Review

An update on current
pharmacotherapy options in
atopic dermatitis
1. Introduction
Sakari Reitamo† & Anita Remitz
2. AD is characterized by both
University of Helsinki, Skin and Allergy Hospital, Dermatology, Helsinki, Finland
barrier dysfunction and
increased TH2 cytokine
Introduction: New knowledge on the pathogenesis of atopic dermatitis (AD)
expression
gives us new treatment options. This review emphasizes long-term treatment
3. Itch as a treatment target in results.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Monash University on 07/21/14

AD Areas covered: This study includes basic pathogenic factors in AD and

4. TCS in AD presents present and future treatment options. Topical corticosteroids treat
5. TCIs in AD the inflammation effectively short term. Topical calcineurin inhibitors (TCIs)
6. Systemic treatment in AD
show better benefit/risk ratio in long-term treatment. For topical treatment,
an effective maintenance treatment results in optimal control of the AD. Of
7. Successful maintenance
systemic immunosuppressive treatments, efficacy has been shown with aza-
treatment improves AD long
thioprine, ciclosporin, methotrexate and mycophenolate-free sodium. With
term
these compounds, the treatment outcome was ~ 50% improvement in clinical
8. Conclusion
signs compared with baseline. New treatments under study include systemic
9. Expert opinion compounds, which suppress the T helper type 2 cells. The importance of
adherence to treatment is often overlooked, although it has a major impact
For personal use only.

on treatment outcome. For the present review, PubMed was used as a

primary source.
Expert opinion: Combination of future TH2-specific systemic treatment with
optimal topical treatment with TCI, especially tacrolimus ointment, could
help to completely control the skin inflammation in AD. The ultimate goal is
to control AD completely, which should help to control the atopic airway
disease as well.

Keywords: adherence, atopic dermatitis, corticosteroids, long-term treatment, maintenance

treatment, pimecrolimus, T-cell subsets, tacrolimus

Expert Opin. Pharmacother. (2014) 15(11):1517-1524

1. Introduction

Atopic dermatitis (AD) is a common inflammatory disease often accompanied by

comorbities such as blepharoconjunctivitis, rhinitis and asthma. Current knowledge
on the presence of subclinical inflammation in atopic skin and the role of filaggrin
mutations in AD challenge us to optimize our treatment modes [1,2]. New knowl-
edge on the role of inflammatory cell subtypes and cytokines has opened up new
treatment possibilities. Many compounds with anti-inflammatory activity have
been tried in the treatment of AD, with the most consistent results having been
obtained with topical corticosteroids (TCS) and topical calcineurin inhibitors
(TCIs). Of the systemic treatments, ciclosporin has been best studied, although in
recent years controlled studies have been performed with other immunosuppressive
treatments as well. Treatments that suppress the inflammation for long term seem
to be most effective both clinically and for the skin barrier function. In the present
review, we aim to evaluate the present treatment modalities of AD and summarize
the most important new developments.

10.1517/14656566.2014.915941 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 1517
All rights reserved: reproduction in whole or in part not permitted
 S. Reitamo & A. Remitz
Article highlights.
. Atopic dermatitis (AD) is an itchy disease, which is
influenced by inherited and environmental factors.
. The main treatments of AD are topical monotherapies
with topical corticosteroids (TCS) or topical calcineurin
inhibitors (TCIs).
. Lack of adherence to treatment is a major cause for
poor treatment outcome.
. Treatment target is to improve skin barrier function. This
is done mainly by anti-inflammatory treatments and to a
lesser degree with emollients and other barrier
strengthening treatments. Filaggrin protein is of major
importance for the barrier function of the skin. Many
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Monash University on 07/21/14
patients have loss-of-function filaggrin genes, which
results in low filaggrin protein levels.
. Baseline severity of AD is of major importance when
various studies are compared. For treatment outcome
different subjective and objective parameters have
been assessed.
. Earlier treatments were mainly treatments of flares.
Maintenance treatment twice weekly prevents flares
effectively. These treatments have been tried for TCS for
up to 24 weeks and for TCI for 1 year. Tacrolimus
ointment has been used as monotherapy and
pimecrolimus usually together with TCS for flares.
. Ciclosporin is the systemic treatment most extensively
studied, although azathioprine and methotrexate can be
For personal use only.
useful in selected patients. None of the current systemic
treatments is specific for any T-cell subsets.
. In future, more specific treatments suppressing TH2 cells
will emerge.
. Long-term safety studies do not show an increase of
infections or cancers with TCI. TCS safety is not well
studied over long term.
. Conflicting reports have been published on AD and
cancer. Patients with AD (and especially severe AD) may
have a higher incidence of lymphoma compared to the
normal population. A possible role of various treatments
needs further studies.
This box summarizes key points contained in the article.
2. AD is characterized by both barrier
dysfunction and increased TH2 cytokine
expression
AD is a common inflammatory skin disease where both
inherited and environmental factors play a role. Up to 20%
of children suffer from AD, and AD is more uncommon in
adults. This suggests that AD has a tendency to heal by itself.
This is seen especially in the milder forms of AD, whereas in
more severe forms the disease tends to last longer, and a great
number of patients have other atopic symptoms, namely
asthma, rhinitis and conjunctivitis. The percentage of adults
having AD associated with rhinitis and asthma is higher
than in children [3]. Although food allergies also tend to
become less severe in adulthood, many patients still suffer
from skin symptoms from inhalant allergens and food aller-
gens such as peanuts and other nuts.
1518 Expert Opin. Pharmacother. (2014) 15(11)
In children, the symptoms of AD often start early and
precede other atopic symptoms such as airway symptoms.
This has led to the term atopic march, which suggests that
AD can lead to other atopic diseases [4,5]. Sensitization to envi-
ronmental antigens occurs only after birth, and the degree of
sensitization correlates with the severity of AD. Presence and
severity of atopic airway diseases such as asthma and rhinitis
also correlates with the severity of AD [6].
The barrier function of the skin is to a large degree
maintained by the epidermal differentiation complex protein
filaggrin, which is located in the stratum corneum of the epi-
dermis. Loss-of-function mutations of the filaggrin gene lead
to an increased risk of AD, allergic sensitization and asthma
in the presence of AD [7]. Patients with active AD or even
clinically dry skin show a reduction in the epidermal filaggrin
protein levels even in the absence of a loss-of-function muta-
tion of the filaggrin gene [8]. In widespread and severe AD, the
low filaggrin levels lead to low levels of degradation products
of filaggrin [9]. These degradation products form together the
so-called natural moisturizing factor. One derivative of
filaggrin is trans-urocanic acid, which in the presence of
ultraviolet radiation forms cis-urocanic acid, which has
immunomodulatory activity. Topical cis-urocanic acid
has recently shown efficacy in the treatment of AD
(Reitamo et al., in preparation). It could be especially useful
in AD patients with filaggrin mutations. Such patients will
have low filaggrin protein levels and therefore low levels of
urocanic acid.
Patients with AD have infections of the skin, such as bacte-
rial folliculitis or Herpes simplex infections. In AD skin, Staph-
ylococcus aureus colonies are normally present [10]. This can be
due to factors affecting both the innate and acquired immuni-
ties. Polypeptides and proteins, which penetrate the impaired
barrier of the skin in AD, have an effect on the maturation of
naive T cells, which instead of developing to TH1 with anti-
microbial activity develop into TH2 cells that increase the
atopic inflammation [4]. Interestingly, although it has been
shown that chronic AD lesions show a cytokine pattern typi-
cal for TH1 cells, it seems that overall the inflammation shows
a deviation towards TH2 [11]. This shows clinically as raised
total immunoglobulin E levels, staphylococcal colonization
of the skin and possibly also increased itch, as a highly itch-
causing cytokine, IL-31 is almost exclusively formed by
TH2 cells [12]. Trying to neutralize the immune dysfunction
by blocking development or function of TH2 cells will be a
major promising research area in the treatment for AD and
asthma at present and the near future in the finding of which
can lead to new treatment strategies in AD [13,14]. In AD,
filaggrin levels are negatively affected by TH2-related
cytokines such as IL-4 or the toll-like receptor 2 present in
TH2 cells. Therefore, blocking the function of the IL-4 by
blocking its receptor seems to be a promising way to treat
AD. Along these lines, other possible targets affecting the
TH2 pathway include thymic stromal lymphopoetin (TSLP)
and IL-13. Interestingly, interventions to reduce S. aureus in
 An update on current pharmacotherapy options in atopic dermatitis
the management of AD has not resulted in any clear improve-
ment of the eczema [15].
3. Itch as a treatment target in AD
Itch is a central symptom in AD. Molecules causing itch
include certain neuropeptides, neuronal protease-activated
receptor 2 and the TH2 cytokine IL-31. All these could be
targets for treatment. TSLP is a proinflammatory cytokine
that is involved in the maturation of TH2 cells. Recently, it
was detected that TSLP can directly stimulate sensory neurons
and thereby cause itch in AD [16]. Blocking TSLP activity
could become an important treatment of AD in future due
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Monash University on 07/21/14
to its double action on TH2 cell maturation and sensory neu-
rons. Antihistamines are effective in the treatment for acute
reactions such as urticaria, but they are not effective in the
treatment of itch in AD. An exception could be the blocking
of the type 3 and 4 histamine receptors, although there are no
study results available at the moment. These and other
possible targets for treatment for AD, which cause itch, have
been reviewed recently [13,14].
4. TCS in AD
For personal use only.
TCS are the primary treatment of AD. TCS have an anti-
inflammatory or otherwise suppressive action through bind-
ing to the glucocorticoid receptor on many cell types, both
inflammatory cells and connective tissue cells. The various
TCS preparations show differences in potency, which is
related to the affinity for the receptor. It has been claimed
that some new TCS show an improved benefit/risk ratio
(therapeutic index) over the older preparations [17,18].
A major problem with the TCS use is their atrophogenic
potential, which is related to their suppression of collagen syn-
thesis. It seems that the new TCS such as methylprednisolone
aceponate and mometasone furoate suppress collagen synthe-
sis to a similar extent as the older TCS such as betamethasone
valerate [19,20].
For mild AD, TCS remain the treatment of choice. For
these patients, a short-term treatment for a few days is often
enough when treatment is followed by regular emollients. In
patients with mild AD such treatment can lead to a long-
term clearance of AD with an emollient containing 10%
urea (Åkerstr€om et al., submitted). For moderate-to-severe
AD, TCS have been used for repeated flare treatments of a
few weeks or until clearance of AD. Treatment has been twice
daily until newer compounds such as mometasone furoate
proved that once-daily is as effective as twice-daily treat-
ment [21]. Now, it has been generally accepted that once-daily
treatment should be the standard use for all TCS in AD [22].
So far, this treatment has been applied mainly for short-
term studies of a few weeks only. Although TCS have been
used for 60 years in the treatment for AD, there have been
only few studies on their optimal long-term use. Long-term
studies of 6 months to 1 year have used flare treatment
Expert Opin. Pharmacother. (2014) 15(11)
followed by emollients in between the flares. These studies
were performed in adult patients with moderate-to-severe
AD, and they were comparative studies versus TCI [23-25].
Although planned for flare treatment only, in one such study
the median use of a mid-potent TCS was 91% of the days [25].
Some patients showed signs of skin atrophy in the form of
striae, which all developed in the last 3 months of the 1-year
study. Similar findings have been observed in another 1-year
study with another mid-potent TCS [23] suggesting that
long-term flare treatment with mid-potent TCS may not be
an ideal long-term treatment for moderate-to-severe AD.
A more innovative approach to use TCS in long-term stud-
ies has been the flare treatment followed by maintenance
treatment. Fluticasone propionate, a mid-potent TCS, was
superior to standard flare treatment in 24-week studies. After
initial clearance with daily TCS, fluticasone cream/ointment
or placebo cream/ointment was used twice weekly until first
relapse. Fluticasone propionate maintenance treatment for
20 weeks was superior to placebo both in adults and
children [26-28]. Mometasone furoate has been successfully
used for maintenance treatment of atopic hand eczema in a
6-month study [29].
These studies have been confirmed with another mid-
potent TCS, methylprednisolone aceponate [30]. Unfortu-
nately, maintenance studies have not been longer than
6 months, so it is difficult to evaluate the atrophogenic effect
of maintenance treatment compared to standard flare treat-
ment. However, as maintenance studies tend to preserve the
skin barrier in a better shape compared with standard flare
treatment, it is probable that less TCS are absorbed through
the skin. It can be concluded that TCS are useful for short-
term relief of acute AD followed by maintenance treatment
for up to 6 months. Another use of TCS in AD is the con-
comitant therapy in patients using oral immunosuppressive
treatment. An important factor for the use of TCS is the
low price compared with other medications.
5. TCIs in AD
TCIs include pimecrolimus and tacrolimus, which show
similar structures. Both are lipophilic and bind to the FK-
binding protein (macrophilin-12), which forms a complex
with calcineurin. Tacrolimus has an approximately threefold
affinity for FK-binding proteins, which implies a threefold
higher calcineurin inhibition potential compared with pime-
crolimus [31]. Inhibition of calcineurin results in blocking of
the early activation of T lymphocytes. Direct comparison of
pimecrolimus cream and tacrolimus ointment in AD shows
that tacrolimus is more effective at a lower concentra-
tion [32,33]. Tacrolimus ointment shows clinical efficacy
comparable to mid-potent TCS such as hydrocortisone buty-
rate [34], methylprednisolone aceponate [35] or fluticasone pro-
pionate [36,37], whereas pimecrolimus cream has not been
compared with TCS of similar efficacy [38].
1519
 S. Reitamo & A. Remitz
In studies, pimecrolimus cream has often been used as
maintenance therapy and TCS has been used for flare treat-
ment. Long-term monotherapy with pimecrolimus cream is
best suited for mild AD as moderate-to-severe AD usually
requires TCS for the flares [39]. Mixing TCS and TCI may
not result in ideal long-term treatment outcome, as shown
when tacrolimus has been used for the face and TCS for
AD lesions in other body regions [40]. In such cases, we would
recommend tacrolimus ointment monotherapy. Addition of
topical pimecrolimus to once-daily fluticasone propionate
showed no therapeutic benefit in the treatment for severe
AD [41]. In 6-month and 1-year long-term studies, tacrolimus
has shown better efficacy than standard corticosteroid
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Monash University on 07/21/14
therapy [24,25]. In long-term safety studies of up to 4 years,
tacrolimus ointment monotherapy has been used for flare
treatment that has continued until all signs of AD including
itch has vanished [42,43]. This treatment modality has success-
fully reduced the symptoms. In 1-year studies of maintenance
treatment with tacrolimus ointment in patients with mild-to-
severe AD, maintenance treatment was continued until the
patient showed signs of mild or more severe disease. When
this occurred, flare treatment was introduced twice daily until
there were no more than minimal signs of AD [44,45]. This
treatment successfully reduced the number of flares, and the
For personal use only.
time to first flare was 7 -- 9 times longer compared to standard
treatment. Patients using maintenance treatment had less itch,
and the skin condition was better during the whole study
compared to standard treatment. Therefore, their skin barrier
was also closer to normal. Except for mild AD, the mainte-
nance treatment did not increase the use of tacrolimus
ointment [44-46].
6. Systemic treatment in AD
Systemic treatment is usually introduced when topical treat-
ment for moderate-to-severe AD is not successful. Before
starting systemic treatment, it is worthwhile to see whether
the patient’s adherence to treatment is optimal, as many
studies show that insufficient use of topical medication is
common [47-49]. For flare treatment, use of oral glucocorticos-
teroids is quite common for short periods. The only con-
trolled study available on their use showed that such
treatment is often followed by serious relapses even when
TCS are used simultaneously [50].
Immunosuppressive medications used in controlled long-
term studies include azathioprine, ciclosporin, methotrexate
and mycophenolate [51-53]. Azathioprine and ciclosporin
have been used in placebo-controlled and comparative
studies, whereas methotrexate and mycophenolate only in
comparative studies [54-57]. Although these compounds have
been used together with TCS and emollients, the improve-
ment from baseline has usually been around 50%, which
does not result in a meaningful improvement of the skin bar-
rier function. In our opinion, the basic problem with all these
compounds that none of them is specific for any T-cell
1520 Expert Opin. Pharmacother. (2014) 15(11)
subtype. Of these, ciclosporin has gone through the most
extensive study program [53]. Oral ciclosporin has been com-
pared to topical tacrolimus, both showed similar efficacy [58].
Ciclosporin is effective against itch; however, treatment is
often accompanied by an increase in IgE levels [59], suggesting
that either TH1 cells are suppressed or TH2 cells activated.
Therefore, it will be of greatest interest to see the effect of
the new more specific medications planned to suppress only
TH2 cells and related cytokines.
7.Successful maintenance treatment
improves AD long term
What can be expected from long-term the maintenance treat-
ment, when both the inflammation is suppressed and the skin
barrier is as close to normal as possible? Is it possible to reverse
the signs and symptoms of AD and the comorbidities? We
have used a maintenance type of treatment with tacrolimus
ointment of AD in more than one thousand patients over
many years. In these patients the signs of TH1/TH2 imbalance
seems to be corrected to significant degree. Tacrolimus
ointment has been also successful in long-term treatment of
sensitive skin areas such as infants and small children [60],
and AD of the face [36] and especially in blepharoconjunctivi-
tis, where treatment was accompanied by a decrease in ocular
pressure [61,62].
After long-term maintenance treatment, AD patients show
improved TH1 type reactions in the skin for recall antigens [25],
eradication of the staphylococcal colonization [63] and a
decrease in the serum IgE levels [64]. Patients also have less
skin infections [43]. In addition, the corticosteroid-induced
skin atrophy is reversed to a significant degree [65]. An interest-
ing observation has been the apparent improvement of atopic
respiratory disease in these patients [66]. No increase in the risk
of skin cancer or lymphoma has been observed [67,68]. In our
hands, topical tacrolimus used as a maintenance treatment is
the optimal long-term treatment. In future, it might be sup-
plemented with TH2-specific systemic therapy in the more
severe cases. A TH2-specific topical treatment could also be
of great interest.
8. Conclusion
AD is an inflammatory skin disease that responds well to
topical anti-inflammatory treatment when the adherence to
treatment is satisfactory, and when flare treatment is followed
by maintenance treatment, usually twice weekly. For mild
AD, TCS are sufficient with the exception of sensitive skin
areas that are best treated with TCI, preferably with
tacrolimus ointment. For moderate and severe AD, the best
long-term treatment outcome is achieved with tacrolimus
ointment used as maintenance treatment, with twice-daily
flare treatment when needed. This treatment mode guarantees
the best possible barrier function for the skin. With an
optimal barrier function and treatment of the subclinical
 An update on current pharmacotherapy options in atopic dermatitis
inflammation, the TH2-dominated inflammation is sup-
pressed, which has further positive effects on filaggrin, the
skin barrier and the atopic airway disease. The application
of barrier strengthening compounds such as urea, cis-urocanic
acid, or possibly ceramides has shown some moderate effects
on skin barrier function, which are not comparable to
suppression of the T-cell-dominated inflammation. When
treatment outcome is not satisfactory, adherence to treatment
should be improved before starting systemic immunosuppres-
sive treatment such as ciclosporin. The main problem with
current systemic treatments is that they do not offer any sub-
class specificity and therefore suppress both TH1 cells as well
as TH2 cells. Therefore, it is difficult to achieve good long-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Monash University on 07/21/14
term treatment results in severe AD, especially when the
disease has lasted for a long time. Ongoing and future studies
aiming at TH2-specific inhibition could overcome this
problem, especially as they will be effective for the airway
symptoms as well. Such treatment should be used together
with tacrolimus ointment. In the future, there could also be
TH2-specific topical treatments available. Additional treat-
ment, especially when maintenance treatment is used, should
consist of barrier-strengthening compounds such as urea and
possibly cis-urocanic acid. In future, it should be possible to
minimize the AD and other atopic symptoms provided the
For personal use only.
adherence to treatment is satisfactory.
9. Expert opinion
To treat AD effectively, we need to overcome the impaired
barrier function and the TH2-dominated inflammation.
Both are dependent on each other, as control of inflammation
leads to an improved barrier function. An improved barrier
function leads to the maturation of TH0 cells towards
TH1 instead of TH2. So far, only minor improvements of
AD have been obtained by treating the barrier function only
with emollients-containing compounds related to the outer
layers of the skin, that is, filaggrin derivatives or lipids such
as ceramides. An exception could be patients with nonfunc-
tional filaggrin mutations, as such patients have low levels of
amino acids, which form the natural moisturizing factor.
Only mild AD seems to respond satisfactory to such treat-
ment without proper anti-inflammatory treatment. The
most effective treatments so far have been topical compounds
such as TCS and TCI. To improve the clinical condition of
AD and modulate the disease towards health, effective long-
term treatment is needed. This is only rarely possible with
TCS as the benefit/risk ratio for such effective treatment is
not very good. A better benefit/risk ratio is achieved with
tacrolimus ointment, which together with proper adherence
to treatment can lead to improvement of both the skin condi-
tion and also rhinitis and asthma. Such improvement includes
Expert Opin. Pharmacother. (2014) 15(11)
signs of TH2 deviation returning towards normal TH1/TH2
balance. Especially in young patients, such treatment is at least
as effective as oral immunosuppressive treatment with ciclo-
sporin or methotrexate, which both lack specificity to T-cell
subsets. Although effective for itch, ciclosporin treatment
can cause signs of TH2 dominance such as an increase in
IgE levels. An explanation for this could be different sensitiv-
ities of TH1 and TH2 subsets to ciclosporin, which has been
shown in vitro. In the future, the main emphasis will be to
develop TH2-specific medications, which should show effi-
cacy at an early stage of TH2 formation. Although no clinical
data are available, we would assume that the suppression of
TSLP would be possibly the most promising new treatment,
as TSLP is involved in the early maturation of TH2 cells
and contributes directly to itch. Other promising compounds
include anti-IL4, anti-IL13 and toll-like receptors class II.
Such treatment, together with topical tacrolimus, should treat
even the most severe AD, which shows widespread AD,
asthma, rhinitis and widespread sensitization to environmen-
tal and possibly also to self antigens, which results in high
IgE levels. A possible further improvement would be topical
compounds specific for TH2 cells. Such treatment should be
continuous as a maintenance type of treatment. It should be
possible to treat young infants as early as possible to prevent
sensitization and thereby the beginning of the atopic march.
With a complete control of the skin inflammation without
compromising the epidermal structure, it will be possible to
study the role of emollients and other compounds not directly
involved in the suppression of T cells or T-cell subsets.
Genetic research has so far been mainly directed towards
T cells and some proteins involved in the protease activation
in the skin. Little attention has been put to the structural pro-
teins involved in the formation of the tight junctions of the
epidermis, although this is the site, where the primary inflam-
matory response is started, as the Langerhans cells reside in the
inner part of the tight junction. In summary, in the next few
years, it should be possible to control even the most severe AD
with a combination of topical and TH2-specific treatment,
which should involve a daily treatment until full control of
the AD followed by proper maintenance type treatment.
This would help to control the atopic airway disease as well.
Declaration of interest
S Reitamo has acted as an expert for ACO Pharma, Astellas
Pharma, Atopix Therapeutics, Chugai Pharma, Dignity
Sciences and MSD. The authors have no other relevant
affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript
apart from those disclosed.
1521
 S. Reitamo & A. Remitz
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Affiliation
Sakari Reitamo†1 MD PhD &
Anita Remitz2 MD PhD
†
Author for correspondence
1
Professor and Specialist in Dermatology,
University of Helsinki, Skin and Allergy Hospital,
Meilahdentie 2, 00250 Helsinki, Finland
Tel: +358 9 471 86482;
Fax: +358 9 471 86561;
E-mail: sakari.reitamo@hus.fi
2
Assistant Professor and Specialist in
Dermatology,
University of Helsinki, Skin and Allergy Hospital,
Meilahdentie 2, 00250 Helsinki, Finland