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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.
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
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.
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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.
EPIDEMIOLOGY
General reviews
Schultz Larsen F, Hanifin J. Epidemiology of atopic dermatitis.
Immunol Allergy Clin North Am 2002;22:1-24.
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.
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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.
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,
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.
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.
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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.
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,
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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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.
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.
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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.
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.
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.
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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.
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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 article offers a good review of allergy/immunology aspects of AD with special emphasis on the
role of eosinophils.
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.
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.
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.
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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.
In this murine model, IgE levels were 100- to 1000fold higher when antigen was given epicutaneously
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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.
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
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.
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.
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Scheinfeld NS, Tutrone WD, Weinberg JM, DeLeo VA. Phototherapy of atopic dermatitis. Clin Dermatol 2003;21:241-8.
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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.
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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-
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.