Dermatol Ther (Heidelb) (2021) 11:315–325 https://doi.org/10.1007/s13555-021-00495-y PRACTICAL APPROACH The Role of Photoprotection in Optimizing the Treatment of Atopic Dermatitis Jaime Piquero-Casals . José Manuel Carrascosa . Daniel Morgado-Carrasco . Mridvika Narda . Carles Trullas . Corinne Granger . Gabriella Fabbrocini Received: December 22, 2020 / Accepted: January 23, 2021 / Published online: February 13, 2021 Ó The Author(s) 2021 ABSTRACT free radicals that can damage proteins, lipids, and DNA. The sum of the external factors that Atopic dermatitis (AD) is a chronic inflamma- an individual is exposed to throughout their tory skin disease with an estimated prevalence lifetime is termed the exposome. Environmen- of 10–15% in children and 2–10% in adults. tal factors such as sun exposure, temperature, Clinically, there is notable phenotypic variabil- and humidity contribute to both AD flares and ity driven by a complex interaction between regional prevalence variation. Literature on genetics, immune function, and the environ- photoprotection in atopic dermatitis is very ment. Impairment of the skin barrier plays a scarce. The use of adequate sunscreens in atopic significant role in the pathogenesis of AD. The dermatitis can ensure the level of photoprotec- apparent beneficial effect of sunlight in patients tion required to prevent skin photoaging and with atopic eczema is questioned due to its skin cancer and to mitigate skin barrier dys- capacity to disrupt the skin barrier and generate function, decrease inflammation, and neutral- ize facial redness. Herein we discuss and review the role of UV radiation and the exposome in the etiology of AD, as well as the role of ade- J. Piquero-Casals (&) quate photoprotection. Dermik, Multidisciplinary Dermatology Clinic, Barcelona, Spain e-mail: j.piquero@dermik.es Keywords: Atopic dermatitis; Eczema; Expo- J. M. Carrascosa some; Nonpharmacologic; Photoprotection; Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma of Skin barrier; Sunscreens; Ultraviolet radiation Barcelona, IGTP, Badalona, Spain D. Morgado-Carrasco Department of Dermatology, Hospital Clı́nic de Barcelona, Universitat de Barcelona, Barcelona, Spain M. Narda  C. Trullas  C. Granger Innovation and Development, ISDIN, Barcelona, Spain G. Fabbrocini Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy 316 Dermatol Ther (Heidelb) (2021) 11:315–325 understanding of the article. To view digital Key Summary Points features for this article go to https://doi.org/10. 6084/m9.figshare.13615931 A topic dermatitis is a common inflammatory skin disease characterized by recurrent eczematous lesions and INTRODUCTION intense itch that can have an adverse effect on quality of life. Atopic dermatitis (AD) is a multifocal disease with a complex pathogenesis. Different triggers Key pathogenic mechanisms include a are involved in AD within the context of atopic dysfunctional epidermal barrier and type diathesis and hypersensitivity reactions of 2-dominated cutaneous inflammation, organs (including skin) that may be caused by which can be targeted by innovative causative factors (physical constitution) and the biological and small-molecule therapies. vulnerability of barrier function [1]. Exposure to solar radiation is today recog- The diagnosis is made clinically, and nized to be a major causative factor of several management consists of education, the dermatological pathologies that range from skin avoidance of triggers that can exacerbate cancer and actinic keratosis, inflammatory der- the condition, skin care measures, and matoses (including AD), and photoaging. The various treatment options. use of topical sunscreens to prevent photoaging Despite progress in the development of and skin cancer is an integral part of the strat- systemic drugs, topical treatments egy for reducing skin exposure to solar radia- continue to be essential for both barrier tion, in combination with other methods such function repair and the delivery of anti- as using protective clothing and avoiding out- inflammatory molecules. door activities during hours corresponding to peak solar radiation [2]. Photoprotection in AD Natural factors such as ultraviolet patients, however, serves dual objectives: radiation (UVR), temperature, and ensuring an adequate level of sun protection humidity also contribute to both AD flares and suppressing the exacerbation of signs and and regional prevalence variation. symptoms of AD that may be induced by solar Exposure to solar ultraviolet radiation can exposure. Unfortunately, adverse skin reactions reduce skin barrier function, and to sunscreens can be common in AD patients. sunscreen use can help to protect against Patients with AD may be at greater risk as they this UV-induced skin barrier impairment. are exposed to a wide variety of potential aller- gens from these products. As such, the recom- Sunscreen-containing moisturizers have mendation that sunscreens should be used dramatically improved photoprotection requires special consideration for AD patients. compliance. These products can provide Another critical aspect to consider is the itching moisturization by decreasing symptomatology, which benefits from the use transepidermal water loss through the of ingredients with emollient and anti-inflam- creation of an environment that is matory properties, as they can help to recover optimal for barrier repair. and maintain skin barrier function. To further complicate matters, while some reports suggest that sun exposure may worsen patient condi- tion, these patients generally enjoy relief from symptoms in the summer months, suggesting DIGITAL FEATURES that some sun exposure may be beneficial [3]. Therefore, the sunscreen recommendation for This article is published with digital features, AD patients must consider this dichotomous including a summary slide, to facilitate relationship between AD and photoexposure. It Dermatol Ther (Heidelb) (2021) 11:315–325 317 is important to understand the unique needs of Exposure to solar UV radiation can reduce the AD patient when attempting to optimize skin barrier function because it can have dra- photoprotection in this context. matic effects on cell cohesion and mechanical The aim of this review is to discuss the fac- integrity that are related to its effects on the tors that make the photoprotection needs of AD intercellular components of the SC, including patients unique, and to provide recommenda- intercellular lipids and corneodesmosomes. tions regarding the characteristics of sunscreens Sunscreen use can help to protect against this for these patients. This article is based on pre- UV-induced skin barrier impairment [9]. Emol- viously conducted studies and does not contain lient-rich moisturizers are the cornerstone of any studies with human participants or animals AD management because they improve barrier performed by any of the authors. Patients gave function, reduce xerosis, itch, and flares, and their written consent for the publication of reduce the need for anti-inflammatory medica- photographs. tion [10]. Sunscreens containing ingredients that have emollient properties and can protect and repair the skin barrier should be recom- ULTRAVIOLET (UV) RADIATION mended in AD patients. AND SKIN BARRIER DYSFUNCTION Sunlight can be a friend or foe to those living with AD. The relationship between AD and The complex interplay among genetics, skin photoexposure is marked by a peculiar dichot- barrier deficiency, immunological derange- omy. The majority of AD patients benefit from ment, and pruritus contributes to the develop- UV radiation therapy and from exposure to the ment, progression, and chronicity of AD. sun in a controlled natural setting [11, 12]. Abnormalities in filaggrin (FLG), other stratum However, an estimated 10% of patients are corneum (SC) constituents, and tight junctions reported to show photoaggravation [13]. At (TJs) induce and promote skin inflammation least two studies from Japan have reported [4]. patients with AD who suffer from recalcitrant FLG is a key epidermal barrier protein facial erythema related to sun exposure [14, 15]. required for the formation of the SC, and is Deguchi et al. [15] demonstrated that 41 (55%) influenced by environmental factors such as of 74 AD patients with persistent facial ery- climate, pollution, and the microbiome [5]. SC thema had experienced exacerbation of the homeostasis relies greatly on FLG and its facial lesions after sun exposure. In 28 of those metabolic process. Epidermal barrier proteins 41 patients, the exacerbation lasted for more also include transglutaminases, keratins, lori- than 48 h. This long-lasting response is consid- crin, intercellular proteins, and TJs. Together, ered to be true photoaggravation by UV all of these form a permeability barrier between radiation. adjacent cells and involve cell adhesion [6]. FLG Photosensitivity in AD is a well-known but is known to be decreased in the epidermis of AD ill-defined phenomenon that seems to be more patients [7], and null mutation of the FLG gene frequent in women, which should be kept in is the strongest risk factor for AD. Due to the mind [16]. This can be difficult to recognize in compromised barrier function, various allergens clinical practice, as the symptoms may also be can easily penetrate into the skin and are more explained by other simultaneous exposures, likely to induce contact dermatitis. The pene- such as humidity, heat, scratching, pollen tration of aeroallergens and irritating microor- exposure, or psychological factors. Also, some ganisms into the dermis contribute to the Th2 skincare products and comorbidities such as immune response observed in lesions [8]. Type polymorphous light eruption could mask or 2 cytokines inhibit the expression of structural worsen the sensitivity to UV radiation [17]. In a cornified barrier proteins such as FLG, loricrin, retrospective analysis of 17 patients with long- involucrin, antimicrobial peptides (AMPs), and standing AD who suddenly developed photo- TJs. sensitivity to UVA, the onset of photosensitivity was reported during spring and summer and 318 Dermatol Ther (Heidelb) (2021) 11:315–325 during exposure to artificial UVR as part of the and squamous cell carcinoma (SCC) and require patients’ treatment regimen [13]. adequate photoprotection measures [24]. Although atopic dermatitis is widely known to be a dermatological condition, the systemic Exposome and Skin Barrier Dysfunction nature of the disease must not be ignored, as indicated by some of the comorbidities. Apart The exposome is defined as the sum of all fac- from allergic conditions, these comorbidities tors that have an effect on skin aging [25]. include an increased risk of cardiovascular dis- Exposomal factors can be categorized into ease, certain cancers, as well as a range of nonspecific (human and natural factors affect- autoimmune and neuropsychiatric diseases ing populations), specific (e.g., humidity, [18]. Systemic immunosuppressive agents that ultraviolet radiation, diet, pollution, allergens, are used to treat moderate to severe AD, such as water hardness), and internal (cutaneous and cyclosporine and azathioprine, increase photo- gut microbiota and host cell interactions) sensitivity and the risk of skin cancer [19]. exposures. Pityriasis alba (PA) is a localized hypopig- AD is susceptible to aggravation by several mented disorder of childhood. It is a hallmark intrinsic or environmental factors (Fig. 1). Flare- of eczema and probably the clinical expression ups may be instigated by allergic or irritant type of an impaired skin barrier in AD patients [20]. responses triggered by viral infections, food and Although PA is very common in children and environmental allergens, cosmetics (especially adolescents with AD, the cause of PA is still perfume), and weather, among other factors unknown. As PA frequently involves facial skin, [26]. Some studies have reported contact sensi- sun exposure may be considered one of the tivity in patients with recalcitrant AD [27]. In a factors involved in the multifactorial mecha- recent retrospective Spanish study, one-third of nism of PA development. Hypopigmentation patients with therapy-resistant AD showed a may be caused by inflammation and an inabil- benefit after positive patch testing and avoiding ity to transfer melanosomes to surrounding the substances that they were sensitized to [28]. keratinocytes. Treatment is often bypassed Exacerbations of AD have been observed because of the self-resolving nature of the con- with greater concentrations of particulate dition, the high cost of treatment options, and a (PM10, PM2.5) and gaseous (NO2, volatile slow response to therapy. Mild cleansers and organic compounds, O3, SO2) air pollutants in sunscreens are recommended in PA, though several studies [29]. The mechanisms through they will not clear PA lesions [21]. which air pollution-induced health effects are Elderly AD must be considered a separate mediated are poorly understood. As air pollu- clinical type of the disease because of its dis- tion-induced health effects require the pene- tinguishing manifestations that differ from the tration of pollutants into the skin, skin barrier childhood manifestation. Apart from the integrity is probably involved. appearance of lichenified eczema at the ante- Additional lifestyle factors that impact AD cubital and popliteal fossa, AD can present in are frequent detergent use, hard water, and the elderly with atypical clinical phenotypes diet [30, 31]. Sleep disturbance is frequently such as prurigo nodularis, nummular eczema, or reported by AD patients. The impact of the generalized eczema more frequently than in itch–scratch cycle and secondary effects of other age groups. On the other hand, older inflammatory cytokines on sleep regulation patients often suffer from asteatosis and pruri- have been described in these individuals [32]. tus due to physiologic skin aging and comor- bidities, for which they take medications that may worsen pruritus and dry skin [22]. SUNLIGHT AND PHOTOTHERAPY Finally, some studies even suggest a reduced risk of malignant melanoma (MM) among AD Controlled sun exposure has several benefits for patients [23], but they have an increased risk of AD patients. In addition to affecting the epi- other skin cancers as basal cell carcinoma (BCC) dermal barrier, UV exposure also modifies the Dermatol Ther (Heidelb) (2021) 11:315–325 319 Fig. 1 Solar UV radiation and other exposome factors in AD immune reaction. The effect on the immune carcinogenesis. The use of artificial lamps that system can either be primarily a local effect on emit narrow-band UVB at 311 nm (NB-UVB) is the cutaneous immune system and/or it can recommended in AD. Medium-dose ultraviolet extend to the systemic immune response. Due A 340–400 nm (UVA1) appears to be as effective to its profound effects on exposed cells and on as NB-UVB but is more time-consuming [39]. local and systemic immune systems, UV can be Phototherapy using UVA1 and NB-UVB could used quite effectively in skin phototherapy for be prescribed for selected AD patients. The AD patients [33]. results from a recent study (Pacifico et al. [40]) UV radiation may also increase the thickness in adult patients with severe AD emphasize that of the stratum corneum though a phenomenon UVA1 phototherapy should be considered called photohardening [34], and reduce the among the first approaches in the treatment of colonization of Staphylococcus aureus in the skin, patients with severe generalized AD. This study thus preventing the well-known superantigen- also demonstrated that in darker-skinned linked exacerbations of AD [35]. Several studies patients, a high dose of UVA1 is more effective have suggested that higher temperatures and than a medium dose of UVA1. NB-UVB appears lower latitudes may be associated with a lower to be similarly effective to medium-dose UVA1 prevalence of AD [36–38]. Also, sun exposure but is less time-consuming. On the other hand, can improve the mood, which is essential for a UVB excimer laser and excimer lamp might be AD patients who suffer from this chronic dis- the best options for clearing localized therapy- ease that can limit their daily activities. On the resistant lesions [40]. other hand, the long-term cumulative damage of solar radiation includes photoaging and skin 320 Dermatol Ther (Heidelb) (2021) 11:315–325 AD AND VITAMIN D Although avobenzone and octocrylene are involved in allergic and photoallergic contact Solar radiation exposure of the skin is the main dermatitis (PACD) reactions [50], the available source of vitamin D. Low levels of vitamin D, data show that they are rare sensitizers and may especially vitamin D3, have been linked to be considered safe [51]. Octocrylene is a pho- dermatological disorders, including AD [41, 42]. tostable UVB and UVAII absorber that photo- Furthermore, vitamin D supplementation may stabilizes avobenzone and works with other UV provide a modest benefit in AD, particularly filters to deliver broad photoprotection. during winter disease flares [43]. As such, it may appear that the regular use of sunscreen may be counterproductive for vitamin D levels. How- SUNSCREENS FOR AD PATIENTS ever, a cross-sectional, nationally representative survey of 5920 adults aged 18–60 years in the US People affected by AD can be especially vulner- showed that frequent sunscreen did not able to UV light and can find it more of a decrease vitamin D levels [44]. Sunscreens do challenge to find sunscreen products that work not completely block the cutaneous absorption for their skin. Sunscreen-containing moisturiz- of UVR; a minor fraction of UVB radiation ers have dramatically improved photoprotec- penetrates the skin, even through high-SPF tion compliance. These products can provide sunscreens [45]. moisturization by decreasing transepidermal water loss (TEWL) through the creation of an environment that is optimal for barrier repair. SUNSCREENS AND CONTACT DERMATITIS The Vehicle in AD Sunscreens Patients with AD present skin barrier dysfunc- tion and increased penetration of allergens, Using an appropriate combination of ingredi- they frequently use emollients and topical ents in a sunscreen formula has the potential to medications, and they may be predisposed to mitigate barrier dysfunction in AD patients developing allergic contact dermatitis (ACD) (Table 1). The use of occlusive agents such as [46]. ACD is an important comorbidity and can dimethicone and petrolatum as well as humec- exacerbate AD. tants such as glycerin and hyaluronic acid can Contact dematitis or phototoxic and pho- help to restore the corneocyte and intercellular toallergic cutaneous reactions to topical sun- lipid organization [52]. Topical dexpanthenol screens are rare in the general population and acts like a moisturizer, improving stratum cor- can be due to UV filters, fragrances, preserva- neum hydration, stimulating epithelialization, tives, or other ingredients. Repeated exposure to reducing TEWL, and maintaining skin softness UV filters due to their presence in nonsunscreen and elasticity [53]. Dexpanthenol also mitigates cosmetic products possibly facilitates sensitiza- the itching. Another ingredient is bisabolol, an tion and may explain why some patients react active plant extract that is isolated from Ger- to chemically unrelated UV filters [47]. Since man chamomile and thought to have anti-irri- allergic/photoallergic reactions to sunscreens tant, anti-inflammatory, and skin-soothing may be less rare in AD patients, adverse reac- properties [54]. tions to sunscreens should be minimized. For Two other functional ingredients used in this reason, is important for dermatologists to sunscreen vehicles that are suitable for skin with be aware of reactions to active UV filters [48], atopic dermatitis are alpha-tocopherol and and a photopatch test should always be per- ectoine. Topical application of alpha-toco- formed in the case of suspected contact sensi- pherol, the most prominent naturally occurring tivity to these products [49]. Among chemical form of vitamin E, inhibited UVB-induced filters, benzophenone-3 (oxybenzone) is the photocarcinogenesis and DNA photodamage in leading allergen and photoallergen [48]. C3H mice in vivo [55]. On the other hand, Dermatol Ther (Heidelb) (2021) 11:315–325 321 Table 1 Criteria for sunscreens suitable for skin with atopic dermatitis Criteria for sunscreens suitable for skin with atopic dermatitis Avoids patient-specific AD triggers Mineral-based sunscreen ingredients: titanium dioxide (TiO2) and zinc oxide (ZnO) or a combination of chemical and inorganic filters Improved sensory attributes for better compliance SPF 30 or greater Provides broad-spectrum protection from both UVB and UVA rays Lightweight texture that protects and repairs an impaired skin barrier Water resistant Noncomedogenic and formulated to minimize skin allergies (hypoallergenic) Contains functional vehicle ingredients such as dexpanthenol, ectoine, vitamin E, bisabolol Table 2 Summary of useful nonfilter ingredients in sunscreens for AD patients Ingredient Property Dexpanthenol Moisturizer; improves stratum corneum hydration, reduces transepidermal water loss, maintains skin softness and elasticity, and mitigates itch Vitamin E (alpha- Antioxidant; inhibits UVB-induced photocarcinogenesis and DNA photodamage tocopherol) Ectoine Water-binding properties; topical application was shown to improve skin hydration and barrier function in AD subjects Bisabolol Anti-irritant, anti-inflammatory, and antimicrobial properties; relieves pruritus ectoine is a low-molecular tetrahydropyrim- red and inflamed, hypersensitive, and warm. idine ingredient with water-binding properties. Light, refreshing O/W emulsions that allow Topical application was shown to improve skin perspiration may therefore be appropriate dur- hydration and barrier function in mild to ing this phase. Moisturizing sprays can also be moderate AD [56] (Table 2). comfortable and easy-to-use options. Regarding the age of the patient, children benefit from Prescribing a Sunscreen for a Specific W/O vehicles and physical filters, whereas ado- Patient with AD lescents need noncomedogenic products and sometimes tinted sunscreens for camouflage. It When a physician prescribes a topical drug or is important to note that unctuous creams can cosmetic for the treatment/management of AD, have an occlusive effect and generate miliaria or he or she takes into consideration the age of the acneiform eruptions. When chronic eczema patient, the affected area, and the activity phase (hyperpigmented and thickened lichenified of the eczema. The same holds true for sun- plaques) affects nonfacial areas, it is very screens. In the acute phase, the lesional skin is important to provide hydration and W/O sun- screens. The physical activity of the patient is 322 Dermatol Ther (Heidelb) (2021) 11:315–325 also very important. When performing outdoor inorganic particulate filters (zinc oxide and sports such as running or tennis, water-resistant titanium dioxide) is UVB/UVA, and these UV sunscreens or even products that can be applied filters show low rates of sensitization and low to wet skin are needed. Furthermore, they allergenic potential. The first generation of should be safe in the event of accidental contact these inorganic UV filters yielded an unsatis- with the eyes. factory whitened appearance when they were applied to the skin due to their large particle Choosing UV Filters for AD Sunscreens size and high refractive index. However, the micronized versions of these particles, nano UV filters are the active ingredients of sunscreen zinc oxide and nano titanium dioxide, are products, and can be classified into organic almost completely transparent and as such (chemical) and inorganic UV filters. Organic more cosmetically appealing. Although con- filters can absorb UVB, UVA, or both radiations cerns have been raised about the ability of these through their aromatic moieties, while inor- metal oxide nanoparticles to penetrate into the ganic filters attenuate UVB/UVA mainly by skin and generate reactive oxygen species, absorption, along with some scattering. UV fil- published studies suggest that the microsized ters are regulated globally as either cosmetics, and nanosized ZnO and TiO2 particles used in quasi-drugs, or over-the-counter (OTC) drugs. sunscreen products do not penetrate into the Prior to their approval, UV filters are subjected skin, they are not toxic, irritating, sensitizing, or to a stringent level of testing to detect possible photosensitizing, and they do not pose a risk to safety issues. Despite this, the safety of sun fil- humans [57]. ters has been challenged on the basis that they The use of a combination of liposoluble and may cause contact and photocontact allergies, water-soluble UV filters may allow the total may be endocrine disruptors, or may penetrate amount of UV filters needed to achieve broad- the skin, resulting in systemic exposure. Before spectrum sun protection to be reduced, which recommending a sunscreen product for a sub- could decrease adverse skin reactions and the ject with AD, the patient should be asked about impact of the sunscreen on the marine previous irritant or ACD and/or photoallergic/ environment. phototoxic cutaneous reactions. It is important to recommend a broad-spectrum sunscreen that CONCLUSION has been developed to minimize the incidence of skin allergies, and to instruct the patient to AD is a chronic and highly prevalent skin dis- apply a small amount of the sunscreen on the order [58] that can seriously degrade quality of inside of the forearm for a few days to check if life. UV radiation plays an important role in the there is a skin reaction. If the AD subject does pathogenesis of AD and can aggravate this dis- not have a prior history of intolerance to order. Appropriate skin care, including the reg- chemical filters, a broad-spectrum sunscreen ular use of moisturizers, is the cornerstone of that has an SPF of 30 or higher and is based on therapy for AD. Due to the propensity of AD chemical filters or on a combination of chemi- patients to suffer from dryness, pruritus, and cal and inorganic filters should be recom- impairment of the skin barrier, broad-spectrum mended. These types of sunscreens have better sunscreens for AD patients should ideally con- sensory attributes and consumer compliance tain ingredients that have emollient/moisturiz- than sunscreens based only on inorganic filters. ing properties and can repair the skin barrier. For AD subjects with a history of ACD or pho- These adequately formulated sunscreens will toallergic/phototoxic cutaneous reactions deliver the required UVB/UVA protection while induced by chemical sun filters, a broad-spec- also moisturizing the skin, repairing skin barrier trum sunscreen with an SPF of 30 or higher that dysfunction, relieving itch, and possibly reduc- is based exclusively on physical (inorganic) fil- ing inflammation and providing camouflage. ters is best. The UV action spectrum of the Dermatol Ther (Heidelb) (2021) 11:315–325 323 ACKNOWLEDGEMENTS REFERENCES 1. Munera-Campos M, Carrascosa JM. Innovation in Funding. The journal’s Rapid Service Fee was atopic dermatitis: from pathogenesis to treatment. supported by ISDIN. Actas Dermosifiliogr. 2020;111(3):205–21. 2. Krutmann J, Passeron T, Gilaberte Y, Granger C, Authorship. All named authors meet the Leone G, Narda M, Schalka S, Trullas C, Masson P, International Committee of Medical Journal Lim HW. Photoprotection of the future: challenges Editors (ICMJE) criteria for authorship for this and opportunities. J Eur Acad Dermatol Venereol. article, take responsibility for the integrity of 2020;34(3):447–54. the work as a whole, and have given their 3. Napolitano M, Monfrecola G, Fabbrocini G, Fattore approval for this version to be published. D, Patrı́ A, Patruno C. Impact of sun exposure on adult patients affected by atopic dermatitis. G Ital Disclosures. Jaime Piquero-Casals, José Dermatol Venereol. 2020;17. Manuel Carrascosa, Daniel Morgado-Carrasco 4. Rerknimitr P, Otsuka A, Nakashima C, Kabashima and Gabriella Fabbrocini served as a consultant K. The etiopathogenesis of atopic dermatitis: barrier to ISDIN. Mridvika Narda, Corinne Granger, disruption, immunological derangement, and pru- and Carles Trullas are employed by ISDIN. ritus. Inflamm Regen. 2017;5(37):14. 5. Ahn K, Kim BE, Kim J, Leung DY. Recent advances Compliance With Ethics Guidelines. This in atopic dermatitis. Curr Opin Immunol. article is based on previously conducted studies 2020;13(66):14–21. and does not contain any studies with human participants or animals performed by any of the 6. Kim BE, Leung DYM. Significance of skin barrier dysfunction in atopic dermatitis. Allergy Asthma authors. Patients gave written consent for pub- Immunol Res. 2018;10(3):207–15. lication of photographs. 7. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Data Availability. Data sharing is not Y, Liao H, Lee SP, et al. Common loss-of-function applicable to this article as no datasets were variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermati- generated or analyzed during the current study. tis. Nat Genet. 2006;38:441–6. Open Access. This article is licensed under a 8. Agrawal R, Woodfolk JA. Skin barrier defects in Creative Commons Attribution-NonCommer- atopic dermatitis. Curr Allergy Asthma Rep. 2014;14(5):433. https://doi.org/10.1007/s11882- cial 4.0 International License, which permits 014-0433-9. any non-commercial use, sharing, adaptation, distribution and reproduction in any medium 9. Berkey C, Biniek K, Dauskardt RH. Screening sun- or format, as long as you give appropriate credit screens: protecting the biomechanical barrier function of skin from solar ultraviolet radiation to the original author(s) and the source, provide damage. Int J Cosmet Sci. 2017;39(3):269–74. a link to the Creative Commons licence, and indicate if changes were made. The images or 10. Langan SM, Irvine AD, Weidinger S. Atopic der- other third party material in this article are matitis. Lancet. 2020;396(10247):345–60. included in the article’s Creative Commons 11. Patrizi A, Savoia F, Giacomini F, Tabanelli M, licence, unless indicated otherwise in a credit Gurioli C. The effect of summer holidays and sun line to the material. If material is not included exposure on atopic dermatitis. G Ital Dermatol in the article’s Creative Commons licence and Venereol. 2009;144(4):463–6. your intended use is not permitted by statutory 12. Kemp AS, Ponsonby AL, Pezic A, Cochrane JA, regulation or exceeds the permitted use, you Dwyer T, Jones G. The influence of sun exposure in will need to obtain permission directly from the childhood and adolescence on atopic disease at copyright holder. To view a copy of this licence, adolescence. Pediatr Allergy Immunol. 2013;24(5): 493–500. visit http://creativecommons.org/licenses/by- nc/4.0/. 324 Dermatol Ther (Heidelb) (2021) 11:315–325 13. Ellenbogen E, Wesselmann U, Hofmann SC, Leh- 25. Krutmann J, Bouloc A, Sore G, Bernard BA, Passeron mann P. Photosensitive atopic dermatitis—a T. The skin aging exposome. J Dermatol Sci. neglected subset: clinical, laboratory, histological 2017;85(3):152–61. and photobiological workup. J Eur Acad Dermatol Venereol. 2016;30(2):270–5. 26. Silverberg NB. A practical overview of pediatric atopic dermatitis, part 2: triggers and grading. 14. Omoto M, Sugiura H, Uehara M. Histopathological Cutis. 2016;97(5):326–9. features of recalcitrant erythema of the face in adult patients with atopic dermatitis. J Dermatol. 27. Tamagawa-Mineoka R, Masuda K, Ueda S, et al. 1994;21:87–91. Contact sensitivity in patients with recalcitrant atopic dermatitis. J Dermatol. 2015;42:720–2. 15. Deguchi H, Danno K, Sugiura H, Uehara M. Sun exposure is an aggravating factor responsible for the 28. López-Jiménez EC, Marrero-Alemán G, Borrego L. recalcitrant facial erythema in adult patients with One-third of patients with therapy-resistant atopic atopic dermatitis. Dermatology. 2002;204(1):23–8. dermatitis may benefit after patch testing. J Eur Acad Dermatol Venereol. 2019;33(10):e377–8. 16. Ten Berge O, van Weelden H, Bruijnzeel-Koomen CA, de Bruin-Weller MS, Sigurdsson V. Throwing a 29. Hassoun Y, James C, Bernstein DI. The effects of air light on photosensitivity in atopic dermatitis: a pollution on the development of atopic disease. retrospective study. Am J Clin Dermatol. Clin Rev Allergy Immunol. 2019;57(3):403–14. 2009;10(2):119–23. 30. Danby SG, Brown K, Wigley AM, Chittock J, Pyae 17. Rutt VL, Reed KX, Liu X, Richard EG, Purcell SM. PK, Flohr C, Cork MJ. The effect of water hardness Photosensitive atopic dermatitis exacerbated by on surfactant deposition after washing and subse- UVB exposure. Cutis. 2017;100(3):180–4. quent skin irritation in atopic dermatitis patients and healthy control subjects. J Invest Dermatol. 18. Brunner PM, Silverberg JI, Guttman-Yassky E, Paller 2018;138(1):68–77. AS, Kabashima K, Amagai M, Taieb A. Increasing comorbidities suggest that atopic dermatitis is a 31. Passeron T, Krutmann J, Andersen ML, Katta R, systemic disorder. J Invest Dermatol. 2017;137(1): Zouboulis CC. Clinical and biological impact of the 18–25. exposome on the skin. J Eur Acad Dermatol Venereol. 2020;34(Suppl 4):4–25. 19. Andersen YMF, Egeberg A, Skov L, Thyssen JP. Comorbidities of atopic dermatitis: beyond rhinitis 32. Li JC, Fishbein A, Singam V, et al. Sleep disturbance and asthma. Curr Dermatol Rep. 2017;6(1):35–41. and sleep-related impairment in adults with atopic dermatitis: a cross-sectional study. Dermatitis. 20. Jadotte YT, Janniger CK. Pityriasis alba revisited: 2018;29:270–7. perspectives on an enigmatic disorder of childhood. Cutis. 2011;87(2):66–72. 33. Rodenbeck DL, Silverberg JI, Silverberg NB. Pho- totherapy for atopic dermatitis. Clin Dermatol. 21. Fenner J, Silverberg NB. Skin diseases associated 2016;34(5):607–13. with atopic dermatitis. Clin Dermatol. 2018;36(5): 631–40. 34. Jekler J, Larko O. Combined UVA-UVB vs. UVB phototherapy for atopic dermatitis: a paired-com- 22. Patruno C, Napolitano M, Argenziano G, et al. parison study. J Am Acad Dermatol. 1990;22:49–53. Dupilumab therapy of atopic dermatitis of the elderly: a multi-centre, real-life study. J Eur Acad 35. Faergemann J, Larko O. The effect of UV-light on Dermatol Venereol. 2020. https://doi.org/10.1111/ human skin microorganisms. Acta Derm Venereol. jdv.17094 (Epub ahead of print. PMID: 1987;67:69–72. 33332697). 36. Silverberg JI, Hanifin J, Simpson EL. Climatic factors 23. Synnerstad I, Fredrikson M, Ternesten-Bratel A, are associated with childhood eczema prevalence in et al. Low risk of melanoma in patients with atopic the United States. J Invest Dermatol. 2013;133: dermatitis. J Eur Acad Dermatol Venereol. 1752–9. 2008;22(12):1423–8. 37. Fuertes E, Flohr C, Silverberg JI, Standl M, Strachan 24. Jensen AO, Svaerke C, Körmendiné Farkas D, Olesen DP, ISAAC Phase Three Study Group. Global asso- AB, Kragballe K, Sørensen HT. Atopic dermatitis and ciations between UVR exposure and current eczema risk of skin cancer: a Danish nationwide cohort prevalence in children from ISAAC phase three. study (1977–2006). Am J Clin Dermatol. J Invest Dermatol. 2017;137(6):1248–56. 2012;13(1):29–36. Dermatol Ther (Heidelb) (2021) 11:315–325 325 38. Kantor R, Silverberg JI. Environmental risk factors 49. Jansen R, Osterwalder U, Wang SQ, et al. Photo- and their role in the management of atopic der- protection part II. Sunscreen: development, effi- matitis. Expert Rev Clin Immunol. 2017;13(1): cacy, and controversies. J Am Acad Dermatol. 15–26. 2013;69(6):867.e1-14. 39. Gambichler T, Othlinghaus N, Tomi NS, Holland- 50. Avenel-Audran M, Dutartre H, Goossens A, et al. Letz T, Boms S, Skrygan M, Altmeyer P, Kreuter A. Octocrylene, an emerging photoallergen. Arch Medium-dose ultraviolet (UV) A1 vs. narrowband Dermatol. 2010;146:753–7. UVB phototherapy in atopic eczema: a randomized crossover study. Br J Dermatol. 2009;160(3):652–8. 51. Berardesca E, Zuberbier T, Sanchez Viera M, Mari- novich M. Review of the safety of octocrylene used 40. Pacifico A, Iacovelli P, Damiani G, Ferraro C, Caz- as an ultraviolet filter in cosmetics. J Eur Acad zaniga S, Conic RRZ, Leone G, Morrone A. ‘‘High Dermatol Venereol. 2019;33(Suppl 7):25–33. dose’’ vs. ‘‘medium dose’’ UVA1 phototherapy in Italian patients with severe atopic dermatitis. J Eur 52. Draelos ZD. The multifunctional value of sun- Acad Dermatol Venereol. 2019;33(4):718–24. screen-containing cosmetics. Skin Ther Lett. 2011;16(7):1–3. 41. Kechichian E, Ezzedine K. Vitamin D and the skin: an update for dermatologists. Am J Clin Dermatol. 53. Ebner F, Heller A, Rippke F, et al. Topical use of 2018;19(2):223–35. dexpanthenol in skin disorders. Am J Clin Derma- tol. 2002;3:427–33. 42. Wei J, Jaleel T, MacLeod AS, Ji JS. Inverted U-shaped relationship between vitamin D and ever-reported 54. Arenberger P, Arenbergerová M, Drozenová H, eczema in US adults. Allergy. 2019;74(5):964–75. Hladı́ková M, Holcová S. Effect of topical heparin and levomenol on atopic dermatitis: a randomized 43. Sidbury R, Tom WL, Bergman JN, et al. Guidelines four-arm, placebo-controlled, double-blind clinical of care for the management of atopic dermatitis: study. J Eur Acad Dermatol Venereol. 2011;25(6): section 4. Prevention of disease flares and use of 688–94. adjunctive therapies and approaches. J Am Acad Dermatol. 2014;71:1218–33. 55. McVean M, Liebler DC. Prevention of DNA photo- damage by vitamin E compounds and sunscreens: 44. Linos E, Keiser E, Kanzler M, Sainani KL, Lee W, roles of ultraviolet absorbance and cellular uptake. Vittinghoff E, Chren MM, Tang JY. Sun protective Mol Carcinog. 1999;24(3):169–76. behaviors and vitamin D levels in the US popula- tion: NHANES 2003–2006. Cancer Causes Control. 56. Marini A, Reinelt K, Krutmann J, Bilstein A. Ectoine- 2012;23(1):133–40. containing cream in the treatment of mild to moderate atopic dermatitis: a randomized, com- 45. Kannan S, Lim HW. Photoprotection and vitamin parator-controlled, intra-individual double-blind, D: a review. Photodermatol Photoimmunol Pho- multi-center trial. Skin Pharmacol Physiol. tomed. 2014;30:137–45. 2014;27(2):57–65. 46. Napolitano M, Fabbrocini G, Patruno C. Allergic 57. Osmond-McLeod MJ, Oytam Y, Kirby JK, Gomez- contact dermatitis in patients with atopic dermati- Fernandez L, Baxter B, McCall MJ. Dermal absorp- tis: a retrospective study. J Allergy Clin Immunol tion and short-term biological impact in hairless Pract. 2019;7(7):2459–61. mice from sunscreens containing zinc oxide nano- or larger particles. Nanotoxicology. 2014;8(Suppl 47. Uter W, Gonçalo M, Yazar K, Kratz EM, Mildau G, 1):72–84. Lidén C. Coupled exposure to ingredients of cos- metic products: III. Ultraviolet filters. Contact Der- 58. Laughter MR, Maymone MBC, Karimkhani C, et al. matitis. 2014;71(3):162–9. The burden of skin and subcutaneous diseases in the United States from 1990 to 2017. JAMA Der- 48. Heurung AR, Raju SI, Warshaw EM. Adverse reac- matol. 2020;156(8):874–81. tions to sunscreen agents: epidemiology, responsi- ble irritants and allergens, clinical characteristics, and management. Dermatitis. 2014;25:289–326.