Figures
Abstract
Background
Obstructive sleep apnea (OSA) is associated with systemic inflammation and induces various comorbid medical diseases. To date, no study has explored the relationship between OSA and atopic dermatitis (AD), an inflammatory and autoimmune skin disorder. This study investigated the longitudinal risk for AD in patients with OSA.
Methods
A random sample of 1,000,000 individuals from Taiwan's National Health Insurance database was collected. From this sample, 1222 patients with newly-diagnosed OSA between 2000 and 2005 were identified and compared with a matched cohort of 18330 patients without OSA. All patients were tracked for 5.5 years from the index date in order to identify which patients subsequently developed AD.
Results
During the 5.5-year follow-up period, the incidence rates of AD in the OSA cohort and comparison groups were 9.81 and 6.21 per 1000 person-years, respectively. After adjustment for age, gender, diabetes, hypertension, coronary heart disease, obesity, allergy, allergic rhinitis, asthma, monthly income, and geographic location, patients with OSA were 1.5-times more likely to develop AD than patients without OSA (95% CI = 1.15–1.95, p = 0.0025). The hazard risk for AD was greater in male OSA patients and young OSA patients (0–18 and 19–34 years), adjusted HRs being 1.53 (95% CI = 1.14–2.06, p = 0.005), 4.01(95% CI = 1.57–10.26, p = 0.0038) and 1.75(95% CI = 1.00–3.04, p = 0.0483), respectively. The log-rank test indicated that OSA patients <35-years-old had significantly higher cumulative incidence rates of AD than those patient of the same age in the comparison group (p = 0.0001).
Citation: Tien K-J, Chou C-W, Lee S-Y, Yeh N-C, Yang C-Y, Yen F-C, et al. (2014) Obstructive Sleep Apnea and the Risk of Atopic Dermatitis: A Population-Based Case Control Study. PLoS ONE 9(2): e89656. https://doi.org/10.1371/journal.pone.0089656
Editor: Tesfaye Mersha Baye, Cincinnati Children's Hospital Medical center, United States of America
Received: May 13, 2013; Accepted: January 24, 2014; Published: February 25, 2014
Copyright: © 2014 Tien et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Atopy is defined as a condition that involves hyperreactivity to allergic triggers. The prevalence of atopic dermatitis (AD), a chronic inflammatory and pruritic skin disease [1], appears to be increasing, especially in industrialized counties. Although not a life-threatening disease, AD negatively impacts health and quality of life and increases the medical burden. The cause of AD is poorly understood; however, theories include an impaired epidermal barrier, immune system dysregulation, and an inflammatory reaction of the skin [2]. Increasing evidence suggests that AD is more than a local inflammatory disease and may be the result of systemic inflammation. Chemokines, cytokines, T-cells and other inflammatory cells appear to contribute to the initiation and maintenance of this disease [3].
Obstructive sleep apnea (OSA) is a sleep disorder caused by recurrent episodes of upper airway collapse and is characterized by repetitive episodes of apnea/hypopnea and oxygen desaturation during sleep [4]. Recurring arousal from sleep, daytime sleepiness, and fatigue are signs of disturbed sleep. The prevalence of OSA in the general population is approximately 20% [5]. OSA is recognized as a potential cause of many debilitating medical problems, including ischemic heart disease, hypertension, insulin resistance, type 2 diabetes, and mental illness [6]–[8]. Although the underlying pathogenesis linking OSA to these comorbidities is not fully understood, more and more evidence suggests that the systemic inflammation and the procoagulant and thrombotic activity in OSA can lead to endothelial dysfunction, atherosclerosis, and cardiovascular events [9].
OSA has been extensively studied in relation to metabolic and cardiovascular disease (CVD) but rarely in relation to dermatologic disease. Psoriasis, a chronic immune-mediated inflammatory skin disease, is thought to be associated with OSA, metabolic syndrome, and CVD [10]–[12]. The interaction between OSA and psoriasis is very complex and likely linked via systemic inflammation [10], [13], [14]. Few reports have investigated the association between OSA and AD. Some cross-sectional studies have suggested that some OSA features might be associated with atopy, although longitudinal studies are lacking. Chng et al. found atopy to be associated with snoring and other features of OSA [15]. One questionnaire study of children showed an association between snoring and eczema. A case study suggested that continuous positive airway pressure for OSA might resolve dyshidrotic eczema by reducing pro-inflammatory cytokines [16]. Marsell et al. reported that risk factors for snoring were similar to those for allergic disorders [17]. Because both OSA and AD are considered systemic inflammatory diseases, it is reasonable to hypothesize that there might be a relationship between one condition and the development of the other condition. The current study used a national population-based cohort in Taiwan to investigate the risk for the development of AD in patients with OSA over a 5.5-year period.
Methods
Data sources
Taiwan launched a single-payer National Health Insurance (NHI) program on March 1, 1995, and as of 2009, the NHI has collected one of the largest and most complete population-based datasets in the world. Data used in this study came from a subset of the NHI database, the Longitudinal Health Insurance Database 2000 (LHID2000), which contains all claims data between 1996 and 2009 from one million beneficiaries randomly selected in 2000 for follow-up study. There are no significant differences in age, gender, and healthcare costs between the sample group and all enrollees. The LHID2000 provides encrypted patient identification numbers, gender, date of birth, dates of admission and discharge, the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes of diagnoses and procedures, details of prescriptions, registry of Catastrophic Illness Patient Database, and costs covered by Taiwan's NHI. The institutional review board of Chi Mei Medical Center approved the protocol of this study. The requirement of informed consent was waived because the datasets were devoid of identifiable personal information.
Study sample
A retrospective cohort study was conducted with two study groups: a new-onset OSA group and a matched non-OSA (comparison) group recruited from 2000-2006. OSA was defined in a patient if (1) he or she had at least two outpatient service claims with the codes of OSA (ICD-9-CM code 78051, 78053, 78057, 32723) at any hospital or local medical clinic and received a polysomnography test or (2) he or she had a single hospitalization for OSA among the 5 claims diagnosis codes. AD was defined in patients if they had been diagnosed on two occasions with AD by dermatologists. Patients diagnosed with OSA before 2000 were excluded, and patients who were diagnosed with AD (ICD-9-CM code 691) before OSA was diagnosed were also excluded. Sex, age, and date of first registration into the NHI program were recorded. Patients not diagnosed with OSA were randomly selected from the dataset and matched with the OSA group by sex, age (±30 days), and index date of first registration into the NHI program and then categorized into the non-OSA group at a ratio of 15 non-OSA for each OSA patient.
For both groups, the geographic area of residence and monthly income (record as NT$) as well as baseline co-morbidities, including diabetes mellitus (ICD-9-CM code: 250), hypertension (ICD-9-CM code: 401-405), coronary heart disease (ICD-9-CM code: 410-414), obesity (ICD-9-CM code: 278), allergy (ICD-9-CM code: 9953, 7080, V150 and V196), allergic rhinitis (ICD-9-CM code: 477) and asthma (ICD-9-CM code: 493) were recorded. These represent critical factors that can affect the risk of AD (ICD-9-CM code: 691). AD might be mediated by oxidative stress and circulating inflammatory cytokines [2], [18]. Since diabetes, hypertension, and coronary heart disease are well-established with increasing inflammatory factors and oxidative stress, these factors were taken in consideration and adjusted for [19], [20]. Obesity was thought to be associated with AD and could represent a trigger for AD [21], [22]. Allergy, allergic rhinitis, and asthma are associated with adaptive immune system dysfunction and are thought to be associated with AD [23]. These comorbidities were included if they presented in an inpatient setting or in three or more ambulatory care claims coded one year before the index medical care date. Person-years (PY) of the follow-up time were calculated for each person until AD diagnosis, death, or the end of the follow-up period in 2009.
Statistical analyses
All statistical operations were performed using the SAS 9.3 statistical package (SAS Institute, Inc., Cary, North Carolina, USA). Pearson's χ2 tests were used to compare differences in the baseline characteristics, comorbid medical disorders, and sociodemographic status between the two groups. The incidence rate was calculated as the number of AD cases during the follow-up divided by the total person-years for each group by sex and age. Stratified Cox proportional hazard regression, stratified by gender and age group (0–18, 19–34, 35–49, and >50 yr), was performed to calculate the risk for AD between patients with OSA compared to those patients without OSA during the follow-up period. A Kaplan-Meier analysis was used to calculate the cumulative incidence rates for AD between the two cohorts, and the log-rank test was used to analyze the differences between survival curves. A two-sided P value <0.05 was considered significant.
Results
A summary of the baseline characteristics and comorbid conditions of the two groups is shown in Table 1. A total of 1222 OSA patients and 18330 age-, gender-, and index date-matched non-OSA patients were followed for 5.5 years. Approximately 3% of the group was 0–18 years old, 21% was 19–34 years old, 39% was 35–49 years old, and 37% was ≥50 years old. Eighty percent were males. Patients with OSA had a higher prevalence of diabetes mellitus (DM), hypertension (HTN), coronary heart disease (CHD), obesity, allergy, allergic rhinitis, and asthma. Additionally, patients with OSA had a higher economic status and were more likely to live in central and northern Taiwan than the comparison group.
Table 2 shows the risk for AD for OSA patients stratified by age and gender. During the 5.5-year follow-up period, the incidence rates for AD for the OSA and non-OSA cohorts were 9.81 and 6.21 per 1000 person-years, respectively. Patients with OSA were at significantly higher risk for AD than those without OSA (crude HR = 1.58, 95% CI = 1.23–2.04, P = 0.0004). After adjusting for age, gender, DM, HTN, CHD, obesity, allergy, allergic rhinitis, asthma, monthly income, and geographic location, OSA patients were 1.5–fold more likely to develop AD (adjusted HR = 1.5, 95% CI = 1.15–1.95, P = 0.0025). The adjusted HRs were most pronounced in the younger age groups 0–18 years and 19–34 years (adjusted HR = 4.01, 95% CI = 1.57–10.26, P = 0.0038 and adjusted HR = 1.75, 95% CI = 1.00–3.04, P = 0.0483, respectively). There were no group differences in risk for AD in the age groups 35–49 years and ≥50 years. Males with OSA were 1.53-times more likely to develop AD than males without OSA after adjusting for confounders (adjusted HR = 1.53, 95% CI = 1.14–2.06, P = 0.0050). No difference in risk for AD was identified among women with and without OSA (adjusted HR = 1.39, 95% CI = 0.79–2.46, P = 0.2522). Kaplan-Meier analysis revealed that OSA patients <35 years of age had a higher cumulative incidence rate for AD than those patients of the same age in the comparison cohort (log-rank test P<0.0001) (Figure 1). In patients >35 years of age, there was no significant difference in cumulative incidence rate for AD between the two groups (log-rank test P = 0.0519) (Figure 2).
Discussion
Many studies have reported OSA to be comorbid with cardiovascular disease, HTN, type 2 DM, and insulin resistance, but few have investigated the possible relationship between OSA and dermatologic diseases. To the best of our knowledge, this is the first study to investigate the relationship between the OSA and risk for AD. The incidence rate for AD in patients with OSA was 9.81 per 1000 person-years. This study also showed that the incidence for AD was 1.5-times higher in patients with OSA than it was in the age- and gender-matched comparison groups during a 5.5-year follow-up period, after adjusting for age, gender, medical comorbidities, geographic area, and monthly income. The medical comorbidities that were adjusted for have been noted in the literature as risk factors for AD. Although the HR decreased after adjustment, OSA patients still had a significantly higher risk for AD. Subgroup analysis found the risk for developing AD was greater in men with OSA (adjusted HR: 1.53) and younger OSA patients age 0–18years and 19–35 years (adjusted HRs 4.01 and 1.75, respectively).
The prevalence of AD is estimated at 2% to 10% in adults in Europe, where the incidence has grown 2- to 3-fold [24], [25]. One community-based survey in Taiwan by Chen et al. reported the prevalence of AD to be 4.33%, higher than a previous report [26]. Although the prevalence of AD varies from country to country, its incidence appears to be increasing. AD is a very common, pruritic, relapsing inflammatory skin disorder associated with a poor quality of sleep [27]. AD may further aggravate the severity of daytime hypersomnolence in patients with OSA. The wide range of prevalence worldwide seems to suggest expression of this disease may be influenced by racial, environmental, and many other unidentified factors [25]. Although the pathomechanisms underlying AD are not fully understood, the chronic relapsing nature of this disease requires careful monitoring both for the disease itself as well as its associated risk factors. OSA and AD may share similar pathogenic pathways [28]. One study by Al Lawati et al. reported that ethnicity was a risk factor for OSA and that Asians appeared to be at greater risk for OSA at a given body mass index [29]. These findings along with the results of the current study suggest that clinicians in Asia should be aware of the increased risk for AD among patients with OSA.
Although the underlying mechanism contributing to the association between OSA and AD is likely complex, some possible explanations for our findings should be considered. First, obesity is a strong risk factor for OSA, and OSA is a major complication of obesity [30], [31]. According to a study by Hersoug and Linneberg, there is increasing epidemiologic evidence that obesity also increases the risk for AD [21]. This study suggested that obesity might induce decreased immune tolerance and result in atopy [21]. In obese subjects, increases in the circulating levels of interleukin-6 (IL-6) and leptin, and decreases in IL-10 have been reported to down-regulate the immunologic activity of regulatory T-lymphocytes [32]–[35]. Additionally, Vieira et al. reported that obese subjects had a higher frequency of specific IgE positivity than non-obese subjects [36]. These changes could possibly decrease the immunologic tolerance to antigen and possibly result in atopic disease. AD is a disease of altered skin barrier and immune system dysregulation. A defect in filaggrin (FLG) may induce skin barrier dysfunction [37]. One study by Silverberg et al. showed that obesity might act as a trigger in disease associated with FLG mutations and suggested that obesity can be a trigger for AD or exacerbate it [22]. The association between OSA and AD may be in part due to obesity, and this issue merits further investigation. Since obesity was controlled in the present study, the relationship between OSA and AD survived. Obesity alone does not explain the relationship between OSA and AD.
A population-based study by Chung et al investigating the risk factors for AD in Taiwan found DM, CHD, and HTN to be significantly associated with AD (OR = 1.54, P<0.001; OR = 1.36, P<0.001; and OR = 1.22, P<0.001, respectively) [38]. DM increases the expression of pro-inflammatory factors and induces both oxidative stress and endothelial dysfunction [20]. HTN can contribute to oxidative stress, which is an important molecular mechanism associated with cardiovascular disease and tissue injury [19]. One review study by Okayama showed that inflammatory skin diseases like AD are mediated by oxidative stress [18]. Since DM, HTN, and CHD are associated with increasing systemic inflammatory factors and oxidative stress, the association among DM, HTN, and CHD, and AD observed by Chung et al in Taiwan is not surprising [38].Although the true mechanisms contributing to the associations between these comorbidities and AD remain unknown, oxidative stress and systemic inflammation might play substantial roles in this relationship. Therefore, our study examined DM, CHD, and HTN as confounders for AD.
Repeated episodes of hypoxemia during sleep are characteristic of OSA. Periodic hypoxia can lead to activation of sympathetic tone and stimulate the rennin-angiotensin-aldosterone system [39]. Angiotensin II stimulates the release of reactive oxygen species (ROS) and pro-inflammatory cytokines, which initiate and perpetuate oxidative stress and systemic inflammation [40]. The cytokines and chemokines in the circulation and skin cells orchestrate the inflammation reaction in atopic skin [2]. One review study by Okayama showed that inflammatory skin diseases like AD are mediated by oxidative stress [18]. Therefore, one link between OSA and AD might be related to the oxidative stress and systemic inflammation. Furthermore, AD is characterized as a T-helper-2 (TH2) mediated inflammatory skin disease. The sympathetic activation in OSA increases the release of catecholamine which might induce TH2 [41].
A neurocognitive disorder associated with OSA may result from frequent arousals and fragmented sleep. Patients may suffer from psychological problems including daytime sleepiness, poor memory and concentration, irritable mood, anxiety, and emotional stress [29], [42], [43]. Clinical observations have found that psychological stress might act not only as a trigger for but also aggravate the presence of AD [41], [44]. A complete psychological evaluation and specialized care may help alleviate the symptoms of AD and even prevent outbreaks [44], [45].
Age and gender may play a role in modifying the occurrence of AD in patients with OSA. We found a clear relationship between our younger population of OSA patients and increased likelihood of developing AD. Individuals who were diagnosed with OSA later in life were at much less risk for AD. We also found male patients were at higher risk for AD. One prospective clinical epidemiologic study in eastern India showed the prevalence of AD in children to have a slight female-to-male preponderance [46]. Montnemery et al., who conducted a questionnaire study of 12071 adults in Sweden ranging in age from 20 to 59 years [24], found AD to be more frequently reported by women. One previous 8-year national study in Taiwan reported the prevalence of AD to be higher in younger populations and reported that the prevalence decreased with age [47]. That same study reported the prevalence of AD to be lower in females than in males before the age of 8 years, but to increase in females beyond 8 years of age [47]. The underlying reason for the relationship between gender and incidence of AD in OSA patients is unclear. Sex hormones might influence mast cell activation and allergic sensitization. Estradiol promotes sensitization and IgE production, and testosterone suppresses IgE production [48], [49]. AD may, in part, be a consequence of low testosterone in male patients [50]. There is a variable degree of hypogonadism associated with OSA. Male OSA patients may have low testosterone levels, and female OSA patients may have low estradiol levels [31]. Any possible association would be conjecture at this point and would need further investigation.
This study has some limitations. The diagnoses of OSA and AD were based on diagnostic codes recorded by the physician in the NHI claims database; therefore, some registration bias might be involved. To ensure the accuracy of these diagnostic codes, only the OSA patients diagnosed by polysomnography or by two patient claims records citing OSA a primary diagnosis were recorded. The AD patients were those patients who had been diagnosed on 2 occasions with AD by dermatologists. Disease severity could not be assessed from our dataset, and it was not possible to report the association between the severity of OSA and the occurrence of AD. Furthermore, individual information including occupation, mental health, environmental factors, and family history were not available. Further study to investigate the effects of these factors is needed. The strength of this study, however, is that it has a longitudinal, large population-based design. The database covers nearly all of Taiwan's residents, so referral and selection biases were minimized.
In conclusion, we found that patients with OSA are at higher risk for developing AD. The risk was more pronounced in the younger age groups and in men. Further studies are needed to explore the mechanisms underlying these relationships.
Acknowledgments
This study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by the National Health Research Institutes (Registered number 100057). The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health, or the National Health Research Institutes.
Author Contributions
Conceived and designed the experiments: KJT CWC JJW SFW. Performed the experiments: SYL NCY CYY FCY. Analyzed the data: KJT JJW SFW. Contributed reagents/materials/analysis tools: CWC SYL NCY CYY. Wrote the paper: KJT SFW.
References
- 1. Spergel JM, Paller AS (2003) Atopic dermatitis and the atopic march. J Allergy Clin Immunol 112: S118–127.
- 2. Homey B, Steinhoff M, Ruzicka T, Leung DY (2006) Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 118: 178–189.
- 3. Chan LS (2008) Atopic dermatitis in 2008. Curr Dir Autoimmun 10: 76–118.
- 4. Rosario IC (2011) Obstructive sleep apnea: a review and update. Minn Med 94: 44–48.
- 5. Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, et al. (2009) Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. WMJ 108: 246–249.
- 6. Monahan K, Redline S (2011) Role of obstructive sleep apnea in cardiovascular disease. Curr Opin Cardiol 26: 541–547.
- 7. Ioja S, Weir ID, Rennert NJ (2012) Relationship between sleep disorders and the risk for developing type 2 diabetes mellitus. Postgrad Med 124: 119–129.
- 8. Lin WC, Winkelman JW (2012) Obstructive sleep apnea and severe mental illness: evolution and consequences. Curr Psychiatry Rep 14: 503–510.
- 9. Lurie A (2011) Inflammation, oxidative stress, and procoagulant and thrombotic activity in adults with obstructive sleep apnea. Adv Cardiol 46: 43–66.
- 10. Dalamaga M, Papadavid E, Vlami K (2013) Unmasking the Janus face of the association between psoriasis, metabolic syndrome and obstructive sleep apnea. Sleep Breath 17: 449–450.
- 11. Karaca S, Fidan F, Erkan F, Nural S, Pinarcı T, et al. (2013) Might psoriasis be a risk factor for obstructive sleep apnea syndrome? Sleep Breath 17: 275–280.
- 12. Yang YW, Kang JH, Lin HC (2012) Increased risk of psoriasis following obstructive sleep apnea: a longitudinal population-based study. Sleep Med 13: 285–289.
- 13. Buslau M, Benotmane K (1999) Cardiovascular complications of psoriasis: does obstructive sleep apnoea play a role? Acta Derm Venereolo 79: 234.
- 14. Papadavid E, Vlami K, Dalamaga M, Giatrakou S, Theodoropoulos K, et al. (2012) Sleep apnea as a comorbidity in obese psoriasis patients: a cross-sectional study. Do psoriasis characteristics and metabolic parameters play a role? J Eur Acad Dermatol Venereolo 27: 820–826.
- 15. Chng SY, Goh DY, Wang XS, Tan TN, Ong NB (2004) Snoring and atopic disease: a strong association. Pediatr Pulmonol 38: 210–216.
- 16. Matin A, Bliwise DL, Wellman JJ, Ewing HA, Rasmuson P (2002) Resolution of dyshidrotic dermatitis of the hand after treatment with continuous positive airway pressure for obstructive sleep apnea. South Med J 95: 253–254.
- 17. Marshall NS, Almqvist C, Grunstein RR, Marks GB, Childhood Asthma Prevention Study (2007) Predictors for snoring in children with rhinitis at age 5. Pediatr Pulmonol 42: 584–591.
- 18. Okayama Y (2005) Oxidative stress in allergic and inflammatory skin diseases. Curr Drug Targets Inflamm Allergy 4: 517–519.
- 19. Montezano AC, Touyz RM (2012) Oxidative stress, Noxs, and hypertension: experimental evidence and clinical controversies. Ann Med 44: S2–S16.
- 20. Fiorentino T, Prioletta A, Zuo P, Folli F (2013) Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr Pharm Des 19: 5695–5703.
- 21. Hersoug LG, Linneberg A (2007) The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Allergy 62: 1205–1213.
- 22. Silverberg JI, Silverberg NB (2012) Atopic Dermatitis: Update on Pathogenesis and Comorbidities. Current Dermatology Reports 1: 168–178.
- 23. Zheng T, Yu J, Oh MH, Zhu Z (2011) The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res 3: 67–73.
- 24. Montnemery P, Nihlén U, Göran Löfdahl C, Nyberg P, Svensson A (2003) Prevalence of self-reported eczema in relation to living environment, socio-economic status and respiratory symptoms assessed in a questionnaire study. BMC Dermatol 3: 4.
- 25. Bieber T (2010) Atopic dermatitis. Ann Dermatol 22: 125–137.
- 26. Chen GY, Cheng YW, Wang CY, Hsu TJ, Hsu MM, et al. (2008) Prevalence of skin diseases among schoolchildren in Magong, Penghu, Taiwan: a community-based clinical survey. J Formos Med Assoc 107: 21–29.
- 27. Beattie PE, Lewis-Jones MS (2006) A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol 155: 145–151.
- 28. Mannarino MR, Di Filippo F, Pirro M (2012) Obstructive sleep apnea syndrome. Eur J Intern Med 23: 586–593.
- 29. Al Lawati NM, Patel SR, Ayas NT (2009) Epidemiology, risk factors, and consequences of obstructive sleep apnea and short sleep duration. Prog Cardiovasc Dis 51: 285–293.
- 30. Shochat T, Pillar G (2003) Sleep apnoea in the older adult: pathophysiology, epidemiology, consequences and management. Drugs Aging 20: 551–560.
- 31. Attal P, Chanson P (2010) Endocrine aspects of obstructive sleep apnea. J Clin Endocrinol Metab 95: 483–495.
- 32. Kershaw EE, Flier JS (2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89: 2548–2556.
- 33. Manigrasso MR, Ferroni P, Santilli F, Taraborelli T, Guagnano MT, et al. (2005) Association between circulating adiponectin and interleukin-10 levels in android obesity: effects of weight loss. J Clin Endocrinol Metab 90: 5876–5879.
- 34. De Rosa V, Procaccini C, Calì G, Pirozzi G, Fontana S, et al. (2007) A key role of leptin in the control of regulatory T cell proliferation. Immunity 26: 241–255.
- 35. Bulló M, García-Lorda P, Megias I, Salas-Salvadó J (2012) Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obes Res 11: 525–531.
- 36. Vieira VJ, Ronan AM, Windt MR, Tagliaferro AR (2005) Elevated atopy in healthy obese women. Am J Clin Nutr 82: 504–509.
- 37. Boguniewicz M, Leung DY (2011) Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 242: 233–246.
- 38. Chung SD, Keller JJ, Lin HC (2012) Association of erectile dysfunction with atopic dermatitis: a population-based case-control study. J Sex Med 9: 679–685.
- 39. Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, Cofield SS, Harding SM, et al. (2007) Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest 131: 453–459.
- 40. Das U (2005) Angiotensin-II behaves as an endogenous pro-inflammatory molecule. J Assoc Physicians India 53: 472–476.
- 41. Buske-Kirschbaum A, Geiben A, Höllig H, Morschhäuser E, Hellhammer D (2002) Altered responsiveness of the hypothalamus-pituitary-adrenal axis and the sympathetic adrenomedullary system to stress in patients with atopic dermatitis. J Clin Endocrinol Metab 87: 4245–4251.
- 42. Malhotra A, White DP (2002) Obstructive sleep apnoea. Lancet 360: 237–245.
- 43. Akmal MK, Ezat M, Raafat O, Hamed H, Bediwy A (2013) Association of depression, anxiety, and impairment in executive functions in patients with obstructive sleep apnea. Middle East Current Psychiatry 20: 30–34.
- 44. Morren M-A, Przybilla B, Bamelis M, Heykants B, Reynaers A, et al. (1994) Atopic dermatitis: triggering factors. J Am Acad Dermatol 31: 467–473.
- 45. Schut C, Weik U, Tews N, Gieler U, Deinzer R, et al. (2012) Psychophysiological effects of stress management in patients with atopic dermatitis: a randomized controlled trial. Acta Derm Venereol 93: 57–61.
- 46. Kumar MK, Singh PK, Tahir MMA (2012) The clinico-epidemiological profile and the risk factors associated with the severity of atopic dermatitis (AD) in eastern Indian children. Journal of Clinical and Diagnostic Research [serial online] 6: 1162–1166.
- 47. Hwang CY, Chen YJ, Lin MW, Chen TJ, Chu SY, et al. (2010) Prevalence of atopic dermatitis, allergic rhinitis and asthma in Taiwan: a national study 2000 to 2007. Acta Derm Venereol 90: 589–594.
- 48. Chen W, Mempel M, Schober W, Behrendt H, Ring J (2008) Gender difference, sex hormones, and immediate type hypersensitivity reactions. Allergy 63: 1418–1427.
- 49. Cho S, Kim HJ, Oh SH, Park CO, Jung JY, et al. (2010) The influence of pregnancy and menstruation on the deterioration of atopic dermatitis symptoms. Ann Dermatol 22: 180–185.
- 50. Canguven O (2013) The role of low testosterone associated with erectile dysfunction with atopic dermatitis. J Sex Med 10: 618.