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11]

CME Article

Atopic Dermatitis: Update on Comorbidities and Therapeutic Advances

Abstract Katie Kim,

Atopic dermatitis (AD) is a chronic inflammatory disorder that primarily affects the skin. Recent Caitlin Crimp1,
literature has expanded our knowledge of associated comorbidities. In this review, we will Robert Sidbury1,2
discuss sleep loss, attention deficit hyperactivity disorder, obesity, and anemia as they relate to Pacific Northwest University
AD. We will also review two recently approved medications and how they fit into the therapeutic of Health Sciences, Yakima,
1
ladder. University of Washington
School of Medicine,
2
Keywords: Atopic dermatitis, co‑morbidity, therapy, obesity, peanut allergy Department of Pediatrics,
Division of Dermatology,
Pengenalan sleep fragmentation, and less nonrapid eye Seattle Children’s Hospital,
movement sleep in children with AD.[5] University of Washington School
Atopic dermatitis (AD) is a common, of Medicine, Seattle, WA, USA
Fishbein et al. corroborated most of these
chronic inflammatory skin condition that
findings in a separate cohort.[6] Both studies
manifests with recurring pruritic rashes.
revealed an inverse relationship between
With a worldwide prevalence of up to 20%,
the severity of AD and sleep disturbances.
AD typically presents in childhood and
affects approximately 3.2 million children Why and how AD affects sleep is
in the United States. [1] In 2015, the cost incompletely understood. Itch and
of AD was reported to be $5.297 billion scratching movements are certainly
in the US alone. The National Eczema disruptive but may not tell the entire story.
Association recently characterized the The role of melatonin and neuroendocrine
physical, psychosocial, and financial dysregulation has been investigated.[5-12]
impact in a “Burden of Disease” review Muñoz-Hoyos et al. found low levels of
by Drucker et al.[2] In addition to circulating melatonin in pediatric patients
well-described comorbidities such as food with AD exacerbations.[9] Chang et al. have
allergy and asthma, new associations such shown that melatonin supplementation
as sleep loss, attention deficit hyperactivity benefits sleep in AD patients, although
disorder (ADHD), obesity, and anemia have this has not been replicated to date and
been described.[3] In this review, we will our personal experience has been less
discuss these newer putative comorbidities, impressive.[13] Larger controlled studies will
as well as fascinating data on peanut be necessary to better understand the role
allergy prevention as it relates to eczema of melatonin in AD care.
patients. Finally, we will briefly review two
recently approved medications: crisaborole Attention deficit hyperactivity disorder
and dupilumab, and how they fit into our An association between ADHD and
Address for correspondence:
therapeutic armamentarium. Prof. Robert Sidbury,
AD was first postulated in 2009, since Department of Pediatrics,
that time multiple studies from diverse Division of Dermatology, Seattle
Sleep Disruption Children’s Hospital, University
populations have demonstrated a link.
of Washington School of
Sleep disturbance negatively impacts quality Schmitt et al. performed a systemic review Medicine, Seattle, WA 98105,
of life in many AD patients.[4] Patients with included 20 studies that concluded patients USA.
moderate-to-severe AD lose up to 2.1 h with atopic disease were more likely to E-mail:
of sleep a night, while parents lose on have ADHD.[14] Yaghmaie et al., utilizing the robert.sidbury@
seattlechildrens.org
average 1.9 h. Chang et al. demonstrated 2007 National Survey of Children’s Health,
a significant reduction in sleep efficacy, found that children with AD have an Access this article online
longer sleep onset latency, an increase increased incidence of ADHD compared to
Website: www.ijpd.in
in wakefulness after sleep onset, more those without AD.[15] This
DOI: 10.4103/ijpd.IJPD_92_18
association is stronger in earlier onset and
Quick Response Code:
[16]
This is an open access journal, and articles are distributed
under the terms of the Creative Commons
more severe AD.
Attribution-NonCommercial-ShareAlike 4.0 License, which allows
others to remix, tweak, and build upon the work non-commercially,
as long as appropriate credit is given and the new creations are How to cite this article: Kim K, Crimp C,
licensed under the identical terms. Sidbury R. Atopic dermatitis: Update on
comorbidities and therapeutic advances. Indian J
For reprints contact: reprints@medknow.com Paediatr Dermatol 2019;20:1-4.

© 2018 Indian Journal of Paediatric Dermatology | Published by Wolters Kluwer - Medknow 1

[Downloaded free from http://www.ijpd.in on Wednesday, February 26, 2020, IP: 112.215.245.11]
Kim, et al.: Atopic dermatitis update
There are several hypotheses to explain this association.
Initial investigation explored the role of inflammatory
cytokines. During an allergic reaction, inflammatory
cytokines activate neuroimmunologic pathways and alter
central neurotransmitter metabolism, potentially resulting
in symptoms of ADHD.[17,18] Sleep loss has also been
considered a common denominator. Multiple investigators
have shown a stronger association between AD and ADHD
when sleep disruption is present.[19,20] Children with AD and
sleep disruptions are 2.5 times more likely to be diagnosed
with ADHD.[20] There is also a positive correlation between
the severity of AD and ADHD. [15,20] Finally, the use
offirst-generation antihistamines, as well as the presence
of multiple comorbidities positively, correlates with the
likelihood of AD patients developing ADHD, but further
investigation is necessary.[21,22]
Obesity
A more traditional concern of providers caring for infants
with severe AD is often concerned with the failure to thrive.
Recent data have linked the opposite end of that spectrum:
Obesity. Several theories have been proposed to explain this
link. At an early age, developing immune systems are more
vulnerable to hypersensitivity reactions.[23] Obesity can lead
to a proinflammatory state which could predispose toward
atopic diseases.[24] Prolonged obesity >2.5 years or onset
before 5 years of age is associated with the development
of AD.[25] This strength of association is greater in a
patient with more severe AD.[26,27] Adult studies have
shown similar findings.[28] An alternative explanation is that
obesity is a consequence of AD, but not due to a shared
pathomechanism; AD and its resultant impact on activities
can increase the risk of obesity as well as cardiovascular
disease due to a more sedentary lifestyle. [29] It should be
noted that there is a mixed literature with some studies
showing no association between obesity and AD.[30-32]
Anemia
A recent cross-sectional study has also suggested that
children with AD are almost two times more likely to be
diagnosed with anemia.[33] The mechanism is unknown but
may be due to iron deficiency or anemia of chronic disease.
Although further studies will be needed to confirm this
link, it is prudent that providers consider this possibility in
patients with AD who complain of fatigue. Sleep disruption
is a ready explanation and can potentially obscure an
alternative diagnosis like anemia unless proactively
considered.
Food Allergies, Eczema, and Primary Peanut
Allergy Prevention
Children with AD are likelier to develop IgE-mediated food
sensitization with reported rates from 15% to 40%.[34,35] A
much smaller percentage, however, clearly benefit from
selected food avoidance pointing out two things as
2 Indian Journal of Paediatric Dermatology | Volume 20 | Issue 1 | January-March 2019
follows: (a) AD is multifactorial and rarely due solely to
food allergy and (b) false-positive IgE tests in the setting
of AD are common. In 2010, a multidisciplinary expert
panel at the US National Institute of Allergy and Infectious
Diseases (NIAIDs) discouraged routine allergy testing not
guided by history. They specifically recommended testing
in children <5-year-old with persistent AD despite optimal
topical therapy or with a history of an immediate reaction
after ingestion of a specific food.[36] Testing for food allergy
in atopic infants is complicated by the low positive
predictive value of food-specific serum IgE and skin-prick
tests in this population.[34,37] These NIAID guidelines do
not recommend arbitrary elimination diets, as allergen
avoidance has not been shown to conclusively reduce the
severity of AD or prevent allergy development. [36] These
recommendations were amended in 2017, to accommodate
fascinating data about the development of peanut allergy.[38]
The NIAID addendum guidelines are based on the results
of the Learning Early About Peanut (LEAP) study that
found a significant reduction in peanut allergy when peanut
products were introduced early in at-risk infants (defined
as those with prior egg allergy, severe eczema, or both).[39]
The LEAP study definition of high-risk infants was based
on a prior study that found egg allergy and severe eczema
to be risk factors for peanut sensitization (odds ratio [OR]
2.31 [95% confidence interval [CI] 1.39–3.86] and OR
2.47 [95% CI 1.14–5.34], respectively). [40] The LEAP trial
randomized 640 children between 4 and 11 months of age at
high risk of developing peanut allergy to consume or avoid
peanut products until 5 years of age, at which time a peanut
oral food challenge was conducted to assess for allergy. Of
those infants with negative initial skin-prick peanut testing,
there was an 86.1% relative reduction in the prevalence of
peanut allergy in the consumption group (1.9% allergic)
compared to the avoidance group (13.7% allergic).[39]
These impressive results led to the addendum NIAID
guidelines that recommend the introduction of peanut
products at 4–6 months of age in infants with prior
egg allergy, severe eczema, or both with preemptive
peanut-SIgE or skin-prick testing to risk-stratify infants for
the safety of peanut introduction. The guidelines further
recommend peanut introduction at about 6 months of age
for infants with mild-to-moderate eczema; ad hoc peanut
introduction according to family and cultural norms for
infants without eczema; and no recommendation for prior
allergy testing in these groups.[38] Dermatologists will be on
the frontlines as the population at greatest risk of peanut
allergy are those with severe AD; early evaluation by SIgE
level or referral for skin-prick testing will be necessary for
patients to benefit from early peanut consumption.
Although these guidelines represent an exciting change
in practice and opportunity for providers caring for AD
patients to reduce the increasing rates of peanut allergy,
there will no doubt be implementation challenges. The
practical implications and long-term consequences of early
peanut protein introduction in patients with AD will define
themselves over time. In the short term, dermatologists
who care for infants with eczema will need to tailor their
approach to peanut protein testing and introduction.
Therapeutic Advances
Crisaborole
Crisaborole ointment, a topical phosphodiesterase
inhibitor, was approved in 2017, by the US food and drug
administration (FDA) for the treatment of mild-to-moderate
AD in patients 2 years and older. In phase 3 trials, nearly
one-third of patients in the treatment group achieved the
primary outcome of clear or almost clear by Investigator
Global Assessment (IGA) (33% vs. 25% P < 0.001).[41]
There were no serious adverse events, although application
site stinging was seen more commonly in the treatment
group (4.4% vs. 1.2% P < 0.001%). Early experience
with this novel product has suggested that stinging
was underrepresented in the pivotal trials. As with the
topical calcineurin inhibitors 17 years earlier, clinicians
will develop strategies to mitigate this complaint and
incorporate this new, nonsteroidal option into the
therapeutic armamentarium.
Dupilumab
Before March 29, 2017, the only US FDA approved the
systemic medication for moderate-to-severe AD was
prednisone. The advent of dupilumab, now approved
for patients older than 18 years of age, has providing
a considerably more appealing option. Dupilumab is
a biologic agent that inhibits interleukin (IL)-4/IL-13
signaling, a critical pathway in the AD inflammatory
cascade. Pivotal phase 3 trials showed that dupilumab
300 mg subcutaneous (SC) administered every other week
was as effective in achieving clear or almost clear on an
IGA as a weekly injection (39% vs. 38%); both doses
were significantly superior to placebo (10% P < 0.001).[42]
The most noteworthy adverse event was conjunctivitis,
seen in roughly 1 out of 10 dupilumab-treated patients.
Although no patients dropped out, subsequent cases of
scarring ectropion have been reported. [43] The etiology is
unknown, but speculation has queried the role of demodex
and eosinophils.[44] Interestingly, a similar conjunctivitis
signal was neither seen in phase 2 pediatric data in Europe
nor has it been seen in dupilumab trials in other atopic
diseases (e.g., asthma and polyposis). Dermatologists
using dupilumab should refamiliarize themselves with the
diagnosis and management of conjunctivitis.[45]
Conclusion
Emerging research reveals that AD may be a systemic
disease much as we think of psoriasis. [46] Comorbidities
associated with AD span from mental health disorders to
obesity, anemia, and even cardiovascular disease. [3] Further
Indian Journal of Paediatric Dermatology | Volume 20 | Issue 1 | January-March 2019
Immunol 2013;131:428-33.
research will be required to clarify causation versus mere
association, but providers taking care of AD patients
would do well to consider the whole patient, not just the
skin. Broader thinking of this sort, coupled with rapid
development of new, targeted therapies, will mean better
outcomes for AD patients.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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