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A. Electromagnetic Spectrum (in order of decreasing energy)navigator

  1. Cosmic Rays
  2. Gamma Rays
  3. X-Rays
  4. Ultraviolet
  5. Visible
  6. Infrared
  7. Radiowaves

B. UV Waves are Biologically Most Important for Skin [4,12]navigator

  1. UVA - long wave, 320 - 400 nm
    1. UVA1: 340-400nm
    2. UVA2: 320-340nm
  2. UVB - middle wave, 290 - 320 nm
  3. UVC - short wave, 200-290 nm

C. Photobiologynavigator

  1. Solar energy interacts with chromophores allowing photochemistry to occur
  2. Photochemistry leads to photoproducts with altered cell function
  3. Altered cell function leads to Biologic Responses
  4. Beneficial and Adverse Effects both occur
  5. UVB primarily responsible for erythema in sunburn
  6. UVA implicated in photoaging and phototoxicity

D. Skin Opticsnavigator

  1. Radiation impinges on skin: reflection (remittance) and absorption
  2. Skin color due to remittance and absorption by pigments
  3. Melanin absorbs evenly and efficiently over whole visible spectrum
  4. Redness is due to elevated Hb content of dermis (absorbs green and blue)
  5. Longer and visible UV absorbed by melanin
  6. Shorter UV radiation absorbed by proteins

E. Main Functions of Melaninnavigator

  1. Sunscreen
  2. Camouflage
  3. Sunlight Absorption leads to heat retention and sensation of Warmth

F. Skin Types and Reactions to Sun Exposure [14]navigator

  1. Type I: always burns, never tans
  2. Type II: usually burns, rarely tans
  3. Type III: seldom burns, gradually tans
  4. Type IV: rarely burns, tans easily
  5. Type V: very rarely burns, tans very easily (pigmented)
  6. Type VI: never burns, tans very easily (deeply pigmented)

EFFECTS OF UV ON NORMAL SKIN [8,12]

A. Overview of Adverse Effectsnavigator
  1. Acute Events
    1. Erythema (Sunburn) - mainly due to UVB
    2. Photosensitivity - three forms; phototoxicity mainly due to UVA
    3. Immunologic Changes (immunosuppression)
    4. Pigmentation Changes
  2. Chronic Events
    1. Photoaging - mainly due to UVA; probably due to increased matrix metalloproteinases [5]
    2. Pigment alterations
    3. Premalignant actinic keratoses
    4. Frank Carcinogenesis - accumulated DNA damage (basal and squamous carcinoma)
    5. Likely causative for malignant melanoma [8]

B. Sunburn [13] navigator

  1. Mainly due to UBV (UVA in photoaging)
  2. Components of Sunburn
    1. Erythema
    2. Edema
    3. Tenderness
  3. Vascular response to UVB is usually biphasic:
    1. Immediate mild erythema (up to 30 minutes post exposure)
    2. Delayed erythema begins in 2-6 hours (maximal ~20 hours), ends in a few days
  4. Increased vascular permeability causes erythema and edema
    1. Secondary to keratinocyte damage
    2. Direct effects of light on endothelium
    3. Possible roles for neutrophils
  5. Blistering may also occur
  6. UV initially reduces DNA synthesis, but this is normal and increases within 72 hours
  7. Immunosuppression occurs (mechanisms not entirely clear)
  8. Treatment of Sunburn
    1. No treatment has been shown to be clearly effective if begun after erythema appears
    2. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce erythema if begun before redness appears; also reduce pain of sunburn
    3. Topical glucocorticoids applied before erythema appears may also be effective
    4. Emollients, antioxidants, antihistmaines, glucocorticoids do not decrease time to healing
    5. Symptom relief with emollients, cold compresses, topical anesthetics
    6. Acetaminophen (Tylenol®, others) and NSAIDs also reduce pain of sunburn
  9. Suncreen Overview [4,12,13]
    1. Clearly reduce sunburn, photoaging, actinic keratoses
    2. Reduce squamous carcinomas but not basal cell carcinomas of the skin [9]
    3. Most organic compounds used in sunscreens reduce UVB much more than UVA
    4. Therefore, most commercial agents are combinations of active compounds
    5. Sun protection factor (SPF) is ratio of time required to produce minimal erythema of the skin covered by sunscreen product to time required for erythema on bare skin
    6. Frequent (every 2 hours) and substantial application required for desired protection
    7. Reduces development of new nevi ~50% in white children [10]
    8. May reduce melanoma risk
    9. Sunscreens do not apparently affect 25-hydroxyvitamin D3 levels
    10. Strongly recommend routine use of SPF >15 in all persons
  10. Specific Sunscreen Agents [4]
    1. Avobenzone (Parsol 1789) inhibits UVA1/2 (320-400nm), but loses activity within 2 hours
    2. Ecamsule (Anthelios SX®) blocks UVB, UVA1 and UVA2 (290-400nm)
    3. Ensulizole (phyenyl benzimidazole sulfonic acid) blocks UVB (290-320nm)
    4. Homosalate blocks UVB (295-315nm)
    5. Menthyl anthranilate (Meradimate®) blocks UVB and UVA2 (260-380nm)
    6. Octinoxate (octyl methoxycinnamate) blocks UVB (290-320nm)
    7. Octisalate (octyl salicylate) blocks UVB (280-320nm)
    8. Octocryene blocks UVB (250-360nm)
    9. Oxybenzone (benzophenone-3) blocks UVB and UVA2 (270-350nm)
    10. Inorganic physical sunblocks (titanium dioxide, zinc oxide) scatter all forms of radiation

C. Photosensitivity Disorders [6,7] navigator

  1. There are three major types of photosensitivity disorders
    1. Phototoxic Reactions
    2. Photoallergic Reactions
    3. Drug Induced Lupus Erhythmatosus (DILE)
  2. Photoactivated chemicals have been identified
    1. These are activated by light
    2. Visible (400-800nm) and UV (200-400nm) light can induce reactions
    3. UVA (320-400nm) is most commonly associated with photoactivation of drugs
    4. Biological activity changes with activated molecules
    5. Production of toxic molecules leads to phototoxic reactions
    6. Production of haptens and other allergens leads to photoallergic reactions
  3. Most common cause of photosensitivity disorders are Psoralens
    1. Found in fruits (limes, lemons, figs) and vegetables (celery, parsnips)
    2. Also found in drugs
    3. Typically produce erythema and hyperpigmentation in host exposed to sun
    4. These reactions are similar to phototoxic drug reactions
  4. Phototoxic Drug Reaction
    1. Direct cellular damage produced by photoproducts
    2. UV-A most commonly involved
    3. Generation of toxic metabolites (singlet oxygen, free radicals, DNA dimers, others)
    4. Sulfa Drugs are common causes: diuretics, antibiotics, hypoglycemics
    5. Tetracyclines: Doxycycline > Tetracycline > Minocycline
    6. Other: phenothizaines, nalidixic acid, NSAIDs, amiodarone, ACE inhibitors, others
    7. Resemble sunburns: rapid onset of of burning, erythema, edema, occasional vesiculation
    8. Light skinned persons more suceptible to phototoxic reactions than dark skinned
    9. Pseudoporphyria, similar to porphyria cutanea tarda, is a variant phototoxic reaction
    10. Pseudoporphyria has been described with sulfonamides, griseofulvin, tetracyclines
  5. Photoallergic Drug Reactions
    1. Both immediate (Type I) and delayed (Type IV) hypersensitivity reactions involved
    2. Divided into photocontact dermatitis and systemic photoallergic reactions
    3. Photocontact dermatitis occurs with topical agents
    4. Systemic photoallergic reactions occur with systemically administed drugs
    5. Both types are usually associated with longer wavelength UV-A (>315nm)
    6. Absorbed energy induces structural change in drug, converting it to a hapten
    7. Presence of IgE or certain IgGs to haptens lead to immediate hypersensitivity
    8. Epidermal Langerhans cells present novel hapten-modified proteins as new antigens
    9. Result is delayed type hypersensitivity (Type IV) reaction
    10. Common with thiazide diuretics and topical benzocaine
    11. Increased incidence in HIV+ persons, other immunocompromised persons
    12. Symptoms include pruritic red scaly patches, papules, plaques
    13. Mainly occur in light exposed areas
    14. Eliminate exposure to agent; anti-histamines may be required

D. Photodermatoses [7]navigator

  1. Affects ~10% of normal population (often considered photosensitivity)
  2. Acute Photodermatoses
    1. Polymorphous Light Eruption - very common
    2. Subacute Cutaneous Lupus Erythematosus (see above)
    3. Drug-Induced Phototoxicity (see above)
    4. Solar Urticaria - rare; pruritus and urticaria within minutes of sun exposure
    5. Photoallergy - usually caused by sunscreens; rare
  3. Polymorphous Light Eruption (sun-poisoning)
    1. Papules erupt usually ~24 hours post-exposure
    2. Most common on arms and hands
    3. Female to Male 3:1
    4. Avoidance of light and protection from sun with topical sunscreen is recommended
    5. Topical or oral glucocorticoids short term
    6. For severe cases, oral hydroxychloroquine (Plaquenil®) 400mg per day is often effective
  4. Solar Urticaria
    1. Rare disorder with
    2. Caused by mast cell degranulation
    3. Pruritus and hives (urticaria) within minutes of sun exposure
    4. Antihistamines and desensitization with phototherapy
  5. Chronic Photodermatoses
    1. Photoexacerbated eczematous (atopic) dermatitis
    2. Systemic Lupus Erythematosus
    3. Actinic prurigo - rare; intensely pruritic papules and nodules, often chelitis, scarring
    4. Prophyria cutanea tarda
    5. Dermatomyositis - mild to moderate exacerbation with light exposure
  6. Systemic Lupus Erythematosus
    1. Exacerbated by light exposure
    2. Many patients have very good response to hydroxychloroquine
  7. Porphyria cutanea tarda
    1. Photoxensitization by heme-breakdown (porphyrin) compounds in skin
    2. Due to dificiency of uroporphyrinogen decarboxylase
    3. Fragile skin, milia, pigmentation disorders, vesicles and bullae

E. UV Induced Pigmentation navigator

  1. Mostly effects of UVA radiation
  2. Melanosomes move out of melanocytes into keratinocytes
  3. Wavelength dependence
    1. UVA: Dark pigmentation in basal layer = suntan
    2. UVB: Light color and increased pigment throughout dermis
    3. UVC: no effect

F. UV Induced DNA Damage [8]navigator

  1. DNA damage is apparently the major toxic effect of UV, mainly UVB
  2. UVB causes DNA mutations, may block cell division and lead to cell death
  3. Pyrimidine (thymine) dimers appear to be most important
    1. Normally removed by specific DNA repair enzymes
    2. Deficiency in these enzymes leads to skin cancers
    3. Xeroderma pigmentosum is a disease of abnormal DNA and increased skin cancers
  4. Cumulative UV dose corresponds to DNA damage in keratinocytes
  5. Melanocytes and DNA Damage
    1. Melanocytes tolerate steady UV exposure by upregulating pigment levels
    2. Intermittent intense exposure to UV radiation after low UV baselines leads to damage
    3. Thus, melanoma risk associated with intermittent intense UV exposure
  6. UVA may cause damage indirectly by increasing reactive oxygen species
  7. PUVA (psoralen+UVA) increases risk of melanoma and basal cell carcinomas [2]

G. Skin Cancer navigator

  1. Radiation (Sun) Exposure Effects on Skin Tumors
    1. Basal Cell Carcinoma increased
    2. Squamous Cell Carcinoma increased
    3. Melanoma risk increased (mainly in caucasians)
    4. Melanoma risk increased 5.4X in psoralen-UVA treated patients after 15 years [2]
  2. Mainly due to UVB radiation; UVA may be implicated in some cancers
  3. Risk Factors
    1. Sun exposure
    2. Skin pigments
    3. Genetic: Celtic Origin, DNA repair defects (xeorderma pigmentosum, others)
    4. Suppression of immune system - increased skin cancers in immunosuppressed patients [13]
  4. Prevention - avoidance and/or sunscreen lotions
  5. Sunscreen Lotions [9]
    1. More effective against UVB than UVA
    2. Daily sunscreen (15 SPF) use for 4.5 years did not reduce the incidence of first basal cell carcinoma (BCC) or the total number of BCC in a study of 1383 persons
    3. Daily use of sunscreen (15 SPF) reduces the number of number of squamous cell carcinoma (SCC) but not the incidence of first SCC with use over 4.5 years
    4. Supplemental ß-carotene 30mg qd did not reduce incidence of BCC or SCC [9]
  6. Recommend use of SPF >15 until improved agents are available for prevention

H. Photoaging [1]navigator

  1. Appearance
    1. Telangiectasias
    2. Leathery, nodular yellow surface
    3. Deep wrinkles
    4. Purpura
    5. Mottled pigmentation is common
    6. Frequent benign, premalignant, and malignant lesions
    7. Effects of gravity (drooping)
  2. Pathology [5]
    1. Epidermal hyperplasia with thickened stratum corneum
    2. This allows more tolerance to UVB radiation
    3. Plays role in photoaging and Actinic (Solar) Keratosis
    4. Epidermal hyperplasia, hypertrophy of sebaceious glands
    5. Dermal thickening with matrix hyperplasia but loss of mature collagen
    6. Decrease in mature collagen with increased non-collagenous matrix substance
    7. Increased ratio of Type III to Type I Collagen
    8. Increase in elastin fibers
  3. Down regulation of immune system cells
    1. Especially Langerhans Cells in epidermis
    2. Also dermal immune cells (T lymphocytes)
    3. Probably plays role in development of skin tumors (see above)
  4. Pigmentation Changes
    1. Ephiledes (freckles)
    2. Melasma (liver spots) - hyperpigmented macules
    3. Solar lentigo
  5. Pathophysiology [5]
    1. Chronic UV light exposure exacerbates intrinsic aging effects
    2. UV induced skin repair and hyperplasia leads to thickening
    3. Aging likely contributes to reduced mature collagen and normal cross linking
    4. Increased matrix metalloproteinases likely contribute to mature collagen destruction
    5. These matrix metalloproteinases include collagenase, a gelatinase, and stromelysin
    6. Tretinoin (all-trans-retinoic acid) inhibits induction of matrix metalloproteinases
  6. Treatment [1,3]
    1. Topical tretinoin (0.05%, Renova®) - apply for daily 4-6 months daily
    2. Topical tazarotene also approved by FDA for prevention of fine wrinkles
    3. alpha-hydroxy acids - including lactic acid, glycolic acid
    4. Sunscreen must be used with alpha-hydroxy acids because skin is hypersensitive to UVB
    5. Fluorouracil cream used to treat actinic keratoses
    6. Various ablative and nonablative resurfacing / rejuvenation treatments
    7. Dermabrasion removes epidermis to various depths
    8. Botulinum toxin A (Botox®) to treat wrinkles of upper face due to muscle hypertonicity
    9. Chemical peals
    10. Skin fillers - bovine collagen, hyaloronic acid
  7. Sunscreens
    1. Sunscreens effectively reduce photoaging, actinic keratosis, squamous cell carcinoma
    2. Minimum sun protection factor (SPF) of 15 is strongly recommended
    3. SPF for UVB is generally reliable; non-opaque sunscreens have UVA SPF of ~3
    4. SPF (UVB) 15 provides 93%, SPF 45 provides 98% block from UVB rays
    5. Only opaque (physical) sunscreens (titanium dioxide or zinc oxide) effectively block UVA

PHOTOTHERAPY

A. UVB Therapynavigator
  1. Much more efficient than sun
  2. Activity
    1. Suppression of keratinocyte DNA synthesis by radiation
    2. Reduction in CD4+ cells locally (and suppression systemically)
    3. Increase in local CD8+ suppressor type cells (see above)
  3. Effective in:
    1. Psoriasis
    2. Pityriasis rosea
    3. Uremic pruritus
    4. Pruritus associated with liver disease
    5. Narrow band UVB effective in atopic dermatitis [11]

B. UVA Radiation + Photoactive Psoralan (PUVA) [14]navigator

  1. Psoralen
    [Figure] "Structure of Psoralen"
    1. Oral photoactive agent
    2. Deposits in many dividing cell types
    3. UVA radiation activates phototoxic effects of psoralen forming C4 psoralen-pyrimidine cycloadducts on DNA
  2. Effective in:
    1. Psoriasis
    2. Vitiligo
    3. Lichen Planus
    4. Pityriasis rubra pilaris
    5. Mycoses fungoides (Cutaneous T cell lymphoma)
  3. Broad band UVA not effective in atopic dermatitis

C. Laser Therapynavigator

  1. Specific wavelengths for absorption by specific molecules
  2. Example is hemoglobin absorption leading to vascular specificity
  3. Tumor uptake of photoactive compounds used in laser therapy

References navigator

  1. Stern RS. 2004. NEJM. 350(15):1526 abstract
  2. Stern RS, Nichols KT, Vakeva LH. 1997. NEJM. 336(15):1041 abstract
  3. Drugs for Photoaging. 1997. Med Let. 39(1007):78 abstract
  4. Ecamsule Suncreen Agent. 2007. Med Let. 49(1261):41 abstract
  5. Lautenschlager S, Wolf HC, Pittelkow MR. 2007. Lancet. 370(9586):528 abstract
  6. Vassileva SG, Mateev G, Parisch LC. 1998. Arch Intern Med. 153(18):1993
  7. Morison WL. 2004. NEJM. 350(11):1111 abstract
  8. Gilchrest BA, Eller MS, Geller AC, Yaar M. 1999. NEJM. 340(17):1341 abstract
  9. Green A, Williams G, Neale R, et al. 1999. Lancet. 354(9080):723
  10. Gallagher RP, Rivers JK, Lee TK. 2000. JAMA. 283(22):2955 abstract
  11. Reynolds NJ, Franklin V, Gray JC, et al. 2001. Lancet. 357(9273):2013
  12. Sunscreens. 1999. Med Let. 41(1052):43 abstract
  13. Parrish JA. 2005. NEJM. 353(25):2712 abstract
  14. Stein RS. 2007. NEJM. 357(7):682 abstract