FormalPara Key Points
Daily moisturization is the bedrock of atopic dermatitis (AD) management, as recommended by all international guidelines.
Therapeutic moisturizers developed specifically for the treatment of AD demonstrate improved skin barrier and reduced incidence of flares in clinical trials.
Healthcare providers can help improve the skin condition of patients by informed recommendation of clinically proven, scientifically validated therapeutic nonprescription moisturizers and encouragement to use the product regularly.

Introduction

Atopic dermatitis (AD) affects more than 18 million people in the USA [1]. Daily moisturization is the standard or “bedrock” of the basic disease management of AD [2, 3]. A comprehensive review of 14 independent published guidelines from across the globe (USA, UK, Europe, Japan, Korea, Singapore, Canada, South Africa, and individual European countries) revealed that daily moisturization was a consistent recommendation for AD management [4].

Guidelines recommend liberal application of moisturizer on lesional and nonlesional skin, ideally at least twice daily [4, 5]. In mild AD, a daily moisturizer may be the primary therapy but should also be continued as complementary therapy when treating moderate and severe disease [2, 3]. Reviews of this subject area have revealed similar recommendations [6,7,8,9]; however, these studies were mainly focused on the active ingredients applied or on less recent or selected studies, respectively.

The objective of this review was to evaluate and present the clinical data behind commercially available products in a succinct guide based on accepted scientific criteria, so that healthcare providers can make informed choices and recommendations to their patients for proven therapies.

Clinical Evidence That Moisturizers Can Improve Outcomes in Atopic Dermatitis (AD)

AD is characterized by compromised epidermal barrier integrity. Even the skin of a patient that is not flaring is compromised and has imperfect barrier function [10,11,12,13,14]. The purpose of daily moisturization is to repair and support the skin barrier, thereby reducing the risk of flares.

To evaluate the clinical efficacy of daily emollient therapy for improving the skin barrier of patients with AD, we conducted a review of clinical studies of moisturizers in AD treatment. We searched the PubMed database using the terms “atopic dermatitis” OR “atopic” OR “eczema” plus all combinations of “barrier,” “topical,” “steroid-free,” “moisturizer,” and “moisturization.” Reference lists were also reviewed, particularly those from a 2017 Cochrane database review [15] and a 2018 evidence-based review [9].

Clinical studies were selected to provide practicing dermatologists with relevant data on commercially available, clinically tested nonprescription moisturizers to enable them to make informed recommendations. Clinical trials were selected that included study subjects with a diagnosis of AD or who were at high risk for developing AD. Studies had to include objective, biophysical barrier measures of transepidermal water loss (TEWL) and/or corneometry (see Table 1) to assess their efficacy at improving the skin barrier. If validated clinical assessment scales were included in these studies, these results were also reviewed. In addition, we selected studies that examined the ability of daily moisturization to prevent disease onset (primary prevention) or AD flares (secondary prevention).

Table 1 Validated skin assessments commonly used in atopic dermatitis studies

Studies that only assessed clinical symptoms or measured moisturization at 24 h after a single application were excluded, as were studies reporting on medical devices, products requiring a prescription (e.g., Atopiclair, EpiCeram), and studies testing single ingredients such as glycerol [16]. Studies were limited to those published from January 2006 until December 2019 that tested products that are currently on the market.

Summary of Clinical Study Findings

The literature search identified 13 different nonprescription and cosmetic products tested in pediatric populations and 11 tested in adult populations with AD. Overall, clinical studies demonstrated that daily moisturization increased skin hydration and decreased TEWL in both children and adults (Table 2). While the majority of studies tested twice-daily application, once-daily treatment also showed skin barrier improvements. The analyses were mostly comparisons with baseline values, demonstrating improvements over time. Side-by-side comparisons (split-body) of treatment versus no treatment also indicated that, in almost all cases, moisturization improved skin barrier integrity compared with no treatment.

Table 2 Clinical studies of moisturizers for the treatment of atopic dermatitis

Flare studies indicated that daily moisturization significantly reduced the number of flares compared with untreated skin. A pooled analysis of six of the studies (n = 607) included in the Cochrane study, looking specifically at prevention of flares, demonstrated that daily moisturization significantly reduced the number of flares compared with untreated controls (p < 0.0006) [15].

Two studies investigated the ability of daily moisturization to proactively prevent flares in patients with AD. These randomized, 6-month studies investigating the effect of twice-daily moisturizer compared with no treatment demonstrated that both the US Eucerin Eczema Relief Body Cream and the Swedish Canoderm Cream significantly lengthened time to flare and reduced the total number of flares, in pediatric and adult populations, respectively [44, 39]. The median time to flare was > 180 days with daily moisturizer treatment in both studies, versus 28 and 30 days in the untreated groups of the pediatric and adult studies, respectively [44, 39]. Pooled analyses of these studies indicated that daily moisturization significantly reduced the risk of flare (p = 0.001) and the rate of flare by a factor of 3.74 (p = 0.0002) compared with untreated controls [15].

In addition to preventing flares in patients diagnosed with AD, proactive treatment of high-risk neonates reduced the development of AD [37]. This study was predicated on the knowledge that a family history of AD, allergic rhinitis, or asthma increases the likelihood of an infant developing AD. In this study, 124 neonates with a first-degree relative with one of these conditions were randomized to receive full body coverage (scalp excluded) of an emollient (Aquaphor Healing Ointment, 50% paraffin in white petrolatum, Cetaphil Cream, Doublebase Gel, or sunflower oil) daily, starting at or before 3 weeks of age. At 6 months, only 22% of neonates receiving daily emollient therapy developed AD versus 43% in the control group, corresponding to a significant risk reduction of 50% [37]. Several studies of proactive moisturization of high-risk infants support the effectiveness of primary prevention of AD [47], although another study by the original investigators showed a protective but nonsignificant effect of daily use of a therapeutic moisturizer (AD diagnosed in only 13.2 vs. 25.0% in the control group at 12 months), likely because the study was underpowered [42].

Many of the studies reviewed were not randomized controlled trials (RCTs). Large-scale RCTs are the gold standard for pharmaceutical approvals, but the high costs associated with these trials are impractical when testing nonprescription product formulations that will not be covered by insurance but need to be available to consumers at a reasonable cost.

Moreover, topical nonprescription formulations have multiple components that contribute to their efficacy, rendering “placebo-controlled” studies impossible. Consequently, most “controls” are an untreated group or an untreated side of a patient in the case of split-body studies. Although rare, a few vehicle-controlled studies exist [36, 43] that eliminate multiple key “active” ingredients and compare outcomes with the complete formulation.

Currently, there is no gold standard for nonprescription product testing. The endpoints chosen in this literature search—TEWL, corneometry, symptom relief—appear to be robust measures. Time to flare and number of flares versus untreated controls could also be considered objective and relevant measures. However, study design details such as sample size, length of study, controls, and blinding were not standardized. Moreover, pruritus is among the primary symptoms of AD, yet assessment measures for pruritus are not standardized and are frequently omitted from study designs.

Types of Moisturizers

Moisturizers come in many formulations, ranging from oils and ointments to lotions and gels. Moisturizers are not created with equal component ingredients; some can actually worsen skin function and even induce skin irritation [48, 49]. Traditionally, ointments and occlusives were thought to be the most beneficial for eczema because of their protective effects, whereas creams were assumed to provide better moisturization than lotions because of their greater viscosity. However, these premises are no longer true as modern technology has allowed the development of efficacious, more aesthetically pleasing formulations that improve compliance and therefore outcomes [50].

Moisturizers have evolved from providing basic barrier protection (occlusives) to hydrating care (humectant enriched) to products that address specific skin conditions (therapeutic).

Occlusives include ointments (mostly water-free lipid formulas) and basic water-in-oil creams and lotions (emulsions or suspensions of water into hydrophobic emollients and oils) that reduce TEWL and protect the skin against external irritants.

Humectant-enriched moisturizers include cream and lotion formulations of oil-in-water and water-in-oil emulsions as well as hydrogels. Incorporating humectant ingredients ranging from glycerin to natural moisturizing factor (NMF) components of the skin (e.g., urea, lactate, amino acids, pyrrolidone carboxylic acid, hyaluronic acid), these moisturizers hydrate the skin by attracting and binding water.

Therapeutic moisturizers are not restricted to any formulation type, as they are designed to address the specific symptoms of diseased skin. These formulations improve and support the skin barrier as well as hydration but also include ingredients that reduce inflammation or restore lipids, depending on the skin pathology being treated. Further, a true therapeutic moisturizer should be clinically evaluated and demonstrate efficacy for the respective conditions they are intended to treat [48].

Therapeutic moisturizers are formulated with ingredients that address the symptoms or contributory factors that may exacerbate the severity of the disease or condition (e.g., itch, inflammation, barrier disruption, ceramide deficiency). The formulation should have the physical properties that provide adequate absorption of ingredients and a pH of 4–5 to re-establish the normal physiological pH of skin. An aesthetically elegant product can potentially improve compliance.

Classifying Moisturizers

Understanding where therapeutic moisturizers for AD fit in among the plethora of topical agents can be complicated. The FDA classifies topical products as cosmetics, over-the-counter (OTC) drugs, prescription drugs, or prescription medical devices (Table 3). Cosmetic products are limited by the FDA to only claim effects on the appearance of the skin (per the US Federal Food and Cosmetic Act of 1938). Drugs are agents that have a pharmacologic action; prescription drugs require extensive clinical testing and approval by the FDA before being introduced to the market. OTC drugs must comply with their relevant OTC drug monograph, a guidance of acceptable ingredients and concentrations, disease indications, claims, dosing, and labeling. In contrast to prescription drugs, products conforming to existing OTC drug monographs can be marketed without FDA approval.

Table 3 US FDA categorization of topical products used in atopic dermatitis

In order for any US moisturizer to be able to make claims of symptom relief for eczema, the FDA has designated only two ingredients as “allowed actives”: (1) under the FDA’s OTC External Analgesic monograph, hydrocortisone can claim use for the temporary relief of itching and inflammation due to eczema and (2) under the FDA’s OTC Skin Protectant monograph, colloidal oatmeal can claim to provide temporary skin protection and relief of minor skin irritations and itching due to eczema [51]. These effects have been previously established in the literature and thus approved by the FDA. If a product does not contain either hydrocortisone or colloidal oatmeal, nor comply with the regulations in the relevant OTC monographs, no claims can be made regarding eczema relief.

In the USA, AD therapeutic moisturizers are nonprescription and may be classified as either cosmetic formulations or OTC drug products; these products typically avoid ingredients that may exacerbate diseased skin, such as fragrances [2, 50].

Several prescription barrier creams (e.g., Atopiclair, EpiCeram) are indicated for AD. Categorized as class II medical devices, these require a premarket FDA 501(k) submission, whereby the device must demonstrate “substantial equivalence” to already approved medical devices. These products do not need to demonstrate safety and clinical efficacy through rigorous clinical trials mandated by the FDA new drug application process [3]. Studies of barrier creams have shown them to be safe and to reduce the incidence of flares [5, 52]; however, several comparative studies have shown no greater efficacy than achieved with nonprescription moisturizers [53, 54]. Notably, many of the ingredients included in barrier creams when first developed (e.g., ceramides, NMFs) are now included in nonprescription moisturizers formulated for the treatment of eczema [3]. Moreover, barrier creams are more expensive than nonprescription products [3, 53], and insurance coverage may be improbable.

Therapeutic Moisturizers for the Treatment of AD

For AD, therapeutic moisturizers need to provide essential barrier care (Table 4). Several AD therapeutic moisturizers have demonstrated their ability to decrease TEWL and increase skin hydration (e.g., Cetaphil Restoraderm moisturizer and wash, Eucerin Eczema Body Cream, Eucerin Flare-Up Treatment) and reduce the number of flares (e.g., Canoderm Cream, Eucerin Eczema Relief Body Cream, Eucerin AtopiControl Lotion) (see Table 2).

Table 4 The importance of essential skin barrier repair in atopic dermatitis

Sometimes termed “emollient plus” [2], AD therapeutic moisturizers go beyond basic emollients to include ingredients that provide skin protection, essential lipids, and antipruritic, anti-inflammatory, and antioxidant properties to help counter the symptoms of AD (Table 5).

Table 5 Key ingredients in nonprescription therapeutic moisturizers for atopic dermatitis

Colloidal oatmeal contains a mixture of various dermatologic active compounds that provide moisturizing, skin-protectant, anti-inflammatory, antioxidant, and antipruritic effects. The starches and β-D-glucans in oatmeal help to create an occlusive barrier that both moisturizes and relieves itch, whereas antioxidants such as avenanthramides, vitamin E, and ferulic acid have demonstrated anti-inflammatory activity [51].

Ceramides are important barrier lipids in preventing TEWL. Moisturizers may address ceramide deficiencies in AD by adding them to the formulation, by adding ingredients that can upregulate de novo ceramide production (e.g., urea [62, 63], niacinamide [64]), or by changing the physiologic milieu to support and promote ceramide production (e.g., lactic acid [62, 65]).

Maximizing Outcomes for Patients with AD

Healthcare providers can maximize patient outcomes by stressing the benefits of daily emollient therapy to their patients, particularly highlighting flare prevention. Evidence has consistently shown that daily application of a therapeutic moisturizer improves the skin barrier and reduces the number and frequency of flares. These outcomes can result in greater quality of life and potential cost benefits by reducing the number of lost days at work [66]. For neonates, those at high risk of developing AD can delay or even avoid AD by proactive treatment with a therapeutic moisturizer (primary prevention) [37].

Recommending clinically proven therapeutic moisturizers to patients is key to a successful therapeutic outcome. Instructions should stress that moisturizers should be applied liberally and daily—ideally twice. Recommendations should be based on formula composition and the strength of clinical data supporting the formulation [48]. Clinical demonstrations should include both objective measures of skin hydration and TEWL and validated clinical scales to assess symptom improvement. Product selection should also consider patients’ experience and preference [67, 68], as therapeutic efficacy can be provided in aesthetically pleasing, lighter formulations that can improve compliance.

Topical corticosteroids are generally recommended as the next step in the treatment of AD, particularly for the targeted treatment of flares. Topical steroid formulations may include penetration enhancers designed to enhance the delivery of active steroid to its target, which may weaken the barrier. Consequently, maintaining daily moisturization is important when topical steroids are added to the treatment regimen [50].

Limitations

This review does not attempt to assess the quality of the studies reviewed (extensively evaluated by van Zuuren et al. [15]) but rather presents a practical guide for the clinician of therapeutic moisturizers and the data and studies that support their use.

Minimal clinically important differences (MCIDs [69]) were not addressed in any of the cited publications or this review because of a lack of information on both thresholds for objective biophysical measures (TEWL and corneometry) and MCID evaluations for nonprescription interventions for patients with mild to moderate conditions. Instead, we took a positive statistical difference in TEWL, corneometry, and reduction of flare incidence as evidence of the product being beneficial to the patient.

Furthermore, we focused on the effects of the products on clinical and biophysical skin measures. It is beyond the scope of this review to classify the products as being occlusive, humectant-enriched, or therapeutic, as many of them may span several classes.

Conclusions

Therapeutic moisturizers should be used daily as the bedrock of AD management, underlying all additional treatments. Evidence has shown that, in many cases, reinforcing a back-to-basics approach with daily moisturization can be sufficient for the treatment of mild AD, strengthening the skin barrier and reducing the symptoms and outbreaks of AD. This review identified several proven and available consumer products that have been clinically tested using objective measures. Understanding what makes a moisturizer therapeutic, and how they differ from cosmetic products and prescription barrier creams, will help healthcare providers make informed choices to optimize outcomes for their patients. Healthcare provider recommendations on the right choice of moisturizers for the patient should be based on clinical evidence and patients’ preference and willingness to use. Twice-daily moisturization should be the mainstay of treatment for AD.