American Journal of Clinical Dermatology (2020) 21:641–655 https://doi.org/10.1007/s40257-020-00529-9

REVIEW ARTICLE

Efcacy of Nonprescription Moisturizers for Atopic Dermatitis: An Updated Review of Clinical Evidence

Adelaide A. Hebert1 · Frank Rippke2 · Teresa M. Weber3 · Noreen Heer Nicol4

Published online: 10 June 2020 © The Author(s) 2020

Abstract Twice-daily moisturization is recommended by international guidelines as the bedrock of the management of atopic dermatitis (AD). Moisturizers should be selected based on proven clinical efectiveness in improving the skin barrier and improving the symptoms of AD. We searched the PubMed database for clinical trials assessing daily moisturization for the treatment of AD published between 2006 and 2019. Studies had to assess the efcacy of commercially available moisturizers using objective measures of corneometry, transepidermal water loss, or incidence of fare as endpoints, and treatments had to be currently available to patients. Clinical studies showed that moisturization (typically twice daily) signifcantly improved the skin barrier in adults and children with AD. Longer-term fare studies showed that daily moisturization reduced the incidence of fares and extended the time between fares. Proactive moisturization of infants at high risk of developing AD may reduce its manifestation. Therapeutic moisturizers for AD are specifcally formulated with ingredients that target symptoms of AD, such as itch, infammation, or compromised skin barrier. The US FDA requires that any moisturizer available in the USA and claiming to treat AD must contain colloidal oatmeal. Healthcare providers can maximize compliance and outcomes by educating patients on the benefts of liberally applying a therapeutic moisturizer twice daily to support the skin barrier and help reduce the incidence of fares. Specifc recommendations should be for clinically tested moisturizers evaluated using objective, validated skin assessments.

1 Introduction Key Points Atopic dermatitis (AD) afects more than 18 million people in the USA [1]. Daily moisturization is the standard or “bed- Daily moisturization is the bedrock of atopic dermatitis rock” of the basic disease management of AD [2, 3]. A com- (AD) management, as recommended by all international prehensive review of 14 independent published guidelines guidelines. from across the globe (USA, UK, Europe, Japan, Korea, Therapeutic moisturizers developed specifcally for the Singapore, Canada, South Africa, and individual European treatment of AD demonstrate improved skin barrier and countries) revealed that daily moisturization was a consistent reduced incidence of fares in clinical trials. recommendation for AD management [4]. Healthcare providers can help improve the skin condition of patients by informed recommendation of clinically proven, scientifcally validated therapeutic nonprescrip- * Adelaide A. Hebert tion moisturizers and encouragement to use the product [email protected] regularly. 1 Department of Dermatology, University of Texas McGovern Medical School, 6655 Travis, Suite 980, Houston, TX 77030, USA 2 Research and Development, Beiersdorf, Hamburg, Germany Guidelines recommend liberal application of moisturizer 3 Research and Development, Beiersdorf Inc., Wilton, CT, on lesional and nonlesional skin, ideally at least twice daily USA [4, 5]. In mild AD, a daily moisturizer may be the primary 4 College of Nursing, University of Colorado, Anschutz therapy but should also be continued as complementary Medical Campus, Aurora, CO, USA

Vol.:(0123456789) 642 A. A. Hebert et al. therapy when treating moderate and severe disease [2, 3]. of AD or who were at high risk for developing AD. Stud- Reviews of this subject area have revealed similar recom- ies had to include objective, biophysical barrier measures mendations [6–9]; however, these studies were mainly of transepidermal water loss (TEWL) and/or corneometry focused on the active ingredients applied or on less recent (see Table 1) to assess their efcacy at improving the skin or selected studies, respectively. barrier. If validated clinical assessment scales were included The objective of this review was to evaluate and present in these studies, these results were also reviewed. In addi- the clinical data behind commercially available products in tion, we selected studies that examined the ability of daily a succinct guide based on accepted scientifc criteria, so that moisturization to prevent disease onset (primary prevention) healthcare providers can make informed choices and recom- or AD fares (secondary prevention). mendations to their patients for proven therapies. Studies that only assessed clinical symptoms or meas- ured moisturization at 24 h after a single application were excluded, as were studies reporting on medical devices, 2 Clinical Evidence That Moisturizers Can products requiring a prescription (e.g., Atopiclair, Epi- Improve Outcomes in Atopic Dermatitis Ceram), and studies testing single ingredients such as glyc- (AD) erol [16]. Studies were limited to those published from Janu- ary 2006 until December 2019 that tested products that are AD is characterized by compromised epidermal barrier currently on the market. integrity. Even the skin of a patient that is not faring is compromised and has imperfect barrier function [10–14]. The purpose of daily moisturization is to repair and support 3 Summary of Clinical Study Findings the skin barrier, thereby reducing the risk of fares. To evaluate the clinical efcacy of daily emollient therapy The literature search identifed 13 diferent nonprescrip- for improving the skin barrier of patients with AD, we con- tion and cosmetic products tested in pediatric popula- ducted a review of clinical studies of moisturizers in AD tions and 11 tested in adult populations with AD. Overall, treatment. We searched the PubMed database using the clinical studies demonstrated that daily moisturization terms “atopic dermatitis” OR “atopic” OR “eczema” plus all increased skin hydration and decreased TEWL in both combinations of “barrier,” “topical,” “steroid-free,” “mois- children and adults (Table 2). While the majority of stud- turizer,” and “moisturization.” Reference lists were also ies tested twice-daily application, once-daily treatment reviewed, particularly those from a 2017 Cochrane database also showed skin barrier improvements. The analyses were review [15] and a 2018 evidence-based review [9]. mostly comparisons with baseline values, demonstrating Clinical studies were selected to provide practicing der- improvements over time. Side-by-side comparisons (split- matologists with relevant data on commercially available, body) of treatment versus no treatment also indicated that, clinically tested nonprescription moisturizers to enable in almost all cases, moisturization improved skin barrier them to make informed recommendations. Clinical trials integrity compared with no treatment. were selected that included study subjects with a diagnosis

Table 1 Validated skin assessments commonly used in atopic dermatitis studies Assessment Assessment type Description Outcome

TEWL Biophysical Tewa Meter or similar device directly measures water High values indicate defective barrier function; low loss from skin in g/m2/h values indicate tight barrier Corneometry Biophysical Corneometer indirectly measures hydration by detecting High values indicate greater hydration; low values capacitance changes due to water content in skin indicate dry skin SCORAD Clinical Measure of ­signsa and ­symptomsb on scale of 0–103 High score indicates more severe clinical phenotype EASI Clinical Measure of ­signsc on scale of 0–72 High score indicates more severe clinical phenotype ADSI Clinical Measure of signs and ­symptomsd on scale of 0–15 High score indicates more severe clinical phenotype

ADSI Atopic Dermatitis Severity Index, EASI Eczema Area and Severity Index, SCORAD Scoring Atopic Dermatitis, TEWL transepidermal water loss a Redness, swelling, oozing/crusting, excoriation, lichenifcation, dryness b Itching, sleeplessness c Erythema, edema/papulation, excoriation, lichenifcation d Erythema, pruritus, exudation, excoriation, lichenifcation Nonprescription Moisturizers in Atopic Dermatitis 643

Flare studies indicated that daily moisturization sig- “placebo-controlled” studies impossible. Consequently, most nifcantly reduced the number of fares compared with “controls” are an untreated group or an untreated side of a untreated skin. A pooled analysis of six of the studies patient in the case of split-body studies. Although rare, a few (n = 607) included in the Cochrane study, looking spe- vehicle-controlled studies exist [36, 43] that eliminate mul- cifcally at prevention of fares, demonstrated that daily tiple key “active” ingredients and compare outcomes with moisturization signifcantly reduced the number of fares the complete formulation. compared with untreated controls (p < 0.0006) [15]. Currently, there is no gold standard for nonprescrip- Two studies investigated the ability of daily moisturi- tion product testing. The endpoints chosen in this literature zation to proactively prevent fares in patients with AD. search—TEWL, corneometry, symptom relief—appear to be These randomized, 6-month studies investigating the efect robust measures. Time to fare and number of fares versus of twice-daily moisturizer compared with no treatment untreated controls could also be considered objective and demonstrated that both the US Eucerin Eczema Relief relevant measures. However, study design details such as Body Cream and the Swedish Canoderm Cream signif- sample size, length of study, controls, and blinding were cantly lengthened time to fare and reduced the total num- not standardized. Moreover, pruritus is among the primary ber of fares, in pediatric and adult populations, respec- symptoms of AD, yet assessment measures for pruritus are tively [44, 39]. The median time to fare was > 180 days not standardized and are frequently omitted from study with daily moisturizer treatment in both studies, versus designs. 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 sig- 4 Types of Moisturizers nifcantly reduced the risk of fare (p = 0.001) and the rate of fare by a factor of 3.74 (p = 0.0002) compared with Moisturizers come in many formulations, ranging from oils untreated controls [15]. and ointments to lotions and gels. Moisturizers are not cre- In addition to preventing fares in patients diagnosed ated with equal component ingredients; some can actually with AD, proactive treatment of high-risk neonates worsen skin function and even induce skin irritation [48, reduced the development of AD [37]. This study was 49]. Traditionally, ointments and occlusives were thought predicated on the knowledge that a family history of AD, to be the most benefcial for eczema because of their protec- allergic rhinitis, or asthma increases the likelihood of an tive efects, whereas creams were assumed to provide better infant developing AD. In this study, 124 neonates with moisturization than lotions because of their greater viscos- a frst-degree relative with one of these conditions were ity. However, these premises are no longer true as modern randomized to receive full body coverage (scalp excluded) technology has allowed the development of efcacious, more of an emollient (Aquaphor Healing Ointment, 50% paraf- aesthetically pleasing formulations that improve compliance fn in white petrolatum, Cetaphil Cream, Doublebase Gel, and therefore outcomes [50]. or sunfower oil) daily, starting at or before 3 weeks of Moisturizers have evolved from providing basic bar- age. At 6 months, only 22% of neonates receiving daily rier protection (occlusives) to hydrating care (humectant emollient therapy developed AD versus 43% in the control enriched) to products that address specifc skin conditions group, corresponding to a signifcant risk reduction of 50% (therapeutic). [37]. Several studies of proactive moisturization of high- Occlusives include ointments (mostly water-free lipid risk infants support the efectiveness of primary preven- formulas) and basic water-in-oil creams and lotions tion of AD [47], although another study by the original (emulsions or suspensions of water into hydrophobic investigators showed a protective but nonsignifcant efect emollients and oils) that reduce TEWL and protect the of daily use of a therapeutic moisturizer (AD diagnosed skin against external irritants. in only 13.2 vs. 25.0% in the control group at 12 months), Humectant-enriched moisturizers include cream and likely because the study was underpowered [42]. lotion formulations of oil-in-water and water-in-oil Many of the studies reviewed were not randomized con- emulsions as well as hydrogels. Incorporating humectant trolled trials (RCTs). Large-scale RCTs are the gold standard ingredients ranging from glycerin to natural moisturizing for pharmaceutical approvals, but the high costs associated factor (NMF) components of the skin (e.g., urea, lactate, with these trials are impractical when testing nonprescrip- amino acids, pyrrolidone carboxylic acid, hyaluronic tion product formulations that will not be covered by insur- acid), these moisturizers hydrate the skin by attracting ance but need to be available to consumers at a reasonable and binding water. cost. Therapeutic moisturizers are not restricted to any for- Moreover, topical nonprescription formulations have mul- mulation type, as they are designed to address the specific tiple components that contribute to their efcacy, rendering symptoms of diseased skin. These formulations improve 644 A. A. Hebert et al. [ 20 ] [ 21 ] Simpson et al. et al. Simpson Hon et al. [ 19 ] Hon et al. et al. Simpson [ 22 ] Hon et al. Bianchi et al. [ 18 ] et al. Bianchi References Na et al. [ 17 ] et al. Na afected areas afected areas on both sides of body as neces - sary ~ 50% use allowed TCS needed TCS to all to TCS No Concomitant medications No Usual TCS potency Low as Usual TCS ↓ ( p < 0.05), EASI ( p < 0.05) at d 7, 14, 21 vs. untreated ( p < 0.001), ↓ TEWL ( p < 0.0001) vs. cleansing gel alone Hydration ↑ Hydration Treatment vs. vs. Treatment untreated vehicle, or active control, comparator NA NA NA NA SCORAD ↓ SCORAD

to both sides to of body ( p < 0.05); ↓ EASI on both sides body ( p < 0.05) ( p < 0.0001); ↑ hydration ( p < 0.0001); TEWL NS ( p = 0.039); ↑ Corneometry ( p = 0.021); TEWL NS ( p < 0.01); ↑ Hydration ( p < 0.0001) ( p = 0.016); TEWL NS; NS; SCORAD use ↓ TCS ( p = 0.024) ( p < 0.001); ↓ TEWL ( p = 0.06) Hydration ↑ Hydration Treatment vs. vs. Treatment pretreatment Statistical comparisonsStatistical SCORAD ↓ SCORAD ↓ SCORAD ↓ TEWL ↑ Hydration SCORAD ↓ SCORAD alone Untreated Vehicle, active, active, Vehicle, or untreated Comparators None Cleansing gel None None None EASI TEWL, corneometry TEWL corneometry, TEWL corneometry TEWL, SCORAD Corneometry, Corneometry, Endpoints SCORAD, SCORAD, SCORAD, SCORAD, TEWL, Corneometry, body 4 wk; other half untreated body; TID to TID to body; afected areas body + QD cleansing gel 28 d 2 wk lotion skin general and surface as needed to localized areas, 4 wk and forearms afected areas BID to half of BID to Treatment Treatment regimen QD 4 wk entire QD 4 wk entire and BID face BID QD wash; QD to least At BID 4 wk to blinded, split- side Study design Study OL OL 2-arm RCT, OL evaluator- RCT, OL OL a ­ condition mild AD mild AD, no fares 13.9 y mild–mod AD AD AD ), age, ( n ), age, Patient AD 30 pts, 5–19 y, 5–19 y, 30 pts, 1–4 y, 54 pts mean age 24 pts, 42 > 3 pts, y, 3–36 mo, 56 pts, 5–18 y, 33 pts, - c c Clinical studies of moisturizers for the dermatitis of atopic treatment of moisturizersClinical studies for b b c c derm Moistur izer plus body ­ wash Restoraderm Restoraderm ­ Moisturizer raderm lotion and wash ­ regime ­ Cream ­ Cream ­ balm - Cetaphil Restora 2 Table Product Cetaphil - Cetaphil Resto Curel Moisture Moisture Curel Skin barrier: Pediatric studies Pediatric Skin barrier: Atobarrier Avene Xeracalm Xeracalm Avene Nonprescription Moisturizers in Atopic Dermatitis 645 [ 26 ] [ 23 ] Wananukul et al. et al. Wananukul Schario et al. [ 24 ] Schario et al. References De Lucas et al. et al. De Lucas Weber et al. [ 25 ] et al. Weber Weber et al. [ 25 ] et al. Weber dropout No Concomitant medications >3 days TSC TSC >3 days No No No 1% HC; TEWL performed not 16 vs. Codex Codex 16 vs. ( p < 0.038); ↓ TEWL (wk 16) forehead, p = 0.024; - fore arm, p = 0.039 vs. SCORAD Codex; NS diference SCORAD NS vs. NS vs. SCORAD Treatment vs. vs. Treatment untreated vehicle, or active control, comparator Hydration wk ↑ Hydration NA NA NA - treatments treatments ( p < 0.001); ↓ TEWL ( p = 0.03); HC TEWL NS forearm and forearm leg (wk 4 and 12); ↓ TEWL wk forearm, 12, leg, wk 4; ↓ SCORAD ( p < 0.014) (p = 0.035) forearm; ↓ TEWL ( p = 0.061) (trend) cheek ↓ EASI ( p = 0.002) ( p ≤ 0.001) full - panel; ↑ hydra tion ( p ≤ 0.001) lesion in active and sur skin rounding (subgroup) ( p ≤ 0.001) in active lesion and surrounding skin; ↓ ADSI ( p < 0.001) SCORAD both both ↓ SCORAD Treatment vs. vs. Treatment pretreatment Statistical comparisonsStatistical at ↑ Hydration 14 d: ↓ TEWL 28 d: NS; Hydration ↑ Hydration Hydration ↑ Hydration d ­ cream Codex lotion and lotion Codex 1% HC Vehicle, active, active, Vehicle, or untreated Comparators None None None TEWL for TEWL for forehead, leg; forearm, SCORAD TEWL ADSI Corneometry; SCORAD, Endpoints TEWL, EASI Corneometry Corneometry, - body except body except cream face; and face to BID, forearms. 16 weeks HC fare, active other half, to 4 wk lower legs (full lower panel); BID 2 active wk to lesions and sur skin rounding (subgroup) lesions active and surround - ing skin Lotion to entire entire to Lotion half of BID to Treatment Treatment regimen BID 28 days BID 2 wk to BID 2 wk to participant- blinded side Study design Study OL Randomized, OL OL DB, split- RCT, a ­ condition mild–mod AD, no lesions - eczema, predis AD posed to mild–mod y, AD active y, lesions sub - group mild–mod y, AD, active fares mild–mod y, AD, active fares ), age, ( n ), age, Patient AD 19 pts, 6 mo–3 y, 6 mo–3 y, 19 pts, 2–4 y, 38 pts, 3 mo–12 64 pts, 3 mo–12 26 pts, 3 mo–12 29 pts, 3 mo–14 55 pts, b c (continued) c b,d b ­ Cream Relief Body Relief ­ Cream Atopic Atopic ­ Lotion Relief Flare-up Flare-up Relief ­ Treatment ­ Lotion Med Ice Plant Body Care and Lotion Ice Intensive Plant Eucerin Eczema 2 Table Product Dermacare Eucerin Eczema Eucerin Soothing Dr Hauschka Dr Hauschka 646 A. A. Hebert et al. [ 20 ] [ 27 ] Simpson et al. et al. Simpson et al. Simpson Koppes et al. [ 29 ] et al. Koppes Seghers et al. [ 28 ] Seghers et al. References Weber et al. [ 30 ] et al. Weber [ 30 ] et al. Weber mented NR NR None Concomitant medications TCS use docu - TCS No No - ence in ↓ TEWL vs. or ↑ hydration PAI ECC or vs. untreated ( p < 0.05) untreated vs. ( p < 0.01) ↑ hydration minor; untreated vs. in SCORAD, in SCORAD, - TEWL; ↑ hydra HC tion vs. ( p = 0.018) 1 and 2. No difer 1 and 2. No 3. ↓ TEWL vs. All ↑ hydration TEWL NS; change Treatment vs. vs. Treatment untreated vehicle, or active control, comparator NA NS diferences NA NA

( p < 0.001); ↑ TEWL ( p = 0.1); ↑ Hydration ( p < 0.001) ( p < 0.001); ↓ TEWL ( p < 0.05); ↑ Hydration ( p < 0.001) ( p ≤ 0.001); ↓ TEWL ( p < 0.05) ( p = 0.006); ↓ TEWL ( p = 0.035) of lesions active NR NR Treatment vs. vs. Treatment pretreatment Statistical comparisonsStatistical SCORAD ↓ SCORAD ↓ SCORAD ↑ Hydration ↑ Hydration 1. ECC 2. PAI 3. Untreated Untreated Vehicle, active, active, Vehicle, or untreated Comparators None 1% HC None None corneometry corneometry TEWL, corneometry TEWL, corneometry TEWL TEWL TEWL, TEWL, Endpoints SCORAD, SCORAD, SCORAD, Corneometer, Corneometer, on forearm on forearm irritated with SDS 24 h then TID, treated. 5 d leg; other for untreated 27 d afected areas lesions active legs lower lesions active Nonlesional skin Nonlesional 1 lower BID to Treatment Treatment regimen BID 4 wk to all BID 4 wk to BID 6 wk to BID 2 wk to BID 2 wk to blinded tor-blinded Study design Study RCT, evaluator- RCT, - investiga RCT, OL split-side RCT, OL OL a ­ condition AD history AD controlled mild–mod AD active mild–mod AD mild–mod AD mild–mod AD, lesions active ), age, ( n ), age, Patient AD 30 pts, 18–55 y, 18–55 y, 30 pts, 18–65 y, 20 pts, 7–37 y, 40 pts, 23–51 y, 48 pts, 33 > 18 pts, y, 33 > 18 pts, y, c c c b (continued) b c Restoraderm Restoraderm ­ Moisturizer ­ Cream Relief Body Relief ­ Cream ­ Eczema Restoraderm Restoraderm ­ Moisturizer Relief Flare-up Flare-up Relief ­ Treatment Cetaphil Moisture Curel 2 Table Product Eucerin Eczema Dermalex Dermalex Skin barrier: Adult studies Adult Skin barrier: Cetaphil Eucerin Eczema Nonprescription Moisturizers in Atopic Dermatitis 647 [ 33 ] [ 32 ] [ 36 ] et al. [ 31 ] et al. [ 37 ] Nasrollahi et al. et al. Nasrollahi Draelos [ 34 ] Draelos Bomstein et al. et al. Bomstein et al. Gayraud Angelova-Fischer Angelova-Fischer [ 35 ] Wakeman References Simpson et al. et al. Simpson allowed calcineurin inhibitors NR No No No Concomitant medications Oral treatments treatments Oral TCS and TCS in SCORAD, in SCORAD, - TEWL, hydra tx; tion between pH signifcantly Euc - ↑ Linola vs. erinum corneometry ( p < 0.001) vs. untreated between tx for tx for between TEWL, corneom - or SCORAD etry, TEWL improved vs. and hydration - statisti untreated; NR cal analysis ( p < 0.00001); NS no. of fares groups between ( p < 0.05) NS diferences NS diferences Treatment vs. vs. Treatment untreated vehicle, or active control, comparator TEWL and NA NS diferences NS diferences Numerically 59 vs. 39 d 59 vs. 22 vs. 43% fare 43% fare 22 vs. d14 and d21 ( p < 0.001); ↑ Hydration ( p < 0.001); ↓ TEWL ( p < 0.001) (p < 0.001) ( p < 0.01); ↑ Hydration (p < 0.05); ↓ SCORAD ( p < 0.01) ( p < 0.01); ↑ Hydration ( p < 0.01) NR Treatment vs. vs. Treatment pretreatment Statistical comparisonsStatistical SCORAD at ↓ SCORAD ↑ Hydration ↓ TEWL ↓ TEWL anhydricum anhydricum ointment com - pounded with 5% urea Eucerinum Vehicle, active, active, Vehicle, or untreated Comparators Untreated site Untreated None Vehicle 1% HC Untreated Untreated TEWL, corneometry TEWL, corneometry corneometry, corneometry, SCORAD corneometry fare SCORAD, SCORAD, Endpoints SCORAD, SCORAD, Corneometry fare to Time TEWL, TEWL, Incidence of forearms other forearm; untreated body 6 mo 2–3/d 4 wk Treatment Treatment regimen BID 7 days to to BID 7 days BID 3 wk TID 2 wk BID 14 d to BID 6 mo ≥1 ×/day full body Study design Study DB, split-side OL split- OL, RCT, OL OL, split-body ​ RCT ​ RCT a ­ condition mild–mod AD, lesions active mild–severe AD, active lesions mild–mod AD, lesions active mild–mod AD AD history mild–mod AD, lesion active neonates > 3 aged wk ), age, ( n ), age, Patient AD 20 pts, 12–65 y, 12–65 y, 20 pts, 20 > 18 pts, y, 2–45 y, 20 pts, 25 > 18 pts, y, 20–72 y, 32 pts, 123 ≤ 7 pts, y, 124 high-risk c - or b b c d c ­ oil c

Dou - c c (continued) b ­ Repair ­ Soothe ­ cream ­ Cream Skin sive sive oleic acid- moisturizer) Eczema Ther apy Sunfower Sunfower ­ Cetaphil Control Acute Acute Control ­ Cream blebase gel, Receutics Active Active Receutics 2 Table Product Suvex Suvex Incidence of fares and time-to-fare studies and time-to-fare Incidence of fares Atoderm Inten - Linola-F (Lin - Aquaphor, Kamedis CALM Kamedis CALM Eucerin- Atopi 648 A. A. Hebert et al. et al. [ 43 ] et al. [ 40 ] [ 42 ] Angelova-Fischer Angelova-Fischer Åkerström et al. et al. Åkerström Stettler et al. [ 38 ] et al. Stettler Wirén et al. [ 39 ] et al. Wirén [ 44 ] et al. Weber Ma et al. [ 41 ] Ma et al. References McClanahan et al. McClanahan et al. TCS allowed allowed TCS other areas to of body both bathing No No No Concomitant medications Cosmetics and Cosmetics Mild cleanser for 71.4% ( p < 0.01); 60% decline in relapse; ΔTEWL > for V; ↓ SCORAD vs. and ↓ itch V ( p < 0.001); ↑ hydration (p < 0.01) ( p = 0.0129) between groups. between 47 fare: to Time 50 d; incident vs. 14.5% 4 vs. fares: vs. 89 d; 12 wk: vs. 75% fared 50 vs. (p = 0.08) median ( p = 0.01); TEWL NS fared ( p = 0.002); 21 65% fared vs. ( p = 0.006); > 180 30 median d vs. Relapse: 28.6 vs. 28.6 vs. Relapse: Treatment vs. vs. Treatment untreated vehicle, or active control, comparator 22 vs. 15 d 22 vs. SCORAD NS SCORAD Time to fare: 62 fare: to Time >180 vs. 30 d >180 vs. 25.0% 13.2 vs. 22 d Mean 55 vs. in nonlesional skin; higher in lesional treatments TEWL similar Treatment vs. vs. Treatment pretreatment Statistical comparisonsStatistical SCORAD both both ↓ SCORAD with - d out glycerol lient cream choice, as choice, needed Body wash alone Body wash Vehicle Vehicle, active, active, Vehicle, or untreated Comparators Stelatopia emol - Stelatopia Miniderm Untreated Untreated Emollient of hydration, hydration, itch SCORAD, TEWL at 3 wk (fare) Time to fare (d) fare to Time TEWL, Relapse, Endpoints SCORAD, fare SCORAD, Time to relapse, relapse, to Time relapse to Time Incidence of AD fare to Time n = 19 wash + wash lotion body, entire 12 wk and treatment V on forearms, 12 wk nated areas, nated areas, 22 wk nated areas, 6 mo 12 mo body, n = 23; untreated BID BID Bilateral Treatment Treatment regimen BID 3 mo desig - BID to desig - BID to entire to Daily BID 6 mo for tor-blinded body Study design Study ​ RCT ​ RCT ​ RCT - investiga RCT, ​ RCT split- DB, RCT, ​ RCT a ­ condition mo, stabilized mild AD AD cleared AD cleared mild–mod AD, cleared neonates > 3 aged wk mild–mod AD, fares no active history of y, AD, no fares ), age, ( n ), age, Patient AD 108 pts, 2–49 108 pts, 18–65 y, 44 pts, 172 > 18 pts, y, 2–12 y, 64 pts, 100 high-risk 18–65 y, 25 pts, 7 mo–12 43 pts, b c b b b c ­ Lotion (continued) c ­ wash Relief Body Relief ­ Cream raderm lotion and Cream 5% Cream Cream 5% Cream Restoraderm Restoraderm ­ moisturizer ­ SensiDaily Control Control Eucerin Eczema - Cetaphil Resto 2 Table Product Canoderm Canoderm Cetaphil Bepanthen Eucerin- Atopi Nonprescription Moisturizers in Atopic Dermatitis 649 et al. [ 46 ] et al. [ 45 ] De Belilovsky De Belilovsky Mengeaud et al. et al. Mengeaud References casone 0.05% Allowed Concomitant medications Flares: QD futi - Flares: randomized controlled trial, controlled randomized SCORAD between groups; between in fares: decrease 80% pts 93 vs. using 1% HC SCORAD NS SCORAD Treatment vs. vs. Treatment untreated vehicle, or active control, comparator NA ​ RCT patients, QD once daily, ( p < 0.01) both groups; 93% decrease saw in no. of fares ( p < 0.0001); of fares No. from decreased 0.42/mo 2.4 to ( p < 0.0001) SCORAD ↓ SCORAD Treatment vs. vs. Treatment pretreatment Statistical comparisonsStatistical SCORAD ↓ SCORAD Physiogel AI cream, pts AI cream, Physiogel afected areas 1% HC BID to 1% HC BID to Vehicle, active, active, Vehicle, or untreated Comparators None SCORAD, fares SCORAD, Endpoints SCORAD, fares SCORAD, week(s), y year(s) wk week(s), , V vehicle, tx treatment TID three loss, corticosteroids, topical times daily, TEWL transepidermal water body, 3 wk body, TCS for fares for TCS BID to entire entire BID to Treatment Treatment regimen BID 3 mo + QD tion-blinded Study design Study OL observa - RCT, a not reported, applicable, NR not OL open label, PAI signifcant, not NS not ­ condition y, mod AD, y, cleared mild–mod AD, fares active ), age, ( n ), age, Patient AD 108 pts, 6 mo–6 108 pts, 5 mo–5 y, 92 pts, b b moderate, NA mod moderate, (continued) ­ cream ­ Cream lient lient Not marketed in the USA marketed Not the shipped to USA Can buy online in or have All patients had AD, severity, and faring if reported status listed (EASI scores) All patients had AD, severity, in the USA Marketed

Eczema Area and Severity Index, ECC Eucerin mo HC hydrocortisone, Calming Cream, Index, and Severity DB double-blind, EASI Eczema Area BID twice daily, dermatitis, Index, AD atopic Dermatitis ADSI Atopic Severity month(s), sodium dodecyl sulfate, TCS Scoring Dermatitis, sulfate, Atopic SDS sodium dodecyl 2 Table Product a b c d Stelatopia emol - Stelatopia Exomega Emol - Exomega 650 A. A. Hebert et al. and support the skin barrier as well as hydration but also In order for any US moisturizer to be able to make claims include ingredients that reduce inflammation or restore of symptom relief for eczema, the FDA has designated only lipids, depending on the skin pathology being treated. two ingredients as “allowed actives”: (1) under the FDA’s Further, a true therapeutic moisturizer should be clini- OTC External Analgesic monograph, hydrocortisone can cally evaluated and demonstrate efficacy for the respec- claim use for the temporary relief of itching and infamma- tive conditions they are intended to treat [48]. tion due to eczema and (2) under the FDA’s OTC Skin Pro- Therapeutic moisturizers are formulated with ingre- tectant monograph, colloidal oatmeal can claim to provide dients that address the symptoms or contributory fac- temporary skin protection and relief of minor skin irritations tors that may exacerbate the severity of the disease or and itching due to eczema [51]. These efects have been condition (e.g., itch, inflammation, barrier disruption, previously established in the literature and thus approved by ceramide deficiency). The formulation should have the the FDA. If a product does not contain either hydrocortisone physical properties that provide adequate absorption of or colloidal oatmeal, nor comply with the regulations in the ingredients and a pH of 4–5 to re-establish the normal relevant OTC monographs, no claims can be made regarding physiological pH of skin. An aesthetically elegant product eczema relief. can potentially improve compliance. In the USA, AD therapeutic moisturizers are nonpre- scription and may be classifed as either cosmetic formu- 4.1 Classifying Moisturizers lations or OTC drug products; these products typically avoid ingredients that may exacerbate diseased skin, such Understanding where therapeutic moisturizers for AD ft in as fragrances [2, 50]. among the plethora of topical agents can be complicated. Several prescription barrier creams (e.g., Atopiclair, The FDA classifes topical products as cosmetics, over-the- EpiCeram) are indicated for AD. Categorized as class II counter (OTC) drugs, prescription drugs, or prescription medical devices, these require a premarket FDA 501(k) medical devices (Table 3). Cosmetic products are limited submission, whereby the device must demonstrate “sub- by the FDA to only claim efects on the appearance of the stantial equivalence” to already approved medical devices. skin (per the US Federal Food and Cosmetic Act of 1938). These products do not need to demonstrate safety and Drugs are agents that have a pharmacologic action; prescrip- clinical efcacy through rigorous clinical trials mandated tion drugs require extensive clinical testing and approval by by the FDA new drug application process [3]. Studies of the FDA before being introduced to the market. OTC drugs barrier creams have shown them to be safe and to reduce must comply with their relevant OTC drug monograph, a the incidence of fares [5, 52]; however, several compara- guidance of acceptable ingredients and concentrations, dis- tive studies have shown no greater efcacy than achieved ease indications, claims, dosing, and labeling. In contrast to with nonprescription moisturizers [53, 54]. Notably, many prescription drugs, products conforming to existing OTC of the ingredients included in barrier creams when frst drug monographs can be marketed without FDA approval. developed (e.g., ceramides, NMFs) are now included in

Table 3 US FDA categorization of topical products used in atopic dermatitis Cosmetics (appearance or cleans- Drugs (agents with pharmacologic action) Medical devices (physically medi- ing): available without prescription ated efects): requires prescription OTC nonprescription drugs Prescription drugs

FDA regulated, not FDA approved FDA regulated, not FDA approved FDA approval requires NDA with Premarket 501(k) submission demonstration of safety and requires demonstration of efcacy required substantial equivalence to an existing barrier cream (limited clinical efcacy testing part of device application) Limited to claim only efects on Comply with FDA OTC drug Barrier cream products have the appearance of the skin monographs physically (not chemically) mediated efects No claims of efects on structure, For eczema, only products function, or disease treatment containing 0.007–2% colloidal allowed oatmeal (OTC skin protectant) or 1% HC (OTC external analgesic) are allowed to make claims about efects on eczema symptoms

HC hydrocortisone, NDA new drug application, OTC over the counter Nonprescription Moisturizers in Atopic Dermatitis 651 nonprescription moisturizers formulated for the treatment skin-protectant, anti-infammatory, antioxidant, and anti- of eczema [3]. Moreover, barrier creams are more expen- pruritic efects. The starches and β-D-glucans in oatmeal sive than nonprescription products [3, 53], and insurance help to create an occlusive barrier that both moisturizes and coverage may be improbable. relieves itch, whereas antioxidants such as avenanthramides, vitamin E, and ferulic acid have demonstrated anti-infam- 4.2 Therapeutic Moisturizers for the Treatment matory activity [51]. of AD Ceramides are important barrier lipids in preventing TEWL. Moisturizers may address ceramide defciencies in For AD, therapeutic moisturizers need to provide essential AD by adding them to the formulation, by adding ingredi- barrier care (Table 4). Several AD therapeutic moisturiz- ents that can upregulate de novo ceramide production (e.g., ers have demonstrated their ability to decrease TEWL and urea [62, 63], niacinamide [64]), or by changing the physi- increase skin hydration (e.g., Cetaphil Restoraderm mois- ologic milieu to support and promote ceramide production turizer and wash, Eucerin Eczema Body Cream, Eucerin (e.g., lactic acid [62, 65]). Flare-Up Treatment) and reduce the number of fares (e.g., Canoderm Cream, Eucerin Eczema Relief Body Cream, Eucerin AtopiControl Lotion) (see Table 2). 5 Maximizing Outcomes for Patients Sometimes termed “emollient plus” [2], AD therapeutic with AD moisturizers go beyond basic emollients to include ingredi- ents that provide skin protection, essential lipids, and anti- Healthcare providers can maximize patient outcomes by pruritic, anti-infammatory, and antioxidant properties to stressing the benefts of daily emollient therapy to their help counter the symptoms of AD (Table 5). patients, particularly highlighting fare prevention. Evidence Colloidal oatmeal contains a mixture of various der- has consistently shown that daily application of a therapeutic matologic active compounds that provide moisturizing,

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

Strengthens the barrier that protects against environmental triggers (e.g., skin irritants, aeroallergens, dust mites, pet dander) Decreases moisture loss that perpetuates damage and can provoke infammatory processes Promotes a healthy microbiome via induction of antimicrobial peptides Maintains stratum corneum acidifcation, which protects against pathogens Reduces recurrence of fares when used daily Prevents onset of atopic dermatitis when applied early in life to at-risk children

Table 5 Key ingredients in nonprescription therapeutic moisturizers for atopic dermatitis Therapeutic properties Examples of ingredients

Skin protectant Colloidal ­oatmeala [51] Antipruritic Hydrocortisoneb, ­mentholc, pramoxine HCl­ c, menthoxypropan- ediol [55, 56], colloidal ­oatmeala [51] Anti-infammatory Licochalcone A [57], ­hydrocortisoneb, colloidal ­oatmeala [51] Antioxidant Glycyrrhetinic acid [58], licochalcone A [57] Essential barrier lipids Ceramides [59], plant oils rich in linoleic acid [60], urea (to upregulate ceramide production) NMF Lactic acid, amino acids, PCA, urea [61] pH bufer Acidic bufers optimizing pH between 4 and 5 (e.g., citric acid)

NMF natural moisturizing factor, OTC over the counter, PCA pyrrolidone carboxylic acid a Active ingredient under the US FDA Skin Protectant OTC drug monograph allowed to claim use for eczema indication and the temporary relief of its symptoms b Active ingredient under the US FDA External Analgesic OTC drug monograph, allowed to claim use for the temporary relief of itching and infammation due to eczema c Active ingredient under the US FDA External Analgesic OTC drug monograph, allowed to claim use for the immediate relief of itching due to minor skin irritations, infammation, and rashes due to eczema 652 A. A. Hebert et al. moisturizer improves the skin barrier and reduces the num- 7 Conclusions ber and frequency of fares. These outcomes can result in greater quality of life and potential cost benefts by reducing Therapeutic moisturizers should be used daily as the bed- the number of lost days at work [66]. For neonates, those at rock of AD management, underlying all additional treat- high risk of developing AD can delay or even avoid AD by ments. Evidence has shown that, in many cases, reinforc- proactive treatment with a therapeutic moisturizer (primary ing a back-to-basics approach with daily moisturization can prevention) [37]. be sufcient for the treatment of mild AD, strengthening Recommending clinically proven therapeutic moistur- the skin barrier and reducing the symptoms and outbreaks izers to patients is key to a successful therapeutic out- of AD. This review identifed several proven and available come. Instructions should stress that moisturizers should consumer products that have been clinically tested using be applied liberally and daily—ideally twice. Recommen- objective measures. Understanding what makes a moistur- dations should be based on formula composition and the izer therapeutic, and how they difer from cosmetic products strength of clinical data supporting the formulation [48]. and prescription barrier creams, will help healthcare provid- Clinical demonstrations should include both objective ers make informed choices to optimize outcomes for their measures of skin hydration and TEWL and validated clini- patients. Healthcare provider recommendations on the right cal scales to assess symptom improvement. Product selec- choice of moisturizers for the patient should be based on tion should also consider patients’ experience and prefer- clinical evidence and patients’ preference and willingness ence [67, 68], as therapeutic efcacy can be provided in to use. Twice-daily moisturization should be the mainstay aesthetically pleasing, lighter formulations that can improve of treatment for AD. compliance. Topical corticosteroids are generally recommended as the Acknowledgements The authors thank Jodie Macoun, PhD, Cube next step in the treatment of AD, particularly for the targeted Information Ltd, for editorial assistance in the preparation of this manuscript, funded by Beiersdorf Inc. treatment of fares. Topical steroid formulations may include penetration enhancers designed to enhance the delivery of Author Contributions AAH: Conception and validation of the pro- active steroid to its target, which may weaken the barrier. ject, drafting of initial manuscript, critical review, approval of the Consequently, maintaining daily moisturization is important fnal manuscript. TMW: Conception of the project, drafting of initial when topical steroids are added to the treatment regimen manuscript, critical review and revision of the manuscript, approval of the fnal manuscript. FR: Contribution of data collection and data [50]. analysis, critical review and revision of the manuscript, approval of the fnal manuscript. NHN: Conception and validation of the project, critical review, approval of the fnal manuscript.

6 Limitations Compliance with Ethical Standards

This review does not attempt to assess the quality of the Funding A.A. Hebert and N.H. Nicol received compensation from studies reviewed (extensively evaluated by van Zuuren et al. Beiersdorf Inc. for time spent preparing this manuscript. Beiersdorf [15]) but rather presents a practical guide for the clinician of Inc. funded editorial assistance by Jodie Macoun, PhD, Cube Informa- tion Ltd, as well as Open Access of this article. therapeutic moisturizers and the data and studies that sup- port their use. Minimal clinically important diferences (MCIDs [69]) Conflicts of interest In the previous 12 months, Adelaide A. Hebert has received honoraria from Beiersdorf, Biofrontera, Cassiopea, Der- were not addressed in any of the cited publications or this mira, Dermavant, Ferrer, Galderma, La Roche-Posay, Novartis, Ortho, review because of a lack of information on both thresholds ReLife, and Sun and research grants from Cutanea, Brickell, Cassio- for objective biophysical measures (TEWL and corneome- pea, Dermira, GSK, Leo, Mayne, Novan, Pfzer, Promius, Sienna, and try) and MCID evaluations for nonprescription interventions SymBio. In the previous 12 months, Noreen Heer Nicol has served as an advisory board member for Eli Lilly & Co. Frank Rippke and for patients with mild to moderate conditions. Instead, we Teresa Weber are employees of Beiersdorf. took a positive statistical diference in TEWL, corneometry, and reduction of fare incidence as evidence of the product Open Access This article is licensed under a Creative Commons Attri- being benefcial to the patient. bution-NonCommercial 4.0 International License, which permits any Furthermore, we focused on the efects of the products non-commercial use, sharing, adaptation, distribution and reproduc- tion in any medium or format, as long as you give appropriate credit on clinical and biophysical skin measures. It is beyond the to the original author(s) and the source, provide a link to the Creative scope of this review to classify the products as being occlu- Commons licence, and indicate if changes were made. The images or sive, humectant-enriched, or therapeutic, as many of them other third party material in this article are included in the article’s may span several classes. Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory Nonprescription Moisturizers in Atopic Dermatitis 653 regulation or exceeds the permitted use, you will need to obtain permis- 16. Breternitz M, Kowatzki D, Langenauer M, Elsner P, Fluhr JW. sion directly from the copyright holder. To view a copy of this licence, Placebo-controlled, double-blind, randomized, prospective study visit http://creat​iveco​mmons​.org/licen​ses/by-nc/4.0/. of a glycerol-based emollient on eczematous skin in atopic derma- titis: biophysical and clinical evaluation. Skin Pharmacol Physiol. 2008;21:39–45. 17. Na JI, Hwang JS, Park HJ, Kim DH, Park WS, Youn SW, et al. A new moisturizer containing physiologic lipid granules alleviates References atopic dermatitis. J Dermatolog Treat. 2010;21(1):23–7. 18. 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