Atopic dermatitis (AD), or atopic eczema, is a chronic, recurrent, and multifactorial inflammatory disease characterized by eczema, dry skin (xerosis), and pruritus in variable degree, but generally intense, which compromises different dimensions of quality of life: symptomatic, functional, emotional, interpersonal and professional relationships. Due to its high prevalence, especially in childhood, in addition to quality of life, it impacts family dynamics and costs of the healthcare system.1–4

The scientific knowledge about the different aspects of AD and atopic diathesis has advanced considerably in recent years. Its pathogenesis is complex, involving immune-mediated mechanisms, and its understanding is advancing in relation to genetic predisposition, structural and functional changes in the epidermal barrier, innate and adaptive immune responses, colonization of the skin by microorganisms, bacteria and fungi, reactivity to house dust mites, neurobehavioral elements, and triggers for exacerbation of the subclinical disease.5

Numerous genetic-based factors and environmental stimuli interact in the same individual, leading to the triggering or worsening of AD. Such complexity of elements justifies the variability of its phenotypic expression, intensity, and clinical course. Ethnic, geographic, climatic, pollution, and occupational factors comprise the main circumstances that contribute to this variability in the clinical presentation of AD. There is also variation in the clinical picture related to patients age group, which also correlates with the pattern of environmental exposure and other atopic conditions (allergic asthma and rhinitis, food allergy, allergic conjunctivitis, and eosinophilic esophagitis).5,6

This article constitutes a multidisciplinary narrative review of the current aspects of AD pathogenesis, which, although not fully elucidated, can be understood based on the interaction of unique aspects such as genetic predisposition; changes in the skin barrier; activation of keratinocytes by mechanical, physical or chemical stressors; imbalance of the innate and adaptive immunity responses/loss of immune tolerance; intrinsic and extrinsic factors as disease triggers or aggravating factors; associated organic comorbidities, and sensitization of the pruritus neural pathways, so that a bidirectional neural and immune interaction is established in AD.5,7

Hypersensitivity is the most common comorbidity of AD. About 70% of children with AD are sensitized to one or more antigens. Moreover, atopic diathesis has a strong genetic burden. Most children with AD have at least one parent with respiratory allergies, skin allergies, or both. The child of one allergic parent is two to three times more likely to develop atopy, which increases to three to five times more when both parents are allergic.8

The main route for sensitization and perpetuation of food-induced hypersensitivity lesions is the cutaneous one. The gastrointestinal route, mainly in the interval between the 4th and 6th months of life, is generally associated with the induction of tolerance, as regulatory T and B cells have been described as playing a role in regulating the pathogenesis of AD and food allergy, as well as in the development of tolerance to the foods involved.9,10

The skin barrier dysfunction that occurs in AD increases permeability to allergens and irritants, contributing to loss of hydration and persistence of subclinical skin inflammation.9,11 The formation of subclinical inflammatory lesions and the absorption of food antigens through the skin, whether due to contamination in dust or the use of products containing food proteins, leads to sensitization in infants with AD.9

Based on the findings of barrier alteration and the development of food allergy, the prophylactic use of emollients in children with AD and the risk of food allergy was idealized; however, the BEEP study showed that emollients can increase the risk of AD due to the colonization of pathogens on the skin, and S. aureus colonization is associated with an increased risk of food allergy.11

In a murine model, skin colonized by S. aureus leads to the activation of dermal antigen-presenting cells after exposure of inflamed skin to exogenous food allergens, expansion of germinal center IgE + B cells, and generation of IgE specific to food allergens, in addition to inflammatory cytokines (IL-4, IL-5, thymic stromal lymphopoietin (TSLP) and IL-33). Furthermore, it was demonstrated that epicutaneous exposure combined with staphylococcal enterotoxin B increased allergenic responses to eggs and peanuts. Thus, cutaneous microbial dysbiosis also contributes to barrier dysfunction, modulating allergic sensitization.12

Therefore, infants with eczema are exposed to food antigens through the skin, inducing immune cells, and producing IgE antibodies (allergic sensitization).13 This implies the importance of not only inducing oral immunological tolerance but also preventing allergic sensitization through the skin, aiming to reduce other hypersensitivities.10 Allergy to peanuts was also shown to be associated with the use of skin products containing peanut oil in England.10 It is important to highlight that, in Brazil, many oils used for skin hydration contain food antigens such as peanut, coconut, almond, and grape oil, among others.

In the HealthNut study, 5,276 children with AD were monitored during the first four years of life, demonstrating an increased risk of developing food allergies, such as peanut and egg allergies.13 A systematic review involving 66 studies revealed that food sensitization in children with AD was six times greater compared to healthy controls at three months of age.10

Several studies have confirmed an association between food allergies and more severe AD, as well as an association between the early and persistent development of AD and food allergies, observing a greater likelihood of sensitization to common foods such as milk, eggs, and peanuts. In short, early-onset AD is related to the development of food allergies. Conversely, food allergy worsens AD or increases the risk of comorbidities, including anaphylaxis.8,10,14

Upper and lower-airway allergies are common in patients with AD. Dermatophagoides pteronyssinus, Dermatophagoides farinae, pollen, and cockroaches are the most relevant allergens. However, as AD has different immune response profiles, cases without association with asthma and rhinitis are frequent, especially in late-onset ADs, with a more cellular response than an IgE-dependent one.15

Exposure to aeroallergens can trigger skin reactions in AD, suggesting direct contact with the skin as the main stimulus route. There are several possible mechanisms for aeroallergens to trigger AD. By penetrating the compromised skin barrier of AD, intact allergens can be captured, processed, and presented by antigen-presenting cells via IgE-facilitated presentation.14 The IgE-antigen complex is then internalized and degraded, with subsequent antigen presentation in the major histocompatibility complex class II to T lymphocytes.14 In fact, serum IgE values ​​are associated with respiratory, but not cutaneous, disease activity.14 However, allergens can also be phagocytosed and presented for recognition by T lymphocytes, respectively, without IgE involvement.15

AD is also associated with Ocular Surface Disease (OSD). Between 25% and 50% of patients with severe AD (Odds Ratio [OR = 2.17]), asthma and rhinitis (OR = 1.76), and childhood-onset AD (OR = 1.34) are associated with OSD. The immunopathogenic mechanism involves adaptive T-cell immunity against allergens or pathogens on the ocular surface. Clinically, OSD includes conjunctivitis, keratoconjunctivitis sicca, blepharitis, keratoconus, and infectious and non-infectious keratitis (corneal inflammation), with conjunctivitis being the most common among them.16

The most common conjunctivitis subtypes are allergic (seasonal and perennial), followed by papillary, vernal (chronic inflammation of the outer edge of the palpebral conjunctival mucosa), atopic blepharoconjunctivitis (due to inflammation of the eyelid and surrounding conjunctiva), atopic and infectious keratoconjunctivitis. Atopic keratoconjunctivitis is associated with a risk of progressive corneal damage and visual loss. There is a high risk of bacterial conjunctivitis (from Staphylococcus spp.) and viruses (adenovirus and Herpes simplex). Conjunctivitis in patients with AD requires a multidisciplinary approach due to the risk of visual impairment.16

Treatment with anti-IL-4/IL-13 biologicals is associated with conjunctival inflammation, especially after three months of dupilumab use, in a restricted number of adult patients (6%–30%), which occurs especially when high basal serum levels of Thymus and Activation-Regulated Chemokine / CCL17 (TARC) and total IgE are observed. These cases progress with a decrease in globose epithelial cells in the conjunctiva, with a reduction in mucin production, increased infiltration of immune cells, tear film instability, barrier dysfunction, and conjunctival inflammation.16

AD is usually the first step in the development of the so-called “atopic march”, as the epidermal barrier dysfunction favors the permeation of antigens associated with its onset. The atopic march refers to the sequential progression to allergic rhinitis, food allergy or asthma; however, even such progression has a genetic basis. In a study carried out in the USA, in 18,596 children with AD, it was observed that African-American children showed progression from AD to asthma, while those of European-American descent progressed from AD to allergic rhinitis and Asian children progressed from AD to IgE-mediated food allergy. The risk of asthma among children of African-American ancestry was six times higher than among children of European-American ancestry.17

The TSLP alarmin produced by keratinocytes subjected to stress, allergens, or pathogens, causes the activation of dendritic cells and the secretion of chemokines, which attract type 2 helper T lymphocytes (Th2) to the skin, releasing pro-allergenic cytokines (type 2 inflammation cytokines, such as IL-4, IL-13, IL-5, IL-31). In AD, the unregulated and excessive production of cytokines, especially IL-4 and IL-13, causes the inhibition of the expression of epidermal proteins such as filaggrin, loricrin, and involucrin, which reinforces defects in the epidermal barrier, favoring the permeation of allergens and pathogens, feeding back the disease. The dysregulated type 2 inflammation cytokine response occurs in different anatomical sites of the body. At the level of the bronchi, IL-4 and IL-13 act by mediating inflammation and remodeling changes in the airways, predisposing the development of type 2-related asthma (50%–70% of asthmatics).18

In the context of chronic rhinosinusitis (CRS), damage to the upper airway epithelial barrier initiates and perpetuates type 2 inflammation, and environmental factors such as viruses and other stimuli generate alarmins such as TSLP, IL-25, and IL-33, which increase nasal inflammation. Among asthmatic patients, there is a prevalence of approximately 40% of CRS with polyposis, and AD is more common among these patients with CRS with nasal polyposis, compared to those with CRS without polyposis. This type 2 inflammation mechanism is believed to be shared simultaneously, predisposing and amplifying the host immune response to external stimuli, as it occurs in allergic conjunctivitis and eosinophilic esophagitis.18

AD is more prevalent in some families, with genetic factors accounting for 82% of the risk of developing AD, versus 18% for environmental factors.19 Moreover, children with both parents with a history of atopy are five times more likely to develop early-onset AD and persistent phenotype, compared to children with parents without AD history.20

The heritability of AD in monozygotic and dizygotic twins is 72%–86% and 21%–23%, respectively.21 The clinical subgroup most often associated with genetic transmission is patients with early-onset and resolution in adolescence, in addition to males.22

The high variation in prevalence and the different characteristics of atopic diathesis associated with ethnicities, such as the increased genetic heritability of asthma in black children, and the low prevalence of AD in Central Asian populations, have stimulated dozens of studies on AD and population groups.23,24 In spite of this fact, larger genome-wide research is needed to rigorously explain how ancestral-based genetic alterations act at a genetic-social interface.25

A study with Mendelian randomization identified an association between age at onset of diabetes and also alcohol use with AD.26 A recent systematic review of 30 studies with Mendelian randomization determined that body mass index, intestinal flora, gastroesophageal reflux, and the IL-18 pathway were causal factors for AD, while AD was a causal factor for comorbidities such as heart failure, rheumatoid arthritis, and conjunctivitis.27

In Brazil, the general prevalence of AD in indigenous communities (1.9%) was lower than that observed in the population of big cities, despite not being stratified by age, and the fact that there is an expectation of a higher proportion of children in less urbanized areas.2,28

The skin constitutes the largest organ of the human being and it functions as a protective barrier separating the body from the external environment, protecting humans from thermal, actinic, osmotic, chemical, infectious, and mechanical aggressions. The epidermis, dermis, and subcutaneous tissue together with eccrine glands, pilosebaceous follicles, and other skin appendages form an integrated structure that interacts, promoting this protective function.

The multilayer structure, which is one of the main characteristics of the skin barrier, performs interdependent functions. The stratum corneum is the outermost portion of the skin, which acts as the main physical barrier, in an arrangement that is similar to bricks (corneocytes, with polar chemical characteristics) and cement (intercellular substance, predominantly lipids and ceramides, with nonpolar characteristics), which, together with the occlusion (tight junction - TJ) zones, consisting of claudins and occludins also expressed in the granulosa layer of the epidermis and in the intercellular space of the keratinocytes of the sweat gland ducts, regulate the inflow and efflux of fluids and electrolytes in and out of the skin.44

Cell-cell contacts, especially in the human epidermis, are essential for tissue structuring and homeostasis. Adherens junctions, consisting of cadherins (trans- and cis-cadherin dimers) and nectins, mediate cell-cell adhesion. The TJs, including their claudins, occludins, and junctional adhesion molecules (e.g., ZO-1), establish the apical-basolateral polarity of keratinocytes and regulate the paracellular (intercellular) transport of ions and solutes. The expression of subunit proteins such as claudins and occludins is reduced by exposure to allergens and staphylococcal strains, compromising barrier integrity in AD.45,46

Thus, the epidermal structure of intercellular adhesion performs a complex protective function, which, together with the cutaneous immune system, contributes to the first line of defense against microbial pathogens and environmental insults.

A dysfunctional skin barrier is more prevalent in patients with AD (Table 2), and this deficit has several clinical consequences, as these patients are characterized by high reactivity to environmental stimuli and pathogens, reinforcing the role of restoring the skin barrier and protection against triggers for disease control. Transepidermal water loss results in skin dryness and desquamation, a high pH increases bacterial proliferation, while less adhesion between the corneocytes favors the penetration of allergens and irritants, which can trigger an exacerbated inflammatory response.47

Barrier functions in AD patients vary at different stages of the disease. Using pH and transepidermal water loss (TEWL) measurements, differences in these parameters were observed between eczematous skin and apparently healthy areas in AD patients. Notably, even unaffected skin in AD patients showed differences when compared to healthy subjects skin. In AD, there is an average increase in pH from 4.99 to 5.68 and TEWL increases from 6 to 30 g/m2h.48

One of the main genetic factors associated with AD is the mutation in the FLG gene, which produces function impairment leading to a compromised skin barrier. Filaggrin is a monomeric subunit of a protein packaged in keratohyaline granules, produced in terminal keratinocytes, involved in the maintenance of the skin permeability barrier.49 This structural protein binds to keratinocyte filaments to increase the density of filament bundles, flattening the keratinocytes to their terminal shape, crucial for skin strength and integrity.49 Profilaggrin, produced from the FLG gene, is broken down into monomeric filaggrin, which in turn is degraded by proteases into free amino acids, functioning as natural hydration factors to retain water, maintain the skin pH and strengthen the stratum corneum, offering chemical and microbial protection.49

Mutations in the FLG gene can result in functional loss or a smaller number of intra-exonic repeat units, which lead to protein deficiency, altering corneocyte morphology. This compromises the para-cellular barrier, allowing allergens and haptens to pass through. Although FLG mutations can contribute to AD, they are not sufficient to cause the disease alone, as some individuals with null alleles do not develop it.50

Around 25% to 50% of AD patients have a mutation in the FLG gene as a predisposing factor, especially in extrinsic phenotypes.50 However, it is known that this variation in the gene loss of function has ethnic variations, with values ​​reaching 50% in Europe and 25% in Asia; however, African-American patients have a lower frequency of the mutation, with the FLG2 gene mutation being more impactful for the disease.51FLG methylation is also correlated with AD risk, supporting the epigenetic contributions for disease development.52

The predominant Th2 imbalance in AD is implicated in reduced FLG expression, contributing to the barrier defect. Moreover, there is evidence that the expression of similar proteins, such as filaggrin-2 and hornerin, increase the risk of AD.53

Other molecules participate in the process of stratum corneum formation. With the loss of the nucleus, the cells are flattened and the keratin molecules become parallel, creating the cornified envelope connected with extracellular lipids. The cohesion strength of the stratum corneum depends on the formation of covalent bonds of lysine and glutamine, in which precursor proteins are incorporated into keratin, such as involucrin, cornifin, loricrin, keratolinin, and desmosomal proteins, such as envoplakin and periplakin.54

The lipid matrix of the stratum corneum is defective in AD skin due to an alteration in the expression of enzymes involved in the synthesis and processing of free fatty acids and ceramides. Lipid-rich lamellar granules in the granular layer of the epidermis provide the hydrophobic seal in the more superficial epidermal layers. The lipid matrix damaged after processing by lipid processing enzymes becomes a mixture of ceramides, cholesterol, and free fatty acids (FFAs). In cases of AD, there is a decreased amount of ceramides and those present are shorter.55 This reduction occurs in both affected and unaffected skin, especially in those with filaggrin abnormalities. Furthermore, a reduction in the relationship between ceramide and cholesterol was identified in the stratum corneum of these patients.56 This may be controlled by increased activity of lipid-processing enzymes or be a result of underlying Th2 inflammation, substantiating the importance of keeping subclinical inflammation under control to prevent recurrence, as demonstrated with proactive therapy.57,58

The elevated pH of the stratum corneum and the increased activity of serine proteinase promote the inactivation and degradation of acid sphingomyelinase and β-glucocerebrosidase, which are the enzymes required for ceramide synthesis.59 Elevated serine proteinase activity reduces secretion from lamellar bodies through plasminogen activator type 2 signaling and results in the abnormal transfer of several substances that are secreted from the lamellar body.60 This is ultimately related to the reduction of extracellular lipids reported in AD patients.

In damaged skin, the lengths of the chains of ceramides, free fatty acids, and esterified fatty acids are also shortened, which results in abnormalities in the epidermal lipid organization and consequent changes in the permeability of the skin barrier. In patients with chronic AD, increased kallikrein activity can also lead to these changes in lipid structure by inducing degradation of very long-chain fatty acid elongation protein.59

In addition to genetic changes, chronic inflammation associated with AD favors skin barrier dysfunction, as discussed below. The release of cytokines such as IL-4, IL-13, and IL-31 contributes to changes in cell differentiation and proliferation in the epidermis. Likewise, the Th2 tone of the disease suppresses the production of antimicrobial peptides and IFNα, favoring bacterial and viral infections.

Skin barrier dysfunction fundamentally favors the impact of environmental elements on the pathogenesis of AD. The bidirectional interaction of the external environment with human health and disease is called exposome, complementing the lifelong interactions between genes and environment in the pathogenesis of diseases. It can be classified as (i) General external factors, such as climate, biodiversity, urbanization (household fungi and mites), and socioeconomic contexts; (ii) Specific external factors: allergens, pollutants (particulate molecules – PM10, nanoparticles, nitrogen dioxide, ozone), detergents, metals, pollens, tobacco smoke, diet, sweat, lifestyle factors and microbes, and (iii) ) Internal factors: inflammation, metabolism, and oxidative stress exposome.61

Exposomes are key regulators in the interaction between the dysfunctional epidermal barrier, microbiome, genome, and immune dysregulation in AD. This deregulation of the epidermal barrier initiates a vicious cycle of inflammation that becomes chronic in AD, which is supported by changes in the microbiome (dysbiosis) and its imbalance, demonstrating the importance of epidermal barrier homeostasis to prevent or restore skin health in AD.61

An example of environmental pressure that can determine alarmin secretion by keratinocytes in the epidermis is the exposure to high concentrations of particulate matter with an average size <2.5 µm emitted by forest fires, which disrupts the epidermal barrier by damaging structural proteins (filaggrin and E -cadherin), and lipids in the epidermis. In addition to particulate matter, acicular nanoparticles (diameter up to 270 nm) of titanium dioxide, but not globular nanoparticles of the same diameter, were internalized by normal human keratinocytes and produced pro-inflammatory cytokines, such as IL1-α, IL-1β, IL-6, TNF-α and IL-8, inducing skin inflammation.62,63

Exposure to synthetic detergents is associated with an increased risk of eczema related to the working activities of cleaning professionals, potentially through TEWL. An increase in the number of cases of AD exacerbation has been observed due to the increased use of disinfectants during the COVID-19 pandemic.61,64

Tobacco smoke, whether through active or passive exposure, delivers benzene to the skin, which interferes with the inhibitory ability of TREG cells to secrete IL-10 and exert anti-inflammatory effects, which results in a higher prevalence of AD in children with relatives who smoke.61

Moreover, allergens with proteolytic properties, such as certain pollens and group 1 house dust mites, promote disruption of the epidermal barrier and contribute to a vicious cycle of inflammation-microbial dysbiosis and skin barrier fragility.61,65 These elements support desensitization therapies aimed at reducing reactivity to these agents, especially in the presence of respiratory allergies.

In general, the deficit in the skin barrier in AD is an important component of allergic sensitization in these patients, and also a relevant factor in disease exacerbations. In cases with controlled disease (i.e., with subclinical inflammation), exposure to irritants, dust, detergents, and hot baths/showers in winter are elements recognized as triggers of clinical recurrence, which reinforces the importance of maintaining therapies aimed at recovering the skin barrier and proactive strategies to prolong AD clinical remission.57,58

The polymorphism of the clinical presentations of AD is supported by a genetic basis, levels of skin barrier impairment, and patterns of immune response imbalance. Tables 3 and 4 summarize the different phenotypic aspects of AD and their relationship with serum IgE levels, in addition to patterns of more active immune responses in different ethnic groups. The recognition of these phenotypic aspects and their underlying pathophysiological basis can also guide the best therapeutic option.

About 70% to 80% of adults with AD have elevated serum levels of IgE and specific IgEs to several allergens (extrinsic, allergic or exogenous phenotype), in whom the severity of skin lesions correlates with serum IgE levels. Moreover, clinical improvement in eczematous lesions has been reported in allergen-free environments with specific IgE. In spite of that, omalizumab is not effective in the treatment of extrinsic AD eczema, and AD should not be justified solely by the occurrence of elevated serum IgE. However, the presence of IgEs specific to certain allergens plays a role in the development of eczematous dermatitis resulting from IgE-mediated delayed-type hypersensitivity, functioning primarily as an amplifier of other factors involved in the pathogenesis of AD.79,80

On the other hand, in intrinsic AD (endogenous, atopic, or non-IgE-allergic), no sensitization to environmental allergens is detected and serum IgE levels are normal. Instead, skin inflammation is often attributed to factors such as a compromised skin barrier, imbalances in the skin microbiota, and immune system dysfunction. Intrinsic AD tends to be more persistent and less responsive to conventional treatments. This phenotype may not meet the usual diagnostic criteria for AD (e.g.; Hanifin and Rajka), leading to diagnostic delay and inappropriate therapies.81

Some patients may also experience an intense and chronic pruritus sensation, known as neuropathic pruritus. This phenotype is associated with abnormalities in the peripheral and central nervous pathways, and the lower pruritus threshold and recurrent scratching may contribute to the inflammation persistence in AD.

It is important to note that intrinsic and extrinsic phenotypes are not mutually exclusive, and some patients may exhibit characteristics of both phenotypes or migrate from the predominance of one to the other, during the course of the disease. Recognizing these differences can be useful in guiding therapeutic management, especially regarding the identification of environmental triggers.

Morphologically, according to the skin lesion pattern, a network of different cytokines takes the lead in the inflammatory response, with therapeutic implications. In acute eczema, the lesions are supported by tissue expression of IL-1alpha and IL-1beta, IL-33, IL-4, IL-13, and IL-22. In subacute eczema, the main cytokines are IL-4, IL-13, IL-25, IL-31, IL-33 and TLSP. In chronic eczema, there is a predominance of Th1 and Th17 cytokines: IFNγ, TNFα, IL-17A, IL-17F.82

Finally, series from different original ethnic groups also share phenotypes linked to the protagonism of the pathogenic components of AD (Table 4). However, globalization and population miscegenation, as it occurs in Brazil, tend to reduce the preponderance of phenotypes linked to ethnicity in the clinical presentation of AD.83

Human skin is a rich ecosystem inhabited by a diversity of microorganisms, including bacteria, fungi, and viruses, with bacteria from the Actinobacteria, Firmicutes, and Proteobacteria phyla being the most prevalent ones. Fungi, such as Malassezia spp., and Demodex spp. mites are also important components of the skin microbiota. These microorganisms, mainly commensals, interact directly with the host, act as protection against pathogens, stimulate the skin barrier, and regulate the immune response; however, their imbalance can contribute to the exacerbation of AD.84–86

The composition of the skin microbiota starts at birth, differing between newborns born via the vaginal route and via cesarean section. This composition is influenced by several factors throughout life, including changes in skin pH, humidity, pollution, and sebum production.87–89 Changes in the microbiome may precede the development of AD, with puberty marking another phase of significant change due to the influence of sex hormones.90–93

The skin microbiota participates in the maintenance of the skin barrier function, influencing cell differentiation and regeneration. For instance, coagulase-negative staphylococci, such as S. hominis, produce substances that inhibit the growth of S. aureus.94–96

Patients with AD frequently exhibit dysbiosis, manifested by a decrease in microbial diversity, with a skin environment that favors the growth of S. aureus, associated to an increase in skin pH and antimicrobial component deficiencies.97–102

A healthy skin flora is necessary to maintain the microbial barrier, as certain bacteria in healthy skin suppress virulent bacteria and induce the expression of antimicrobial peptides (AMPs), controlling inflammation. The skin pH helps to determine skin microbial populations, and an increased pH can increase susceptibility to infections. A healthy flora, along with normal expression of skin proteins, enzymes, proteases, and balance of inflammatory cytokines, are crucial for maintaining a normal acidic pH of the skin.99

S. aureus infection inhibits the expression of late differentiation factors in keratinocytes, such as filaggrin, loricrin, keratin 1 and 10 and desmocollin 1, which can further compromise the skin barrier. Additionally, bacterial components of S. aureus are associated with altered intercellular lipid composition.103,104

The treatment of skin diseases with antibiotics and antibacterial agents can be effective; however, prolonged use increases the risk of promoting bacterial resistance. Recent therapies, such as dupilumab and tralokinumab, favor skin microbiota rebalancing in patients with AD.94,105 The use of probiotics, prebiotics, and postbiotics is also explored to fight skin dysbiosis.95

There is less information regarding intestinal microbiota and AD. The human intestine hosts more than 100 trillion microorganisms and is influenced by factors such as genetics, diet and medical treatments. The composition of the intestinal microbiota affects immune development and disorders can lead to conditions such as inflammatory diseases and obesity. Dysbiosis in the intestinal microbiota is linked to AD, characterized by a decrease in microbial diversity and an increase in the presence of harmful bacteria such as Clostridium difficile. This imbalance can lead to increased intestinal permeability, with dysfunction of the interepithelial occlusion zones in the intestine, allowing bacterial toxins to permeate the epithelium and impact the local and systemic immune response, including in the skin.106 Dietary factors, particularly the Western diet, contribute to intestinal dysbiosis and AD by altering the intestinal microbial genes and inflammatory responses.107

AD impacts the quality of life of patients and their families, whose chronic contingency manifests itself, neuropsychologically, in several ways, including anxiety, depression, disruptive behavior disorders, neurological development disorders, attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder, and suicidal ideation, with these associations especially striking in severe cases of AD.108–110

The prevalence of ADHD in children with AD was estimated at 7.1% (95% CI 5.4–8.9%), while in children without AD, it was 4.1%, in an Israeli case series.111 These children experience sleep problems at higher rates than those with AD alone. Sleep deprivation in the first three years of life is linked to hyperactivity and lower cognitive performance at age six, demonstrating that insufficient sleep can have lasting effects on neurocognitive development.112 Mothers of infants with AD report more pronounced feelings of depression and anxiety compared to mothers of children without AD. Moreover, parents of children with AD report that disrupted sleep is directly related to their own levels of anxiety and depression.113,114

A longitudinal study that followed 1,578 children until age 10 showed that AD in childhood and sleep problems are significant predictors of conduct and emotional disorders at age 10.115 Research also associates ADHD with the use of antihistamines (OR = 1.88; 95% CI 1.04‒3.39), although studies on cetirizine did not find any significant differences compared to placebo in the children’s behavioral and developmental assessments.116,117

Moreover, the presence and intensity of pruritus are positively correlated with symptoms of depression, anxiety, and stress throughout life. The high incidence of mental health symptoms in children with AD may be partially due to the coexistence of other conditions. Studies have shown that atopic comorbidities are associated with higher prevalence rates of several psychological conditions, such as autism and ADHD.110

Adolescents with AD report high rates of shame, avoidance of social activities, and fewer friends, while children with AD are bullied and have more negative experiences with peers and teachers.118,119 Mild to moderate AD is associated with a 29% to 84% increase in the risk of internalizing behavior problems from ages four to 16, although it is not directly linked to an increase in the risk of depression from ages nine to 18.120 Additionally, such behaviors in childhood are related to depression and anxiety in adulthood.121

A systematic review indicated that approximately one in six individuals with AD has clinical depression, one in four has depressive symptoms, and one in eight has suicidal ideation.122 Patients with AD have greater chances of clinical depression and depressive symptoms when compared to healthy individuals, albeit similar to people with other chronic dermatological disorders. Finally, almost one-third of parents of children with AD are depressed, and there is a high prevalence of suicidal ideation among patients with AD.122

Pharmacological treatment of AD reduces anxiety and depression scores in patients with moderate to severe disease, while non-pharmacological interventions lead to reductions in anxiety scores.123 Moreover, psychological interventions led to improved quality of life and reduced eczema and pruritus severity scores.124

An association was identified between AD and other neuropsychiatric disorders, including autism (OR = 2.14; 95% CI 1.39‒3.29), ADHD (OR = 1.78; 95% CI 1.21‒2.62), personality and behavioral disorders and schizophrenia (OR = 1.45; 95% CI 1.23‒1.72),125 in addition to a new association between AD and an increased risk of developing dementia (OR = 2.02; 95% CI 1.24‒3.29).126 This highlights the complexity and severity of the impact of AD on the mental health and quality of life of patients and their families.

Although the relationship between AD and neuropsychiatric conditions is highlighted, the underlying cause of these associations is not fully understood, as well as the interaction between dermatological symptoms (e.g., pruritus) and the worsening of neuropsychiatric symptoms. A better understanding of these dynamics should lead to primary and secondary prevention strategies to reduce the neuropsychiatric impact of AD, such as early interventions in high-risk patients and measures to improve the quality of life of patients and their families.

The chronic inflammatory state can lead to major cardiovascular events (angina, acute myocardial infarction, cardiac arrhythmias, etc.), heart failure, venous thromboembolism, and lymphoproliferative malignancies in patients with AD.27

In a cohort study in the United Kingdom population, which evaluated 625,083 adults with AD followed for at least five years, without receiving immunosuppressive therapy, compared to another 2,678,888 adults without AD, matched by gender and age, it was observed that among adults with severe AD (10,543 patients) there was a 1.86-fold increased risk of non-Hodgkin's lymphoma and a 21.05-fold increased risk of cutaneous T-cell lymphoma.127

Patient care data in the United Kingdom between 1994 and 2025 demonstrated that adults with severe AD are at increased risk of myocardial infarction (Hazard Ratio/ Instantaneous Hazard Ratio [HR = 1.27; 95% CI 1.15‒1.39]), cerebrovascular accidents (HR = 1.21; 95% CI 1.13‒1.30) and pulmonary embolism (HR = 1.39; 95% CI 1.21‒1.60), when compared to adults without AD.128

Despite the known association between systemic comorbidities and AD, and the importance of identifying these conditions, the direct causal relationship between chronic inflammation in AD and such conditions is not yet known, nor is it known whether effective AD treatment reduces the incidence of these comorbidities.

AD is a complex, chronic, and recurrent multifactorial condition that has variable phenotypes, resulting from the interaction between the genetic basis, skin barrier defect, immune response profiles, and reactivity to environmental exposure. A better understanding of its pathogenesis leads to the possibility of intervention in the preponderant worsening factors, in each circumstance, as well as to promoting the reduction of the basal disease activity, in subclinical cases, prolonging periods of remission.

None declared.

Paulo Ricardo Criado: Study planning, drafting and editing of the manuscript, approval of the final version of the manuscript.

Roberta Fachini Jardim Criado: Study planning, drafting and editing of the manuscript, approval of the final version of the manuscript.

Mayra Ianhez: Study planning, drafting and editing of the manuscript, approval of the final version of the manuscript.

Hélio Amante Miot: Study planning, drafting and editing of the manuscript, approval of the final version of the manuscript.

Caio César Silva de Castro: Study planning, drafting and editing of the manuscript, approval of the final version of the manuscript.

Roberto Bueno-Filho: Study planning, drafting and editing of the manuscript, approval of the final version of the manuscript.

Dr. Paulo Criado: Advisory board - Pfizer, Galderma, Takeda, Hypera, Novartis, Sanofi; clinical research - Pfizer, Novartis, Sanofi, Amgen and Lilly; Speaker: Pfizer, Abbvie, Sanofi-Genzyme, Hypera, Takeda, Novartis.

Dr. Roberta Fachini Jardim Criado: Advisory board - Pfizer, Takeda, Hypera, Novartis, Sanofi; clinical research - Pfizer, Novartis, Sanofi and Lilly; Speaker: Pfizer, Abbvie, Sanofi-Genzyme, Hypera, Takeda, Novartis.

Dr. Mayra Ianhez: Advisory Board - Galderma, Sanofi, Pfizer, Novartis, Abbvie, Janssen, UCB-Biopharma, Boehringer-Ingelheim; Speaker - Galderma, Sanofi, Pfizer, Theraskin, Novartis, Abbvie, Janssen, Leopharma, FQM.

Dr. Caio Castro: Advisory Board - Sanofi, Aché, Sun-Pharma, Galderma. Speaker - Abbvie, Jansen, Novartis, Sanofi, Leo-Pharma. Clinical Research - Abbvie, Pfizer, Jansen, Sanofi.

Dr. Roberto Bueno-Filho: Advisory board - Janssen, Novartis; clinical research – Sanofi, Janssen and Lilly; Speaker: Pfizer, Janssen, Sanofi, Novartis.

Dr. Hélio Miot: Advisory Board – Johnson & Johnson, L’Oréal, Theraskin, Sanofi and Pfizer; clinical research - Abbvie, Pierre-Fabre, Galderma and Merz.