitis)
(The Basics)" and "Patient education: Giving your child over-the-
counter medicines (The Basics)" and "Patient education: Topical
corticosteroid medicines (The Basics)")
●Beyond the Basics topics (see "Patient education: Eczema (atopic
dermatitis) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The goals of treatment for atopic dermatitis are to reduce

symptoms (pruritus and dermatitis), prevent exacerbations, and
minimize therapeutic risks. (See 'Introduction' above.)
●The optimal management requires a multipronged approach that
involves the elimination of exacerbating factors, restoration of the
skin barrier function and hydration of the skin, patient education,
and pharmacologic treatment of skin inflammation (algorithm 1).
(See 'General approach' above.)
●We suggest that patients with mild to moderate atopic dermatitis
be initially treated with topical corticosteroids and emollients
(Grade 2B). The choice of the corticosteroid potency should be
based upon the patient's age, body area involved, and degree of
skin inflammation:
•For patients with mild atopic dermatitis, we suggest a low-
potency (groups 5 and 6 (table 1)) corticosteroid cream or
ointment (eg, desonide 0.05%, hydrocortisone 2.5%). Topical
corticosteroids can be applied once or twice daily for two to
four weeks.
•For patients with moderate disease, we suggest medium- to
high-potency (groups 3 and 4 (table 1)) corticosteroids
(eg, fluocinolone 0.025%, triamcinolone 0.1%, betamethasone 
dipropionate 0.05%). (See 'Topical corticosteroids' above.)
•The face and skin folds are areas that are at high risk for
atrophy with corticosteroids. Initial therapy in these areas
should start with a low-potency corticosteroid (group 6 (table
1)), such as desonide 0.05% ointment for up to three weeks.
(See 'Topical corticosteroids' above.)
●We suggest that patients with atopic dermatitis involving the face
or skin folds that is not controlled with topical corticosteroids be
treated with a topical calcineurin inhibitor
(ie, tacrolimus or pimecrolimus) (Grade 2B). (See 'Topical
calcineurin inhibitors' above.)
●We suggest proactive therapy to prevent relapse in adolescents
and adults with moderate to severe atopic dermatitis (picture 1A-B)
that responds to continuous therapy with topical corticosteroids or
calcineurin inhibitors (Grade 2A). We suggest medium- to high-
potency topical corticosteroids (groups 3 to 5 (table 1)) rather than
topical calcineurin inhibitors for proactive, intermittent therapy
(Grade 2B). Topical corticosteroids are applied once daily for two
 consecutive days per week for up to 16 weeks. (See 'Maintenance
and prevention of relapses' above.)
●We suggest dupilumab, rather than conventional
immunosuppressant agents, for patients with moderate to severe
disease unresponsive to topical therapy alone for whom
phototherapy is not feasible or acceptable (Grade 2A). Dupilumab
is also an option for patients who are not candidates for or failed
previous treatment with conventional immunosuppressive agents
(algorithm 1). Dupilumab, phototherapy, and conventional
immunosuppressive agents are not suitable for infants and young
children. In children older than six years and adolescents, they
should be used when optimal topical therapy has failed and the
disease has a significant impact on the quality of life. (See 'Patients
with moderate to severe disease' above.)

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Role of allergy in atopic dermatitis (eczema)

Role of allergy in atopic dermatitis (eczema)

Author
Jonathan M Spergel, MD, PhD

Section Editor
Scott H Sicherer, MD, FAAAAI

Deputy Editor
Elizabeth TePas, MD, MS
Disclosures

All topics are updated as new evidence becomes available and our peer review
process is complete.

Literature review current through: Oct 2013. | This topic last updated: Aug 14,

2012.

INTRODUCTION  — There is some controversy with regard to the role of allergy in

atopic dermatitis (eczema). Some clinicians believe that allergic responses to
aeroallergens are a rare cause of exacerbations of atopic dermatitis (AD) and that
food allergy is generally not a factor. Other clinicians believe that allergy plays a
strong role in exacerbating AD in some patients [ 1 ]. They believe that food
allergies trigger symptoms primarily in young children and environmental allergens
play a greater role in older children and adults.

Despite its name, atopic dermatitis itself is not a type I allergy, nor is it necessarily
associated with allergic sensitization. However, overall, the data indicate that
allergy plays a role in selected patients with AD.

The epidemiology, clinical manifestations, diagnosis, and treatment of AD, as well

as the role of delayed type hypersensitivity to chemicals in topical medications and
skin care products in exacerbating AD, are discussed separately.
(See "Epidemiology, clinical manifestations, and diagnosis of atopic dermatitis
(eczema)" and "Treatment of atopic dermatitis (eczema)" .)

ATOPIC ASSOCIATIONS  — Patients with AD have higher rates of allergic

diseases than the general population. Up to 80 percent of children with AD develop
asthma and/or allergic rhinitis later in childhood [ 2 ]. The converse is true as well;
a higher rate of AD is seen in teenagers with asthma than those without asthma
(RR 4.5, 95% CI 3.1-6.5) [ 3 ]. Ten to 20 percent of patients with AD have food-
induced urticaria/anaphylaxis [ 4,5 ], compared with 1 to 3 percent of the general
population [ 6,7 ]. In infants with eczema, the prevalence of IgE-mediated food
allergy confirmed by double-blind, placebo-controlled food challenge, except in
patients with a history of anaphylaxis and positive specific IgE, ranges from 33 to
63 percent [ 4,8-12 ]. Earlier onset (<3 months of age) and more severe AD is
associated with high egg, milk and/or peanut-specific IgE [ 13 ]. Patients with AD
and concomitant egg, peanut, or dust mite allergy are more likely to have AD that
persists beyond five years of age [ 14 ].

AD is also associated with elevated serum IgE. A high total serum IgE level is a
strong risk factor for AD in children from birth to six years of age [ 15 ]. IL-13
variants are associated with slightly higher total IgE levels and sensitization to food
allergens, most commonly hen's egg, in young children with AD [ 16 ]. In adults,
elevated total IgE is associated with persistent eczema with a wide distribution after
10 years of follow-up [ 17 ].

ALLERGEN SENSITIZATION  — Numerous studies have demonstrated an

increased rate of sensitization to both food and aeroallergens in patients with AD
[ 18 ]. On average, 50 percent of children and 35 percent of adults with AD are
sensitized to common allergens. However, these proportions vary widely (7 to 78
percent) [ 19,20 ].
Evidence of allergen sensitization is not proof of clinically relevant allergy.
Confirming clinical reactivity is especially important when food allergies are
suspected in young children, since avoidance of food allergens can put growing
children at nutritional risk. (See "Nutritional issues in food allergy" and 'Food
allergies' below.)

Infants and young children with AD are more commonly sensitized to foods (wheat
and egg sensitization are most prevalent) [ 20,21 ]. Children over five years and
adults are more commonly sensitized to aeroallergens (dust mite sensitization is
most prevalent in both children and adults) [ 22 ]. A higher rate of dust mite
sensitization in patients with AD is also seen with atopy patch testing [ 23 ].

Several studies have compared allergic sensitization patterns in patients with AD

from different countries. The findings demonstrate a wide variability in sensitization
patterns between countries and confirm that allergic sensitization is associated with
higher socioeconomic status:

 In the International Study of Asthma and Allergies in Childhood (ISAAC),

28,591 children aged 8 to 12 years from 20 countries were examined for
flexural eczema and skin tested to at least six common aeroallergens [ 24 ].
The point prevalence of AD ranged from <1 to 14 percent. The percentage
of children who had at least one positive skin prick test ranged from 0 to 74
percent. The association of AD and allergic sensitization was stronger in
affluent versus nonaffluent countries (OR 2.69, 95% CI 2.31-3.12 versus
1.17, 0.81-1.70).
 Similar findings were seen in a study of five- to six-year-old children with AD
and allergic sensitization in East and West Germany [ 25 ]. Only 36 percent
of children with AD in East Germany were skin prick test positive to at least
one food or inhalant allergen, compared with 50 percent of children with AD
in West Germany.
 In a randomized early prevention trial for asthma, baseline evaluation of
2184 infants with AD from atopic families included total serum IgE and
specific IgE to eight food and inhalant allergens [ 26 ]. A total of 53 percent
of infants had IgE ≥30 kU/L, with the percentage ranging from 35 to 67
percent in 12 different countries. Ninety-six percent of the infants had
complete specific IgE results. Over half of these infants were sensitized
(specific IgE ≥ 0.70 kU/L); 19 percent, monosensitized; and 37 percent,
polysensitized. Nearly one-half were sensitized to at least one food and one-
third were sensitized to one or more inhalant allergens (percentages — egg
white, 42; cow's milk, 27; peanut, 24; house dust mite, 21; cat dander, 13;
tree pollen, 8; grass pollen, 8; and Alternaria, 4). Rates of specific allergen
sensitization varied widely between countries. As an example, the rate of
egg white sensitization was 54 percent in Australia and 23 percent in
Belgium.

FOOD ALLERGIES  — Two types of dermatologic manifestations are believed to be

associated with food allergies: urticaria/anaphylaxis and food-exacerbated AD. Only
the second type of reaction is examined here. (See "Food-induced
anaphylaxis" and "New onset urticaria" .)

In food-exacerbated AD reactions, ingestion of the food acutely is thought to cause

a flare of the patient's atopic dermatitis (increased erythema and pruritus of
eczematous lesions) [ 27 ]. The flare occurs within minutes to a few hours if the
reaction is IgE-mediated, but may take hours to days if the reaction is non-IgE
mediated. The patient has persistent lesions if the food is eaten chronically.
(See "Clinical manifestations of food allergy: An overview" .)

The diagnosis of food allergy involves two steps: identification of the food
sensitization and confirmation of clinical allergy [ 28 ]. Identification involves
history taking and allergy testing. Patients are unlikely to have food allergies as a
trigger of their severe AD if they have periods of clear skin on a regular diet without
medication. Food allergy is a more likely trigger if the onset or worsening of AD
correlates with exposure to the food. Infants with AD and food allergy may have
additional findings that suggest the presence of food allergy, such as vomiting,
diarrhea, and failure to thrive [ 29 ]. (See "History and physical examination in the
patient with possible food allergy" .)

Food allergy can be evaluated by either prick skin testing or in vitro testing for
food-specific IgE. Eosinophilia may be a predictor of food allergy in patients with AD
[ 30 ]. (See "Diagnostic evaluation of food allergy" .)

In patients with AD, the rate of sensitization to foods ranges from 30 to 80 percent,
depending upon the population, but the actual rate of confirmed food allergy is
much lower [ 20,31-33 ]. As an example, 52 percent of children in a birth cohort
who developed AD during the first six years of life were sensitized to at least one
food allergen, but only 15 percent had challenge-confirmed food allergy [ 20 ].
Wheat was the most common food to which patients were sensitized, but egg was
the most common food to which patients were allergic, as confirmed by food
challenge.

Most patients with food sensitization and AD fall into a gray area in which the test is
neither negative nor above the 95 percent positive predictive value (PPV). Other
patients may have suspected non-IgE mediated food allergy, for which no
standardized diagnostic tests are available. Food challenges need to be performed
in these cases to confirm clinical reactivity to the food(s) in question and prevent
malnutrition from inappropriate food avoidance [ 29 ].

Clinical reactivity can be confirmed by double-blind, placebo-controlled food

challenge (DBPCFC) for suspected IgE-mediated allergy or reproducible findings
upon elimination and reintroduction of the food for suspected non-IgE mediated
allergy. There is a risk of a more severe reaction, including anaphylaxis, when foods
are reintroduced [ 34 ]. The rate of food-exacerbated AD varies with the severity of
the eczema. Approximately 1 to 3 percent of children with mild AD, 5 to 10 percent
with moderate AD, and 20 to 33 percent with severe AD have food-induced AD
[ 35 ]. Food-exacerbated AD is rare in adults. (See "Oral food challenges for
diagnosis and management of food allergies" and "Diagnostic evaluation of food
allergy" .)

The following studies are illustrative:

 A subset of patients with AD (22 percent) was identified in a birth cohort of

512 children followed until two years of age [ 31 ]. The children with AD
were evaluated for food allergy. Food allergy was diagnosed based upon a
history of an immediate reaction to a food allergen and a positive skin
prick test/specific serum IgE or a history of suspected food allergy with no
immediate reaction and either an open elimination/challenge test
(performed twice, considered allergic if positive both times) or DBPCFC.
 Thirty-two percent of children in the above study were sensitized to at least
one allergen [ 31 ]. However, clinical reactivity was confirmed in only 18
percent. Two children developed AD after they had developed tolerance to
the food. The rest of the children (16 percent) developed AD and adverse
reactions to food simultaneously and were considered to have food-
exacerbated AD. Six children had non-IgE mediated cow's milk allergy only.
Eight children had IgE-mediated food allergy. The mean SCORAD index, a
measure of AD severity, was higher in children with non-IgE or IgE-
mediated food allergy than children without food allergy (28 and 30 versus
20, respectively).
 Other studies have reported similar findings with regard to the frequency of
food-induced AD reactions in relation to the severity of AD. Food allergies
play a role in exacerbating AD in up to 33 percent of patients with severe
AD, 10 to 20 percent with moderate AD, and 6 percent with mild AD
[ 4,8,36 ].
 In another birth cohort study, 22 percent (122/562) of children had AD.
Fifteen percent (18/122) were confirmed to have food allergy (by skin prick
test, specific IgE, and food challenge). Most children were also sensitized to
other foods that they tolerated. Self-reported food allergy was confirmed in
less than one-third of cases.
 In a study of 3- to 15-year-old patients with AD and suspected food
allergies, 75 percent (52/69) had positive challenges (average two foods,
range one to three), based upon comparing pre- and post-challenge
photographs of representative skin lesion sites [ 37 ]. Most patients had
negative specific IgE to the challenge-positive foods. Exclusion of these
foods from the diet for three months led to significant clinical improvement.
 A meta-analysis showing lack of benefit of exclusion diets in patients with
AD is held up by some as evidence of lack of a role for food allergy in AD
[ 38 ]. However, 9 out of 10 of the randomized trials in this meta-analysis
enrolled patients with AD who were not selected for a suspicion of food
allergy based upon clinical history and/or test results. The single trial that
did select for patients with suspected food allergy (positive specific IgE to
egg and suspected egg allergy) demonstrated that an egg elimination diet
led to improvements in the extent and severity of AD in half of infants with
AD.

Food elimination diets  — The findings above highlight that foods should not be
eliminated from the diet randomly without firm clinical suspicion. Nor should foods
be excluded from the diet long-term (as opposed to short-term for diagnostic
purposes) based upon positive skin or in vitro tests or patient history alone.

Test results should be correlated with the clinical history and clinical reactivity
confirmed when necessary by DBPCFC or elimination/challenge test. Elimination of
food allergens in patients with AD and confirmed food allergy can lead to significant
clinical improvement. Patients should be evaluated at regular intervals to determine
if the food allergy has resolved. (See "The natural history of childhood food
allergy" .)

ENVIRONMENTAL ALLERGIES  — There are less data on the role of

environmental allergies in AD, compared with food allergies. The data available
suggest that environmental allergens are a trigger of AD in a small subset of
children and adults. Patients who have environmental allergies as a trigger of AD
have persistent disease with chronic exposure to an allergen in the environment.
Aeroallergens  — Exposure to aeroallergens may occur by inhalation or by direct
skin contact.

There are several lines of evidence that support the concept that immune responses
in AD skin can be elicited by aeroallergens in sensitized patients:

 In one study of schoolchildren, sensitization to aeroallergens, particularly cat

and dust mite, correlated with disease severity [ 39 ]. These children had
persistent AD on areas of exposure (eg, on areas of their arms not covered
by a shirt).
 Atopy patch tests (APT) to aeroallergens elicit delayed type eczematous
reactions on uninvolved skin in 40 to 85 percent of patients with AD [ 22,40-
44 ]. Rates of positive APT are generally lower in young children with mild
AD and higher in older children and adults with moderate-to-severe AD.
Positive APT reactions are also more frequent in patients that have AD in an
air-exposed distribution pattern. However, APT results do not always
correlate with disease extent, severity, or localization [ 44 ]. Dust mites are
consistently the most common positive aeroallergen, and also appear to be
the most clinically relevant [ 22 ]. (See "Future diagnostic tools for food
allergy" .)
 Intranasal and bronchial challenges with aeroallergens cause pruritus and
flare up of AD lesions in some patients with AD [ 45,46 ].
 Effective measures to reduce house dust mite allergen improve AD [ 28 ].
 T cells that selectively respond to Dermatophagoides pteronyssinus (Der p
1) and other aeroallergens have been isolated from AD skin lesions and
allergen patch test sites [ 47-49 ].

An additional line of evidence in support of the role of environmental allergies in AD

is that therapies used for other atopic diseases are also effective in AD. Dust mite
subcutaneous immunotherapy in adults with chronic moderate AD improved eczema
severity scores (SCORAD) and reduced use of topical glucocorticoids [ 50,51 ].
Anti-IgE ( omalizumab ) therapy improved AD in patients with concomitant asthma
[ 52-54 ]. (See "Management of severe refractory atopic dermatitis (eczema)" .)

Malassezia  — Malassezia yeast is part of the normal cutaneous microflora, and is

found predominantly in lipid-rich areas, such as the head and neck. Immune
reactions, both IgE and T cell-mediated, to Malassezia species can also worsen AD
[ 55,56 ]. IgE specific to Malassezia has been found in adolescent and adult
patients with refractory head and neck AD. These patients may respond to
antifungal therapy (eg, a one to two month course of
daily itraconazole or ketoconazole followed by long-term weekly treatment). In
addition, topical calcineurin inhibitors may inhibit the growth of Malassezia.

SUMMARY

 Although there has been some controversy with regard to the role of allergy
in atopic dermatitis (eczema), the bulk of the data indicate that allergy plays
a role in selected patients with AD. (See 'Introduction' above.)
 Infants and young children with AD are more commonly sensitized to foods,
whereas children over five years and adults are more commonly sensitized
to aeroallergens. However, evidence of allergen sensitization is not proof of
clinically relevant allergy. (See 'Allergen sensitization' above.)
 In patients with AD, the rate of sensitization to foods (positive skin or in
vitro test) ranges from 30 to 80 percent, depending upon the population.
The rate of confirmed food allergy is much lower. Food allergies play a role
 in exacerbating AD in up to 33 percent of patients with severe AD, 10 to 20
percent with moderate AD, and 6 percent with mild AD. Elimination of food
allergens in patients with AD and confirmed food allergy can lead to
significant clinical improvement. (See 'Food allergies' above.)
 Foods should not be eliminated from the diet randomly without any clinical
suspicion. Nor should foods be excluded from the diet long-term (as opposed
to short-term for diagnostic purposes) based upon positive skin or in vitro
tests or patient history alone. Test results should be correlated with the
clinical history and clinical reactivity confirmed when necessary by double-
blind, placebo-controlled food challenge, or elimination/challenge test.
(See 'Food elimination diets' above.)
 The data on the role of aeroallergens in exacerbating AD are less extensive.
Dust mites are consistently the most common positive aeroallergen, and
also appear to be the most clinically relevant. Immune reactions, both IgE
and T cell-mediated, to Malassezia species can also worsen AD.
(See 'Environmental allergies' above.)

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