Mechanisms
Atopic dermatitis (AD), commonly known as eczema, is a chronic skin disorder associated with skin barrier dysfunction that is characterized by dry, itchy skin (pruritus). Interleukin-31 (IL-31) secreted by T-helper 2 (T
H2) cells induces the itchy symptoms. The role of IL-31 in the pathogenesis of AD and novel therapeutic strategies targeting its receptor have been recently reviewed [
4].
AD patients have an altered skin microbiome composition characterized by an increased colonization of
Staphylococcus aureus (
S. aureus) which is associated with disease severity. In addition, AD patients have a reduced expression of toll-like receptor-2 (TLR2) receptors in Langerhans cells (LC) and inflammatory dendritic epidermal cells (IDEC) compared to healthy controls [
5]. Ex vivo human skin models were treated with the TLR2 ligand Pam3Cys, a mimic of
S. aureus. In contrast to healthy skin, LC and IDEC lacked maturation and had a strong spontaneous migratory activity. The supernatant of AD skin showed significantly reduced levels of IL-6 and IL-10 and an overexpression of IL-18.
A novel mechanism involved in epidermal barrier dysfunction was recently reported in a mouse model of allergic inflammation and in AD patients [
6]. It was found that IL-24 downregulates filaggrin expression and is produced in keratinocytes by the stimulation of IL-13 in a periostin-dependent manner. Elevated levels of IL-24 and activated STAT3 were found in the epidermis of the mouse model and of AD patients.
The role of the pruritogenic mediator endothelin-1 (ET-1) in the pathogenesis of AD was recently investigated in mouse bone marrow-derived dendritic cells (BMDCs) [
7]. ET-1 was significantly upregulated in the epidermis of AD patients and stimulated the production of Th1 and Th17 cytokines from BMDCs in a concentration-dependent manner. This switch to a Th17/Th1 response may contribute to the chronic lesions in AD patients.
Studies in a human AD-like mouse model revealed novel mechanistic insights that support a link between cell infiltration of the hypodermis to local mast cell activation and elevated levels of sphingosine-1-phosphate (S1P) after antigen exposure [
8]. Neuromedin U (NMU) released from keratinocytes induces the degranulation of mast cells via pertussis toxin-sensitive G protein-coupled receptors [
9].
Exposure to air pollution aggravates the symptoms of AD in children in the population studies. Variability in the individual patient’s response from individual susceptibility needs to be explored. In 89 children aged 0–6 years with AD, daily manifestation of symptoms was recorded for an average of 257 days and confronted to pollution levels [
10]. In the overall analysis, ozone, particulate matter < 10 μm (PM
10), NO
2, SO
2, and CO had a significantly positive association, whereas temperature and relative humidity were negatively associated with AD symptoms. However, responses of AD children to air pollution and weather variables were inconsistent among individuals.
Epidemiologic studies
Earlier studies have shown an association between the month of birth and the severity of atopic dermatitis. In one study, Armenian children were investigated for the severity of their eczema in relation to the month of birth. It was found that children born in the winter had more severe eczema. The authors hypothesized, in relation to earlier findings, that the severity of eczema could be related to an early exposure to common environmental allergens [
11].
Data of the epidemiology of atopic dermatitis were collected in an online survey from patients in the US, Canada, France Germany, Italy, Spain, UK, and Japan [
12]. The respondents were characterized and selected if they met the UK Working Party/ISAAC criteria and had been previously diagnosed by a physician. There was a decreased prevalence of AD with age and, except for the US, a higher prevalence among women. Only a small portion suffered severe AD across all regions. The severity of AD varied according to the different assessment scales used (Patient-Oriented SCORAD, Patient-Orientated Eczema Measure, and Patient Global Assessment).
The plan for the Preventing Atopic Dermatitis and ALLergies (PreventADALL) in children study has been recently reported [
13]. Its main objectives are the prevention of allergic diseases by assessing early-life risk factors, including microbial diversity, diet, lifestyle, and gene–environment interactions, using simple cost-efficient strategies. Children born by cesarean section and by assisted birth are at an increased risk of developing flexural eczema in childhood/early adulthood [
14].
There are limited and conflicting reports on the long-term clinical course of AD. A systematic review and meta-analysis of 2080 references and 7 birth cohort studies with a total of 13,515 participants indicated that there is a similar prevalence of AD in childhood and adolescence [
15]. Undergoing thymectomy in early childhood was associated with a reduced risk of AD but was only statistically significant in a model where time-dependent changes were not included [
16].
Severity scores
Reliability and validity of the AD Symptom Score (ADSS) were studied in 307 children and adolescents with AD [
17]. Parents or caregivers were asked to record daily symptoms of the patients (itching, sleep disturbance, erythema, dryness, oozing, and edema) using a scale of 0–4. The ADSS was found be a useful tool for the self-assessment of skin symptoms in children with AD.
A recent study has validated the use of patient-reported AD severity assessment using a single question with a simple scoring system of mild, moderate and severe [
18]. The responses from 265 adult patients significantly correlated with other outcome measures, including oSCORAD, SCORAD, EASI, BSA, NRS-itch, POEM, and DLQI, and were further confirmed by a dermatologist.
Multimorbidities
The association between AD and cardio-metabolic risk factors is not fully understood, partly due to the lack of validated questionnaire-based methods to identify adults with AD. In an attempt to investigate the association of cardio-metabolic risk factors in AD patients, data collected from 9656 Danish adults were analyzed using three different cardiovascular risk questionnaires [
19]. There was a large discrepancy in the results from each questionnaire and so a definite conclusion could not be reached. These results highlight the need for clinical diagnosis of AD by a dermatologist and the fact that responses from questionnaires should be carefully interpreted.
In a nationwide, population-based cohort study (Taiwan’s National Health Insurance Research Database), the association between obstructive sleep apnoea (OSA) and AD was sought in 120,736 children [
20]. This study revealed an increased risk of obstructive sleep apnoea in children with AD. Therefore, comprehensive evaluation and aggressive risk reduction for obstructive sleep apnoea are recommended in these patients.
AD can significantly impact quality-of-life to the point that it can affect mental health. Data collected from the Danish health registry and a population-based questionnaire indicated that AD patients had an increased risk of mild anxiety, depression and suicidal ideation compared to non-AD subjects but did not result in psychiatric hospitalization or suicide [
21]. Early antihistamine exposure for the treatment of AD was associated with increased attention-deficit/hyperactivity disorder symptoms in children aged 6–12 years. The study questionnaire asked parents whether their child had used systemic antihistamines to treat AD but did not distinguish between sedating and non-sedating H1-antihistamines. The authors noted that there is a need to further investigate the role of sleeping problems and its treatment with (sedating) antihistamines in young children concerning early-life development and the potential risk for ADHD in children with AD [
22].
Prevention and treatment
The protective effect of the Bacillus Calmette–Guerin (BCG) vaccination to reduce the risk of allergic diseases, including AD, is unclear. A recent study from the Danish Calmette (2012–2015) found that the clinical outcome of the BCG vaccination differed for children with and without atopic predisposition [
23]. The cumulative incidence of AD was reduced by 16% in infants with an atopic predisposition. Oral antigen administration in mice has a protective effect against AD by promoting the increased expression of genes involved in the regulation of Th2 inflammatory responses and skin barrier function [
24].
A randomized, double-blinded, placebo-controlled trial assessed the effects of melatonin administration on disease severity and sleep quality in 70 children with AD [
25]. Overall, melatonin supplementation had beneficial effects on disease severity, serum total IgE levels, and on the Children’s Sleep Habits Questionnaire (CSHQ).
The efficacy of allergen-specific subcutaneous immunotherapy (SIT) as a curative treatment for atopic dermatitis remains controversial. A murine model was established to investigate the clinical efficacy of SIT [
26]. The DfE-treated NC/Nga mice showed clinical, histological and immunological improvement with elevated levels of IL-10 producing Treg cells and NK cells.
The potential use of superoxide dismutase 3-transducer (SOD3) mesenchymal stem cells (MSCs), as a novel cell-based therapy for AD, was demonstrated in a mouse model of OVA-induced AD-like skin inflammation [
27]. Mice with AD that received a subcutaneous administration of SOD3-MSCs showed an improvement of skin thickening and inflammation compared to control mice. The reduced skin inflammation was attributed to the inhibition of the histamine H
4 receptor, MAPK/NFkB activation and JAK/STAT signalling.
Maternal exposure to a farming environment protects newborns against allergic diseases including AD by modulating the neonatal TLR-Tregs-Th axis [
28].
In cats and dogs, there are pathogenetic similarities with human AD. This is often a difficult disease for animals and their owners [
29].