Atopic Eczema: Genetic Associations and Potential Links to Developmental Exposures

Abstract

Atopic eczema (AE), or atopic dermatitis (AD), is a common inflammatory skin disease with a disrupted epidermal barrier and an allergic immune response. AD/AE is prominently characterized by a symptomatic itch and transient skin lesions. Infants compose a significant percentage affected. Two models have been proposed to explain AD/AE skin pathology: the gut microbiome-focused inside-outside model and the outside-inside model concentrating on the disrupted skin barrier/skin microbiome. Gene disruptions contributing to epidermal structure, as well as those in immune system genes, are implicated. Over 30 genes have been linked to AD/AE with Flg and Tmem79/Matt alterations being common. Other linked disruptions are in the interleukin-1 family of cytokines/receptors and the T_H2 gene family of cytokines. Inheritable epigenetic modifications of the genes or associated proteins may also be involved. Skin barrier disruption and the allergic immune response have been the main foci in mechanistic studies of AD/AE, but the role of the environment is becoming more apparent. Thus, an examination of in utero exposures could be very helpful in understanding the heterogeneity of AD/AE. Although research is limited, there is evidence that developmental exposure to environmental tobacco smoke or phthalates may impact disease. Management for AD/AE includes topical corticosteroids and calcineurin inhibitors, which safely facilitate improvements in select individuals. Disease heterogeneity warrants continued research not only into elucidating disease mechanism(s), via identification of contributing genetic alterations, but also research to understand how/when these genetic alterations occur. This may lead to the cure that those affected by AD/AE eagerly await.

Introduction

Atopic, or allergic, diseases affect a significant number of individuals worldwide. Allergies are on the rise and affect up to 30% of adults and 40% of children. ¹ Although much information has been garnered concerning the genetic and environmental links to allergic diseases such as atopic asthma, hay fever, and atopic dermatitis/atopic eczema (AD/AE), the detailed mechanisms behind them continue to be under debate. As such, improving disease management, by targeting clinical manifestations, rather than disease prevention, is the immediate goal.

AD/AE is an underappreciated member of the allergic disease family that affects many newborns as well as those of multiple age cohorts. ^2,3 AD/AE is of global concern as it affects about 20% of children in the developed world and it has been correlated to the future development of atopic asthma and other allergy-based diseases; it has also been linked to autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. ^4,5 Greater than 60% of infants with moderate to severe AD/AE also suffer from various food allergies in the first 2 years of life, a condition that shifts toward respiratory allergens as the child ages. ^6,7 Further extending concern is the finding that AD/AE has been linked to an increase in anxiety, depression, social self-consciousness, and even autism in affected children. ⁸ From an economic impact view, 1 study estimated that management treatments for AD/AE could constitute up to 10% of an annual household income. ⁹ This review article outlines the general pathology of AD/AE, two commonly proposed models that attempt to explain it, important aspects of its genetic identity, not only from the view of skin barrier disruption,but also from an immunological response perspective. Stepping away from the implicated genetic alterations contributing to the mechanism of the disease, insights on some in utero exposures that may be contributing to AD/AE development are discussed. Finally, some of the most promising treatments, which concentrate on disease management, are addressed.

Skin Barrier Structure and Disruption in AD/AE

The skin provides the first line of immunological defense against pathogens or allergens that may enter the body. The disruption of the skin barrier causes not only water loss but also a vulnerability to infection. In order to fully understand AD/AE, one must have a cursory knowledge of epidermal structure.

The stratum corneum (SC) is the outer epidermal layer of the skin that is the true first line of defense against environmental exposures. This protective layer of epithelial cells, or keratinocytes, gains a mechanical strength via proteins, such as keratins, which provide resilience to the cellular cytoskeleton. Without the mechanical strength provided by keratins, the skin becomes more fragile, which clinically manifests itself as blistering in response to even mild trauma. The SC incorporates tight junctions and corneodesmosomes between its component cells, which not only aid in preventing water loss but also prevent environmental allergen or bacterial exposures. ¹⁰ Furthermore, the lipid, acid, and enzymatic components of the SC are just as important as the cellular components to proper function and homeostasis. For instance, altered ceramide structure or elevated skin pH have been linked to dominant Staphylococcus aureus colonization in the recurrent eczematic lesions of those affected by AE ¹¹ ; S aureus can make up more than 90% of an individual lesion’s bacterial composition. ^12,13 Epidermal serine proteases, such as the membrane-anchored channel-activating serine protease 1, which is also known as Prss8, have been found to be essential for proper formation of the SC in mice; knockout of this gene led to improper skin development, dehydration, and postnatal fatality. ¹⁴ Defects in any 1 or more of the genes that contribute to the formation of this resilient skin barrier have been pinpointed as prime contributors to AD/AE of varying severity degrees. However, there are opposing explanations of the role this epidermal skin layer disruption has in the drive of the disease.

Atopic Dermatitis/Atopic Eczema: A Generalized Immunological Characterization

AD/AE is a complex allergic disease where the immune response to a skin-penetrating agent is best described as an overactive acute T_H2 response. Cytokines such as interleukin (IL)-4, IL-5, IL-13, and IL-31, as well as immunoglobulin type E (IgE) antibodies dominate the active response. ^15,16 The IL-1 family of cytokines, such as IL-1α, IL-1β, IL-18, and IL-33, which aid in initiating the T_H2 response, are also important contributors to disease pathogenesis. ^17,18 Furthermore, in mouse models of AD/AE, house dust mite (HDM) allergen-specific IgG₁ and IgG_2a antibodies were shown to be induced. ¹⁹

AD/AE is at its basis a failure of the skin, itself an innate first line of defense, to keep pathogens or allergens out of the body. As an allergic disease, an investigation into understanding of cause of AD/AE requires reference back to the “hygiene hypothesis.” David Strachan proposed this hypothesis to explain the significant rise in allergic disease in industrialized countries when compared to the lower prevalence of allergies in populations living in more underdeveloped areas. Strachan’s study of a large cohort of British children revealed that the occurrence of allergic disease in the households was significantly related to the number of older children present. He believed that unhygienic contact of younger siblings with older siblings promoted an exposure to infectious agents, gut microbiota, and parasites. Such childhood exposures contributed to the development of natural immune tolerance and thus a decrease in susceptibility to allergic diseases. ²⁰ Supporting this idea were other studies that found a decrease in asthma development in children living on farms when compared with rural environmental controls, as well as an investigation that revealed an inverse correlation between infections and allergic or autoimmune disease development. ^21,22 Furthermore, the intestinal microbiota has been shown to play a role in the proper development of the immune system and thus may have a role in the development of allergic disease. ²³

Atopic Dermatitis/Atopic Eczema: The Inside-Outside Model Versus The Outside-Inside Model

An investigation of the literature shows 2 prominent mechanistic models used to explain the allergic response and pathology of AD/AE: the inside-outside model and the outside-inside model. Both models acknowledge the epidermal permeability defect found in AD/AE but utilize it differently to provide an explanation for the drivers of the disease.

The inside-outside model of AD/AE at its core links the aberrant immunological response with gut microbiota diversity differences between atopic and non-atopic individuals. ²⁴ There is mounting evidence for the involvement of microbial intestinal individual disparities in allergic disease involving Bifidobacterium, Lactobacillus, Escherichia coli, and Clostridium. A clinical study investigating infants in the first year of life showed that children who tested positive for food allergy had consistently lower levels of Bifidobacterium intheir stool samples when compared to nonallergic children; a lower prevalence of Lactobacillus coupled with higher counts of S. aureus and intestinal coliforms was also found in the same allergic infants. ²⁵ Specifically, in relation to AD/AE, a Japanese study showed that reduced fecal Bifidobacterium counts correlated to the clinically defined severity of AD/AE: The lower the fecal Bifidobacterium content, the more severe the AD/AE symptoms were. ²⁶ In contrast, other studies do not support these findings, which may be explained by the fact that earlier studies lacked an investigation of intestinal Bifidobacterium species. Supporting this hypothesis is a pediatric study in which infants with AD/AE were found to have higher levels of Bifidobacterium adolescentis, whereas healthy children had higher levels of Bifidobacterium bifidum. ²⁷ Some studies did not observe any Bifidobacterium differences between children with or without AD/AE but instead found a correlation between AD/AE development in infants with higher levels of intestinal E coli and Clostridium difficile. ^28,29 To date, there is no consistent association between AD/AE development and gut microbiotia composition. In addition to contrasting findings in terms of the specific bacterial species found, some studies have identified no consistent, significant differences in the numbers of individual gut bacteria found in AD/AE versus control individuals, even when utilizing cutting-edge molecular identification techniques. ^30,31 It is worth noting that the overall study of gut microbiota and its link to allergic disease may be more informative if sex differences in study participants are routinely considered, as diet has been shown to have sex-specific effects on the gut microbiome. ³² In addition to sex consideration, the impact of genetically modified foods, by mothers who breast-feed (developmental effect) or in children/adults with AD/AE who eat whole foods (direct effect) on gut microbiota diversity, could also yield interesting data. ³³

The outside-inside mechanistic model of AD/AE implicates the epidermal barrier defect as the main promoter of disease, in contrast with changes in the gut microbiota. ³⁴ The skin barrier disruptions in AD/AE have a genetic basis and it is reasonable to propose that these individuals would be more vulnerable to immunogen exposures via the skin, particularly by skin microbes. Multiple studies analyzing the skin microbiome, including those that utilized molecular microbial identification, indicate that colonizing S. aureus is the dominant microbe found on the skin of individuals with AD/AE, correlating with disease severity; it is not found as the dominant microbe on the skin of patients with genetically characterized primary immunodeficiencies who also display AD/AE-like lesions. ^{35 –37}

Association does not always indicate causation, as S. aureus dominance may just be a consequence of the disrupted epidermis. However, if eliminating or reducing the bacterium correlates with a reduction in the clinical manifestations of AD/AE, there is support for a causative link between S. aureus and AD/AE. A 3-month study utilizing emollient treatment in patients with AD/AE reduced the amount of Staphylococcus on the skin, resulting in symptom reduction in 72% of the study participants; molecular identification methods were used to assess the presence of Staphylococcus, providing further validation of these results. ³⁸ Antibiotic treatments also resulted in a reduction of skin-colonizing Staphylococcus in patients with AD/AE, correlating with a reduction in disease symptoms. ³⁹ Unfortunately, due to the prevalence of multiple antibiotic strains of S. aureus, the usefulness of antibiotics such as mupirocin and methicillin to curtail AD/AE symptoms in certain individuals may be short lived. ^40,41 Furthermore, studies have shown that modifying the skin barrier from birth via the use of moisturizers can effectively prevent AD/AE. The exact mechanism by which this enhanced moisture exerts its preventative effect is not understood in detail; however, it is believed that an enhanced skin barrier, which prevents allergen penetration into the epidermis, is involved. ^42,43

Multiple studies have shown that the strains of S. aureus associated with the clinical skin pathology of patients with AD/AE are toxigenic strains, including those expressing the T cell activating superantigens, staphylococcal enterotoxin C, staphylococcal enterotoxin A, and toxic shock syndrome toxin-1. ^44,45 These findings further support the abnormal T-cell functions that are known to play a critical role in AD/AE, such as enhanced IL-4 and IL-13 production, which drive T_H2 immune responses. ^46,47

The outside-inside hypothesis is very attractive due to a study showing the deactivation of the filaggrin gene (Flg) being linked to as many as 20% of AD/AE cases in Northern European populations. While Flg gene alterations are an important consideration, they do not explain all cases of AD/AE, as only 1 in 5 patients with AD/AE in Northern European and Asian populations are associated with Flg gene mutations and less than 5% of African American individuals with AD/AE have mutations in the Flg1 gene. ^48,49 Importantly, IL-4 and IL-13 have been shown to downregulate the activity of genes important in epidermal differentiation, such as loricrin, involucrin, and S100/A11. Loricrin and involucrin are proteins involved in skin barrier integrity and formation, whereas S100/A11 is a calcium-binding protein whose expression levels are positively correlated with Flg gene expression; enhancing keratinocyte S100/A11 expression in the presence of increased calcium, in turn, enhances Flg gene expression in keratinocytes. ^50,51 Furthermore, continued research will deepen our genetic understanding about the plethora of different barrier components of the skin epidermis, highlighting their importance to patients afflicted with AD/AE on an individualized basis.

Genetic Implications in AD/AE

AD/AE is a profoundly heterogenic disease and many gene alterations have been associated with not only the skin barrier dysfunction, but also with the underlying immunological response. Both genetic components warrant detailed investigation, as individualized therapies may be custom tailored based on the genotyping of patients with AD/AE.

Gene Mutations That Affect Skin Barrier Structure

Filaggrin loss-of-function gene mutations comprise between 15% and 55% of cases of AD/AE and affect a variety of ethnic populations. ^52,53 The Flg is located on chromosome 1 in humans and chromosome 3 in mice, where it was originally identified. Subsequently, the gene was associated with the epidermal differentiation complex, which includes over 70 genes involved in skin barrier formation and epithelial differentiation. ⁵⁴ When properly functioning, Flg encodes for the rather large precursor protein, profilaggrin, which is more than 400 kDa in size; this equates to a single mRNA of about 13,000 nucleotide bases. Profilaggrin is cleaved into 10 or more filaggrin subunits, the active form of the protein. Filaggrin contributes to the structural integrity of the SC, playing an important role in skin barrier formation that when impaired can lead to AD/AE. ^55,56 The protein does this by facilitating the flattening of keratinocytes in the SC upper layer as well as by breaking down into trans-urocanic acid and pyrrolidine carboxylic acid, which both contribute to keeping the outer layer of skin moisturized and pH balanced. ^57,58

Filaggrin loss-of-function mutations are mutations that do not allow the full-length profilaggrin protein (and thus functional filaggrin) to be produced. Nearly 50 filaggrin mutations have been characterized, most of which are located within exon 3, which encodes almost the entire, full-length profilaggrin protein. ⁵⁹ As there are 2 copies of the filaggrin gene in each cell, mutation in only 1 of the 2 copies results in a reduced phenotypic effect (skin flakiness). Another common skin disease, ichthyosis vulgaris, characterized by scaly skin, is also associated with loss-of-function mutations in Flg. ⁶⁰ In addition to AD/AE and ichthyosis vulgaris, Flg gene mutations have been linked to affected individuals having an increased risk for and severity of other allergic diseases later in life, including atopic asthma and hay fever. ^61,62 Interestingly, in subsequent mouse studies, Flg ^−/− mice were shown to have no prolonged symptoms with age, inferring that Flg mutations have primarily a neonatal influence on AD/AE. ^55,63 With these studies in mind, in 2013, mutations in a second major gene were linked to AD/AE: Tmem79 (Matt).

Tmem79, or Matt, encodes for the protein mattrin, which like filaggrin is primarily expressed in the SC. The Matt gene is located on chromosome 3 in mice and chromosome 1 in humans, closely linked with the Flg gene. Matt’s 5 exons encode an approximately 43 kDa protein that has 5 transmembrane domains. Like Flg, the wild-type function of Matt has been found to be interrupted by 1 of a multitude of nonsense mutation types in a cytoplasmic region of the protein. The initial nonsense mutation was identified as a base-pair substitution in exon 3 of the gene, which in turn alters an amino acid (and thus wild-type protein function) located between the second and third transmembrane domains of the protein. ⁶⁴ Matt mutations were found to be associated with human AD/AE cases after the DNA sequencing of 55 Irish cases that were Flg^−/− , thus indicating that these disease cases were independent of Flg. Matt mutation is also responsible for the matted hair phenotype, which as described in mice includes hair fibers that adhere to one another and associate with baldness. Furthermore, these mice have moist, oily hair, which indicates that the mutation alters the lipid composition of the SC surface. ⁶⁵ Importantly, unlike Flg mutations, Matt mutations are responsible for spontaneous AD/AE, which is not seen in single or double Flg mutant mice. This was demonstrated by treatment of Matt null mice with HDM allergen. ¹⁹ Although Matt mutations have been found to be associated with spontaneous AD/AE, the detailed mechanism by which this phenotype arises still needs to be elucidated, namely through a detailed study of the secretion system in the epidermis.

Although Flg and Matt are the genes of most immediate interest in the molecular characterization of AD/AE, several other mutations in genes related to the epithelial barrier have been identified that may also play a role in the disease. Located on human chromosome 5, SPINK5, is a gene that encodes a serine protease inhibitor, LEKT1, which affects the regulation of proteolysis contributing to the normal skin permeability barrier function. ⁶⁶ Specifically, SPINK5 activities appear to play a role in the anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in SPINK5, most of which cause early transcript termination, have commonly been found in Asian populations affected by AD/AE. ^67,68 Further supporting the importance of protease signaling in the skin and AD/AE is a French study linking SPINK5 mutations to AD/AE-like lesions in Netherton syndrome, another genetic-based skin disease. ⁶⁹

A Flg-like gene, called Flg-2, with a normal function associating with epithelial barrier formation, is commonly found mutated in African Americans with persistent AD/AE. Furthermore, this protein, which in addition to its contribution to epithelial barrier function, also displays antimicrobial activity against Pseudomonas aeruginosa. ⁷⁰ However, overall skin structure and proper barrier function is not just about the individual epithelial cells but how adjacent epithelial cells interact with one another.

Studies have shown that defects in tight junctions, which connect adjacent cells, have been found in biopsied skin samples from patients with AE but not in healthy skin samples. Specifically, claudin-1, a protein encoded by the CLDN1 gene, that facilitates epithelial tight junction strength, appears to be involved in AD/AE, as it was found to be significantly reduced in AD/AE clinical skin samples but not in healthy or other control skin samples. ⁷¹ As a result of a defect in tight junction strength, environmental antigens have greater access to initiate the pro-inflammatory response that the skin barrier disruption facilitates. AD/AE is a complex disease and not only is a thorough investigation warranted of genes associated with epidermal barrier dysfunction and cell-to-cell interaction, but also of genes associated with the accompanying dysregulated immune response.

Gene Mutations That Do Not Affect Skin Barrier Structure

Considering the interplay of the skin barrier dysfunction and a hyperactive immune system in AD/AE, an investigation into genetic alterations affecting normal immune function is warranted.

As the immune system is a two-faceted system, with innate and acquired components, AD/AE development and/or severity may be affected not only by alterations in genes involved in the initial immunogen recognition event, but also by genes contributing to the overall immune response. The alterations characterized to date are primarily mutational sequence changes, but epigenetic changes in the genes must also be considered.

Pattern recognition receptors, such as the toll-like receptors (TLRs), are proteins found on the surfaces of innate immune cells such as macrophages, monocytes, and dendritic cells. They are important in the recognition of foreign antigens and facilitating an active immune response against them. Mutations in TLRs will not only impair the immune response against opportunistic agents in AD/AE, such as bacteria, viruses, and allergens, but also as a result, modify the normal cytokine response to such antigens. In fact, mutations that either prevent the production of TLR2 or TLR4, or alter the amino acid sequences of either of these TLRs, have been correlated with AD/AE through the alteration of typical cytokine profiles. ^72,73 Mutations in the genes of several other TLRs have also been linked to AD/AE. ^74,75 An assessment of the variety of TLR mutations associated with AD/AE reveals the importance to investigate this disease from the standpoint of the cellular proteins sensing the invading antigen/allergen, as well as assessing potential defects in the resulting cytokine profile; these defects direct back to the T_H1/T_H2 paradigm and alterations in it.

The IL-1–based SC inflammation has been associated with the previously addressed Flg mutations in AD/AE. ¹⁷ Under normal circumstances, the IL-1 family of cytokines, which also includes IL-18 and IL-33, play master regulator roles in the innate immune response to foreign antigens that overcome barriers, such as the skin. ⁷⁶ Cells such as macrophages, dendritic cells, B cells, and epithelial cells secrete IL-1 family cytokines in response to foreign antigen/allergen detection to facilitate a pro-inflammatory response against the immunogen. The IL-18 gene mutations have been reported in multiple AD/AE studies and mutations in the antagonist receptor gene of another IL-1 family cytokine, IL-36, have been identified in another inflammatory skin disorder, psoriasis. ^{77 –80} These findings warrant further investigation not only into potential dysregulation of the IL-1 family of cytokine receptors but also continued investigation into T_H2 cytokines such as IL-4, IL-5, and IL-13.

The link between disease and heritable DNA alterations that do not directly alter the DNA sequence is at the forefront of modern biological research. Epigenetic modifications may affect DNA directly or the proteins that are associated with DNA and include methylation and acetylation. Epigenetic profiles are sensitive and can change in response to the environment, diet, and aging. ⁸¹ Nutrition or pollutant exposure during the perinatal period, a time of development, including that of the immune system, might have lasting, heritable epigenetic effects. ⁸² In a mouse model, developmental exposure to a diet high in methyl donors, including folic acid and vitamin B12, resulted in offspring with increased incidence of allergic inflammation. ⁸³ Furthermore, thymic stromal lymphopoietin (TSLP), which is produced by skin cells, has been found to play a key role in dendritic cell facilitated T_H2 responses associated with AD/AE. ⁸⁴ Overexpression of TSLP in the skin cells of those with AD/AE has been linked to the DNA demethylation of a TSLP regulatory region, a modification that would allow for prolonged gene transcription and thus a prolonged T_H2 response. ⁸⁵ Environmental tobacco smoke (ETS) exposure has been linked to the TSLP methylation defect, supporting the idea that genetics alone cannot provide an explanation for AD/AE prevalence. ⁸⁶

Environment: Developmental Exposures and AD/AE

One must also turn to the environment to understand many diseases and not only to direct environmental exposures but also to a consideration of the highly underappreciated developmental exposures. Since the advent of industrialization, many new chemicals have been introduced into our environment, most of which had not been extensively studied beforehand. Furthermore, paralleling industrialization, there has been a 2- to 3-fold increase in the prevalence of AD/AE in developed countries, encouraging an investigation of environmental factors and potential disease contribution. ^87,88

The in utero exposure to environmental factors is often overlooked in terms of its connection to allergic disease development. The prevailing mindset is one of which that if a substance doesn’t cause harm upon direct exposure, even if of a repeated nature, that further studies into its potential role in disease are unjustified. As the immune system develops in utero, factors that influence this development may have a long-term effect on the development of allergic disease. Although research in this area is limited and no clear-cut conclusions have been made, several types of in utero exposures have been implicated in the development of AD/AE in the resulting offspring. Two exposures of interest include ETS and phthalates.

Smoking is still a very popular cultural activity worldwide. In 2012, indoor pollution caused by agents such as ETS and airborne particulates accounted for approximately 4.3 million premature deaths. ⁸⁹ Furthermore, it is also concerning that over 100 different chemical substances in ETS have been linked to severe health problems. ⁹⁰ It has been shown that there may be a connection between the development of respiratory infections such as asthma in the offspring of mothers who had been exposed to tobacco smoke during pregnancy ^{91 –93} and that the timing of the in utero exposure is important in terms of disease development. ^94,95 Surprisingly, a Swedish study indicated that direct exposure to tobacco smoke contributes to preventing atopic disorders in both the smokers and their children. ⁹⁶ However, multiple studies have shown a link between in utero ETS exposure and the increased incidence of AD/AE in offspring. ^97,98 One study followed a cohort of 678 German preschool children prenatally exposed to maternal smoking or exposure through lactation. These exposures both correlated to the development of postnatal AD/AE. ⁹⁷ A study in Britain investigated a representative child cohort of children living in disadvantaged areas and those living in more advantaged areas, which were characterized by early life features including no smoking during pregnancy. This British study found that AD/AE was more common in more advantaged children, who were at less risk for prenatal and early postnatal exposures, such as ETS. ⁹⁹ However, support for the link between maternal ETS exposure and AD/AE specifically during development is still under debate as other studies could only significantly link in utero ETS exposures to an increased risk for allergic respiratory disorders in offspring, including asthma, ^100,101 while a Danish study using significant predictors of atopic diseases identified by logistic regression subsequently tested for the genetic modification of these predictors using variance components analysis; the study found no effect of maternal smoking during pregnancy on the risk of AD/AE or hay fever development in resultant offspring. ¹⁰² An investigation of the peer-reviewed literature reveals a paucity of studies examining a potential link between ETS and AD/AE development. Instead many studies are focused on investigating a potential link between ETS and asthma. Regardless, the potential link of ETS to allergic respiratory disorders, such as atopic asthma, warrants continued study of ETS as a developmental exposure that could contribute to AD/AE, as AD/AE has been shown to elevate risk for atopic asthma. ² The timing/extent of the exposure and an individual’s genetic makeup are likely to be critical factors involved in determining disease development and subsequent pathology.

Previously, HDM was addressed in the discussion of Matt gene mutations and the development of spontaneous AD/AE. Butylbenzyl phthalate (BBzP) is a component of HDM. ¹⁰³ Phthalates, such BBzP, are found in fertilizers and commonly utilized in plastics production to increase their flexibility, such as in vinyl flooring and in children’s toys. ¹⁰⁴ Developmental exposure to phthalates can occur via the aforementioned routes, through the processing/packaging procedures that many foods undergo, as well as through their inclusion in personal care products, such as cosmetics. ¹⁰⁵ Several studies have linked developmental phthalate exposure to AD/AE in children. An African American and Dominican cohort showed that the prenatal concentration of metabolite of BBzP found in a mother’s prenatal urine was associated with development of early-onset AD/AE in her children. ¹⁰⁶ In Poland, prenatal exposure to several phthalates, including BBzP, was found not only to increase the risk of food allergies but also AD/AE in the offspring. ¹⁰⁷ Investigation of another commonplace phthalate, bis(2-ethylhexyl) phthalate (DEHP), demonstrated that developmental exposure induced an AD/AE-like phenotype post-HDM sensitization, including the upregulation of an eosinophil-recruiting chemokine associated with allergic responses, eotaxin; eosinophils are a hallmark innate immune cell found in allergic disease. ¹⁰⁸ The DEHP is widely used in polyvinyl chloride products and is found in industrialized countries. Mechanistically, it appears that phthalates may induce IL-4 and IL-1 family cytokines, which, when taken together, is in line with the T_H2 pro-inflammatory cytokine response seen in AD/AE. ¹⁰⁹ However, as with many other environmental exposures, there are studies that find no relationship between developmental phthalate exposure and the development of allergic disease. It is evident that similar to other chemicals used in plastics, such as the more media-hyped bisphenol A, more clinical cohort studies are needed to solidify any links between in utero phthalate exposures and AD/AE development. The role of phthalate exposures during different stages of immune system development and the potential influence this may have on AD/AE is not well known. Only a handful of studies have investigated phthalates in the context of maternal exposure and specifically their impact on AD/AE. However, while research continues, the use of other confirmed-to-be-safe alternatives in manufacturing processes must be explored.

In very limited studies, several other maternal exposures have shown to have a possible link to the development of allergic diseases in offspring. Dexamethasone is a steroid used to treat a range of inflammatory conditions ranging from rheumatoid arthritis to chronic obstructive pulmonary disease to cancer. It is given to pregnant women who are at risk for giving birth prematurely to promote fetal lung development or if the fetus displays congenital adrenal hyperplasia (CAH), a condition which causes a variety of physical abnormalities in the fetus, particularly in formation of the female genitalia. In addition to being associated with low birth weight and possible cognitive issues, a very recent study has shown maternal dexamethasone exposure to be associated with the development of allergic disease, particularly asthma, as it enhances the IL-5 levels in preterm infants. ^{110 –112} This indicates that dexamethasone could potentially have an impact on AD/AE development as well. Other agents that are still being studied for their developmental impact on allergic disease are folic acid, prenatal maternal stress, marine pollutants, and antibiotics. ^{113 –116} Again, despite all these potential maternal exposure links, overwhelming study data that support their impact on the development of allergic disease, namely AD/AE, does not yet exist.

Treatment

As is the case with other allergic diseases such as atopic asthma, there are no cures for AD/AE. The disease provides an opportunity to target one or both of the contributing factors: skin barrier disruption and/or the allergic immune response. There are several disease management therapies that have been administered to individuals of all ages to treat AD/AE-associated flares, with an underlying hope that children affected by the disease early in life grow out of it with age. The most common topical treatments to date include skin moisturizers, or emollients, to be used liberally on a frequent basis, or in terms of targeting the immune response, prescription-based corticosteroid, and calcineurin-inhibition therapies. There are also more targeted biologic immunotherapies in development as well.

The dry, itchy skin that characterizes AD/AE emphasizes the importance of implementing management treatments that replenish epidermal lipid and water content. Emollients, by helping to reform a barrier in the skin, safely soften the skin and help it remain hydrated. ¹¹⁷ Emollients also may include supplemental antioxidant and antibacterial components which may aid in treatment, specifically by influencing the skin microbiome. ^118,119 Emollient use should be tailored on an individualized basis, but should incorporate as few additives as possible in order to avoid potential allergic reactions to components such as fragrance. ¹²⁰

The overall inflammation aspect of AD/AE is typically targeted first with topical corticosteroids. Proper use of topical corticosteroids per physicians’ recommendations has shown that effectiveness comes with little to no health risk as shown by a review of clinical trial data, although a side effect of repeated steroid use may include Cushing syndrome, a disorder that can result in bone loss, high blood pressure, and in some cases, type 2 diabetes. ¹²¹ Topical corticosteroids may differ in formulations and concentration, but as a general rule, long-term treatment in children favors lower potency corticosteroids, whereas short-term treatment of localized areas such as the face and thinner skin, where severe lesions may be prevalent, utilizes higher potency treatment. ^122,123 Topical corticosteroids may be used in combination with other treatments such as wet wrapping, which aims to keep the skin hydrated. ¹²⁴

Calcineurin inhibitors are often implemented as secondary, short-term treatments to topical corticosteroids, or as an alternative to such treatments. Calcineurin inhibitors do not cause skin atrophy, as found with some topical corticosteroid treatments, which are valuable features when treating delicate areas of affected skin. ¹²⁵ Calcineurin is serine/threonine protein phosphatase which is involved in T cell activation by activating an important transcription factor. In 2005, the US Food and Drug Administration issued a warning concerning the elevated risk of certain cancers that may be associated with long-term use of topical calcineurin inhibitors such as tacrolimus and pimecrolimus as there was a lack of long-term safety data. ¹²⁶ Although there have not been enough clinical studies to support this association, it is worth noting 1 very recently published Asian study which found the development of B cell acute lymphoid leukemia in pediatric patients with eczema who used topical tacrolimus; this association was significant in study participants aged 16 years or younger. ¹²⁷ Current clinical topical treatment utilizing calcineurin inhibitors such as ciclosporin can be used for 1 to 2 years, but ultimately the cessation of use causes disease pathology to return. ¹²⁸ Although the topic of safety frequently comes up with topical treatments for AD/AE, the overall data supports a favorable risk-to-benefit ratio until more long-term/effective treatments are developed.

Research and technological developments continue to elucidate more potential links to genes that may be involved in the disease pathways of AD/AE, many of which are involved in the immune response. Several biologic drugs are being developed which specifically target individual immune aspects, attempting to change overall disease course. The specificity of such drugs may also help eliminate any potential side effects, such as toxicity and transient effectiveness, linked with more broadly targeted immunosuppressive agents.

Dupilumab is a drug currently in phase trials that is aimed at the treatment of severe AD/AE in adults. AD/AE is driven by a pro-T_H2 response, characterized by pro-inflammatory cytokines such as IL-4 and IL-13. Dupilumab is a fully human monoclonal antibody that can specifically target and block the pathways of both cytokines, thus impeding the T_H2 response. A recent study incorporating patients with moderate to severe AD/AE from several countries showed the clinical efficacy of dupilumab without any significant safety concerns. ¹²⁹ It is worth noting that prior to studies on AD/AE, dupilumab demonstrated clinical effectiveness in moderate to severe atopic asthmatics, whereby it reduced levels of T_H2-associated inflammatory markers, reduced eosinophil levels, and improved overall lung function. ¹³⁰ It remains to be seen if dupilumab will be tested in infants/children, who make up a significant cohort of those affected with AD/AE. Regardless, the clinical success to date with this drug is promising for its future approval and implementation in the treatment for multiple allergy-based conditions. In contrast to specifically targeting an aspect of the T cell–mediated response found in AD/AE, other biologics specifically target aspects of the allergic B cell response.

Rituximab is an antibody against CD20, an antigen found on the surface of B cells. ¹³¹ The antibody-based blockade of CD20 on the B cell surface may impact B cells in multiple ways: It may induce B cell death via antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity, or by apoptosis. ¹³² Theoretically, a reduction in B cells should reduce overall IgE production and B cell antigen presentation, which lead to T_H2 cell cytokine and mediator release, as well as T cell–dependent B cell activation. ¹³³ A 2008 study showed promising results in patients suffering from severe AD/AE. After 4 weeks of treatment, up to 70% improvement in the Eczema Area and Severity Index score was seen in all patients, which remained constant for up to 24 weeks in 5 of 6 study participants. ¹³⁴ Furthermore, a pregnant woman with severe AD/AE lesions who received only a single dose of rituximab (1000 mg) showed a reduction in total body surface lesions from 90% to 5%; this drastic improvement was maintained for 17 months and induced no side effects. ¹³⁵ Although these aforementioned studies show the potential benefits of rituximab, it appears to be still be on a case-by-case basis, as in another study 2 patients with severe AD/AE were given 2 doses of 500 mg rituximab 2 weeks apart but showed no clinical improvement ¹³⁶ ; a more recent study continues to demonstrate this clinical ineffectiveness. ¹³⁷

Although CD20 impacts overall B cell levels, the elevated IgE levels found in AD/AE are not significantly affected by rituximab therapy in the aforementioned studies, as IgE-secreting plasma B cells do not express CD20. ^134,135 In this regard, consideration of other biologics, omalizumab and ligelizumab in particular, which specifically target circulating IgE, may be of use in combination therapy for 80% of the patients with AD/AE who showcase elevated IgE levels. ¹³⁸ Several other biologics are currently being investigated targeting IL-1, IL-5, IL-22, IL-31, or TSLP. ¹³⁹

Probiotics are microorganisms, such as bacteria and yeast, that are introduced into the body for a beneficial purpose. ¹⁴⁰ There is limited evidence for a connection between the gut microbiome and allergic disease, via the previously mentioned inside-outside model of AD/AE, hence why probiotics may provide benefit. Probiotics have been shown to suppress the T_H2-mediated allergic responses seen in AD/AE, thus contributing to a T_H1/T_H2 balance and an increase in the population of regulatory T cells. ^141,142 An epidemiological study conducted in Norway involved administration of probiotic milk products during pregnancy/infant periods and observed that the probiotic intake correlated to a reduced incidence of AD/AE in the offspring. ¹⁴³ Another study administered the bacterium, Bifidobacterium longum BB536, beginning at 1 month prenatally and continuing postnatally through 18 months. The study concluded that the AD/AE incidence in B. longum BB536 administered participants was lower than in any of the controls used. ¹⁴⁴ There are still many lesser understood considerations about the potential clinical use of probiotics, including timing, type/strain of probiotic, route of administration, duration of treatment, and diet. Furthermore, a study published in late 2016 of 250 mother–child pairs revealed that a beneficial effect of probiotic therapy may be dependent on the intrinsic gut microbes at early infancy. ¹⁴⁵

Conclusions

AD/AE continues to be a global disease that affects individuals of a wide age from the defining standpoints of skin barrier disruption and an inappropriate immunological response profile. Its potential links to developmental exposures are sorely underinvestigated, but are very important to understand so that the best strategies can be formulated against the origins of the disease, especially in the 8.8 million children believed to be plagued by skin allergies, a population that due to their age also faces the most difficulty managing the disease; the overwhelming majority of these children are between the ages of a few months up to age 4. ¹⁴⁶ AD/AE’s impact on quality of life can be severe, as the itch it causes, at minimum, distracts from sleep and day-to-day activities. Furthermore, infants with AD/AE are prone to an increased risk of developing other disorders, including atopic asthma, inflammatory bowel disease, and rheumatoid arthritis. ¹⁴⁷ AD/AE is a complex disease involving multiple genetic and environmental factors, with much yet to be elucidated concerning the mechanism(s) involved. Progress is continuing to be made on identifying all the key genes involved, including their polymorphisms and epigenetic profiles, in lieu with implicated environmental factors. One day, we may not able just to manage, but hopefully prevent/cure this allergic disease through personalized, subtype management strategies that focus on a defined disease mechanism.