685077

research-article2016
CMSXXX10.1177/1203475416685077Journal of Cutaneous Medicine and SurgeryMayba and Gooderham

Review Article

Journal of Cutaneous Medicine and Surgery

Review of Atopic Dermatitis and 2017, Vol. 21(3) 227­–236

© The Author(s) 2016
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DOI: 10.1177/1203475416685077
https://doi.org/10.1177/1203475416685077
journals.sagepub.com/home/jcms

Julia N. Mayba1 and Melinda J. Gooderham2,3,4

Abstract
Atopic dermatitis is one of the most common skin disorders in the developed world, affecting up to 20% of children and
1% to 3% of adults. This review concisely explains the pathophysiology and epidemiology of atopic dermatitis, as well
as potential challenges facing its successful treatment. Furthermore, mainstay topical treatment modalities are evaluated,
such as emollients, topical corticosteroids, and topical calcineurin inhibitors. The use of topical corticosteroids and topical
calcineurin inhibitors in combination is discussed, as studies have indicated encouraging results. The proactive use of topical
corticosteroids and topical calcineurin inhibitors is also investigated, in order to bring attention to a new possibility in long-
term management of atopic dermatitis. Last, new and upcoming topical medications are described, including Janus kinase
inhibitors, phosphodiesterase-4 inhibitors, and benvitimod. Although topical corticosteroids and topical calcineurin inhibitors
can be very effective in the treatment of atopic dermatitis, it is important that practitioners are aware of mechanistically
unique and new treatments for patients for whom more traditional topical therapies have failed. Overall, this review article
hopes to serve as a comprehensive overview of currently available topical treatments for atopic dermatitis, while shedding
light on new treatments coming in the future.

Keywords
atopic dermatitis, topical corticosteroids, topical calcineurin inhibitors, topical Janus kinase inhibitors, topical phosphodiesterase-4
inhibitors

Introduction AD tends to present on the face, neck, and extensor surfaces.

Pathophysiology
As the largest organ of the human body, skin provides many
vital functions, including protection against physical and
chemical injury, prevention of body water loss, temperature
regulation, immunological function, and sensation.1 Atopic
dermatitis (AD) is a common disorder of the skin with a
complex pathophysiology, developing in individuals with a
genetic predisposition and exogenous provocation factors.2
More specifically, the cause of AD is thought to be related to
epidermal barrier defects and immune dysregulation of the
innate and adaptive immune system.
Barrier abnormalities are caused by many factors, such as
chemical exposure, microorganisms,3 low temperature, and
low humidity.4,5 The filaggrin gene (FLG) also plays a sig-
nificant role in skin barrier formation. FLG regulates termi-
nal epidermal differentiation, creates a template for assembly
of the cornified envelope, and provides a substrate for natu-
ral moisturising factor. Consequently, mutations in FLG can
cause AD in a particular subset of patients.6
The AD phenotype begins with pruritus, erythema, and
dermatitic plaques that may weep, crust, or scale, depending
on the duration of the lesions.7 In infants and young children,
In older children and adults, lesions are typically lichenified
and found on flexural surfaces of the extremities.8
Epidemiology
AD develops in 85% of patients before the age of 5 years,
usually clearing by adolescence, but may persist into adult-
hood in a subset of patients.9 In developed countries, it is one
of the most common skin disorders, affecting up to 20% of
children and 1% to 3% of adults.10 It has been shown that the
prevalence of AD is increasing.11 The rate at which the preva-
lence is increasing suggests that environmental factors, pos-
sibly associated with lifestyle ‘Westernization’, are promoting
the rise rather than genetic changes.12
1
University of Manitoba Faculty of Health Sciences, College of Medicine,
Winnipeg, MB, Canada
2
Queen’s University, Kingston, ON, Canada
3
SKiN Centre for Dermatology, Peterborough, ON, Canada
4
Probity Medical Research, Waterloo, ON, Canada
Corresponding Author:
Melinda J. Gooderham, SKiN Centre for Dermatology, 775 Monaghan Rd,
Peterborough, ON K9J 5K2, Canada.
Email: mgooderham@centrefordermatology.com
228 Journal of Cutaneous Medicine and Surgery 21(3)
AD has been shown to run in families, with a 2-fold
increased risk of developing AD if one parent has the disease
and a 3-fold greater risk if both parents are affected.13 AD is
considered the first step in the progression of the allergic
triad, known as the ‘atopic march’, where there is an evolu-
tion of atopic disease that starts with atopic dermatitis, which
then progresses to asthma and allergic rhinitis.14
There are no concrete data indicating what proportion of
patients with AD go on to develop food allergies, although
they are associated.15 Overall, the aforementioned allergic
disorders are linked through atopy, the predisposition for
immunoglobulin E (IgE)–mediated responses to environ-
mental stimuli.16
Challenges Facing Topical Therapy
As with any medical intervention, topical therapy of AD
faces challenges to its successful implementation in
patients. One of the main difficulties is patient adherence,17
but there are many other challenges as well. Physicians
have found that the main obstacles to treating AD are not
finding the proper treatment, but finding a way to commu-
nicate with the patient and the parent(s) to understand the
disease and its treatment, in order to encourage proper
adherence.18,19
One way some jurisdictions have tackled this issue in the
pediatric population is through education,20 specifically by
supporting ‘eczema schools’. These schools function in vari-
ous ways depending on the country or city, the cultural con-
text, the training of the local clinicians, and the facilities
available to run such programming.21 What may appear sim-
ply as poorly managed AD due to poor adherence is often
connected to more significant issues, such as misdiagnosis,
poor living conditions, unemployment, financial strain, and
social and cultural differences. This is where the value of
having a comprehensive team comes into play, as many of
these issues can be explored.22
Topical Therapies
Nonmedical Therapy—Bleach Baths
Bleach baths are an antiseptic technique largely used for the
treatment of moderate to severe AD in patients with frequent
bacterial skin infections.23 Their utility lies in their antistaph-
ylococcal activity, including that against methicillin-resistant
Staphylococcus aureus.24 Bleach baths are not only useful
for active skin infections but also for maintenance therapy, as
cultures do not show bacterial clearance in most patients.23
Traditionally, concentrations of dilute bleach baths range
from 0.005% to 0.009% (0.25 cup bleach in half a tub of
water to 0.5 cup bleach in half a tub of water, respectively).25
The antimicrobial effect of bleach baths is likely attributable
to its ability to cause irreversible aggregation of bacterial
proteins.26
In 1 clinical trial of patients 6 months to 17 years of age
with moderate to severe AD and clinical signs of secondary
bacterial infection, patients randomised to the treatment arm
bathed in 0.005% bleach (sodium hypochlorite) for 5 to 10
minutes twice weekly and received intranasal mupirocin
ointment treatment twice daily for 5 consecutive days each
month. Patients in the placebo arm bathed in plain water
baths and applied petrolatum intranasally twice daily for 5
consecutive days each month. At 1 and 3 months of treat-
ment, the treatment group demonstrated significant mean
reduction from baseline in Eczema Area and Severity Index
(EASI) scores compared to the placebo group. Although 1 of
the 31 patients reported itching and irritation of the skin with
bleach baths, no patients withdrew from the study due to
intolerance of the baths.27
In comparison to antibiotic treatment of skin infections
secondary to AD, antiseptic agents, such as bleach baths,
have been found to be better tolerated and less likely to
induce bacterial resistance.24 Currently, literature concern-
ing the role of bleach baths and other antiseptic agents in
AD management is promising. Nonetheless, future studies
are required to assess long-term efficacy and safety of these
agents, especially with respect to continuous use.
Nonmedical Therapy—Emollients and
Moisturisers
One of the fundamental principles behind the effective long-
term treatment of atopic dermatitis is the maintenance of the
patient’s skin barrier. This may be achieved in a variety of
ways, such as the use of emollients and moisturisers and more
appropriate bathing habits—namely, using tepid versus hot
water and mild versus strong soaps.7 Emollients are a very
effective treatment modality in the range of mild to severe
disease,28 so much so that regular use of emollients can drasti-
cally reduce the amount of topical steroid usage in more
severe patients.21 In fact, regular application of emollients in
neonates at high risk for developing AD can help prevent its
development. One study demonstrated that application of
full-body emollient therapy at least once per day, initiated
within 3 weeks of birth, had a statistically significant protec-
tive effect on the incidence of AD in the infants at 6 months
compared to those who did not use emollients. Importantly,
there were no adverse events related to emollient applica-
tion.29 Another neonatal study also demonstrated significantly
decreased incidence of AD with regular emollient application
in the first 32 weeks of life compared to controls. This study
also investigated allergic sensitisation in both the intervention
and control groups, and it was found that the proportion of
infants sensitised by egg white allergen was similar in both.30
It is important to note the distinction between the terms
emollient and moisturiser. Colloquially, they are often used
synonymously; however, moisturisers often include humec-
tants, such as urea and alpha hydroxy acids, which hydrate
Mayba and Gooderham 229
the stratum corneum, whereas an emollient refers to a mate-
rial designed to soften the skin.2 However, for simplicity,
they will be considered synonymous in this review.
Despite the proven efficacy of these substances, there are
barriers to patient compliance regarding their use. For exam-
ple, petroleum, a highly effective occlusive, is greasy and can
be messy, which may negatively affect patient adherence.31
Ideally, emollients should be applied once or twice daily,
within 3 minutes of bathing for optimal occlusion of a
hydrated stratum corneum.7
There have been many emollient preparations with varied
effectiveness at improving skin barrier function in patients
with atopic dermatitis.7 For instance, 1 trial found a barrier-
improving cream (with 5% urea) to be superior to a reference
cream.32 Another trial found that a ceramide-dominant, bar-
rier repair emollient decreased transepidermal water loss
(TEWL) compared to nonceramide-dominant moisturisers.33
In addition to urea and ceramides, compounds such as glyc-
erin, lactic acid, hyaluronic acid, and nicotinamide are other
additives commonly found in moisturisers.7 Simpson and
Dutronc34 reported a series of trials showing the effects of a
moisturiser designed for patients with AD containing a
ceramide precursor, FLG breakdown products, humectants,
emollients, and occlusives. Skin hydration was assessed to
be superior to 2 reference moisturisers after a single applica-
tion. The ceramide product was also superior at restoring the
skin barrier after disruption with a 24-hour patch of sodium
dodecyl sulfate compared to the reference products.34
Furthermore, the ceramide product was also tested in a split-
body design on 127 patients with AD who used topical ste-
roids on all lesional areas but also used the ceramide product
on only half of the body. The ceramide + topical steroid-
treated side had superior hydration and more rapid and sig-
nificant improvement in EASI score at days 7, 14, and 21
compared to the side using only topical steroid, although
effect sizes were small due to milder disease (P < .05).34
In addition, it has been found that severe AD is associated
with a lower degree of bacterial biodiversity, specifically an
underrepresentation of Actinobacter, Proteobacteria, and
Cyanobacteria.35 An increased proportion of Staphylococcus
is known to play a role in atopic dermatitis severity.36
Therefore, it is not surprising that untreated AD flares have
reduced microbiome diversity and high Staphylococcus pro-
portions compared to baseline, postflare, and intermittent-
treatment flares.35 In many patients with AD, recurrent
Staphylococcus aureus skin infections are a problem. In such
patients, dilute bleach baths twice weekly have been shown
to reduce the severity of AD, thus helping prevent
reinfection.8
Medical Therapy—Prescription Emollient Devices
Recently, there has been development of prescription emol-
lient devices (PEDs) for the treatment of AD. They intend to
serve a structural role in skin barrier function and do not
exert their effects by any chemical interactions.23 These
products contain preparations with distinct ratios of lipids
that mimic endogenous skin composition and creams con-
taining palmitoylethanolamide, glycyrrhetinic acid, or other
hydrolipids. They are recommended for 2 to 3 times daily
application depending on the particular agent.23 Some barri-
ers facing these agents include their high cost and the fact
that there are now several over-the-counter moisturisers
available that contain ceramides, FLG breakdown products,
and other endogenous skin compounds, albeit not with iden-
tical composition to PEDs.23
These PEDs are different from over-the-counter moistur-
isers, as they have been approved by the US Food and Drug
Administration (FDA) as 510(k) medical devices.31 Under
this classification, approval of these products does not rely
on clinical efficacy data, compared to what is required for
FDA approval of medications. Consequently, publications
regarding the efficacy and safety of such products for AD
treatment are limited.37
Medical Therapy—Topical Corticosteroids
Topical corticosteroids (TCSs) have become the mainstay
treatment of AD since their introduction to dermatology in
the 1950s. They have a variety of mechanisms of action that
contribute to their efficacy in treating AD, which include
anti-inflammatory, antiproliferative, and immunosuppres-
sive effects.38 More specifically, they suppress the quantity
and activity of many inflammatory cell types and cytokines,
including neutrophils, monocytes, lymphocytes, Langerhans
cells, interleukins (ILs, including IL-1α, IL-1β, IL-2),
tumour necrosis factor (TNF), and granulocyte-monocyte
colony stimulating factor (GM-CSF). They also induce anti-
inflammatory proteins, such as lipocortin, vasocortin, and
vasoregulin.38 Their efficacy has been demonstrated with a
wide variety of preparations and strengths, with more than
110 different randomised control trials performed to date.39
They are the recommended first-line therapy for acute con-
trol of moderate to very severe AD.40
The potency of corticosteroids is measured with a vaso-
constrictor assay, where skin blanching is assessed in
healthy volunteers after topical application of the steroid.41
Based on this assay, topical corticosteroids have been
grouped into 7 groups, classes 1 to 7, in order of decreasing
potency (Table 1).38
Corticosteroids exist in various vehicles, including oint-
ments, creams, lotions, gels, sprays, and foams.38 Certain
preparations are more suited for specific areas of the body.
Specifically, ointments are best for glabrous areas, such as
palms and soles, as well as drier areas of the body, such as the
trunk and extremities.38 Creams can be used in numerous
areas, including flexural and genital areas.42 Foams, sprays,
and gels are more cosmetically appealing and easier to use in
hair-bearing areas, such as the scalp, and are preferred in oily
areas, like the face.38
230 Journal of Cutaneous Medicine and Surgery 21(3)

Table 1.  Representative Topical Corticosteroids From Various the face or groin. Mid-potency agents can also be used in
Steroid Classes and Their Formulations. children and adults but for shorter treatment periods.
Class/Generic Name Formulation However, longer term therapy with mid-potency steroids
may be necessary to treat chronic lesions involving the trunk
Class 1: Very high potency   and extremities. Ultra-high and high-potency steroids are
  Betamethasone dipropionate 0.05% G O (diprolene) indicated for short-term treatment of lichenified areas in
 Clobetasol 0.05% C F G L O S adults.38
  Diflorasone diacetate 0.05% O For the application of TCSs, a general rule of thumb sug-
  Halobetasol propionate 0.05% C O gests that therapy should be initiated with the lowest potency
Class 2: High potency  
agent that will sufficiently control the disease. However, this
 Amcinonide 0.1% O
should be balanced to avoid prolonged use of an agent of
  Betamethasone dipropionate 0.05% C (diprolene)
insufficient potency. For acute flares, TCS application is rec-
 Desoximetasone 0.05% G, 0.25% C O
ommended daily until the inflammatory lesions are con-
 Fluocinonide 0.05% C G O S
 Halcinonide 0.1% C
trolled, for up to several weeks at a time.23 Higher potency
  Mometasone furoate 0.1% O agents should be used for relatively brief periods (less than 2
Class 3: High potency   weeks of everyday use for class 1 agents), followed by
 Amcinonide 0.1% C L switching to lower potency TCSs or other agents for mainte-
  Betamethasone dipropionate 0.05% C (nondiprolene) nance after the initial flare is controlled.38
  Betamethasone valerate 0.1% O In situations where AD lesion severity must be quickly
 Desoximetasone 0.05% C reduced, wet-wrap therapy (WWT) has been shown to be
  Diflorasone diacetate 0.05% C useful in the setting of significant flares and recalcitrant dis-
  Fluticasone propionate 0.005% O ease.23 A topical agent, such as a TCS, is applied and first
 Halcinonide 0.1% O S covered by a wetted layer of gauze followed by a dry second/
 Triamcinolone 0.1% O outside layer. In more generalised disease, clothing prepared
Class 4: Mid-potency   in a similar way can be used instead. This helps occlude the
  Betamethasone valerate 0.12% F topical agent for increased penetration, while also decreasing
  Fluocinolone acetonide 0.025% O water loss and providing a physical barrier against scratch-
 Flurandrenolide 0.05% O ing. The wrap can be worn up to 24 hours at a time, for up to
  Hydrocortisone valerate 0.2% O 2 weeks.43 It should be noted that when using mid- to high-
  Mometasone furoate 0.1% C potency TCSs, care should be taken to avoid the possibility
 Triamcinolone 0.1% C of hypothalamic-pituitary-adrenal (HPA) axis suppression,
Class 5: Mid-potency   although short courses of WWT have not been associated
  Betamethasone dipropionate 0.05% L with prolonged adrenal suppression.44 TCSs can cause cuta-
  Betamethasone valerate 0.1% C
neous side effects, including purpura, telangiectasia, striae,
  Fluocinolone acetonide 0.025% C
focal hypertrichosis, and acneiform or rosacea-like erup-
  Fluticasone propionate 0.05% C
tions. The most concerning of these effects, however, is skin
 Flurandrenolide 0.05% C
atrophy, which can occur with any TCS, but more so in
  Hydrocortisone butyrate 0.1% C
  Hydrocortisone valerate 0.2% C
higher potency agents with occlusion, on thinner skin and in
Class 6: Low potency   older patients.45 TCSs may also exacerbate preexisting or
  Alcometasone dipropionate 0.05% C O coexisting dermatoses, such as rosacea, perioral dermatitis,
  Betamethasone valerate 0.1% L and tinea infections.38 Some patients can develop allergic
 Desonide 0.05% C L O contact dermatitis/type IV hypersensitivity to TCSs or other
  Fluocinolone acetonide 0.01% C S ingredients in their formulations, such as propylene glycol
Class 7: Low potency   and preservatives.23 In the event the patient’s lesions fail to
  Hydrocortisone acetate 0.5% C L O, 1% C O F respond or worsen with TCS application, patch testing should
  Hydrocortisone hydrochloride 0.25% C L, 0.5% C L O be done to determine if the allergen is the TCS itself or a
S, 1% C L O S, 2% L, component of the vehicle.46 Although documented in sys-
2.5% C L O S temic corticosteroid use, the association between TCSs and
Abbreviations: C, cream; F, foam; G, gel; L, lotion; O, ointment; S, solution.
the development of cataracts and glaucoma is not clear.
From Peterson JD, Chan LS (2006). A comprehensive management guide Nonetheless, it is encouraged that TCSs be used with caution
for atopic dermatitis. Dermatol Nurs. 2006;18(6):531-543. Used with in the periocular area.45 There is the potential for high- and
permission of the publisher, Jannetti Publications, Pitman, NJ. Includes ultra-high-potency steroids to be absorbed systemically to a
representative examples and not all available agents.
degree causing systemic side effects, such as HPA axis sup-
pression. The risk is low but increases with prolonged con-
Low-potency steroids are used in infants and patients with tinuous use of TCSs, large areas of application, and in
mild acute exacerbation of disease or sensitive areas such as patients also receiving corticosteroids in other forms (orally,
Mayba and Gooderham 231
Table 2.  Topical Calcineurin Inhibitors Available for the
Treatment of Atopic Dermatitis, Their Formulations and
Strengths, and Indications for Use.
Agent Formulation/Strength Indication
Tacrolimus 0.03% O (ages 2+) Moderate/severe
0.1% O (ages 15+) atopic dermatitis
Pimecrolimus 1% C (ages 2+) Mild/moderate
atopic dermatitis
Abbreviations: C, cream; O, ointment.
intranasally, or inhaled).47 Overall, TCSs have a good safety
profile,45 and currently there is no indication for monitoring
of systemic side effects for patients with AD using TCSs.23
Medical Therapy—Topical Calcineurin Inhibitors
Topical calcineurin inhibitors (TCIs) including tacrolimus
and pimecrolimus are invaluable second-line agents to TCSs.
They are both approved for the short-term treatment of active
AD lesions and tacrolimus also for chronic maintenance
treatment.31 TCIs inhibit the transcription of proinflamma-
tory cytokine genes, such as IL-2, which are dependent on
the nuclear factor of activating T-cells (NF-AT). This is done
by blocking the catalytic function of calcineurin, leading to
inhibition of the transport of NF-AT to the cell nucleus.48 A
key benefit of TCIs is the fact that they are nonsteroidal
immunomodulators and consequently do not cause the
adverse events (AEs) associated with TCSs.31 Currently, 2
TCIs are approved for treatment of AD: tacrolimus 0.03%
ointment (in children aged 2-15 years and adults) and 0.1%
ointment (in adolescents older than 15 years and adults) for
moderate to severe AD, as well as pimecrolimus 1% cream
for mild to moderate AD, 2 years and older49 (Table 2). Both
have demonstrated short-term (3 weeks) and long-term (24
months) safety and efficacy in the treatment of AD in adults
and children.49 During therapy, TCIs are applied on a twice-
daily basis to sites of active dermatitis.31 TCIs are particu-
larly useful in highly sensitive areas, such as skin folds and
the face, where TCS application has the greatest degree of
risk for causing side effects.23
There has been concern regarding the safety of tacrolimus
ointment and pimecrolimus cream since the FDA placed a
black-box warning on their product labels in 2006. This warn-
ing was based on rare reports of cancer in patients using TCIs
and a theoretical risk of malignancy based on their mechanism
of action.7 However, in contrast to oral calcineurin inhibitors
used to prevent graft rejection, topical administration of tacro-
limus and pimecrolimus results in a negligible amount of sys-
temic absorption, even when applied to large body surface
areas. To date, there have been no data linking TCIs with an
increased incidence of lymphoproliferative disease.50
Specifically, 1 study showed that application of tacrolimus
ointment 0.1% twice daily intermittently or continuously to
affected areas for up to 4 years resulted in improved efficacy
parameters with no increased incidence of serious adverse
effects.51 Common AEs in the study included skin burning,
pruritus, skin infection, skin erythema, flu-like symptoms, and
headache.51 The most common side effects encountered with
TCI use in the clinical setting are pruritus, stinging, and burn-
ing at the application site, which typically resolve after a few
days of continued use.7
It has been shown in 3 studies that tacrolimus ointment
0.1% is superior compared to pimecrolimus cream 1% in
reducing the clinical signs and symptoms of AD regarding
efficacy and speed of onset. Both agents had a similar safety
profile.52
Medical Therapy—TCI and TCS Combination
TCIs and TCSs may be combined for the treatment of AD.
Traditionally, an acute flare may have started treatment with
a 4- to 7-day course of medium- to high-potency TCS, fol-
lowed by application of emollients twice daily to prevent or
delay the onset of the next flare.7 Now, however, there is
increasing evidence showing that TCSs should first be used
to control the flare, followed by TCIs while in remission, to
spare TCS use and to prevent relapse.23 Some clinical trials
have explored the combination of TCIs and TCSs concomi-
tantly and sequentially with encouraging results. One ran-
domised controlled trial evaluated the concomitant use of
tacrolimus ointment and clocortolone pivalate 0.1%, a mild
TCS, against either drug alone for the treatment of AD.
Statistically significant improvements in various efficacy
parameters were observed with combination therapy com-
pared to either drug alone.53 Concerning the sequential use of
TCSs followed by TCIs, 1 trial compared patients applying
0.05% betamethasone butyrate propionate ointment bid for 4
days followed by the application of 0.1% tacrolimus oint-
ment bid or white Vaseline emollient bid for the following 3
days. After 4 weeks, it was found that the TCS/TCI sequen-
tial therapy improved lichenification and chronic papules in
patients with AD more efficiently than the TCS/emollient
sequential therapy.54
Medical Therapy—Proactive Use of Topical Anti-
Inflammatories (TCS and TCI)
Since proper AD management should encompass effective
management of an AD flare and overall flare prevention, it is
essential to determine the best proactive approach to mini-
mise AD flares.
There are different methods to manage AD, where reac-
tive treatment refers to treating only active lesions with anti-
inflammatories, while proactive treatment refers to treating
active lesions with topical anti-inflammatories but continu-
ing application of lower doses of anti-inflammatories to
those sites during remission as well. Out of 6 randomised
232 Journal of Cutaneous Medicine and Surgery 21(3)

Table 3.  Summary Table of Emerging Topical Therapies for the Treatment of Atopic Dermatitis.

Therapy Preparation Mechanism of Action Common Adverse Events Clinical Trials

Tofacitinib 2% ointment JAK3 > JAK1 > JAK2 inhibitor Nasopharyngitis, application site pain, NCT0200118161
application site pruritus, headache
Crisaborole (AN2728) 2% ointment Boron-based benzoxaborole Application site pain, dermatitis, NCT0130150866
PDE-4 inhibitor pruritus NCT01602341
NCT02118792
NCT02118766
NCT01652885
Benvitimod 0.5%, 1%, 2% Nonsteroidal anti-inflammatory Folliculitis, contact dermatitis, NCT00837551
(GSK2894512,WBI-1001) cream headache NCT0109873467
NCT02564055

Abbreviations: JAK, Janus kinase; PDE-4, phosphodiesterase-4.

control trials on proactive treatment, 4 studied tacrolimus, 4
studied fluticasone propionate, and 1 studied methylpred-
nisolone aceponate.55-60
Tacrolimus was investigated over 40 to 52 weeks, and the
TCSs were examined over 16 to 20 weeks. In all 6 studies, the
reduction in disease relapse risk was significant for all proac-
tive treatments versus placebo. Similarly, the individual stud-
ies revealed that there is a considerable difference between
the treatment and control groups, with respect to the median
time to first relapse. These results were encouraging, as more
than 50% of the treatment group did not have a single relapse
during the studies. Adverse effects in these studies were simi-
lar between intervention and control groups, of which the
most common included localised skin irritation and upper
respiratory tract symptoms. In addition, no skin atrophy or
telangiectasia attributable to the study drug was reported.55-60
Only 1 study found evidence of potential adrenal suppression
in 2 of 44 patients who completed the 40-week safety follow-
up with a cosyntropin stimulation test.55
Within these studies was specific evidence supporting the
proactive use of TCSs to decrease disease flares.61 For
instance, 1 study found that twice-weekly intermittent dosing
of fluticasone propionate cream 0.05% compared to its vehi-
cle base reduced the risk of relapse when added to regular
daily emollient therapy in adult and pediatric patients with
stable AD.55
Concerning proactive treatment using TCIs, 1 pediatric
study compared patients who applied tacrolimus ointment
0.03% once daily 3 times per week to patients who applied
vehicle once daily 3 times per week, for up to 40 weeks. It
was found that the patients treated with tacrolimus 0.03%
experienced significantly more disease-free days compared
to vehicle (mean: 174 days for tacrolimus vs 107 days for
vehicle; P = .0008), significantly longer time to their first
disease relapse (median: 116 days for tacrolimus [95% con-
fidence interval (CI), 56-188] vs 31 days for vehicle [95%
CI, 29-113 days]; P = .04), and significantly fewer disease
relapse days (mean: 47 days for tacrolimus vs 76 days for
vehicle; P = .04). Both the tacrolimus 0.03% and vehicle
groups exhibited a similar safety profile.59
A clinical trial of adult patients with AD found that over 12
months, twice-weekly proactive tacrolimus 0.1% ointment
application was an effective treatment in most patients to pre-
vent, delay, and reduce AD exacerbations.56 Compared to
patients who applied vehicle ointment proactively twice
weekly, patients who applied 0.1% tacrolimus ointment proac-
tively twice weekly significantly reduced the number of sub-
sequent disease exacerbations requiring substantial therapeutic
intervention (median difference, 2; P < .001; Wilcoxon rank
sum test). In addition, the tacrolimus 0.1% patients also had a
significant reduction in the percentage of disease exacerbation
treatment days (median difference, 15.2%; P < .001) and
increased time to the first disease exacerbation (median 142 vs
15 days; P < .001; stratified log-rank test). Furthermore, the
AE profile was similar in both the vehicle and tacrolimus
0.1% treatment groups.56
The most important clinical findings were elucidated from
2 studies56,60 that demonstrated that patients with severe and
moderate to severe eczema in the proactive group used less
topical anti-inflammatories overall than their counterparts in
the control groups, with less risk of relapse. Overall, the pro-
active approach appears to be most beneficial to patients with
severe eczema that frequently relapses. This is a promising
result and should be investigated further to support promoting
a proactive approach, ultimately leading to better disease con-
trol at lower cost and lower drug exposure.
New and Upcoming Topical Therapies
Apart from TCSs and TCIs, there has been more recent
development of new topical therapies for AD treatment,
which are discussed below and summarised in Table 3.
Janus Kinase Inhibitors
Janus kinases (JAKs) are a group of tyrosine kinases com-
prising JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2),
mainly found in hematopoietic cells.62 JAKs are required for
signaling initiated by several cytokines (IL-4, IL-12, IL-23,
thymic stromal lymphopoietin [TSLP], and interferon-γ
Mayba and Gooderham 233
[IFN-γ]) implicated in the pathogenesis of inflammatory skin
diseases, such as psoriasis and AD.63
The small size of JAK inhibitors has proven to be of ben-
efit for their use topically.62 Ruxolitinib is a small-molecule
selective inhibitor of JAK1/JAK2, while tofacitinib is a
potent inhibitor of JAK3 with some activity against JAK1
and, to a lesser extent, JAK2.62,63 The aforementioned JAK
inhibitors have been studied for the topical treatment of
inflammatory skin disease, and their use in the treatment of
AD is starting to gain interest. Specifically, a study of topical
tofacitinib and oclacitinib demonstrated impressive antipru-
ritic and anti-inflammatory responses in mouse models.64
A recent randomised phase IIa trial evaluated the clinical
efficacy and safety of 2% tofacitinib ointment compared to
vehicle ointment. Tofacitinib demonstrated a significantly
greater mean percent change from baseline in EASI scoring
than vehicle, −81.7% vs −29.9%, respectively, after 4 weeks
of twice-daily application. Furthermore, tofacitinib also
exhibited significant improvement in pruritus at week 4 of
treatment. The most common treatment-emergent adverse
event (TEAE) in tofacitinib patients was infection, of which
nasopharyngitis was the most reported infection. However,
all infections were mild to moderate and resolved before
study completion. Interestingly, more TEAEs were observed
in vehicle-treated patients than in tofacitinib patients.65
Phosphodiesterase-4 Inhibitors
Crisaborole is a small-molecule, boron-based benzoxaborole
phosphodiesterase-4 (PDE-4) inhibitor that modulates mul-
tiple immune and inflammatory pathways.66,67 Its low molec-
ular weight allows for excellent skin penetration,66 and in
vitro analysis has demonstrated crisaborole’s ability to
inhibit the production of cytokines, including IFN-γ, TNF-α,
IL-2, IL-5, and IL-10.68 Once crisaborole reaches the sys-
temic circulation, it is rapidly metabolised to inactive metab-
olites, thus limiting its systemic exposure.69 Clinical trials
have studied the efficacy and safety of crisaborole in 2%
topical ointment formulation. A phase Ib pediatric study of
34 patients with extensive AD found that crisaborole was
rapidly absorbed, with limited systemic exposure. Twenty-
three patients experienced 1 or more TEAEs, and 95% of
these were of mild/moderate severity. Mean severity scores
for AD signs and symptoms improved throughout the study,
with 47.1% of patients achieving treatment success.67 These
findings suggest that crisaborole is well tolerated, safe, and
effective in patients as young as 2 years of age.67 A phase II
clinical trial of AD in adults demonstrated that 68% of
patients treated with crisaborole experienced a greater
improvement in atopic dermatitis severity index (ADSI)
scores compared to those treated with vehicle. Eleven of the
25 patients experienced AEs, but none of them were severe
and no patients discontinued treatment due to AEs.70 The
most commonly reported AEs were application site pain,
dermatitis, and pruritus.66
Currently, phase III clinical trial data are being analysed
to further evaluate the safety and efficacy of crisaborole for
AD in children and adults.66
Benvitimod
Benvitimod (2-isopropyl-5-((E)-2-phenylethenyl) benzene-
1,3-diol, GSK-2894512, WBI-1001) is a small molecule that
has been shown to decrease production of proinflammatory
cytokines and migration of T cells.71 Specifically, it inhibits
the expression of cytokines, including IFN-γ, IL-2, and TNF-
α. It also inhibits the migration of peripheral blood mononu-
clear cells and inhibits the infiltration and activities of T cells.72
A clinical trial investigating the use of benvitimod for the
treatment of mild to severe AD in adults randomised the
patients 1:1:1 to receive placebo, benvitimod 0.5% cream, or
benvitimod 1.0% cream. After 6 weeks of twice-daily applica-
tion, patients treated with benvitimod 0.5%, 1.0% cream, and
placebo demonstrated improvement in investigator global
assessment (IGA) scores of 43.0%, 56.3%, and 14.7%, respec-
tively. In addition, patients treated with benvitimod also had
greater improvements in their EASI and SCORAD, as well as
their pruritus severity scores, compared to placebo patients.
The most common adverse events related to treatment with
benvitimod were folliculitis, contact dermatitis, and headache.
Overall, benvitimod appears to be well tolerated and effica-
cious in the adult AD population.71 Currently, phase II trials
are being conducted by GSK to further investigate the use of
benvitimod cream (GSK-2894512) for the treatment of AD.
Conclusions
In summary, the treatment of AD is primarily based on the
proper use of topical agents. First and foremost, it is essential
that the skin barrier is protected and maintained with the use of
emollients, as this can mitigate the excessive and unnecessary
use of TCSs.28 Furthermore, emollients also play a significant
role in diversifying and maintaining the skin microbiome,
which is important considering that worsening AD is strongly
associated with dysbiosis of the skin.73 Inevitably, however, in
certain patients, use of emollients is insufficient to control AD
completely. In these patients, it is critical for them to use topi-
cal anti-inflammatories in their preferred formulation to
achieve optimal medication adherence.74 As discussed, there is
a role for both TCSs and TCIs in AD management. TCSs are
highly effective at improving AD in many areas of the body,38
while TCIs have the unique therapeutic niche of safely treating
sensitive areas of the body without the AEs associated with
TCSs.23
Once control of AD lesions is achieved, proactive use of
TCIs and TCSs can effectively prevent AD flares, as com-
pared to proactive use of nonmedicated vehicle.61 Hopefully,
by adopting a proactive approach, the period between AD
patient flares can be extended to a point where the patient’s
quality of life is not severely compromised.
234 Journal of Cutaneous Medicine and Surgery 21(3)
It is also important to consider future therapies for the
treatment of AD, as it is well documented that many patients
with AD still experience a significant degree of suffering
from this chronic disease despite access to currently avail-
able therapies, due to lack of efficacy or associated phobias
or side effects of treatment.75
Acknowledgments
We thank Dr Alex Weiler for his review of the literature on the
proactive management of atopic dermatitis.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: Dr Melinda Gooderham has been an investigator, speaker,
and/or advisory board member for AbbVie, Amgen, Celgene,
Boehringer Ingelheim, Dermira, Coherus, Eli Lilly, Medimmune,
Roche, Regeneron, Sanofi Genzyme, Pfizer, Novartis, and UCB.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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PC, Dermatologist