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Photosensitivity and Other Reactions to Light

Photosensitivity and Other Reactions to Light

David R. Bickers

SOLAR RADIATION

Sunlight is the most visible and obvious source of comfort in the environment. The sun provides the beneficial effects of warmth and vitamin D synthesis; however, acute and chronic sun exposure also have pathologic consequences. Few effects of sun exposure beyond those affecting the skin have been identified, but cutaneous exposure to sunlight is the major cause of human skin cancer and can exert immunosuppressive effects as well.

The sun's energy reaching the earth's surface is limited to components of the ultraviolet (UV), the visible, and portions of the infrared spectra. The cutoff at the short end of the UV is at approximately 290 nm; this is due primarily to stratospheric ozone formed by highly energetic ionizing radiation, thereby preventing penetration to the earth's surface of the shorter, more energetic, potentially more harmful wavelengths of solar radiation. Indeed, concern about destruction of the ozone layer by chlorofluorocarbons released into the atmosphere has led to international agreements to reduce production of these chemicals.

Measurements of solar flux indicate that there is a twentyfold regional variation in the amount of energy at 300 nm that reaches the earth's surface. This variability relates to seasonal effects; the path of sunlight transmission through ozone and air; the altitude (4% increase for each 300 m of elevation); the latitude (increasing intensity with decreasing latitude); and the amount of cloud cover, fog, and pollution.

The major components of the photobiologic action spectrum capable of affecting human skin include the UV and visible wavelengths between 290 and 700 nm. In addition, the wavelengths beyond 700 nm in the infrared spectrum primarily emit heat and under certain circumstances may exacerbate the pathologic effects of energy in the UV and visible spectra.

The UV spectrum reaching the earth represents <10% of total incident solar energy and is arbitrarily divided into two major segments: UV-B, and UV-A. This includes the wavelengths between 290 and 400 nm. UV-B consists of wavelengths between 290 and 320 nm. This portion of the photobiologic action spectrum is the most efficient in producing redness or erythema in human skin and hence is sometimes known as the “sunburn spectrum.” UV-A represents those wavelengths between 320 and 400 nm and is approximately 1000-fold less efficient in producing skin redness than is UV-B.

The wavelengths between 400 and 700 nm are visible to the human eye. The photon energy in the visible spectrum is not capable of damaging human skin in the absence of a photosensitizing chemical. Without the absorption of energy by a molecule there can be no photosensitivity. Thus the absorption spectrum of a molecule is defined as the range of wavelengths absorbed by it, whereas the action spectrum for an effect of incident radiation is defined as the range of wavelengths that evoke the response.

Photosensitivity occurs when a photon-absorbing chemical (chromophore) present in the skin absorbs incident energy, becomes excited, and transfers the absorbed energy to various structures or to oxygen.

UV RADIATION (UVR) AND SKIN STRUCTURE AND FUNCTION

Skin consists of two major compartments: the outer epidermis, a stratified squamous epithelium, and the underlying dermis rich in matrix proteins such as collagen and elastin. Both of these compartments are susceptible to damage from sun exposure. The epidermis and the dermis contain several chromophores capable of absorbing incident solar energy including nucleic acids, proteins, and lipids. The outermost epidermal layer, the stratum corneum, is a major absorber of UV-B, and <10% of incident UV-B wavelengths penetrate through the epidermis to the dermis. Approximately 3% of radiation below 300 nm, 20% of radiation below 360 nm, and 33% of short visible radiation reaches the basal cell layer in untanned human skin. In contrast, UV-A readily penetrates to the dermis and is capable of altering structural and matrix proteins that contribute to the aged appearance of chronically sun-exposed skin, particularly in individuals of light complexion.

Epidermal DNA, predominantly in keratinocytes, absorbs UV-B and undergoes structural changes including the formation of cyclobutane dimers and 6,4-photoproducts. These structural changes are potentially mutagenic and can be repaired by mechanisms that result in their recognition and excision and the reestablishment of normal base sequences. The efficient repair of these structural aberrations is crucial, since individuals with defective DNA repair are at high risk for the development of cutaneous cancer. For example, patients with xeroderma pigmentosum (XP), an autosomal recessive disorder, are characterized by variably deficient repair of UV-induced photoproducts, and their skin phenotype often manifests the dry, leathery appearance of prematurely photoaged skin as well as basal cell and squamous cell carcinomas and melanoma in the first two decades of life. Studies in mice using knockout gene technology have verified the importance of functional genes regulating these repair pathways in preventing the development of UV-induced cancer. Furthermore, incorporation of a bacterial DNA repair enzyme, T4N5 endonuclease, into liposomes in a product applied to skin of patients with XP selectively removes cyclobutane pyrimidine dimers and reduces the degree of solar damage and skin cancer.

Cutaneous Optics and Chromophores

Chromophores are endogenous or exogenous chemical components that can absorb physical energy. Endogenous chromophores are of two types: (1) chemicals that are normal components of skin, including nucleic acids, proteins, lipids, and 7-dehydrocholesterol, the precursor of vitamin D; and (2) chemicals, such as porphyrins, synthesized elsewhere in the body that circulate in the bloodstream and diffuse into the skin. Normally, only trace amounts of porphyrins are present in the skin, but in selected diseases known as the porphyrias, increased amounts are released into the circulation from the bone marrow and the liver and are transported to the skin, where they absorb incident energy both in the Soret band, around 400 nm (short visible), and to a lesser extent in the red portion of the visible spectrum (580 to 660 nm). This results in the generation of reactive oxygen species that can mediate structural damage to the skin, manifest as erythema, edema, urticaria, or blister formation.

Acute Effects of Sun Exposure

The acute effects of skin exposure to sunlight include sunburn and vitamin D synthesis.

SUNBURN

This painful skin condition is caused predominantly by UV-B. Generally speaking, an individual's ability to tolerate sunlight is inversely proportional to the degree of melanin pigmentation. Melanin, a complex tyrosine polymer, is synthesized in specialized epidermal dendritic cells known as melanocytes and is packaged into melanosomes that are transferred via dendritic process into keratinocytes, thereby providing photoprotection and simultaneously darkening the skin. Sun-induced melanogenesis is a consequence of increased tyrosinase activity in melanocytes that in turn may be due to a combination of eicosanoid and endothelin-1 release. The Fitzpatrick classification of human skin is a function of the efficiency of the epidermal-melanin unit and can usually be ascertained by asking an individual two questions: (1) Do you burn after sun exposure? and (2) Do you tan after sun exposure? The answers to these questions permit division of the population into six skin types varying from type I (always burn, never tan) to type VI (never burn, always tan) (Table 1).

Sunburn is due to vasodilatation of dermal blood vessels. There is a lag in time between skin exposure to sunlight and the development of visible redness (usually 4 to 12 h), suggesting that an epidermal chromophore causes delayed production and/or release of vasoactive mediator(s), or cytokines, that diffuse to the dermal vasculature to evoke vasodilatation.

The action spectrum for sunburn erythema includes the UV-B and UV-A. Photons in the UV-B are at least 1000-fold more efficient than photons in the UV-A in evoking the response. However, UV-A may contribute to sunburn erythema at midday when much more UV-A than UV-B is present in the solar spectrum. UV-induced activation of nuclear factor-κB (NF-κB)-dependent gene transactivation can augment release of several proinflammatory cytokines including interleukin (IL) 1B, 1L-6, vascular endothelial growth factor, and tumor necrosis factor α. Local accumulation of these cytokines occurs in sunburned skin. It is of interest that nonsteroidal anti-inflammatory drugs can reduce sunburn erythema, perhaps by blocking I-κB kinase 2, the enzyme essential for nuclear translocation of cytosolic NF-κB.

VITAMIN D PHOTOCHEMISTRY

Cutaneous exposure to UV-B causes photolysis of epidermal 7-dehydrocholesterol converting it to pre-vitamin D₃, which then undergoes a temperature-dependent isomerization to form the stable hormone vitamin D₃. This compound then diffuses to the dermal vasculature and circulates systemically where it is converted to the functional hormone 1,25-dihydroxy vitamin D₃ [1,25(OH)₂D₃]. Vitamin D metabolites from the circulation or those produced in the skin itself can augment epidermal differentiation signaling. Aging substantially decreases the ability of human skin to photocatalytically produce vitamin D₃. This, coupled with the widespread use of sunscreens that filter out UV-B, has led to concern that vitamin D deficiency may become a significant clinical problem in the elderly. Nonetheless, at least one double-blind placebo-controlled trial has shown that a broad-spectrum sunscreen applied topically for several months has no significant effect on measured plasma vitamin D metabolites.

Chronic Effects of Sun Exposure: Nonmalignant

The clinical features of photodamaged sun-exposed skin consist of wrinkling, blotchiness, and telangiectasia and a roughened, irregular, “weather-beaten” leathery appearance. Whether this photoaging represents accelerated chronologic aging or a separate and distinct process is not clear.

Within chronically sun-exposed epidermis, there is thickening (acanthosis) and morphologic heterogeneity within the basal cell layer. Higher but irregular melanosome content may be present in some keratinocytes, indicating prolonged residence of the cells in the basal cell layer. These structural changes may help to explain the leathery texture and the blotchy discoloration of sun-damaged skin.

The dermis and its connective tissue matrix are the major site for sun-associated chronic damage, manifest as solar elastosis, a massive increase in thickened irregular masses of abnormal elastic fibers. Collagen fibers are also abnormally clumped in the deeper dermis of sun-damaged skin. The chromophore(s), the action spectra, and the specific biochemical events orchestrating these changes are only partially understood. Chronologically aged, sun-protected skin and photoaged skin share important molecular features including connective tissue damage, elevated matrix metalloproteinase levels, and reduced collagen production.

Chronic Effects of Sun Exposure: Malignant

One of the major known consequences of chronic skin exposure to sunlight is nonmelanoma skin cancer. The two types of nonmelanoma skin cancer are basal cell carcinoma and squamous cell carcinoma. There are three major steps for cancer induction: initiation, promotion, and progression. Exposure of human skin to sunlight results in initiation, a step whereby structural (mutagenic) changes in DNA evoke an irreversible alteration in the target cell (keratinocyte) that begins the tumorigenic process. Exposure to a tumor initiator such as UV-B is believed to be a necessary but not sufficient step in the malignant process, since initiated skin cells not exposed to tumor promoters do not generally develop tumors. The second stage in tumor development is promotion, a multistep process whereby chronic exposure to sunlight evokes epigenetic changes that culminate in the clonal expansion of initiated cells and cause the development, over many years, of premalignant growths known as actinic keratoses, a minority of which may progress to form skin cancer. Based on extensive studies it seems clear that UV-B is a complete carcinogen, meaning that it can act as both a tumor initiator and a promoter.

The third and final step in the malignant process is malignant conversion of benign precursors into malignant lesions, a process thought to require additional genetic alterations in already transformed cells. Skin carcinogenesis is thought to be caused by the accumulation of mutations in the tumor suppressor gene p53 as a result of UV-induced DNA damage. Indeed both human and murine UV-induced skin cancers have unique p53 mutations (C → T and CC → TT transitions) that are present in the majority of these lesions. Studies have shown that sunscreens can substantially reduce the frequency of these signature mutations in p53 and can dramatically inhibit the induction of tumors. The p53 mutations are present in normal human skin, in actinic keratoses, and in nonmelanoma skin cancers including basal cell and squamous cell carcinomas.

Basal cell carcinomas also manifest mutations in the tumor-suppressor gene known as patched, which results in activation of hedgehog signaling, and enhanced activity of smoothened, which in turn causes downstream activation of transcription factors that augment cell proliferation. Thus, these tumors can manifest mutations in both p53 and in patched.

Sun exposure causes nonmelanoma and melanoma cancers of the skin, although the evidence is far more direct for its role in nonmelanoma (basal cell and squamous cell carcinoma) than in melanoma. Approximately 80% of nonmelanoma skin cancers develop on exposed body area, including the face, the neck, and the hands. Major risk factors include male sex, childhood sun exposures, older age, fair skin, and residence at latitudes closer to the equator. Whites of darker complexions (e.g., Hispanics) have one-tenth the risk of developing such cancers compared to fair-skinned individuals. Blacks are at substantially reduced risk for all forms of skin cancer. One million individuals in the United States develop nonmelanoma skin cancer annually, and the lifetime risk for a fair-skinned individual to develop such a neoplasm is estimated at approximately 15%. A consensus exists that the incidence of nonmelanoma skin cancer in the population is increasing at the rate of 2 to 3% per year, for unknown reasons.

The relationship of sun exposure to melanoma development is less clear-cut, but suggestive evidence supports an association. Melanomas occasionally develop by the teenage years, indicating that the latent period for tumor growth is less than that of nonmelanoma skin cancer. Melanomas are among the most rapidly increasing of all human malignancies. Epidemiologic studies of immigrant populations of similar ethnic stock indicate that individuals born in one area or who migrate to the same locale before age 10 have higher age-specific melanoma rates than individuals arriving later. It is thus reasonable to conclude that life in a sunny climate from birth or early childhood increases the risk of melanoma. In general, risk does not correlate with cumulative sun exposure but may relate to the duration and extent of exposure in childhood.

Meta-analysis of 17 case-control studies in patients with melanoma concluded that the protective effect of sunscreens against this type of tumor could not be substantiated. Since no prospective studies are available to address this issue, it seems reasonable to recommend that patients at risk for melanoma utilize photoprotection such as sun avoidance, high sun protective factor (SPF) sunscreens, and protective clothing.

Immunologic Effects

Exposure to solar radiation suppresses both local and systemic immune responses. The action spectrum for UV-induced immunosuppression closely mimics the absorption spectrum of urocanic acid. UV-induced trans-cis isomerization of urocanic acid in the stratum corneum leads to its systemic absorption and consequent immunosuppressive effects. Furthermore administration of modest doses of UV-B to human skin reduces the degree of allergic sensitization to the potent contact allergen, dinitrochlorobenzene. This is associated with depletion of epidermal Langerhans cells.

Higher doses of UV-radiation evoke diminished immunologic responses to antigens introduced either epicutaneously or intracutaneously at sites distant from the irradiated site. These suppressed responses are also associated with the induction of antigen-specific suppressor T lymphocytes and may be mediated by as yet undefined factors that are released from epidermal cells at the irradiated site. One important consequence of chronic sun exposure and the concomitant immunosuppression is enhanced risk of skin cancer. Perhaps the most graphic demonstration of the role of immunosuppression in enhancing the risk of nonmelanoma skin cancer has come from studies of patients receiving organ transplantation who are on chronic immunosuppressive antirejection drug regimens. More than 50% of transplant patients develop basal and squamous cell carcinomas, and these cancers are the most common malignancy arising in renal transplant recipients. These patients require close periodic monitoring and rigorous photoprotection using sunscreens, protective clothing, and sun avoidance.

PHOTOSENSITIVITY DISEASES

The diagnosis of photosensitivity requires a careful history to define the duration of the signs and symptoms, the length of time between exposure to sunlight and the development of subjective complaints, and visible changes in the skin. The age of onset can also be a helpful clue; for example, the acute photosensitivity of erythropoietic protoporphyria almost always begins in childhood, whereas the chronic photosensitivity of porphyria cutanea tarda (PCT) typically begins in the fourth and fifth decades. A history of exposure to topical and systemic drugs and chemicals may provide important clues. Many classes of drugs can cause photosensitivity on the basis of either phototoxicity or photoallergy. Fragrances such as musk ambrette that were previously present in numerous cosmetic products are also potent photosensitizers.

Examination of the skin may also offer important clues. Anatomic areas that are naturally protected from direct sunlight such as the hairy scalp, the upper eyelids, the retroauricular areas, and the infranasal and submental regions may be spared, whereas exposed areas show characteristic features of the pathologic process. These anatomic localization patterns are often helpful, but not infallible, in making the diagnosis. For example, airborne contact sensitizers that are blown onto the skin may produce dermatitis that can be difficult to distinguish from photosensitivity, despite the fact that such material may trigger skin reactivity in areas shielded from direct sunlight.

Many dermatologic conditions may be caused or aggravated by sunlight (Table 2). The role of light in evoking these responses may be dependent on genetic abnormalities ranging from well-described defects in DNA repair that occur in XP to the inherited abnormalities in heme synthesis that characterize the porphyrias. In certain photosensitivity diseases, the chromophore has been identified, whereas in the majority, the energy-absorbing agent is unknown.

Polymorphous Light Eruption

After sunburn, the most common type of photosensitivity disease is polymorphous light eruption (PLE), the mechanism of which is unknown. Many affected individuals never seek medical attention because the condition is often transient, becoming manifest each spring with initial sun exposure but then subsiding spontaneously with continuing exposure, a phenomenon known as “hardening.” The major manifestations of PLE include pruritic (often intensely so) erythematous papules that may coalesce into plaques in a patchy distribution on exposed areas of the trunk and forearms. The face is usually less seriously involved.

The diagnosis can be confirmed by skin biopsy and by performing phototest procedures in which skin is exposed to multiple erythema doses of UV-A and UV-B. The action spectrum for PLE is usually within these portions of the solar spectrum.

Treatment of this PLE includes the use of sunscreens and the induction of hardening by the cautious administration of artificial UV-B and/or UV-A radiation for 2 to 3 weeks in the spring.

Phototoxicity and Photoallergy

These photosensitivity disorders are related to the topical or systemic administration of drugs and other chemicals. Both reactions require the absorption of energy by a drug or chemical resulting in the production of an excited-state photosensitizer that can transfer its absorbed energy to a bystander molecule or to molecular oxygen, thereby generating tissue-destructive chemical species.

Phototoxicity is a nonimmunologic reaction caused by drugs and chemicals, a few of which are listed in Table 3. The usual clinical manifestations include erythema resembling a sunburn reaction that quickly desquamates, or “peels,” within several days. In addition, edema, vesicles, and bullae may occur.

Photoallergy is much less common and is distinct in that the immune system participates in the pathologic process. The excited-state photosensitizer may create highly unstable haptenic free radicals that bind covalently to macromolecules to form a functional antigen capable of evoking a delayed hypersensitivity response. Some of the drugs and chemicals that produce photoallergy are listed in Table 4. The clinical manifestations typically differ from those of phototoxicity in that an intensely pruritic eczematous dermatitis tends to predominate and evolves into lichenified, thickened, “leathery” changes in sun-exposed areas. A small subset (perhaps 5 to 10%) of patients with photoallergy may develop a persistent exquisite hypersensitivity to light even when the offending drug or chemical is identified and eliminated, a condition known as persistent light reaction.

A very uncommon type of persistent photosensitivity is known as chronic actinic dermatitis. These patients are typically elderly men with a long history of preexisting allergic contact dermatitis or photosensitivity. They are usually exquisitely sensitive to UV-B, UV-A, and visible wavelengths.

Diagnostic confirmation of phototoxicity and photoallergy can often be obtained using phototest procedures. In patients with suspected phototoxicity, determining the minimal erythema dose (MED) while the patient is exposed to a suspected agent and then repeating the MED after discontinuation of the agent may provide a clue to the causative drug or chemical. Photopatch testing can be performed to confirm the diagnosis of photoallergy. This is a simple variant of ordinary patch testing in which a series of known photoallergens is applied to the skin in duplicate and one set is irradiated with a suberythema dose of UV-A. Development of eczematous changes at sites exposed to sensitizer and light is a positive result. The characteristic abnormality in patients with persistent light reaction is a diminished threshold to erythema evoked by UV-B. Patients with chronic actinic dermatitis usually manifest a broad spectrum of UV hyperresponsiveness and require rigorous photoprotection for relief of their symptoms.

The management of drug photosensitivity involves first and foremost the elimination of exposure to the chemical agents responsible for the reaction and minimization sun exposure. The acute symptoms of phototoxicity may be ameliorated by cool, moist compresses, topical glucocorticoids, and systemically administered NSAIDs. In severely affected individuals, a rapidly tapered course of systemic glucocorticoids may be useful. Judicious use of analgesics may be necessary.

Photoallergic reactions require a similar management approach. Furthermore, patients with persistent light reaction and chronic actinic dermatitis must be meticulously protected against light exposure. In selected patients in whom chronic systemic high-dose glucocorticoids pose unacceptable risks, it may be necessary to employ cytotoxic agents such as azathioprine or cyclophosphamide.

Porphyria

The porphyrias are a group of diseases that have in common inherited or acquired derangements in the synthesis of heme. Heme is an iron-chelated tetrapyrrole or porphyrin, and the nonmetal chelated porphyrins are potent photosensitizers that absorb light intensely in both the short (400 to 410 nm) and the long (580 to 650 nm) portions of the visible spectrum.

Heme cannot be reutilized and must be continuously synthesized, and the two body compartments with the largest capacity for its production are the bone marrow and the liver. Accordingly, the porphyrias originate in one or the other of these organs, with the end result of excessive endogenous production of potent photosensitizing porphyrins. The porphyrins circulate in the bloodstream and diffuse into the skin, where they absorb solar energy, become photoexcited, generate reactive oxygen species, and evoke cutaneous photosensitivity. The mechanism of porphyrin photosensitization is known to be photodynamic, or oxygen-dependent, and is mediated by reactive oxygen species such as singlet oxygen and superoxide anions.

Porphyria cutanea tarda is the most common type of human porphyria and is associated with decreased activity of the enzyme uroporphyrinogen decarboxylase associated with a number of gene mutations. There are two basic types of PCT: (1) the sporadic or acquired type, generally seen in individuals ingesting ethanol or receiving estrogens; and (2) the inherited type, in which there is autosomal dominant transmission of deficient enzyme activity. Both forms are associated with increased hepatic iron stores.

In both types of PCT, the predominant feature is a chronic photosensitivity characterized by increased fragility of sun-exposed skin, particularly areas subject to repeated trauma such as the dorsa of the hands, the forearms, the face, and the ears. The predominant skin lesions are vesicles and bullae that rupture, producing moist erosions, often with a hemorrhagic base, that heal slowly with crusting and purplish discoloration of the affected skin. Hypertrichosis, mottled pigmentary change, and scleroderma-like induration are associated features. Biochemical confirmation of the diagnosis can be obtained by measurement of urinary porphyrin excretion, plasma porphyrin assay, and by assay of erythrocyte and/or hepatic uroporphyrinogen decarboxylase. Multiple mutations of the uroporphyrinogen decarboxylase gene have been identified in human populations, including exon skipping and base substitutions. Some patients with PCT have associated mutations in the HFE gene linked to hemochromatosis. This could contribute to the iron overload seen in PCT, although iron status as measured by serum ferritin, iron levels, and transferrin saturation is no different from that in PCT patients without HFE mutations. Prior hepatitis C infection appears to be an independent risk factor for PCT.

Treatment of PCT consists of repeated phlebotomies to diminish the excessive hepatic iron stores and/or intermittent low doses of the antimalarial drugs chloroquine and hydroxychloroquine. Long-term remission of the disease can be achieved if the patient eliminates exposure to porphyrinogenic agents.

Erythropoietic protoporphyria originates in the bone marrow and is due to a decrease in the mitochondrial enzyme ferrochelatase secondary to numerous gene mutations. The major clinical features include an acute photosensitivity characterized by subjective burning and stinging of exposed skin that often develops during or just after exposure. There may be associated skin swelling and, after repeated episodes, a waxlike scarring.

The diagnosis is confirmed by demonstration of elevated levels of free erythrocyte protoporphyrin. Detection of increased plasma protoporphyrin helps to differentiate lead poisoning and iron-deficiency anemia, in both of which elevated erythrocyte protoporphyrin levels occur in the absence of cutaneous photosensitivity and of elevated plasma protoporphyrin levels.

Treatment consists of reducing sun exposure and the oral administration of the carotenoid β-carotene, which is an effective scavenger of free radicals. This drug increases tolerance to sun exposure in many affected individuals, although it has no effect on deficient ferrochelatase.

An algorithm for managing patients with photosensitivity is illustrated in

PHOTOPROTECTION

Since photosensitivity of the skin results from exposure to sunlight, it follows that absolute avoidance of the sun would eliminate these disorders. Unfortunately, contemporary life-styles make this an impractical alternative for most individuals, and this has led to a search for better approaches to photoprotection.

Natural photoprotection is provided by structural proteins in the epidermis, particularly keratins and melanin. The amount of melanin and its distribution in cells is genetically regulated, and individuals of darker complexion (skin types IV to VI) are at decreased risk for the development of acute sunburn and cutaneous malignancy.

Other forms of photoprotection include clothing and sunscreens. Clothing constructed of tightly woven sun-protective fabrics, irrespective of color, affords substantial protection. Wide-brimmed hats, long sleeves, and trousers all reduce direct exposure. Sunscreens are now considered to be over-the-counter drugs and category I ingredients are recognized by the U.S. Food and Drug Administration (FDA) as monographed and safe and effective. These are listed in Table 5. Sunscreens are rated for their photoprotective effect by their SPF. The SPF is simply a ratio of the time required to produce sunburn erythema with and without sunscreen application. The monograph stipulates that sunscreens must be rated on a scale ranging from minimal (SPF 2 and 12) to moderate (SPF 12 and 30) to high (SPF ≥30, labeled as 30+). No SPF number >30 can be placed on the label.

In addition to light absorption, a critical determinant of the sustained photoprotective effect of sunscreens is their water-resistance. The FDA monograph has also defined strict testing criteria for sunscreens making this claim.

Some degree of photoprotection can also be achieved by limiting the time of exposure during the day. Since the majority of an individual's total lifetime sun exposure may occur by the age of 18, it is important to educate parents and young children about the hazards of sunlight. Simply eliminating exposure at midday will substantially reduce lifetime UV-B exposure.

PHOTOTHERAPY AND PHOTOCHEMOTHERAPY

UV can also be used therapeutically. The administration of UV-B alone or in combination with topically applied agents can induce remissions of psoriasis and atopic dermatitis.

Photochemotherapy in which topically applied or systemically administered psoralens are combined with UV-A (PUVA) is also effective in treating psoriasis and in the early stages of cutaneous T cell lymphoma and vitiligo. Psoralens are tricyclic furocoumarins that, when intercalated into DNA and exposed to UV-A, form adducts with pyrimidine bases and eventually form DNA cross-links. These structural changes are thought to decrease DNA synthesis and relate to the improvement that occurs in psoriasis. The reason that PUVA photochemotherapy is effective in cutaneous T cell lymphoma is not clear.

In addition to its effects on DNA, PUVA photochemotherapy also stimulates melanin synthesis, and this provides the rationale for its use in the depigmenting disease vitiligo. Oral 8-methoxypsoralen and UV-A appear to be most effective in this regard, but as many as 100 treatments extending over 12 to 18 months may be required to promote satisfactory repigmentation.

Not surprisingly the major side effects of long-term UV-B phototherapy and PUVA photochemotherapy mimic those seen in individuals with chronic sun exposure and include skin dryness, actinic keratoses, and an increased risk of melanoma and nonmelanoma skin cancer. Despite these risks, the therapeutic index of these modalities continues to be excellent.

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