Received: 22 October 2018 Revised: 2 November 2018 Accepted: 19 November 2018

DOI: 10.1111/dth.12787

REVIEW ARTICLE

What's new in the treatment of atopic dermatitis?

Annunziata Dattola1 | Luigi Bennardo2 | Martina Silvestri2 | Steven Paul Nisticò2

1
Department of Dermatology, University of
Rome “Tor Vergata”, Rome, Italy Abstract
2
Department of Health Sciences, Unit of Atopic dermatitis (AD) is a pruritic, chronic and inflammatory skin disease, with an usual onset in
Dermatology, “Magna Graecia” University, the pediatric age. Several drugs are used in the treatment of this skin disease. Drugs as steroid,
Catanzaro, Italy
calcineurin inhibitors, and moisturizing creams are widely used in the treatment of this disease
Correspondence
but often patients are not satisfied with the obtained results. New drugs like dupilumab or crisa-
Luigi Bennardo, Department of Health
Sciences, Unit of Dermatology, “Magna borole seem to be a promising option for moderate and severe forms of AD. This article analyzes
Graecia” University, Catanzaro, Italy. the newest therapy available today for the treatment of AD.
Email: luigibennardo10@gmail.com

KEYWORDS

atopic dermatitis, new drugs

1 | I N T RO D UC T I O N with barrier dysfunction at the level of the SC (Barnes, 2010). The

Atopic dermatitis (AD) is a chronic and inflammatory pruritic skin dis-
ease with a multifactorial etiology including various components. It is
a complex disease caused by the interplay between multiple environ-
mental and genetic factors. AD is typically characterized by a dysre-
gulation of the adaptive and innate immune response and a
heightened IgE-mediated, systemic Th2 response (Barnes, 2010) to
numerous environmental antigens, an epidermal barrier dysfunction,
a microbial colonization, a sometimes intractable pruritus, and
an intrinsic lipid and protein barrier deficiency (D'erme, 2016).
The clinical manifestations of AD vary with age. In infants, the scalp,
face, neck, trunk, and extensor (outer) surfaces of the extremities
are generally affected, whereas the diaper area is usually spared.
Children typically have involvement of the flexural surfaces of the
extremities (i.e., fold/bend at the elbow and back of the knee), neck,
wrists, and ankles. In adolescence and adulthood, the flexural
surfaces of the extremities, hands, and feet are usually affected
(Kapur, Watson, & Carr, 2018). The “brick wall-like” structure of the
stratum corneum (SC), which normally creates a barrier that main-
gene-encoding filaggrin (FLG) is one of the most important pathoge-
netic factors of AD. FLG is essential during barrier formation and it is
expressed at the final stages of keratinocyte differentiation and is
involved in the aggregation of a scaffold-like cornified envelope,
which initiates programmed cell death through keratinization. This
process is essential for the formation of functional epidermal barrier.
In addition, the FLG molecule itself further enhances barrier function
of the skin by provision of important constituents of natural moistur-
izing factor that retain water and maintain low pH of the upper
epidermal layers. A reduced content of ceramides, especially
ceramide I, sebum lipids and water-soluble amino acids in the SC has
also been shown in both lesional and nonlesional skin and character-
ize the typical xerosis of AD. The importance of these findings is
further confirmed by the correlation of enhanced barrier dysfunc-
tion, measured by an assessment of transepithelial water loss and
enhanced penetration of both lipophilic and hydrophilic substances
in individuals with AD; according to this, barrier dysfunction might
be a primary trigger phenomenon, and lead to an increase in antigen

tains water within the body and prevents the entrance of pathogens penetration and priming of specific T cells. Secondary phenomena,

and allergens, is further compromised in AD. The epidermal differen-
tiation complex, the DNA region where a large number of genes
encoding many of the cornified cell envelope precursor proteins,
small proline-rich proteins, members of the S100 family, and inter-
mediate filament-associated protein precursors (i.e., profilaggrin) are
localized, which is an important target of candidate genes associated
for example, inflammation and trauma from scratching (itch remains
an area poorly understood in eczema), will then lead to further barrier
dysfunction. Furthermore, inflammation and cellular responses in AD
have been shown to downregulate the expression of FLG and other
key proteins, which will disrupt the ability of the skin to effect barrier
function (Gutowska-Owsiak et al., 2012).

Dermatologic Therapy. 2018;e12787. wileyonlinelibrary.com/journal/dth © 2018 Wiley Periodicals, Inc. 1 of 4

https://doi.org/10.1111/dth.12787
2 of 4 DATTOLA ET AL.

TABLE 1 New drugs in the treatment of atopic dermatitis

Drug Study Dosage Effectiveness

Tofacitinib Topical Bissonnette et al. (2016) (phase 2% ointment twice a day versus placebo EASI score mean reduction (81.7%
2a trial) ointment vs. 29.9%)
Sistemic Levy et al. (2015) Oral 5 mg twice daily Mean SCORAD index decreased of 66.6%
Crisaborole Paller et al. (2016); FDA approved 2% ointment twice a day ISGA score (AD-301:32.8% vs. 25.4%;
AD-302: 31.4% vs. 18.0%)
Nemolizumab Ruzicka et al. (2017) Subcutaneous 0.1 mg/kg, 0.5 mg/kg, and EASI score respectively of −23, −42.3,
2 mg/kg dose every 4 weeks and −40.9%
Apremilast No sufficient data, only very small
significative studies
Dupilumab SOLO1 and SOLO2; FDA approved Subcutaneous 300 mg weekly/every EASI-75 at week 16: 48, 44–51, and
2 weeks/placebo 15–26%, respectively
Lebrikizumab Simpson et al. (2018); phase 2 trial Subcutaneous 125 mg every 4 weeks EASI-50: 82.4% versus 62.3%, respectively
TREBLE versus placebo
Baricitinib Guttman-Yassky et al. (2018) Oral 2 mg, 4 mg, placebo daily EASI-50: 61% (4 mg) versus 37% (placebo)

The prevalence of AD has increased over the past 30 years. Its
incidence is constantly growing and nowadays affects 2% of the
adults and up to 20% of children (Maarouf, Vaughn, & Shi, 2018). AD
often starts in early infancy; approximately 45% of all cases begin
within the first 6 months of life, 60% during the first year, and 85%
before 5 years of age. In fact, many neonates destined to develop AD
already have measurably increased transepidermal water loss on their
second day of life. Fortunately, up to 70% of children with AD will go
into clinical remission before adolescence (Kapur et al., 2018).
Given the chronic and recurrent nature of AD, long-term treat-
ment is often necessary. A lot of treatments are available to control
AD including moisturizing creams, topical steroids, immunomodula-
tors, light therapy, and so forth (França & Lotti, 2017). However,
patients are often not satisfied with their treatment, especially in the
moderate and severe forms (Nisticò et al., 2017). Side effects associ-
ated to long-term use of drugs such as corticosteroid (atrophy, telean-
gectasia, hypothalamic–pituitary axis suppression due to systemic
absorption) or calcineurin inhibitors (lymphoma or other malignancies)
limit their use in AD. The aim of this review is to examine the develop-
ing and latest drugs available for the treatment of AD.
2 | MAIN TEXT
consents better penetration of the drug. Its mechanism of action con-
sists in blocking phosphodiesterase 4 (PDE4), a key regulator in the
inflammatory cytokine cascade that degrades cyclic adenosine mono-
phosphate (cAMP). The blockage of PDE4 raises cAMP levels, inhibit-
ing proinflammatory cytokines with a major role in the developing of
AD, such as nuclear factor KB. The new drug has been tested as a 2%
ointment in two double blind, randomized clinical trials in patients
with moderate-to-severe AD who applied the drug twice a day. The
drug is effective in reducing inflammation and skin itch in a very short
amount of time. The result was promising and side effects were rare
and limited to the site of application (Kailas, 2017).
IL-31 is a product of TH2 lymphocytes and is believed to have a
major role in the pathophysiology of pruritus and AD. Nemolizumab, a
humanized anti-IL-31 receptor antibody, was subcutaneously adminis-
tered to patients with moderate-to-severe AD. The patient showed
promising results with a reduction of pruritus and of the extension of
the disease. The patients, divided into three groups, received a
0.1 mg/kg, 0.5 mg/kg, and 2 mg/kg dose every 4 weeks and showed a
reduction in pruritus analogue scale, respectively, of 43.7, 59.8,
63.1%, changes in eczema area and severity index (EASI) score,
respectively, of −23, −42.3, −40.9 (Fioranelli, Roccia, & Lotti, 2017;
Ruzicka et al., 2017).
Dupilumab is a fully human monoclonal antibody that is directed

Tofacitinib is an approved JAK inhibitor for the treatment of rheuma- against the shared alpha subunit of the IL-4 receptors that blocks IL-4

toid arthritis, which inhibits JAK1, JAK3 and to a minor extent JAK2. related to IL-13 signaling. Dupilumab modulates the AD molecular

Because of its structure and the important suppression of the immune signature and other TH2-associated biomarkers. The dose-dependent

response, it could be used for the treatment of various immune-
mediated skin diseases such as psoriasis, alopecia areata, AD, vitiligo
in both oral and topical forms (Tavakolpour, 2018). A phase 2 clinical
trial showed that 2% topical tofacitinib applied twice daily was more
effective than placebo ointment (Bissonnette et al., 2016). The sys-
temic form of the drug was also used to treat recalcitrant and nonre-
sponding AD. In these patients, SCORAD index decreased by 66.6%
from 36.5 to 12.2 (p < .05) during 8 to 29 weeks of treatment (Levy,
Urban, & King, 2015).
Crisaborole, a new no steroidal drug has been investigated for
chronic treatment in AD. It was approved by Food and Drug Adminis-
tration (FDA) in 2016. Crisaborole contains a boron atom, which
decrease in K16, a marker of keratinocyte proliferation and innate
immunity, suggests that the epidermal abnormalities associated with
AD might be reduced with dupilumab treatment. Dupilumab treat-
ment, as monotherapy or as part of combination therapy, was associ-
ated not only with improvement in skin lesions but also with rapid and
substantial reductions in pruritus, which is a major contributor to the
reduced quality of life experienced by patients with AD. In SOLO
1 and SOLO 2, trials were enrolled 671 and 708 patients, respectively.
In the two trials, an improvement of at least 75% on the EASI (EASI-
75) at Week 16 was reported in significantly more patients receiving
each regimen of dupilumab than among those receiving placebo.
Results in patients receiving dupilumab were significantly better than
DATTOLA ET AL.
those in the placebo groups in additional measures of clinical severity,
including EASI-50, EASI-90, body-surface area affected, and scores
like SCORAD and GISS (Simpson et al., 2016). Dupilumab treatment
resulted in highly reproducible improvements across all clinical end
points when the drug was administered as monotherapy and when it
was combined with topical glucocorticoids (Beck et al., 2014). The side
effects provoked by the drug were comparable to the placebo and
consisted mainly in injection site reactions, nasopharyngitis, and head-
aches. It represents the first systemic biological drug approved for AD
by FDA and by European Medicines Evaluation Agency (EMEA) and
it may become the first-line treatment in patients unresponsive to
topical steroids or topical calcineurin inhibitors (D'erme, 2016).
Lebrikizumab is a monoclonal anti-IL-13 antibody. IL-13 has an
important role in Type 2 inflammation and is a fundamental patho-
genic mediator in AD. A phase 2 clinical trial assessing the efficacy
and safety of lebrikizumab concluded that this drug led to significant
improvement in severity outcomes (Eichenfield et al., 2017). In the
study, the primary endpoint was the percentage of patients achieving
EASI-50 at Week 12. In all, 209 patients received the study drug and,
at Week 12, significantly more patients achieved EASI-50 with lebriki-
zumab 125 mg every 4 weeks (82.4%, p = .026) than placebo every
4 weeks (62.3%) (Simpson et al., 2018). Another monoclonal anti-IL-13
antibody is tralokinumab, which seems to have a safety and efficacy
profile similar to lebrikizumab. However, the efficacy of anti-IL-13 anti-
bodies seems minor compared to the double anti-IL-4 and anti-IL-13
blockage delivered by dupilumab. Further studies must be executed to
validate anti-IL-13 antibody as a safe and effective therapy for AD
(Hajar, Gontijo, & Hanifin, 2018).
Apremilast is a small molecule inhibitor of PDE4. PDE4 inhibition
leads to an increase of intracellular cyclic adenosine monophosphate
ska-Wcisło, Bebenek, &
levels (Wcisło-Dziadecka, Zbiciak-Nylec, Brzezin
Kaźmierczak, 2017). Its possible utility in the treatment of AD is due to
an increased PDE activity in leucocytes of patients affected by AD, fol-
lowing the same principle described for crisaborole. The orally adminis-
tered drug showed promising results, however, larger studies may be
required to evaluate the real efficacy of the drug and to properly
describe possible side effects.
Baricitinib is a selective JAK1 and JAK2 inhibitors currently
approved for the treatment of moderate and severe active rheumatoid
arthritis in Europe and in other countries. In all, 124 patients affected
by severe AD were enrolled and randomized to topical corticosteroid
and either daily placebo, baricitinib 2 mg or baricitinib 4 mg, respec-
tively, for 16 weeks. The results showed that 61% of patients
randomized to oral 4 mg baricitinib achieved EASI-50, compared with
37% of placebo and the difference was visible since week 4, with a
reduction also in sleep loss and pruritus (Guttman-Yassky et al., 2018).
3 | CO NC LUSIO NS
In the past therapies available for AD were often unsatisfactory
for the patients, with important long-term side effects and limited to
steroids and unspecific immunosuppressant drugs. Recently, thanks to
a better understanding of the physiopathology of AD, specific mono-
clonal antibodies and new topical molecules opened a new era in the
3 of 4
treatment of AD that will lead to an improvement of the condition in
chronic and severe patients.
CON F L I C T S OF IN TE RE S T
The authors declare no conflict of interest.
ORCID
Luigi Bennardo https://orcid.org/0000-0002-0434-1027
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How to cite this article: Dattola A, Bennardo L, Silvestri M,
Nisticò SP. What's new in the treatment of atopic dermatitis?
Dermatologic Therapy. 2018;e12787. https://doi.org/10.1111/
dth.12787