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UVA: GRASPING A BETTER UNDERSTANDING OF THIS FORMIDABLE OPPONENT Leading dermatologists discuss what is now known about the harmful effects of UVA, and they highlight recent clinical advancements in technology.

BY HENRY W. LIM, M.D., AND DARRELL S. RIGEL, M.D.

Back when the very first was substantive formulations have recently effects.4 Erythema () and the introduced in 1928, it was believed that become available in the United States.3 delayed effect of suntanning are the most the short-term harmful effects of ultravi- This article will review recent develop- familiar symptoms associated with UVB olet (UV) radiation exposure, specifically ments in photoprotection. The content is overexposure, and its association with sunburn, were all we had to fear from the based on the Clinical Council on Photo- photocarcinogenesis is well established. sun.1,2 In the succeeding decades, howev- protection, a roundtable meeting of experts C poses virtually no threat er, it has become clear that sunburn is in photoprotection held on Jan. 20, 2007, in because it is absorbed by the ozone layer only the beginning of the pathologic New York,NY,and sponsored by La Roche- of the earth’s atmosphere. effects produced by solar exposure.1 Posay Laboratoire Pharmaceutique. However, research is increasingly demon- Recent years have brought a much strating that UVA is a threat, and a far fuller understanding of the effects of pho- UVA: A CURRENT FOCUS IN greater one than has generally been believed.4 toexposure, their causes, and ways to pro- PHOTODAMAGE UVA radiation is much more abundant tect against them.And, after more than 20 Ultraviolet A (UVA) rays have long than UVB in natural sunlight; it accounts years without the introduction of a single been thought to have minimal harmful for up to 95% of all UV radiation that significant new active sunscreen agent, effects, while only UVB rays were reaches Earth.4 Furthermore, whereas the new photoprotective agents and more believed to have significant deleterious amount of UVB in sunlight varies accord-

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ing to the season, location on the earth, and time of day, the intensity of UVA radiation is more uniform and is present all year round during all daylight hours.4 In addition, while UVB is blocked by window and automobile glass,UVA is not.5 Furthermore, UVA, which has a longer wavelength than UVB, penetrates more deeply into the skin. (See Figure 1, at right.)6 With UVB radiation, it penetrates only into the stratum corneum and is almost fully absorbed before reaching the upper dermis. On the other hand, UVA readily penetrates into the mid-dermis.7 The many negative effects of UV radia- tion on the skin, including erythema, pho- toaging, carcinogenicity, and immunosup- pression, are exhibited in both UVB and UVA by damage to DNA. Until recently, the genotoxic damage caused by UVA radiation has been thought to be less than that caused by UVB.7 But new research has called this thinking into question. In a recent study using a highly accurate quantitative assay based on high-perform- ance liquid chromatography combined with , investigators examined the type and yield of DNA damage in human skin samples exposed to UVA and UVB radiation.8 Cyclobutane pyrimidine dimers, commonly associated with UVB- induced DNA damage, were found in sub- stantial numbers in UVA-exposed skin as Figure 1. Penetration of various wavelengths of light into human skin. well. In addition, UVA-generated dimers were removed at a much lower rate than were UVB-induced dimers. Microscopically, in normally aging tion may be unknowingly obtained. The researchers also demonstrated that skin, the dermis becomes hypocellular; The ability of UVA to penetrate glass is while human skin protects itself very effec- the epidermis atrophies; collagen forms also a factor. Figure 2, next page, tively against UVB-induced DNA damage, a stable, cross-linked matrix; and the illustrates the result of long-term it protects itself only weakly against UVA- vasculature remains intact. In photoaged indoor exposure to UVA radiation.9 induced injury.8 skin, by contrast, the epidermis thickens, the dermis becomes hypercellular (as a The Role of UVA in The Role of UVA in Photoaging result of mast cell and fibroblast propa- Immunosuppression Repeated skin exposure to UV radia- gation), and the vasculature becomes Photoimmunosuppression, a well-docu- tion produces a phototrauma referred to as dilated and twisted.2 mented phenomenon, may play an impor- “dermatoheliosis, or photoaging.Although All portions of the solar spectrum, tant role in the genesis of skin cancer; it photoaging and intrinsic aging can occur including UVA, UVB, and infrared increases the likelihood and severity of simultaneously, the two processes differ radiation, contribute to photoaging.2 infectious diseases, and reduces the effec- significantly, and photoaged skin appears However, UVA is now recognized as tiveness of vaccines.7 Immunosuppression different from intrinsically aged skin, both the single most important wavelength induced by UV appears to start with DNA macro- and microscopically. in causing photoaging.4,2 The ability of damage and trans to cis-urocanic acid iso- Macroscopically, photoaged skin is UVA to deeply penetrate the dermis merization in the stratum corneum, which characterized by fine and coarse wrin- may account for the primacy of its role is associated with the production of kling; dyspigmentation or hyperpigmen- in photoaging, as may the fact that cytokines, histamine, and neuropeptides.7 tation spots, including freckles or lentig- UVA exposure does not produce an Recent research has shown that UVA ines; laxity; sallowness; telangiectasias; erythemal “warning signal,” so that plays a key role in immunosuppression. and actinic keratoses.7,2 higher cumulative doses of UVA radia- Ultraviolet A has been shown to sup-

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Figure 2. Unilateral cutaneous elastosis, one of the best-known manifestations of helioderma, caused by UVA radiation. The patient had worked for 15 years in the same room with the same orientation to a window, so that the left side of her face had been con- tinuously exposed to UVA radiation, while the right side had not. Reprinted with permission from Moulin G et al. Ann Dermatol Venereol. 1994;121:721-723.

press induction and elicitation of the con- It was long thought that UVB was pri- CONTEMPORARY tact and delayed-type hypersensitivity marily responsible for .12 CONSIDERATIONS IN responses to recall antigens.7 So important However, increasing evidence indicates SUNSCREEN USE: BROADENING is the impact of UVA on immunosuppres- that UVA may also play a significant role.4 OUR PATIENTS’ PROTECTION sion that a new sunscreen measure — Based on an analysis of World Health In view of the magnitude of the sun’s immune protection factor — has been pro- Organization data from 45 countries, negative impact on the skin, we might be posed for use along with the current sun Garland and colleagues found that UVA tempted to advise our patients to entirely protection factor (SPF) measure because the was associated with melanoma mortality avoid UV exposure, both outdoor and latter is not an indicator of degree of protec- rates after controlling for UVB and aver- indoor. However, given the impracticality tion from UVA.10 age skin pigmentation.12 of such advice, are vital in pro- Limited but consistent data from studies of viding protection from the photodamag- The Role of UVA in Carcinogenesis tanning salon users also show UVA exposure ing effects of UV rays.16 Strong evidence supports the role of in these beds to be a risk factor for Since their inception, sunscreens have UV exposure in the development of skin melanoma. A recent meta-analysis of case- been known to protect against erythema, cancers, including not only non- control studies and one cohort study con- the acute effect of UV exposure. But they melanoma skin cancers such as squamous ducted between 1984 and 2004 demonstrat- are now understood to protect against many cell and basal cell carcinomas,7 but also ed a significantly increased risk of cutaneous of the long-term effects of UV exposure as malignant melanoma.11 melanoma following the use of sunbeds and well,including photoaging,actinic keratoses, In the case of melanoma, several lines sunlamps.13 These results are supported by a and some skin cancers.17 of epidemiologic evidence, in addition to prospective cohort study of 106,379 Swedish Because UVA rays, especially the other sources of evidence, point particu- and Norwegian women demonstrating that long-wavelength UVA-1, can pass larly to high, intermittent exposure to the use of tanning devices once a month or through clouds and automobile and solar UV radiation as a significant risk more is statistically significantly associated window glass, incidental exposure to factor. These data include findings that with melanoma risk.14 UVA radiation is a daily risk. In view of the incidence of the disease generally In consideration of findings such as these, research findings implicating UVA in the increases with decreasing latitude and the the American Academy of Dermatology has most severe consequences of sun expo- heightened intensity of the sun’s rays. supported regulations prohibiting minors sure, many groups currently recommend The highest recorded rate of from using tanning devices, preventing facil- universal, year-round, daily use of a melanoma in the world occurs in ities from advertising such devices as safe, and broad-spectrum sunscreen — one that Australia, where the annual incidence is urging the placement of a Surgeon General’s protects against both UVB and UVA — up to 20 times the incidence in Europe.11 warning on all such devices.15 with an SPF of at least 15.18-20

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We need to continue to educate patients about the need for daily sunscreen use, about proper sunscreen application, and about the other steps they need to take to protect themselves from UV exposure. (See the patient education handout titled, “Are You Really Protecting Yourself from the Sun’s Dangerous Rays?” and feel free to photocopy it to distribute to your patients.)

A Look at Common Sunscreen Ingredients To provide broad-spectrum photopro- tection, a sunscreen must include a com- bination of organic and inorganic filters. Advances in sunscreen technology have mimicked and built upon the body’s nat- ural cutaneous defenses against UV radi- ation, which include the following: Among the body’s endogenous defenses is the ability of the epidermis to scatter the Figure 3. Full broad-spectrum UVA and UVB protection provided by , majority of visible light rays, which is what , and . Data on file. L’Oreal USA. Clark, NJ; 2006. inorganic UV filters in sunscreens do.17 A second endogenous defense mecha- nism is that urocanic acid in the skin under- Constructing the Ideal inorganic filter. UVA organic absorbers goes UV-initiated isomerization, which is Broad-Spectrum Filter include benzophenones (320 nm to 350 what organic filters cause to happen.17 The ideal broad-spectrum filter must be nm),2 avobenzone (357 nm), and, most A third endogenous defense shield is composed of compatible and complementa- recently,ecamsule (Mexoryl SX) (344 nm).22 melanin, which protects the skin by fil- ry filters that can provide effective protec- UVB organic absorbers include salicylates tering and scattering UV rays and tion over the entire UVA and UVB spec- (~300 nm) and cinnamates (310 nm to 311 changing the absorbed energy into heat trum.The aesthetics of the product also need nm).2 Inorganic filters, which act to reflect energy rather than chemical energy — to be optimized to increase the likelihood of or scatter UVA and UVB, include titanium the same mechanism by which organic adherence.17 The ideal sunscreen should also dioxide and .2 filters protect the skin.17 It is this mech- Both and zinc oxide are anism that causes a sensation of warmth inorganic white particulates, so they must be in sunscreen wearers, something about THE IDEAL BROAD-SPECTRUM reformulated for aesthetic purposes for use which many patients complain.21 in sunscreens, but there is an unfortunate FILTER MUST BE COMPOSED In addition to having light filtering trade-off involved:Smaller particles yield less and scattering capabilities, as well as the OF COMPATIBLE AND white residue on the skin but poorer photo- others mentioned above, photostability is COMPLEMENTARY FILTERS protection, while larger particles offer more another important characteristic of an protection but more white residue, and THAT CAN PROVIDE effective sunscreen. UV filters that are hence the possibility of poor adherence.16,2 photolabile will be rapidly inactivated EFFECTIVE PROTECTION after exposure to UV rays, thus losing OVER THE ENTIRE UVA AND New Products Offering their effectiveness. Several factors con- Broad-Spectrum Protection UVB SPECTRUM. tribute to photostability, including the After two decades without a significant filter, the presence of other filters in the breakthrough in sunscreen ingredients in product, and the vehicle or solvent. Most be photostable in order to ensure functional the United States,3 two new options that UV filters, including avobenzone, octi- longevity on the skin. Finally, its vehicle promise to improve broad-spectrum, noxate, and octyl dimethyl para-amino should be resistant to shedding with rub- photostable UV protection have recently benzoic acid (PABA), are photolabile. bing, sweating, or water immersion.17 been introduced. Thus, other filters, including zinc oxide, All UV filters have a particular absorption One is a new technology trade-named titanium dioxide, octocrylene, methyl- spectrum, which can be extended by com- Helioplex. Several products are available benzylidene camphor, and the salicylates, bining complementary agents. The ideal using the Helioplex technology, which are frequently used in sunscreen prepara- sunscreen would combine UVA organic combines photostable UVB filters, and tions to increase their photostability.17 absorbers, UVB organic absorbers, and an UVA filters avobenzone and in

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a formulation that slows the degradation of *Acknowledgments Press+Release+Archives/Skin+Cancer+and+Sun+ avobenzone to increase its photostability.23,3 Safety/NewPhotoProtectionDeLeo.htm.Accessed February 11, 2007. Another new introduction features Clinical Council on Photoprotection: 11.World Health Organization. Health effects of Mexoryl SX. Mexoryl SX was developed Alicia Barba, M.D., Miami, FL; Diane UV radiation.Available at: for use in combination with avobenzone Berson,M.D.,New York,NY;David A.Colbert, http://www.who.int/uv/health/uv_health2/en/pri and octocrylene for broad-spectrum pro- M.D.,New York,NY;Coyle S. Connolly,D.O., nt.html.Accessed February 13, 2007. 12. Garland CF,Garland FC, Gorham EC. tection. (See Figure 3, previous page.) Philadelphia, PA; Zoe Diana Draelos, M.D., Epidemiologic evidence for different roles of ultra- In this formulation, octocrylene acts to Winston-Salem, NC; Cheryl L. Effron, M.D., violet A and B radiation in melanoma mortality stabilize avobenzone. Available in Europe Anaheim, CA; Patricia K. Farris, M.D., New rates. Ann Epidemiol. 2003;13:395-404. and Canada since 1993, Mexoryl SX is the Orleans, LA; Brad Katchen, M.D., New York, 13. Gallagher RP,Spinelli JJ, Lee TK.Tanning beds, first new photostable short-UVA filter in a NY; Amy B. Lewis, M.D., New Haven, CT; sunlamps, and risk of cutaneous malignant melanoma. Cancer Epidem Biomark Preven. sunscreen formula to be approved by the Mary P.Lupo, M.D., New Orleans, LA; Marta 2005;14:562-566. U.S. Food and Drug Administration and is Rendon, M.D., Boca Raton, FL; James M. 14.Veierod MB,Weiderpass E,Thorn M, et al.A now available in the United States in the Spencer, M.D., New York, NY; and Jessica Wu, prospective study of pigmentation, sun exposure, new sunscreen product Anthelios SX. M.D., Los Angeles, CA. and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst. 2003;95:1530-1538. Anthelios SX is an SPF15 lightweight 15.American Academy of Dermatology.American moisturizing cream that is intended for Academy of Dermatology issues statement endors- daily use. The product protects against References ing the World Health Organization’s recommenda- both UVB and UVA. Fragrance-free and 1.American Academy of Dermatology. New formu- tion to restrict tanning bed use.Available at: lations improve sunscreen effectiveness.Available at: http://www.aad.org/aad/Newsroom/who_endors allergy tested, it is suitable for sensitive skin http://www.aad.org/aad/Newsroom/New+Formul ement.htm.Accessed February 14, 2007. and is oil-free and noncomedogenic. ations+Improve+Sunscreen+Effectiveness.htm. 16. Levy SB. Sunscreens and photoprotection. Accessed February 11, 2007. Available at: Translating New Knowledge of 2. Lowe NJ, Friedlander J. Prevention of photo- http://www.emedicine.com/derm/topic510.htm. damage with sunprotection and sunscreens. In: Accessed December 1, 2006. UVA into Protection for Patients Gilchrest BA, ed. Photodamage. Cambridge, Mass: 17. Kullavanijaya P,Lim HW.Photoprotection. J A large and growing body of research has Blackwell Science; 1995:201-220. Am Acad Dermatol. 2005;52:937-958. identified UVA as a key contributor to 3. Rundle RL. New sunscreens promised advances 18.American Academy of Dermatology.The future photoaging, immunosuppression, and car- in protection. Wall Street Journal. December 27, of sunscreens.Available at: 2005.Available at: www.ascdas.org/news/sun- http://www.aad.org/public/News/NewsReleases/ cinogenesis. Because UVA is present all year screens.htm.Accessed February 9, 2007. Press+Release+Archives/Skin+Cancer+and+Sun+ round and UVA-1 can pass through win- 4. Skin Cancer Foundation.The dangers of tan- Safety/The+Future+of+Sunscreens.htm.Accessed dow glass, patients need to be advised to ning.Available at: http://www.skincancer.org. February 11, 2007. protect themselves every day from UVA. Accessed February 12, 2007. 19. Lim HW,Draelos ZD, Rigel DS, Ruenger TM. 5.Tuchinda C, Srivannaboon S, Lim HW. Growing awareness of the importance Shedding light on complete UV protection. Cosmet Photoprotection by window glass, automobile Dermatol. 2006;19:1-8. of daily UV protection has led glass, and sunglasses. J Am Acad Dermatol. 20.American Academy of Dermatology. 2006 facts researchers and manufacturers to focus 2006;54:845-854. about sunscreen.Available at: on the development of an ideal sun- 6.American Academy of Dermatology. http://www.aad.org/NR/rdonlyres/4D8AD6D2- screen, which would combine photosta- Overexposure to sun can happen indoors and out- AE9B-42FE-B204- doors.Available at: FB55C48C7E4E/0/2006FactsAboutSunscreens.do bility with broad-spectrum, well-bal- http://www.aad.org/aad/Newsroom/Photoprotect c.Accessed February 9, 2007. anced UV protection. Recent advances ion.htm.Accessed February 11, 2007. 21. Draelos ZD. Cosmetics.Available at: in this regard have led to the introduc- 7. Moyal D, Fourtanier A.Acute and chronic effects www.emedicine.com/derm/topic502.htm. tion of important new photoprotective of UV on skin: what are they and how to study Accessed December 1, 2006. them? In: Rigel DS,Weiss R, Lim HW,Dover JS, 22. Moyal D, Chardon A, Kolias N. UVA protec- ingredients and products. It is hoped eds. Photoaging. New York,NY: Marcel Dekker, Inc; tion efficacy of sunscreens can be determined by that advances will continue in the 2004:15-32. the persistent pigment darkening (PPD) method devolvement of new fil- 8. Mouret S, Baudouin C, Charveron M, Favier A, (part 2). Photodermatol Photoimmunol Photomed. ters, improved photosta- Cadet J, Douki T. Cyclobutane pyrimidine dimers 2000;16:250-255. are predominant DNA lesions in whole human 23. Neutrogena. Suncare FAQs.Available at: bility, and new applica- skin exposed to UVA radiation. Proc Nat Acad Sci. http://www.neutrogena.com/acs/faq.asp.Accessed tion methods. ■ 2006;103:13765-13770.Available at: February 9, 2007. http://www.pnas.org/cgi/content/short/103/37/1 Dr. Lim is Chairman and 3765.Accessed February 12, 2007. 9. Moulin G,Thomas L,Vigneau M, Fiere A.A case C. S. Livingood Chair of the of unilateral elastosis with cysts and comedones. DISCLOSURES: Dr. Lim is a consultant for Department of Dermatology at Favre-Racouchot syndrome. Ann Dermatol Venereol. Johnson & Johnson, La Roche-Posay Henry Ford Hospital in 1994;121:721-723. Laboratoire Pharmaceutique, Orfagen Laboratories,and Dow Pharmaceutical Sciences. Detroit, MI. 10.American Academy of Dermatology. New research in sun protection shines the light on sun- Dr.Rigel is Clinical Professor screen and importance of sun-safe behaviors Dr. Rigel is a consultant and speaker for of Dermatology at New York beyond adolescence to lower skin cancer risk. Beiersdorf AG, Johnson & Johnson, La Roche- University Medical Center in Available at: Posay Laboratoire Pharmaceutique, and New York, NY. http://www.aad.org/public/News/NewsReleases/ Neutrogena Corporation.

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Patient Education Handout

Are You REALLY Protecting Yourself from the Sun’s Dangerous Rays? Quiz yourself on whether you are aware of these sun-safe strategies. Use a Sunscreen Every Day. • Sun protection is the most important means of preventing skin cancer and early aging of the skin. Even on the most overcast days, 80% of the sun’s rays will pass through the clouds. And UVA rays — the rays that cause early aging, as well as skin cancer and immune suppression — pass right through window glass. Thus, daily use of a broad-spectrum sunscreen is recommended even when you won’t be going outside. When used on a regular basis, sunscreens actually allow damaged skin to repair itself.

Choose a Sunscreen that Provides Broad-Spectrum Protection. • To protect yourself from all of the sun’s dangerous effects, you need a sunscreen with ingredients that provide protec- tion against UVB and UVA rays. Such ingredients include oxy- benzone, octylmethyl cinnamate or , , salicylates, titanium dioxide, zinc oxide, avobenzone, and ecamsule (Mexoryl SX).

Choose a Sunscreen with an SPF (Sun Protection Factor) of at Least 15. • SPF tells you how much sunburn protection a sunscreen pro- vides. The higher the SPF, the more the sunburn protection. But remember that the sun’s UVA rays lead to other negative effects (like early aging and skin cancer), and SPF tells only about the product’s ability to screen UVB rays. So check for UVA-protective ingredients as well.

Apply Sunscreen Generously. • 1 ounce — about enough to fill a shot glass — is the amount needed to provide enough coverage to exposed areas of the body.

Sources: Moulin G,Thomas L,Vigneau M, Fiere A.A case of unilateral elastosis with cysts and comedones. Favre-Racouchot syndrome. Ann Dermatol Venereol. 1994;121:721-723.American Academy of Dermatology. 2006 facts about sunscreen.Available at: http://www.aad.org/NR/rdonlyres/4D8AD6D2-AE9B-42FE-B204- FB55C48C7E4E/0/2006FactsAboutSunscreens.doc.Accessed February 9, 2007. ✁

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