DOI: 10.1111/pde.

13364

Pediatric
ART AND PRACTICE OF PEDIATRIC DERMATOLOGY Dermatology

Circadian rhythm in atopic dermatitis—Pathophysiology and

implications for chronotherapy

Alexandra R. Vaughn BS1,2 | Ashley K. Clark BS1 | Raja K. Sivamani MD, MS, CAT1,3 |
Vivian Y. Shi MD4

1
Department of Dermatology, University of
California, Davis, Sacramento, CA, USA Abstract
2
College of Medicine, Drexel University, Circadian rhythm is a biological clock that controls a wide range of physiological
Philadelphia, PA, USA
functions throughout the body, including various skin functions. A 24-h diurnal cy-
3
Department of Biological Sciences,
California State University, Sacramento, cle, governed by an endogenous clock in the brain, largely controls cutaneous diur-
Sacramento, CA, USA nal rhythm, which external factors, including temperature, humidity, diet, and stress,
4
Division of Dermatology, Department of
also modulate locally. Circadian rhythm influences cutaneous blood flow and proper-
Medicine, University of Arizona, Tucson,
AZ, USA ties of skin barrier function, such as transepidermal water loss and capacitance, and
has important implications in atopic dermatitis (AD). This review explores how aber-
Correspondence
Vivian Y. Shi, MD, Department of rations in circadian rhythm may play a role in the pathogenesis of AD and proposes
Dermatology, University of Arizona, Tucson,
implementation of chronotherapy to improve treatment outcomes in patients with
AZ, USA.
Email: vshi@email.arizona.edu AD.

KEYWORDS
atopic dermatitis, circadian rhythm, clock genes, eczema, skin barrier, sleep

1 | INTRODUCTION itching is usually worse at night. Emerging evidence suggests that

Atopic dermatitis (AD) is a chronic, inflammatory skin disorder asso-
ciated with defective skin barrier (SB) function and dysregulated
immune response, which external stimuli largely influence. Circadian
rhythm (CR) is an endogenous clock that governs major physiologic
functions, including heart rate, sleep, hormone regulation, and skin
function.1 CR has a diurnal pattern controlled by the 24-h diurnal
cycle that a biological clock located in the suprachiasmatic nuclei
(SCN) in the brain governs centrally and autonomous clocks in the
tissues govern peripherally in response to environmental stimuli
(Figure 1).2 External stimuli, including climate, ultraviolet radiation,
pollutants, mechanical trauma, diet, and stress, modulate cutaneous
CR locally.2
Rhythmic periodicity has been reported in SB function, blood
flow, sebum production, keratinocyte proliferation, inflammatory
response, and sleep pattern (Figure 2).3-5 Skin blood flow in adult
men peaks in the afternoon and late evening, with troughs in early
6
morning. Higher nocturnal blood flow is associated with greater skin
permeability, histamine release, and itching, which may explain why
CR aberrations are involved in the pathogenesis of AD (Table 1), and
chronotherapy may be implemented to maximize therapeutic
benefits.
1.1 | CR and SB function in relation to AD
The stratum corneum (SC) functions as the first line of defense
against the external world, maintains a semipermeable barrier, and
ensures adequate hydration. Natural moisturizing factors help to
retain water, and epidermal and sebaceous lipids provide a lipid coat-
ing to prevent transepidermal water loss (TEWL).2 SB dysfunction in
AD is characterized by the loss of SC hydration, greater TEWL, and
low sebum levels.
Skin barrier biophysical parameters fluctuate in accordance with
CR. Facial sebum production oscillates in 8- and 24-hour patterns3
and is highest in early afternoon and lowest at night.7 Low noctur-
nal sebum production contributes to nighttime pruritus as sebum
forms a hydrolipid film on the skin surface to maintain hydration.
Healthy adults have prominent 8-, 12-, and 24-hour TEWL patterns

Pediatric Dermatology. 2017;1–6. wileyonlinelibrary.com/journal/pde © 2017 Wiley Periodicals, Inc. | 1

2 | Pediatric
Dermatology
on the facial and forearm skin, with peaks at 8:00 AM and 4:00
Eight-hour patterns in capacitance (assessment of hydration) were
also seen in facial and forearm skin, with one large peak in forearm
capacitance at 8:00 PM and smaller peaks at 12:00 PM and 4:00
Other studies in adults have assessed patterns of TEWL with vari-
able results; the general consensus is that TEWL is highest in the
late afternoon and evening, leading to xeroderma and contributing
to nocturnal itch.3,4,8 We suspect similar patterns in children, but
further studies are needed. It is likely that circadian patterns of high
TEWL and low hydration at night contribute to nocturnal itching in
individuals with AD.
On a cellular level, circadian CLOCK genes regulate skin hydra-
tion. CLOCK gene knockout mice had a lack of SC hydration due to
dysfunctional aquaporin-3 proteins (AQP3),9 which are transmem-
brane channels on keratinocytes that facilitate water and glycerol
entry to maintain hydration. Low epidermal AQP3 expression is seen
in chronically sun-exposed and aging skin, and dysfunctional AQP3
proteins are associated with xeroderma and psoriasis.10 These stud-
ies emphasize the importance of circadian genes in regulating SB
properties. Aberrations in SB function enable entry of pathogenic
VAUGHN ET AL.
F I G U R E 1 Circadian rhythm
mechanisms in the skin. The
circadian rhythm initiates with the light
that enter the eyes and central nervous
system. The signal is directed by the
suprachiasmatic nucleus and translates
down through hormonal and neuronal
signals to stimulate cortisol release by the
adrenal glands and melatonin release by
the pituitary gland. The signals lead to
inflammation, leading to the itch–
scratch cycle and further barrier
impairment
PM. microbes, allergens, and irritants to trigger an exaggerated immune
response, resulting in skin inflammation in individuals with AD.
3
AM.
1.2 | CR and immune function in relation to AD
Immune function is under tight circadian control, including regulation
of circulating leukocyte numbers and types and cytokine produc-
tion,11 all of which are relevant in AD. Circulating na€ıve T-cells and
pro-inflammatory cytokines such as interleukin (IL)-12 peak at night
in adults, whereas cytotoxic T-cells and anti-inflammatory cytokines
such as IL-10 peak during the day in vitro.12,13 This diurnal pattern
of immune function parallels nocturnal itching and exaggeration of
AD.14 In addition, the CLOCK:BMAL1 heterodimer controls expres-
sion of human beta-defensin 1 (hBD-1), an antimicrobial peptide that
exhibits circadian oscillation and can be deficient in the skin of chil-
dren and adults with AD.15
CR also influences AD by controlling cortisol fluctuation. Serum
cortisol levels peak in the early morning and then steadily decline
throughout the day to reach trough levels after sleep onset at night.
Basal serum cortisol levels are significantly lower in adults and
VAUGHN ET AL. Pediatric | 3
Dermatology

F I G U R E 2 Circadian rhythm: skin component patterns. Skin blood flow peaks in the afternoon and late evening, with lowest blood flow in
the early morning. Facial sebum production oscillates in 8- and 24-hour patterns and is highest in early afternoon and lowest at night.
Transepidermal water loss is highest in the late afternoon and evening. Circadian rhythm immune function fluctuates with nocturnal peaks of
circulating na€ıve T-cells, interleukin (IL)-12, and other pro-inflammatory cytokines and daytime peaks of cytotoxic T-cells, IL-10, and other anti-
inflammatory cytokines

children with AD than in healthy controls.16 Low nocturnal cortisol
5
levels can partially explain nocturnal itching in individuals with AD.
Infants with mothers who have asthma, hay fever, or eczema and
those not entering daycare in the first 2 months of life have less
variation in diurnal cortisol secretion patterns, a low morning cortisol
surge, and flattened CR.17 Although the exact mechanisms behind
the cortisol alterations seen in children at risk of atopic diseases has
not been elucidated, abnormalities in endogenous cortisol secretion
may be a result of circadian dysregulation.
1.3 | CR, sleep disturbance and melatonin in AD
Nocturnal itching severely disturbs sleep in children with AD, often
resulting in low energy, behavior problems, mood disturbances, and
18
even learning difficulties. Sleep disturbances perpetuate AD by
shifting the immune milieu further toward a Th2 response.18 There-
fore, addressing sleep disturbances and preventing subsequent
behavioral problems should be an integral component of the AD
treatment plan. It is likely that the exact mechanisms causing sleep
disturbance in AD are multifactorial and include phase shifts in
cortisol secretion, abnormal melatonin production, high inflammatory
cytokine levels, and perpetual itch-and-scratch cycles.19
The pineal gland secretes melatonin and beta-endorphins, vital
hormones that regulate CR and provide efficient sleep. Keratinocytes
and immune cells (natural killer cells, mast cells, eosinophils) that
express their own receptors for melatonin also peripherally produce
melatonin.20 Melatonin is secreted in a diurnal pattern, with a steady
increase and peak between 2:00 and 4:00 AM, followed by a gradual
decrease.21 Melatonin supplementation promotes sleep through its
sedating effect, probably by acting on the SCN and its ability to
decrease core body temperature.22
Melatonin supplementation possesses sedating, antioxidative,
immune-modifying effects.20 Schartz and colleagues23 reported that
14 of 18 children with AD had a disrupted melatonin secretion pat-
tern. Plasma melatonin and beta-endorphin levels are low during AD
exacerbations in children.24 Conversely, higher nocturnal melatonin
is associated with less sleep disturbance and less severe AD symp-
toms in children.18 In a double-blind randomized controlled study,
children 1-18 years of age with AD who received melatonin supple-
mentation (3 mg nightly at bedtime for 4 weeks) had significantly
4 | Pediatric VAUGHN ET AL.

Dermatology
T A B L E 1 Evidence of the role of circadian rhythm in atopic dermatitis
Subjects and experimental
Parameter Evidence models
Skin Cutaneous blood flow peaks in afternoon and late evening.6 Adults
physiology Facial sebum production peaks in afternoon and troughs during the night. 7
Adults
Keratinocyte and cutaneous stem cell proliferation highest during the night.33 Stem cell primary human
keratinocytes in culture and
in vivo in mice
Skin barrier Although evidence is conflicting, the general consensus is that transepidermal water loss is highest Adults
function during late afternoon and evening.3,4,8
CLOCK gene expression controls deficient or dysfunction aquaporin-3 proteins, which decreases Mice
stratum corneum hydration.9
Immune CLOCK:BMAL1 heterodimer controls human beta-defensin 1 and its gene expression exhibits Human colon carcinoma cells
function circadian oscillations.15 and human kidney cells in vitro
Pro-inflammatory cytokines (eg, IL-12) and circulating na€ıve T-cells peak at night.12 Adults
Anti-inflammatory cytokines (eg, IL-10) and cytotoxic T-cells peak during the day.13 Human keratinocytes in vitro
Sleep High pro-inflammatory cytokine and T-cell levels at night contribute to nocturnal pruritus and Children
disturbance flares in individuals with AD.34
Low nocturnal cortisol levels may be associated with nocturnal itching in individuals with AD.16,35 Adults and children
Infants of mothers with allergic disease have less variation in diurnal cortisol secretion patterns, a Children
low morning cortisol surge, and flattened circadian rhythm.17
Melatonin Plasma melatonin and beta-endorphin levels decrease during flares in AD in children.24 Children
Melatonin is secreted in a diurnal pattern with a steady increase and peak between 2 and 4 AM, Adults
followed by a gradual decrease.21
Disrupted circadian pattern of melatonin secretion in AD patients.23 Children
Daily melatonin treatment for 4 weeks significantly decreased SCORAD scores and decreased the Children
time to sleep onset in children with AD.18,25
Quality of The itch–scratch cycle and resulting sleep disturbance are major causes of impaired quality of life Children
life in up to 60% of patients with AD.34
Poor sleep in children leads to impaired neurocognitive function, behavioral problems, and mood Children
changes.36

AD, atopic dermatitis; IL, interleukin.

lower SCORing of Atopic Dermatitis (SCORAD) index scores (9.1)
than those receiving placebo (2.2) (P < .001).18 In a separate study
by Chang and colleagues,25 latency to sleep onset in children with
AD was also significantly shorter with melatonin supplementation
than placebo ( 23.4 vs 1.2 minutes; P = .02). Melatonin supple-
mentation alleviated skin inflammation in mice with AD-like dermati-
tis by reducing serum IL-4 and immunoglobulin E levels, suggesting
that melatonin may restore barrier function in AD by limiting
26
immune overactivation.
1.4 | Potential for chronotherapy
The cutaneous CR exerts immense control over SB and immune
functions, with peaks and troughs occurring in approximate 24-hour
patterns. In line with this, drugs can be delivered at optimal time
points in accordance with biologic rhythms to maximize therapeutic
benefits and minimize adverse effects.27 Chronotherapy is the prac-
tice of delivering drugs in synchrony with the CR cycles of a condi-
tion or symptom. Interest is growing in the use of chronotherapy for
the management of a variety of conditions, including essential
hypertension, rheumatoid arthritis, and even cancer. For example,
bedtime administration of methotrexate significantly reduces inflam-
mation and improves symptoms of rheumatoid arthritis.28
Drug-metabolizing cytochrome P450 enzymes function in accor-
dance with circadian patterns in the skin,29 indicating the potential
of chronotherapy in dermatologic diseases, including AD. For exam-
ple, methylprednisolone aceponate is recommended in children with
AD flares because of its efficacy with once-daily dosing, greater
adherence, and minimal adverse effects, which defines the ultimate
goal of chronotherapy in dermatology.30 Implementation of
chronotherapy in AD is a novel and potentially transformative treat-
ment approach. TEWL, hydration, and sebum production have daily
variation patterns and should be considered when using topically
applied medications to alter absorption of topically applied com-
pounds. For example, because TEWL and skin blood flow are highest
in the evening, moisturizers should be applied and topical anti-
inflammatory drugs administered at that time for greater penetrance
and to impart maximum therapeutic benefits.31 In addition, the
administration of topical and systemic immune-modulating treat-
ments may be dosed in accordance with the endogenous morning
VAUGHN ET AL.
cortisol surge to allow synergistic anti-inflammatory effects.32 Proper
implementation of chronotherapy may also lead to better sleep, bet-
ter quality of life for patients and caregivers, and overall lower dis-
ease burden.
2 | DISCUSSION
The role that CR plays in the pathogenesis of AD involves a complex
interplay between endogenous clock, environment, and immune and
SB function. Greater nocturnal cutaneous blood flow, abnormal bar-
rier function, inflammatory responses, and the melatonin secretion
pattern may increase nocturnal pruritus and sleep disturbance in
individuals with AD.5 Melatonin has a favorable safety profile, but its
antioxidative and anti-inflammatory properties in individuals with AD
and appropriate dosing regimens in children require further investi-
gation. Chronotherapy is a promising avenue of research, as evi-
dence of the use of chronotherapy to treat skin diseases is scarce.
More investigation is needed to better understand its efficacy and
safety in practice, which is especially important in children.
CONFLICT OF INTEREST
RKS serves as a scientific advisor to Dermveda. VYS serves on the
advisory board of Menlo Therapeutics and has received honorarium
for a preceptorship lecture sponsored by Novartis.
ORCID
Alexandra R. Vaughn http://orcid.org/0000-0003-2975-0983
Ashley K. Clark http://orcid.org/0000-0002-2880-7629
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