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toPatients withObstructive
26
Sleep Apnea
PedroRedondo
26.1 Introduction
The central nervous system regulates the control of breathing. Central apneas are
produced in the ventilatory control centers of the nervous system when respiratory
effort begins during sleep [1]. Central apneas are usually associated with other medical disorders such as congestive heart failure, stroke, and neurologic disorders or
are secondary to the use of substances that have a respiratory depressant effect, such
as opioids. However, they can also occur at high altitudes [1].
Obstructive sleep apnea (OSA) is a respiratory disorder characterized by narrowing or closing of the upper airways during sleep. Obstruction of the upper airways
may be partial and recurrent (hypopnea) or complete (apnea) with recurrent oxygen
desaturation and periodic changes in heart rate, blood pressure, intrathoracic pressure, and sympathetic activity. In adults, a diagnosis of OSA is considered when ve
or more apneas or hypopneas occur per hour of sleep or when the apnea–hypopnea
index (AHI) is greater than or equal to ve events per hour [1].
The most conservative estimates suggest that the prevalence of OSA is 4% in
males and 2% in females, although it is likely to be higher [1]. Obstructive respiratory evens (apnea or hypopnea) last at least 10s, are associated with a fall in blood
oxygen saturation, and generally conclude with brief awakenings that fragment
sleep and manifest as cortical activation/awakenings on electroencephalograms.
Furthermore, OSA may lead to structural changes in sleep, including shortening or
loss of stage 3 of deep sleep and/or rapid eye movement (REM) sleep.
The skin and the central nervous system are closely connected and have a common embryonic origin, the ectoderm. It is a popular saying that the face, the skin of
the face, is the mirror of the soul, and without doubt, it is evident how restful sleep
P. Redondo (*)
Department of Dermatology, University Clinic of Navarra, Madrid, Spain
e-mail: predondo@unav.es
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
P. M. Baptista et al. (eds.), Obstructive Sleep Apnea,
https://doi.org/10.1007/978-3-031-35225-6_26
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improves the appearance of the skin while, in contrast, the lack of nighttime rest
negatively affects the skin.
Skin disorders are a common comorbidity of sleep apnea, and sleep apnea itself
may deteriorate the skin. Indeed, in a study with patients with OSA, they compared
photographs taken before and after treatment with CPAP and showed that treatment
made patients look younger and more attractive [1].
As for the epidemiologic association of sleep and the skin, a study using data
from the national Danish Registry assessed 19,438 patients with OSA and controls
matched for age and gender and found a higher likelihood of skin disorders in
patients with OSA (OR 1.18 [1.07–1.30]) [2]. This nding was conrmed in a pediatric cohort in the same research group with an OR of 1.32, 95% CI: 1.02–1.71 [3].
These ndings indicate a general relationship that may be bidirectional between
OSA and skin disorders.
OSA is associated with activation of the sympathetic nervous system, systemic
inammation, metabolic dysregulation, and increased coagulation and endothelial
dysfunction [4].
Psychiatric comorbidities [5] in skin disorders such as major depressive disorder
and posttraumatic stress disorder, associated with a high sympathetic tone, are also
commonly associated with OSA [6]. Without doubt, the interface between sleep and
skin disorders is complex and multifactorial [7].
This chapter reviews the literature on the association between OSA and dermatologic disorders. OSA may be an associated factor in complex medical patients
(e.g., diabetic patients with complications) with dermatologic problems which are
refractory to treatment. We will not discuss the possible role of OSA in dermatologic manifestations of systemic diseases, which also may be comorbid with OSA.
P. Redondo
26.2 Pathogenesis
OSA is an inammatory disease associated with obesity and mechanical obstruction
of the airways leading to episodes of tissue hypoxia. Let us rst consider each one
of these factors individually.
– Inammation: OSA is considered a low-grade chronic inammatory disease of
the airways with abnormal neuromuscular control of breathing [8, 9]. A direct
link exists between OSA and skin disease through inammation. This occurs in
psoriasis and atopic dermatitis. The inammation induced by the sleep disrup-
tion caused by OSA, the increase in systemic interleukin (IL)-1, IL-6, and IL-12,
and the fall in IL-10 further exacerbate psoriasis. Psoriasis also increases levels
of TNF-α and IL-17, which is associated with greater atherosclerotic risk and
possibly OSA itself [10]. The heightened inammatory state caused by OSA,
which may occur independently of body mass index [11], may be a predisposing
and/or triggering factor of inammatory dermatoses in patients at greater risk of
developing such disorders. For example, a study of patients with OSA found that
the serum levels of the inammatory mediators IL-23 and C-reactive protein
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were signicantly higher in patients with OSA than to healthy controls [12]. A
3-month course of continuous positive airway pressure (CPAP) therapy led to a
signicant reduction in serum levels of IL-23 and C-reactive protein in patients
with OSA.The changes in the levels of IL-23 were positively correlated with
improvement in AHI scores and C-reactive protein levels [12].
Some studies suggest that OSA increases the release of catecholamines,
which could induce a deviation of Th2 cells in the immune response. Several
so-called proinammatory cytokines such as IL-1 or TNF-α also exert a somnogenic effect. Alteration or dysregulation of these cytokines may lead to
dysfunctional sleep. It is well known that the circadian rhythm of the release
of TNF-α is signicantly disrupted in patients with OSA.The physiologic
nocturnal peaks of this cytokine almost disappear, and an additional daytime
peak occurs. Patients with OSA have high levels of inammatory mediators
such as TNF-α and IL-6, and these abnormalities are reduced by treatment
with CPAP.Several studies have shown that sleepiness is affected by certain
drugs that neutralize TNF-α such as thalidomide, etanercept, and iniximab.
Obese patients with OSA experienced signicant and marked reductions in
sleepiness following treatment with etanercept, which proved to be more
effective than CPAP.It has also been reported that sleep disorders and mental
alertness improve in patients with rheumatoid arthritis when treated with
iniximab.
A recent study has identied 4 cytokines associated with autoimmune disease
whose median serum levels were signicantly different for patients with OSA
who received therapy with CPAC as compared to patients with OSA who received
no treatment: APRIL (5.2 times lower P=3.5×10
P=7.7×10−5), IFN-α-2 (2.9 times higher mayor, P=9.6×10
−11
), CD30 (16 times higher,
−14
) and IL-2 (1.9
times higher, P=0.0003). Cytokine levels in the patients treated with CPAC
were similar to the levels in the control subjects. These ndings suggest that the
levels of these four cytokines are affected by sleep disorders and perhaps by
chronic hypoxia [13].
– Obesity (metabolic syndrome, polycystic ovarian syndrome):
A critical predisposing factor for OSA is excess body weight, and it is estimated
that about 60% of moderate to severe cases of OSA are related to obesity [1].
Alternatively, OSA may increase insulin resistance and exacerbate the metabolic
dysfunction of obesity [4]. Although it is thought that the prevalence of OSA in
children is between 1% and 4%, it may be higher due to the epidemic of childhood obesity [1].
OSA causes oxidative stress. A study [14] showed that the expression of
nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase is elevated
in the leukocytes of patients with OSA, which significantly increases the
oxidative effect of leukocytes. Furthermore, intermittent hypoxia, the
increase in the sympathetic nervous system activity and the hypothalamic–
pituitary axis and the release of proinflammatory cytokines are considered
potential mechanisms of OSA in relation to insulin resistance and glucose
intolerance [15].
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Several skin disorders are associated with obesity, which links with a greater
risk of OSA.Diabetes is a metabolic disorder that may result in obesity and is
associated with skin disorders such as diabetic ulcers. OSA in these patients may
further affect wound healing, thus perpetuating the vicious cycle of diabetic ulcers.
– Mechanical obstruction of the upper airways: several syndromes and genetic
abnormalities with involvement of the skin are associated with anomalies in the
upper airways and a greater risk of OSA.Specically, syndromes with lipodystrophy and some blistering or restrictive scarring diseases may also cause
mechanical obstruction of the upper airways and OSA.
– Hypoxia: skin cancer, especially melanoma, may be associated with OSA due to
the induction of neovascularization signals such as hypoxia-inducible factor
(HIF)-1α and/or vascular endothelial growth factor (VEGF) sent systematically
in OSA in response to the intermittent hypoxia.
Below we will deal in more detail with the skin diseases associated with OSA
as related to these 4 etiopathogenic factors.
P. Redondo
26.2.1 Skin Disease Related toInflammation
26.2.1.1 Psoriasis
Psoriasis is a chronic inammatory disease of the skin of autoimmune origin characterized by the presence of erythematous plaques which are well delimitated and
covered by pearly scales located preferentially on joint surfaces such as the elbows
or knees, and the scalp. It has a chronic progression and is variable both in its clinical features and progression. Thus, there are clinical pictures with very few practically asymptomatic lesions and others which are generalized and accompanied by
nail and joint involvement which causes great functional disability.
Although the cause of the disease is unknown, two basic issues stand out in the
pathogenesis: epidermal hyperplasia due to the increase in the number of germinative cells and the inammatory inltrate in the dermis. The inammation is mediated by CD4+ T lymphocytes which release (together with keratinocytes)
proliferative cytosines which stimulate the proliferation of epidermal cells. The
inammatory response is of the cellular type against a yet unknown autoantigen or
a streptococcal superantigen in the case of psoriasis in postinfectious gouts. A series
of genetic factors that lead to its appearance and development has been identied as
the environmental factors responsible for triggering the episodes. The genetic predisposition toward suffering this disease is associated with the expression of class I
antigens of the HLA Cw6, B13, B17, B27 Bw57 system, and class II DRw7.
Factors that trigger attacks include trauma, infections such as those of the upper
airways caused by beta-hemolytic streptococci, drugs such as lithium salts, betablockers, antimalarials, nonsteroidal anti-inammatories or the sudden discontinuation of the administration of corticoids, situations involving great emotional stress,
and metabolic factors such as states of hypocalcemia and alcohol intake.
The course of psoriasis is unpredictable, with remissions and exacerbations of a
variable length, although it is usually chronic. The complicated forms such as
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arthropathic psoriasis may be disabling and the severe forms such as erythrodermic
and pustular psoriasis may be fatal.
Psoriasis is without doubt, the skin disease with the most solid links to OSA
[16–18]. The estimated frequency of OSA in psoriasis ranges from 13.7% to 61.4%.
A study using data from the Danish National Register of Patients shows a two-way
relationship between OSA and psoriasis, where psoriasis is associated with a greater
risk of OSA and OSA is associated with a greater risk of psoriasis [19]. In addition,
several observational studies [19–26] and one randomized controlled trial [27] have
assessed the relationship between OSA and psoriasis.
A recent study included 12,336 patients with psoriasis aged over 21years and
24,008 controls matched for age and sex. The prevalence of OSA in patients with
psoriasis was higher than in the control group (2.7% and 1.5%, respectively,
P< 0.001). Multivariate analysis adjusting for age, sex, race, body mass index,
chronic obstructive lung disease, hyperthyroidism, hyperlipidemia and peptic ulcer
disease revealed a signicant association between psoriasis and OSA (odds
ratio=1.27, 95% CI: 1.08–1.49, P<0.001) [28].
Another Polish observational study found that patients with OSA were four
times more likely to have psoriasis than the general population with OSA had a twotimes greater risk of developing psoriasis over a period of 3years and that this
increased risk was related to obesity and living in urban areas [26]. A European
study also found a greater prevalence of psoriasis in patients with OSA, regardless
of confounding factors such as obesity and other metabolic conditions [27].
It also appears that comorbidities such as hypertension increase OSA risk in
patients with psoriasis [24]. OSA is associated with an increase in the nocturnal
activity of the sympathetic nervous system which results in elevated blood pressure
and of oxidative and inammatory stress markers. These factors affect the cardiovascular system and may cause severe complications [29]. Furthermore, oxidative
stress and inammatory processes are involved in the pathogenesis of OSA and
psoriasis. The systemic inammation resulting from OSA/psoriasis is accompanied
by autonomic activation / increase in sympathetic tone [16]. The autonomic activation may result from systemic inammation or be simply due to the more signicant
number of awakenings. It has also been speculated that the autonomic activity in
psoriasis leads to a greater incidence of restless leg syndrome, and an increase in the
number of awakenings [16, 30]. Sleep disturbance in psoriasis leads to a greater
frequency of N1 stage sleep, which may cause more frequent pharyngeal collapse
[31]. Moreover, the frequent awakenings in OSA reduce the sleep quality and may
increase itching [26]. This has also been demonstrated in a mouse model of psoriasis in which sleep deprivation exacerbated skin lesions.
Several cytokines common to the pathogenesis of the two diseases have also
been identied. Indeed, transcription factors such as nuclear factor-kB and HIF-I,
which are activated due to the intermittent hypoxia and the oxidative stress resulting
from lesions due to reperfusion, lead to an increased regulation of the expression of
TNF-α and IL-6 [10]. These same cytokines are elevated both in the skin and serum
of patients with psoriasis [32].
Studies into treatment offer further evidence of the link between psoriasis and
OSA.Thus, in three patients with refractive psoriasis and OSA, the severity of the
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P. Redondo
lesions decreased when the patients were treated with CPAP [26]. Although CPAP may
decrease the symptoms of psoriasis, whether the treatment of psoriasis is effective to
improve OSA remains unclear. Thus, when 20 patients with OSA and psoriasis were
treated with adalimumab (an anti-TFN-α agent) for 8weeks, no apparent improvement
in OSA was observed [33]. Although it is unlikely that such short- term treatment with
a TNF-α inhibitor would be effective, long-term data are lacking on the benets of this
approach for comorbid OSA.In addition, OSA is related to other inammatory autoimmune disorders such as lupus erythematosus and rheumatoid arthritis [34].
26.2.1.2 Atopic Dermatitis
Atopic dermatitis (AD) is a chronic relapsing inammatory disease of the skin that
causes intense itching which preferentially affects the exor surfaces of the elbows
and knees and the cephalic pole. Its exact cause is unknown, but it is a multifactorial
disease resulting from the interaction of genetic and environmental factors, defects
in the skin’s barrier function and a series of immunologic factors. Frequently it is
erroneously attributed to “nerves” or “stress.” Patients with AD often have a history
of allergic conditions such as asthma, hay fever, eczema, or test positive in skin
allergy tests. However, the disease is not caused by an external allergen and is rather
seen as endogenous eczema (Fig.26.1).
The prevalence of AD in the general population is between 2% and 5%, and about
15% in children and the young. But incidence has been reported to be as high as 20%
in countries such as the United States, and world-wide incidence is increasing. The
disease begins before the rst year of life in more than 60% of patients, but the frequency falls with age reaching just 5% at 12years. Onset in adulthood is infrequent
although such cases tend to be more severe in their clinical course and progression.
Dysfunction of the skin barrier and dysregulation of the immune system are fac-
tors that trigger AD.The main proteins responsible for epidermal function are laggrin, transglutaminases, keratins, and intercellular proteins. Defects in these proteins
facilitate the entry of microbes and allergens into the skin. The skin barrier dysfunction is considered the rst stage in the development of AD, although dysregulation
of the immune system also disrupts the skin barrier [35, 36].
Fig. 26.1 Scaling
eczematous lesions in an
adult patient with atopic
dermatitis
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Patients with AD have an abnormal cellular and humoral immune response,
facilitating the reaction with environmental antigens, increasing serum IgE, and
abnormalities in lymphocyte subpopulations. Thus, atopic patients are predisposed
toward mounting Th2 responses with the development of responses against inappropriate antigens such as environmental allergens, bacterial superantigens, and
epidermal autoantigens. The onset of AD is associated with the production of Th2
cytokines (IL-4 and IL-13) involved in the acute phase of tissue inammation. In
contrast, IL-5, involved in eosinophils development and survival, predominates in
the chronic form, as do GM-CSF, IL-12, IL-18, IL-11, and TGF-B1. In addition, the
increased expression of chemokines (eotaxin, RANTES) contributes to the inltration of macrophages, eosinophils, and T cells in acute and chronic AD lesions
[37, 38].
A sizable Taiwanese retrospective study of pediatric and adult patients (1222
patients with OSA and 18,330 without OSA) has shown the epidemiologic link
between AD and OSA is shown. The adjusted models showed that patients with a
recent diagnosis of OSA were 1.5 times more likely to develop AD.Furthermore,
this nding was more marked in children (subjects under the age of 18) with a proportion of 4.01, 95% CI: 1.57–10.26 [39].
As we have already mentioned in this chapter, the proinammatory cytokines
associated with OSA, such as IL-6, are accompanied in atopic (allergic) children
by increased regulation of Th2 cytokines. The positive regulation of Th2 contributes to a greater susceptibility to developing AD and the exacerbation of
existing AD.
The main risk factor for OSA in children is adenotonsillar hypertrophy, which is
related to the repeated collapse of the airways [40]. Some published studies have
established the association between AD and adenoids/adenotonsillar hypertrophy as
an established comorbid factor in children [41], although Alexopoulos etal. suggest
that AD is not related to cases in children who snore [42].
Obstruction of the upper airways is also more common in children with AD in
part due to comorbid allergic rhinitis. As for mechanical obstruction, ndings are
mixed regarding the association with adenotonsillar hypertrophy in atopic children
[43], although it is believed that the increase in leukotrienes in the allergic disease
may contribute to r a rise in adenotonsillar hypertrophy, thus placing patients with
AD at risk for apnea [44, 45].
Research into AD improves the detection and evaluation of sleep disorders [46].
Children with AD have a signicantly higher risk of OSA than those without
AD.After adjusting for age, sex, level of urbanization and underlying comorbidities
(craniofacial anomalies, prematurity, laryngomalacia/tracheomalacia, diabetes mellitus, and adenotonsillar hypertrophy), patients with AD had a 1.86 greater risk of
OSA.Thus, it is considered that AD is an independent risk factor for OSA.The risk
for OSA was greater in the youngest children (under 6years of age) and in those
living in urban areas. Given that the onset of AD occurs relatively early in life, the
early identication of risk factors and symptoms is essential to prevent OSA development. This is the rst study [47] that indicates a greater risk for OSA in children
with AD.
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AD is a condition that disrupts sleep in patients suffering from it, which is partly
attributable to the nighttime itching so characteristic of the disease [48]. In addition,
several sleep disorders such as periodic limb movement disorder [49] and OSA are
associated with AD.
High sympathetic tone may be present in certain dermatologic disorders such as
AD [50]. There may be a high level of excitation during sleep, unrelated to the
scratching, even when the AD is in remission.
Similarly, there seems to be an association between OSA and AD in adults [39].
A retrospective cohort study using data from the Taiwanese National Health
Insurance database examined the incidence of AD in 1222 patients recently diagnosed with OSA between 2000 and 2005 compared to a matched cohort of 18,330
controls without OSA [39]. All the patients were followed up for 5.5years. Patients
with OSA were 1.5 times more likely to develop AD than the controls without OSA
(Hazard risk=1.5, 95% CI: 1.15–1.95) after controlling for age, sex, hypertension,
coronary disease, obesity, allergies, allergic rhinitis, asthma, monthly income, and
geographic location.
Episodic nasal congestion in the atopic patient with allergic rhinitis could be
associated with OSA.However, a study of 150 adult patients with OSA [51] found
no signicant differences in polysomnographic ndings, including OSA indices,
between patients with persistent allergic rhinitis (n= 55) and the remaining 95
patients with OSA but without nasal problems.
P. Redondo
26.2.2 Skin Diseases Related toObesity
Without doubt, one of the most signicant risks for OSA is obesity, which is mainly
related to obstruction of the upper airways. Therefore, we must consider those diseases of the skin which have a greater prevalence in patients with obesity.
26.2.2.1 Diabetes
Type 2 diabetes, in particular, is one of the most prevalent diseases in obese patients,
and the presence of diabetes is associated with a higher risk for skin ulcers in peripheral areas with poor vascular circulation. This problem which seems to worsen
when OSA is simultaneously [52]. OSA could increase this risk due to the endothelial dysfunction associated with this disease and the neuropathy of small bers [53].
Curiously, in a case series, treatment with CPAP resulted in a signicant improvement in the granulation of wounds in diabetic patients [54]. Two patients had not
been previously diagnosed with OSA, and another had a previous diagnosis of
severe OSA but did not comply with the CPAP therapy. The two undiagnosed
patients had an AHI of 41 and 49, respectively, and were successfully treated with
CPAP and the standard care for ulcers. Both showed a marked improvement in the
granulation and healing of wounds after CPAP therapy. The third patient refused to
consider CPAP therapy and experienced decient healing of the wound and
Pseudomonal infection despite aggressive wound treatment [54]. Possible untreated
OSA may affect the healing of diabetic foot ulcers.
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