- Email: [email protected]
Sunscreen Use in Photodermatoses
Dermatol Clin 24 (2006) 27 – 33
Sunscreen Use in Photodermatoses Vincent DeLeo, MDT St. Luke’s Roosevelt and Beth Israel Medical Centers, New York, NY, USA
Photodermatoses are a group of conditions and diseases associated with an abnormal sensitivity or reaction to nonionizing radiation. This designation excludes the normal reactions to radiation that occur in the general population such as sunburn and carcinogenicity. Photodermatoses have usually been classified into four major categories: (1) idiopathic, (2) exogenous photochemical, (3) genetic and metabolic, and (4) photoaggravated (Table 1). Although most of these conditions are relatively uncommon, with the exception of polymorphous light eruption (PMLE), most are encountered at some time in the practice of most dermatologists. It is important to correctly identify or classify the type of photosensitivity in a given patient so that the proper treatment can be instituted. The diagnosis of the photosensitive patient has been covered elsewhere [1]. Regardless of the diagnosis, however, in most cases, the management of the photosensitive patient will involve avoidance of, and protection from, sun exposure. This always includes sunscreen usage. In the case of most exogenous photochemical reactions, including phototoxic and photo-allergic contact dermatitis and photodrug reactions, correct identification of the offending agent and avoidance of that chemical will result in clearing of the eruption. Even these patients will sometimes require sunscreen usage for a short period of time until the photosensitizer is cleared from the skin completely. In addition, in some patients with photodrug reactions who are on essential drugs for which there are no
Dr. DeLeo is a consultant for Orfagen (Paris, France). T St. Luke’s Roosevelt and Beth Israel Medical Centers, 1090 Amsterdam Avenue, Suite 11B, New York, NY 10019. E-mail address: [email protected]
adequate alternatives, the photosensitizing agent may be maintained with photoprotection. Sunscreens are essential in these patients.
Action spectrum Theoretically, the method by which the clinician chooses the most effective sunscreen for each patient depends on identification of the wavelength of the photons that are responsible for inducing the sensitivity, the action spectrum. With this information, the clinician can choose a sunscreen with ingredients that absorb or reflect those specific photons. It is not always possible for the practicing dermatologist to determine the inciting wavelengths in a given patient, either because of lack of the necessary phototesting equipment, or because the process cannot be reproduced easily in the artificial setting. Fortunately, the action spectra for the more common photodermatoses have been identified by photobiological researchers. As noted in a recent review of the subject published by Lenane and Murphy [2], and as outlined in Table 1, most patients who suffer from photosensitivity are reacting to radiation that is, partly at least, in the longer wavelength ranges, UVA and visible light or wavelengths greater than 320 nm. As discussed in other sections of this issue, most sunscreen agents available in the United States today offer excellent protection from UVB radiation but only partial protection in the UVA and visible ranges. In addition, because there is no established method for testing and labeling of the level of long wave protection of sunscreens marketed in the United States, it is difficult for the clinician to be able to determine which sunscreens are most efficacious in individuals who need long-wave protection.
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Table 1 Classification and action spectrum of photosensitive skin disease Photosensitive skin disease Idiopathic Polymorphous light eruption Hydroa vacciniforme Solar urticaria Chronic actinic dermatitis Actinic prurigo Exogenous chemical Photoallergic contact dermatitis Photoirritant contact dermatitis Photodrug reactions Genetic and metabolic Porphyria Xeroderma pigmentosa Cockayne’s syndrome Smith-Lemli-Opitz Photoaggravated Lupus erythematosus
UVB
UVA
Visible
+ + + +++ ++
++ ++ ++ ++ ++
— — ++ + —
— — +
+++ +++ +++
— + +
— +++ +++ — — +++
— — — +++ — ++
+++ — — — — —
Abbreviations: +, ++, and +++; relative scale. Data from Lenane P, Murphy GM. Sunscreens and the photodermatoses. J Dermatolog Treatment 2001;12:53 – 7.
droxyacetone and the inorganic iron oxide. Although not approved as sunscreen active ingredients, they are available in products sold in the United States. Four other agents not approved for usage in the United States but used in some products sold in other countries appear to offer much better longrange protection, and they may be available soon in products sold in this country. These include terephthalydene dicamphor sulfonic acid and drometrizole trisiloxane, both developed by L’Ore´al, and methylene-bis-benzotriazole tetramethylbutylphenol and bis-ethylhexyloxyphenol methoxyphenol triazine, developed by Ciba Specialty Chemicals (see Box 1). Unfortunately, there is no way for the clinician to judge the amount of UVA protection in combination agents. It has been suggested that pure inorganic
Box 1. Sunscreen agents offering long-range protection and may be of use in photodermatoses FDA-approved agents
The clinician theoretically is limited to recommending products that contain the UVA filters that have been approved by the US Food and Drug Administration (FDA) (Box 1). In the category of organic or chemical sunscreens, this includes the benzophenones (oxybenzone, dioxybenzone, and sulisobenzone), butylmethoxydibenzoylmethane, also known as avobenzone (Parsol 1789), and methylanthralinate. All, with the exception of avobenzone, are primarily protective in the UVA 2 range; the absorption of avobenzone extends into UVA 1. The approved inorganic screens or physical blockers are titanium dioxide and zinc oxide. When these agents were used originally, they did offer protection that extended into the UVA and visible ranges but at the expense of cosmetic acceptability. To make such agents more acceptable to consumers, the particles have been micronized and coated. Although these agents still offer some protection into the longer ranges, that protection is not as good as that of the older agents. In this regard, it has been shown in in vitro studies that microfine zinc oxide should provide better protection in the UVA 1 range than the same concentration of microfine titanium dioxide [3]. There are other agents of interest that protect against longer wave radiation in the photosensitive individual. These agents include the self tanner dihy-
Chemical or organic Oxybenzone-benzophenone 3 Sulisobenzone-benzophenone 4 Dioxybenzone-benzophenone 8 Butylmethoxydibenzoylmethaneavobenzone (Parsol 1789) Methyl anthranilate Physical or inorganic Titanium dioxide (TiO2) Zinc oxide (ZnO) Other agents available in American products Dihydroxyacetone Iron oxide Agents not approved for use in United States Terephthalydene dicamphor sulfonic acid (Mesoryl SX) Drometrizole trisiloxane (Mexoryl XL) Methylene-bis-benzotriazole tetramethylbutylphenol (Tinosarb M) Bis-ehtylhexyloxyphenol methoxyphenol triazine (Tinosarb S)
sunscreen use in photodermatoses
screens with high sun protection factor (SPF) theoretically should give good long wave protection. It has been suggested that products containing high levels of titanium dioxide and zinc oxide in high SPF chemical-free sunscreens and those that contain avobenzone in combination with the two inorganic agents seem to be reasonable alternatives if the newer non – FDA-approved screens cannot be obtained. In addition, dihydroxyacetone and iron oxide may be of benefit in some individuals.
Published studies There is very little published information assessing the relative protective value of various agents against long-wave radiation in people. Bissonnette and colleagues [4] examined long-wave protection of six different commercially available (in Europe) sunscreens by measuring persistent pigment darkening in human volunteers. This endpoint is one of numerous endpoints that have been used to measure UVA protection. They found that a product containing terephthalydene dicamphor sulfonic acid, avobenzone, and TiO2 was most protective. This was followed by sunscreens that contained avobenzone and the physical blockers TiO2 and ZnO. This study used products with varying concentration of the UVA filters, making it difficult to draw solid conclusions about the relative effectiveness of individual ingredients. It generally is believed, however, that terephthalydene dicamphor sulfonic acid will offer greater protection for the photosensitive patient once it becomes available in the United States. Clinical trials testing the efficacy of sunscreens for preventing development of the various photodermatoses are rare [2]. Additionally, such studies sometimes are complicated by inconsistent diagnostic terminology. The following sections summarize a small number of studies in which various agents were tested for photoprotection in patients with various photosensitive disorders.
Polymorphous light eruption The most common photosensitivity in lightskinned individuals regardless of country of origin is PMLE. The lifetime incidence of this condition in the United States has been reported to be 10% to 15%. Similar rates have been reported from other countries [2]. As a population gets closer to the equator, the incidence rate for that population de-
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creases. This may be because of differences in skin color, but it also suggests that the more sun exposure a population receives, the less likely its members are to develop the sensitivity. The classic history in affected individuals is that the first episode occurs during a sunny vacation with long exposures to sunlight. The reaction classically develops after 2 or 3 days of exposure, and with sun avoidance, the reaction will resolve in a few days to 1 or 2 weeks. The most common reaction pattern is a small papular or papulo – vesicular morphology. The reaction usually involves the chest, arms and legs and routinely spares the face. In most cases, an individual will have a single episode without recurrences. A rarer group of individuals will begin to develop the reaction in a more recurrent fashion, with some individuals developing the reaction with less and less exposure. These are the patients who are likely to seek medical attention. The differential diagnosis in these patients includes lupus erythematosus and photoallergic contact dermatitis, primarily to sunscreens. Although the eruption can be reproduced with artificial light sources in photoprovocation studies, the diagnosis usually can be made from the classical history with histologic confirmation. In reviewing the literature on this and many other forms of photosensitivity, it must be remembered that nomenclature may vary with investigator. In this regard, although some reports suggest that minimal erythema dose (MED) testing may reveal lowered MED in a group of these patients, most studies reveal MED testing in PMLE is normal [5]. To reproduce the eruption, large doses of radiation greater that the MED must be applied to large areas of previously exposed skin. Numerous investigators have done studies to define the action spectrum of PMLE. Although there is variation among reports, overall, it would appear that most patients with PMLE react at least partially to UVA. There are some individuals who are sensitive to UVB alone; however, most patients react to UVA alone or to a combination of both UVB and UVA radiation [5 – 8]. It is likely that those patients who develop reactions to UVB alone get adequate protection from sunscreens and therefore rarely seek medical care (author’s personal observation). Although most authors suggest that UVB/UVA sunscreens offer some protection against development of reactions, they usually suggest that prophylactic phototherapy and photochemotherapy are most efficacious [5 – 10]. Holzle and colleagues [6] showed that 4-isopropyl dibenzoyl methane and methylbenzylidene camphor were capable of preventing photoprovocation of lesions with UVA radiation in the
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laboratory setting. More recently Allas and colleagues [11,12] reported prevention of induction of the lesions of PMLE in 23 patients by a combination sunscreen containing terephthalydene dicamphor sulfonic acid using a UVA/UVB photoprovocation source. A control sunscreen containing UVB blockers and oxybenzone for UVA protection prevented the reactions in only three patients. This product and others like it likely will prove to be important for preventing PMLE and many other types of photosensitivity where longer wavelength radiation plays and etiologic role. A promising new area of research is the use of a combination of new UVA protective sunscreens and potent antioxidants that appear in early studies to protect against development of PMLE in affected patients [13,14].
Solar urticaria Solar urticaria (SU) is diagnosed easily by history. The patient describes an immediate response to sunlight with the development of pruritus, erythema, and sometimes but not always edema or discrete hives. The reaction rarely persists for longer than minutes to hours. Occasionally, systemic reactions including anaphylaxis are possible but exceedingly rare. Patients vary widely in the action spectrum of their reactivity. Usually UVA or even visible radiation is involved. In most, but not all affected individuals, the eruption can be reproduced with artificial sources. It is useful to perform such phototesting to choose the proper screens for protection. Treatment other than avoidance usually consists of antihistamines as for other physical urticarias. Plasmapheresis, phototherapy, and photochemotherapy also have been used [11]. For patients who have UVB sensitivity, high-SPF sunscreens should be helpful. The new agents with UVA activity should be useful in those individuals who have UVA sensitivity. Protection in the visible range may be more difficult to achieve. The physical blockers—titanium and zinc oxides—may offer some protection into the lower visible range. Iron oxide, which is not approved as a sunscreen by the FDA but which is contained in some products (RYPaque) as a tinting agent, has been reported to offer some protection against visible radiation [11]. The more protective these agents are, however, the less cosmetically acceptable they may be. Dihydroxyacetone is the sunless tanning ingredient. Although its SPF is low, it does protect in the UVA and visible ranges and may be useful in SU [3]. This agent should be applied before bed for 2 to 3 nights (follow manufacturer’s instructions)
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until a visible tan develops. It then should be applied 2 to 3 nights per week to maintain the color and photoprotection.
Hydroa vacciniforme Hydroa vacciniforme (HV) is a rare nonfamilial photodermatosis that routinely occurs before puberty. Along with actinic prurigo (AP), it represents the two idiopathic photodermatoses of childhood. The age of onset in a recent review [15] was about 8 years of age. Males and females were affected equally. With sun exposure, affected individuals develop macules that evolve into papules and finally into vesicles that heal with variola-form scarring. The face is affected particularly. First episodes may resemble primary herpes simplex but will be culture-negative. The disease in most individuals is self-limited, with 60% resolving within 4 to 7 years. The action spectrum of the disease seems to be broad, with reproduction by both UVB and UVA [2,15,16]. There are cases of severe hydroa vacciniformelike eruptions associated with lymphoproliferative disease and Epstein-Barr virus infection. The skin manifestation in these individuals is much more severe and not related to sun exposure [17]. There should be no problem in differentiating this malignant disease from HV on clinical and histologic grounds. Purely UVB sunscreens may not prevent the HV reaction. These patients need rigorous avoidance and protection with broad-spectrum screens to prevent eruption and permanent scarring.
Actinic prurigo AP is also known as familial PMLE of Amerindians. In Europe, this condition has been described in non-Indian people. In the United States, the term is used to describe a photodermatosis that develops in childhood in Amerindians from Canada through the United States and into Central and South America. Although it is an inherited disorder, it generally is classified as an idiopathic photosensitivity rather than a genodermatosis. Eighty percent of affected individuals have onset before puberty. The classic lesions are prurigenous papules developing on sun-exposed skin, although the eruption may spread to involve covered areas. It usually is accompanied by a cheilitis and eye involvement. The eruption tends to be chronic rather than recurrent with sun exposure during the sunny months and clearing in the winter. The action spectrum includes UVB and UVA radiation [2].
sunscreen use in photodermatoses
Thalidomide appears to be the drug of choice when such therapy is possible. Avoidance and broadspectrum sunscreens with avobenzone have been shown to be effective in some patients [18], and narrow band UVB phototherapy has been reported to be of benefit if screening is not effective [19].
Chronic actinic dermatitis Chronic actinic dermatitis (CAD) represents an idiopathic photodermatosis of adults. It is rare, and in many cases, a very debilitating disease. The term is used to describe individuals who react to radiation with an eczematous response clinically and histologically. The eruption is confined to sun-exposed areas in early stages, but may spread to involve unexposed skin also. The reaction becomes chronic, probably because very small quantities of radiation induce the pathology. The morphology in severe cases may evolve into a reticuloid appearance with lionine facies and almost tumor-like plaques. Histology also may evolve into that suggestive of cutaneous T-cell lymphoma. The latter cases are sometimes referred to as actinic reticuloid. Some patients even progress to exfoliative erythroderma. The reaction usually is reproduced easily with a lowered MED and an eczematous response to UVB radiation in most patients, with extension into the UVA and even the visible ranges in some [1]. This photodermatosis is considered an end-stage reaction triggered by numerous diverse immunologic events. Some people begin with a contact dermatitis to various allergens, including airborne compositiae reactions from plants and workplace antigens like chromates in cement, and then for unexplained reasons they develop reactions to radiation. Others begin with a photoallergic contact dermatitis and evolve into CAD after the offending agent is removed. In these cases, the reactions have been referred to as persistent light reactivity. Some patients with atopic eczema develop photosensitivity and fit into this classification. Rarely patients with photodrug reactions will continue to react to light alone when the drug is discontinued, and finally patients who have HIV also have been reported to develop this type of photosensitivity [1]. Treatment options include extensive patch and photopatch testing so that all inciting allergens can be avoided. Phototherapy and photochemotherapy have been used with varying success. Broadspectrum sunscreens as outlined in Box 1 should be used but only after patch and photopatch testing to rule out sunscreen allergy.
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Genodermatoses As outlined in the Lenane and Murphy publication [2], the genodermatoses can be divided into those with DNA repair deficiency, pigmentary deficiencies, the porphyrias, and deficiency of cholesterol biosynthetic pathway. The DNA repair deficiencies include in individuals with Xeroderma pigmentosum, trichothiodystrophy, Rothmund Thomson syndrome, and Cockayne’s syndrome. In all of these individuals, rigorous sun avoidance must be practiced. Although broad-spectrum sunscreens may be recommended, high SPF for good UVB protection is most important [20]. Photosensitivity recently has been reported in the Smith-Lemli-Opitz syndrome. Patients with this deficiency of the enzyme 7-dehydrocholesterol reductase have a high mortality rate and exhibit congenital heart disease and mental retardation. Affected individuals have the onset of a sunburn-like erythema within minutes of exposure, and this persists for 1 to 2 days. Phototesting has revealed sensitivity in the UVA range [21]. Avoidance and broad-spectrum sunscreens are therefore necessary. The porphyrias are a group of inherited and acquired diseases that represent deficiencies in the activity of enzymes of the heme biosynthetic pathway. Erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP), and hepatoerythropoietic porphyria (HEP) have their onset in childhood. These individuals develop burning and stinging on exposure to sunlight. People who have CEP and HEP have much more severe photosensitivity, compared with people who have EEP, which is a relatively mild disease. In all of these individuals, sun avoidance and protection are important. In the relatively common porphyria cutanea tarda (PCT), patients complain more of easy bruisability and blistering of the exposed skin, primarily the hands. This is treatable by phlebotomies or antimalarial therapy, with reduction of porphyrin abnormalities and resolution of symptoms. Patients with the mixed porphyries, variegate porphyria (VP), and hereditary coproporphyria (HC), may have similar skin findings to patients who have PCT, but they also may have neurologic symptoms. Treatment of the skin lesions in these patients is based primarily on avoidance and photoprotection. Because the skin lesions in all of the porphyrias are caused by Soret band radiation (400 – 410 nm), screens that protect in the visible range are optimal for affected individuals. Such protection, however, is difficult to achieve. Broad-spectrum sunscreens usually are recommended, but the use of dihydroxyace-
32
tone [22] and iron oxide in combination with the more traditional UVB/UVA screens should be beneficial. Patients with various forms of albinism require broad-spectrum protection to prevent the deleterious effect of lack of natural melanin protection in their skin. Photoaggravated diseases Although there are large numbers of diseases where radiation may aggravate pathology in the skin, the two most important and common of these are lupus erythematosus (LE) and dermatomyositis (DM). Although photosensitivity in DM has not been investigated extensively, studies of the action spectra for various forms of LE have been described. Lehmann [23] studied 128 patients who had LE. The skin lesions of LE were reproducible with artificial light in 64% of patients with subacute cutaneous LE, 42% of patients with discoid LE, and 25% of patients with systemic LE. In those patients with reproducible lesions, the action spectrum was in both the UVB and UVA ranges in 53%, in the UVB range alone in 33%, and in the UVA range alone in 14%. Stege and colleagues [24] studied the effect of three different sunscreen products for preventing artificially produced LE lesions in 11 patients. A screen containing terephthalydene dicamphor sulfonic acid and drometrizole trisoloxane, Parsol 1789, and titanium dioxide was the most protective, preventing lesion development in all 11 patients. Two products with titanium dioxide and Parsol 1789 as UVA screens and different UVB screens were effective in five and three patients only. Callen and colleagues [25] studied sunscreen protection in an open-label study using a screen with Padimate O and Parsol 1789 and found good to excellent protection in 54% of patients. Johnson and Fusaro [26] suggested that dihydroxyacetone would be beneficial in LE patients who have long wave-induced disease.
Summary Most of the photodermatoses are induced by long wave radiation. Sunscreens must be used as part of the treatment of affected individuals. Currently, sunscreens that provide complete photoprotection against UVA and visible radiation and therefore provide protection for affected individuals are not available in the United States. It is hoped that such agents will be available soon.
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References [1] Marks J, Elsner P, DeLeo V. Contact and occupational dermatology. 3rd edition. St. Louis (MO)7 Mosby; 2002. [2] Lenane P, Murphy GM. Sunscreens and the photodermatoses. J Dermatolog Treatment 2001;12:53 – 7. [3] Mitchnick MA, Fairhurst D, Pinnell SP. Microfine zinc oxide as a photostable UV-A/UV-B sunblock agent. J Am Acad Dermatol 1999;40:85 – 90. [4] Bissonnette R, Allas S, Moyal D, et al. Comparison of UVA protection afforded by high sun protection factor sunscreens. J Am Acad Dermatol 2000;43: 1036 – 8. [5] Boonstra HE, van Weelden H, Toonstra J, et al. Polymorphous light eruption: a clinical, photobiologic, and follow-up study of 110 patients. J Am Acad Dermatol 2000;42:199 – 207. [6] Holze E, Plewig G, Hofmann C, et al. Polymorphous light eruption. Experimental reproduction of skin lesions. J Am Acad Dermatol 1982;7:111 – 25. [7] Ortel B, Tanew A, Wolf K, et al. Polymorphous light eruption: action spectrum and photoprotection. J Am Acad Dermatol 1986;14:748 – 53. [8] Holzle E, Plewig G, von Dries R, et al. Polymorphous light eruption. J Invest Dermatol 1987;88:32s – 8s. [9] Honigsmann H. Effect of therapeutic sunscreen cream on phototest reaction in polymorphous light dermatosis. Z Hautkr 1989;64:1065 – 8. [10] McFadden N. UVA sensitivity and topical photoprotection in polymorphic light eruption. Photodermatol 1984;1:76 – 8. [11] Bissonnette R. Prevention of polymorphous light eruption and solar urticaria. Skin Therapy Letter 2002; 7:3 – 5. [12] Allas S, Lui H, Moyal D, et al. Comparison of the ability of 2 sunscreens to protect against polymorphous light eruption induced by a UV-A/UV-B metal halide lamp. Arch Dermatol 1999;135:1421 – 2. [13] Rippke F, Wendt G, Bohnsack K, et al. Results of photoprovocation and field studies on the efficacy of a novel topically applied antioxidant in polymorphous light eruption. J Dermatolog Treat 2001;12:3 – 8. [14] Hadshiew IM, Treder-Conrad C, v Bulow R, et al. Polymorphous light eruption and a new potent antioxidant and UVA-protective formulation as prophylaxis. Photodermatol Photoimmunol Photomed 2004; 20:200 – 4. [15] Gupta G, Man I, Kemmett D. Hydroa vacciniforme: a clinical and follow-up study of 17 cases. J Am Acad Dermatol 2000;42:208 – 13. [16] Sonnex TS, Hawk JL. Hydroa vacciniforme: a review of ten cases. Br J Dermatol 1998;118:101 – 8. [17] Cho KH, Lee SH, Kim CW, et al. Epstein-Barr virusassociated lymphoproliferative lesions presenting as a hydroa vacciniforme-like eruption: and analysis of six cases. Br J Dermatol 2004;151:372 – 80. [18] Fusaro RM, Johanso JA. Topical photoprotection for hereditary polymorphous light eruption of American Indians. J Am Acad Dermatol 1991;24:744 – 6.
sunscreen use in photodermatoses [19] Gambichler T, Breuckmann F, Boms S, et al. Narrowband UV-B phototherapy in the skin conditions beyond psoriasis. J Am Acad Dermatol 2005;52: 660 – 70. [20] Liardet S, Scaletta C, Panizzon R, et al. protection against pyrimidine dimmers, p53, and 8-hydroxy-2deoxyguanine expression in ultraviolet-irradiated human skin by sunscreens: difference between UV-B + UV-A and UV-B alone sunscreens. J Invest Dermatol 2001;117:1437 – 41. [21] Anstey AV, Ryan A, Rhodes LE, et al. Characterization of photosensitivity in the Smith-Lemli-Opitz syndrome: a new congenital photosensitivity syndrome. Br J Dermatol 1999;141:406 – 14. [22] Asawanonds P, Oberlender S, Taylor C. The use of dihydroxyacetone for photoprotection in variegate porphyries. Int J Dermatol 1999;38:916 – 8.
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[23] Lehmann P, Holzle E, Kind P, et al. Experimental reproduction of skin lesions in lupus erythematosus by UV-A and UV-B radiation. J Am Acad Dermatol 1990; 22:181 – 7. [24] Stege H, Budde MA, Grether-Beck S, et al. Evaluation of the capacity of sunscreens to photoprotect lupus erythematosus patients by employing the photoprovocation test. Photodermatol Photoimmunol Photomed 2000;16:256 – 9. [25] Callen JP, Roth DE, McGrath C, et al. Safety and efficacy of a broad-spectrum sunscreen in patients with discoid or subacute cutaneous lupus erythematosus. Cutis 1991;47:130 – 2. [26] Johnson JA, Fusaro RM. Broad-spectrum photoprotection: the roles of tinted auto windows, sunscreens and browning agents in the diagnosis and treatment of photosensitivity. Dermatology 1992;185(4):237 – 41.
Sunscreen Use in Photodermatoses Vincent DeLeo, MDT St. Luke’s Roosevelt and Beth Israel Medical Centers, New York, NY, USA
Photodermatoses are a group of conditions and diseases associated with an abnormal sensitivity or reaction to nonionizing radiation. This designation excludes the normal reactions to radiation that occur in the general population such as sunburn and carcinogenicity. Photodermatoses have usually been classified into four major categories: (1) idiopathic, (2) exogenous photochemical, (3) genetic and metabolic, and (4) photoaggravated (Table 1). Although most of these conditions are relatively uncommon, with the exception of polymorphous light eruption (PMLE), most are encountered at some time in the practice of most dermatologists. It is important to correctly identify or classify the type of photosensitivity in a given patient so that the proper treatment can be instituted. The diagnosis of the photosensitive patient has been covered elsewhere [1]. Regardless of the diagnosis, however, in most cases, the management of the photosensitive patient will involve avoidance of, and protection from, sun exposure. This always includes sunscreen usage. In the case of most exogenous photochemical reactions, including phototoxic and photo-allergic contact dermatitis and photodrug reactions, correct identification of the offending agent and avoidance of that chemical will result in clearing of the eruption. Even these patients will sometimes require sunscreen usage for a short period of time until the photosensitizer is cleared from the skin completely. In addition, in some patients with photodrug reactions who are on essential drugs for which there are no
Dr. DeLeo is a consultant for Orfagen (Paris, France). T St. Luke’s Roosevelt and Beth Israel Medical Centers, 1090 Amsterdam Avenue, Suite 11B, New York, NY 10019. E-mail address: [email protected]
adequate alternatives, the photosensitizing agent may be maintained with photoprotection. Sunscreens are essential in these patients.
Action spectrum Theoretically, the method by which the clinician chooses the most effective sunscreen for each patient depends on identification of the wavelength of the photons that are responsible for inducing the sensitivity, the action spectrum. With this information, the clinician can choose a sunscreen with ingredients that absorb or reflect those specific photons. It is not always possible for the practicing dermatologist to determine the inciting wavelengths in a given patient, either because of lack of the necessary phototesting equipment, or because the process cannot be reproduced easily in the artificial setting. Fortunately, the action spectra for the more common photodermatoses have been identified by photobiological researchers. As noted in a recent review of the subject published by Lenane and Murphy [2], and as outlined in Table 1, most patients who suffer from photosensitivity are reacting to radiation that is, partly at least, in the longer wavelength ranges, UVA and visible light or wavelengths greater than 320 nm. As discussed in other sections of this issue, most sunscreen agents available in the United States today offer excellent protection from UVB radiation but only partial protection in the UVA and visible ranges. In addition, because there is no established method for testing and labeling of the level of long wave protection of sunscreens marketed in the United States, it is difficult for the clinician to be able to determine which sunscreens are most efficacious in individuals who need long-wave protection.
0733-8635/06/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.det.2005.09.004
derm.theclinics.com
28
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Table 1 Classification and action spectrum of photosensitive skin disease Photosensitive skin disease Idiopathic Polymorphous light eruption Hydroa vacciniforme Solar urticaria Chronic actinic dermatitis Actinic prurigo Exogenous chemical Photoallergic contact dermatitis Photoirritant contact dermatitis Photodrug reactions Genetic and metabolic Porphyria Xeroderma pigmentosa Cockayne’s syndrome Smith-Lemli-Opitz Photoaggravated Lupus erythematosus
UVB
UVA
Visible
+ + + +++ ++
++ ++ ++ ++ ++
— — ++ + —
— — +
+++ +++ +++
— + +
— +++ +++ — — +++
— — — +++ — ++
+++ — — — — —
Abbreviations: +, ++, and +++; relative scale. Data from Lenane P, Murphy GM. Sunscreens and the photodermatoses. J Dermatolog Treatment 2001;12:53 – 7.
droxyacetone and the inorganic iron oxide. Although not approved as sunscreen active ingredients, they are available in products sold in the United States. Four other agents not approved for usage in the United States but used in some products sold in other countries appear to offer much better longrange protection, and they may be available soon in products sold in this country. These include terephthalydene dicamphor sulfonic acid and drometrizole trisiloxane, both developed by L’Ore´al, and methylene-bis-benzotriazole tetramethylbutylphenol and bis-ethylhexyloxyphenol methoxyphenol triazine, developed by Ciba Specialty Chemicals (see Box 1). Unfortunately, there is no way for the clinician to judge the amount of UVA protection in combination agents. It has been suggested that pure inorganic
Box 1. Sunscreen agents offering long-range protection and may be of use in photodermatoses FDA-approved agents
The clinician theoretically is limited to recommending products that contain the UVA filters that have been approved by the US Food and Drug Administration (FDA) (Box 1). In the category of organic or chemical sunscreens, this includes the benzophenones (oxybenzone, dioxybenzone, and sulisobenzone), butylmethoxydibenzoylmethane, also known as avobenzone (Parsol 1789), and methylanthralinate. All, with the exception of avobenzone, are primarily protective in the UVA 2 range; the absorption of avobenzone extends into UVA 1. The approved inorganic screens or physical blockers are titanium dioxide and zinc oxide. When these agents were used originally, they did offer protection that extended into the UVA and visible ranges but at the expense of cosmetic acceptability. To make such agents more acceptable to consumers, the particles have been micronized and coated. Although these agents still offer some protection into the longer ranges, that protection is not as good as that of the older agents. In this regard, it has been shown in in vitro studies that microfine zinc oxide should provide better protection in the UVA 1 range than the same concentration of microfine titanium dioxide [3]. There are other agents of interest that protect against longer wave radiation in the photosensitive individual. These agents include the self tanner dihy-
Chemical or organic Oxybenzone-benzophenone 3 Sulisobenzone-benzophenone 4 Dioxybenzone-benzophenone 8 Butylmethoxydibenzoylmethaneavobenzone (Parsol 1789) Methyl anthranilate Physical or inorganic Titanium dioxide (TiO2) Zinc oxide (ZnO) Other agents available in American products Dihydroxyacetone Iron oxide Agents not approved for use in United States Terephthalydene dicamphor sulfonic acid (Mesoryl SX) Drometrizole trisiloxane (Mexoryl XL) Methylene-bis-benzotriazole tetramethylbutylphenol (Tinosarb M) Bis-ehtylhexyloxyphenol methoxyphenol triazine (Tinosarb S)
sunscreen use in photodermatoses
screens with high sun protection factor (SPF) theoretically should give good long wave protection. It has been suggested that products containing high levels of titanium dioxide and zinc oxide in high SPF chemical-free sunscreens and those that contain avobenzone in combination with the two inorganic agents seem to be reasonable alternatives if the newer non – FDA-approved screens cannot be obtained. In addition, dihydroxyacetone and iron oxide may be of benefit in some individuals.
Published studies There is very little published information assessing the relative protective value of various agents against long-wave radiation in people. Bissonnette and colleagues [4] examined long-wave protection of six different commercially available (in Europe) sunscreens by measuring persistent pigment darkening in human volunteers. This endpoint is one of numerous endpoints that have been used to measure UVA protection. They found that a product containing terephthalydene dicamphor sulfonic acid, avobenzone, and TiO2 was most protective. This was followed by sunscreens that contained avobenzone and the physical blockers TiO2 and ZnO. This study used products with varying concentration of the UVA filters, making it difficult to draw solid conclusions about the relative effectiveness of individual ingredients. It generally is believed, however, that terephthalydene dicamphor sulfonic acid will offer greater protection for the photosensitive patient once it becomes available in the United States. Clinical trials testing the efficacy of sunscreens for preventing development of the various photodermatoses are rare [2]. Additionally, such studies sometimes are complicated by inconsistent diagnostic terminology. The following sections summarize a small number of studies in which various agents were tested for photoprotection in patients with various photosensitive disorders.
Polymorphous light eruption The most common photosensitivity in lightskinned individuals regardless of country of origin is PMLE. The lifetime incidence of this condition in the United States has been reported to be 10% to 15%. Similar rates have been reported from other countries [2]. As a population gets closer to the equator, the incidence rate for that population de-
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creases. This may be because of differences in skin color, but it also suggests that the more sun exposure a population receives, the less likely its members are to develop the sensitivity. The classic history in affected individuals is that the first episode occurs during a sunny vacation with long exposures to sunlight. The reaction classically develops after 2 or 3 days of exposure, and with sun avoidance, the reaction will resolve in a few days to 1 or 2 weeks. The most common reaction pattern is a small papular or papulo – vesicular morphology. The reaction usually involves the chest, arms and legs and routinely spares the face. In most cases, an individual will have a single episode without recurrences. A rarer group of individuals will begin to develop the reaction in a more recurrent fashion, with some individuals developing the reaction with less and less exposure. These are the patients who are likely to seek medical attention. The differential diagnosis in these patients includes lupus erythematosus and photoallergic contact dermatitis, primarily to sunscreens. Although the eruption can be reproduced with artificial light sources in photoprovocation studies, the diagnosis usually can be made from the classical history with histologic confirmation. In reviewing the literature on this and many other forms of photosensitivity, it must be remembered that nomenclature may vary with investigator. In this regard, although some reports suggest that minimal erythema dose (MED) testing may reveal lowered MED in a group of these patients, most studies reveal MED testing in PMLE is normal [5]. To reproduce the eruption, large doses of radiation greater that the MED must be applied to large areas of previously exposed skin. Numerous investigators have done studies to define the action spectrum of PMLE. Although there is variation among reports, overall, it would appear that most patients with PMLE react at least partially to UVA. There are some individuals who are sensitive to UVB alone; however, most patients react to UVA alone or to a combination of both UVB and UVA radiation [5 – 8]. It is likely that those patients who develop reactions to UVB alone get adequate protection from sunscreens and therefore rarely seek medical care (author’s personal observation). Although most authors suggest that UVB/UVA sunscreens offer some protection against development of reactions, they usually suggest that prophylactic phototherapy and photochemotherapy are most efficacious [5 – 10]. Holzle and colleagues [6] showed that 4-isopropyl dibenzoyl methane and methylbenzylidene camphor were capable of preventing photoprovocation of lesions with UVA radiation in the
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laboratory setting. More recently Allas and colleagues [11,12] reported prevention of induction of the lesions of PMLE in 23 patients by a combination sunscreen containing terephthalydene dicamphor sulfonic acid using a UVA/UVB photoprovocation source. A control sunscreen containing UVB blockers and oxybenzone for UVA protection prevented the reactions in only three patients. This product and others like it likely will prove to be important for preventing PMLE and many other types of photosensitivity where longer wavelength radiation plays and etiologic role. A promising new area of research is the use of a combination of new UVA protective sunscreens and potent antioxidants that appear in early studies to protect against development of PMLE in affected patients [13,14].
Solar urticaria Solar urticaria (SU) is diagnosed easily by history. The patient describes an immediate response to sunlight with the development of pruritus, erythema, and sometimes but not always edema or discrete hives. The reaction rarely persists for longer than minutes to hours. Occasionally, systemic reactions including anaphylaxis are possible but exceedingly rare. Patients vary widely in the action spectrum of their reactivity. Usually UVA or even visible radiation is involved. In most, but not all affected individuals, the eruption can be reproduced with artificial sources. It is useful to perform such phototesting to choose the proper screens for protection. Treatment other than avoidance usually consists of antihistamines as for other physical urticarias. Plasmapheresis, phototherapy, and photochemotherapy also have been used [11]. For patients who have UVB sensitivity, high-SPF sunscreens should be helpful. The new agents with UVA activity should be useful in those individuals who have UVA sensitivity. Protection in the visible range may be more difficult to achieve. The physical blockers—titanium and zinc oxides—may offer some protection into the lower visible range. Iron oxide, which is not approved as a sunscreen by the FDA but which is contained in some products (RYPaque) as a tinting agent, has been reported to offer some protection against visible radiation [11]. The more protective these agents are, however, the less cosmetically acceptable they may be. Dihydroxyacetone is the sunless tanning ingredient. Although its SPF is low, it does protect in the UVA and visible ranges and may be useful in SU [3]. This agent should be applied before bed for 2 to 3 nights (follow manufacturer’s instructions)
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until a visible tan develops. It then should be applied 2 to 3 nights per week to maintain the color and photoprotection.
Hydroa vacciniforme Hydroa vacciniforme (HV) is a rare nonfamilial photodermatosis that routinely occurs before puberty. Along with actinic prurigo (AP), it represents the two idiopathic photodermatoses of childhood. The age of onset in a recent review [15] was about 8 years of age. Males and females were affected equally. With sun exposure, affected individuals develop macules that evolve into papules and finally into vesicles that heal with variola-form scarring. The face is affected particularly. First episodes may resemble primary herpes simplex but will be culture-negative. The disease in most individuals is self-limited, with 60% resolving within 4 to 7 years. The action spectrum of the disease seems to be broad, with reproduction by both UVB and UVA [2,15,16]. There are cases of severe hydroa vacciniformelike eruptions associated with lymphoproliferative disease and Epstein-Barr virus infection. The skin manifestation in these individuals is much more severe and not related to sun exposure [17]. There should be no problem in differentiating this malignant disease from HV on clinical and histologic grounds. Purely UVB sunscreens may not prevent the HV reaction. These patients need rigorous avoidance and protection with broad-spectrum screens to prevent eruption and permanent scarring.
Actinic prurigo AP is also known as familial PMLE of Amerindians. In Europe, this condition has been described in non-Indian people. In the United States, the term is used to describe a photodermatosis that develops in childhood in Amerindians from Canada through the United States and into Central and South America. Although it is an inherited disorder, it generally is classified as an idiopathic photosensitivity rather than a genodermatosis. Eighty percent of affected individuals have onset before puberty. The classic lesions are prurigenous papules developing on sun-exposed skin, although the eruption may spread to involve covered areas. It usually is accompanied by a cheilitis and eye involvement. The eruption tends to be chronic rather than recurrent with sun exposure during the sunny months and clearing in the winter. The action spectrum includes UVB and UVA radiation [2].
sunscreen use in photodermatoses
Thalidomide appears to be the drug of choice when such therapy is possible. Avoidance and broadspectrum sunscreens with avobenzone have been shown to be effective in some patients [18], and narrow band UVB phototherapy has been reported to be of benefit if screening is not effective [19].
Chronic actinic dermatitis Chronic actinic dermatitis (CAD) represents an idiopathic photodermatosis of adults. It is rare, and in many cases, a very debilitating disease. The term is used to describe individuals who react to radiation with an eczematous response clinically and histologically. The eruption is confined to sun-exposed areas in early stages, but may spread to involve unexposed skin also. The reaction becomes chronic, probably because very small quantities of radiation induce the pathology. The morphology in severe cases may evolve into a reticuloid appearance with lionine facies and almost tumor-like plaques. Histology also may evolve into that suggestive of cutaneous T-cell lymphoma. The latter cases are sometimes referred to as actinic reticuloid. Some patients even progress to exfoliative erythroderma. The reaction usually is reproduced easily with a lowered MED and an eczematous response to UVB radiation in most patients, with extension into the UVA and even the visible ranges in some [1]. This photodermatosis is considered an end-stage reaction triggered by numerous diverse immunologic events. Some people begin with a contact dermatitis to various allergens, including airborne compositiae reactions from plants and workplace antigens like chromates in cement, and then for unexplained reasons they develop reactions to radiation. Others begin with a photoallergic contact dermatitis and evolve into CAD after the offending agent is removed. In these cases, the reactions have been referred to as persistent light reactivity. Some patients with atopic eczema develop photosensitivity and fit into this classification. Rarely patients with photodrug reactions will continue to react to light alone when the drug is discontinued, and finally patients who have HIV also have been reported to develop this type of photosensitivity [1]. Treatment options include extensive patch and photopatch testing so that all inciting allergens can be avoided. Phototherapy and photochemotherapy have been used with varying success. Broadspectrum sunscreens as outlined in Box 1 should be used but only after patch and photopatch testing to rule out sunscreen allergy.
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Genodermatoses As outlined in the Lenane and Murphy publication [2], the genodermatoses can be divided into those with DNA repair deficiency, pigmentary deficiencies, the porphyrias, and deficiency of cholesterol biosynthetic pathway. The DNA repair deficiencies include in individuals with Xeroderma pigmentosum, trichothiodystrophy, Rothmund Thomson syndrome, and Cockayne’s syndrome. In all of these individuals, rigorous sun avoidance must be practiced. Although broad-spectrum sunscreens may be recommended, high SPF for good UVB protection is most important [20]. Photosensitivity recently has been reported in the Smith-Lemli-Opitz syndrome. Patients with this deficiency of the enzyme 7-dehydrocholesterol reductase have a high mortality rate and exhibit congenital heart disease and mental retardation. Affected individuals have the onset of a sunburn-like erythema within minutes of exposure, and this persists for 1 to 2 days. Phototesting has revealed sensitivity in the UVA range [21]. Avoidance and broad-spectrum sunscreens are therefore necessary. The porphyrias are a group of inherited and acquired diseases that represent deficiencies in the activity of enzymes of the heme biosynthetic pathway. Erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP), and hepatoerythropoietic porphyria (HEP) have their onset in childhood. These individuals develop burning and stinging on exposure to sunlight. People who have CEP and HEP have much more severe photosensitivity, compared with people who have EEP, which is a relatively mild disease. In all of these individuals, sun avoidance and protection are important. In the relatively common porphyria cutanea tarda (PCT), patients complain more of easy bruisability and blistering of the exposed skin, primarily the hands. This is treatable by phlebotomies or antimalarial therapy, with reduction of porphyrin abnormalities and resolution of symptoms. Patients with the mixed porphyries, variegate porphyria (VP), and hereditary coproporphyria (HC), may have similar skin findings to patients who have PCT, but they also may have neurologic symptoms. Treatment of the skin lesions in these patients is based primarily on avoidance and photoprotection. Because the skin lesions in all of the porphyrias are caused by Soret band radiation (400 – 410 nm), screens that protect in the visible range are optimal for affected individuals. Such protection, however, is difficult to achieve. Broad-spectrum sunscreens usually are recommended, but the use of dihydroxyace-
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tone [22] and iron oxide in combination with the more traditional UVB/UVA screens should be beneficial. Patients with various forms of albinism require broad-spectrum protection to prevent the deleterious effect of lack of natural melanin protection in their skin. Photoaggravated diseases Although there are large numbers of diseases where radiation may aggravate pathology in the skin, the two most important and common of these are lupus erythematosus (LE) and dermatomyositis (DM). Although photosensitivity in DM has not been investigated extensively, studies of the action spectra for various forms of LE have been described. Lehmann [23] studied 128 patients who had LE. The skin lesions of LE were reproducible with artificial light in 64% of patients with subacute cutaneous LE, 42% of patients with discoid LE, and 25% of patients with systemic LE. In those patients with reproducible lesions, the action spectrum was in both the UVB and UVA ranges in 53%, in the UVB range alone in 33%, and in the UVA range alone in 14%. Stege and colleagues [24] studied the effect of three different sunscreen products for preventing artificially produced LE lesions in 11 patients. A screen containing terephthalydene dicamphor sulfonic acid and drometrizole trisoloxane, Parsol 1789, and titanium dioxide was the most protective, preventing lesion development in all 11 patients. Two products with titanium dioxide and Parsol 1789 as UVA screens and different UVB screens were effective in five and three patients only. Callen and colleagues [25] studied sunscreen protection in an open-label study using a screen with Padimate O and Parsol 1789 and found good to excellent protection in 54% of patients. Johnson and Fusaro [26] suggested that dihydroxyacetone would be beneficial in LE patients who have long wave-induced disease.
Summary Most of the photodermatoses are induced by long wave radiation. Sunscreens must be used as part of the treatment of affected individuals. Currently, sunscreens that provide complete photoprotection against UVA and visible radiation and therefore provide protection for affected individuals are not available in the United States. It is hoped that such agents will be available soon.
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References [1] Marks J, Elsner P, DeLeo V. Contact and occupational dermatology. 3rd edition. St. Louis (MO)7 Mosby; 2002. [2] Lenane P, Murphy GM. Sunscreens and the photodermatoses. J Dermatolog Treatment 2001;12:53 – 7. [3] Mitchnick MA, Fairhurst D, Pinnell SP. Microfine zinc oxide as a photostable UV-A/UV-B sunblock agent. J Am Acad Dermatol 1999;40:85 – 90. [4] Bissonnette R, Allas S, Moyal D, et al. Comparison of UVA protection afforded by high sun protection factor sunscreens. J Am Acad Dermatol 2000;43: 1036 – 8. [5] Boonstra HE, van Weelden H, Toonstra J, et al. Polymorphous light eruption: a clinical, photobiologic, and follow-up study of 110 patients. J Am Acad Dermatol 2000;42:199 – 207. [6] Holze E, Plewig G, Hofmann C, et al. Polymorphous light eruption. Experimental reproduction of skin lesions. J Am Acad Dermatol 1982;7:111 – 25. [7] Ortel B, Tanew A, Wolf K, et al. Polymorphous light eruption: action spectrum and photoprotection. J Am Acad Dermatol 1986;14:748 – 53. [8] Holzle E, Plewig G, von Dries R, et al. Polymorphous light eruption. J Invest Dermatol 1987;88:32s – 8s. [9] Honigsmann H. Effect of therapeutic sunscreen cream on phototest reaction in polymorphous light dermatosis. Z Hautkr 1989;64:1065 – 8. [10] McFadden N. UVA sensitivity and topical photoprotection in polymorphic light eruption. Photodermatol 1984;1:76 – 8. [11] Bissonnette R. Prevention of polymorphous light eruption and solar urticaria. Skin Therapy Letter 2002; 7:3 – 5. [12] Allas S, Lui H, Moyal D, et al. Comparison of the ability of 2 sunscreens to protect against polymorphous light eruption induced by a UV-A/UV-B metal halide lamp. Arch Dermatol 1999;135:1421 – 2. [13] Rippke F, Wendt G, Bohnsack K, et al. Results of photoprovocation and field studies on the efficacy of a novel topically applied antioxidant in polymorphous light eruption. J Dermatolog Treat 2001;12:3 – 8. [14] Hadshiew IM, Treder-Conrad C, v Bulow R, et al. Polymorphous light eruption and a new potent antioxidant and UVA-protective formulation as prophylaxis. Photodermatol Photoimmunol Photomed 2004; 20:200 – 4. [15] Gupta G, Man I, Kemmett D. Hydroa vacciniforme: a clinical and follow-up study of 17 cases. J Am Acad Dermatol 2000;42:208 – 13. [16] Sonnex TS, Hawk JL. Hydroa vacciniforme: a review of ten cases. Br J Dermatol 1998;118:101 – 8. [17] Cho KH, Lee SH, Kim CW, et al. Epstein-Barr virusassociated lymphoproliferative lesions presenting as a hydroa vacciniforme-like eruption: and analysis of six cases. Br J Dermatol 2004;151:372 – 80. [18] Fusaro RM, Johanso JA. Topical photoprotection for hereditary polymorphous light eruption of American Indians. J Am Acad Dermatol 1991;24:744 – 6.
sunscreen use in photodermatoses [19] Gambichler T, Breuckmann F, Boms S, et al. Narrowband UV-B phototherapy in the skin conditions beyond psoriasis. J Am Acad Dermatol 2005;52: 660 – 70. [20] Liardet S, Scaletta C, Panizzon R, et al. protection against pyrimidine dimmers, p53, and 8-hydroxy-2deoxyguanine expression in ultraviolet-irradiated human skin by sunscreens: difference between UV-B + UV-A and UV-B alone sunscreens. J Invest Dermatol 2001;117:1437 – 41. [21] Anstey AV, Ryan A, Rhodes LE, et al. Characterization of photosensitivity in the Smith-Lemli-Opitz syndrome: a new congenital photosensitivity syndrome. Br J Dermatol 1999;141:406 – 14. [22] Asawanonds P, Oberlender S, Taylor C. The use of dihydroxyacetone for photoprotection in variegate porphyries. Int J Dermatol 1999;38:916 – 8.
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[23] Lehmann P, Holzle E, Kind P, et al. Experimental reproduction of skin lesions in lupus erythematosus by UV-A and UV-B radiation. J Am Acad Dermatol 1990; 22:181 – 7. [24] Stege H, Budde MA, Grether-Beck S, et al. Evaluation of the capacity of sunscreens to photoprotect lupus erythematosus patients by employing the photoprovocation test. Photodermatol Photoimmunol Photomed 2000;16:256 – 9. [25] Callen JP, Roth DE, McGrath C, et al. Safety and efficacy of a broad-spectrum sunscreen in patients with discoid or subacute cutaneous lupus erythematosus. Cutis 1991;47:130 – 2. [26] Johnson JA, Fusaro RM. Broad-spectrum photoprotection: the roles of tinted auto windows, sunscreens and browning agents in the diagnosis and treatment of photosensitivity. Dermatology 1992;185(4):237 – 41.