Typically, atopic dermatitis (AD) is a skin disease that is defined as a common, chronic, inflammatory dermatosis characterised by frequent itchiness. This review examines the possible reasons that AD could result in multiple diseases, such as autoimmune, cardiovascular, neurological, and psychiatric diseases.¹

Co-occurring conditions with AD
There seems to be a bidirectional association between AD and comorbidities that are depicted in Figure 1.¹

Figure 1: Diagrammatic representation of atopic disease and its probable comorbidities.

Th: T helper cells.

Probable factors that increase comorbidity prevalence in AD patients

A couple of behavioural changes are reported in patients with AD, such as:¹

• Regular physical activity helps in the primary and secondary prevention of several chronic diseases such as obesity, depression, and cardiovascular diseases. AD in adults is often associated with reduced moderately to vigorous and overall physical activity in the USA.¹
• In certain cases, patients with eczematous skin lesions on their palms and soles might find it difficult to participate in a variety of activities, furthermore increased skin temperature and perspiration are known to flare up triggers.¹
• Sleep interruption and depression, which could be present in AD patients, may worsen the ability to continue regular exercise schedule.¹
• Sleeplessness and social shame due to scarring skin lesions may influence the origin of depression and anxiety among AD patients.¹
• A positive correlation exists between AD and food allergy; however, obesity could be due to prenatal and earlylife antibiotic exposure.¹
• AD is also associated with an increased incidence of eating disorders, with bulimia nervosa and binge eating disorder being the most dominant. Evidence suggests that binge eating disorder is related to a high incidence of obesity.¹
• Incorrect administration of systemic treatment for AD could be a triggering factor. For example, glucocorticosteroids could have side effects such as weight gain, sleep disturbance, mood changes, and hyperglycaemia, or cyclosporine A could have side effects such as renal impairment and high blood pressure.¹
• Regular AD patient interaction with physicians, would facilitate the recognition of diseases that are usually difficult to detect.¹

Cardiovascular diseases and AD connection
When the critical T helper cells are activated in AD, there is a rise in cardiovascular biomarkers in the blood serum, including T helper (Th)1, interferon-gamma (INF-γ), tumour necrosis factor-alpha (TNF-α), and Th17 (C-C motif chemokine ligand 20 (CCL20)) as shown in Figure 2.

Figure 2: Plausible interrelation between atopic disease and cardiovascular diseases.

CXCL: C-X-C motif ligand; CCL: C-C motif chemokine ligand; INF-γ: Interferon gamma; Il: Interleukin; PPI3/elafin: Peptidase inhibitor 3/elafin; S100A12: Calgranulin C, S100A8/A9 (=MRP8/14): Myeloid-related protein 8/14; TNF-β: Tumour necrosis factor-beta.

Older AD patients tend to show more levels of cardiovascular indications as there exists a positive association between cardiovascular indicators and age.¹

However, data on paediatric AD revealed increased levels of multiple cardiovascular markers, such as E-selectin, an endothelial cell adhesion molecule, and several matrix metalloproteinases (MMPs).¹ Moreover, there is no clear evidence to indicate that patients with AD require more extensive cardiovascular monitoring or therapy than is suggested for the general population.¹

Neuropsychiatric diseases and AD connection
The onset and maintenance of the atopic itch are interdependent with the neurological system, cutaneous immune response, and keratinocytes.¹

Epilepsy and AD

• Neuroinflammation–involved in the pathogenesis of epilepsy.¹
• Microglia and astrocytes–main factors involved in neuroinflammation.¹
• Microglial activation–response to pro-inflammatory mediators released from immune cells, containing mast cells.¹
• In the neuroinflammation process, excess levels of inflammatory mediators might influence neurogenesis, neurodegeneration, and permeability of the blood–brain barrier, which could result in an imbalance in neurotransmission, leading to neurological disorders, including epileptic seizures.¹
• The association between AD and neuropsychological comorbidities could be due to genetics: for instance, deletion of chromosome 22q13.2 is a common manifestation among AD, epilepsy, mental retardation, and autism spectrum disorder (ASD).¹

Autism and AD

• A correlation exists between ASD and AD, suggesting that individuals with ASD have a higher risk of developing AD.¹
• Furthermore, comorbid AD is interlinked with an increase in the severity of ASD symptoms.¹
• Neuroinflammation–one of the environmental factors in the pathogenesis of ASD.¹
• Abnormal high levels of IL-1β, IL-6, IL-8, and IL-17 are observed in patients with ASD of all ages.¹
• According to studies on a mouse model, exposure to lipopolysaccharide, IL-17, and polyinosine polycytidylic acid during pregnancy resulted in ASD behaviour in the mice offspring.¹

• Neural cellular adhesion molecule (NCAM) 1 regulates nuclear factor kappa B (NF-κB) transcription in neurons, which alters pro-inflammatory signalling.¹
• Furthermore, according to a mouse model study, as both the epidermis and neural tissues originate from the embryonic neuroectoderm, the presence of neuro- and epidermal toxicity at the onset of AD and ASD could be due to the shared susceptibility of the brain and epidermis in the pathogenesis of both AD and ASD.¹

Attention deficit hyperactivity disorder and AD

• Data shows that attention deficit hyperactivity disorder (ADHD) has a higher prevalence in children with AD.¹
• More the number of atopic diseases in a patient, the more severe their ADHD.¹
• A possibility for a higher risk of atopic disease development among siblings of children with ADHD exists due to common genetic factors.¹
• Sleeping problems in infancy and early exposure to sedative H1-antihistamines that can cross the BBB were suspected as possible contributors to the development of ADHD in later childhood.¹

Depression and AD

• AD could be related to an increased risk of depression, parental depression, suicidality, and anti-depressant use.¹
• A positive but weak correlation between AD and depression in children was also found.¹
• One of the most widely recognised mechanisms to describe the association between AD and psychiatric disorders are the overactivity of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS).¹
• Increased corticotropin-releasing hormone (CRH) and glucocorticoid receptor resistance result in the upregulation of inflammatory cytokines and the continuance of inflammation, while the activation of brain microglia by the same cytokines is a suggested mechanism of concomitant depression.¹

• Notable associations with hypercortisolaemia were found with certain subtypes of depression.¹
• Some studies demonstrated hypothalamic–pituitary–adrenal responses arising from IgE-mediated degranulation of mast cells via centrally released histamine could result in increased CRH and cortisol levels on AD patients.¹
• Data suggests the occurrence of behavioural and emotional disorders, mental retardation, memory impairment, and psychological development disorders among AD children.¹

Autoimmune diseases and AD connection

• Both AD and autoimmune diseases, such as rheumatoid arthritis, have common immunopathogenesis wherein cytokines play vital roles.¹
• Epigenetic changes along with gene variations could likely increase the susceptibilities to both rheumatoid diseases and AD.¹
• Patients with early onset alopecia areata (AA) could have a higher risk for AD.¹
• AD patients are likely to have a higher vitiligo prevalence possibly due to either genetic abnormalities or melanocyte destruction.¹
• However, the occurrence of both AD and type I diabetes (T1D) is found to be inconclusive, suggesting a mostly negative association between these diseases.¹

Conclusion:

• AD appears to be associated with multiple comorbid allergic, cardiovascular, mental health, neurologic, autoimmune, and metabolic conditions and other comorbidities depending on the risk factor exposure, genes, and immune dysregulations.¹
• Identification and management of the immunological causes behind chronic inflammation would help to prevent the development of other comorbidities.¹

Key takeaway

• AD can exist with other medical conditions such as allergies, cardiovascular disorders, mental health disorders, neurologic disorders, autoimmune disorders, metabolic conditions due to a similarity between the causal factors.¹