Applied Research on Atopic Dermatitis with Special Emphasis on the Role of Emollients in This Disorder: A Review

Abstract

Atopic dermatitis is a chronic and multifactorial inflammatory dermatosis. Recurrent eczematous lesions and intense pruritus very often reduce the quality of life of patients, affecting their mental health. For this reason, it is necessary to undertake treatment. Treatment should be characterized by an individual approach to the patient, taking into account the predominant pathogenetic factors in the development of atopic dermatitis and systematic skin care. Soothing the typical symptoms of AD, i.e., dry skin and persistent itching, involves emollients, which counteract xerosis and reduce the feeling of itching. Studies confirm that the regular use of emollients in patients with AD prolongs the period between relapses and alleviates the intensity of symptoms during periods of disease severity. This review paper aims to highlight the challenges that patients with atopic dermatitis face. This work will also present an indication of the rationale for the use of emollients in this condition, as well as an indication of the forms of their application in therapeutic and care preparations.

1. Introduction

Atopic dermatitis (AD) is a chronic inflammatory dermatosis [1,2,3]. Damage to the epidermal barrier can occur for a variety of reasons, whether genetic, environmental or immunological [3,4,5] (Figure 1).

Skin barrier defect is a key element in the course of atopic dermatitis [7]. It consists of abnormalities of the stratum corneum, disorders of tight junctions or antimicrobial peptides [7,8]. The aforementioned elements are responsible for the clinical manifestations of patients with AD such as dry skin. This parameter in turn generates increased transepidermal water loss (TEWL), facilitates the penetration of allergens and disrupts the microbial balance of the skin surface [7,8]. The genetic determinants of AD include a mutation of the filaggrin structural protein (FLG) [7]. The authors of [9] report that the effect of mutations in the filaggrin gene predisposing to atopic dermatitis was noted in 2006. The role of this protein is primarily based on maintaining the structure of the epidermis by synthesizing molecules that retain water. Filaggrin deficiency results in keratinocyte abnormalities and causes impairment of the epidermal barrier, which allows exogenous molecules to penetrate the epidermis [9]. Mutations in filaggrin occurring in C-terminal repeats cause a significant reduction in filaggrin in the epidermis of AD patients. This is because the C-terminal region is essential for the proper processing of profilaggrin into filaggrin [10]. Abnormalities in filaggrin synthesis reduce the amount of natural moisturizing factor and cause an increase in skin pH as a result of the decreased production of transurocapnic acid [11]. Another factor in the defect of the skin barrier is a decrease in cutaneous ceramides, which results in a decrease in TEWL and increases the possibility of allergens and microorganisms penetrating deep into the skin [6] (Figure 1).

According to statistics, the incidence of AD is steadily increasing [1]. According to the Global Report on Atopic Dermatitis 2022, about 223 million people worldwide struggle with AD [12]. Atopic dermatitis affects about 25% of children [11]. During the first years of a person’s life, the prevalence of the disease is comparable in both sexes; it is only after the age of six that the diagnosis of atopic dermatitis increases in females [11]. In a retrospective study that was conducted in South Korea, atopic dermatitis was diagnosed in 944,559 children and in more than one million adults (1,066,453) [2]. In contrast, according to a compilation of information in a publication [7], 3.91% of children in Poland suffer from AD.

The primary goals of treating atopic dermatitis are to reduce inflammation, decrease pruritus or redness and restore the normal skin barrier [13]. Therapeutic strategies in the treatment of AD target the skin—that is, skin care and topical medications, most commonly corticosteroids (ICS) or calcineurin inhibitors. The mainstay of atopic dermatitis treatment used for more than 60 years has been topical corticosteroids [14]. This is because they exhibit anti-inflammatory, antiproliferative and immunosuppressive effects, as well as antipruritic effects [11]. Medium- and high-potency steroids, such as triamcinolone acetonide 0.1%, are used to treat acute inflammatory lesions. In contrast, lower-potency steroids are used on areas covered by a thinner layer of skin, such as the eyelids, facial skin or genitals, because of the risk of atrophy. In a situation where skin lesions occupy more than 20%, general corticosteroid treatment is implemented [11,15,16]. As noted by the authors [17], long-term use of steroids has been associated with many side effects such as rosacea, acne-like rashes, skin atrophy and telangiectasias. A summary of various therapeutic strategies is presented in

Table 1. Summary of therapeutic strategies for atopic dermatitis for all age groups [18,19].

Treatment In Atopic Dermatitis:
Dependent on the severity of AD	During exacerbations—topical application of corticosteroids (hydrocortisone, prednisolone) and calcineurin inhibitors (pimecrolimus and tacrolimus)
Maintenance (for chronic lesions or periodic exacerbations)	Periodic use of topical corticosteroids and calcineurin inhibitors (to prevent recurrence of skin inflammation)
Severe forms	Treatment of the severe form, which is refractory to classical therapeutic strategies—phototherapy, high-potency topical corticosteroids, oral steroid therapy, biologic drugs (Dupilumab), immunosuppressive drugs such as azathioprine, cyclosporine A, mycophenolate mofetil (MMF), psychotherapy
Accompanying	Avoidance of exacerbating factors (desensitization may be attempted), antibiotics (in case of bacterial superinfections, usually S. aureus), antivirals (acyclovir or valacyclovir during Herpes simplex virus superinfections in the form of herpetic eczema), antifungals, antihistamines and sedatives (in case of high intensity of pruritus), phototherapy, psychological help
Supplementary	Continuous use of emollients, even if there are no obvious inflammatory changes on the skin (during periods of remission)

.

Products that reduce the use of steroids in the treatment of AD are emollients, which, according to the authors of [20], have significantly reduced the need for patients to use corticosteroids. The authors of [21] report that the use of emollients is associated with numerous beneficial effects, such as reducing the number of AD exacerbations, prolonging remission periods, reducing eczematous lesions and reducing the amount of corticosteroids needed to achieve a similar therapeutic effect. It has been confirmed that emollients in combination with active treatment (among other steroids) produce significantly better results than steroids alone [21]. Currently, the typical therapeutic strategy undertaken in patients with atopic dermatitis is the simultaneous use of glucocorticosteroids and emollients [21]. One method that combines emollients and steroids is the use of wet-wrap treatment. It involves applying two layers of dressings to the skin. The inner layer is saturated with emollients and a glucocorticosteroid, while the outer layer remains dry. Wet-wrap treatment reduces the sensation of pruritus, cools the skin and prolongs the sensation of hydration, while the use of topical glucocorticosteroids in wet dressings increases their absorption from the skin surface [10]. Emollients achieve the greatest efficacy in mild forms of AD [4,22]. Studies confirm that the concomitant use of glucocorticosteroids during exacerbations and maintenance of regular skin care with emollients can beneficially manage atopic dermatitis and prevent exacerbations [20]. Their action is based on restoring the integrity of the epidermal barrier, which counteracts xerosis and reduces persistent itching, which is one of the most troublesome symptoms. They are commonly used to treat various disorders such as psoriasis, keratosis disorders and xeroderma [4,22]. Emollients can be used either as creams, emulsions or lotions, or as a form of bath preparation as shower gels or shampoos [1].

The use of emollient-like ingredients has been popular since ancient times. The use of substances such as honeys or natural oils, among others, in treatment was already known in ancient Egypt, Rome and China [1,5]. Most likely, the first known description of a patient with AD was created by Gaius Svetonius Tranquillus, and the patient was the famous Emperor Octavian Augustus [5]. This information confirms that atopic dermatitis is a disease that people have faced since the dawn of time. It is for this reason that today, on the basis of accumulated knowledge, we are able to develop more and more targeted and effective therapy for patients with atopic dermatitis [1,5]. Previous studies confirm the effectiveness and safety of emollients for both children and adults. The systematic application of emollients to the skin can reduce the frequency of glucocorticosteroid applications in patients diagnosed with AD [1]. Numerous studies [4,23,24] also prove that the use of emollients from birth can have a preventive effect and thus prevent the development of atopic dermatitis in children with the aforementioned risk factors. The authors of [25] indicate that this risk is reduced by up to 50%. This is primarily due to the restoration of the epidermal barrier, which in turn results in reduced transepidermal water loss [25,26,27]. A parameter that has a beneficial effect on the skin after the use of emollients is the reduction in skin pH [28,29]. Studies have confirmed that acidic skin pH contributes to improved skin barrier function, and its higher values correlate with the course of AD [1,28,29]. For the above reason, the pH of washing products should be in the range of 5-6, since the acidic reaction of the preparations, as mentioned in the article, has a beneficial effect on the skin, without violating the skin barrier [24].

The physiological pH of the skin assumes values <5.0; this has a beneficial effect on the skin’s protective microbiota and supports the maintenance of a normal skin barrier [30]. In progressive AD, the skin barrier is often damaged, increasing the pH of the skin surface and facilitating the proliferation of pathogenic bacteria (such as Staphylococcus aureus) [30], which is highlighted in Figure 1 as a factor affecting skin barrier damage. In general, this is important in the context of the overall treatment of atopic dermatitis in the course of which there is a deficiency of valuable intercellular lipids of the stratum corneum, as well as defects in the filaggrin protein [24]. Any changes in this context in the aforementioned components result in increased transepidermal water loss [24]. The use of emollients should be a key and first line of treatment; it should also take into account the pathogenesis of AD and be a treatment that is clearly personalized and targeted to the individual patient [2,31].

2. Characteristics of Atopic Dermatitis: Types and Clinical Symptoms

Recent studies suggest that atopic dermatitis, as a heterogeneous and multifactorial disease, can be classified into different types. Taking into account all the classifications that have been created to group patients with AD, clinical features and the results of biochemical markers can be indicated as common criteria [2,12,32]. These include clinical symptoms, the state of the epidermal barrier, the level of IgE immunoglobulin in the blood and demographics such as age, gender or ethnicity [2,12,32].

The first such diagnostic criteria for AD were published by Hungarian dermatologist Georg Rajka [5]. Hanifin and Rajka’s criteria, which were published in 1980, are still widely used for diagnostic purposes [33]. They were developed based on clinical experience and the consensus of experienced dermatologists, but without objective clinical validation [34]. To diagnose atopic dermatitis in a patient, he or she should meet three of the four so-called “major” (main) criteria and three of the twenty-three “minor” (secondary) criteria [33] (

Table 2. Diagnostic criteria of atopic dermatitis according to Hanifin and Rajka based on [35].

“GREATER” CRITERIA	“LESSER” CRITERIA
Itching of the skin	Dryness of the skin
Chronic and recurrent course of the disease	Positive results of point skin tests
Typical location of skin lesions	Fish scale or follicular keratosis
Atopy in the patient or family history	Dennie and Morgan’s sign (eye fold)
	Darkening around the eyes
	Increased IgE levels
	Early age of onset of lesions
	Recurrent skin infections
	Non-specific hand and/or foot eczema
	Nipple eczema
	Cheilitis
	Recurrent conjunctivitis
	Corneal cone
	Subcapsular cataract
	Anterior cervical fold
	White dermographism
	Food intolerance
	Itching of the skin after sweating
	Wool intolerance
	White dandruff
	Highlighting of hair follicles
	Facial erythema
	Exacerbation after stress

).

It is noteworthy that only seven of the twenty-three minor criteria are due to immunological disorders, supporting the statement that atopic dermatitis is a multifactorial disease [33].

Currently, the most widely used scale that assesses both objective and subjective symptoms of atopic dermatitis is the SCORing Atopic Dermatitis Index (SCORAD) [36]. It was developed by the European Task Force on Atopic Dermatitis (ETFAD) in 1993. The severity of skin lesions is assessed based on six criteria: erythema, edema, oozing or scabs, lichenization and dry skin (ranging from 0, i.e., no lesions, to 3, i.e., the most severe lesions) [36]. Subjective symptoms (severity of pruritus and sleep disturbance), on the other hand, are assessed on an analog scale (0 to 10). Based on the above criteria, atopic dermatitis is assessed as mild (less than 25 points), moderate (25–50 points) and severe (>50 points) [36,37]. Numerous studies [36,37,38,39] on the validation of the SCORAD scale have confirmed that it is a reliable method in both clinical trials and daily medical practice. The SCORAD scale is sensitive to changes, easy to interpret and has good reproducibility in both the examination and diagnosis of children and adults with different courses of atopic dermatitis [36,37,38,39].

The classification distinguishes between external and internal subtypes of atopic dermatitis. The external subtype is characterized by high serum IgE levels and eosinophilia. In addition, there is an increase in the filaggrin mutation rate in the skin of these patients. The external subtype of AD often coexists with other allergic diseases [32,40]. In a study conducted by the authors [41], it was found that about 35% of children with moderate to severe atopic dermatitis also have another type of food allergy. In contrast, the intrinsic subtype of AD occurs with normal serum IgE levels. It is most common in women and has no atopic background [32,40].

Another classification can be a division that distinguishes between acute and chronic subtypes of AD. We can group atopic dermatitis by ethnic difference [40]. Tests have been conducted that analyzed the Asian endotype of atopic dermatitis. They showed increased TH17 levels in the blood and severe eczematous skin lesions in Japanese atopic dermatitis patients. The study [42] proved that TH17 lymphocytes were more markedly increased in acute eczematous lesions than in chronic conditions. In addition, TH17 lymphocytes were found to be the initial source of pro-inflammatory cytokines that led to eczematous skin lesions. In contrast, the European endotype showed no TH17 activation [40]. This indicates that Asian patients with atopic dermatitis are characterized by its unique subtype, which is based on immune dysfunction [40].

Determining a patient’s atopic dermatitis subtype is crucial to achieving favorable therapy outcomes. It also helps in the development of personalized treatment strategies [2,40]. Pruritus is a common and dominant feature of most subtypes of atopic dermatitis. It causes scratching, which worsens inflammation and can lead to bacterial superinfection, among other things. This condition is called the “Itch-scratch-itch cycle” [1,23,43,44,45] (Figure 2). Frequent bacterial or viral infections in AD patients are related to disorders of non-specific immunity, which are associated with a defective role of neutrophils [15].

Skin lesions in the course of atopic dermatitis are typically eczematous, characterized by papules, vesicles and sometimes scabs. The skin in the area is characterized by marked dryness and flaking [12,23].

3. Phenotypic and Endotypic Differences among Children and Adults with AD

The appearance of lesions and their localization in the course of atopic dermatitis varies depending on the age group. However, the basic features of AD—the presence of atopy and xerosis—are similar in both adults and children [46]. Most often, in infants and children, inflammation and lesions appear on the face, trunk and around the extensors of the lower and upper extremities, and in advanced cases even throughout the body. In adults, on the other hand, the lesions occur in the flexor region, neck, ears, around the eyes, and are more chronic in nature. A typical feature of the condition is dark red erythema on the face and neck [12,32,40]. From the data presented by the researchers in [47], it can be seen that 85% of AD cases manifest themselves before the age of five, thus indicating the greatest severity of symptoms among the younger population [47,48]. The data presented are consistent with population-based studies conducted in the United States, where the prevalence of atopic dermatitis in children was 10.7% and in adults 7.2% [48]. Atopic dermatitis can develop de novo in adulthood (about 25%), and in children AD can resolve before the age of five [11]. However, according to the authors [11,49], one in five pediatric patients with AD will develop symptoms of atopic dermatitis in adulthood. The authors of [32,40] report that a disorder of the immune system, which is not fully developed in the first weeks and months of life, is responsible for atopic lesions in younger patients. Initially, most T lymphocytes are immature and only gradually develop into memory cells [50]. Studies [50] show that immune changes, including T-cell activation and differentiation, occur more rapidly in children with AD. This indicates accelerated activation of these cells, faster differentiation into specific subsets (TH1, TH22, TH17) and the influence of environmental and genetic factors, as well as chronic skin inflammation [40,50,51]. Studies conducted to evaluate lymphocyte levels in newborns with atopic dermatitis have shown low levels of TH1 lymphocytes and high levels of TH2 in cord blood [40,51]. Epigenetic factors are responsible for the above condition, supporting the statement that atopic dermatitis is a typical multifactorial disease [40,51] (Figure 1).

Another study [40] on blood flow cytometry confirmed the delayed development of TH1 lymphocytes populating the skin of children with AD compared to healthy children. Increased blood concentrations of TH2 lymphocytes in both adults and children with AD are noted as a common feature [40].

The authors of [40] indicate that the number of tight junctions between epithelial cells in the skin is reduced and the expression of lipid barrier genes is decreased in children with AD. According to the authors of the above study, this has the effect of exacerbating the epidermal barrier defect in patients with atopic dermatitis despite normal levels of filaggrin protein in the skin [40]. A comparative study was conducted for three age groups (18–40, 41–60 and over 61) of atopic dermatitis patients [40]. The study observed that with age there is a decrease in TH2/TH22 levels with a concomitant increase in TH1/TH17, with a normalized epidermal barrier, which is a differentiating feature for AD occurring in adults compared to that in children [32,40]. Other differences in the course of AD in children and adults are presented in

Table 3. Endotypic and phenotypic and therapeutic differences in atopic dermatitis in children and adults based on [19,40,51,52].

AZS Feature	Children	Adults
Distribution of changes	Face, torso, upper and lower limb extensor area [40,51] Diaper dermatitis is common in infants [19].	All body areas up to 30–40 years of age predominance of lesions in the folds and skin folds [19]
Morphology of the lesions	Inflammation [40,51,52]	Lichenoid, dry lesions [40,51,52]
TH2/TH1 severity	High levels of TH2 in blood and skin, low TH1 [40,51]	TH2 lymphocytes predominate in the early stages of the disease, while TH1/TH17 increases with age [40,51].
Epithelium and lipid barrier	Decreased function, pronounced barrier defect [40,51]	Retained function, less pronounced defect [40,51]
Therapeutic strategy	Therapies that are used in psoriasis can be effective [40,51].	Therapy targeting the skin barrier in earlier stages [40,51]

. The study [32,40] and also the study conducted by the authors of [51] indicated that therapy that is tailored to the age and specific stage of the disease is of great importance.

4. Components of Emollients and Their Effect on the Changes That Occur in Atopic Dermatitis

Most emollient products are based on humectants such as urea, glycerol or sorbitol. These ingredients promote hydration of the stratum corneum, reducing inflammation caused by AD [1,7,23,53]. Inherent in their composition is an occlusive substance, whose main function is to retain water, and prevent it from evaporating from the skin surface [1,23,53]. Occlusive ingredients in emollients, such as Vaseline, can improve skin barrier function and inhibit the production of pro-inflammatory cytokines [12,53]. Petrolatum, paraffin or mineral oils provide protection against adverse external factors and reduce TEWL [7]. Many emollients contain vegetable oils such as olive oil, coconut oil or avocado oil [53]. The authors of [7] state that components of emollients also include substances that seal the skin barrier, such as ceramides, cholesterol and fatty acids. Emollients by composition can be divided into two main groups: neutral emollients (containing only occlusive substances) and active emollients, which are divided by their profile of action—moisturizing and soothing [54]. Currently, an additional group of emollients is distinguished—emollient “plus”—which is included in the figure below [12,54] (Figure 3).

Until recently, emollients did not contain additional active ingredients. Currently, “plus” emollients are used, whose composition is enriched with active ingredients [12]. The most commonly used active substances are as follows: flavonoids—saponins, riboflavin with extracts from young oat shoots and bacterial lysates from species such as Aquaphilus dolomiae or Viteoscilla filiformis [12,20,24]. There are also other substances that have beneficial effects on skin lesions in AD; for example, chamomile added to emollients has an anti-inflammatory effect due to the presence of apigenin, an ingredient that relieves symptoms of atopic dermatitis [53]. Emollients have anti-inflammatory properties if substances such as glycyrrhizinic acid, allantoin or D-panthenol are present in their formulation [19]. On the other hand, emollients with added camphor or menthol have antipruritic properties [19]. The authors of the papers [55,56] assure that the use of emollients with additives such as colloidal oats, avenanthramide or ceramides strengthens the skin barrier and is well tolerated in different age groups. Other researchers [20] emphasize that emollients “plus” restore normal microbial diversity in patients with mild to moderate AD. In their view, this is important because low microbial diversity and excessive colonization with Staphylococcus aureus leads to exacerbations and aggravation of atopic dermatitis. As evidenced by the studies [20,57], emollients supplemented with non-pathogenic Vitreoscilla filiformis bacteria reduce the severity of clinical symptoms as assessed by SCORAD, and also reduce pruritus in patients with AD. Another comparative study [58], which was conducted on a group of 60 patients with moderate AD, found that an emollient “plus” supplemented with Vitreoscilla filiformis bacteria normalized the skin microbiota and reduced the number and severity of eczematous lesions in AD compared to a traditional emollient. The authors of [57] confirm that Vitreoscilla filiformis is an extract that contains essential nutrients for cells and the skin microbiota. According to the aforementioned authors, it has optimal bio-affinity to the skin and mimics the action of beneficial skin microorganisms. Emollients that are enriched with certain vegetable oils—in particular sunflower, borage, corn or sea buckthorn—are beneficial due to the presence of essential fatty acids such as gamma-linolenic acid, linoleic acid, oleic acid, stearic acid, palmitic acid or medium-chain fatty acids (MCFA) in coconut oil [53,59]. The authors of [60] emphasize that natural oils such as sunflower oil, sesame oil and safflower seed oil have been used to restore skin barrier homeostasis. According to studies [7,53], they can improve skin barrier function, thereby reducing inflammation (by activating receptors through peroxisome proliferators). In addition, they help restore microbial homeostasis on the skin surface [7,53]. Restoring microbial balance is important because the stratum corneum is damaged in AD, which is caused by increased levels of endogenous and exogenous stratum corneum chymotryptase enzyme (SCCE), a protease produced by house dust mites or streptococci, among others [15]. This explains why the majority of patients with AD have a co-occurrence of IgE-mediated allergic reactions to airborne allergens which include house dust mites [15].

Table 4. Selected natural ingredients of emollients—action and their effectiveness.

Active Ingredient of Plant Origin	Properties of the Ingredient	Selected Studies Conducted on a Particular Ingredient towards Confirmation of Beneficial Effects on AD	Confirmation of the Properties and Validity of the Indicated Ingredient in AD—Conclusions of the Study
Aloes (Aloe vera)	It has moisturizing, antibacterial and antifungal properties, which can prevent the superinfection of skin lesions in patients with AD [59]. According to the authors of [61], saponins are responsible for the strong antiseptic properties of aloe vera gel. In addition, the presence of salicylic acid shows anti-inflammatory and antibacterial effects. The presence of magnesium lactate in aloe vera gel is responsible for inhibiting the activity of histidine decarboxylase, which reduces the synthesis of histamine (responsible for allergic reactions, pain and itching) [61].	In 2010 and 2015, two animal model studies were conducted during which the effects of aloe vera on IgE levels were examined in animal models of atopic dermatitis. In a group of Balb/c mice with atopic dermatitis that received topical application of aloe vera extract for 10 days, a reduction in serum IgE levels was noted compared to the control group [59].	The results of the study confirm that the medicinal properties of aloe vera may vary depending on its form (fresh aloe vera, gel form, etc.) [59,62]. Freshly prepared aloe vera is more beneficial, while the gel form is enzymatically or microbiologically sensitive [59,62].
Coconut oil (Cocos nucifera L.)	The properties of this oil depend on the pressing method. Virgin coconut oil is considered a better form because the fatty acids are not lost through the processing [59]. Coconut virgin oil is extracted from the fresh and ripe flesh of coconut palm nuts [63]. The authors [63] confirm that virgin coconut oil exhibits anticancer, antimicrobial or anti-inflammatory properties in in vivo studies.	Two clinical trials have been conducted to evaluate the effects of virgin coconut oil on patients with atopic dermatitis [64]. In an in vitro study [63], the effect of virgin coconut oil on reconstructed human epidermal cells was evaluated. The above study showed that topical application of virgin coconut oil had an anti-inflammatory effect (inhibited the activation of pro-inflammatory cytokines such as IL-6, TNF-alpha and IFN-gamma), The authors [63] also confirmed the effect of virgin coconut oil on improving the skin barrier by increasing the synthesis of filaggrin, among other things.	Both studies confirmed the effect of coconut oil on reducing the severity of eczematous lesions in AD [64]. A study [63] confirmed the softening and moisturizing effects of coconut oil for mild to moderate dry skin in patients with AD. The authors of the above study proved that the use of virgin coconut oil is effective in the treatment of skin diseases with dermal–epidermal barrier dysfunction and reduced the expression of structural proteins.
Oat (Avena sativa L.)	It soothes feelings of itching and irritation. Due to the presence of avenanthramides, oatmeal exhibits anti-inflammatory and antioxidant effects [62].	Clinical studies [62] conducted to evaluate the effects of oats on eczematous lesions have shown a reduction in skin redness, dryness, scaling and pruritus after applying oat extracts to the skin.	Oats used in colloidal form as an ingredient in emollients significantly reduced dry skin. According to the authors of [62], colloidal oats reduced the intensity of pruritus. These results confirm the anti-inflammatory and antioxidant effects of colloidal oats in the skin care of patients with AD [62].
Sunflower oil (Helianthus annuus L.)	It contains a high concentration of fatty acids such as linoleic acid, linolenic acid, oleic acid, palmitic acid and stearic acid [65]. According to the authors of [65], refined sunflower oil contains about 90% essential fatty acids (EFAs). According to the authors of [52], EFA deficiency in patients with atopic dermatitis causes an increase in skin barrier permeability, resulting in excessive water loss and loss of Natural Moisturizing Factor. According to studies [60], sunflower seed oil contains higher concentrations of linoleic acid compared to olive oil. Studies [60,65,66] have shown that linoleic acid acted as an agonist of peroxisome proliferator activated receptors (PPAR), which stimulates keratinocyte proliferation and synthesis of lipids, cholesterol or ceramides. Consequently, the skin barrier is strengthened [60,65].	A randomized trial [67] evaluated the effects of isosorbide diesters derived from sunflower oil and coconut oil and their interaction with colloidal oats on clinical symptoms of AD. In in vivo studies [65,68], a cream that contained 2% refined sunflower oil increased epidermal lipid synthesis and increased skin hydration, and decreased TEWL.	Studies [60,65] have shown improved hydration of adult skin without inducing erythema after using sunflower oil. It was also confirmed that the use of a 2% cream with refined sunflower oil reduced the amount of corticosteroids used in atopic dermatitis [65,68]. Topical application of emollients containing sunflower and coconut oil fatty esters reduced pruritus and reduced the amount of topical corticosteroids used [67].
Rosehip oil (Rosa canina L.)	Rosehip oil contains a large amount of essential fatty acids, including linoleic acid (35.9–54.8%) or alpha-linolenic acid (16.6–26.5%), as well as a large number of antioxidants such as tocopherol and carotenoids, so rosehip oil has anti-inflammatory and regenerative effects [60].	In vivo application of rose oil (0.1%) reduced TEWL and increased expression of the structural protein filaggrin in the skin of an animal model [69]. Rose oil (obtained by flower extraction) inhibited proliferation and induced expression of involucrin or filaggrin in keratinocytes in vitro [65].	Research [60] confirms that due to its content of the above components, rosehip oil counteracts the development of inflammation and oxidative stress.
Soybean oil (Glycine max L.)	Soybean oil is characterized by the presence of soy phytosterols (such as genistein), which have positive effects on skin barrier regeneration [60,70]. Genistein has a protective effect on keratinocytes, protecting them from the damaging effects of free radicals responsible for aging at the cellular level [71,72]. Vitamin K in soybean oil soothes skin redness, seals the walls of blood vessels and promotes skin regeneration [71,72]. Soybean oil is a source of unsaturated essential fatty acids mainly linoleic (50%), oleic or palmitic acid [23].	A study [73] related that no increase in IgE and IgG antibodies was observed in people with food allergy to soybeans after soybean oil application to the skin, which indicates that soybean oil applied to the skin has less sensitizing potential. Another study [74] evaluating the effects of soybean oil and anti-itch lauromacrogols contained in a bath lotion in patients with atopic eczema confirmed their efficacy and safety. The above study included 3500 patients, and the average duration of treatment was 42 days. The authors emphasize that the oil was well tolerated and effective in treating dry and itchy skin lesions.	Topical application of soybean oil extracts has been shown to reduce TEWL [60]. Regular use of soybean oil increases skin hydration, relieves inflammation and reduces recurrence [23]. Studies [75] confirm these actions, as anthocyanins from black soybean inhibit the production of reactive oxygen species (ROS) and protein kinases. This has the effect of reducing inflammation [75]. The use of a bath lotion containing soybean oil, among other ingredients, reduced the use of pharmaceuticals, such as steroids, in 60% of patients [74].
Sea buckthorn oil (Hippophae rhamnoides L.).	Oil is obtained from the seeds or pulp of sea buckthorn berries. The berries contain large amounts of vitamin C [76]. The authors of [77] report that the vitamin C content, depending on the variety, varies between 28 and 201 mg/100 g of fresh fruit, so the vitamin C content is 15 times higher than in orange fruit. Its content is responsible for the antioxidant effect of sea buckthorn oil, as well as its protective effect against harmful UVA and UVB radiation. Studies [77] report that the vitamin A content of sea buckthorn oil provides regenerative and anti-aging effects. Sea buckthorn oil obtained from the seeds provides large amounts of palmitoleic acid responsible for stimulating skin regeneration and wound healing [78]. The authors of [76] report that sea buckthorn oil contains gamma-linolenic acid, which improves blood circulation, nutrition and oxygenation of the skin, and in its deeper layers is converted to prostaglandins, which neutralize inflammation.	The authors of [78] report that when applied externally, sea buckthorn oil can reduce sores, scars, discoloration and allergic and inflammatory skin lesions. Other studies [78] have shown that a single application of a cream consisting of natural emollients (40% sea buckthorn oil or 40% olive oil) increases skin hydration more than the use of synthetic emollients (for example, isopropyl myristate).	Sea buckthorn oil relieves symptoms of atopic dermatitis, reducing dryness, irritation, flaking and itching [78]. Sea buckthorn oil has been confirmed to be effective in the treatment of skin dermatoses and to promote the granulation process of hard-to-heal wounds [76].
Hemp oil (Cannabis sativa L.)	Produced from hemp seed. The authors [79] report that hemp oil contains terpenes, which have anti-inflammatory and antioxidant properties. The oil is rich in essential fatty acids (linoleic, linolenic, oleic), as well as saturated acids (such as palmitic) responsible for the mechanical barrier of the skin, which protect it from external factors and water loss. Another study [80] shows that the content of essential fatty acids has a rejuvenating effect. The authors of [79] prove that in hemp oil the ratio of omega-6 to omega-3 fatty acids (3:1) has a beneficial effect, as it regulates the metabolic activity of cells and enhances anti-inflammatory effects. The phytosterol content (mainly β- sitosterol at 70%) in hemp oil is responsible for anti-inflammatory and antimicrobial effects, antioxidant activity and stimulation of collagen synthesis [79].	According to studies conducted in [23,79] to evaluate the effects of hemp oil on patients with AD, it has been proven that its regular use helped reduce pruritus and excessive dry skin. The authors of the above study emphasize that gamma-linolenic acid had an important role in alleviating the symptoms of atopic dermatitis [23,79]. In a study conducted by another group of authors [81], it was noted that the administration of hemp oil orally for a period of 8 weeks to a group of patients with atopic dermatitis resulted in favorable changes in the serum fatty acid profile. The authors of [81] noted an increase in the concentration of gamma-linolenic acid in blood lipids. Based on the survey responses of patients who participated in the study, there was a significant reduction in pruritus and dry skin after hemp oil administration.	All the described studies [23,79,80,81,82,83] confirm the beneficial effects of hemp oil on the skin of patients with atopic dermatitis. The authors of [23] assert that hemp oil increased the hydration of the stratum corneum of the skin, and alleviated inflammation and pruritus. A study [79] confirmed that phytosterols and flavonoids found in hemp oil have anti-allergic and immunostimulating effects on the skin of patients with AD. Other authors [82,83] confirm that essential fatty acids soothe skin irritation and accelerate skin regeneration through anti-inflammatory effects, significantly reducing inflammation in AD. Studies [79] on the effects of phytosterols contained in hemp oil confirm its effect on reducing transepidermal water loss.

summarizes most of the known and used active substances with proven therapeutic properties in AD.

Emollients “plus,” which typically contain allergenic ingredients such as plant proteins derived from peanuts or oats, should not be applied to the skin in children before the age of two, due to the intolerance and allergic properties of some ingredients [24].

Atopic skin, due to a defect in the epidermal barrier, is prone to irritation. For this reason, the authors of [18] recommend the use of emollients free of fragrances, preservatives and dyes.

A rare yet important component of emollients is substances of animal origin such as horse fat oil, which exhibits antimicrobial, anti-inflammatory and antipruritic effects [59]. The effect of horse oil on restoring the skin barrier was evaluated using a specially formulated dissolving microneedle patch (DMN). When applied transdermally, a significant improvement in the density of the epidermis and dermis, as well as an increase in skin elasticity and hydration were reported [59,84].

Another study in this area showed the anti-inflammatory effects of horse oil in reducing erythema and serum IgE immunoglobulin levels in contact hypersensitivity induced in mice. However, at this point, there are no ongoing and documented studies for the use of this oil in the treatment of patients with AD [59].

Another animal-derived ingredient mentioned by the authors [59,85] is lanolin, which is secreted from the sebaceous glands of sheep and obtained through wool processing. A study conducted to evaluate the effect of lanolin on the skin showed that daily use of an emollient with olive oil and lanolin (in a ratio of 30% olive oil and 70% lanolin) significantly improved skin condition compared to a water-in-oil emulsion used (containing neither olive oil nor lanolin) among a study population of newborns (without skin diseases) [86]. Lanolin and its derivatives are among the components of emollients that permanently restore the epidermal barrier, as its effects are longer lasting than those of occlusive emollients [1]. The authors point out that lanolin contained in cosmetics replenishes lipids in the stratum corneum reducing dryness of the skin, protects the skin from drying and cracking [52]. Lanolin is structurally similar to the structure of fetal synovial lipids, which is beneficial for restoring the epidermal barrier among newborns [1]. Until recently, lanolin was a common cause of allergy by the presence of fractions of free lanolin alcohols [1]. The above claims are explained by the concept of the lanolin paradox presented in 1986 by Wolf, who pointed out that lanolin is a component of drugs responsible for sensitization in a large number of patients, but at the same time is a safe compound in the general population [87]. According to the authors of [1], non-allergenic lanolin derivatives (liquid lanolin, as well as acetylated and ethoxylated lanolin alcohols) are currently in use.

Confirmation of the validity of the introduction of natural ingredients into the preparations used in the care of atopic skin was the work conducted by the authors [88,89,90,91]. The aforementioned authors confirmed the significant role of fats and oils in moisturizing the skin, specifically sheep tallow, hemp oil and walnut oil, while taking into account the benefit of introducing enzyme-modified fats into therapeutic preparations. They indicated that the model formulations they obtained may be used as moisturizing formulations and also as a preparation in the treatment of dry skin.

One of the commonly used ingredients of animal origin in emollients is honey [85,92]. Honey is a substance that deeply nourishes the epidermis and is rich in enzymes that naturally exfoliate the skin [85]. It is usually added to the formulation of cosmetics used at night and recommended for dry or mature skin [92]. Honey has humectant properties due to its high glucose and fructose content. Both of these substances can form hydrogen bridges with water [92]. According to the above authors, this increases water retention in the stratum corneum of the skin, which consequently increases hydration. Studies emphasize that honey’s moisturizing effect is also due to the presence of amino acids (proline, arginine, alanine, lysine, glycine, among others) and organic acids (gluconic acid, lactic acid, citric acid, succinic acid or acetic acid), which have corresponding functional groups (such as amine or carboxyl) [93]. They can form hydrogen bonds, enhancing the effect of water retention in the stratum corneum of the skin. According to the authors of [92,93], honey exerts a pH-regulating effect and prevents infections, due to its antimicrobial properties. Three factors contribute to this: the osmotic effect (allowing honey to interact strongly with water, leaving insufficient water for microorganisms), the acidic pH of honey and the release of hydrogen peroxide by the enzyme glucose oxidase.

One of the components of emollients is also ceramides, which, delivered in appropriate concentrations and proportions, improve the skin barrier and moisturize the skin [24,59]. They maintain the integrity of the skin barrier, which helps prevent water loss [24,59]. Studies have shown that the skin of patients with atopic dermatitis usually has reduced levels of ceramides [59]. However, in most cases, the ceramide content of over-the-counter remedies is too low to provide the above effects. When ceramides are provided without the addition of two other key lipids (cholesterol and at least one fatty acid), the epidermal barrier deteriorates [53]. Studies have confirmed that in order to restore normal skin barrier function, these three components should be supplied in a specific ratio [53]. One randomized study involving 100 patients divided into two groups evaluated the efficacy of a cream that contained ceramides and magnesium in the treatment of mild to moderate atopic dermatitis [94]. The authors of the above study compared the use of a cream with ceramides and magnesium to the effects of hydrocortisone and an emollient. After 6 weeks, the group that used ceramides and magnesium cream and hydrocortisone simultaneously showed a significant reduction in the intensity of clinical symptoms as assessed by the SCORAD scale and a reduction in TEWL. In contrast, the group that used ceramides and magnesium cream and an emollient at the same time had a higher score according to the SCORAD scale (indicating the severity of AD disease symptoms) and a higher TEWL. The study showed that all the above-described active ingredients improved the patients’ clinical condition after 6 weeks of use. However, only the simultaneous use of ceramides and magnesium cream in combination with applied hydrocortisone lowered SCORAD by 8.7 units [94].

In contrast, another study showed an increase in skin hydration and a significantly greater reduction in TEWL and a decrease in skin dryness in areas where the ceramide precursor moisturizer was applied, compared to skin to which it was not applied, after a 4-week application of the ceramide precursor moisturizer [95].

5. Use of Emollients in the Care of Skin with Atopic Dermatitis among Children and Adults

The use of emollients is the cornerstone of atopic dermatitis treatment. They help reduce the need for pharmacotherapy, including the use of glucocorticosteroids on the skin. Such management reduces the risk of side effects that follow steroid use, whose potential side effects include the development of Cushing’s syndrome, cataracts or whole-body endocrine disruption [12,17,31]. There are studies confirming that emollients reduce the severity of skin lesions in AD [31,96,97]. In clinical studies of so-called “plus” emollients, it has been noted that their use significantly reduces skin pruritus and improves skin hydration and epidermal barrier function [31]. One study on “plus” emollients, during which patients massaged the appropriate emollient twice a day onto clean and dry skin, showed that on day 21 of use there was a 115% increase in skin hydration and a 52% decrease in TEWL compared to baseline results for these parameters. Pruritus, erythema and exfoliation of the epidermis were reduced in those areas where application with emollient “plus” followed [96]. Another study confirmed that the use of emollients “plus” allowed a significant reduction in the amount of corticosteroids used compared to a control group using a classic emollient [97]. The same authors noted that after 28 days of its use, the skin showed improvement and thus the amount of corticosteroid treatment could be reduced. An additional added value in this study was the reduction in corticosteroid application to the skin in relation to the whole day.

The Cochrane Skin Group conducted a study during which the focus was on comparing the status of atopic dermatitis patients using moisturizers to control groups that did not use emollients with the active ingredients discussed earlier [98]. The study showed that patients were more likely to report an improvement in their skin condition when using a cream that contained urea in its formulation relative to patients using a placebo. It was confirmed that the urea-containing cream reduced skin dryness and reduced the number of recurrent lesions. Similar results were achieved in patients using moisturizing creams containing glycerol or oats [98]. Although there were fewer recurrences in the group using oat cream and the need for topical corticosteroids was reduced, there was a slight increase in the number of reported side effects such as burning, itching, erythema and folliculitis [98]. Nevertheless, study participants found moisturizing creams to be effective in reducing skin lesions and reducing pruritus compared to a control group that did not use emollients. And for allergic problems, the authors of [24,98] point to emollients with the simplest formulation with the least number of ingredients. On the other hand, the authors’ research led to the conclusion that ointments or creams containing 5–10% urea or 5–10% salicylic acid should be used in the chronic phase of atopic dermatitis [11].

The North American Contact Dermatitis Group conducted a study of three fragrance markers and six essential oils among them tea tree oil, which has anti-inflammatory effects on the skin lesions of AD patients [59]. The results of the above researchers confirmed the beneficial effect of tea tree oil on skin lesions in AD. Tea tree oil did not cause allergic reactions in 45% of patients allergic to other essential oils.

According to another study conducted by authors in a similar area, about one-third of adult patients developed contact allergies to the components of the emollients they used [24,59]. Most often, type IV sensitization appeared due to preservatives, fragrances or tocopherol included in emollients [24,59]. Another group of authors confirmed that the most common symptoms of type IV contact allergies included erythema, increased eczematous lesions and increased intensity of pruritus [23].

The authors of [53,99] emphasize that products should be chosen carefully, tailoring them to the needs of patients with atopic dermatitis. A 2017 study showed that topical application of moisturizers in mice, twice a day for 4 days, caused changes in the epidermis of varying severity. These changes included an increase in TEWL, an increase in skin surface pH and a decrease in skin hydration [53,99]. The same authors confirm that commercially available products may provide short-term relief, while if they exacerbate skin barrier disruption, they may initiate a vicious cycle (exacerbate skin dryness), requiring additional applications of skin care products. In contrast, other authors point out that one should be wary of over-the-counter emollients with a “dermatologically tested” label [97]. As it turned out, during a survey of companies, of the twenty-five companies that responded to the questionnaire, only four of them disclosed the number of people tested, and thirteen of them said that a dermatologist was present at one of the testing stages [59,97]. According to the authors of [59], such labeling can mislead patients, and skin care products that are widely available are not always safe.

6. Effect of Emollients on the Prevention of AD among Newborns and Children

Currently, we can distinguish three strategies in the prevention of atopic dermatitis: primary, secondary and tertiary prevention [23,100]. According to the recommendations of the Polish Dermatological Society, primary prophylaxis includes children at high risk but without disease symptoms. It involves prolonged breastfeeding (up to 4–6 months of age), limiting exposure to airborne allergens and using emollients from the first day of life [100]. Secondary prophylaxis of AD, on the other hand, applies to patients with fairly early symptoms of the disease, but without its advancement. It involves the introduction of appropriate care of the skin covered with lesions (use of emollients every 4–6 h) and avoidance of irritants, as well as elimination of allergens that exacerbate symptoms. And tertiary prevention, which applies to full-blown patients, focuses on reducing the severity of symptoms, preventing recurrence and the development of other allergic diseases. It is based on psychological counseling and patient education. Tertiary prophylaxis also includes the use of antihistamines and specific immunotherapy, which is used to prevent the development of symptoms from other organs [19,23,100,101].

More recently, emollients have been recommended for the prevention of primary atopic dermatitis in newborns. There are randomized trials that showed a 32% and 50% reduction in the risk of atopic dermatitis with regular use of emollients from birth in newborns with risk factors [24,25]. One study analyzed the effect of using emollients on improving the skin barrier and skin microbiota in 6-month-old infants with a positive family history of AD. According to the authors [28], reduced skin pH and increased Streptococcus salivarius in the skin microbiota after long-term use of emollients may have a preventive effect on the development of AD in children. The acidic pH of the skin counteracts the bacterial dysbiosis of the skin characteristic of atopic dermatitis [28]. Streptococcus salivarius strains have been shown to reduce the production of pro-inflammatory cytokines and chemokines interleukin-6 and interleukin-1 and -8 [28,102,103]. They also reduce TNF-alpha production in in vitro epithelial assays. S. salivarius stimulates TH1 lymphocytes and antagonizes TH2, and it is for this reason that its increased participation on the skin surface reduces inflammation initiated by TH2 lymphocytes in atopic dermatitis [28,102,103].

The Barrier Enhancement for Eczema Prevention study evaluated the impact of daily use of emollients during a child’s first year of life [104]. The study included 1394 infants with risk factors for developing AD. They were randomly divided into a group using emollients and a control group without the use of emollients [104]. According to the authors of the above study, the diagnosis of AD was made in 31% of infants in the group using emollients prophylactically and 28% of infants in the control group. Atopic dermatitis was diagnosed in these children between 12 and 60 months of age. The incidence of atopic dermatitis between the groups was thus comparable, and daily use of emollients in the first year of life did not significantly prevent the development of the disease. Similar results were obtained in a population-based study conducted at Oslo University Hospital and Ostfold Hospital Trust in Oslo and Karolinska University Hospital in Stockholm, which included 2397 newborns born between 2015 and 2017 [105]. They were assigned to four groups: a control group without skin care with infant feeding guidelines maintained, a group using skin softeners, a food intervention group (supplementing feeding with peanuts, cow’s milk, wheat and eggs) and a final group that combined skin and food interventions. As it turned out, AD was diagnosed in 8% of infants in the group with no skin or nutritional interventions, 11% of infants in the group that used emollients, 9% in the group that used supplemental feeding, and 5% in the group that combined skin and nutritional interventions. Thus, the introduction of emollients and appropriate supplemental nutrition did not reduce the development of atopic dermatitis for the infants studied.

7. Recommendations in the Use of Emollients in Atopic Dermatitis and Their Synergism with Other Behaviors and Therapies

Referring to the recommendations of dermatological societies in Europe (EADV, ETFAD) and in the United States (American Academy of Dermatology), it should be noted that they recommend the use of emollients in mild AD during periods of remission, while during exacerbations they indicate combining them with topical corticosteroids or calcineurin inhibitors [1]. The European Task Force on Atopic Dermatitis (ETFAD) recommends using large amounts of emollients in patients with AD—namely, a minimum of 30 g/day or 1 kg/month for an adult [24]. According to the European Academy of Dermatology and Venereology (EADV), on the other hand, the correct amount of emollient used per skin surface in children should be 150–200 g per week, while in adults it should be 500 g [1,106]. The authors of [23] do not recommend applying too many emollients to the skin, as a high frequency and large amounts can cause folliculitis or childhood seborrheic dermatitis. Also important in the application of emollients to the skin is the method of application, namely with clockwise circular motions [23].

Yet, in the context of the prevention of atopic dermatitis in newborns and children, the American College of Allergy, Asthma and Immunology says that further research is needed to evaluate the effect of emollients on the prevention of atopic dermatitis in newborns, as well as to determine whether the type of emollient applied, frequency, duration and age are relevant to the prevention of atopic dermatitis [107]. A similar position is represented by the European Task Force on Atopic Dermatitis, which does not provide recommendations for primary prevention of AD, as the quality and quantity of data in this area is not satisfactory [24].

The American Academy of Pediatrics recommends a skin care regimen based on the use of fragrance-free emollients after bathing [14]. The authors of [14] note that bathing in patients with AD can be carried out in lukewarm water for 10 to 15 min every 2 or 3 days. One randomized study evaluated the effect of bathing frequency on the severity of AD symptoms among 28 children (between 6 months and 10 years of age) [108]. Symptom improvement was measured using the SCORAD scale. As it turned out, bathing frequency had no significant effect on the course of AD. ETFAD recommends regular baths or showers in lukewarm 34–37 °C water from two to seven times a week using mild surfactants, and the preferred products should be galenic forms—syndets or emollients for washing based on softening oils. Bath emollients usually contain paraffin and synthetic fatty acid esters such as isopropyl myristate. These ingredients lubricate and soften the epidermis. At the same time, they are lightweight and allow oxygen and water exchange in the skin [1,18,24,109,110]. Sometimes emollients in the form of lotions, creams or cleansing products may contain antimicrobial ingredients (such as chlorhexidine) to limit the development of bacterial superinfections in AD [24,109,110]. Studies have proven that the use of harsh detergents and alkaline soaps adversely affected the skin lesions of patients with AD [23,24]. The ban on the use of soaps in atopic dermatitis is called the “Scholtz procedure” in the United States [18]. According to the authors of [111], it is extremely important to educate AD patients about skin care management especially in the context of children with atopic dermatitis. Unfortunately, studies continue to show that a significant percentage of patients with atopic dermatitis use soap for washing (about 40%) and do not use emollients after bathing (about 25%) [111].

In acute inflammation, topical anti-inflammatory treatment should be implemented first, followed by emollient care [24,53,112]. The authors of [10] emphasize that the application of emollients directly to acute inflammatory lesions may result in increased pruritus and burning of the skin. In acute inflammation, the so-called “wet-wrap” dressing is used, which involves bandaging the skin with moist compresses after applying emollients or anti-inflammatory drugs. This has an anti-inflammatory, antipruritic and cooling effect [18].

8. Conclusions

In summary, the above work aimed to indicate the validity of including emollients in therapy and skin care in atopic dermatitis. The meta-analysis we performed consistently set the direction of approach in this condition. We specifically focused on reports from the last few years to show the latest, least invasive behavior in this area. Therefore, taking into account the work of scientists and their guidelines, as well as the guidelines of health organizations from around the world on the treatment and care of skin with AD, it should be clearly stated that patients should use concomitant emollients along with anti-inflammatory drugs (if necessary). On the other hand, it should be noted that the choice of emollients should depend on the patient’s condition, the season or the area on the body affected by lesions. In general, it is worth noting that the minimization of the components of emollients in terms of coloring agents or fragrances, as well as their composition based on natural raw materials, brings the affinity of a given preparation to the skin of a healthy person closer, which thus affects the effectiveness and safety of the emollient.