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Seminar
Atopic dermatitis
Donald Y M Leung, Thomas Bieber
Atopic dermatitis is a highly pruritic chronic inflammatory skin disorder affecting 10–20% of children worldwide.
Symptoms can persist or begin in adulthood. It is also the most common cause of occupational skin disease in adults.
This disease results from an interaction between susceptibility genes, the host’s environment, pharmacological
abnormalities, skin barrier defects, and immunological factors. New management approaches have evolved from
advances in our understanding of the pathobiology of this common skin disorder.
Atopic dermatitis is a highly pruritic chronic inflammatory
skin disease that commonly presents during early infancy
and childhood but can persist or start in adulthood.1
Interest in this disease has been sparked by reports of its
increasing prevalence and the significant adverse effects it
can have on quality of life. At least two types of atopic
dermatitis have been identified: an extrinsic type
associated with IgE-mediated sensitisation, which affects
70–80% of patients; and an intrinsic type without IgE-
mediated sensitisation, which affects 20–30% of patients.2
Here, we will discuss some of the advances in our
understanding of this disease and new treatment
approaches that have been introduced.
Epidemiology
Atopic dermatitis is a major public-health problem
worldwide with a lifetime prevalence in children of
10–20%, and a prevalence of 1–3% in adults.3 Prevalence
of this disease has increased by two to three-fold during the
past three decades in industrialised countries, but remains
much lower in agricultural regions such as China, eastern
Europe, and rural Africa. Moreover, higher prevalences
have been recorded in urban regions than in rural regions
of developed countries, and the disease is more common in
higher social class groups.4
Wide variations in prevalence have been identified
within countries inhabited by similar ethnic groups,
suggesting that environmental factors determine
expression of atopic dermatitis.5 Results of comparative
studies in former east and west Germany have confirmed
that lifestyle and environment play a major part in
expression of atopic diseases, including atopic dermatitis.6
Some of the risk factors associated with the rise in atopic
disease include small family size, increased income and
education, migration from rural to urban environments,
and increased use of antibiotics—ie, the so-called western
lifestyle.7 These observations are lent support by studies8 in
which allergic responses were shown to be driven by
T-helper type (Th) 2 immune responses, whereas
infections are induced by Th1 immune responses. Since
Lancet 2003; 361: 151–60
Division of Pediatric Allergy and Immunology, National Jewish
Medical and Research Center, Denver, CO, USA, and Department
of Pediatrics, University of Colorado Health Sciences Center,
Denver, CO (Prof D Y M Leung MD); Department of Dermatology,
University of Bonn, Bonn, Germany (Prof T Bieber MD)
Correspondence to: Prof Donald Y M Leung, National Jewish Medical
and Research Center, 1400 Jackson Street, Room K926, Denver,
CO 80206, USA
(e-mail: leungd@njc.org)
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For personal use. Only reproduce with permission from The Lancet Publishing Group.
Th1 responses antagonise development of Th2 cells, a
decreased number of infections or the absence of Th1
polarising signals (such as endotoxin) during early
childhood could predispose children to enhanced Th2
allergic responses.
Clinical diagnosis
Atopic dermatitis offers a wide clinical spectrum ranging
from minor forms such as pityriasis alba (dry depigmented
patches) or hand eczema to major forms with
erythrodermic rash. The most common forms include the
clinical features listed in panel 1.9 Of the major features,
pruritus and chronic or relapsing eczematous lesions with
typical shape and distribution are essential for diagnosis.
Although pruritus can occur throughout the day, it is
usually worse in the early evening and night. Pruritis
results in scratching, lichenification, and prurigo papules.
Patients with atopic dermatitis have a reduced threshold
for pruritus. Allergens, reduced humidity, excessive
sweating, and low concentrations of irritants can
exacerbate pruritus and scratching.
Acute and subacute skin lesions (figure 1) are often
seen in children and are characterised by intensely pruritic
erythematous papules associated with excoriation and
serous exudate. Chronic atopic dermatitis is characterised
by lichenification, papules, and excoriations. At all stages
of this disease, patients usually have dry lacklustre skin.
The distribution and skin reaction pattern varies
according to the patient’s age and disease activity. During
infancy, atopic dermatitis is generally more acute and
mainly affects the face, scalp, and extensor surfaces of the
extremities. In older children and in those who have long-
standing skin disease, the patient develops lichenification
and localisation of the rash to the flexural folds of the
extremities. Chronic hand eczema can be the primary
manifestation of many adults with atopic dermatitis.
Panel 2 lists other disorders that share symptoms and
signs with atopic dermatitis. These should be considered
and ruled out before a diagnosis of atopic dermatitis is
made.
Search strategy and selection criteria
We did a computer-aided search of PubMed from 1990
through May, 2002, for aspects of atopic dermatitis pertinent
to this review, to supplement our existing awareness of the
primary published work. We searched using the keywords
atopic dermatitis and eczema. Because of limitations on the
number of citations, we made selections from the 2043
reports published on atopic dermatitis in the past decade to
support our interpretations with criteria for assessing
experimental studies and evidence-based medicine.
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Panel 1: Clinical features of atopic dermatitis*
Essential features
Pruritus
Facial and extensor eczema in infants and children
Flexural eczema in adults
Chronic or relapsing dermatitis
Frequently associated features
Personal or family history of atopic disease
Xerosis
Cutaneous infections
Non-specific dermatitis of the hands or feet
Raised serum IgE concentrations
Positive immediate-type allergy skin tests
Early age of onset
Other features
Ichthyosis, palmar hyperlinearity, keratosis pilaris
Pityriasis alba
Nipple eczema
White dermatographism and delayed blanch response
Anterior subcapsular cataracts, keratoconus
Dennie-Morgan infraorbital folds, orbital darkening
Facial erythema or pallor
*Other skin disorders that can mimic atopic dermatitis should be
excluded.
Pathophysiology
Interactions between susceptibility genes, the host’s
environment, pharmacological abnormalities, and
immunological factors contribute to the pathogenesis of
atopic dermatitis.10 Most of the progress made in
understanding the immunology of this disease is related to
the IgE-mediated or extrinsic form of the disease. Clearly,
atopic dermatitis has an immunological basis—as
confirmed by the observation that primary T-cell
immunodeficiency disorders frequently have raised
concentrations of serum IgE and eczematoid skin lesions
that are cleared after successful bone marrow
transplantation.11 In animals, atopic dermatitis does not
occur in the absence of T cells.12
Figure 1: Clinical (upper) and histological (lower) findings in
acute and chronic atopic dermatitis
Acute (left) and chronic (right) lesions in atopic dermatitis.
Magnification ⫻100.
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Panel 2: Differential diagnosis of atopic dermatitis
Chronic dermatoses
Seborrhoeic dermatitis
Contact dermatitis (allergic or irritant)
Nummular eczema
Psoriasis
Ichthyoses
Congenital disorders
Netherton's syndrome
Familial keratosis pilaris
Infections and Infestations
Scabies
HIV-associated dermatitis
Dermatophytosis
Malignant diseases
Cutaneous T-cell lymphoma (Mycosis, fungoides/Sézary
syndrome)
Letterer-Siwe disease
Immunological disorders
Dermatitis herpetiformis
Pemphigus foliaceus
Graft versus host disease
Dermatomyositis
Immunodeficiencies
Wiskott-Aldrich syndrome
Severe combined immunodeficiency
Hyper-IgE syndrome
DiGeorge syndrome
Metabolic disorders
Zinc deficiency
Pyridoxine (vitamin B6) and niacin
Multiple carboxylase deficiency
Phenylketonuria
The systemic immune response
Most patients with atopic dermatitis have peripheral
blood eosinophilia and increased serum IgE
concentrations. Nearly 80% of children with atopic
dermatitis develop allergic rhinitis or asthma, suggesting
that allergen sensitisation through the skin predisposes
people to respiratory diseases.13 Peripheral blood
mononuclear cells from patients with atopic dermatitis
have a decreased capacity to produce interferon ␥, which
is inversely correlated with serum IgE concentrations.
This association could be due to a deficiency of
interleukin 18, an inducer of interferon ␥ production.14
An increased frequency of allergen-specific T cells
producing interleukin 4, 5, and 13, but little interferon ␥,
in the peripheral blood of patients with atopic dermatitis
has also been recorded.15 These immunological changes
are important because interleukins 4 and 13 are the only
cytokines that induce germline transcription at the
⑀ exon, thereby promoting isotype switching to IgE.
These cytokines also induce expression of vascular
adhesion molecules such as VCAM-1, which are
involved in eosinophil infiltration and downregulate
Th1-type cytokine activity. By contrast, interferon ␥
inhibits synthesis of IgE, proliferation of Th2 cells, and
expression of the interleukin 4 receptor on T cells.
Interleukin 5 plays a key part in development, activation,
and survival of eosinophils. The cytokine micromilieu in
which T-cell development takes place, pharmacological
factors, the costimulatory signals used during T-cell
activation, and the antigen-presenting cell determine the
outcome of the T-cell response.16–18
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Skin pathology and immunopathology
Clinically unaffected skin of patients with atopic
dermatitis is not normal, but reveals a sparse perivascular
T-cell infiltrate.19,20 Acute eczematous skin lesions are
characterised by marked epidermal intercellular oedema
(spongiosis) (figure 1). Antigen-presenting cells (eg,
Langerhans cells, inflammatory dendritic epidermal cells,
and macrophages) in lesional and, to a lesser extent in
skin without lesions, have IgE molecules (figure 2).21 In
dermis with acute lesions, there is a striking infiltration of
CD4 activated T cells. Chronic lichenified lesions are
characterised by an acanthotic epidermis with elongation
of the rete ridges, parakeratosis, and only minimum
spongiosis (figure 1). Chronic lichenified lesions have an
increased number of IgE-bearing Langerhans cells and
inflammatory dendritic epidermal cells in the epidermis,
and macrophages dominate the dermal mononuclear
cell infiltrate. These lesions also contain eosinophils,
which are thought to contribute to inflammation and
tissue injury through production of reactive oxygen
intermediates and proinflammatory cytokines and release
of toxic granule proteins.
Cytokine expression—Two approaches have provided
important information about the cytokine pattern
expressed in acute versus chronic atopic dermatitis
(figure 3). First, analyses of biopsy samples from
unaffected skin of patients with atopic dermatitis, as
compared with healthy non-atopic skin, have an increased
number of Th2 cells expressing mRNA of interleukins 4
and 13.22,23 When compared with healthy skin or
unaffected skin of patients with atopic dermatitis,
Figure 2: Dendritic cells in atopic dermatitis skin lesion
Expression of CD1a (upper) and IgE (lower). Magnification ⫻100.
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SEMINAR
naturally occurring lesional skin has significantly more
cells expressing mRNA of interleukins 4, 5, and 13.
However, acute atopic dermatitis does not contain
significant numbers of cells expressing mRNA of
interferon ␥ or interleukin 12. By contrast, chronic atopic
dermatitis skin lesions have significantly fewer cells
expressing mRNA of interleukins 4 and 13, but increased
numbers of cells expressing mRNA of interleukin 5, GM-
CSF, interleukin 12, and interferon ␥ than do those of
acute atopic dermatitis.
In another approach using the atopy-patch test
technique as a model, lesions induced by house dust
mites were shown to have two phases: an initial phase
with mostly Th2 cells producing interleukin 4 and a
subsequent phase after 24–48 h with mainly Th1 cells
producing interferon ␥.24 This switch is probably started
by local production of interleukin 12 from infiltrating
eosinophils, or inflammatory dendritic epidermal cells,
or both.
Activated T cells also induce keratinocyte apoptosis,
contributing to the spongiotic process seen in acute atopic
dermatitis.25 This process is mediated by interferon ␥
derived from T cells, which upregulates Fas on
keratinocytes. The lethal hit is delivered to keratinocytes
by membranous and soluble Fas-ligand produced by
epidermotropic T cells.
Antigen-presenting cells—Atopic dermatitis skin
contains an increased number of IgE-bearing Langerhans
cells and inflammatory dendritic epidermal cells
expressing the high-affinity receptor for IgE.26 These
antigen-presenting cells seem to have an important role in
allergen presentation to Th2 and Th1 cells, respectively.27
In this regard, high-affinity receptors for IgE contribute
to the capture and internalisation of allergens before their
processing and antigen presentation to T cells in atopic
skin. Langerhans cells positive for these receptors can also
migrate to the lymph nodes and stimulate naive T cells,
thereby contributing to expansion of the pool of Th2 cells.
The clinical importance of these cells is supported by the
observation that Langerhans cells with high-affinity
receptors for IgE need to be present to provoke
eczematous skin lesions by application of aeroallergens on
the skin of atopic patients.28
Inflammatory cell infiltration—Interleukin 16, a
chemoattractant for CD4 T cells, is more highly expressed
in acute than chronic atopic dermatitis skin lesions.29,30
The C-C chemokines, T cells expressed and secreted
(RANTES), monocyte chemotactic protein 4 (MCP4),
and eotaxin are also increased in atopic dermatitis skin
lesions and probably contribute to the chemotaxis
of eosinophils expressing CCR3 and Th2 lymphocytes
into the skin.31,32 Cutaneous T-cell-attracting chemokines
could have a role in the preferential attraction of
cutaneous lymphoid antigen T cells to the skin.33 Selective
recruitment of Th2 cells expressing CCR4 into skin with
atopic dermatitis might also be mediated by the
chemokines MDC and TARC, which are increased in
atopic dermatitis.34–36 Persistent skin inflammation in
chronic lesions could be because of expression of
interleukin 5 and GM-CSF in the skin, which lengthen
survival of eosinophils, monocyte-macrophages, and
Langerhans cells.37
Mechanical trauma also induces release of tumour
necrosis factor ␣ and many other proinflammatory
cytokines from epidermal keratinocytes.38 Epidermal
keratinocytes from patients with atopic dermatitis
produce significantly higher concentrations of RANTES
after stimulation with tumour necrosis factor ␣ and
interferon ␥.39 In atopic dermatitis, but not non-atopic
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Uninvolved
Allergens
Th2
Monocytes
CLA+Th2 cells
Figure 3: Immunological pathways in atopic dermatitis
IL=interleukin. Modified from reference 10 with permission from Mosby/Elsevier Science, St Louis.
dermatitis, keratinocytes are also an important source of
thymic stromal lymphopoietin, which activates dendritic
cells to prime naive Th cells to produce interleukins 4 and
13 and tumour necrosis factor ␣.40 These observations
might explain the link between scratching and the
triggering of Th2-mediated skin inflammation in atopic
dermatitis.
Genetics
Atopic dermatitis is a genetically complex, familially
transmitted disease with a strong maternal influence.
Parental atopic dermatitis confers a higher risk to
offspring than does parental asthma or allergic rhinitis,
suggesting the existence of genes specific to atopic
dermatitis. Several chromosomal regions contain
pathophysiologically relevant candidate genes, especially
on chromosome 5q31–33 since it contains a clustered
family of Th2 cytokine genes—ie, interleukins 3, 4, 5, and
13, and GM-CSF.41 Results of a case-control compar-
ison42 have suggested a genotypic association between the
T allele of the –590C/T polymorphism of the interleukin 4
gene promoter region with atopic dermatitis. That this
allele is associated with increased activity of the
interleukin 4 gene promoter suggests that it might affect
atopic dermatitis predisposition. Similarly, variants of
the interleukin 13 coding region, a gain-of-function
polymorphism in the ␣ subunit of the interleukin 4
receptor (16q12), and a functional mutation in the
promoter region of RANTES (17q11) have a role in
expression of atopic dermatitis. Atopic dermatitis has
been controversially linked to markers at chromosome
11q13, including the gene encoding for the ␤ chain of the
high affinity receptor for IgE.43 Atopic dermatitis has also
been associated with a low-producer transforming growth
factor ␤-cytokine genotype,44 which could contribute to
increased skin inflammation.
Genome-wide linkage studies have also been done to
identify susceptibility loci for atopic dermatitis. Lee and
colleagues45 suggested that atopic dermatitis is linked to
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Acute Chronic
Microbial
Scratching toxins
Cytokines
Chemokines
IL 13
IL 4
IL 5
ThO IL 12 Th1 IFN ␥
Macrophages
IgE Eosinophils
Circulation
chromosome 3q21, a region that encodes the costimu-
latory molecules CD80 and CD86. By contrast, Cookson
and coworkers46 reported that both atopic dermatitis and
psoriasis were linked to loci on chromosome 1q21 and
17q25, suggesting that common candidate genes are
involved in control of skin inflammation. Since most of
these studies included patients with raised concentrations
of IgE—ie, patients with the IgE-mediated (extrinsic)
type—the genetic background of the non-allergic
(intrinsic) type remains elusive. However, since these
patients usually have the same family history of atopic
diseases as the classical IgE-mediated form, at least one
set of common genes unrelated to IgE-biology is expected.
Immunological triggers
Foods
Food allergens induce skin rashes in nearly 40% of
children with moderate to severe atopic dermatitis.47 Food
allergies in patients with atopic dermatitis might induce
dermatitis and contribute to severity of skin disease in
some patients, whereas in others urticarial reactions, or
non-cutaneous symptoms are elicited. Infants and young
children with food allergies generally have positive
immediate skin tests or serum IgE directed to various
foods, especially egg, milk, wheat, soy, and peanut.48
Importantly, T cells specifc to food allergens have been
cloned from the skin lesions of patients with atopic
dermatitis, providing direct evidence that foods can
contribute to skin inflammation.49 In mice with atopic
dermatitis, oral sensitisation with foods results in
eczematous skin lesions on repeat oral food challenges.50
Aeroallergens
Pruritus and skin lesions can develop after intranasal or
bronchial inhalation challenge with aeroallergens in
sensitised (specific IgE) patients with atopic dermatitis.51
Epicutaneous application of aeroallergens (eg, house dust
mites, weeds, animal danders, and moulds) by atopy
patch test on unaffected atopic skin elicits eczematoid
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reactions in 30–50% of patients with atopic dermatitis.52
By contrast, atopy patch tests are usually negative in
patients with respiratory allergy and in healthy volunteers.
A combination of effective measures for reduction of
house dust mites has been associated with significant
improvement in atopic dermatitis.53,54 The degree of IgE
sensitisation to aeroallergens is directly associated with the
severity of atopic dermatitis.55 The isolation from skin
lesions with atopic dermatitis and allergen patch test sites
of T cells that selectively respond to Dermatophagoides
pteronyssinus and other aeroallergens provides further
evidence that the immune response in atopic dermatitis
skin can be elicited by aeroallergens.52
Autoallergens
In the 1920s, several investigators56 reported that human
skin dander could trigger immediate hypersensitivity
reactions in the skin of patients with severe atopic
dermatitis, suggesting that these patients made IgE
against autoantigens in the skin. Most sera from patients
with severe atopic dermatitis contain IgE antibodies
directed against human proteins.57 Although the
autoallergens characterised to date are mainly intracellular
proteins,58 they have been detected in IgE immune
complexes of atopic dermatitis sera, suggesting that
release of these autoallergens from damaged tissues could
trigger responses mediated by IgE or T cells. This notion
is supported by the observation that IgE autoallergen
titres decrease with successful treatment of atopic
dermatitis with ciclosporin,59 suggesting that although IgE
immune responses are initiated by environmental
allergens, allergic inflammation can be maintained by
human endogenous antigens, especially in severe atopic
dermatitis.
Staphylococcus aureus
Increased numbers of S aureus are found in over 90% of
atopic dermatitis skin lesions. The importance of this
organism is lent support by the observation that, in
patients with atopic dermatitis with secondary infection,
treatment with a combination of anti-staphylococcal
antibiotics and topical glucocorticoids produces superior
clinical effects than does treatment with topical
glucocorticoids alone.60 One strategy by which S aureus
exacerbates or maintains skin inflammation in atopic
dermatitis is by secreting superantigens, which stimulate
marked activation of T cells and macrophages.61,62 An
analysis of the peripheral blood skin-homing CLA+
T cells from these patients and T cells in their skin lesions
shows that they have undergone a T-cell receptor V␤
expansion consistent with superantigenic stimulation.63,64
Most patients with atopic dermatitis make specific IgE
antibodies directed against staphylococcal superantigens;
these super antigens to IgE correlate with the severity of
disease.62 Superantigens augment synthesis of allergen-
specific IgE and induce glucocorticoid resistance,
suggesting that superantigens could increase severity of
atopic dermatitis through several mechanisms.65,66
Fulfilling Koch’s postulates, application of atopic
dermatitis superantigens to the skin induces dermatitis.67
Increased binding of S aureus to skin is probably related
to underlying atopic dermatitis inflammation. This
observation is lent support by the finding that treatment
with topical glucocorticoids or tacrolimus reduces
S aureus counts on atopic skin.68,69 Scratching probably
enhances S aureus binding by disturbing the skin barrier
and exposing extracellular matrix adhesins for S aureus
such as fibronectin and collagens. In studies70,71 of
S aureus binding to skin lesions undergoing Th1 versus
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Th2 inflammatory responses, bacterial binding was
significantly greater at skin sites with Th2-mediated
inflammation than at those with Th1-mediated
inflammation because of expression of fibronectin
induced by interleukin 4. Atopic dermatitis skin is also
deficient in antimicrobial peptides needed for host
defense against bacteria, fungi, and viruses.72 Thus, once
S aureus binds to atopic dermatitis skin, inadequate host
defence allows bacteria to colonise and predispose
patients to infection.
Management
Successful management of atopic dermatitis requires a
multipronged approach involving skin care, identification
and elimination of flare factors, and anti-inflammatory
treatment.73 Randomised controlled trials are especially
important in assessing the effects of treating atopic
dermatitis because of the substantial placebo effect in this
disease.
Skin care
In atopic dermatitis, the disturbed function of the skin
barrier is probably the result of reduced ceramide
concentrations and results in dry skin (xerosis) and
enhanced transepidermal water loss.74 Irritants such as
soaps or detergents, contact with chemicals, smoke,
alcohol and astringents found in toiletries, and abrasive
clothing can worsen the xerosis. Soaps with minimum
defatting activity and a neutral pH are preferred. Xerosis
contributes to development of epithelial microfissures and
cracks, which allows entry of skin pathogens, irritants, and
allergens. Wet dressings can be used on severely affected
or chronic lesions refractory to skin care. Dressings can be
an effective barrier against persistent scratching, allowing
more rapid healing of excoriated lesions.
Every attempt should be made to allow patients to be as
normally active as possible. Some sports such as
swimming might be better tolerated than other sports
involving intense perspiration, and physical contact, but
chlorine should be rinsed off immediately after swimming
and the skin lubricated.
Identification and elimination of triggering factors
Potential allergens can be identified by taking a careful
history and doing selective allergy tests. Negative skin
prick tests or serum tests for allergen-specific IgE have
a high predictive value for ruling out suspected allergens.
Positive skin or in-vitro allergy tests, especially to
foods, often do not correlate with clinical symptoms and
should be confirmed with controlled food challenges,
elimination diets, or atopy patch tests. Avoidance of
foods implicated in controlled challenges results in
clinical improvement.47,75 As a rule, extensive elimination
diets, which in some cases can be nutritionally deficient,
are useless. Most children who are allergic to food
outgrow their food hypersensitivity in the first few years of
life, making it less relevant as trigger factor when older.
Extended avoidance of house dust mites in sensitised
patients with atopic dermatitis results in improvement of
their skin disease. Avoidance measures include use of
house dust mite-proof encasings on pillows, mattresses,
and boxsprings; washing bedding in hot water weekly;
removal of bedroom carpeting; and decreasing indoor
humidity levels.53,54
Unlike allergic rhinitis and extrinsic asthma,
immunotherapy with aeroallergens has not been proven to
be effective in treatment of atopic dermatitis. Well
controlled studies are still needed to determine the role of
immunotherapy in this disease, and this approach should
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be reserved for individuals who have a clear cut
demonstrable history of aeroallergen induced atopic
dermatitis—eg, seasonal exacerbations to pollen.
Topical anti-inflammatory agents
Glucocorticoids—Topical glucocorticoids are frequently
used to control acute exacerbation of atopic dermatitis.
However, once control of atopic dermatitis is achieved
with a daily regimen of topical glucocorticoids, long-term
control can be maintained with twice weekly applications
of topical fluticasone to regions that have healed but are
prone to developing eczema.76 Side-effects from topical
glucocorticoids are directly related to the potency ranking
of the compound and the length of use, so the clinician
needs to instruct the patients and to balance the need for a
more potent steroid with the potential for side-effects.
Therefore, ultra-high-potency glucocorticoids should be
used only for very short periods of time and in regions that
are lichenified but not on the face or intertriginous areas.
Tacrolimus—Topically applied FK-506, or tacrolimus, a
calcineurin inhibitor that acts by binding with high affinity
to the 12 kDa macrophilin, has been successfully used in
treatment of atopic dermatitis. Tacrolimus inhibits
activation of several key cells involved in atopic dermatitis,
including T cells, dendritic cells, mast cells, and
keratinocytes.77 Multicentre blinded vehicle-controlled
phase-3 trials with 0·03% and 0·1% tacrolimus ointment,
have shown tacrolimus to be both effective and safe in
adults and children.78–80 Local burning sensation has been
the only common adverse event and most patients have
greatly reduced pruritus within 3 days of starting
treatment. In adults, but not children, a dose-response
effect was seen between 0·03% and 0·1% tacrolimus,
especially for patients with severe skin disease.
Long-term open-label studies81 with tacrolimus
ointment applied on up to 100% body surface area have
been done in adults and children with sustained efficacy
and no important side-effects—eg, no increased skin
infections. In addition, unlike topical glucocorticoids,
tacrolimus ointment is not atrophogenic and has been
used safely for facial and eyelid eczema. Of note, three
children with Netherton syndrome, who responded to
treatment with 0·1% tacrolimus ointment, had
substantial percutaneous absorption of the drug, with
serum concentrations well above the therapeutic range.82
In retrospect, this observation is not surprising, since
patients with Netherton syndrome have a skin barrier
dysfunction that puts them at risk for increased
percutaneous absorption of topical drugs. Since patients
with Netherton syndrome are sometimes misdiagnosed
as having atopic dermatitis, this diagnosis should be
considered in any infant or child with extensive
erythroderma resistant to treatment and monitored for
blood tacrolimus concentrations as deemed appropriate
by the care provider. Increased blood concentrations of
tacrolimus have generally not been reported in patients
with moderate to severe atopic dermatitis. Indeed,
quantifiable tacrolimus blood concentrations are isolated
and transient occurrences seen only early in treatment.
However, the potential risk of systemic absorption must
be considered in any child with extensive skin disease
because of their high ratio of body surface area to
weight. In this situation, especially if patients develop
infection or changes in liver or kidney function, plasma
drug concentrations should be obtained. 0·03%
tacrolimus ointment has been approved for short-term
and intermittent long-term use in for children
2–15 years of age with moderate to severe atopic
dermatitis; and 0·03% and 0·1% for adults.
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Pimecrolimus—Ascomycin compounds such as
pimecrolimus, which has the same mechanism of action as
tacrolimus, have been developed in topical and oral forms.
Like tacrolimus, they inhibit production of Th1 and
Th2 cytokines, and inhibit mediator release from mast
cells and basophils.83 1% pimecrolimus is effective and
safe in adults and children with atopic dermatitis.84,85
Pimecrolimus cream ointment 1% has been approved for
short-term and intermittent long-term use in mild-
moderate atopic dermatitis for patients 2 years and older.
When used as maintenance therapy, topical pimecrolimus
reduces the number of flares caused by atopic dermatitis
and reduces requirements for corticosteroid therapy.86
The approval of topical calcineurin inhibitors for
treatment of atopic dermatitis is a great advance in our
management options for this disease. However, we should
still develop guidelines for use of topical corticosteroids
versus calcineurin inhibitors. Topical calcineurin
inhibitors can be advantageous over topical corticos-
teroids in some circumstances, including treatment of
patients who do not respond well to topical steroids,
patients with steroid phobia, and treatment of face and
neck dermatitis where ineffective, low-potency topical
corticosteroids are usually used because of fears of
steroid-induced skin atrophy. The potential use of topical
calcineurin inhibitors as maintenance therapy is also
intriguing for prevention of atopic dermatitis flares.86
However, although systemic absorption of these
compounds are low, the drugs need to be carefully
monitored to rule out the possibility that skin cancers and
increased viral skin infections will appear when such
agents are used long-term.
Tar preparations—Coal tar preparations have anti-
pruritic and anti-inflammatory effects on the skin but are
less active than glucocorticoids. Their use is restricted to
chronic lesions and they can induce folliculitis and photo-
sensitivity. There is a theoretical risk of tar being a
carcinogen based on observational studies of workers
using tar components in their occupations.
Anti-infectious management
Antistaphylococcal antibiotics can be helpful in treatment
of poorly-controlled patients who are heavily colonised or
infected with S aureus.87 Topical mupirocin or fusidic acid
is useful in treatment of localised impetiginised lesions. In
patients with extensive superinfection with sensitive
S aureus strains, a course of systemic antibiotics such as
erythromycin and the newer macrolide antibiotics
(azithromycin and clarithromycin) is usually beneficial.
However, for macrolide-resistant S aureus, a penicillinase-
resistant penicillin (dicloxacillin, oxacillin, or cloxacillin)
and first-generation cephalosporins might be preferred.
Atopic dermatitis can be complicated by recurrent viral
skin infections such as warts and mollusca contagiosa
which can reflect local defects in T-cell function.88 Herpes
simplex, resulting in Kaposi’s varicelliform eruption
or eczema herpeticum can be a serious infection. After
an incubation period of 5–12 days, many itchy
vesiculopustular lesions erupt in a disseminated pattern;
vesicular lesions are umbilicated, tend to crop, and
often become haemorrhagic and crusted (figure 4). The
presence of punched-out erosions, vesicles, or infected
skin lesions that do not respond to oral antibiotics should
initiate a search for herpes simplex. Antiviral treatment for
cutaneous herpes simplex infections is of crucial
importance in patients with widespread atopic dermatitis
since life-threatening dissemination has been reported. In
patients with atopic dermatitis, smallpox vaccination or
even exposure to vaccinated individuals can cause a severe
THE LANCET • Vol 361 • January 11, 2003 • www.thelancet.com

Figure 4: Eczema herpeticum
Magnification ⫻4.
widespread skin rash called eczema vaccinatum similar in
appearance to eczema herpeticum.
Patients with atopic dermatitis have increased
prevalence of fungal infections compared with non-atopic
controls. The role of Malassezia furfur (Pityrosporum
orbiculare) in atopic dermatitis has been of particular
interest. M furfur is a lipophilic yeast commonly present in
the seborrheic regions of the skin and in the scalp. IgE
antibodies against this organism are frequently found in
patients with atopic dermatitis and most frequently in
patients with head and neck dermatitis.89 The potential
importance of M furfur and other dermatophyte infections
is further supported by the reduction of atopic dermatitis
skin severity in such patients after treatment with
antifungal agents.
Phototherapy
Natural sunlight is frequently beneficial to patients with
atopic dermatitis. However, if the sunlight occurs
together with high heat or humidity, thereby triggering
sweating and pruritus, it can be deleterious to patients.
Broad-band ultraviolet B, broad-band ultraviolet A,
narrow-band ultraviolet B (311 nm), ultraviolet A-1
(340–400 nm), and combined ultraviolet A and B
phototherapy can be useful adjuncts in treatment of
atopic dermatitis.90,91 Photochemotherapy with psoralen
and ultraviolet A (PUVA) should be restricted to patients
with severe, widespread atopic dermatitis, although few
investigators have compared this treatment with other
modes of phototherapy. Short-term adverse effects with
phototherapy can include erythema, skin pain, pruritus,
and pigmentation. Potential long-term adverse effects
include premature skin aging and cutaneous malignant
diseases.
Extracorporeal photopheresis consists of the passage of
psoralen-treated leukocytes through an extracorporeal
ultraviolet A light system. Clinical improvement in skin
lesions associated with reduced IgE concentrations have
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For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
been reported in a few patients with severe, resistant
atopic dermatitis who were given extracorporeal
photopheresis and topical glucocorticoids.
Systemic treatment
Antihistamines—Reduction of skin inflammation and
dryness with topical glucocorticoids and skin care,
respectively, will often symptomatically reduce pruritus.
Systemic antihistamines act mainly by blocking the H1
receptors on dermal mast cells. Since histamine is only
one of many mediators that can induce pruritus, some
patients might derive minimum benefit from treatment
with antihistamines. Results of studies92 of the
effectiveness of newer non-sedating antihistamines in
control of pruritus have varied greatly, although these
drugs could be useful in patients with atopic dermatitis
and concomitant urticaria.
Since pruritus is usually worse at night than during the
day, sedating antihistamines such as hydroxyzine or
diphenhydramine offer an advantage when used at
bedtime. Doxepin hydrochloride has both tricyclic
antidepressant and H1-histamine and H2-histamine
receptor blocking effects. If nocturnal pruritus remains
severe, short-term use of a sedative to allow adequate rest
might be appropriate. Treatment of atopic dermatitis
with topical antihistamines is useless and can induce
cutaneous sensitisation.
Systemic glucocorticoids—Use of systemic gluco-
corticoids, such as oral prednisone, is rarely indicated,
since the clinical improvement is frequently followed by a
severe rebound flare at discontinuation. Short courses of
oral glucocorticoids are sometimes appropriate for an
acute exacerbation while other treatment measures are
being instituted. In this case, it is important to taper the
dose and begin intensified skin care, especially with
topical glucocorticoids and bathing followed by
application of emollients, to prevent rebound flares.
Interferon gamma—Interferon gamma downregulates
Th2 cell function. Treatment with recombinant
interferon gamma results in clinical improvement.93
Reduction in clinical severity of atopic dermatitis
correlated with the ability of this drug to decrease blood
eosinophilia. However, influenza-like symptoms are
commonly seen side-effects early in the treatment course
and limit use of this treatment.
Ciclosporin—Ciclosporin is a potent immuno-
suppressive drug that acts mostly on T cells by
suppressing cytokine transcription. The drug binds to
intracellular cyclophilin and thereby acts in a similar way
to tacrolimus and pimecrolimus. Children and adults
with severe atopic dermatitis refractory to conventional
treatment, can benefit from short-term ciclosporin, with
improved quality of life.94 However, discontinuation of
treatment generally results in relapse flares. Raised serum
creatinine or more substantial renal impairment and
hypertension are specific side-effects of concern.
Antimetabolites—Mycophenolate mofetil is a purine
biosynthesis inhibitor used as an immunosuppressant in
organ transplantation, has been used for treatment of
refractory inflammatory skin disorders.95 Short-term oral
mycophenolate mofetil 2 g daily as monotherapy results
in clearing of skin lesions in adults with atopic dermatitis
resistant to other treatment including topical and oral
steroids and PUVA. The drug is generally well tolerated,
with the exception of occasional herpes retinitis. Dose-
related bone marrow suppression has also been recorded.
Not all patients benefit from treatment. Therefore, the
drug should be discontinued if patients do not respond
within 4–8 weeks.
157
SEMINAR
Methotrexate is an antimetabolite with potent inhibitory
effects on inflammatory cytokine synthesis and cell
chemotaxis. It has been used for patients with recalcitrant
atopic dermatitis, though controlled trials are few.
Azathioprine is a purine analogue with anti-
inflammatory and antiproliferative effects, which has
been used for severe atopic dermatitis, though no
controlled trials have been reported. Myelosuppression is
an important adverse effect, and thiopurinemethyl
transferase concentrations can predict individuals at risk.
Complementary approaches
Emotional stressors—Patients with atopic dermatitis often
respond to frustration, embarrassment, or other stressful
events with increased pruritus and scratching, and stress
can induce immunological changes in such patients.96,97
Psychological assessment or counselling should be
considered in patients who have difficulty with emotional
triggers or psychological problems contributing to
difficulty in managing their disease. Relaxation,
behavioural modification, or biofeedback can be helpful in
patients with habitual scratching.
Other treatments—Leucocytes from patients with
atopic dermatitis have increased cAMP-PDE enzyme
activity. Monocytes from such patients produce raised
concentrations of PGE2 and interleukin 10, which both
inhibit production of interferon ␥ by T cells. Topical
application of PDE inhibitors has shown clinical benefit in
atopic dermatitis.17 Intravenous immunoglobulin reduces
skin inflammation in patients with refractory atopic
dermatitis.98 Results of several studies have also suggested
that patients with atopic dermatitis benefit from treatment
with traditional Chinese herbal therapy.99 The possibility
of hepatic toxic effects, cardiac side-effects, or
idiosyncratic reactions, however, is a concern. The
specific ingredients of the herbs also remain to be
elucidated and some preparations have been found to be
contaminated with glucocorticoids.100
Future directions
Atopic dermatitis is often the first presentation of an
individual destined to a lifetime of allergy and asthma.
Since the skin is a highly sensitising organ that contributes
greatly to the systemic allergic response, highly effective
treatments need to be developed to reduce skin
inflammation in this disease. Advances are likely to need
better definitions for the various clinical phenotypes of
atopic dermatitis, including identification of the genes
leading to the disease, a better understanding of the
immunoregulatory abnormalities underlying it, and new
paradigms for preventing relapses of this skin disorder.
Such advances will probably be tied to development of
pharmacogenetics and targeting of effective treatments to
subsets of patients with atopic dermatitis.
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Uses of error
Laboratory diagnosis
Caroline Mackie Ogilvie
Scientists working in the area of laboratory diagnosis are in
general further removed from the consequences of error
than clinicians who have direct contact with the patients.
But none of us likes to get things wrong, and diagnostic
errors in my own field of genetics, such as failing to identify
an abnormal chromosome on karyotype analysis, tend to
plunge one into gloom and self-reproach for several days, if
not weeks, depending on one’s personality.
In the diagnostic laboratory, the final result of a test may
be prone to error from various sources: inherent errors in
the test, leading to incorrect “output”; errors in the
interpretation of the output (such as the example given
above); and clerical errors in the transfer of information.
Inherent errors in the test are sometimes not appreciated;
for instance, there is a considerable literature on the
abnormal chromosome constitution of a large proportion
of early human embryos in vitro, a conclusion based on
data obtained using a technique called FISH
(Fluorescence In Situ Hybridization). However, the
inherent error rate using FISH is under-appreciated, and it
is possible that many of these so-called abnormalities may
in fact have been due to FISH errors. Our department is
part of a successful Preimplantation Genetic Diagnosis
(PGD) centre, in which both FISH-based and PCR-based
tests are used to diagnose genetic abnormality in single
cells from human cleavage-stage embryos. These tests are
technically very demanding and are prone to output errors
such as those caused by signal overlap (FISH) or single
tube contamination (PCR). The nature of such single cell
work makes error estimations difficult, but we do our best,
Genetics Centre, Guy’s and St Thomas’ Hospital, London SE1 9RT, UK (C M Ogilvie DPhil)
160
For personal use. Only reproduce with permission from The Lancet Publishing Group.
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and these estimates are discussed with prospective
patients. Our programme has been running successfully for
three years; however, we were shocked and saddened
recently to hear that an affected baby had been born
following transfer of an embryo diagnosed as free from a
serious genetic condition. The couple had declined
prenatal diagnosis. Thorough evaluation of the test results
showed that the interpretation of the output was correct.
Therefore the possibilities were that either there had been
an output error in the test, or that there had been
spontaneous natural conception. Statistical analysis
revealed that a single abnormal pregnancy was at this point
well within our estimated error rate. Detailed analysis of
protocols revealed areas that could be improved—for
instance, better counselling of couples with respect to the
use of contraception during their PGD cycle. Although the
potential error rate could be reduced further by
introducing extra parameters into the test, we realised that
any additional measurements to increase the sensitivity
would also decrease the specificity, thus increasing the
chance of excluding normal embryos from transfer due to
errors in the new measurements. As many women
undergoing PGD have small embryo cohorts, a decrease in
test specificity could significantly jeopardise their chances
of establishing a pregnancy. This case has given rise to
useful discussions on the nature and value of error
estimation, and the best and clearest way of presenting
these complex ideas to our patients. We hope that
knowledge of this error will encourage more couples to opt
for prenatal diagnosis following PGD.
THE LANCET • Vol 361 • January 11, 2003 • www.thelancet.com