Comorbidities Associated with Atopic Dermatitis

Introduction

Atopic Dermatitis (AD) has long been recognized as being closely associated with other atopic conditions, but more recent studies have uncovered multiple previously unrecognized extracutaneous disease associations. Many patients with AD have comorbid infectious, autoimmune, respiratory, neuropsychiatric, musculoskeletal and potentially even cardiovascular and malignant disorders (Table 6-1). Recognizing the comorbidities of AD, especially in its moderate to severe form, highlights why some consider AD a systemic disease. Identifying and understanding these comorbidities has the potential to help improve therapeutic decision making and overall clinical outcomes. This chapter will summarize recent developments in the understanding of the comorbid health disorders associated with AD.

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Atopic Comorbidities

AD usually begins early in life. The atopic march refers to the propensity for AD to be followed by the serial occurrence of allergic diseases, especially food allergies, asthma and allergic rhinoconjunctivitis. The exact sequence of the subsequent allergic diseases may vary. Adult patients may also suffer from increased frequencies of hand eczema and allergic contact dermatitis, although these conditions are not classically included as components of the atopic march. Population-based studies National Survey of Children’s Health (NSCH) have found that 19.8% and 34.3% of children and 8.0% and 7.5% of adults with AD have comorbid asthma and hay fever in the United States, respectively. The prevalence and severity of asthma and hay fever are also worsened with the severity of AD (Figure 6-1).

Although allergic sensitization in patients with AD has been widely recognized, the mechanisms behind these associations is highly debated. Allergic sensitization may result from transcutaneous penetration of allergens and subsequent activation of the immune system, resulting in atopic disease. In a study of 619 exclusively breastfed infants, children with AD were found to have dramatically higher rates of positive skin-prick tests to different foods at 3 months, with the highest rates in those with more severe AD. Given that these infants had not yet been exposed to food besides breastmilk, transcutaneous sensitization was hypothesized to be a contributing factor. Results like these, which highlight the important role of barrier defects in AD, further justify the extensive application of moisturizers in the treatment of AD. Emollients likely contribute more than just barrier substitution, given that petrolatum application increases expression of barrier proteins and antimicrobial peptides and decreases proinflammatory cytokines. Preliminary studies suggest that proactive application of emollients to infants at risk for AD, beginning as neonates, reduces AD development and/or severity. Longitudinal studies are currently investigating the ability of early emollient application to decrease sensitization to antigens and development of the atopic march.

Loss-of-function mutations in filaggrin (FLG) are present in 15% to 45% of patients with AD, and such mutations are associated with an increased risk of asthma in addition to AD. FLG expression is also suppressed in keratinocytes of patients with AD through T_h2 and T_h22 cytokines. Thus, inherited barrier defects (FLG loss-of-function mutations) and immune activation in AD (T_h2 and T_h22 cytokines) may both contribute to barrier dysfunction in a positive feedback loop. The migration of sensitized T cells and/or immunoglobulin E (IgE) into the nose and airways may then facilitate upper and lower airway disease. The activation of T_h2 inflammatory pathways has been found to play a primary role in both AD and asthma. Although the role of IgE in asthma and hay fever is well established, its role in AD remains controversial given that both total and allergen-specific IgE levels are within normal limits in a large subset of patients with AD (Figure 6-2). Additionally, omalizumab (an anti-IgE monoclonal antibody) has been shown to be ineffective in AD despite having good efficacy in asthma. Ligelizumab is another humanized monoclonal antibody directed against IgE. A phase 2 trial comparing the efficacy of ligelizumab vs cyclosporine or placebo in the treatment of moderate-to-severe AD found that ligelizumab had no beneficial effect on improvement of Eczema Area and Severity Index (EASI) scores at week 12 compared with placebo. Overall, it is possible that T_h2 inflammation is a common pathway for AD and atopic disease, with elevated IgE occurring secondarily.

The presence of atopic comorbidities may affect the management of patients with AD, since they may lead to worsening of the underlying AD. For example, patients with hay fever and AD can present with intense pruritus, severe lichenification and excoriations of the eyelids and periorbital area, madarosis (loss of eyelashes and/or eyebrows) secondary to chronic rubbing and scratching, eyelid edema and Dennie-Morgan fold (extra transverse infraorbital crease). Eyelid dermatitis is often refractory to topical therapies secondary to frequent exacerbations from repeated allergen exposure. In these patients, treating the underlying atopic comorbidity can help improve the symptoms of AD. For example, antihistamine eyedrops and nonsedating oral antihistamines can be very effective at treating the underlying hay fever, thereby secondarily improving eyelid dermatitis.

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Neuropsychiatric Comorbidities

The cutaneous symptoms of AD can lead to fatigue, stigma and psychosocial distress. This section gives an overview of recent studies that have found associations between AD and several neuropsychiatric disorders, including depression, anxiety, attention deficit/hyperactivity disorder (ADHD), cognitive dysfunction and other neurodevelopmental disorders. In addition, this section also presents studies linking AD to sleep disturbance, which increases risk of psychological disorders in AD patients.

Sleep Disturbance

The severe itch and pain present in patients with AD can lead to sleep disturbance and reduced quality of sleep. In a case-control study of sleep impairment, patients with AD were demonstrated by actigraphy (an objective assessment of sleep characteristics) to wake up in the middle of the night more frequently and spend more time awake than control patients, while patient-reported outcomes of poor sleep quality and daytime dysfunction were also higher. More severe AD has been reported to be associated with poorer sleep in another study. Scratch-time and restless nocturnal movement is increased in both adults and children with AD. A typical AD flare disrupts sleep for an average of 8.4 nights per flare (extrapolated to ~81 days per patient-year).

Other studies have shown that AD is associated with higher rates of sleep disturbance among the adult and pediatric population in the United States regardless of severity, with 10.8% of children with AD experiencing 4 or more nights of impaired sleep, 1 in 3 adults reporting fatigue and insomnia, and 1 in 4 adults reporting regular daytime sleepiness. Adults with AD are more likely to feel unrested during daytime and have higher rates of reduced overall health compared to those with AD alone. When fatigued, adults with AD have greater difficulty in performing everyday tasks, decreasing their ability to work, do finances, or perform hobbies. Sleep disturbance is also a major factor contributing to poor quality of life in children with AD. High rates of sleep disturbance and impaired quality of life are potential contributing factors to higher incidence of mental health disorders in adult and pediatric AD patients, discussed in the subsections below.

Depression

Two large population-based studies in the United States revealed that one in three adults with AD reported one or more symptoms of depression (National Health and Nutrition Examination Survey) (NHANES), with approximately one in five meeting the sleep, interest, guilt, energy, concentration, appetite, psychomotor, suicidal (SIGECAPS) criteria for major depressive disorder in one study (NHANES) or being diagnosed with depression in the other study (National Health Interview Survey) (NHIS). In the same population (NHANES), one in 10 patients had Patient Health Questionnaire scores consistent with moderate or severe depression. Similarly, studies in adolescent and adult patients in Taiwan and male patients in Korea have uncovered higher rates of major depressive disorder in patients with AD compared to those without, and a study in the United States (National Survey of Children’s Health) (NSCH) revealed that pediatric patients with AD are more likely to have depression currently or in their lifetime compared to those without. Additionally, severe AD is associated with higher rates of depression in children. Two systematic reviews and meta-analyses found a positive association between both adult and childhood AD and depression. While the link with depression was particularly high in moderate-to-severe AD, it was not consistently observed in mild AD. Depression incidence was also higher in parents of children with AD, compared to those without AD. However, depression incidence was not significantly higher in AD patients compared to those with other dermatologic disorders such as psoriasis or acne.

Anxiety

The same US study (NSCH) that demonstrated higher rates of depression among pediatric AD patients also revealed significantly higher incidence of anxiety compared to children without AD. Increased AD severity was associated with higher rates of anxiety, increasing from 5.5% in children with mild AD to 16.3% in children with severe AD. An increased odds ratio for anxiety was also shown for adult AD patients based on a quantitative analysis of 13 studies in a systematic review and meta-analysis.

Suicidal Ideation

A US study of adult patients found a significantly higher rate of patients thinking they would be better off dead among AD patients compared to those without AD. Other studies have similarly found significantly higher rates of suicidal ideation in patients with AD, identifying higher severity of AD, depression symptoms and younger age as factors predictive of suicidality. These findings were corroborated by two systematic reviews and meta-analyses which found an increased odds ratio for suicidal ideation among adolescents and adults with AD.

Attention Deficit/Hyperactivity Disorder

A large US study of 19 cohorts of children aged 2-17 and one adult cohort demonstrated that AD is associated with attention deficit disorder (ADD) and attention deficit/hyperactivity disorder (ADHD). Higher incidence of ADD/ADHD in pediatric AD patients was associated with sleep disturbance, headaches, history of anemia and obesity, while higher rates of ADHD in adult AD patients were associated with asthma, insomnia and headaches. In a German study of pediatric patients 3 to 17 years of age, AD was also found to be associated with higher odds of ADHD, but among younger children (aged 3 to 11) this association was only apparent in children with sleep disturbance. A 43% risk increase in ADHD symptoms or diagnosis in pediatric AD patients was reported in a meta-analysis of four studies. While these and similar studies do not allow a conclusion on causality, a longitudinal study in Taiwan found that atopic disease of any kind in early childhood led to increased risk of ADHD and autism spectrum disorder later in life, but did not report on the individual contribution of AD.

Cognitive Dysfunction

A prospective, dermatology practice-based study of adult patients with AD revealed a high incidence of cognitive dysfunction as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function 8-item Short-Form. PROMIS Cognitive Function T-scores were numerically lower among patients with moderate-to-severe AD than in those with mild or clear/almost clear AD, but cognitive dysfunction had a negative impact on health-related quality of life at all AD severity levels. Importantly, changes from baseline in PROMIS Cognitive Function T-scores were weakly but significantly negatively correlated with changes from baseline in several AD outcome severity measures, indicating that cognitive function improved as AD symptoms cleared.

AD also affects cognitive function and development in children. One analysis of NHIS survey data (2008-2018) showed significantly higher prevalences of memory impairment, ADHD and developmental delays in children with AD compared to those without. Interestingly, male children with AD had increased odds of developmental delays compared to female children with AD. The causes of this difference are unclear but may involve sex differences in the peripheral immune response.

The mechanisms behind the association of AD with cognitive dysfunction in children and adults are still poorly understood. In some cases, AD-associated systemic inflammation may directly affect neuronal signaling or development. Alternatively, burdensome symptoms of AD such as pruritus and sleep disturbance may cause distraction and fatigue, only secondarily affecting cognition. Finally, reverse causation cannot be excluded, as patients with cognitive dysfunction may exhibit lower treatment adherence and AD trigger avoidance.

Other Neuropsychiatric Disorders

A US study in pediatric patients has found that AD is associated with other neurodevelopmental disorders, including conduct disorder and autistic spectrum disorders, with adjusted odds ratios of 1.87 and 3.04, respectively.

Conclusions

While the association between AD and many mental disorders is clear, the underlying mechanisms driving neuropsychiatric disorders in AD are not yet understood. Potential causes include reduced quality of life, chronic itch and sleeplessness. A potential physiological cause may lie in increased level of proinflammatory cytokines, which have been linked with depression, anxiety and autistic spectrum disorder and have been proposed to be capable of passing the blood-brain barrier to affect behavior.

Mental health comorbidity is an important consideration in the management of patients with AD. It is important to recognize that many of these mental health symptoms (eg, depression, anxiety, impaired concentration) are also symptoms of AD. In many instances, these symptoms resolve with improved control of itch and visual aspects of the disease. As such, patients who experience mental health symptoms secondary to their AD may warrant use of a systemic agent to improve disease control. In patients with chronic AD, mental health symptoms may be indicative of standalone mental health disorders. In either case, patients experiencing mental health symptoms would likely benefit from referral to a mental health specialist. For this reason, it is important that health care providers managing patients with AD screen for mental health symptoms and treat or refer appropriately.

Injuries and Fractures

Patients with AD are at increased risk for injury, due to a combination of risk factors, including sleep disturbances, distraction from chronic itch, sedating antihistamine use and psychological comorbidity. In a US population-based study (NSCH) of 27,556 children 0 to 5 years of age, AD was found to be associated with high rates of injuries requiring medical attention, an association only partially mediated by psychiatric and behavioral disorders. AD was also associated with higher odds of injury causing limitation in a study of adults (NHIS), with those who reported fatigue, sleep disturbance, or psychological or behavioral problems at greatest risk. Patients with AD may also independently have increased risk of fractures. In a study of 3049 patients aged 8 to 19 years (NHANES), AD was found to be associated with significantly lower overall bone mineral density (BMD) z scores (and z score ≤2) for the total femur and total lumbar spine. Covariates with the greatest effect on low BMD in the study were low parathyroid hormone and albumin, higher basophil count, Hispanic ethnicity and Body Mass Index (BMI) less than the fifth percentile.

An Australian case-control study found that AD was associated with low BMD, particularly in those who had used cyclosporine. However, not all studies reported an associated of AD with low BMD: a study of 60 Dutch children with moderate to severe AD found no significant difference in BMD, even in patients who had received oral corticosteroids and/or cyclosporine. A study of 4972 adult patients found that AD was associated with lower overall BMD t score for the femur and lumbar spine, as well as osteopenia and osteoporosis of the trochanter. Osteoporosis was associated with ever having used oral corticosteroids daily for a month or longer. Other studies in adults had mixed results, with some finding that AD was associated with lower BMD, and others finding no significant difference.

Since diseases characterized by chronic inflammation (eg, rheumatoid arthritis, systemic lupus erythematosus) are associated with bone loss and skeletal remodeling, it is possible that the chronic inflammation in AD similarly predisposes to bone loss and increased fracture risk. Possibly contributing to impaired BMD and increased fracture risk are systemic (and perhaps topical) corticosteroid use and low serum vitamin D levels occurring in patients with AD.

The associations between AD, low BMD, fractures and other injuries have important clinical implications. First, use of systemic corticosteroids is not encouraged since they could worsen risk of fracture and osteoporosis. Cyclosporine, methotrexate, azathioprine, phototherapy and emerging systemic agents in the pipeline for AD may be reasonable alternatives for patients with an inadequate response to topical therapy. Second, use of sedating medications, especially antihistamines, should not be recommended for daytime use. In addition, both nonsedating and sedating antihistamines commonly cause dizziness and orthostasis, which increases the risk of falls and other injuries. If required, patients should be counseled on the risk of injury.

Autoimmune Diseases

Autoimmune diseases are often a result of the complex interplay between environmental triggers and predisposing genetic risk factors. One analysis of adult patient data from the Atopic Dermatitis in America Survey found that AD is associated with autoimmune disease, and that the extent of this association increases with AD severity. A cross-sectional study of the 2002-2012 National Impatient Sample data revealed an increased overall prevalence of autoimmune disease among both adults and children with AD. AD was associated with 18 out of 32 autoimmune diseases the authors examined in adults and 13 out of 24 autoimmune diseases examined in children. Other studies have found an association between AD and a variety of specific autoimmune diseases, including systemic lupus erythematosus, chronic urticaria, vitiligo, alopecia areata, inflammatory bowel disease and celiac disease. Conflicting results exist regarding the association between AD and rheumatoid arthritis, thyroid disease and autoimmune nephropathy. Since multiple sclerosis is marked by a heightened T_h1 response, it was hypothesized to be inversely associated with AD; however, a meta-analysis has failed to find a significant association in either direction. As with atopic comorbidities, patients with AD may be genetically predisposed to be at higher risk of developing certain autoimmune diseases. A genome-wide association study identified several susceptibility loci for AD associated with autoimmunity and immune regulation. Elevated pro-inflammation pathways in patients with AD may also increase the risk of autoimmune diseases.

Infections

Patients with AD are at a higher risk for infections due to a variety of factors, including skin-barrier dysfunction, decreased expression of antimicrobial peptides, aberrant toll-like receptor signaling and innate immunity, increased colonization with Staphylococcus aureus in lesional and non-lesional skin, and use of topical and/or systemic immunosuppressing medications. An analysis of 2006-2012 data from the National Emergency Department Sample found an association between AD and cutaneous infections in both adults and children. This analysis included a wide spectrum of pathogens and infections. Cutaneous infections with a higher prevalence in both adults and children with AD included bacterial infections (furuncles and carbuncles, impetigo, cellulitis, erysipelas, methicillin-resistant and methicillin-sensitive S aureus infections), viral infections (molluscum contagiosum, cutaneous warts, herpes simplex, herpes zoster, eczema herpeticum), and fungal infections (dermatophytosis and candidiasis). Among adult patients with AD, a higher prevalence of sexually transmitted infections (genital warts and genital herpes) was also observed. As there is such a well-recognized association between AD and skin infections, susceptibility to cutaneous infections is included as one of the minor Hanifin & Rajka diagnostic criteria.

Importantly, AD is not limited to an increased risk of cutaneous infections. Higher rates of recurrent ear infections were identified in a study of the 2007-2008 NSCH. Another study of the 2007 NHIS found that children with AD had higher rates of influenza/pneumonia, sinus infections, head or chest colds and strep throat. Higher odds of warts were identified only in children with AD and other atopic disease. In adults, a study of the 2012 NHIS found AD to be associated with higher odds of influenza/pneumonia, strep throat, head or chest cold, sinus infection, gastroenteritis and chickenpox. These population-based studies demonstrated a consistently increased risk of extra-cutaneous infections; however, they utilized surveys, which are vulnerable to misclassification bias.

An analysis of 2002-2012 National Inpatient Study data found that AD was associated with 32 of the 38 serious infections examined — both cutaneous and extra-cutaneous. The cutaneous infections with the largest effect sizes were eczema herpeticum, erysipelas and cellulitis. Extra-cutaneous, multi-organ and systemic infections included encephalitis, endocarditis, infectious arthropathy, enterocolitis and septicemia. Additionally, a systematic review and meta-analysis of seven studies on bacterial and mycobacterial infections found increased odds of ear infections, strep throat and urinary tract infections among children and adults with AD. Altogether, both adults and children with AD appear to be at higher risk of infections. Ongoing and future basic science, translational and clinical research efforts will hopefully shed light on the precise mechanisms of increased infection risk in AD.

Cancer

There are mixed findings regarding the relationship between AD and the risk of cancer. A meta-analysis found a small but significant increase in the odds of developing any type of lymphoma in patients in cohort studies (relative risk = 1.43; 95% CI, 1.12-1.81), but not case-control studies, with severity of disease being a significant risk factor. Two population-based studies of large Danish and English cohorts reported an increased risk of lymphoma in patients with AD of any severity in England and those with moderate-to-severe AD in Denmark. The mechanisms behind the association between AD and lymphoma are not currently understood. One possibility is that chronic inflammation may promote carcinogenesis and skewing towards a T_h2 response may divert immunity from tumor-protective T_h1 responses. Certain treatments for moderate to severe AD, such as the systemic immunosuppressants cyclosporine and azathioprine, have also been shown to increase the risk for malignancy. Topical calcineurin inhibitors were initially thought to be associated with an increased risk of lymphoma due to results from a regional health record database study. One large pharmacovigilance study in Europe found evidence of slightly increased lymphoma risk in adults using tacrolimus or pimecrolimus and children using tacrolimus, but whether this association is causal has not been established. By contrast, a nested case-control study with a cohort of almost 300,000 patients with AD found no association. Additionally, a longitudinal cohort of 7,457 children with AD found no increase in malignancy. Findings such as these have called into question whether the warnings of possible carcinogenicity and restrictions regarding their use in children under 2 years of age are justified. In fact, current American Academy of Dermatology (AAD) guidelines recommend the off-label use of 0.03% tacrolimus or 1% pimecrolimus ointment in patients with AD <2 years of age with mild to severe disease.

In contrast to a possible increased risk of lymphoma, studies have reported conflicting findings regarding the relationship between AD and several other types of cancer, as well as cancer overall. The two large English and Danish cohort studies found no evidence of increased overall cancer prevalence among AD patients. An inverse relationship has been identified between AD and acute lymphoblastic leukemia and actinic keratosis. No association has been found between AD and acute myelogenous leukemia, basal cell carcinoma, squamous cell carcinoma, and bladder cancer. In a systematic review and meta-analysis, AD was associated with a statistically significant increase in keratinocyte carcinoma, renal cancer, central nervous system cancers and pancreatic cancer risk, based on the 8 cohort studies analyzed. On the basis of 48 case-control studies, the same meta-analysis also revealed a statistically significant decrease in central nervous system cancers, pancreatic cancer and lung and respiratory system cancers. This analysis uncovered no evidence of association between AD and other cancer types, including breast, colorectal, head and neck, male genitourinary, myeloma and melanoma. Other studies have also demonstrated inverse or no association of pancreatic, brain and skin cancers with AD. A history of allergy has been shown to be inversely associated and early-onset basal cell carcinoma, but not with squamous cell carcinoma or melanoma. Reasons for the identified inverse relationships may include increased immune surveillance and eradication of dysregulated cells by systemic inflammation, or the reported immunoglobulin E (IgE)-facilitated cross-presentation of tumor antigens by dendritic cells.

Obesity and Cardiovascular Disease

Patients with AD have multiple potential risk factors for cardiovascular and cerebrovascular risk, including chronic sleep disturbance, sedentary lifestyle, higher rates of cigarette smoking and alcohol consumption and others. This section will discuss evidence for these various risk factors.

Obesity

Many studies exist regarding the association between AD and obesity in children. A systematic review and meta-analysis of 30 studies found that patients who were overweight and/or obese had significantly higher odds of AD than patients of normal weight.These results were consistent among both children and adults, and in studies conducted in North America and Asia, but not Europe. In another study of 132 children 4 to 17 years of age with active moderate to severe AD and 143 healthy controls, AD was associated with central obesity, as judged by elevated BMI, waist circumference ≥85th percentile, and waist to height ratio of ≥0.5.

The relationship between AD and obesity is likely multifactorial, including side effects of medications commonly used in AD, poor diet, and decreased physical activity (see below). Systemic corticosteroids have been linked to increased appetite, substantial weight gain, central obesity, and metabolic syndrome. In addition, systemic antihistamines, such as diphenhydramine, hydroxyzine and doxepin, are associated with weight gain, especially at high doses. Clinicians should consider these potential side effects prior to prescribing these medications in AD and other inflammatory disorders.

Blood Pressure

In the previously described case-control study of children and adolescents with active moderate to severe AD, in addition to central obesity, AD was found to be associated with higher systolic and diastolic blood pressure. AD overall, in particular severe/very severe AD, was associated with higher odds of a systolic blood pressure in the ≥90th percentile. Interestingly, elevated systolic and diastolic blood pressure were associated with obesity in the healthy controls, but not the AD patients, suggesting that blood pressure elevations occurring in AD may be independent of adiposity.

Sleep Disturbance

Sleep disturbance in the absence of AD is in-of-itself linked to an increased risk of cardiovascular disease and/or mortality. In a meta-analysis of 13 prospective studies including 122,501 patients, a 45% increased risk of developing or dying from cardiovascular disease was identified in patients who had difficulty initiating or maintaining sleep or had disturbed nights of sleep. Another meta-analysis of 141 reports including 3,582,016 patients found that both short (<7 hours per night) and long sleep duration (≥9 hours per night) were associated with increased all-cause mortality and cardiovascular events.

Thus, it is logical that sleep disturbances in patients with AD would contribute to excess cardiovascular risk. In a study on the association of AD and cardiovascular risk, data were analyzed from adults aged 18 to 85 years from the 2010 and 2012 NHIS. The study found that adults with AD had higher odds of poor health behaviors (eg, initiating cigarette smoking, higher odds of consuming of alcoholic beverages), less physical activity (eg, lower odds of daily vigorous physical activity, lower frequency of vigorous physical activity in the past week), and higher prevalences of self-reported class II/III obesity, hypertension, prediabetes, diabetes and high cholesterol. In addition, there were significant interactions between AD and sleep disturbances: AD with fatigue, daytime sleepiness, or insomnia was associated with even higher odds of obesity, hypertension, prediabetes, diabetes and high cholesterol than AD alone. However, AD and cardiovascular risk factors were self-reported in these studies, possibly leading to misclassification.

Physical Activity

Data from two cross-sectional studies including 133,107 children aged 6 to 17 enrolled in the 2003-2004 and 2007-2008 NSCH were analyzed to study the association between physical activity and childhood AD, asthma and hay fever. The study found that childhood AD, in particular severe AD, was associated with decreased odds of vigorous physical activity. Moderate and severe AD and AD with sleep disturbance were associated with decreased odds of sports participation in the previous year. Severe AD and AD associated with sleep disturbance were also associated with increased odds of having five or more hours of daily screen time (television and video games). However, physical activity was assessed using caregiver reports, which can be imprecise. In a second study of data from 3,252 adults aged 18-85 in the 2005-2006 NHANES whose daily activity was objectively measured, AD was found to be associated with significantly lowered total counts of daily activity and less moderate to vigorous physical activity. No association was found between AD and sedentary time or light physical activity. Together, these studies indicate that AD is associated with decreased vigorous physical activity and/or increased sedentary activity in both US children and adults.

Findings of decreased physical activity are very clinically relevant in the management of AD. Many patients are unable to tolerate vigorous physical activities, such as jogging and other forms of exercise, owing to worsening of their itch and AD lesions from excess heat and sweat. Consequently, many patients will simply avoid any physical activities that may worsen their symptoms. It is important to consider decreased physical activity among other activities of daily living that are negatively impacted in the therapeutic management AD. Patients who avoid or are unable to be physically active because of their AD require more aggressive management and improved long-term disease control. Anecdotally, some effective strategies include the proactive application of topical anti-inflammatory agents, exercising in an environment with cooler temperature, and immediately taking a cool shower after exercise. However, these conservative approaches may not be adequate, and patients may require systemic therapy to achieve sufficient long-term control to prevent exercise-induced flares.

Cardiovascular Disease

Three US population-based cohorts (2005 to 2006 NHANES [n=4,970], and 2010 [n=27,157] and 2012 NHIS [n=34,525]) were analyzed for an association between AD and increased occurrence of cardiovascular disease and events. In the NHANES cohort, flexural eczema in the past year was associated with significantly higher odds of coronary artery disease, heart attack and congestive heart failure, but not with stroke. In NHIS 2010 and 2012, a 1-year history of eczema was associated with significantly higher odds of coronary artery disease, angina, heart attack, other heart disease, stroke and peripheral vascular disease. However, AD and cardiovascular risk factors were self-reported, potentially leading to misclassification. In another study of adults with AD, psoriasis and retrospectively matched controls, adults with AD were found to have increased coronary artery calcium scores using cardiac computed tomography angiography (CCTA) 18-segment models of the coronary tree, and mild single-vessel disease compared to controls and patients with psoriasis. In contrast, patients with psoriasis had more coronary stenosis and 3-vessel or left main artery disease compared to those with AD.

In an analysis of data from the 2002-2012 National Inpatient Sample, 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 (Figure 6-3). In particular, AD was associated with increased odds of hypertension, obesity, congestive heart failure, peripheral vascular disease, peripheral and vascular atherosclerosis, pulmonary circulation disorders, late effects of cerebrovascular disease and other cerebrovascular disease. This study confirms an association between physician-diagnosed AD and cardiovascular/cerebrovascular disease; however, given that this was a hospital cohort, it is likely that the included patients had more severe AD.

One systematic review and meta-analysis examined the risk of major cardiovascular outcomes in AD patients, including angina, myocardial infarction (MI), heart failure, stroke, ischemic stroke and cardiovascular death. While no association between AD and cardiovascular outcomes overall was uncovered, in the examined cohort studies a slight positive association between AD and MI, stroke, ischemic stroke and angina was noted. This analysis additionally revealed a potential trend of increasing cardiovascular event risk with increasing AD severity.

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Conclusions

Taken together, results from the discussed studies indicate that AD is associated with increased cardiovascular risk. The association is likely multifactorial, with contributions from chronic sleep disturbance, higher blood pressure, decreased physical activity, increased cigarette smoking and alcohol consumption and other factors. Future studies are needed to determine whether elevated cardiovascular risk is modifiable, so that overall health outcomes can be improved in patients with AD.

Although our understanding of the association between AD and cardiovascular risk is still nascent, there are several clinically relevant considerations. First, AD patients should be counseled on improving lifestyle, including smoking cessation, reducing excess alcohol intake and increasing physical activity. Second, clinicians should aim to optimize long-term control of AD, particularly sleep quality, while exercising extreme caution.