Atopic dermatitis (AD) (eczema) is a chronic inflammatory skin disease associated with heterogeneous and frequently changing symptoms and signs. Symptoms of AD include itchy and painful skin, sleep disturbances and fatigue, and mental health symptoms. Skin symptoms of AD include erythema (redness), lichenification (skin texture worsened by chronic friction), scales, oozing or oozing, and prurigo (itchy eruptions) nodules. Together, these factors lead to severe functional impairment, limiting the ability to perform activities of daily living, and leading to psychosocial distress and stigma.
However, the effects of AD appear to be more than just "surface." Many patients suffer from co-morbid infections, autoimmune, respiratory, neuropsychiatric, musculoskeletal, and possibly even cardiovascular disease. Some authors have wondered whether AD is a systemic disease, that is, having global effects in addition to direct cutaneous signs and symptoms. This review will summarize recent advances in the understanding of comorbid health disorders associated with AD.
Infect
There are many potential risk factors for infection in AD patients, including skin barrier dysfunction secondary to reduced expression of epidermal lipids and mechanical damage caused by scratching, reduced expression of antimicrobial peptides, abnormal Toll-like receptor signaling and innate immunity, increased Colonization of S. aureus in lesional and nonlesional skin, and use of topical and/or systemic immunosuppressive drugs (e.g., corticosteroids, calcineurin inhibitors, etc.). In fact, there is a well-known association between AD and skin infections, e.g.
Recent studies have shown that AD is also associated with extracutaneous infections. First, a study of 91,642 children in the 2007-2008 National Survey of Children's Health (NSCH) found that children with AD had higher rates of recurrent ear infections. Subsequently, a study of 9,417 children from the 2007 National Health Interview Survey (NHIS) found that children with AD (with or without atopy) had influenza/pneumonia, sinus infections, head or Chest colds and strep throat were significantly more likely to occur, while only children with AD and other specific diseases had higher rates of warts. Next, a study of 34,613 adults in the 2012 NHIS found that adults with AD had more severe symptoms of influenza/pneumonia, strep throat, head or chest colds, sinus infections, gastroenteritis, and The odds of chickenpox are significantly higher. These population-based studies indicate that the risk of extracutaneous infections continues to increase. However, the survey they employed may be susceptible to misclassification bias. That is, some subjects with self-reported and/or caregiver-reported AD may actually have different skin diseases. However, previous studies have observed good agreement between self-reported AD and physician-diagnosed AD. Furthermore, we conducted a multicenter study to validate the question used in the NSCH and determined that the sensitivity and specificity of this question for AD were 0.70 and 0.96, respectively. It is worth noting that this question has high specificity, meaning that those who answer positively are likely to have AD. Therefore, we believe that self- and/or caregiver-reported AD is sufficiently valid for epidemiological studies. Nonetheless, one might worry that AD patients who respond negatively to corresponding questions will be misclassified.
More recently, a study of the 2002–2012 Nationwide Inpatient Study, which included a representative US hospital cohort (n=72,108,077 adult discharged patients), found that AD was significantly associated with 32 of 38 serious infections examined, Includes skin, upper respiratory tract, lower respiratory tract or lung, heart, brain, bone and gastrointestinal tract infections. The skin infections that have the greatest impact are eczema herpetica, erysipelas, and cellulitis. Extracutaneous, multiorgan, and systemic infections include encephalitis, endocarditis, infectious arthropathy, enterocolitis, and sepsis. AD is associated with higher rates of most infections other than psoriasis, including herpetic eczema, erysipelas, cellulitis, herpes simplex and herpes zoster, acute pharyngitis, bronchitis, endocarditis, and sepsis.
Of note, comorbidities are more likely to be found in hospital datasets due to detection bias (i.e. people are more likely to receive further diagnoses after their first diagnosis in the healthcare system) and the inclusion of patients with more severe disease. However, these potential biases are less likely to arise in population-based studies. Combining population-based and hospital-based confirmatory studies, rates of extracutaneous and systemic infections appear to be higher in children and adults with AD.
Several important questions remain to be answered. First, what are the precise mechanisms underlying the increase in AD infections, particularly extracutaneous infections? Can such infections be prevented by improving long-term control of signs and symptoms of AD? Are these infections primarily iatrogenic? Are there other effective strategies to prevent serious infections in AD? Future basic science, translational, and clinical research is currently underway and will hopefully shed light on these important questions.
sleep disorder
There are many potential risk factors for sleep disturbance in patients with AD, including itch-scratch cycles, poor sleep hygiene, altered itch due to circadian rhythms, and secondary effects of inflammatory cytokines on sleep regulation.
Early studies have shown that sleep quality is severely impaired in childhood and AD in adults, with overall sleep duration reduced, awakenings more frequent and prolonged, overall sleep efficiency reduced, and increased daytime dysfunction reported. Actigraphy and infrared films (objective measures of sleep) show that adults and children with AD experience fragmented sleep, with increased number of nighttime awakenings, longer awakening times, lower overall sleep efficiency, increased scratching, and restless nocturnal activity. .
In children with AD, sleep disturbance is the second most common symptom after itching and one of the most troublesome factors in terms of quality of life (QOL). The International Living with Atopic Eczema Study, a multicenter questionnaire-based study of 1,098 adults, found that patients experienced an average of 8.4 nights of disrupted sleep with a typical AD episode, or about 81 days per patient per year. A 2012 NHIS study of 34,613 adults found that 25-33% of U.S. adults who reported having eczema reported fatigue, frequent daytime sleepiness, and frequent insomnia. Adults who self-reported having eczema were also more likely to report short or long sleep duration. The authors found that eczema and fatigue, sleepiness and insomnia were significant predictors of poorer overall health, sick days and doctor visits, and that eczema combined with sleep symptoms was more likely to lead to worse outcomes than sleep symptoms or eczema alone. A National Health and Nutrition Examination Survey (NHANES) study of 5,563 adults found that U.S. adults with AD more often reported short sleep duration, difficulty falling asleep, nighttime awakenings, early morning awakenings, and leg twitching during sleep. and leg cramps. and are more likely to feel restless, excessively sleepy during the day, and feel sleep deprived. Sleep disorders can have very detrimental effects on AD patients, including poor academic and work performance, impaired health-related quality of life (HRQOL), considerable financial burden, and increased risk of psychological disorders, motorcycle accidents, and work-related injuries. Taken together, these studies indicate that sleep disturbances are common and burdensome in patients with AD, necessitating therapeutic and preventive interventions.
Additionally, as discussed below, sleep disturbance may be a major driver of other comorbid health conditions, including cardiovascular risks and events.
Cardiovascular risk factors and events
Multiple potential risk factors for excess cardiovascular risk in AD include chronic sleep disturbances, sedentary physical activity, higher rates of smoking and alcohol consumption, and the use of systemic treatments such as corticosteroids and cyclosporine A. side effect.
Multiple studies have found an association between AD and obesity in children and adults in clinical and US population-based cohorts. Given the large number of published studies on this topic, we performed a systematic review and meta-analysis to determine whether there is a consistent association between AD and obesity; 30 studies found that overweight and/or obese patients were more likely to be more susceptible to obesity than normal weight patients The chances of developing AD are higher. These results are important for both children and adults and for studies conducted in North America and Asia (but not Europe). These results provide the highest level of evidence supporting the association between AD, overweight, and obesity.
Sleep disturbances themselves are associated with an increased risk of cardiovascular disease and/or death. A meta-analysis of 13 prospective studies including 122,501 participants found that difficulty initiating or maintaining sleep or having restless or disturbed sleep was associated with a 45% increased risk of cardiovascular disease or death. Another meta-analysis of 141 reports including 3,582,016 participants found that both short sleep duration (<7 hours per night) and long sleep duration (≥9 hours per night) were associated with all-cause mortality and cardiovascular disease. Increasing events related. It is logical that sleep disturbances in AD play an important role in the development of excess cardiovascular risk.
In a seminal study of the association between AD and cardiovascular risk, data from 27,157 and 34,525 adults aged 18-85 years in the 2010 and 2012 NHIS were analyzed. Adults with eczema were found to have higher odds of starting smoking and at an earlier age, higher odds of consuming alcoholic beverages, lower odds of daily vigorous physical activity, lower frequency of vigorous physical activity in the past week, and II/ Prevalence of class III obesity, hypertension, prediabetes, diabetes, and high cholesterol. Additionally, there were considerable correlations between self-reported eczema and sleep disturbance, with eczema being associated with fatigue, daytime sleepiness or insomnia, and with obesity, hypertension, prediabetes, diabetes, and elevated cholesterol levels compared with eczema alone. is more likely. These results are very suggestive and reproducible in both cohorts, but AD and cardiovascular risk factors were self-reported, potentially leading to misclassification.
An attempt was then made to determine the association between AD and hypertension in children. A pediatric dermatology practice-based multicenter case-control study was conducted in 132 US children and adolescents with active moderate-to-severe AD and 143 healthy controls. Moderate to severe AD was found to be associated with central obesity, as judged by elevated body mass index (BMI), waist circumference ≥85th percentile, and waist circumference-to-height ratio ≥0.5. AD is also associated with higher systolic and diastolic blood pressure in age, sex, and height percentiles. Overall, AD, especially severe/very severe AD, is associated with higher odds of systolic blood pressure ≥90%. An interesting observation is that elevated systolic and diastolic blood pressure are associated with obesity in healthy controls but not in AD patients. This suggests that the increase in blood pressure that occurs in AD may not be related to obesity. It is also interesting that AD is particularly associated with higher systolic blood pressure in Hispanic/Latino and Asian patients, suggesting that there may be racial/ethnic differences in these associations. This is an important consideration when interpreting cohort studies in which these racial/ethnic groups are underrepresented.
It then sought to determine whether the association between AD and smoking was consistent in the scientific literature. A systematic review and meta-analysis (n=86 observational studies) was conducted and found that AD was associated with higher odds of active and passive smoking, but not maternal smoking during pregnancy. Taken together, these results provide the highest level of evidence linking AD to active and passive exposure to cigarette smoke.
Next we tried to confirm the association between AD and reduced physical activity. A systematic review of the literature was first performed to determine whether AD is consistently associated with reduced physical activity. Unfortunately, few studies were found to have been conducted, with varying study design, methodological rigor, and results. It is clear that more research is needed in this area.
The association between childhood AD (as well as asthma and hay fever) and physical activity was therefore studied. analyzed data from two cross-sectional studies, including 133,107 children aged 6-17 years who participated in the NSCH in 2003-2004 and 2007-2008, and found that caregiver-reported eczema, particularly severe eczema, was associated with odds of strenuous physical activity related to reduction. Moderate and severe eczema and eczema associated with sleep disturbance (only 0-3 nights of adequate sleep) were associated with decreased odds of past-year sports participation. Severe eczema and eczema associated with sleep disturbance (only 0-3 nights of adequate sleep) were also associated with increased odds of 5 or more hours of screen time per day (TV and video games). One limitation of this study is that physical activity was assessed using caregiver report, which may not be accurate. The next study analyzed data from 3,252 adults aged 18-85 years in the 2005-2006 NHANES, where daily physical activity was objectively measured using actigraphy (or accelerometry). AD was found to be associated with significantly lower mean total daily activities and less moderate to vigorous physical activity, but not with sedentary time or light physical activity. Taken together, these data suggest that AD is associated with reduced vigorous physical activity and/or increased sedentary activity in children and adults in the United States.
Finally, given the observed increases in cardiovascular risk factors, it was sought to determine whether AD itself is associated with increased rates of cardiovascular disease and events. Data from three US population cohorts were analyzed: the 2005-2006 NHANES (n=4,970) and the 2010 (n=27,157) and 2012 (n=34,525) NHIS. In NHANES, past-year eczema curvature (using the International Asthma and Childhood Allergy Study definition of AD) was associated with significantly higher odds of coronary artery disease, heart disease, and congestive heart failure, but not stroke, whereas in NHIS In 2010 and 2012, a self-reported 1-year history of eczema was associated with significantly higher odds of coronary heart disease, angina, heart attack, other heart disease, stroke, and peripheral vascular disease. These associations remained significant in multivariable models controlling for asthma and hay fever or body mass index, smoking history, alcohol use in the past year, and vigorous activity in the past 30 days as covariates. Although these results were reproducible across the three cohorts, AD and cardiovascular risk factors were self-reported, potentially leading to misclassification.
A subsequent study of adults with AD (n=31), psoriasis (n=58) and retrospectively matched controls (n=33) found that using cardiac computed tomography angiography (CCTA) 18- vs. normal Coronary tree segmental model and mild single-vessel disease in adults with AD compared with patients with psoriasis. However, patients with psoriasis have more coronary artery stenosis and three-vessel or left aortic disease than patients with AD. These results suggest that cardiovascular risk is increased through objective assessment.
Subsequently, AD was reported as an independent risk factor for ischemic stroke in a large Taiwanese ethnic study. Similarly, using the Danish National Patient Registry, patients with severe AD were found to have an increased risk of cardiovascular disease. However, this association did not remain significant in multivariable models controlling for socioeconomic status, smoking, comorbidities, and medication use, suggesting that the observed differences in cardiovascular risk were related to lifestyle factors rather than AD. related to inflammation. In a recent study of female nurses in the United States, nonfatal stroke was associated with a history of AD in a model that once controlled for age. However, stroke was no longer significant after controlling for hypertension, hypercholesterolemia, and diabetes. This suggests that these cardiovascular risk factors may be responsible for the increase in stroke in AD and may be part of a causal model. In contrast, AD is not associated with nonfatal myocardial infarction. However, this study has several major limitations, including a lack of assessment of current versus past history of AD, a lack of assessment of AD severity, and a lack of generalizability to the U.S. population because it was based on a group of female nurse practitioners. . Two important points are required to correctly interpret these studies. First, AD appears to indirectly increase the risk of cardiovascular disease and events through multiple cardiovascular risk factors. In other words, AD is associated with increased odds or risks of obesity, high blood pressure, high cholesterol, diabetes, smoking, etc. These are well-established causes of heart disease and appear to be causal pathways for the association between AD and cardiovascular disease. Therefore, the above-mentioned Danish study and the Nurses' Health Study showed significant loss of association in multivariable models controlling for cardiovascular risk factors and need to be interpreted with caution. Even in these studies, patients with AD are at higher risk for cardiovascular disease and/or events. However, this risk is mediated by cardiovascular risk factors. Overall, most studies support at least an indirect and possibly direct association between AD and increased cardiovascular risk.
Data from the Nationwide Inpatient Sample were analyzed from 2002 to 2012, which includes a representative sample of 20% of all hospitalizations in the United States (n=72,108,077 adults). AD was found to be associated with significantly increased odds of cardiovascular risk and disease, similar to that observed in psoriasis, hidradenitis, pemphigus, and pemphigoid. In particular, AD is associated with an increased incidence of hypertension, obesity, congestive heart failure, peripheral vascular disease, peripheral and vascular atherosclerosis, pulmonary circulation disorders, delayed effects of cerebrovascular disease, and other cerebrovascular diseases. This study confirms the association between physician-diagnosed AD and cardiovascular/cerebrovascular disease. However, given that this was a hospital cohort, the included patients were likely to have more severe AD.
In conclusion, the results of the above studies indicate that AD is associated with increased cardiovascular risk. This association is likely multifactorial and includes chronic sleep disturbance, reduced physical activity, and increased smoking and alcohol consumption. Although increasing evidence supports the association between AD and cardiovascular disease, many important questions remain. Can the excess cardiovascular risk in AD patients be modified? That is, could one or more interventions be implemented to reduce cardiovascular risk in patients with AD? Can optimal control of AD signs and symptoms reduce the risk of cardiovascular disease in AD patients? Future research is needed to answer these questions and potentially improve overall health outcomes for AD patients. This is an exciting and rapidly developing area of research.
Other things to note
Of note, the association between AD and cardiovascular and other comorbidities was of moderate effect size (odds or hazard ratio ≤2) for some outcomes. That is, only a small proportion of AD patients may actually develop these comorbidities. Furthermore, it is important to consider that very large data sets, such as those used in the above studies, may not detect significant associations even with modest effect sizes. Therefore, different associations must be reproducible across multiple cohorts, study designs, and methods. Notably, most of the above associations have been replicated in multiple cohorts or studies. However, a critical question that remains is how to identify or predict those subgroups of patients who are at higher risk for various comorbidities.
in conclusion
AD is associated with a number of comorbid health conditions, including extracutaneous, multiorgan, and systemic infections, and cardiovascular disease. Taken together, these show that AD is indeed a systemic disease. The origins of these comorbidities are likely multifactorial, with the combined effects of skin barrier disruption, immune dysregulation, severe symptom burden, and iatrogenic complications. Many of these comorbidities are directly related to AD severity and inadequate disease control. Therefore, many of these comorbidities may be clinically relevant and can be prevented or mitigated by optimizing AD control. On the other hand, some of these comorbidities may be unavoidable. Nonetheless, they may still pose significant harm to the health of AD patients, thus requiring enhanced surveillance, early detection, and management. Considerable research is still needed to better improve our understanding of the relationship between AD and its many coexisting health conditions. Finally, it is critical to identify treatments and/or other strategies that may prevent or mitigate increased infectious and cardiovascular risks in AD patients.
