PERIODIC

SYNOPSIS

Atopic dermatitis
Eric L. Simpson, MD, and Jon M. Hanifin, MD
Portland, Oregon

GENERAL REFERENCES
Bieber T, Leung DYM. Atopic dermatitis. New York: Marcel Dekker;
2002.
Leung DYM, Boguniewicz M, Howell MD, Nomura I, Hamid QA.
New insights into atopic dermatitis. J Clin Invest 2004;113:
651-7.
Rajka G. Essential aspects of atopic dermatitis. Berlin: SpringerVerlag; 1989.
Williams HC. Atopic dermatitisthe epidemiology, causes and
prevention of atopic eczema. Cambridge (UK): Cambridge
University Press; 2000.

The 3 monographs can be useful sources for

information on atopic dermatitis (AD). The text by
Rajka, although much older, continues to be the most
comprehensive general reference source. Among
the newer texts, Bieber and Leung provide a more
immunologically directed review, and Williams
emphasizes epidemiological views. The recent
journal review by Leung et al provides current
information.

INTRODUCTION
AD is a chronic inflammatory skin disease that
usually occurs in persons with a personal or family
history of other atopic conditions, such as asthma
and allergic rhinitis. The prevalence is high, especially in children, and it has risen considerably in
recent decades, leading to considerable epidemiological study. The past 30 years have also seen an
enormous outpouring of laboratory investigations,
primarily in the immunological realm. New concepts
of causation have proliferated, whereas many old
ones have regressed. It is interesting to look back at

From the Department of Dermatology, Oregon Health & Science

University.
This report reflects the best data available at the time the report
was prepared, but caution should be exercised in interpreting
the data; the results of future studies may require alteration of
the conclusions or recommendations set forth in this report.
Funding sources: None.
Conflicts of interest: None identified.
Correspondence to: Jon M. Hanifin, MD, Oregon Health & Science
University, Department of Dermatology, 3181 SW Sam Jackson
Park Rd, Portland, OR 97239-3098. E-mail: hanifinj@ohsu.edu.
J Am Acad Dermatol 2005;53:115-28.
0190-9622/$30.00
2005 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2005.01.130

ideas that seem illogical now to appreciate that the

same affinity for new and fashionable trends continues today in our confused and frustrated pursuit of
clarity. This is especially true in the immunological
realm where nearly every assay gives results that
differ from normal controls. As a result, long lists of
abnormalities have been described, but many are
uninterpretable and perhaps meaningless because
they were not subjected to comparisons with other
eczemas or with other atopic conditions. It is impossible and uncritical in a synopsis to reference every
paper describing defects in AD, but we have tried to
select those that seem most relevant for continued
study.

NOMENCLATURE
Key points
d Multifaceted uncertainty about AD terminology
has developed in recent years, fixating mainly on
IgE in the definition of atopy.
d Most revised naming systems attempt to categorize patients with AD as atopic (or those with
high total/specific IgE levels) and non-atopic
(or those with normal levels of IgE).
d Recently proposed names for those AD patients
without elevated IgE levels or associated allergies
include:
d Atopiform dermatitis
d Nonallergic dermatitis
d Intrinsic AD
d Nonallergic atopic eczema/dermatitis syndrome
d Nonatopic eczema
d Typical AD features without elevated IgE levels
probably best describes pure AD and illustrates
the fact that IgE is not a prerequisite for either the
development or the diagnosis of this eczematous
disease.
Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey
RF, et al. Revised nomenclature for allergy for global use: report
of the Nomenclature Review Committee of the World
Allergy Organization, October 2003. J Allergy Clin Immunol
2004;113:832-6.

This committee has published the most recent

example of a proposed naming system for AD based
on IgE reactivity. As other studies have concluded
(see Flohr et al given below), the presence or
115

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116 Simpson and Hanifin

absence of IgE reactivity has little relevance in the

diagnosis of AD or treatment of the skin disease.
Hanifin JM. Atopiform dermatitis: do we need another confusing
name for atopic dermatitis? Br Dermatol 2002;147:430-2.

Defining disease susbsets is valuable in AD gene

linkage studies. However, applying different names
to AD, depending on the presence or absence of IgE
reactivity, does little to advance the diagnosis or
treatment of this disease. Renaming AD to reflect IgE
status implies to clinicians that IgE status alters the
management of atopic skin disease, a view not
substantiated by the literature.
Flohr C, Johansson SGO, Wahlgren C-F, Williams H. How atopic is
atopic dermatitis? J Allergy Clin Immunol 2004;114:150-8.

The literature regarding atopy, defined as the

tendency to become sensitized and produce IgE
antibodies, is reviewed as related to AD. The presence of atopy was found to have minimal value in the
diagnosis or prognosis of AD. IgE may purely be an
epiphenomenon and not an important pathogenic
factor. This should serve as an example of why the
definition of atopy needs to be re-examined. A more
reliable and inclusive definition would recognize
atopy as a genetically predisposed diathesis manifesting a variety of exaggerated responsesvasodilatation, reactive airways, pruritus, in addition to IgE
overproductionto a variety of environmental
stimuli, including irritants, microbes, drugs, and
allergens.

DIAGNOSIS
Key points
d The Hanifin-Rajka criteria remain a standard for
the diagnosis of AD, although they are somewhat
cumbersome for routine clinical use and too
complex for epidemiological studies.
d The United Kingdom Working Party criteria provide a validated instrument for epidemiological
studies. Cultural factors may reduce its sensitivity
in some areas of the world and nonspecific
inclusion of patients with ichthyosis and familial
atopy is a concern mitigating against its use for
clinical and genetic cohort studies.
Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, Pride HB.
Consensus Conference on Pediatric Atopic Dermatitis. J Am
Acad Dermatol 2003;49:1088-95.

The 2001 American Academy of Dermatology

(AAD) Consensus Conference suggested universal
criteria for AD, more inclusive of infants and various
ethnicities. Although not yet validated, they provide
a reliable, abbreviated, practical set of criteria for the
diagnosis of AD in all age groups.

EPIDEMIOLOGY
General reviews
Schultz Larsen F, Hanifin J. Epidemiology of atopic dermatitis.
Immunol Allergy Clin North Am 2002;22:1-24.

Defining AD for epidemiological studies is challenging. Questionnaires, although an efficient means

of gathering data, can lack specificity and introduce
bias. This review outlines the challenges of performing accurate epidemiological studies in AD. A critical
look at the data pertaining to AD prevalence, time
trends, and risk factors is presented.
Williams HC. Epidemiology of atopic dermatitis. Clin Exp Dermatol
2000;25:522-9.

This article is a concise review of risk factors,

natural course, and prevention of AD. Research gaps
are identified, such as nonallergic mechanisms of
AD development, disease severity measurements,
adult AD studies, and studies of emollients in AD.
Prevalence and distribution
Williams HC, Robertson C, Stewart A, Ait-Khaled N, Anabwani G,
et al. Worldwide variation in the prevalence of symptoms of
atopic eczema. J Allergy Clin Immunol 1999;103:125-38.

There is great worldwide variation in the prevalence of AD, ranging from 0.6% to 20.5%. This large
consortium evaluated 463,801 children from 56 different countries using self-reporting of the symptoms
of AD. This study established the global geographic
differences in AD prevalence with the general pattern of increasing prevalence with higher latitudes.
Laughter D, Istvan J, Tofte S, Hanifin J. The prevalence of atopic
dermatitis in Oregon schoolchildren. J Am Acad Dermatol
2000;43:649-55.

The prevalence of AD in the northwest region of

the United States is 17.2%, similar to rates seen in
northern Europe and in Japan.
Yura A, Shimizu T. Trends in the prevalence of atopic dermatitis in
school children: longitudinal study in Osaka Prefecture, Japan,
from 1985 to 1997. Br J Dermatol 2001;145:966-73.

Studies published before 1993 have shown that

the worldwide prevalence of AD has increased over
the past 3 decades. This survey of 4 million primary
school children in Osaka Prefecture confirmed an
increase in AD lifetime prevalence from 15.0% to
24.1% between 1985 and 1997. Importantly, the
increase seen in this study leveled off after 1993.
Positive correlations of AD with higher social class
and air pollution were confirmed.
Muto T, Hsieh SD, Sakurai Y, Yoshinaga H, Suto H, Okumura K, et al.
Prevalence of atopic dermatitis in Japanese adults. Br J
Dermatol 2003;148:117-21.

The prevalence of adult AD is significant. This

cross-sectional survey of 10,762 adults older than
30 years of age in Japan revealed point, 1-year,

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and lifetime prevalences of 2.9%, 3.0%, and 3.3%,

respectively.

RISK FACTORS
Key points
d The prevalence of AD is higher in developed
countries and urban areas, although the reasons
are unclear.
d AD is more prevalent in higher latitudes.
d Migrant studies reveal that AD prevalence increases in populations that move from an area of
low to high prevalence. These data support a role
of environmental factors in the expression of AD.
d The rate of AD increases show a correlation to
higher social class, in contrast to many other
chronic diseases.
d Despite much research on cord blood IgE levels
and other immunological markers, a family history of atopic disease remains the strongest predictor for the development of AD.
d The cumulative data show no strong racial differences in the prevalence of AD.
d Most studies confirm a slight female preponderance of AD.
d Rural living and larger family size are protective
factors in the development of AD. Early microbial
exposure during infancy has been proposed as
the underlying mechanism of these observations
(hygiene hypothesis)
Ben-Gashir MA, Seed PT, Hay RJ. Predictors of atopic dermatitis
severity over time. J Am Acad Dermatol 2004;50:349-56.

Young age at onset, respiratory allergy, and urban

living predict more severe disease.
Benn CS, Melbye M, Wohlfahrt J, Bjorksten B, Aaby P. Cohort study
of sibling effect, infectious diseases, and risk of atopic dermatitis during first 18 months of life. BMJ 2004;328:217-23.

The authors explore and dissect possible mechanisms behind the hygiene hypothesis. This cohort
study of 13,070 children from Denmark showed no
protective effect of early clinically detectable infections on the development of AD. Factors associated
with microbial exposure such as farm residence, pet
keeping, and day care did show a modest protective
effect. This article suggests subclinical microbial
exposures are protective factors against AD rather
than overt infection.
McIntire JJ, Umetsu SE, Macaubas C, Hoyte EG, Cinnioglu C,
Cavalli-Sforza LL, et al. Hepatitis A virus link to atopic disease.
Nature 2003;425:576.

Considerable interest has focused on the TH2 cytokine gene cluster in the region of 5q31-33, which
shows association with increased IgE production. This
study has suggested a link with TIM-1 on 5q33.2,

Simpson and Hanifin 117

which, in susceptible individuals, binds hepatitis A

virus, decreasing TH2 activity and protecting against
asthma/atopy. This finding provides molecular support for the hygiene hypothesis speculations in
which microbial factors are thought necessary to
restore TH1/TH2 balance in protecting against atopy.

QUALITY OF LIFE
Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic eczema: its impact
on the family and financial cost. Arch Dis Child 1997;76:159-62.

Having a child with moderate to severe AD affects

a family more than having a child with type 1 diabetes
mellitus.
Ben-Gashir MA, Seed PT, Hay RJ. Quality of life and disease severity
are correlated in children with atopic dermatitis. Br J Dermatol
2004;150:284-90.

Quality of life is reduced in 5- to 10-year-old

children with AD and is related to disease severity.
Schiffner R, Schiffner-Rohe J, Landthaler M, Stol W. Treatment of
atopic dermatitis and impact on quality of life. A review with
emphasis on topical non-corticosteroids. Pharmacoeconomics
2003;21:159-79.

Topical immunomodulators, topical steroids,

phototherapy, and cyclosporine all have been
shown to improve the quality of life in patients
with AD. However, no comparisons have been made
between therapeutic regimens. The authors conclude that there is only one answer to the question
Which treatment best improves quality of life in
patients with AD?we dont know. A future research agenda is outlined.

COST OF CARE
Lapidus CS, Schwarz DF, Honig PJ. Atopic dermatitis in children:
who cares? who pays? J Am Acad Dermatol 1993;28:699-703.

Cost of care for patients in the United States with

AD between 1990 and 1991 was estimated to be $364
million. Pharmaceuticals represented the largest expense. Expenditures for emergency department
visits were very substantial. Better disease education
and more frequent follow-up clinic visits may reduce
the need for costly emergency department visits.
Kemp AS. Cost of illness of atopic dermatitis in childrena societal
perspective. Pharmacoeconomics 2003;21:105-13.

This article is a nice comprehensive review of data

involving both the economic and societal costs of the
disease.
Ellis CN, Drake LA, Prendergast MM, Abramovits W, Boguniewicz
M, Daniel R, et al. Cost of atopic dermatitis and eczema in the
United States. J Am Acad Dermatol 2002;46:361-70.

In the United States, the economic cost of AD is

similar to the cost of other chronic diseases, such as
emphysema and epilepsy.

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118 Simpson and Hanifin

GENETICS
Key points
d AD is a hereditary disease with high concordance
in identical twin pairs.
d There is also a familial association between AD
and allergic respiratory disease.
d Over the years, elevated IgE levels, asthma, and
AD have been linked to almost every chromosome.
d Phenotypic ascertainment varies considerably in
different studies and undermines the reliability of
some reports.
d Many linkage projects have not focused on AD
alone, but have included studies of respiratory
atopy and IgE reactivity. Careful gene linkage
studies may be able to distinguish which genes
relate to the TH2/IgE component compared with
those associated with the nonallergic variant of AD
as a model for the specific eczematous disease.
d Previous studies have shown colocalization of
certain loci not only with AD, but with psoriasis,
asthma, rheumatoid arthritis, and insulin-dependent diabetes mellitus.
Lee Y-A, Wahn U, Kehrt R, Tarani L, Businco L, Gustafsson D, et al.
A major susceptibility locus for atopic dermatitis maps to
chromosome 3q21. Nat Genet 2000;26:470-3.

A northern European study indicated linkage at

chromosome 3q21, suggesting possible candidate
genes for CD80 and 86 (B7.1, B7.2) costimulatory
molecules, which can interact with CD28/CTLA4 to
mediate T-cell interactions. CD 80 and 86 candidate
molecules serve a fundamental pathway of immune
activation.
Hummelshoj T, Bodtger U, Datta P, Malling HJ, Oturai A, Poulsen
LK, et al. Association between an interleukin-13 promoter
polymorphism and atopy. Eur J Immunogenet 2003;30:355-9.

This recent northern European study tested welldefined patient groups with allergy-associated AD,
or with other atopic conditions. They confirmed two
other reports of an association with the interleukin
13 (IL-13) gene promoter polymorphism in the 5q3133 cytokine cluster. The study suggested a C to T
exchange localized to position e1024 and, in combining data from the 3 studies, demonstrated a strong
association.
Cookson WOCM, Ubhi B, Lawrence R, Abecasis GR, Walley AJ, Cox
HE, et al. Genetic linkage of childhood atopic dermatitis to
psoriasis susceptibility loci. Nat Genet 2001;27:372-3.

AD without asthma was identified on chromosome 1q21 and 17q25. In contrast, patients with AD
and asthma, as well as those with asthma alone,
mapped to chromosome 20p. This suggests AD
without asthma may represent a different genetic
subtype. As with previous linkage studies in AD,

these loci mapped closely to psoriasis susceptibility

loci. This group did not confirm the previous susceptibility locus on 3q21 found by Lee et al described
above; however, it is likely several genes contribute
to the full expression of AD.
Becker KG, Barnes KC. Underlying disease specificity of genetic loci
in atopic dermatitis. J Invest Dermatol 2001;117:1325-7.

Several studies have suggested shared linkages

between AD and psoriasis at several loci. Other inflammatory and autoimmune diseases have mapped
closely to loci identified in AD. Such colocalization
may not be specific for AD, but rather it may define loci
for common basic immunoregulatory mechanisms.
Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii M. Association
of SPINK5 gene polymorphisms with atopic dermatitis in the
Japanese population. Br J Dermatol 2003;148:655-69.
Walley AJ, Chavanas S, Moffatt MF, Esnouf RM, Ubhi B, Lawrence R,
et al. Gene polymorphism in Netherton and common atopic
disease. Nat Genet 2001;29:175-8.

AD and IgE reactivity are two major components

of Netherton disease. These two studies, from the
United Kingdom and Japan, have shown the SPINK5
Netherton disease gene glu420lys polymorphism
associated with AD. This gene codes for the LEKTI
proteinase inhibitor, a defect of which might
have considerable implication for inflammatory
pathways relating to proteinase-activated receptors
on keratinocytes and mast cells.

PATHOGENESIS
Key points
d Investigations of AD are replete with widely
varied concepts of causation.
d From the time of Besnier, we were given the
concept that AD is the itch that rashes. From
those early speculations came the concept (and the
name) of neurodermatitis, which, in turn and in
tandem with Freudian psychodynamics, led to the
theory that AD was a disease of psychological
instability. These represent only two from a long
list of AD concepts that have come and gone
through the past century.
d Mast cell/histamine causation, IgE, eosinophils
and TH2 cells are more recent causative conceptual entries, but all remain speculative and difficult to prove.
d In contrast, if we consider those pathogenic
aspects that are generally accepted as fact, we
can assert that AD is:
d An inflammatory skin disease
d A strongly familial condition with genetic
associations extending to allergic rhinoconjunctivitis and asthma
d A disease that can be transferred by bone
marrow cells

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The past few years have generated productive

additions of studies in dendritic cells, keratinocytes, and neuroinflammatory elements. These
developments are helping to increase awareness
of other important pathogenic elements, in addition to the immunological anomalies, that contribute to the inflammation that is so relevant to AD.
The widely disparate elements in AD pathogenesis force the consideration that a unifying, basic
concept may be necessary to explain the many
abnormal systems and that fundamental defects in
signaling and regulatory pathways are a logical
realm of investigation.

Signaling and regulation

Key points
d Pharmacophysiologic abnormalities, such as cholinergic hyperreactivity and reduced adrenergic
responses were early indicators of altered cellular
regulation in AD.
d Mononuclear leukocyte cultures showed reduced
cyclic AMP responses (caused by increased cAMPphosphodiesterase [PDE] hydrolysis), accounting
for the inflammatory and immune hyperactivity
characteristic of AD and other atopic diseases.
d Increased PDE is found in umbilical cord blood
cells of infants predisposed to AD.
d PDE inhibitors correct the defect and reduce the
overproduction of IgE, IL-4, IL-10, and other
cytokines in cell cultures and have anti-inflammatory effects when applied topically to AD lesions.
d More recent studies of signaling have focused on
keratinocytes and on detailed pathways that have
functional associations with cytokine production,
interactions with immune/inflammatory pathways,
and the induction of spongiosis and epidermal
proliferation (see Keratinocyte studies below).
d Development of T 2 immune responses is assoH
ciated with abnormal regulation of cytokine and
signaling pathways in keratinocytes. Proinflammatory cytokine gene expression is under control
of transcription factors such as AP-1 and NF-kB
whose synthesis and activation result from phosphorylation of kinases such as MAPK and ERK.
d The MAP-kinase and other signaling pathways
can mediate microbial stimulation of macrophage
IL-12 production via toll-like receptors (TLRs),
which in turn up-regulates the TH1 responses that
are often deficient in AD.
Girolomoni G, Pastore S. The role of keratinocytes in the
pathogenesis of atopic dermatitis. J Am Acad Dermatol
2001;45(Suppl):S25-8.

This article provides a useful review for the

important research realm of keratinocyte effects on

Simpson and Hanifin 119

inflammation in AD. Irritation or skin injury in AD

triggers excessive keratinocyte production of granulocyte-macrophage colony-stimulating factor (GMCSF), IL-1, and tumor necrosis factor a (TNF-a).
These factors may stimulate chemokines such as
RANTES, which attract infiltrating immune and inflammatory cells, including T cells, monocytes, and
eosinophils. The keratinocyte cytokines also activate
and recruit dendritic cells, augmenting both innate
and adaptive immune responses.
Akdis CA, Akdis M, Trautmann A, Blaser K. Immune regulation in
atopic dermatitis. Curr Opin Immunol 2000;12:641-6.

This article is an excellent, comprehensive review

of the many facets of keratinocyte and immune
interactions.
Hanifin JM, Chan SC. Monocyte phosphodiesterase abnormalities
and dysregulation of lymphocyte function in atopic dermatitis.
J Invest Dermatol 1995;105(Suppl):84S-88S.

This article reviews previous work on the role of

PDE in the dysregulation of immune and inflammatory cells in AD.
Wild JS, Sur S. CpG oligonucleotide modulation of allergic inflammation. Allergy 2001;56:365-76.

This article reviews evidence for microbial CpG

DNA activation of immune cells, the role of TLRs in
initiating signaling pathways and the downstream
expression of cytokines and other mediators that can
enhance TH1 function.
Keratinocyte studies
Key points
d A number of reports in recent years have begun
to focus attention on the epidermis in AD.
d Epidermal barrier abnormalities have great relevance to management of AD.
d Recent studies into the mechanisms of spongiosis,
the hallmark of AD, have focused on keratinocyte
apoptosis mediated by T lymphocytes.
d Keratinocytes in AD produce mediators that activate and regulate immune and inflammatory cells.
Trautmann A, Akdis M, Kleeman D, Altmauer F, Simon HU, Graeve
T, et al. T cell-mediated Fas-induced keratinocyte apoptosis
plays a key pathogenic role in eczematous dermatitis. J Clin
Invest 2000;106:25-35.

Epidermal spongiosis represents the initial event

in the development of the hallmark clinical feature of
ADthe eczematous lesion. This study suggests a
basic general mechanism for eczematization and
barrier disruption in AD. Biopsy specimens from
lesional AD or nickel allergic contact dermatitis
(ACD) reactions showed keratinocyte apoptosis,
which precedes spongiosis. In this in vitro system,
interferon gamma (IFN-g) induced Fas receptor (Fas
R) on keratinocytes. Activated T cells, or their

120 Simpson and Hanifin

supernatants containing soluble Fas ligand, initiated

apoptosis. The requirements for T-cell activation and
dependency on specific antigens are unclear. It
highlights the importance of TH1/keratinocyte interactions in pathogenesis of eczematous lesions and
provides a model for studies of signaling pathways in
AD lesions.
Warnnissorn P, Nakao A, Suto H, Ushio H, Yamaguchi N, Yagita H,
et al. Tumour necrosis factor-related apoptosis-inducing
ligand expression in atopic dermatitis. Br J Dermatol
2003;148:829-31.

TNF-related apoptosis-inducing ligand (TRAIL) is

a member of the TNF-a family. TRAIL induces
apoptosis in tumor cells and virus-infected cells.
TRAIL-positive mononuclear cells are present in
greater numbers in lesional skin of patients with
AD compared with nonlesional AD skin, normal
controls, and psoriasis lesional skin. TRAIL-positive
macrophages may be specific to lesional skin and
may mediate keratinocyte apoptosis.
Iordanov MS, Sundholm AJ, Simpson EL, Hanifin JM, Ryabinina OP,
Choi RJ, et al. Apoptosis-induced activation of epidermal
growth factor receptor in keratinocytes: implications for
restricting epidermal damage in dermatitis. J Invest Dermatol
2005 (in press).

This study confirms the development of apoptosis

via the Fas signaling pathway, which in turn appears
to initiate epidermal proliferation via the epidermal
growth factor receptor in a human ACD model.
Proliferation has been almost completely overlooked in basic studies of AD, yet the lichenification
from keratinocyte proliferation that accompanies the
chronic phase of AD is a major obstacle to successful topical therapy. These new studies have identified a cascade of possible molecular sites at which to
target therapies to prevent spongiosis and to limit
lichenification.

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barrier. In contrast, the outside-in paradigm stresses

the importance of stratum corneum dysfunction in
driving cutaneous inflammation. Skin barrier repair
approaches are discussed, but formal studies are
needed to verify the importance of physiologic lipid
replacement as a useful adjunctive treatment in AD.
Hara J, Higuchi K, Okamata R, Kawashima M, Imokawa G. High
expression of sphingomyelin deacylase is an important determinant of ceramide deficiency leading to barrier disruption in
atopic dermatitis. J Invest Dermatol 2000;115:406-13.

Low stratum corneum ceramide levels may contribute to AD skin barrier dysfunction. Altered
sphingomyelin metabolism in keratinocytes may
account for this finding. The sphingomyelin deacylase-like enzyme appears to be overexpressed in AD
skin, leading to a relative ceramide deficiency in the
stratum corneum of AD skin. An alternative explanation may be that altered sphingomyelin metabolism is an epiphenomenon resulting from an altered
signaling cascade that leads to spongiosis.

NEUROGENIC INFLAMMATION
Key points
d Neurogenic inflammation and/or itch can result
from 3 main neurogenic mechanisms:
d Autonomic neuromediators, such as acetylcholine, induce sweating and itch.
d Neuropeptides (such as substance P and
calcitonin gene-related peptide) released by
cutaneous nerves and infiltrating immune
cells can generate itch.
d Proteinase-activated receptors (PARs) are
emerging as the main mediators of itch in
AD as opposed to histamine pathways.
d Studies reveal atopic skin exhibits altered levels of
nerve fibers, neuropeptides, neuropeptide receptors, and neuropeptidases.

Pastore S, Giustizieri ML, Mascia F, Giannetti A, Kaushansky K,

Girolomoni G. Dysregulated activation of activator protein 1 in
keratinocytes of atopic dermatitis patients with enhanced
expression of granulocyte/macrophage-colony stimulating factor. J Invest Dermatol 2000;115:1134-43.

Steinhoff M, Stander S, Ansel JC, Schmelz M, Luger T. Modern

aspects of cutaneous neurogenic inflammation. Arch Dermatol
2003;139:1479-88.

These authors have been at the forefront in

identifying pathways by which keratinocytes may
regulate downstream immune responses in AD. GMCSF overexpression and altered AP-1 regulation in
keratinocytes from lesional AD skin may influence
the presence of activated dendritic cells in the
epidermis and dermis of AD skin.

Steinhoff M, Nisius U, Ikoma A, Fartasch M, Heyer G, Skov PS, et al.

Proteinase-activated receptor-2 mediates itch: a novel pathway
for pruritus in human skin. J Neurosci 2003;23:6176-80.

Elias PM, Feingold KR. Does the tail wag the dog? Role of the
barrier in the pathogenesis of inflammatory dermatoses and
therapeutic implications. Arch Dermatol 2001;137:1079-81.

The current treatment strategies in AD focus on

T-cell inhibition as a means of normalizing the skin

This state-of-the-art review presents current facts

and concepts relating to neuroinflammation and itch.

PARs are a new family of G-proteinecoupled

receptors that become active after cleavage by
proteases. PARs are found on sensory neurons,
keratinocytes, mast cells, and endothelial cells.
Four PARs have been molecularly identified, and
PAR-2 appears to be an important mediator of neurogenic inflammation. PAR-2 agonists recruit leukocytes and cause pruritus and edema by stimulating

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the release of neuropeptides in peripheral tissues.

PAR-2 and its endogenous ligand, mast cell tryptase,
are increased in AD skin. Pruritus evoked via PAR2
activation is greater in patients with AD than in
controls and is independent of histamine release.
The authors conclude that PAR-2 signaling is an
important link between the sensory nervous system
and inflammation in AD.
Katayama I, Bae S-J, Hamasaki Y-I, Igawa K, Miyazaki Y, Yokozeki H,
et al. Stress response, tachykinin, and cutaneous inflammation.
J Invest Dermatol 2001;6:81-6.

This mouse model delves into the mechanisms of

stress-related itch and topical glucocorticoid withdrawal syndrome. Long-term use of glucocorticoids
and endogenous glucocorticoids released under
stressful conditions can alter skin reactivity via their
effects on tachykinins.

IMMUNOLOGICAL FEATURES
AD presents a complex immunological picture
that can generally be considered to have two
facetsimmune deficiency and immune hyperresponsiveness. The pathogenic links between these
two aspects are far from being clear, but considerable
investigation has been proceeding in recent years.
Immune deficiency
Key points
d Selective immune deficiency, at least in the
skin, is reflected by the tendency of herpes simplex virus (HSV) and vaccinia to extend beyond
typical margins and by the difficulty in sensitizing patients to Rhus and dinitrochlorobenzene.
d Clinical experience suggests that patients also
have more prolonged and extensive infections
with warts and molluscum contagiosum.
d Subnormal delayed hypersensitivity/contact allergy reactions in AD are assumed to be the
general mechanistic explanation for the susceptibility to these cutaneous viral infections.
d Interestingly, little is known about the pathogenic
mechanisms underlying these deficient responses. Some possible explanations have emerged:
d AD monocytes have increased production of
IL-10 (a consequence of abnormal PDE activity), a cytokine that accentuates TH2 responses and inhibits TH1 cellular immune
function.
d IL-12 expression, considered important in
stimulating IFN-a and other TH1 and proinflammatory factors, is reduced.
d Regulatory T-cell abnormalities may damp
the immune response against viral and other
infections.

Simpson and Hanifin 121

Reduced expression of defensins and other

antimicrobial peptides (AMPs) may allow
greater susceptibility to cutaneous infections
in AD. Evidence indicates that excess IL-10 as
well as TH2 cytokines may underlie the deficient AMP response.

Leung DYM, Howell MD. Elevated levels of IL-10 in intrinsic and

extrinsic atopic dermatitis is associated with deficiency in
antimicrobial peptide production [abstract]. J Allergy Clin
Immunol 2004;113:S96.

This study confirms earlier work showing increased IL-10 expression and accounts for reduced
AMP production in AD skin.
Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T,
et al. Endogenous antimicrobial peptides and skin infections in
atopic dermatitis. N Engl J Med 2002;347:1151-60.

Antimicrobial protein defects in AD skin suggest

another possible explanation for the altered skin
infection susceptibility. Innate AMPs, defensins and
cathelicidins, are deficient in the skin of patients with
AD compared with psoriasis patients. Specificity is
unclear because levels were comparable to those in
normal skin, and this study lacked other eczema
controls, though an earlier study from Sweden
suggested similar levels in ACD. The findings are,
however, novel and potentially exciting.
Howell MD, Jones JF, Kisich KO, Streib JE, Gallo RL, Leung DYM.
Selective killing of vaccinia virus by LL-37: implications for
eczema vaccinatum. J Immunol 2004;172:1763-7.

The cathelicidin LL-37 inhibits the growth of

the vaccinia virus in vitro. Knock-out mice lacking
cathelicidins had more pox development after scarification with vaccina than control mice. Defensins
had no effect on vaccinia growth. These findings
present a possible mechanism for eczema vaccinatum.
Wollenberg A, Zoch C, Wetzel S, Plewig G, Przybilla B. Predisposing
factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases. J Am Acad Dermatol
2003;49:198-205.

Early age at AD onset and total IgE levels correlate

to a higher risk of development of eczema herpeticum (EH). The use of corticosteroids does not
increase the risk of developing EH, and undertreated
areas are the likely sites of involvement.
Immune hyperresponsiveness
Key points
d Activated T cells reside in lesional skin of patients
with AD. Activation of T cells may occur from
many sources. Irritants stimulating keratinocyte
responses may be the most prevalent initiator,
and superantigens and allergens are also considered possible sources of activation.

122 Simpson and Hanifin

There are increased TH2 responses in skin, blood,

and lymph nodes that contribute to the respiratory allergy and food allergy that often accompanies AD.
AD monocytes and dendritic cells have increased
production of IL-10, a cytokine that inhibits TH1
function and accentuates TH2 responses. Viewing
AD as a purely TH2-mediated disease, however,
oversimplifies this immunologically complex disease as T cells from skin of chronic lesions have
been shown to express a TH1-skewed cytokine
profile.
A popular working hypothesis suggests the presence of a TH2-stimulated acute response followed by a switch to TH1-mediated chronic
inflammation. A weakness of this concept is the
strong, conflicting evidence (cited above) for IFNgestimulated Fas initiation of eczema.
The study of regulatory T cells in AD and atopic
diseases is only in the early stages, and one
regulatory mechanism, IL-10, is confused by the
prominent monocyte IL-10 overexpression in AD.
The relative contributions of T cells and monocytes and their relevance to atopic immune regulation remain to be delineated.

Grewe M, Bruijnzeel-Koomen CAFM, Schopf E, Thepen T, Langeveld-Wildschut AG, Ruzicka T, et al. A role for Th1 and Th2 cells
in the immunopathogenesis of atopic dermatitis. Immunol
Today 1998;19:359-61.

This article is a review of studies suggesting

that, in allergen patch tests, early reactions are
TH2 mediated and later, the responses have TH1
characteristics.
Santamaria Babi LF, Picker LJ, Perez Soler MT, Drzimalla K, Flohr P,
Blaser K, et al. Circulating allergen-reactive T cells from patients
with atopic dermatitis and allergic contact dermatitis express
the skin-selective homing receptor, the cutaneous lymphocyteassociated antigen. J Exp Med 1995;181:1935-40.

Although not specific for AD, CLA1 T cells bind

endothelial E-selectin and are prominent in AD
lesions.
Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J,
et al. Relation of CD41CD251 regulatory T-cell suppression of
allergen-driven T-cell activation to atopic status and expression
of allergic disease. Lancet 2004;363:608-15.
Ou L-S, Goleva E, Hall C, Leung DYM. T regulatory cells in atopic
dermatitis and subversion of their activity by superantigens.
J Allergy Clin Immunol 2004;113:756-63.

Regulatory T cells (Tregs, CD41CD251 T cells,

known in the past as suppressor T cells) may be
increased in AD, though evidence appears to be
conflicting in these two studies; decreased Treg
activity was reported in atopic individuals
without AD.

J AM ACAD DERMATOL
JULY 2005

Hijnen D, de Bruin-Weller M, Oosting B, Lebre C, de Jong E,

Bruijnzeel-Koomen C, et al. Serum thymus and activationregulated chemokine (TARC) and cutaneous T cell-attracting
chemokine (CTACK) levels in allergic diseases: TARC and CTACK
are disease-specific markers for atopic dermatitis. J Allergy Clin
Immunol 2004;113:334-40.

Serum levels of the T-cell chemokine thymus and

activation-regulated chemokine (TARC; CCL-17) are
greatly elevated in AD and apparently correlate with
disease severity. Whether this is a specific marker for
AD awaits ACD comparison, but an appealing scenario suggests that TARC might initiate T-cell recruitment to the dermoepidermal junction where these
cells interact with keratinocytes to trigger apoptosis/
spongiosis.
Dendritic cells
Key points
d Dendritic cells (DCs) are prominent in the epidermis and in the cellular infiltrates of AD. Studies
have demonstrated several features that suggest a
role for DCs in the pathogenesis of AD.
d Increased IgE-bearing DCs (FceRI) in AD skin
may amplify TH2 responses to antigens passing
through the epidermis.
d Monocyte survival is increased in patients with AD.
d Inflammatory dendritic epidermal cells may augment TH1-associated eczema.
d High monocyte IL-10, low IL-12 may account for
reduced TH1 immunity and for exaggerated TH2
responses.
Bieber T. Fc epsilon RI-expressing antigen-presenting cells: new
players in the atopic game. Immunol Today 1997;18:311-3.

This review of the identification of the highaffinity receptor of IgE (FceRI) on the surface of
monocytes and dendritic cells helped clarify the role
and relevance of variable expression on different
antigen-presenting cells.
Wollenberg A, Mommaas M, Oppel T, Schottdorf EM, Gunther S,
Moderer M. Expression and function of the mannose receptor
CD206 on epidermal dendritic cells in inflammatory skin
diseases. J Invest Dermatol 2002;118:327-34.

A dendritic cell subset with distinct markers,

inflammatory dendritic epidermal cells, is present
in lesional AD sites and may enhance TH1 eczematous responses.
Allam J-P, Klein E, Bieber T, Novak N. Transforming growth factorb1 regulates the expression of the high-affinity receptor for IgE
on CD341 stem cell-derived CD1a1 dendritic cells in vitro.
J Invest Dermatol 2004;123:676-82.
Lee HJ, Lee HP, Ha SJ, Byun DG, Kim JW. Spontaneous expression
of mRNA for IL-10, GM-CSF, TGF-beta, TGF-alpha, and IL-6 in
peripheral blood mononuclear cells from atopic dermatitis. Ann
Allergy Asthma Immunol 2000;84:553-8.

Subnormal transforming growth factoreb levels

in blood and tissues of patients with AD may

J AM ACAD DERMATOL
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influence FceRI expression and differentiation of

dendritic cells.
Mast cells and histamine
Key points
d There is conflicting evidence for increased
mast cells and histamine in AD lesions, but most
studies that showed an increase were not
controlled.
d Studies of psoriasis, lichen planus, and other
chronic inflammatory skin conditions showed
similarly increased mast cell numbers, suggesting
that these are nonspecific inflammatory accompaniments.
d A direct histamine role in eczematization and AD
itch remains speculative.
(Hanifin JM. [1992] Do mast cells play a role in atopic dermatitis? In: Kaliner M, Metcalfe D, editors. The mast cell in health
and disease. New York: Marcel Dekker; 1992. p. 639-51).
d

Antihistamines are ineffective in treating AD.

Akdis CA, Blaser K: Histamine in the immune regulation of allergic

inflammation. J Allergy Clin Immunol 2003;112:15-22.
Van der Pouw Kraan TCTM, Snijders A, Boeije LCM, de Groot ER,
Alewijnse AE, Leurs R, et al. Histamine inhibits the production of
interleukin-12 through interaction with H2 receptors. J Clin
Invest 1998;102:1866-73.

Simpson and Hanifin 123

Their role has been widely investigated in the

cutaneous late-phase reaction (LPR) to injected
allergens; however, the LPR has little resemblance
to AD and its relevance is unclear.
Human studies have demonstrated that systemic
therapy with anti-IL-5 reduces eosinophilia, but
have shown little clinical effect.
Recent studies in human asthma, as well as in
murine models, have cast doubt on the inflammatory role of eosinophils and have tended to
shift focus to connective tissue remodeling.

Ott NL, Gleich GJ, Peterson EA, Fujisawa T, Sur S, Leiferman KM.
Assessment of eosinophil and neutrophil participation in atopic
dermatitis: comparison with the IgE-mediated late-phase reaction. J Allergy Clin Immunol 1994;94:120-8.

This is an important study reviewing evidence for

eosinophil participation in AD inflammation and
distinguishing characteristics of AD from those of
the LPR.
Beck LA, Leung DYM. Allergen sensitization through the skin
induces systemic allergic responses. J Allergy Clin Immunol
2000;106(Suppl):S258-63.

This article offers a good review of allergy/immunology aspects of AD with special emphasis on the
role of eosinophils.

Histamine may influence immune/inflammatory

regulation through H2 receptors to inhibit IL-12 and
increase IL-10.

Phipps S, Flood-Page P, Menzies-Gow A, Ong YE, Kay AB. Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and
tenascin deposition in allergen-challenged human atopic skin.
J Invest Dermatol 2004;122:1406-12.

Giustizieri ML, Albanesi C, Fluhr J, Gisondi P, Norgauer J,

Girolomoni G: H1 histamine receptor mediates inflammatory
responses in human keratinocytes. J Allergy Clin Immunol
2004;114:1176-82.

Anti-IL-5, given intravenously, decreases eosinophils in asthma and AD but has little effect on clinical
disease. In experimentally induced human LPRs,
anti-IL-5 greatly lowers eosinophil levels but does
not reduce the size of the reaction.

Histamine may act on keratinocytes via the H1

receptor to amplify inflammatory T-cell reactions.
Schecter NM, Brass LF, Lavker RM, Jensen PJ. Reaction of mast cell
proteases tryptase and chymase with protease activated
receptors (PARs) on keratinocytes and fibroblasts. J Cell Physiol
1998;176:365-73.

Mast cell tryptase may cleave PARs to trigger

neurogenic inflammation.
Eosinophils
Key points
d Eosinophils contain abundant quantities of cationic granule proteins including major basic
protein, eosinophil cationic protein, eosinophilderived neurotoxin, and eosinophil peroxidase.
All can cause injurious microbial and tissue effects, and deposition has been demonstrated in
AD lesions.
d These cells might be important effectors in AD,
though they are not specific and are present in a
wide variety of cutaneous inflammatory disorders.

Wills-Karp M, Karp CL. Eosinophils in asthma: remodeling a tangled

tale. Science 2004;305:1726-9.

This article reviews new information questioning

the pathogenic role of eosinophils in skin and
bronchial inflammation and suggesting they may
relate more to subepithelial remodeling, not generally considered germane to AD.

FLARE FACTORS
Microbes
Key points
d Viral upper respiratory tract infections represent
the most common and consistent flare factor in
infants and children; however, little is known
about the mechanism.
d Staphylococcal infection as a trigger for AD has
been an active area of research for more than
3 decades since the finding that more than 90% of
adult patients are colonized with Staphylococcus
aureus.

124 Simpson and Hanifin

Superantigens have been a focus of considerable

research as a mechanism to explain T-cell activation in AD. It has been an attractive concept but
overzealously promoted, with many uncontrolled
studies and indications that the same findings may
apply to various inflammatory skin diseases as
well as to normal skin.

Akdis M, Simon H-U, Weigl L, Kreyden O, Blaser K, Akdis CA. Skin

homing [cutaneous lymphocyte-associated antigen-positive]
CD81 T cells respond to superantigen and contribute to
eosinophilia and IgE production in atopic dermatitis. J Immunol
1999;163:466-75.

CD41T cells are thought to be the key effector

cells in driving TH2 inflammation in AD. This work
revealed that, as with CD41 cells, CD81 T cells in
patients with AD also respond to superantigens and
secrete high levels of TH2 cytokines.
Psychological stress
Garg A, Chren MM, Sands LP, Matsui MS, Marenus KD, Feingold KR,
et al. Psychological stress perturbs epidermal permeability
barrier homeostasis: implications for the pathogenesis of
stress-associated skin disorders. Arch Dermatol 2001;137:
53-9.

Psychological stress was shown in the 1950s to

cause rapid-onset clinical itch/scratch responses in
AD subjects. Previous mouse models have shown
that psychological stress also negatively affects skin
barrier function. In this study, the ability to repair the
skin barrier was diminished in students during final
examinations as compared with school vacation
periods. Exacerbation of skin diseases, such as AD,
by psychological stress may be explained by perturbations of skin barrier function.
Allergy and IgE
Key points
d Immunological conceptualizations centered on
allergy have dominated research in AD over the
past 25 years, outnumbering other investigative
areas by a large ratio. Frequently positive radioallergosorbent tests (RASTs) and skin prick tests
are described to patients as allergies.
d Allergy is defined as an adverse health effect that
results from stimulation of a specific immune
response. Failure to adhere to this definition
results in enormous misinformation that confuses
patients and other physicians.
d True IgE-mediated allergies are clearly more frequent in AD, and it is important to recognize
clinically significant immediate urticarial and respiratory symptoms/reactions to foods or inhalants. These carry a risk of anaphylaxis and, even
when mild, may initiate stress-induced itching
that can worsen an eczematous condition.

J AM ACAD DERMATOL
JULY 2005

Tan BB, Weald D, Strickland I, Friedmann PS. Double-blind

controlled trial of effect of housedust-mite allergen. Lancet
1996;347:15-8.

This study showed that the severity of AD decreased after house dust mite reduction compared
with control subjects using sham mite reduction
procedures. This study was well performed; however, these positive results have been offset by
several subsequent negative studies in both children
and adults using dust mite reduction strategies.
Beltrani V, Hanifin J. Atopic dermatitis, house dust mites, and
patch testing. Am J Contact Dermatitis 2002;13(June):80-2.

Pro and con arguments are laid out regarding

the importance of dust mite allergens and dust mite
patch testing in the pathophysiology and treatment
of AD. The allergist perspective points to studies of
AD exacerbation after inhaled protein challenge.
The alternative view cites the lack of well-controlled
studies linking dust mite to AD flares. In fact, most
patients with AD have disease reduction in tropical
climates where dust mite populations are highest.

RESPIRATORY ATOPY AND THE ATOPIC

MARCH
Key points
d The atopic march refers to the sequential development of AD, allergic rhinitis, and asthma. Longitudinal studies reveal that AD is a risk factor for
the future development of allergic airway disease.
d The risk of the development of asthma correlates
to the severity of AD.
d Animal models suggest epicutaneous exposure to
protein antigens can lead to allergen sensitization,
excess IgE production, and allergic airway disease.
d Long-term studies now under way will assess
whether more aggressive treatment of AD during
infancy might later reduce the impact of asthma
and allergies.
Spergel JM, Mizoguchi E, Brewer JP, Martin TR, Bhan AK, Geha RS.
Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin
Invest 1998;101:1614-22.

Epicutaneous sensitization leads to respiratory hyperresponsiveness in a mouse model. This is an important

study linking skin sensitization and respiratory allergy.
Herrick CA, MacLeod H, Glusac E, Tigelaar AE, Bottomly K. Th2
responses induced by epicutaneous or inhalational protein
exposure are differentially dependent on IL-4. J Clin Immunol
2000;105:765-75.
Herrick CA, Xu L, McKenzie AN, Tigelaar RE, Bottomly K. IL-13 is necessary, not simply sufficient, for epicutaneously induced Th2 responses to soluble protein antigen. J Immunol 2003;170:2488-95.

In this murine model, IgE levels were 100- to 1000fold higher when antigen was given epicutaneously

J AM ACAD DERMATOL
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versus the nasal route. The skin is a potent site for

TH2-mediated sensitization to protein antigens, but is
independent of IL-4 in contrast to respiratory sensitization models. IL-13, structurally related to IL-4,
appears to be the major mediator driving TH2
responses during epicutaneous sensitization.

FOOD ALLERGY
Key points
d Type I urticarial reactions probably occur in approximately one third of patients with AD, though
these are usually from tertiary centers seeing
patients with severe disease.
d Positive food allergy tests are common in children
with AD, but skin prick testing and RASTs poorly
predict actual food reactions in patients.
d The clinical relevance of food allergy to the
worsening of eczematous lesions in AD is controversial. Studies regarding eczematous reactions
are hampered by the difficulty of differentiating
early- from late-phase reactions in a disease characterized by frequent fluctuations in disease
severity.
d There are no good data to support the routine use
of elimination diets as adjunctive therapy in AD
if no clinical evidence of type I reactions have
occurred.
Lack G, Fox D, Northstone K, Golding J. Factors associated with the
development of peanut allergy in childhood. N Engl J Med
2003;348:977-85.

This article reports a study performed by allergists

discounting maternal diet as a contributing factor to
the development of peanut allergy. Furthermore, the
strongest predictive factor for the development of
peanut allergy was a history of application of peanut
oil to inflamed skin. This provides further evidence,
albeit indirect, that epicutaneous IgE sensitization
may play a role in allergic diseases.
Sampson H, Ho DG. Relationship between food-specific IgE
concentration. J Allergy Clin Immunol 1997;100:444-51.
Sampson HA. Utility of food-specific IgE concentrations in
predicting symptomatic food allergy. J Allergy Clin Immunol
2001;107:891-6.

A retrospective analysis of RAST levels of foodspecific IgE to egg, milk, peanut, and fish was
performed as compared with double-blind, placebo-controlled food challenges. RAST threshold
levels were determined for predicting with 95%
confidence a clinically relevant immediate food
reaction. These cut-off values were then used to
prospectively analyze 100 consecutive children and
showed very good positive predictive values, but
lower sensitivities. These cut-off values provide an
alternative to double-blind, placebo-controlled food

Simpson and Hanifin 125

challenges and help clinicians counsel patients when

confronted with elevated food-specific IgE levels.

THERAPY
General references
Hanifin JM, Cooper KD, Ho VC, Kang S, Krafchik BR, Margolis DJ,
et al. Guidelines of care for atopic dermatitis. J Am Acad
Dermatol 2004;50:391-404. [www.eblue.org]
Hoare C, Li Wan Po A, Williams H. Systematic review of treatments
for atopic eczema. Health Technol Assess 2000;4:1-191.

The key points throughout this section were

synthesized primarily from the summary findings of
these two exhaustive evidence-based reviews of
therapies for AD. They are invaluable resources for
any practitioner treating patents with AD.
Topical corticosteroids
Key points
d Topical steroids continue to be the mainstay of
AD therapy, although there is a paucity of data
that examine the effects of prolonged topical
steroid use on the growth curve and bone-density
of children.
d An effective general strategy to skin management
is as follows:
d Step 1. Induction of remission
d Step 2. Stabilization and maintenance
d Step 3. Rescue of flares
d Rapid flares of AD are best treated with 5 to 7 days
of a medium- to high-potency topical corticosteroid ointment. The goal of this approach is to
induce partial remission of disease activity. Safer
long-term topical maintenance strategies then
must follow this induction phase.
Hanifin JM, Gupta AK, Rajagopalan R. Intermittent dosing of
fluticasone propionate cream for reducing the risk of relapse
in atopic dermatitis patients. Br J Dermatol 2002;147:528-37.

This study introduces a long-term maintenance

treatment strategy for AD, based on inducing remission with twice-daily fluticasone cream, then using
twice-weekly corticosteroid as maintenance to areas
of skin previously affected. This is a safe and effective method of using corticosteroids once disease
activity has been stabilized.
Thomas KS, Armstrong S, Avery A, Li Wan Po A, ONeill C, Young S,
et al. Randomised controlled trial of short bursts of a potent
topical corticosteroid versus prolonged use of a mild preparation for children with mild or moderate atopic eczema. BMJ
2002;324:768.

Shorter periods of medium-potency topical corticosteroid use are as effective as a longer course of
low-potency corticosteroids in controlling AD flares.
This approach can minimize the time patients are
exposed to topical steroids. Maintenance therapy
follows once disease has been stabilized.

J AM ACAD DERMATOL
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126 Simpson and Hanifin

Topical calcineurin inhibitors

Key points
d Tacrolimus and pimecrolimus are safe and effective in reducing the severity of AD symptoms in
children and adults.
d Tacrolimus has a favorable safety profile for up to
4 years of use
d Tacrolimus and pimecrolimus are useful for maintenance therapy after establishing acute control of
disease flares with topical corticosteroids.
d The calcineurin inhibitors are especially helpful
in head and neck dermatitis where steroid use
should be limited.
(Hanifin JM, Paller A, Eichenfield L, Clark R, Korman N, Weinstein G,
et al. Long-term (up to 4 years) efficacy and safety of tacrolimus
ointments in patients with atopic dermatitis. J Am Acad
Dermatol 2005 (in press).)
Iskedjian M, Piwko C, Shear N, Langley RG, Einarson TR. Topical
calcineurin inhibitors in the treatment of atopic dermatitis: a
meta-analysis of current evidence. Am J Clin Dermatol
2004;5:267-79.

Success rates are similar for tacrolimus and

pimecrolimus in the treatment of AD. No comparison
of efficacy can be made without head-to-head studies, but tacrolimus studies generally involved patients with more severe disease than pimecrolimus
studies did. This article is a good review of all
randomized controlled trials involving the two available calcineurin inhibitors.
Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, et al.
Efficacy and safety of pimecrolimus cream in the long-term
management of atopic dermatitis in children. Pedatrics
2002;110(1 pt 1):e2.
Pimecrolimus cream used for the first signs and symptoms of AD
significantly reduced disease flares and corticosteroid use. This
study serves as a model for relapse prevention strategies using
calcineurin inhibitors.
Nakahara T, Koga T, Fukagawa S, Uchi H, Furue M. Intermittent
topical corticosteroid/tacrolimus sequential therapy improves
lichenification and chronic papules more efficiently than intermittent topical corticosteroid/emollient sequential therapy in
patients with atopic dermatitis. J Dermatol 2004;31:524-8.

Although the study was unblinded, the authors

examined the idea of combining topical immunomodulators with intermittent topical steroids to improve clinical outcomes and reduce the adverse
effects of long-term steroid use. Subjects were
treated with topical steroid 4 days per week and
tacrolimus ointment 3 days per week. The combination treatment showed greater improvement in
long-term AD lesions than intermittent steroids
alone.
Phototherapy
Key points
d Broadband UVA and UVB, narrowband UVB,
combination UVAB, oral and bath psoralen

plus ultraviolet A (PUVA), and UVA1 have all

shown clinical safety and efficacy in the treatment
of AD.
One study has shown narrowband UVB to be as
effective as bath PUVA in AD

(Der-Petrossian M, Seeber A, Honigsmann H, Tanew A. Half-side

comparison study on the efficacy of 8-methoxypsoralen bathPUVA versus narrow-band ultraviolet B phototherapy in patients with severe chronic atopic dermatitis. Br J Dermatol
2000;142:39-43).
d

Studies are needed in comparison of narrowband

UVB to broadband UVB, UVAB, and to UVA1.

Scheinfeld NS, Tutrone WD, Weinberg JM, DeLeo VA. Phototherapy of atopic dermatitis. Clin Dermatol 2003;21:241-8.

This article provides a good overall review of

phototherapy for AD.
Reynolds NJ, Franklin V, Gray JC, Diffey BL, Farr PM. Narrow-band
ultraviolet B and broad-band ultraviolet A phototherapy in
adult atopic eczema: a randomized controlled trial. Lancet
2001;357:2012-6.

Narrowband UVB is safe and effective for the

adjunctive treatment of moderate to severe AD and is
more effective than broadband UVA.
Krutmann J, Diepgen TL, Luger TA, Grabbe S, Meffert H,
Sonnichsen N, et al. High-dose UVA1 therapy for atopic
dermatitis: results of a multicenter trial. J Am Acad Dermatol
1998;38:589-93.

UVA1 is more effective in controlling AD than

UVAB combination therapy and medium-potency
topical steroids. UVA1 is emerging as a new therapy
for acute flares of AD. The utility of UVA1 is hindered
by the high temperatures generated during treatment, which can be intolerable to patients. Cooling
systems have been devised to improve tolerability
and may improve efficacy.
Systemic therapy
Patients with severe AD frequently have a disabling chronic condition that requires aggressive,
definitive therapy both to induce remission and
to maintain control. As an example, phototherapy,
both for onset and duration of effectiveness, is
greatly aided by remittive systemic therapy. Oral
or intramuscular corticosteroids are neither safe
nor practical except for brief, 1-week courses to
control acute crises. Safer systemic therapy for
prolonged controlthe obvious need in a chronic
condition like ADis best achieved with other
immunosuppressants.
Sidbury R, Hanifin J. Systemic therapy for atopic dermatitis. Clin
Exp Dermatol 2000;25:559-66.

A comprehensive review of agents and strategies

for managing difficult AD is presented.

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VOLUME 53, NUMBER 1

Akhavan A, Rudikoff D. The treatment of atopic dermatitis

with systemic immunosuppressive agents. Clin Dermatol
2003;21:225-40.

Clinical guidelines are created in this review for

the safe and effective use of cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, and
interferon gamma as systemic therapies for AD.
Cyclosporine
Key points
d Cyclosporine is the best-studied immunosuppressant for the treatment of AD.
d Several studies have proven its safety and efficacy
in the treatment of adult and childhood AD.
d Hypertension and renal toxicity limit the continuous use of cyclosporine, except in patients with
the most severe disease.
d Dose levels of 5 mg/kg are usually necessary to
induce remission of AD in patients with severe
disease for whom cyclosporine is appropriate.
Berth-Jones J, Graham-Brown RA, Marks R, Camp RD, English JS,
Freeman K, et al. Long-term efficacy and safety of cyclosporine
in severe adult atopic dermatitis. Br J Dermatol 1997;136:
76-81.

Intermittent, 12-week courses of cyclosporine

serve as an alternative strategy to continuous therapy
and have been shown to be more effective than
UVAB phototherapy.
Azathioprine
Key points
d Generally, the middling responses, along with
high incidence of adverse events, place this therapy behind cyclosporine in the therapeutic ladder
for severe AD.
d Onset of effect is slow and patients are often
discouraged by the prolonged course with effects
that are not dramatic.
d As with use in bullous disease, dosing should be
adjusted according to thiopurine methyltransferase genotype/levels.
Berth-Jones J, Takwale A, Tan E, Barclay G, Agarwal S, Ahmed I,
et al. Azathioprine in severe adult atopic dermatitis: a doubleblind, placebo-controlled, crossover trial. Br J Dermatol
2002;147:324-30.

This randomized, placebo-controlled study confirmed the efficacy of azathioprine as adjunctive

treatment for AD seen in previous open-label studies. Clinical scores improved by 26% in the azathioprine group versus 3% in the placebo group (P \
.01). Gastrointestinal disturbances were common
with this treatment. Blood cell counts and liver
function tests need to be followed closely.

Simpson and Hanifin 127

Mycophenolate mofetil
Grundmann-Kollman M, Podda M, Ochsendorf F, Boehncke W-H,
Kaufmann R, Zollner TM. Mycophenolate mofetil is effective in
the treatment of atopic dermatitis. Arch Dermatol
2001;137:870-3.

This inhibitor of purine synthesis decreased clinical scores by more than 50% in an open-label study
of 10 adults with AD. The majority of patients had a
prolonged remission as measured at the 12-week
follow-up time point. Mycophenolate mofetil adds
an immunosuppressant to the AD treatment armamentarium with a better safety profile than cyclosporine or azathioprine, but controlled studies are
needed to prove efficacy.
Interferon gamma
Key points
d This therapy, given by daily subcutaneous injection at bedtime, can provide rapid and lasting
benefit.
d The expense of IFN-g limits its use, but for
patients with severe disease for whom cyclosporine therapy failed, it can be a welcome alternative.
d Once stabilized, some patients can be maintained
on alternate-day or once-weekly dosing.
Stevens SR, Hanifin JM, Hamilton T, Tofte SJ, Cooper KD. Longterm effectiveness and safety of recombinant human interferon-gamma therapy for atopic dermatitis despite unchanged
serum IgE levels. Arch Dermatol 1998;134:799-804.

Treatment effectiveness can be maintained with

up to 2 years of continuous therapy. Improvement in
skin scores were seen despite no changes in IgE
levels. Eosinophils were reduced in this study, indicating a TH2 to TH1 switch likely was occurring in AD
immunocytes. This study highlights the importance
of cellular immune defects, over humoral defects, as
the most important driving force in AD.
Anti-IgE therapy
Key points
d A humanized antibody, omalizumab, has less
than 5% murine composition and has been marketed for allergic asthma, usually given as
monthly injections.
d Questions arise as to its potential for AD but there
is no evidence for an IgE role in eczema, and
generally the total IgE levels in AD are too high to
be neutralized.
Antihistamines and leukotriene inhibitors
Key points
d Although they do not have direct effects on the
pruritus associated with AD, sedating antihistamines can be helpful to improve sleep in flaring

J AM ACAD DERMATOL
JULY 2005

128 Simpson and Hanifin

patients and to reduce symptoms of accompanying respiratory allergy.

Leukotriene inhibitors, developed for asthma,
have received considerable word-of-mouth testimonial support, and a few unblinded trials have
been reported; however, negative results have
been associated with controlled trials, which seldom get reported.

Klein PA, Clark RA. An evidence-based review of the efficacy of

antihistamines in relieving pruritus in atopic dermatitis. Arch
Dermatol 1999;135:1522-5.

This evidenced-based review of the literature

found no evidence to support the effectiveness
of nonsedating antihistamines in the treatment
of AD.
Miscellaneous treatments
Key points
d There is no definitive evidence that routine diet
restriction or allergen avoidance has a role in the
treatment of AD except in cases where acute
clinically relevant reactions have occurred.
d No therapeutic value has been proven for dietary
supplementation or alternative therapy for AD.
d Preliminary studies of massage therapy, hypnotherapy, and biofeedback have been encouraging.
Van Gool CJAW, Zeegers MPA, Thijs C. Epidemiology and health
services research oral essential fatty acid supplementation in
atopic dermatitisa meta-analysis of placebo-controlled trials.
Br J Dermatol 2004;150:728-40.

This meta-analysis of oral fatty-acid replacement

studies concluded they provided no improvement.

NURSING
Cork MJ, Britton J, Butler L, Young S, Murphy R, Keohane SG.
Comparison of parent knowledge, therapy utilization and
severity of atopic eczema before and after explanation and
demonstration of topical therapies by a specialist dermatology
nurse. Br J Dermatol 2003;149:582-9.

This study underscores the need for patient education regarding the disease and treatments.
Caregivers have difficulty remembering the relevant
potencies of topical steroids and therapy is compro-

mised unless patients and/or family members have

good understanding.
Hanifin JM, Tofte SJ. Patient education in the long-term management of atopic dermatitis. Dermatol Nursing 1999;11:284-9.

The key to successful treatment of AD lies in

disease education and compliance with topical therapies. No patient with AD should leave your office
without understanding the concepts discussed in this
practical review. This article is a must for nursing staff
who help care for patients with AD.

PREVENTION
Key points
d No good evidence exists for primary prevention
of AD except one controlled study of perinatal
lactobacillus cultures.
d Moisturizers can improve the barrier function in
patients with AD and serve as an important
secondary prevention measure. Few data exist
on the types of moisturizers that are most effective
for this purpose.
d Studies regarding breastfeeding as a primary preventive measure in AD have not shown a consistent protective effect.
Kalliomaki M, Salminen S, Poussa T, Arvilommi H, Isolauri E.
Probiotics and prevention of atopic disease: 4-year follow-up
of a randomized placebo-controlled trial. Lancet 2003;
361:1869-71.

The preventive effects of probiotics on AD appear

to extend beyond infancy. This follow-up study
revealed a relative risk of 0.57 (confidence interval
0.33-0.97) for the intervention group at 4 years. In
other words, probiotics cut the risk of developing AD
in half. Skin prick test reactivity showed no differences between groups.
Heine RG, Hill DJ, Hosking CS. Primary prevention of atopic
dermatitis in breast-fed infants: what is the evidence? J Pediatr
2004;144:564-7.

After reviewing all RCTs involving breastfeeding as

primary prevention, the authors conclude breastfeeding during the first 4 months has a protective
effect when compared with cows milk, but on its own
does not constitute an effective prevention strategy.