Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory dermatologic condition that affects 12-13 percent of children, and approximately seven percent of adults in the United States.^1-3While AD does not discriminate in race or geographic location, the incidence is higher in developed countries and urbanized areas. In many cases, the onset of AD occurs prior to the age of five years and has a predilection for females, a commonality among many autoimmune diseases.⁴ Nearly 50 percent of children affected will have symptoms that persist into adulthood, starting with AD in infancy and progressing to hay fever and asthma later in childhood. Affected patients often have a positive family history for this atopic triad as well as food allergies.^5,6

The principal features of AD include severe pruritus and xerosis associated with an underlying hyperreactivity to various ordinary environmental stimuli, including exposure to food allergens, irritants, and infection. AD commonly presents with erythematous papules with various degrees of oozing, crusting, excoriation, and lichenification. While the severity of signs and symptoms of the disease may vary with patient age and stage of lesions, AD is known to impose a substantial burden on patient quality of life, often causing social and functional limitations, psychological distress, and overall diminished satisfaction with life for both patients and family members affected by AD.⁷

Additionally, AD is associated with various comorbidities, both atopic as well as non-atopic. Atopic comorbidities may include allergies, hay fever, and asthma; non-atopic comorbidities may include sleep disturbance, cardiovascular disease, depression, anxiety, suicidal ideations, and increased risk of bacterial and viral infections.^8,9 This article aims to address the common comorbidities associated with AD. Acknowledgment and identification of such comorbidities are crucial to the successful management of AD and the improvement of patient quality of life.

Comorbidities

Atopic Comorbidities. Patients with increased levels of total or allergen-specific immunoglobulin E (IgE) upon exposure to allergens and a genetic predisposition for AD may develop the “atopic march.”¹⁰ The atopic march is a term used to describe the tendency for AD to begin earlier in life followed by a sequential development of atopic comorbidities such as hay fever, asthma, and allergies later on. This suggests that AD serves as a causative entry point for successive comorbidities.¹¹ The risk of progression to atopic march is inversely associated with the patient’s age of onset of AD. Due to an inappropriate skin barrier function—often a mutation in the filaggrin gene FLG, a filament-associated protein that binds to keratin fibers in epithelial cells—patients with AD are at increased risk for transcutaneous penetration of allergens, resulting in the subsequent development of atopic disease.¹²

According to multiple US population-based studies, atopic dermatitis is associated with a statistically significant increase in the prevalence of various atopic comorbidities in comparison to population controls without AD. Based on data from the National Survey of Children’s Health, children with AD often have associated atopic comorbidities such as hay fever, asthma, and food allergies with one-year prevalences of 34.4 percent, 19.8 percent, and 15.1 percent, respectively, in the United States.¹³ Prevalence in adults is similar according to the National Health Interview Survey (NHIS) (28.4 percent for hay fever, 18.7 percent for asthma, 13.2 percent for food allergies).² Additionally, according to a study of exclusively breastfed infants at the age of three months, children with AD exhibited increased sensitization to foods such as egg whites, cow’s milk, and peanuts. Allergic sensitization was measured via skin prick testing, as this is a more specific indicator of subsequent food allergy later in life than is serum-specific IgE levels.¹⁴ This relationship was hypothesized to be due to the transcutaneous penetration of food allergens and sensitization via antigen-presenting cells.¹⁴ The extent and severity of a patient’s atopic dermatitis are directly proportional to and the strongest known predictors of the severity of the atopic comorbidity.

Additional factors may affect atopic comorbidity severity. For example, hay fever is closely associated with increased patient age and household income, but lower education status.¹⁵ In contrast, asthma is reportedly associated with younger patient age and lower education status, but increased household size.¹⁵ It is essential to identify such atopic comorbidities in patients with AD, as such concurrent conditions may result in exacerbation of underlying AD.

Non-Atopic Comorbidities. AD is also associated with numerous non-allergic comorbidities, alluding to the idea that this disorder may be more systemic than originally believed. Such comorbidities include increased risk of infections, cardiovascular disease, sleep disturbance, and mental health disorders such as suicidal ideations, depression, and anxiety.^8,9

Patients with AD are frequently colonized with the bacteria Staphylococcus aureus (S. aureus) and have increased susceptibility to skin infections, both bacterial and viral, compared with the average healthy individual. According to data from the National Inpatient Sample (NIS), hospitalized AD patients have reportedly higher prevalence of systemic, cutaneous, and multi-organ infections.¹⁶ It is postulated that increased predisposition to such infections is due to epidermal barrier defects in addition to the fundamental inflammatory nature of AD. AD pathogenesis involves increased type 2 helper T-cells (Th2), a proinflammatory cytokine, as well as a decreased Th1/Th2 ratio. This inflammatory aspect, along with an increased risk of infection, sets patients with AD apart from patients with psoriasis, which is known to have underlying epidermal barrier defects primarily based on transepidermal water loss.^17-19

Th2 cytokines diminish the expression of ordinarily constitutive antimicrobial peptides, such as dermcidin in sweat.²⁰ This Th2-mediated change in antimicrobial peptide expression is further known to be associated with AD flares. Th2-induced inflammation results in fibronectin and fibrinogen expression on the surface of the skin, allowing for increased attachment of S. aureus in patients with AD.²¹ Patients with AD have a greater susceptibility to developing disseminated viral infections such as herpes simplex virus (eczema herpeticum), coxsackievirus (eczema coxsackium), poxvirus (molluscum contagiosum), and varicella-zoster virus (chickenpox).²² Additionally, patients with AD are more susceptible to extra-cutaneous infections—such as gastrointestinal (>1.6 odds ratio; p-value <0.001),²³ urinary tract infections (3.1 odds ratio; p-value <0.0001),²⁴ and respiratory tract infections such as sinusitis (2.6 odds ratio; p-value <0.0001)²⁴—which are directly proportional to the number of allergic diseases in the patient.²⁵

AD is also associated with cardio-metabolic comorbidities. The association between patients with AD and cardiovascular disease is multifactorial, with numerous shared potential risk factors such as mental health comorbidities, chronic sleep disturbance, alcohol and tobacco consumption, and obesity. According to the 2002-2012 NIS, patients with AD have higher odds of cardiovascular risk as well as long-term sequelae of cardiovascular disease.²⁶ The strongest association is seen with cerebrovascular disease, atherosclerosis, congestive heart failure, and peripheral vascular disease.²⁶ Patients with AD are at increased risk for congestive heart failure and coronary artery disease, with the greatest risk among those with more severe and longer-term AD, as seen with many comorbidities associated with AD.^27,28 This comorbidity association may be due to lifestyle factors (consumption of alcohol and tobacco or a sedentary lifestyle), genetics, or underlying systemic inflammation.^27,29,30

In a US multicenter, dermatology-based case-control study, active moderate to severe AD was associated with higher diastolic and systolic blood pressure as well as central obesity.³⁰ Significant associations exist between self-reported AD and chronic sleep disturbances. AD that is associated with excessive daytime sleepiness, exhaustion, and insomnia is linked to a higher risk of obesity, blood pressures, pre-diabetes and diabetes, and cholesterol levels than in patients with AD alone.²⁹ Overall, the association between AD and cardiovascular comorbidities is complex and multifactorial, with several contributing factors as previously mentioned.

The most burdensome symptoms in patients with AD are pruritus, xerosis, and skin inflammation, followed by skin pain and disturbance of sleep.³ AD is a condition that substantially limits patient daily quality of life, with reportedly 51.3 percent of adults experiencing a limitation to their everyday lifestyle, 39.1 percent experiencing limited social interaction, and 16.7 percent feeling dissatisfied with life according to a United States population-based cross-sectional study.³ There is growing evidence indicating an association between AD and psychiatric disorders and symptoms such as suicidal ideations, depression, and anxiety.

With the stigma, social isolation, and poor quality of life that often accompany AD, it is no wonder that there is a strong psychological component to this skin condition. According to a meta-analysis of 36 studies, approximately one in five individuals (20.1 percent) affected by AD experiences concomitant depression. Patients with AD experienced increased rates of clinical depression (14.9 percent versus 12.6 percent in non-AD individuals), antidepressant use (29.3 percent versus 20.3 percent), and suicidality (12.2 percent versus 6.4 percent).³¹

There is a temporal relationship between the early development of AD and the ensuing risk for mental health disorders. The opposite is also true, with early childhood development of mental health disorders resulting in a subsequent increased risk of AD.^32,33 These studies highlight the relationship between AD and psychiatric conditions, illuminating the idea that such psychiatric conditions may be modifiable with the treatment of AD, correlate with disease severity, and are often overlooked by physicians.

Conclusion

Atopic dermatitis is associated with numerous comorbidities, both atopic and non-atopic, relating to allergies, infections, cardiovascular conditions, and mental health disorders in addition to the expected cutaneous signs and symptoms. Such comorbidities may warrant alternative or more aggressive treatments in patients with atopic dermatitis to achieve appropriate control of symptoms and prevent long-term complications. Understanding and treating these comorbidities may improve overall patient outcomes as well as help alleviate the various burdens associated with atopic dermatitis.

To learn more about this atopic dermatitis, consider attending the inaugural 2020 San Diego Dermatology Symposium online from September 11-13, 2020 (https://www.sddermsymposium.org/). Faculty will discuss this more in depth during the meeting, which will be virtual this year.

The authors received no funding for this article.

Disclosures: Dr. Wu is or has been an investigator for AbbVie, Amgen, Eli Lilly, Janssen, Novartis; a consultant for AbbVie, Almirall, Amgen, Bristol-Myers Squibb, Celgene, Dermira, Dr. Reddy’s Laboratories, Eli Lilly, Janssen, LEO Pharma, Novartis, Promius Pharma, Regeneron, Sun Pharmaceutical, and UCB, Valeant Pharmaceuticals North America LLC; and a speaker for AbbVie, Celgene, Novartis, Regeneron, Sanofi Genzyme, Sun Pharmaceutical, UCB, Valeant Pharmaceuticals North America LLC. Ms. Ghamrawi and Dr. Ghiam do not have any potential conflicts of interest.

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