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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: [email protected] Paediatr Dermatol 2019;20:1-4.

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

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Kim, et al.: Atopic dermatitis update

There are several hypotheses to explain this association. follows: (a) AD is multifactorial and rarely due solely to
Initial investigation explored the role of inflammatory food allergy and (b) false-positive IgE tests in the setting
cytokines. During an allergic reaction, inflammatory of AD are common. In 2010, a multidisciplinary expert
cytokines activate neuroimmunologic pathways and alter panel at the US National Institute of Allergy and Infectious
central neurotransmitter metabolism, potentially resulting Diseases (NIAIDs) discouraged routine allergy testing not
in symptoms of ADHD.[17,18] Sleep loss has also been guided by history. They specifically recommended testing
considered a common denominator. Multiple investigators in children <5-year-old with persistent AD despite optimal
have shown a stronger association between AD and ADHD topical therapy or with a history of an immediate reaction
when sleep disruption is present.[19,20] Children with AD and after ingestion of a specific food.[36] Testing for food allergy
sleep disruptions are 2.5 times more likely to be diagnosed in atopic infants is complicated by the low positive
with ADHD.[20] There is also a positive correlation between predictive value of food-specific serum IgE and skin-prick
the severity of AD and ADHD. [15,20] Finally, the use tests in this population.[34,37] These NIAID guidelines do
offirst-generation antihistamines, as well as the presence not recommend arbitrary elimination diets, as allergen
of multiple comorbidities positively, correlates with the avoidance has not been shown to conclusively reduce the
likelihood of AD patients developing ADHD, but further severity of AD or prevent allergy development. [36] These
investigation is necessary.[21,22] recommendations were amended in 2017, to accommodate
fascinating data about the development of peanut allergy.[38]
Obesity
The NIAID addendum guidelines are based on the results
A more traditional concern of providers caring for infants
of the Learning Early About Peanut (LEAP) study that
with severe AD is often concerned with the failure to thrive.
found a significant reduction in peanut allergy when peanut
Recent data have linked the opposite end of that spectrum:
products were introduced early in at-risk infants (defined
Obesity. Several theories have been proposed to explain this
as those with prior egg allergy, severe eczema, or both).[39]
link. At an early age, developing immune systems are more
The LEAP study definition of high-risk infants was based
vulnerable to hypersensitivity reactions.[23] Obesity can lead
on a prior study that found egg allergy and severe eczema
to a proinflammatory state which could predispose toward
to be risk factors for peanut sensitization (odds ratio [OR]
atopic diseases.[24] Prolonged obesity >2.5 years or onset
2.31 [95% confidence interval [CI] 1.39–3.86] and OR
before 5 years of age is associated with the development
2.47 [95% CI 1.14–5.34], respectively). [40] The LEAP trial
of AD.[25] This strength of association is greater in a
randomized 640 children between 4 and 11 months of age at
patient with more severe AD.[26,27] Adult studies have
high risk of developing peanut allergy to consume or avoid
shown similar findings.[28] An alternative explanation is that
peanut products until 5 years of age, at which time a peanut
obesity is a consequence of AD, but not due to a shared
oral food challenge was conducted to assess for allergy. Of
pathomechanism; AD and its resultant impact on activities
those infants with negative initial skin-prick peanut testing,
can increase the risk of obesity as well as cardiovascular
there was an 86.1% relative reduction in the prevalence of
disease due to a more sedentary lifestyle. [29] It should be
peanut allergy in the consumption group (1.9% allergic)
noted that there is a mixed literature with some studies
compared to the avoidance group (13.7% allergic).[39]
showing no association between obesity and AD.[30-32]
These impressive results led to the addendum NIAID
Anemia guidelines that recommend the introduction of peanut
A recent cross-sectional study has also suggested that products at 4–6 months of age in infants with prior
children with AD are almost two times more likely to be egg allergy, severe eczema, or both with preemptive
diagnosed with anemia.[33] The mechanism is unknown but peanut-SIgE or skin-prick testing to risk-stratify infants for
may be due to iron deficiency or anemia of chronic disease. the safety of peanut introduction. The guidelines further
Although further studies will be needed to confirm this recommend peanut introduction at about 6 months of age
link, it is prudent that providers consider this possibility in for infants with mild-to-moderate eczema; ad hoc peanut
patients with AD who complain of fatigue. Sleep disruption introduction according to family and cultural norms for
is a ready explanation and can potentially obscure an infants without eczema; and no recommendation for prior
alternative diagnosis like anemia unless proactively allergy testing in these groups.[38] Dermatologists will be on
considered. the frontlines as the population at greatest risk of peanut
allergy are those with severe AD; early evaluation by SIgE
Food Allergies, Eczema, and Primary Peanut level or referral for skin-prick testing will be necessary for
Allergy Prevention patients to benefit from early peanut consumption.
Children with AD are likelier to develop IgE-mediated food Although these guidelines represent an exciting change
sensitization with reported rates from 15% to 40%.[34,35] A in practice and opportunity for providers caring for AD
much smaller percentage, however, clearly benefit from patients to reduce the increasing rates of peanut allergy,
selected food avoidance pointing out two things as there will no doubt be implementation challenges. The

2 Indian Journal of Paediatric Dermatology | Volume 20 | Issue 1 | January-March 2019

practical implications and long-term consequences of early research will be required to clarify causation versus mere
peanut protein introduction in patients with AD will define association, but providers taking care of AD patients
themselves over time. In the short term, dermatologists would do well to consider the whole patient, not just the
who care for infants with eczema will need to tailor their skin. Broader thinking of this sort, coupled with rapid
approach to peanut protein testing and introduction. development of new, targeted therapies, will mean better
Therapeutic Advances outcomes for AD patients.

Crisaborole Financial support and sponsorship

Crisaborole ointment, a topical phosphodiesterase Nil.

inhibitor, was approved in 2017, by the US food and drug Conflicts of interest
administration (FDA) for the treatment of mild-to-moderate
There are no conflicts of interest.
AD in patients 2 years and older. In phase 3 trials, nearly
one-third of patients in the treatment group achieved the References
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4 Indian Journal of Paediatric Dermatology | Volume 20 | Issue 1 | January-March 2019