Drugs (2014) 74:757769

DOI 10.1007/s40265-014-0219-3

REVIEW ARTICLE

Advances in the Diagnosis and Therapeutic Management

of Atopic Dermatitis
Christian Vestergaard Mette Deleuran

Published online: 13 May 2014

! Springer International Publishing Switzerland 2014

Abstract Atopic dermatitis is a very prevalent disease

that affects children as well as adults. The disease has a
severe impact on quality of life for the patients and their
families. The skin in atopic dermatitis patients is a site of
both a severe inflammatory reaction dominated by lymphocytes and decreased skin barrier function. The treatment of the disease is mainly aimed at reducing the
inflammation in the skin and/or restoring the skin barrier
function. However, most of the treatments used today
singularly aim at reducing the inflammation in the skin.
Depending on the severity of the disease, the anti-inflammatory treatment may be topical or systemic, but basic
treatment, no matter the severity, should always be emollients. In addition, new studies have shown good effects of
psychosocial interventions, such as eczema schools, for
patients and their families. This review covers the latest
trends in the treatment of atopic dermatitis.

C. Vestergaard ! M. Deleuran (&)

Department of Dermatology, Aarhus University Hospital,
P.P. rumsgade 11, 8000 Aarhus C, Denmark
e-mail: mettdele@rm.dk

Key Points
Atopic dermatitis is both an inflammatory skin
disease and a disease of the skin barrier function.
Anti-inflammatory treatment is topical but systemic
therapy may be added in severe cases. Treatment
should always be combined with skin barrier
regeneration (moisturizer), and occasionally with
antibacterials.
New emerging biological therapies for atopic
dermatitis are promising.

1 Introduction
Atopic dermatitis (AD) is a chronic or chronically relapsing eczematous disease that affects between 15 and 20 %
of all children in affluent countries [1]. The classical
symptoms are intense pruritus in the affected areas, often
with clinically visible eczema, typically in the flexural
areas of the body [2]. The lesions may be complicated with
bacterial super-infection with Staphylococcus aureus or
viral infections such as Herpes simplex virus [3]. In 60 %
of paediatric cases, the onset of the disease is before the
age of 1 year and in 85 % of the cases before the age of 5
years [4]. Apart from the impact on the patient, the disease
affects the quality of life of the patients family to the same
degree as having a child with diabetes mellitus [5].
Classically, the diagnosis of AD is made on the basis of
the Hanifin and Rajka [6] criteria from 1980, and it is a
clinical diagnosis. There is a long-standing discussion on
whether IgE-mediated allergies are part of the pathogenesis

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of AD and this debate is even more pertinent after the

finding of the importance of filaggrin mutations as the basis
of approximately one-third of all AD patients in Northern
Europe, but with much higher variations in the rest of the
world [7, 8].
The severity of AD dictates the level of treatment. In
mild to moderate cases, topical immunomodulators or
steroids may be used both in a proactive manner to prevent
flare-ups, and as treatment of acute eczema. In moderate to
severe cases, systemic immunomodulatory therapy may be
necessary even in children [9]. However, in all cases the
basic therapy is moisturizers to alleviate the dry skin and
the impaired skin barrier function [10].
This review will discuss the latest trends in diagnosis,
pathogenesis and treatments of AD.

2 The Diagnosis of Atopic Dermatitis (AD)

In the clinic the diagnosis of AD is made on the basis of
The Hanifin and Rajka [6] criteria from 1980 (Table 1), of
which the patient must have at least three major and three
minor criteria. The distribution of the eczema depends on
the age of the patient. In the infantile stage, the face, the
scalp and the extensor sides of the extremities are typically
affected whereas in the childhood phase the eczema is
typically located in the flexural folds of the extremities as
well as the hands and the face. In teenagers and adults the
flexural areas are still the most common sites but the hands
and feet are often involved as well as the face and neck
[11]. The latter is often described as head and neck dermatitis and can be a sign of sensitisation to Malassezia
furfur, which is a skin commensal [12]. In severe cases, the
entire skin organ may be involved and the patients may
develop erythroderma. The affected skin shows a typical
eczema with a maculopapular rash, with or without vesicles, desquamation and excoriations [1]. In certain cases,
the eczema may present itself as a nummular eczema with
sharply demarcated edges, as a pityriasiform lichenoid
eczema or as a follicular-type AD, characterized by plaqueshaped, lichenoid desquamation eczema, which is common
in the Japanese population [13]. Post-inflammatory hypopigmentation is often seen in healed skin in fair skin types
and hyperpigmentation in darker skin types.
A hallmark of AD, and one of the minor criterion in the
Hanifin and Rajka criteria, is dry skin or xerosis, though the
prevalence varies between 48 and 100 % compared with
1440 % in healthy controls [11, 14]. Furthermore, sweatinduced itch, skin reactions upon food intake, hand eczema,
positive skin prick testing, facial erythema and disease
activity influenced by environmental factors are more
prevalent among patients with AD than among healthy
controls [11]. Other signs of AD that are not included in the

C. Vestergaard, M. Deleuran

Hanifin and Rajka criteria are earlobe rhagades (fissures at

the base of the earlobes), atopic winter feet (juvenile
plantar dermatitis), and retro-auricular fissuring.

3 Pathogenesis of AD
Until recently, AD has been perceived as a disease driven
by T helper 2 (Th2; lymphocytes that express interleukin
[IL]-4, IL-5, IL-6 and IL-10), based on the IL-4-dominated
response achieved when peripheral blood mononuclear
cells (PBMCs) from AD patients are stimulated with, for
example, lipopolysaccharide (LPS) [15]. This perception
was supported by the fact that approximately 80 % of all
AD patients had increased serum concentrations of
immunoglobulin E (IgE) [16]. However, over the last
decade this has changed immensely. The perception of IgE
as a central molecule in the pathogenesis has been challenged and it has been suggested that it may just be an
epiphenomenon to the severe inflammation taking place
[8]. The Th2 paradigm has also been questioned as a result
of animal experiments, which show that neither Th2 lymphocytes nor the Th2 pathway are a prerequisite for ADlike eczema [17, 18]. Lastly, the skin barrier function has
drawn much more attention after the milestone publication
showing that lack of filaggrin, due to loss of function
mutations in the FLG gene, increased the risk of having AD
13.4-fold [19].
3.1 Inflammation of the Skin in AD
Classically, the inflammation in AD is described as a
biphasic response with an initial Th2-dominated cytokine
profile; for example, high production of IL-4, IL-5 and IL13 followed by a mixed Th1/Th2 response (e.g., additional
production of IL-2 and interferon-c [IFN-c]) [20]. IL-22
that originates from the Th22 lymphocytes has been
implied in the acute phase of AD as it increases the epidermal growth but down-regulates the skin barrier function
[21, 22], along with IL-31, which also induces pruritus
[23]. Furthermore, the keratinocytes play an active role in
the production of inflammatory signals, as they produce the
skin-specific CC-chemokine-ligand 27 (CCL27) and the
Th2 inducing CCL17 [24, 25]. The latter can also be
induced in dermal dendritic cells by thymic stromal lymphopoietin (TSLP), which is also produced by the keratinocytes. Another cytokine produced by the dendritic cells
in the dermis of AD patients is IL-25 (IL-17E) [26]. This
cytokine is known to induce a Th2 response and has been
found increased not only in AD patients, but also in the
airway epithelium of asthma patients. Interestingly, IL-25
is released from mast cells when the FceRI receptors are
cross-linked by antigens binding to IgE [27]. This may

Diagnosis and Management of Atopic Dermatitis

Table 1 The Hanifin and Rajka
criteria for the diagnosis of
atopic dermatitis [6]

759

Must have three or more basic features:

Pruritus
Typical morphology and distribution:
Flexural lichenification or linearity in adults
Facial and extensor involvement in infants and children
Chronic or chronically relapsing dermatitis
Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Plus three or more minor features:
Xerosis
Ichthyosis/palmar hyperlinearity/keratosis pilaris
Immediate (type I) skin test reactivity
Elevated serum IgE
Early age of onset
Tendency towards cutaneous infections (esp. Staphylococcus aureus and Herpes simplex)/impaired cellmediated immunity
Tendency towards non-specific hand or foot dermatitis
Nipple eczema
Cheilitis
Recurrent conjunctivitis
DennieMorgan infraorbital fold
Keratoconus
Anterior subcapsular cataracts
Orbital darkening
Facial pallor/facial erythema
Pityriasis alba
Anterior neck folds
Itch when sweating
Intolerance to wool and lipid solvents
Perifollicular accentuation
Food intolerance
Course influenced by environmental/emotional factors
White dermographism/delayed blanch

provide a link between food allergies and the flare-ups of

AD.
IL-33 is a member of the IL-1 family, and is described
as a member of the alarmin family [28]. It is released
from keratinocytes upon mechanical stimuli, and binds to
the ST2 receptors that are expressed on mast cells and Th2
lymphocytes, which suggests that IL-33 may be involved in
the early events of AD [29, 30].
In the chronic stages of AD, a more mixed response can
be observed. As already mentioned, more Th1 lymphocytes
can be observed in the skin. The expression of IFN-c is
preceded by IL-12, a cytokine that can be induced in
monocytes by IL-4 [31]. However, recent results have
demonstrated that Th17 lymphocytes, which are usually
associated with psoriasis, are part of the T lymphocyte
infiltrate found in chronic lesions of AD skin [32]. IL-17 is
described as a master regulator of antimicrobial peptides
(AMPs) and may be a key to the decreased expression of

AMPs in AD skin, and the following increased numbers of

skin infections [33].
3.2 Barrier Function and Filaggrin
AD patients have a decreased skin barrier that leads to an
increased trans-epidermal water loss (TEWL) [34, 35] but
also to an increased risk for the patient to acquire allergies
[36]. The composition of the skin barrier is very complex,
but one of the major constituents of the barrier is the outermost layer of the epidermis, the stratum corneum. The
keratinocytes in this layer have undergone apoptosis,
excluded their nuclei and have become completely filled
with keratin [37]. Keratin filaments are tightly cross-linked
by filaggrin molecules and thus a lack of filaggrin leads to a
poorer aggregation of keratin. Filaggrin is encoded by the
FLG gene as profilaggrin, which is made up by 812 filaggrin repeats [38]. Heavy phosphorylation protects

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filaggrin from breakdown [39] until it reaches the stratum

granulosum, in which several proteases including matriptase, prostasin, as well as caspase 14 are situated [4042].
In 2006, Palmer et al. [19] described the significantly
increased risk (OR 13.4) of developing AD in patients
heterozygous for loss of function mutations in the FLG
gene. Filaggrin mutations exist globally but they vary from
population to population. Although defects in this gene to
date have the best correlation with developing AD,
between 44 and 85 % of patients with AD do not have
mutations in the filaggrin gene [34].
Inflammation itself is also able to induce functional
filaggrin defects through down-regulation of filaggrin
production or filaggrin maturation [43]. IL-4 and Il-13,
both classical Th2-type cytokines, down-regulate filaggrin
on a transcriptional level [44]. IL-25, which may be considered as a Th2-inducing cytokine, also down-regulates
filaggrin expression on a transcriptional level [26]. IL-22
that is produced by skin homing T lymphocytes (Th22) and
dendritic cells from the skin down-regulate filaggrin and
profilaggrin on both mRNA and protein levels [21]. IL-31,
which is produced mainly by Th2 lymphocytes but also
mast cells, dendritic cells and monocytes, is strongly
associated with itch, since blocking of this cytokine may
alleviate this symptom [23]. IL-31 also induces IL-20 and
IL-24 in HaCaT cells and through this down-regulates filaggrin expression [45]. Cytokines typically associated with
a Th1 response, such as tumour necrosis factor (TNF)-a
[46] and IL-17A, also down-regulate filaggrin [47].

C. Vestergaard, M. Deleuran

4.1 Basic Treatment

4.1.1 Emollients
Emollients are the mainstay of therapy in AD and should
be applied concomitantly with any other therapy chosen.
Although the mechanism of action for emollients is largely
unknown, several studies have shown that application of
emollients, both in the short and long term, have a steroidsparing effect [48]. However, the use of emollients only
without specific treatment of the inflammatory reaction
may increase the risk of disseminating skin infections [49].
Emollients containing intact proteins such as oats and
peanut may increase the risk of allergies [50, 51].
4.2 Topical Treatment
The use of topical treatment is often the first choice of
pharmacological treatment in AD, either with glucocorticoids or calcineurin inhibitors. The effect of the drug is
determined by three factors: the strength of the drug, the
dosage of the drug, and the application of the drug [52].
Dosing of topical treatment might seem difficult but when
using the fingertip unit (FTU) it is quite simple. One FTU
equals the amount of ointment/cream that can be expressed
from the distal crease of the index finger to the fingertip
(approximately 0.5 g of cream). This covers the body
surface area corresponding to two palms.
Topical treatment can be applied on a daily basis during
acute flares, and twice or thrice weekly as a proactive
treatment during periods of remission.

4 Treatment of AD
4.2.1 Topical Glucocorticoids
The main goal of therapy for AD is relief from the itch and
possibly inhibition of the inflammatory reaction in the skin.
Treatment modalities can be divided into basic therapy,
topical therapy and systemic therapy. Basic therapy
includes non-pharmacological therapies such as emollients
and baths, and avoidance strategies of both specific and
non-specific provoking factors. Topical therapy includes
treatment with topical glucocorticoids and topical calcineurin inhibitors (TCIs) and this may be used either as
acute therapy or as proactive treatment. Systemic therapy
includes the use of immunosuppressants such as systemic
glucocorticoids, azathioprine, cyclosporine A, methotrexate, and in some instances mycophenolate. Phototherapy
and coal tar baths are classic dermatological treatments and
do have an effect in AD. Biologics have so far not been
registered for the treatment of AD, as they have in psoriasis, but early studies indicate that this may happen in the
future. Other modalities such as psychosomatic counselling
and education through eczema schools also have increasing
evidence and are recommended.

Glucocorticoids partly exert their action through binding to

steroid receptors in the cytosol of the cell. The receptor
complex then translocates into the nucleus of the cell,
where it inhibits the expression of inflammatory cytokines
(transrepression), induces the expression of anti-inflammatory cytokines (transactivation) and inhibits the production of structural cytokines [53]. Topical steroids are
grouped according to potency into groups IIV (Europe)
and groups IVII (US), and are effective against inflammation in the skin. In Europe, group I corresponds to the
products with the weakest potency. This is in contrast to
the US, where group I topical corticosteroids corresponds
to the products with the strongest potency. The potency
reflects both the effect of the topical treatment but also the
risk of side effects. One well performed treatment per day,
compared with two, is sufficient to obtain effect of the
treatment [54]. Once the symptoms are controlled, treatment should be tapered either through decrease of application frequency or of potency of the glucocorticoid.

Diagnosis and Management of Atopic Dermatitis

Proactive treatment with application of fluticasone propionate twice weekly during remission periods significantly
reduced flare-ups of the eczema [55].
The use of high-potency steroids increases the risk for
systemic side effects, although the risk for hypothalamuspituitary-adrenal axis suppression is very low [56]. However, high-potency steroids also restore the skin barrier
significantly faster than low-potency steroids, and thus
shorter treatment periods are needed [57]. The restoration
of the skin barrier through glucocorticoids is probably due
to the inhibition of the skin-disrupting effect of inflammation, as shown by betamethasone valerate, which by
itself actually inhibits rate-limiting enzymes for lipid synthesis [58].
4.2.2 Topical Calcineurin Inhibitors
Tacrolimus and pimecrolimus are macrolides that exert
immunosuppression through inhibition of the calciumdependent dephosphorylation of the transcription factor
nuclear factor of activated T cells (NFAT) that is required for
the transcription of inflammatory cytokines such as IL-2 [59].
Both have efficacy in both long- [60, 61] and short-term [62,
63] studies, and have shown a high degree of efficacy in
proactive treatment over a 1-year period with regard to
reduction of both severity and number of flare-ups. The
efficacy of 0.1 % tacrolimus equals that of a corticosteroid of
medium potency [64], whereas pimecrolimus is weaker [65].
There have been controversies over the safety of the drugs,
especially with regard to the risk of non-melanoma skin
cancer and lymphoma. However, a follow-up study over
6 years has shown no increased risk of lymphoma after the
use of TCIs and the photocarcinogenic effect of the drugs has
also been examined and found to be non-existent when used
topically [66]. However, since the systemic use of calcineurin
inhibitors in solid organ transplant patients significantly
increases the risk for non-melanoma skin cancer, the use of
sunscreens is still recommended when using these drugs [64].
4.3 Antibacterials and Antiseptics
Most patients with AD are colonized with S. aureus on
both affected and unaffected skin [67]. A systematic review
found no clear evidence of benefit from the use of antibacterial soaps, antibacterial bath additives or topical
antibacterials/antiseptics [68]. The studies included in the
review were, however, quite small. A randomized controlled trial (RCT) in children with AD showed beneficial
effects of intranasal mupirocin ointment combined with
baths containing sodium hypochlorite (bleach baths) on
disease activity in children [69]. Oral antibacterials are not
recommended when the skin is not clinically infected, but
should be used as a short-term treatment for clinically

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super-infected AD with oozing, crusts, pustules and/or

fissures. Cephalosporins, penicillinase-resistant penicillins,
or clindamycin are preferred for this purpose [70, 71]. In
most countries, methicillin-resistant strains of S. aureus
(MRSA) are an increasing problem, and it is very difficult
to clear the bacteria from patients with active skin disease.
In this context, bleach baths are a useful supplementary
treatment [72].
4.4 UV Phototherapy
Ultraviolet (UV) phototherapy for AD has been used for
many years. Treatments include broadband (BB)-UVB,
narrowband (NB)-UVB, UVA/B, UVA1 and psoralen (P)UVA. Most patients experience significant benefits. A
limitation is that the effectiveness of UV phototherapy is
short term, moderate and followed by recurrence of
symptoms within a few months, especially in patients with
severe AD.
A recent systematic review included 19 RCTs and 905
patients. The studies were clinically and qualitatively heterogeneous, but the authors concluded that UVA-1 and
NB-UVB appear to be the most effective treatment
modalities for the reduction of clinical signs and symptoms
of AD [73].
UV treatments should not be started when the skin is
acutely inflamed and oozing, as this will often result in a
poor outcome of the treatment. The patient should be
treated with emollients, topical corticosteroids and antibacterials, if indicated, for some days before UV treatment
is started. This may not be necessary for high-dose UVA1.
The carcinogenic effects of UV phototherapy limit their
use for long-term maintenance treatment.
There are limited data on the use of phototherapy for
children with AD. Darne et al. [74] performed a prospective comparative cohort study including 55 children with
moderate to severe AD. Twenty-nine children were treated
with NB-UVB for 12 weeks and 26 children served as
controls. There was a 61 % reduction in Six Area Six Sign
Atopic Dermatitis (SASSAD) score in the treated group
compared with a 6 % increase in the unexposed cohort, and
the quality of life was improved in the treated group [74].
These data are supported by two other retrospective
studies on the use of NB-UVB in children with AD [75,
76]. Further studies are needed to evaluate the long-term
safety in treating children with phototherapy.
4.5 Systemic Immunosuppressive Therapy
4.5.1 Corticosteroids
There are very limited data documenting the effect of
systemic corticosteroids, but clinical experience shows that

762

they are rapidly effective in controlling the symptoms of a

severe flare in AD.
If a patient has moderate to severe chronic disease, one
should consider starting another systemic immunosuppressive treatment in combination with topical treatment,
while tapering the systemic corticosteroid, due to the
severe long-term side effects of systemic corticosteroids,
and the risk of flare after stopping the treatment [77].
4.5.2 Cyclosporine A
Cyclosporine A is the best-documented systemic treatment
for severe AD, licensed in many countries for this indication in adults. A meta-analysis pooling data from eight
RCTs demonstrated its effectiveness compared with placebo [78], and this conclusion has been confirmed in a very
recent systematic review including 14 trials [79]. Both
short-term and long-term use may help control severe AD
[80, 81].
The advantage of cyclosporine A is its rapid onset of
action. While most patients experience very few subjective
side effects, they have to be carefully monitored due to the
risk of severe side effects, in particular nephrotoxicity,
liver impairment and hypertension. The recommended dose
is between 2.5 and 5 mg/kg/day. It is beneficial to the
patient to start with 45 mg/kg/day to gain good control of
the disease and then taper off to the lowest effective dose.
When the drug is discontinued, around half of the patients
experience a rapid relapse, half remain in remission for
about 3 months and a few patients experience a rebound
phenomenon [80].
4.5.3 Methotrexate
Many clinicians have used methotrexate for severe AD in
both adults and children, but until recently only a few open,
uncontrolled case series had documented its effectiveness in
adults [8284]. In 2010, an RCT compared the use of methotrexate versus azathioprine for severe AD in adults. A total
of 42 patients were included and the treatment period was
12 weeks [85]. The mean relative reduction in the eczema
severity score (SCORAD) was 42 and 39 %, respectively. No
serious adverse events were observed in the study.
A recent RCT including 40 children has also demonstrated its effect in children between 7 and 14 years of age
[86]. Methotrexate 7.5 mg/week was compared with
cyclosporine A 2.5 mg/kg/day for 12 weeks. The mean
reduction in SCORAD was 49.3 and 44.7 %, respectively.
Both drugs were well tolerated.
The primary side effects for methotrexate are cytopenias,
liver function abnormalities and gastrointestinal side effects.
Methotrexate is teratogenic and women of childbearing age
must use a safe contraception method [87]. This also includes

C. Vestergaard, M. Deleuran

men treated with methotrexate who have fertile female

partners. If well tolerated, the major advantage of methotrexate is that it can be used for many years in chronic cases,
with a weekly dose between 7.5 and 25 mg in adults. The
recommended therapeutic dose range for children with psoriasis is 0.20.7 mg/kg/week [88] and we use the same dose
interval in children with AD. Methotrexate treatment in
children should not exceed adult dosing.
The patients should be informed about the slow onset of
action, which is up to 12 weeks, before the maximal effect
can be expected. If gastrointestinal side effects occur, or
the patient does not respond to the oral treatment, subcutaneous administration may be considered.
4.5.4 Azathioprine
Azathioprine is a frequently used immunosuppressive drug
in the management of severe AD in many countries, but
hardly ever used in other countries. This difference is
primarily based on clinical tradition. Main adverse effects
are cytopenias, gastrointestinal side effects, viral infections, and a small increase in skin carcinomas, especially in
patients with marked UV exposure. A typical maintenance
dose is between 1.5 and 3.0 mg/kg/day. Like methotrexate,
it has a slow onset of action.
A few patients have a low level or lack of the enzyme
thiomethylpurine transferase (TPMT), with a resultant
increased risk of developing severe myelosuppression.
Measurement of TPMT level before prescribing the drug, or
starting with a small test dose of azathioprine, under close
weekly laboratory monitoring, is necessary. Patients with
normal levels of TPMT can also develop myelosuppression.
A few controlled studies have so far been published documenting the effect in adult patients with severe AD. BerthJones et al. [89] demonstrated a 26 % reduction in the SASSAD score in the azathioprine-treated group compared with a
3 % reduction in the placebo group. The treatment period was
3 months. The dropout rate was quite high, but a significant
reduction in pruritus, sleep loss and fatigue in the active group
was observed. In 2006, an RCT including 63 patients was
performed. Forty-two patients were treated with azathioprine
for 12 weeks. Patients with normal levels of TPMT received
azathioprine 2.5 mg/kg/day and patients with reduced TPMT
activity received 1 mg/kg/day. A mean reduction of 37 % in
disease activity was observed in the azathioprine-treated
group compared with 20 % in the placebo group [90].
Azathioprine is also effective in controlling severe AD
in children [91].
4.5.5 Mycophenolate
Mycophenolate mofetil can be considered as a third-line
drug in the treatment of severe AD. Standard doses are

Diagnosis and Management of Atopic Dermatitis

between 0.5 and 1.5 g twice daily in adults. Clinical

experience, case reports and small open studies suggest
benefit in patients with severe AD [92, 93]. The most
prominent adverse events are cytopenias and gastrointestinal problems, and it is very important to know that mycophenolate is a teratogen [94, 95]. If gastrointestinal side
effects are a problem, a small open study suggests the use
of mycophenolate sodium as an alternative [96]. The drug
is formulated in an enteric-coated form and none of the ten
patients studied discontinued the drug due to adverse
events. The effect of this drug has been confirmed in a
larger study comparing mycophenolate sodium with lowdose cyclosporine A for adult patients with severe AD [97].
4.6 Biologics
During the last years, a limited number of studies have
been published indicating an effect of some biological
agents on AD. However, the future looks promising, as
different biological treatments for AD are in the pipeline,
but so far no specific biologic therapy for AD has been
approved by the drug agencies.
4.6.1 Interferon-c
The main adverse effects of IFNc are flu-like symptoms,
and this has limited the use of the drug. IFNc treatment for
severe, recalcitrant AD should be considered as a third-line
option for patients who do not respond to or do not tolerate
other systemic treatments.
A double-blind, placebo-controlled study including 83
patients demonstrated more than 50 % improvement in
physicians overall assessment in 45 % of patients treated
with daily subcutaneous injections of 50 lg/m2 IFNc for
12 weeks compared with 20 % in the placebo group [98].
Two smaller studies have shown that the treatment can be
continued for up to 2 years [99, 100].
4.6.2 Anti-CD20
Rituximab is an anti-CD20 monoclonal antibody directed
against B cells. Six patients with severe AD were treated
with rituximab 1,000 mg intravenously at day 0 and 14. All
patients experienced a significant improvement of their
eczema, and the treatment was well tolerated [101]. This
effect could not be confirmed in a case report of two
patients with severe AD [102].
4.6.3 Anti-IL-5
IL-5 is essential for eosinophil growth, differentiation and
migration, and these cells play a role in the pathogenesis of
AD. In an RCT, two single doses of 750 mg of

763

mepolizumab (an anti-IL-5 recombinant humanized

monoclonal antibody) were given 1 week apart, to patients
with moderate to severe AD. Forty patients participated in
the study and the effect was assessed on day 14. A decrease
in peripheral blood eosinophils and a moderate clinical
improvement (\50 %) was observed [103].
4.6.4 Anti-IgE
Omalizumab is a humanized monoclonal mouse antibody
directed against IgE. It is registered for the treatment of
severe asthma, and it has also been shown to be effective in
chronic urticaria.
Some reports describe a beneficial effect in patients with
moderate to severe AD [104106]. However, a 2:1-randomized, double-blind, placebo-controlled study including
20 patients with an investigator global assessment score C2
did not reveal a superior effect of omalizumab over placebo
in reversing pre-existing chronic atopic disease in adults.
The total treatment period was 16 weeks [107].
4.6.5 Anti-IL-4 Receptor
Dupilumab, a new human monoclonal antibody that targets
the IL-4Ra subunit and inhibits the effect of IL-14 and IL13, has shown very promising results. In an RCT with
dupilumab 300 mg (n = 55) or placebo (n = 54) weekly
for 12 weeks, the Eczema Area and Severity Index (EASI)
score improved significantly by 74 versus 23 % [108].
Another study showed that 100 % of patients (n = 21)
treated with dupilumab and topical corticosteroids
achieved EASI 50 compared with 50 % treated with placebo and corticosteroids (n = 10) [109].
4.6.6 Intravenous Immunoglobulins (IVIG)
IVIG treatment has been tried for both adults and children
with severe, treatment-refractory AD. Conflicting results
have been obtained, suggesting that the treatment may be
helpful in primarily paediatric cases of the disease.
A small open study including ten adult patients showed
a very limited effect of the treatment after 2 months [110].
In 2011, Jee et al. [111] published an RCT including 40
children, of whom 30 received IVIG with a 1-month
interval for 3 months compared with 10 children who
received placebo. A significant reduction in SCORAD was
observed in the IVIG-treated group compared with the
placebo group after 3 months. Five patients in the active
group did not complete the study due to adverse effects.
Another RCT compared a single dose of IVIG 2 g/kg in
six children with cyclosporine A 4 mg/kg/day in eight
children for 3 months. As expected, cyclosporine A was
significantly more effective than IVIG, due to the single

764

C. Vestergaard, M. Deleuran

4.7 Other Immunotherapies

life. In the Western world the most prevalent food allergies

are against milk, egg, peanut, hazelnut and fish [117].
Children with AD should be considered for food allergy
evaluation if there is a suspicion found in the clinical history. Food provocation tests are conducted in order to
confirm or reject the diagnosis, to find the threshold of the
allergy, but also to investigate if a child has developed
tolerance to the food over time.

4.7.1 Allergen-Specific Immunotherapy (ASIT)

4.8.2 Probiotics

Patients with severe AD often suffer from complicating type I

allergies and ASIT may be a useful complementary treatment
for patients with moderate to severe chronic AD and complicating allergic asthma and/or rhino-conjunctivitis.
An RCT by Werfel et al. [113] has shown that ASIT
with house dust mite (HDM) preparations significantly
improved the disease activity, measured by SCORAD, in
patients sensitized to HDM, in a dose-dependent manner
over an observation period of 1 year. These results have
been confirmed in another study over 12 weeks using birch
pollen extracts in patients sensitized to this allergen [114].

There have been a number of studies dealing with the effect

of probiotics on AD. Most studies have shown beneficial
effects of the use of supplementation with probiotics in
mothers and infants in preventing development and
reducing the severity of AD [118].
The results taken together are conflicting, however, due
to differences in study design, dosage and strain of the
probiotic [119].

dose of IVIG, but initially there was a good effect of both

treatments [112]. Concomitant treatment with topical corticosteroids, antihistamines and antibacterials were allowed
in this study, and this may have influenced the outcome.
In conclusion, IVIG may be considered as a last resort
treatment in severe treatment-refractory AD in children.

4.7.2 Immunoadsorption
A pilot study including 12 patients with severe, treatmentrefractory AD was performed. All patients had a high
SCORAD and very high IgE values, in spite of a combination of topical and systemic treatments [115]. Patients
were treated with a total of ten immunoadsorptions, in
order to reduce high titres of circulating antibodies. Serum
IgE was reduced more than 90 % after each treatment, but
returned to initial concentrations shortly after the last
treatment. In spite of this, all patients experienced a highly
significant reduction in SCORAD and pruritus. Larger
controlled trials with this promising but expensive and
time-consuming treatment are warranted.
4.8 Dietary Factors
4.8.1 Food Allergy
Food allergy is most prevalent in young children with
moderate to severe eczema. A Danish population-based
study found that 14.8 % of children suffered from food
allergy and of these, 90 % had AD [116]. An undetected
food allergy may result in severe allergic reactions in the
child, including respiratory symptoms and anaphylaxis, but
it may also worsen the AD.
It is quite rare that a teenager or adult develops food
allergy for the first time, and a substantial proportion of
children suffering from allergy against primarily milk and
egg will grow out of their allergy during the first years of

4.8.3 c-Linolenic Acid

Studies on essential fatty acid supplementation in AD have
indicated beneficial effects in some patients with AD, but a
recent Cochrane Systematic Database review concluded
that oral borage oil and evening primrose oil, which both
contain c-linolenic acid, lack effect on eczema. Improvement was similar to respective placebos used in the
included trials [120].
4.9 Psychosomatic Approaches
A recent study by Chrostowska-Plak and co-workers
evaluated the relationship between pruritus and stress,
health-related quality of life (HRQoL) and depression in
adult patients with AD, and it was shown that patients with
symptoms suggesting depression had more intense pruritus
compared with the rest of the patients [121].
Psychological stress can induce exacerbations in eczema
activity [122], and illness representations and coping are
highly associated with self-rated physical impairment in
AD patients [123].
Further, it has been shown that psychological interventions
have a positive effect on itch and scratching behaviour. Stress
management programmes may therefore be a useful addition
to standard treatment in patients with AD [122].
4.9.1 Therapeutic Patient Education and Eczema Schools
Poor adherence to the treatment is frequent in patients with
AD. This may be due to fear of unwanted side effects, but
also to the time-consuming procedures related to topical
treatment regimens.

Diagnosis and Management of Atopic Dermatitis

The German Atopic Dermatitis Intervention Study

(GADIS), which included 823 children and adolescents,
showed that age-related educational programmes are
effective in the long-term management of AD [124].
A position paper describing the objectives and recommendations for patient education in AD has recently been
published [125], and in spite of cultural and financial differences between countries, a recent survey has shown that
there is a consensus among experts to integrate education
into the treatment of AD [126].

5 Conclusion
AD is a multi-etiological disease. The skin is characterized
by an inflammatory reaction primarily made up of Th2/
Th22 lymphocytes as well as Tc2 lymphocytes, but other
cell types such as dendritic cells, eosinophils and mast cells
may also play an important role. It is therefore safe to
consider AD as an inflammatory skin disease. Furthermore,
the research over the past 1015 years has shown that a
decreased barrier function in the skin also plays a significant role in the pathogenesis of AD. Recent studies have
linked these etiologies together because the inflammatory
reaction can influence the barrier function and vice versa.
Thus, the treatment for AD should ideally inhibit the
inflammatory reaction and re-establish the skin barrier
function. From this review of the latest trends in the
treatment of AD it is clear that most, if not all, of the
treatments are aimed at the inflammatory reactions. As
recommended by the EADV/ETFAD/EFA/ESPD and
GA2LEN [52, 127], the basic therapy of AD should be
application of moisturisers and then, depending on the
severity, an anti-inflammatory treatment should be added.
In mild to moderate cases, topical treatment with either
corticosteroids or calcineurin inhibitors may be used,
whereas in moderate to severe cases systemic immunosuppressive drugs can be added. The evidence level for
most systemic drugs is low and the use of these varies
greatly between the countries of Europe [128]; however,
some patients do need more than topical treatment.
Several studies have demonstrated that patient education
can have a very deep impact on the quality-of-life score for
AD patients and their families, and thus psychosocial
interventions are of equal importance as the immunosuppressive drugs. Thus, this kind of treatment should be
instigated as soon as possible for patients with moderate to
severe AD.
No AD-specific biological treatments are registered at
the moment, but phase I and II trials are being carried out.
There is a dire need for effective biological treatments that
target this disease specifically, with fewer adverse events

765

than the traditional treatments we have described here,

especially for patients with severe, chronic disease.
Acknowledgments Mette Deleuran is an investigator, speaker and/
or an advisor for AbbVie A/S, MSD, Pierre Fabre Dermo-cosmetique,
Meda Pharma, Leo Pharma, and Regeneron. Christian Vestergaard is
an investigator and/or speaker for Abbvie A/S, Leo Pharma, Novartis
and Astellas. No sources of funding were used to prepare this review.

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