Clinics in Dermatology (2014) 32, 73–79
Photodermatoses, including phototoxic and photoallergic reactions (internal and external) Zekayi Kutlubay, MD ⁎, Ayşegül Sevim, MD, Burhan Engin, MD, Yalçın Tüzün, MD . . Cerrahpaşa Medical Faculty, Department of Dermatology, Istanbul University, Fatih, Istanbul, 34098 Turkey
Abstract Photodermatoses are caused by an abnormal reaction mainly to the ultraviolet component of sunlight. Photodermatoses can be broadly classified into four groups: immunologically mediated photodermatoses, chemical- and drug-induced photosensitivity, photoaggravated dermatoses, and DNA repair-deficiency photodermatoses. In this review, we focus mainly on chemical- and drug-induced photosensitivity, namely, phototoxicity and photoallergy. © 2014 Published by Elsevier Inc.
Photosensitivity can be caused by many different topical or systemic exogenous agents. These agents are usually compounds with unsaturated double bonds, which absorb ultraviolet A wavelength energy. Drugs and chemicals that are most frequently responsible for phototoxic and photoallergic reactions will be discussed briefly. Pathophysiology, clinical manifestations, and histopathologic investigations of both phototoxicity and photoallergy are summarized separately. The main differences between these two entities, including clinical appearance, pathophysiologic mechanisms, and time of onset, will be emphasized. Photosensitivity is a challenging area of dermatology, with a wide range of morbidities, both for the physician and the patient. For the exact diagnosis and precise control of photosensitivity, a systematic approach is vital. Avoidance of direct sunlight and sun-tanning facilities, as well as photosensitizing agents, usage of clothing with ultraviolet filters, and appropriate sunscreen can all minimize the risk for photosensitivity effects. A combination of measures, including phototherapy in different modalities and topical and systemic drugs, can be beneficial in the management of photodermatoses. ⁎ Corresponding author. Tel.: 00902124143000-21546. E-mail address: [email protected] (Z. Kutlubay). 0738-081X/$ – see front matter © 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.clindermatol.2013.05.027
Introduction Photodermatoses can be broadly classified into four groups: immunologically mediated photodermatoses, chemical- and drug-induced photosensitivity, photoaggravated dermatoses, and inherited disorders with defective DNA repair or with chromosomal instability.1 Immunologically mediated photodermatoses are solar urticaria, polymorphous light eruption, hydroa vacciniforme, actinic prurigo, and chronic actinic dermatitis.2 This large group of diseases is also called primary idiopathic photodermatoses, because these diseases consist of ultraviolet (UV)-induced cutaneous lesions with an unknown cause. Chemical- and drug-induced photosensitivity can be caused by topical or systemic exogenous agents, as is the case in phototoxicity and photoallergy; these reactions can also be caused by endogenous agents like in cutaneous porphyrias and pellagra.1 Photoaggravated dermatoses, or so-called secondary photodermatoses, are the result of increased sensitivity to UV radiation caused by the underlying disease. Acne vulgaris, atopic dermatitis, bullous pemphigoid, carcinoid syndrome, cutaneous T-cell lymphoma, Darier disease, dermatomyositis, disseminated superficial actinic porokeratosis, erythema multiforme, Grover disease, lichen planus, lupus erythematosus, pemphigus, pityriasis rubra pilaris,
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psoriasis, reticular erythematous mucinosis, rosacea, seborrheic dermatitis, and viral infections are examples of photoaggravated dermatoses.1,2 Inherited disorders with defective DNA repair mechanisms or with chromosomal instability can be listed as ataxiatelangiectasia, Bloom syndrome, Cockayne syndrome, Hailey-Hailey disease, Hartnup disease, Kindler syndrome, Rothmund-Thomson syndrome, trichothiodystrophy, and xeroderma pigmentosum.3 Photosensitivity is the reaction of skin to exogenous or endogenous agents.4 These agents are usually compounds with unsaturated double bonds, which absorb ultraviolet A (UVA) wavelength energy. Exogenous agents can be used systemically or topically, and cutaneous porphyrias are examples of photosensitivity induced by endogenous agents.5 Photosensitivity induced by exogenous agents is classified into two groups: phototoxicity and photoallergy (Table 1). Phototoxicity is a direct tissue injury, caused by phototoxic agent and radiation, which can be seen in every individual. In contrast, photoallergy is a delayed-type hypersensitivity reaction. It is caused by chemicals that are modified by absorbing photon energy. It does not occur during the first exposure and has a sensitization phase. The incidence of photosensitivity is rather low, and phototoxic reactions are far more common than photoallergic reactions.2 The prevalence of exogenous drug-induced photosensitivity is not known, but data from photodermatology referral centers show 7% to 15% for phototoxicity and 4% to 8% for photoallergy.6 In studies performed in the United States and Europe, the incidence rate of photoallergic contact dermatitis in patients who are photopatch-tested is between 1.4% to 12.0%. Age distribution is rather homogeneous, but for drug-induced photosensitivity, the elderly population is more susceptible.6 More than 300 types of medications are responsible for photosensitivity.7 Among topical phototoxic agents, the most commonly used ones are fluorescein, fluorouracil, furocoumarins, retinoids, rose bengal, and tar. For systemic phototoxic agents, the list is much longer. Many antifungals Table 1
such as griseofulvin; antimalarials such as chloroquine and quinine; antimicrobials such as sulfonamides, tetracyclines, trimethoprim, quinolones, amiodarone, and quinidine; and diuretics such as furosemide, thiazides, psoralens, and sulfonylureas can cause phototoxic reactions. The photoallergic chemicals can also be classified into topical and systemic agents. Topical agents refer mostly to sunscreen ingredients, such as benzophenones, para-aminobenzoic acid (PABA) derivatives, cinnamates, and fragrance chemicals (methyl coumarins, musk ambrette, and sandalwood oil). Surface disinfectants, skin cleansers such as chlorhexidine, hexachlorophene, pesticides, and topical nonsteroidal anti-inflammatory agents are also topical agents. Systemic photoallergens can be listed as griseofulvin, quinolone, quinine, ketoprofen, and pyridoxine.8
Phototoxicity Pathophysiology More than one mechanism is usually involved in the pathophysiology of phototoxicity. A photosensitizer chemical absorbs UVA radiation energy. Before this absorption, the substance being at its ground state rises to an excited state molecule, with the effect of UV energy. This excited state chemical is involved in oxygen-dependent reactions, and at the end of these reactions cytotoxic injury is observed. These pathways of reactions can be studied in two major classes: type 1 and 2 reactions.7 During type 1 reactions, an electron is transferred to the excited state photo sensitizer, and this reaction results in free radical formation. These free radicals are involved in oxidation-reduction reactions and occurring peroxides cause cell damage.9 Type 2 reactions are, in contrast, energy transfer processes. Here again, transfer of energy to ground state oxygen causes oxygen radical formation. These radicals interact with unsaturated fatty acids, and in the end,
Differences and similarities between phototoxicity and photoallergy
Clinical presentation Pathophysiology Histology
Onset and occurrence Dose Cross-reactivity Diagnosis
Phototoxicity
Photoallergy
Sunburnlike reaction, erythema, edema with vesicles and bullae Direct tissue injury Epidermal necrosis, dermal edema with eosinophilic keratinocytes, dermal infiltrate of lymphocytes, macrophages, and neutrophiles Occurs after first exposure and starts minutes to hours after exposure Large doses needed None Clinical and phototests
Pruritic eczematous lesions Type IV delayed hypersensitivity Spongiotic dermatitis, dermal lymphohistiocytic infiltrate
No reaction after first exposure, starts 24-48 hours after exposure Small doses are enough Common Clinical and photopatch tests
Photodermatoses
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hydroperoxides are formed. These substances eventually lead to oxidation of lipids and proteins. All these photodynamic processes are seen in cases of porphyrin-, quinolone-, nonsteroidal anti-inflammatory drug-, tetracycline-, amitriptyline-, imipramine-, sulfonylurea-, hydrochlorothiazide-, chlorpromazine-, and furosemide-induced phototoxicities.8 Apart from those chemicals, irradiation of phenothiazines, chlorpromazine, tetracyclines, and quinolones produces stable photoproducts, which are again responsible for tissue damage. In one other mechanism, a photosensitizer binds to its biological substrate with the help of radiation. During this reaction, an excited state molecule bonds covalently to a ground state molecule. 8-Methoxypsoralen bonds to the pyrimidine bases of DNA molecules forming cross-links between DNA strands. Biologically active products of complement activation, mast-cell–derived mediators, eicosanoids, proteases, and polymorphonuclear leukocytes may also take part in the process of phototoxicity. It is usually the case with porphyrins, chlorpromazine, and demeclocycline, where inflammation and inflammatory cells participate in tissue injury. Photosensitizer plus electromagnetic radiation also induce apoptosis, together with cytotoxicity, and this property of the process is used in clinics to treat premalignant and malignant skin conditions.
Clinical manifestations Phototoxicity usually shows its effects minutes to hours after exposure to the phototoxic agent, UV radiation. The only exception is psoralen-induced phototoxicity. In that case, acute response first appears after 24 hours and peaks at 48 to 72 hours. All the symptoms are dose dependent, meaning they depend on both the dose of the drug that is used and the dose of the UV radiation to which the individual is exposed. The clinical picture may vary from a mild or even asymptomatic phase to a severe sunburn.10 The patient may report a burning and stinging sensation, especially on areas of the body that have been exposed to sun, such as the forehead, nose, V area of the neck, ears, and dorsa of the hands. Erythema and edema are the characteristic findings. Pruritus usually accompanies, and in severe reactions even vesicles and bullae may be seen. In differential diagnosis, one may easily notice the sparing of areas where UV radiation has not reached, such as the postauricular areas, the submental area, the nasolabial folds, and under clothing. Skin lesions may resolve with different degrees of hyperpigmentation (Figure 1).4 Pseudoporphyria is a clinical form of phototoxicity. The most common drug causing this is naproxen. The skin findings in this phenomenon are similar to those in
Fig. 1 This patient illustrates photodermatitis on the face, neck, and chest.
porphyria cutanea tarda. It is usually evidence of a severe phototoxic reaction, with erythema, edema, vesicles, and subepidermal blisters. Histologic findings and immunofluorescence findings are also indistinguishable from porphyria cutanea tarda. The diagnosis is made considering the history of sun exposure and chemical use, and most importantly the normal porphyrin profile, in the case of pseudoporphyria. Apart from naproxen, other drugs such as amiodarone, celecoxib, beta-lactam antibiotics, cyclosporine, ciprofloxacin, furosemide, imatinib, oral contraceptives, nalidixic acid, oxaprozin, ketoprofen, mefenamic acid, tetracyclines, and voriconazole can also induce this type of reaction. In the case of voriconazole, especially in immunesuppressed patients and for the usage duration longer than 12 weeks, accelerated photo-induced changes can be seen. These changes include pseudoporphyria, photoaging, lentigines, premature dermatoheliosis, and even squamous cell carcinoma and melanoma in cases of use longer than 12 months.11 Photo-onycholysis can also be observed as a manifestation of acute phototoxicity. Fluoroquinolones, tetracyclines,
76 and psoralens are among the medicines that are reported to be responsible for this damage. It is the painful separation of the distal nail from the nail bed, whereas the nail plate focuses UV energy on the nail bed.8 Blue-gray pigmentation is another clinical form of phototoxicity. It is usually seen in sun-exposed areas presumably and is associated with many different drugs and chemicals.10 Amiodarone, chlorpromazine, clozapine, imipramine, and less commonly desipramine among tricyclic antidepressants may cause this type of phototoxicity. Minocycline, for instance, may result in blue-gray pigmentation of the face, mostly on acne scars, and less commonly on shins and forearms. In the pathophysiology of this type of pigmentation, a drug metabolite–melanin complex plays an important role. In case of argyria exposure, a slate-gray pigmentation is observed, which involves the nail lunulae, mucous membranes, and sclerae. In this case, silver granules produced during a photochemical reaction are deposited in the dermis. Telangiectasia on sun-exposed areas can occur as a result, especially when using calcium channel blockers such as nifedipine, amlodipine, felodipine, and diltiazem, antibiotics such as cefotaxime, and the antidepressant venlafaxine. Phytophotodermatitis (grass dermatitis) is also a particular form of phototoxicity, induced by plant extracts, especially seen in gardeners or after being in close contact with plants.12 Striped, sharply delineated erythema corresponding to the trails of grass brushing on the skin is typical for this type of reaction.2 The course of phototoxicity in most patients is usually self-limited. The symptoms reduce after discontinuation of the responsible agent. In some cases, even after the patient stops taking the drug, the symptoms persist, even for years. In those cases, chronic actinic dermatitis may develop on the areas of phototoxicity. The clinical findings can be listed as primarily pruritus and lichenification, together with secondary excoriation on sun-exposed regions. This type of reaction is more commonly seen with thiazides, quinidine, amiodarone, and quinine. With chronic exposure to both chemical agents and UV radiation, as seen in patients who have received long-term psoralen + ultraviolet A (PUVA) photochemotherapy, longterm cutaneous effects are seen. Phototoxicity in chronic exposure is known to affect DNA, which, in turn, causes premature aging of the skin, lentigines, squamous cell carcinoma, and melanoma.
Phototoxic agents Agents, drugs, or chemicals that cause phototoxicity can either be used topically or systemically. Among topical agents, fluorouracil and retinoids cause serious UVinduced hypersensitivity because of their irritant effect on the skin.
Z. Kutlubay et al. Furocoumarins are also a common causative agent for phototoxic reactions, especially among those with certain occupations such as bartenders, chefs, and gardeners, as well as patients receiving topical photochemotherapy with psoralens.7 In addition, occupational and medical exposure to coal tar not only causes phototoxic reactions, but also increases the risk for nonmelanoma skin cancers. Most systemic agents produce a sunburnlike reaction, as well as an eczematous photoallergic response. In almost all of the agents, the action spectra are in the UVA range. For porphyrins and fluorescein, the spectra of action are visible light. Eculizumab, a humanized immunoglobulin G monoclonal antibody that binds to and inhibits complement protein C5 and is approved for paroxysmal nocturnal hemoglobinuria, was also reported to cause phototoxic reactions.13
Histopathology In classic, nonchronic phototoxic reactions, necrotic keratinocytes, epidermal spongiosis, and dermal edema are seen. In severe cases, epidermal necrosis is also observed. A mild inflammatory infiltrate, consisting of neutrophiles, lymphocytes, and macrophages, is almost always found in the specimen. In the case of slate-gray pigmentation, increased dermal melanin together with dermal deposits of the drug and its metabolite are found. In pseudoporphyria, dermal-epidermal separation at the lamina lucida level, the same as porphyria cutanea tarda, is detected. Also at the dermal-epidermal junction and around the nearby blood vessels, immunoglobulin deposits can easily be seen. In the case of lichenoid eruption, findings are similar to those of lichen planus. Spongiosis, dermal eosinophils, plasma cell infiltrates, and an increased number of necrotic keratinocytes and cytoid bodies may help in distinguishing the two entities.
Photoallergy Pathophysiology Photoallergy is a delayed-type hypersensitivity reaction, occurring in the presence of a photoallergic substance and UV radiation. The wavelength of the radiation is an important factor, and for most of the substances, UVA radiation is necessary. The photoallergen absorbs UVA radiation, enters an excited state, and afterward releases energy to the surroundings. During this process, the molecule bonds with a carrier protein and forms a complete antigen. Halogenated salicylanilides, chlorpromazine, and para-aminobenzoic acid are thought to be the causes of photoallergy by means of this
Photodermatoses mechanism. Sulfanilamide and chlorpromazine also form a stable product after being exposed to UVA radiation, and then together with a carrier protein form a complete antigen. After this complete antigen is composed, the mechanism is similar to contact allergy. Langerhans cells take up the antigen and process it, and afterward migrate to regional lymph nodes to present the antigen to T lymphocytes. Then these activated T lymphocytes start to circulate around the exposed site and start an inflammatory response, only after which cutaneous lesions develop.
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Management of phototoxicity and photoallergy
Symptoms usually occur within 24 to 48 hours after exposure to the photoallergen and UV radiation. The symptoms are more prominent in sensitized individuals. The clinical morphology is identical to that of allergic contact dermatitis; however, the distribution of the skin lesions can help in differential diagnoses. In photoallergic dermatitis, mostly body parts that are prone to sun exposure are affected. In severe cases, the lesions may also be seen in covered areas of the body, as well as in sun-exposed areas. The clinical manifestations usually disappear without any significant postinflammatory hyperpigmentation. The most common cause of photoallergy, especially in the United States and Europe, is sunscreen products. UV filters, especially benzophenone-3, are the leading cause of photoallergic dermatitis.14 Also, antimicrobial agents are a rather common cause. For the topical causative agents, nonsteroidal anti-inflammatory agents are the leading drugs responsible for photoallergy. Long-term exposure to chlorpromazine, dioxopromethazine, ketoprofen, musk ambrette, halogenated salicylanilides, and quinidine, together with chronic UV radiation, may also cause chronic actinic dermatitis, as in the case of phototoxicity.
The best set of actions should be identified first to avoid the causative phototoxic or photoallergic agent; furthermore, avoiding UV radiation is essential, and sunscreens with efficient UVA filters should be used regularly. For symptomatic treatment of acute reactions, topical corticosteroids are the drug of choice. Antihistamines may also be helpful. In the case of severe reactions, systemic corticosteroids can also be used. Short-term usage (prednisone 1 mg/kg) from 1 to 2 weeks can be initiated for acute and severe exacerbations.15 For patients with slate-gray pigmentation, lichenoid eruption, pseudoporphyria, and photodistributed telangiectasia, only symptomatic therapy is given. In those cases, it can take a few months for the condition to be resolved. After resolution of the acute event, if there is marked hyperpigmentation, depigmentation methods can be used. A combination of 0.1% retinoic acid, 5.0% hydroquinone, and 1% hydrocortisone, or laser therapy can be attempted.2 While handling most photodermatoses, preventive UV phototherapy or psoralen plus UVA, or both, can be used. The “hardening” phenomenon is one of the basic features of prophylactic phototherapy in photosensitive individuals. Its mechanism is thought to be about increased melanization, stratum corneum thickening, and depletion of hypothetical antigens. In the case of persistence of significant photosensitivity, low-dose broadband or narrowband ultraviolet B (UVB) or PUVA therapy two to three times a week may be the treatment of choice, especially in acquired idiopathic photodermatoses. The treatment is usually initiated during spring, and an average of 15 sessions is usually enough to induce hardening. To maintain this hardening state, patients are told to expose themselves to midday sunlight for 15 to 20 minutes without sunscreen weekly.
Photoallergens
Sunscreen usage
In case of photoallergy, topical agents are usually the most common cause of the skin lesions. Sunscreen products, topical antimicrobials, and topical nonsteroidal anti-inflammatory drugs are most frequently used in everyday practice.7 Systemic agents, in contrast, are much less frequent.
On a summer’s day, the UV energy received (daily dose) is composed of approximately 3.5% UVB and 96.5% UVA.11 While choosing the most effective sunscreen for each patient, identification of the photon wavelength responsible for inducing the sensitivity reaction is important. This can often be done by the determination of a minimal erythema dose (MED) to UVA and UVB radiation.16 UVB and UVA filters are categorized into organic and inorganic filters. There are many efficient UVB filters, but only a limited number of organic UVA filters are available, such as the benzophenones (oxybenzone, dioxybenzone, and sulisobenzone), butyl methoxydibenzoylmethane (commonly known as avobenzone), and methyl anthranilate.17 All except avobenzone are primarily protective only against UVA-2 (320-340 nm), whereas the absorption of avobenzone
Clinical manifestations
Histopathology Histopathologic findings related to photoallergy are similar to those of allergic contact dermatitis, as is the morphologic appearance. Epidermal spongiosis together with dermal mononuclear cell infiltrates are the typical histologic features.
78 extends into UVA-1 (340-400 nm). Because avobenzone is photolabile, degradation occurs rapidly on exposure to sunlight, and by combining it with photostable UV filters, such as octocrylene, salicylates, or oxybenzone, it can be photostabilized. Inorganic sunscreens or physical blockers are titanium dioxide and zinc oxide, which offer protection from UVB to visible ranges.18 Sunscreen efficacy is measured first by its sun protection factor, which is a globally accepted index of protection from erythema after a single exposure to solar-simulated radiation, primarily the effect from UVB exposure, and to a lesser extent from UVA-2.
Differential diagnosis of phototoxicity and photoallergy All types of nonspecific dermatitis can be included in differential diagnosis of photosensitivity. Allergic contact dermatitis caused by inhaled allergens particularly affects skin folds such as nasolabial folds and eyelids. These areas receive very small amounts of UV irradiation; thus, they are not expected to be involved in photo-induced reactions. Allergic contact dermatitis can also be seen in the postauricular region and under the chin, where sun exposure is unlikely. Both allergic contact dermatitis and irritant contact dermatitis are observed mainly at sites where direct contact of the inhalant or contact allergen takes place, either sun-exposed or sun-protected areas. Other photodermatoses are also included in differential diagnoses. In the case of polymorphous light eruption, symptoms appear a few hours after the sun exposure, and pruritic papules, plaques, and rare vesicles can be seen. The lesions usually tend to be observed at sun-exposed sites and are resolved in a few days. Lesions of solar urticaria are also found in sun-exposed areas, typically occurring minutes after sun exposure, morphologically similar to pruritic urticarial plaques, and in the end are resolved within a few hours.
Approaching patients with phototoxicity and photoallergy While evaluating patients with photosensitivity, a detailed history including the relationship between eruption and sun exposure, duration of lesions, effect of windowglass-filtered sunlight, exposure to photosensitizing agents, family history, age of onset, seasonal variation, and systemic symptoms is crucial. A physical examination into the morphology and distribution—specifically presence of symptoms on the head, face, neck, arms, legs, and torso, and absence underneath the chin, lips, nasolabial folds, and postauricular
Z. Kutlubay et al. area—can provide further diagnostic clues. Advanced tests, such as antinuclear antibody titers, skin biopsies, phototesting, photopatch testing, and porphyrin levels can also help in diagnosis. A history of exposure to known photosensitizers is a risk factor for identifying the cause. For sun exposure, patients should be questioned extensively about window-glassfiltered sunlight. UVB radiation is filtered out by window glass, and phototoxic and photoallergic reactions are prominently caused by UVA radiation. In addition, examining the distribution of the cutaneous lesions will help both to distinguish the reaction from other types of dermatitis and to identify the type of photosensitizer responsible. In the case of systemic photosensitizers, widespread eruption is usually observed. With topical photosensitizers, however, lesions are found in regions that are exposed to both the photosensitizer chemical and the UV radiation. If there are vesicular and bullous lesions with severe symptoms and complaints of a burning sensation, the incidence is probably associated with phototoxicity, whereas eczematous eruptions with pruritus usually suggest photoallergy. In some rare cases, a skin biopsy may be needed for differentiating the two conditions. Necrotic keratinocytes is a characteristic feature of phototoxicity, whereas spongiotic dermatitis is associated with photoallergy. Phototests and photopatch tests also play an important role in the evaluation and diagnosis of patients with known photosensitivity, especially in cases for whom physical examination and history are not sufficient for making a decision or for determining the causative agent.15 During phototesting and photopatch testing, the MED should first be determined. Duplicate sets of photoallergens are applied symmetrically on the body surface, preferably on the back, and then covered by an opaque tape.19 Then UVA radiation is applied, in increasing dosages, and MEDs are added. The MED for UVA and UVB is defined as the lowest dose of radiation that produces perceptible erythema covering the entire irradiated area.1 The MED for UVA radiation is lower than the normal population in the case of phototoxicity and photoallergy.15 Phototesting is an important step in the evaluation of the photosensitive patient. A template with several exposable windows is used, and the patient’s back, abdomen, or inner forearms, where there is no lesion, is exposed to different doses of UVA, UVB, and visible monochromatic or broadspectrum radiation. Systemic immunosuppressants and topical agents should be discontinued 2 weeks before phototesting. The cutaneous response is assessed by observing immediate urticarial lesions, as in the case of solar urticaria, and also the MED. Photoprovocation testing is performed to induce lesions 3 to 4 consecutive days with exposure to the same site, and within 24 hours, lesions usually develop.15 Phototesting is the most beneficial in the diagnosis of idiopathic or immunologically mediated photodermatoses, whereas in porphyrias and genodermatoses, the test is not as beneficial.
Photodermatoses Photopatch testing, in contrast, is performed when photoallergic contact dermatitis is suspected. Two sets of photoallergen panels are placed on uninvolved sites of the skin, preferably on the upper back. Because it is a known fact that photoallergens can also cause contact hypersensitivity, photopatch tests are done in duplicates. One set is removed after 24 hours and irradiated with UVA of 5 to 10 J cm. After 48 and 72 hours, both the irradiated and unirradiated sides are evaluated for a positive reaction, meaning the presence of erythema, edema, and/or vesiculation. If there is a positive reaction at both sites, it indicates allergic contact dermatitis, whereas a positive reaction at the unirradiated site with a stronger reaction at the irradiated site is interpreted as both allergic contact dermatitis and photoallergic contact dermatitis. In the case of irritant dermatitis, an erythema appears with well-defined borders, and this erythema disappears rapidly. Photopatch testing is contraindicated in cases of suspected phototoxicity. Nevertheless, only 10% of patients undergoing photopatch testing have clinically relevant positive results.20 Photopatch tests are often negative for photoallergy with medications delivered by enteral or parenteral routes, because a specific metabolite is actually responsible for the occurrence of the cutaneous lesions, not the medication itself.2 The list of agents used for photopatch tests varies greatly among countries, but the substances commonly used can be listed as follows6: tetrachlorosalicylanilide 0.1%, 5-bromo-4′-chlorosalicylanilide 1.0%, hexachlorophene 1.0%, bithionol 1.0%, sulfanilamide 5.0%, promethazine hydrochloride 0.1%, chinoidine sulfate 1.0%, musk ambrette 5.0%, fragrance mix 8.0%, 4-aminobenzoic acid 10.0%, 2-ethylhexyl-4-dimethylaminobenzoate 10.0%, 1-(4-isopropylphenyl)-3-phenyl-1,3-propandion 10.0%, 4-tert butyl-4′-methoxy dibenzoylmethane 10.0%, isoamyl4 methoxycinnamate 10.0%, 2-ethylhexyl-4-methoxycinnamate 10.0%, 3-(4 methylbenzylidene) camphor 10.0%, 2phenyl-5-benzimidazole sulfonic acid 10.0%, oxybenzone 10.0%, and sulisobenzone 10.0%.
Conclusions Photosensitivity is a challenging area for both the physician and the patient. For the exact diagnosis and precise control of the photosensitivity, a systematic approach is vital. Avoidance of direct sunlight, sun-tanning facilities, and photosensitizing agents, and the usage of clothing with UV filters and appropriate sunscreen can all minimize the risk for photosensitivity effects. A combination of measures, including
79 phototherapy in different modalities and topical and systemic drugs, can be beneficial in managing photodermatoses.
References 1. Santoro FA, Lim HW. Update on photodermatoses. Semin Cutan Med Surg. 2011;30:229-238. 2. Lehmann P, Schwarz T. Photodermatoses: diagnosis and treatment. Dtsch Arztebl Int. 2011;108:135-141. 3. Inamadar AC, Palit A. Photosensitivity in children: an approach to diagnosis and management. Indian J Dermatol Venereol Leprol. 2005;71:73-79. 4. Hawk JLM. Abnormal cutaneous effects of UVR exposure: the photodermatoses. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s Textbook of Dermatology. 8th ed. West Sussex, UK: Wiley-Blackwell; 2010:29.9-315. 5. Roelandts R. Photodermatology Quo vadis? Actas Dermosifiliogr. 2009;100:66-72. 6. Trakatelli M, Charalampidis S, Novakovic LB, et al. Photodermatoses with onset in the elderly. Br J Dermatol. 2009;161:69-77. 7. Lehmann P. Diagnostic approach to photodermatoses. J Dtsch Dermatol Ges. 2006;4:965-975. 8. Lim HW. Abnormal responses to ultraviolet radiation: photosensitivity induced by exogenous agents. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, editors. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw Hill; 2012:1066-1074. 9. Siani AM, Casale GR, Sisto R, et al. Short-term UV exposure of sunbathers at a Mediterranean Sea site. Photochem Photobiol. 2009;85:171-177. 10. Lehmann P. Sun exposed skin disease. Clin Dermatol. 2011;29: 180-188. 11. Cowen EW, Nguyen JC, Miller DD, et al. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol. 2010;62:31-37. 12. Kar HK, Langar S, Arora TC, et al. Occurrence of plant sensitivity among patients of photodermatoses: a control-matched study of 156 cases from New Delhi. Indian J Dermatol Venereol Leprol. 2009;75: 483-487. 13. Balagula Y, Newman SB, Lacouture ME. Photodermatosis associated with eculizumab (Soliris): a novel monoclonal antibody directed against the complement protein C5. Am J Hematol. 2010;85:392-393. 14. Kerr A, Ferguson J. Photoallergic contact dermatits. Photodermatol Photoimmunol Photomed. 2010;26:56-65. 15. Bylaite M, Grigaitiene J, Lapinskaite GS. Photodermatoses: classification, evaluation and management. Br J Dermatol. 2009;161:61-68. 16. Fourtanier A, Moyal D, Seite S. UVA filters in sun-protection products: regulatory and biological aspects. Photochem Photobiol Sci. 2012;11: 81-89. 17. Deleo V. Sunscreen use in photodermatoses. Dermatol Clin. 2006;24: 27-33. 18. Medeiros VL, Lim HW. Sunscreens in the management of photodermatoses. Skin Therapy Lett. 2010;15:1-3. 19. Victor FC, Cohen DE, Soter NA. A 20-year analysis of previous and emerging allergens that elicit photoallergic contact dermatitis. J Am Acad Dermatol. 2010;62:605-610. 20. Kerr HA, Lim HW. Photodermatoses in African Americans: a retrospective analysis of 135 patients over a 7-year period. J Am Acad Dermatol. 2007;57:638-643.
Photodermatoses, including phototoxic and photoallergic reactions (internal and external) Zekayi Kutlubay, MD ⁎, Ayşegül Sevim, MD, Burhan Engin, MD, Yalçın Tüzün, MD . . Cerrahpaşa Medical Faculty, Department of Dermatology, Istanbul University, Fatih, Istanbul, 34098 Turkey
Abstract Photodermatoses are caused by an abnormal reaction mainly to the ultraviolet component of sunlight. Photodermatoses can be broadly classified into four groups: immunologically mediated photodermatoses, chemical- and drug-induced photosensitivity, photoaggravated dermatoses, and DNA repair-deficiency photodermatoses. In this review, we focus mainly on chemical- and drug-induced photosensitivity, namely, phototoxicity and photoallergy. © 2014 Published by Elsevier Inc.
Photosensitivity can be caused by many different topical or systemic exogenous agents. These agents are usually compounds with unsaturated double bonds, which absorb ultraviolet A wavelength energy. Drugs and chemicals that are most frequently responsible for phototoxic and photoallergic reactions will be discussed briefly. Pathophysiology, clinical manifestations, and histopathologic investigations of both phototoxicity and photoallergy are summarized separately. The main differences between these two entities, including clinical appearance, pathophysiologic mechanisms, and time of onset, will be emphasized. Photosensitivity is a challenging area of dermatology, with a wide range of morbidities, both for the physician and the patient. For the exact diagnosis and precise control of photosensitivity, a systematic approach is vital. Avoidance of direct sunlight and sun-tanning facilities, as well as photosensitizing agents, usage of clothing with ultraviolet filters, and appropriate sunscreen can all minimize the risk for photosensitivity effects. A combination of measures, including phototherapy in different modalities and topical and systemic drugs, can be beneficial in the management of photodermatoses. ⁎ Corresponding author. Tel.: 00902124143000-21546. E-mail address: [email protected] (Z. Kutlubay). 0738-081X/$ – see front matter © 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.clindermatol.2013.05.027
Introduction Photodermatoses can be broadly classified into four groups: immunologically mediated photodermatoses, chemical- and drug-induced photosensitivity, photoaggravated dermatoses, and inherited disorders with defective DNA repair or with chromosomal instability.1 Immunologically mediated photodermatoses are solar urticaria, polymorphous light eruption, hydroa vacciniforme, actinic prurigo, and chronic actinic dermatitis.2 This large group of diseases is also called primary idiopathic photodermatoses, because these diseases consist of ultraviolet (UV)-induced cutaneous lesions with an unknown cause. Chemical- and drug-induced photosensitivity can be caused by topical or systemic exogenous agents, as is the case in phototoxicity and photoallergy; these reactions can also be caused by endogenous agents like in cutaneous porphyrias and pellagra.1 Photoaggravated dermatoses, or so-called secondary photodermatoses, are the result of increased sensitivity to UV radiation caused by the underlying disease. Acne vulgaris, atopic dermatitis, bullous pemphigoid, carcinoid syndrome, cutaneous T-cell lymphoma, Darier disease, dermatomyositis, disseminated superficial actinic porokeratosis, erythema multiforme, Grover disease, lichen planus, lupus erythematosus, pemphigus, pityriasis rubra pilaris,
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psoriasis, reticular erythematous mucinosis, rosacea, seborrheic dermatitis, and viral infections are examples of photoaggravated dermatoses.1,2 Inherited disorders with defective DNA repair mechanisms or with chromosomal instability can be listed as ataxiatelangiectasia, Bloom syndrome, Cockayne syndrome, Hailey-Hailey disease, Hartnup disease, Kindler syndrome, Rothmund-Thomson syndrome, trichothiodystrophy, and xeroderma pigmentosum.3 Photosensitivity is the reaction of skin to exogenous or endogenous agents.4 These agents are usually compounds with unsaturated double bonds, which absorb ultraviolet A (UVA) wavelength energy. Exogenous agents can be used systemically or topically, and cutaneous porphyrias are examples of photosensitivity induced by endogenous agents.5 Photosensitivity induced by exogenous agents is classified into two groups: phototoxicity and photoallergy (Table 1). Phototoxicity is a direct tissue injury, caused by phototoxic agent and radiation, which can be seen in every individual. In contrast, photoallergy is a delayed-type hypersensitivity reaction. It is caused by chemicals that are modified by absorbing photon energy. It does not occur during the first exposure and has a sensitization phase. The incidence of photosensitivity is rather low, and phototoxic reactions are far more common than photoallergic reactions.2 The prevalence of exogenous drug-induced photosensitivity is not known, but data from photodermatology referral centers show 7% to 15% for phototoxicity and 4% to 8% for photoallergy.6 In studies performed in the United States and Europe, the incidence rate of photoallergic contact dermatitis in patients who are photopatch-tested is between 1.4% to 12.0%. Age distribution is rather homogeneous, but for drug-induced photosensitivity, the elderly population is more susceptible.6 More than 300 types of medications are responsible for photosensitivity.7 Among topical phototoxic agents, the most commonly used ones are fluorescein, fluorouracil, furocoumarins, retinoids, rose bengal, and tar. For systemic phototoxic agents, the list is much longer. Many antifungals Table 1
such as griseofulvin; antimalarials such as chloroquine and quinine; antimicrobials such as sulfonamides, tetracyclines, trimethoprim, quinolones, amiodarone, and quinidine; and diuretics such as furosemide, thiazides, psoralens, and sulfonylureas can cause phototoxic reactions. The photoallergic chemicals can also be classified into topical and systemic agents. Topical agents refer mostly to sunscreen ingredients, such as benzophenones, para-aminobenzoic acid (PABA) derivatives, cinnamates, and fragrance chemicals (methyl coumarins, musk ambrette, and sandalwood oil). Surface disinfectants, skin cleansers such as chlorhexidine, hexachlorophene, pesticides, and topical nonsteroidal anti-inflammatory agents are also topical agents. Systemic photoallergens can be listed as griseofulvin, quinolone, quinine, ketoprofen, and pyridoxine.8
Phototoxicity Pathophysiology More than one mechanism is usually involved in the pathophysiology of phototoxicity. A photosensitizer chemical absorbs UVA radiation energy. Before this absorption, the substance being at its ground state rises to an excited state molecule, with the effect of UV energy. This excited state chemical is involved in oxygen-dependent reactions, and at the end of these reactions cytotoxic injury is observed. These pathways of reactions can be studied in two major classes: type 1 and 2 reactions.7 During type 1 reactions, an electron is transferred to the excited state photo sensitizer, and this reaction results in free radical formation. These free radicals are involved in oxidation-reduction reactions and occurring peroxides cause cell damage.9 Type 2 reactions are, in contrast, energy transfer processes. Here again, transfer of energy to ground state oxygen causes oxygen radical formation. These radicals interact with unsaturated fatty acids, and in the end,
Differences and similarities between phototoxicity and photoallergy
Clinical presentation Pathophysiology Histology
Onset and occurrence Dose Cross-reactivity Diagnosis
Phototoxicity
Photoallergy
Sunburnlike reaction, erythema, edema with vesicles and bullae Direct tissue injury Epidermal necrosis, dermal edema with eosinophilic keratinocytes, dermal infiltrate of lymphocytes, macrophages, and neutrophiles Occurs after first exposure and starts minutes to hours after exposure Large doses needed None Clinical and phototests
Pruritic eczematous lesions Type IV delayed hypersensitivity Spongiotic dermatitis, dermal lymphohistiocytic infiltrate
No reaction after first exposure, starts 24-48 hours after exposure Small doses are enough Common Clinical and photopatch tests
Photodermatoses
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hydroperoxides are formed. These substances eventually lead to oxidation of lipids and proteins. All these photodynamic processes are seen in cases of porphyrin-, quinolone-, nonsteroidal anti-inflammatory drug-, tetracycline-, amitriptyline-, imipramine-, sulfonylurea-, hydrochlorothiazide-, chlorpromazine-, and furosemide-induced phototoxicities.8 Apart from those chemicals, irradiation of phenothiazines, chlorpromazine, tetracyclines, and quinolones produces stable photoproducts, which are again responsible for tissue damage. In one other mechanism, a photosensitizer binds to its biological substrate with the help of radiation. During this reaction, an excited state molecule bonds covalently to a ground state molecule. 8-Methoxypsoralen bonds to the pyrimidine bases of DNA molecules forming cross-links between DNA strands. Biologically active products of complement activation, mast-cell–derived mediators, eicosanoids, proteases, and polymorphonuclear leukocytes may also take part in the process of phototoxicity. It is usually the case with porphyrins, chlorpromazine, and demeclocycline, where inflammation and inflammatory cells participate in tissue injury. Photosensitizer plus electromagnetic radiation also induce apoptosis, together with cytotoxicity, and this property of the process is used in clinics to treat premalignant and malignant skin conditions.
Clinical manifestations Phototoxicity usually shows its effects minutes to hours after exposure to the phototoxic agent, UV radiation. The only exception is psoralen-induced phototoxicity. In that case, acute response first appears after 24 hours and peaks at 48 to 72 hours. All the symptoms are dose dependent, meaning they depend on both the dose of the drug that is used and the dose of the UV radiation to which the individual is exposed. The clinical picture may vary from a mild or even asymptomatic phase to a severe sunburn.10 The patient may report a burning and stinging sensation, especially on areas of the body that have been exposed to sun, such as the forehead, nose, V area of the neck, ears, and dorsa of the hands. Erythema and edema are the characteristic findings. Pruritus usually accompanies, and in severe reactions even vesicles and bullae may be seen. In differential diagnosis, one may easily notice the sparing of areas where UV radiation has not reached, such as the postauricular areas, the submental area, the nasolabial folds, and under clothing. Skin lesions may resolve with different degrees of hyperpigmentation (Figure 1).4 Pseudoporphyria is a clinical form of phototoxicity. The most common drug causing this is naproxen. The skin findings in this phenomenon are similar to those in
Fig. 1 This patient illustrates photodermatitis on the face, neck, and chest.
porphyria cutanea tarda. It is usually evidence of a severe phototoxic reaction, with erythema, edema, vesicles, and subepidermal blisters. Histologic findings and immunofluorescence findings are also indistinguishable from porphyria cutanea tarda. The diagnosis is made considering the history of sun exposure and chemical use, and most importantly the normal porphyrin profile, in the case of pseudoporphyria. Apart from naproxen, other drugs such as amiodarone, celecoxib, beta-lactam antibiotics, cyclosporine, ciprofloxacin, furosemide, imatinib, oral contraceptives, nalidixic acid, oxaprozin, ketoprofen, mefenamic acid, tetracyclines, and voriconazole can also induce this type of reaction. In the case of voriconazole, especially in immunesuppressed patients and for the usage duration longer than 12 weeks, accelerated photo-induced changes can be seen. These changes include pseudoporphyria, photoaging, lentigines, premature dermatoheliosis, and even squamous cell carcinoma and melanoma in cases of use longer than 12 months.11 Photo-onycholysis can also be observed as a manifestation of acute phototoxicity. Fluoroquinolones, tetracyclines,
76 and psoralens are among the medicines that are reported to be responsible for this damage. It is the painful separation of the distal nail from the nail bed, whereas the nail plate focuses UV energy on the nail bed.8 Blue-gray pigmentation is another clinical form of phototoxicity. It is usually seen in sun-exposed areas presumably and is associated with many different drugs and chemicals.10 Amiodarone, chlorpromazine, clozapine, imipramine, and less commonly desipramine among tricyclic antidepressants may cause this type of phototoxicity. Minocycline, for instance, may result in blue-gray pigmentation of the face, mostly on acne scars, and less commonly on shins and forearms. In the pathophysiology of this type of pigmentation, a drug metabolite–melanin complex plays an important role. In case of argyria exposure, a slate-gray pigmentation is observed, which involves the nail lunulae, mucous membranes, and sclerae. In this case, silver granules produced during a photochemical reaction are deposited in the dermis. Telangiectasia on sun-exposed areas can occur as a result, especially when using calcium channel blockers such as nifedipine, amlodipine, felodipine, and diltiazem, antibiotics such as cefotaxime, and the antidepressant venlafaxine. Phytophotodermatitis (grass dermatitis) is also a particular form of phototoxicity, induced by plant extracts, especially seen in gardeners or after being in close contact with plants.12 Striped, sharply delineated erythema corresponding to the trails of grass brushing on the skin is typical for this type of reaction.2 The course of phototoxicity in most patients is usually self-limited. The symptoms reduce after discontinuation of the responsible agent. In some cases, even after the patient stops taking the drug, the symptoms persist, even for years. In those cases, chronic actinic dermatitis may develop on the areas of phototoxicity. The clinical findings can be listed as primarily pruritus and lichenification, together with secondary excoriation on sun-exposed regions. This type of reaction is more commonly seen with thiazides, quinidine, amiodarone, and quinine. With chronic exposure to both chemical agents and UV radiation, as seen in patients who have received long-term psoralen + ultraviolet A (PUVA) photochemotherapy, longterm cutaneous effects are seen. Phototoxicity in chronic exposure is known to affect DNA, which, in turn, causes premature aging of the skin, lentigines, squamous cell carcinoma, and melanoma.
Phototoxic agents Agents, drugs, or chemicals that cause phototoxicity can either be used topically or systemically. Among topical agents, fluorouracil and retinoids cause serious UVinduced hypersensitivity because of their irritant effect on the skin.
Z. Kutlubay et al. Furocoumarins are also a common causative agent for phototoxic reactions, especially among those with certain occupations such as bartenders, chefs, and gardeners, as well as patients receiving topical photochemotherapy with psoralens.7 In addition, occupational and medical exposure to coal tar not only causes phototoxic reactions, but also increases the risk for nonmelanoma skin cancers. Most systemic agents produce a sunburnlike reaction, as well as an eczematous photoallergic response. In almost all of the agents, the action spectra are in the UVA range. For porphyrins and fluorescein, the spectra of action are visible light. Eculizumab, a humanized immunoglobulin G monoclonal antibody that binds to and inhibits complement protein C5 and is approved for paroxysmal nocturnal hemoglobinuria, was also reported to cause phototoxic reactions.13
Histopathology In classic, nonchronic phototoxic reactions, necrotic keratinocytes, epidermal spongiosis, and dermal edema are seen. In severe cases, epidermal necrosis is also observed. A mild inflammatory infiltrate, consisting of neutrophiles, lymphocytes, and macrophages, is almost always found in the specimen. In the case of slate-gray pigmentation, increased dermal melanin together with dermal deposits of the drug and its metabolite are found. In pseudoporphyria, dermal-epidermal separation at the lamina lucida level, the same as porphyria cutanea tarda, is detected. Also at the dermal-epidermal junction and around the nearby blood vessels, immunoglobulin deposits can easily be seen. In the case of lichenoid eruption, findings are similar to those of lichen planus. Spongiosis, dermal eosinophils, plasma cell infiltrates, and an increased number of necrotic keratinocytes and cytoid bodies may help in distinguishing the two entities.
Photoallergy Pathophysiology Photoallergy is a delayed-type hypersensitivity reaction, occurring in the presence of a photoallergic substance and UV radiation. The wavelength of the radiation is an important factor, and for most of the substances, UVA radiation is necessary. The photoallergen absorbs UVA radiation, enters an excited state, and afterward releases energy to the surroundings. During this process, the molecule bonds with a carrier protein and forms a complete antigen. Halogenated salicylanilides, chlorpromazine, and para-aminobenzoic acid are thought to be the causes of photoallergy by means of this
Photodermatoses mechanism. Sulfanilamide and chlorpromazine also form a stable product after being exposed to UVA radiation, and then together with a carrier protein form a complete antigen. After this complete antigen is composed, the mechanism is similar to contact allergy. Langerhans cells take up the antigen and process it, and afterward migrate to regional lymph nodes to present the antigen to T lymphocytes. Then these activated T lymphocytes start to circulate around the exposed site and start an inflammatory response, only after which cutaneous lesions develop.
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Management of phototoxicity and photoallergy
Symptoms usually occur within 24 to 48 hours after exposure to the photoallergen and UV radiation. The symptoms are more prominent in sensitized individuals. The clinical morphology is identical to that of allergic contact dermatitis; however, the distribution of the skin lesions can help in differential diagnoses. In photoallergic dermatitis, mostly body parts that are prone to sun exposure are affected. In severe cases, the lesions may also be seen in covered areas of the body, as well as in sun-exposed areas. The clinical manifestations usually disappear without any significant postinflammatory hyperpigmentation. The most common cause of photoallergy, especially in the United States and Europe, is sunscreen products. UV filters, especially benzophenone-3, are the leading cause of photoallergic dermatitis.14 Also, antimicrobial agents are a rather common cause. For the topical causative agents, nonsteroidal anti-inflammatory agents are the leading drugs responsible for photoallergy. Long-term exposure to chlorpromazine, dioxopromethazine, ketoprofen, musk ambrette, halogenated salicylanilides, and quinidine, together with chronic UV radiation, may also cause chronic actinic dermatitis, as in the case of phototoxicity.
The best set of actions should be identified first to avoid the causative phototoxic or photoallergic agent; furthermore, avoiding UV radiation is essential, and sunscreens with efficient UVA filters should be used regularly. For symptomatic treatment of acute reactions, topical corticosteroids are the drug of choice. Antihistamines may also be helpful. In the case of severe reactions, systemic corticosteroids can also be used. Short-term usage (prednisone 1 mg/kg) from 1 to 2 weeks can be initiated for acute and severe exacerbations.15 For patients with slate-gray pigmentation, lichenoid eruption, pseudoporphyria, and photodistributed telangiectasia, only symptomatic therapy is given. In those cases, it can take a few months for the condition to be resolved. After resolution of the acute event, if there is marked hyperpigmentation, depigmentation methods can be used. A combination of 0.1% retinoic acid, 5.0% hydroquinone, and 1% hydrocortisone, or laser therapy can be attempted.2 While handling most photodermatoses, preventive UV phototherapy or psoralen plus UVA, or both, can be used. The “hardening” phenomenon is one of the basic features of prophylactic phototherapy in photosensitive individuals. Its mechanism is thought to be about increased melanization, stratum corneum thickening, and depletion of hypothetical antigens. In the case of persistence of significant photosensitivity, low-dose broadband or narrowband ultraviolet B (UVB) or PUVA therapy two to three times a week may be the treatment of choice, especially in acquired idiopathic photodermatoses. The treatment is usually initiated during spring, and an average of 15 sessions is usually enough to induce hardening. To maintain this hardening state, patients are told to expose themselves to midday sunlight for 15 to 20 minutes without sunscreen weekly.
Photoallergens
Sunscreen usage
In case of photoallergy, topical agents are usually the most common cause of the skin lesions. Sunscreen products, topical antimicrobials, and topical nonsteroidal anti-inflammatory drugs are most frequently used in everyday practice.7 Systemic agents, in contrast, are much less frequent.
On a summer’s day, the UV energy received (daily dose) is composed of approximately 3.5% UVB and 96.5% UVA.11 While choosing the most effective sunscreen for each patient, identification of the photon wavelength responsible for inducing the sensitivity reaction is important. This can often be done by the determination of a minimal erythema dose (MED) to UVA and UVB radiation.16 UVB and UVA filters are categorized into organic and inorganic filters. There are many efficient UVB filters, but only a limited number of organic UVA filters are available, such as the benzophenones (oxybenzone, dioxybenzone, and sulisobenzone), butyl methoxydibenzoylmethane (commonly known as avobenzone), and methyl anthranilate.17 All except avobenzone are primarily protective only against UVA-2 (320-340 nm), whereas the absorption of avobenzone
Clinical manifestations
Histopathology Histopathologic findings related to photoallergy are similar to those of allergic contact dermatitis, as is the morphologic appearance. Epidermal spongiosis together with dermal mononuclear cell infiltrates are the typical histologic features.
78 extends into UVA-1 (340-400 nm). Because avobenzone is photolabile, degradation occurs rapidly on exposure to sunlight, and by combining it with photostable UV filters, such as octocrylene, salicylates, or oxybenzone, it can be photostabilized. Inorganic sunscreens or physical blockers are titanium dioxide and zinc oxide, which offer protection from UVB to visible ranges.18 Sunscreen efficacy is measured first by its sun protection factor, which is a globally accepted index of protection from erythema after a single exposure to solar-simulated radiation, primarily the effect from UVB exposure, and to a lesser extent from UVA-2.
Differential diagnosis of phototoxicity and photoallergy All types of nonspecific dermatitis can be included in differential diagnosis of photosensitivity. Allergic contact dermatitis caused by inhaled allergens particularly affects skin folds such as nasolabial folds and eyelids. These areas receive very small amounts of UV irradiation; thus, they are not expected to be involved in photo-induced reactions. Allergic contact dermatitis can also be seen in the postauricular region and under the chin, where sun exposure is unlikely. Both allergic contact dermatitis and irritant contact dermatitis are observed mainly at sites where direct contact of the inhalant or contact allergen takes place, either sun-exposed or sun-protected areas. Other photodermatoses are also included in differential diagnoses. In the case of polymorphous light eruption, symptoms appear a few hours after the sun exposure, and pruritic papules, plaques, and rare vesicles can be seen. The lesions usually tend to be observed at sun-exposed sites and are resolved in a few days. Lesions of solar urticaria are also found in sun-exposed areas, typically occurring minutes after sun exposure, morphologically similar to pruritic urticarial plaques, and in the end are resolved within a few hours.
Approaching patients with phototoxicity and photoallergy While evaluating patients with photosensitivity, a detailed history including the relationship between eruption and sun exposure, duration of lesions, effect of windowglass-filtered sunlight, exposure to photosensitizing agents, family history, age of onset, seasonal variation, and systemic symptoms is crucial. A physical examination into the morphology and distribution—specifically presence of symptoms on the head, face, neck, arms, legs, and torso, and absence underneath the chin, lips, nasolabial folds, and postauricular
Z. Kutlubay et al. area—can provide further diagnostic clues. Advanced tests, such as antinuclear antibody titers, skin biopsies, phototesting, photopatch testing, and porphyrin levels can also help in diagnosis. A history of exposure to known photosensitizers is a risk factor for identifying the cause. For sun exposure, patients should be questioned extensively about window-glassfiltered sunlight. UVB radiation is filtered out by window glass, and phototoxic and photoallergic reactions are prominently caused by UVA radiation. In addition, examining the distribution of the cutaneous lesions will help both to distinguish the reaction from other types of dermatitis and to identify the type of photosensitizer responsible. In the case of systemic photosensitizers, widespread eruption is usually observed. With topical photosensitizers, however, lesions are found in regions that are exposed to both the photosensitizer chemical and the UV radiation. If there are vesicular and bullous lesions with severe symptoms and complaints of a burning sensation, the incidence is probably associated with phototoxicity, whereas eczematous eruptions with pruritus usually suggest photoallergy. In some rare cases, a skin biopsy may be needed for differentiating the two conditions. Necrotic keratinocytes is a characteristic feature of phototoxicity, whereas spongiotic dermatitis is associated with photoallergy. Phototests and photopatch tests also play an important role in the evaluation and diagnosis of patients with known photosensitivity, especially in cases for whom physical examination and history are not sufficient for making a decision or for determining the causative agent.15 During phototesting and photopatch testing, the MED should first be determined. Duplicate sets of photoallergens are applied symmetrically on the body surface, preferably on the back, and then covered by an opaque tape.19 Then UVA radiation is applied, in increasing dosages, and MEDs are added. The MED for UVA and UVB is defined as the lowest dose of radiation that produces perceptible erythema covering the entire irradiated area.1 The MED for UVA radiation is lower than the normal population in the case of phototoxicity and photoallergy.15 Phototesting is an important step in the evaluation of the photosensitive patient. A template with several exposable windows is used, and the patient’s back, abdomen, or inner forearms, where there is no lesion, is exposed to different doses of UVA, UVB, and visible monochromatic or broadspectrum radiation. Systemic immunosuppressants and topical agents should be discontinued 2 weeks before phototesting. The cutaneous response is assessed by observing immediate urticarial lesions, as in the case of solar urticaria, and also the MED. Photoprovocation testing is performed to induce lesions 3 to 4 consecutive days with exposure to the same site, and within 24 hours, lesions usually develop.15 Phototesting is the most beneficial in the diagnosis of idiopathic or immunologically mediated photodermatoses, whereas in porphyrias and genodermatoses, the test is not as beneficial.
Photodermatoses Photopatch testing, in contrast, is performed when photoallergic contact dermatitis is suspected. Two sets of photoallergen panels are placed on uninvolved sites of the skin, preferably on the upper back. Because it is a known fact that photoallergens can also cause contact hypersensitivity, photopatch tests are done in duplicates. One set is removed after 24 hours and irradiated with UVA of 5 to 10 J cm. After 48 and 72 hours, both the irradiated and unirradiated sides are evaluated for a positive reaction, meaning the presence of erythema, edema, and/or vesiculation. If there is a positive reaction at both sites, it indicates allergic contact dermatitis, whereas a positive reaction at the unirradiated site with a stronger reaction at the irradiated site is interpreted as both allergic contact dermatitis and photoallergic contact dermatitis. In the case of irritant dermatitis, an erythema appears with well-defined borders, and this erythema disappears rapidly. Photopatch testing is contraindicated in cases of suspected phototoxicity. Nevertheless, only 10% of patients undergoing photopatch testing have clinically relevant positive results.20 Photopatch tests are often negative for photoallergy with medications delivered by enteral or parenteral routes, because a specific metabolite is actually responsible for the occurrence of the cutaneous lesions, not the medication itself.2 The list of agents used for photopatch tests varies greatly among countries, but the substances commonly used can be listed as follows6: tetrachlorosalicylanilide 0.1%, 5-bromo-4′-chlorosalicylanilide 1.0%, hexachlorophene 1.0%, bithionol 1.0%, sulfanilamide 5.0%, promethazine hydrochloride 0.1%, chinoidine sulfate 1.0%, musk ambrette 5.0%, fragrance mix 8.0%, 4-aminobenzoic acid 10.0%, 2-ethylhexyl-4-dimethylaminobenzoate 10.0%, 1-(4-isopropylphenyl)-3-phenyl-1,3-propandion 10.0%, 4-tert butyl-4′-methoxy dibenzoylmethane 10.0%, isoamyl4 methoxycinnamate 10.0%, 2-ethylhexyl-4-methoxycinnamate 10.0%, 3-(4 methylbenzylidene) camphor 10.0%, 2phenyl-5-benzimidazole sulfonic acid 10.0%, oxybenzone 10.0%, and sulisobenzone 10.0%.
Conclusions Photosensitivity is a challenging area for both the physician and the patient. For the exact diagnosis and precise control of the photosensitivity, a systematic approach is vital. Avoidance of direct sunlight, sun-tanning facilities, and photosensitizing agents, and the usage of clothing with UV filters and appropriate sunscreen can all minimize the risk for photosensitivity effects. A combination of measures, including
79 phototherapy in different modalities and topical and systemic drugs, can be beneficial in managing photodermatoses.
References 1. Santoro FA, Lim HW. Update on photodermatoses. Semin Cutan Med Surg. 2011;30:229-238. 2. Lehmann P, Schwarz T. Photodermatoses: diagnosis and treatment. Dtsch Arztebl Int. 2011;108:135-141. 3. Inamadar AC, Palit A. Photosensitivity in children: an approach to diagnosis and management. Indian J Dermatol Venereol Leprol. 2005;71:73-79. 4. Hawk JLM. Abnormal cutaneous effects of UVR exposure: the photodermatoses. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s Textbook of Dermatology. 8th ed. West Sussex, UK: Wiley-Blackwell; 2010:29.9-315. 5. Roelandts R. Photodermatology Quo vadis? Actas Dermosifiliogr. 2009;100:66-72. 6. Trakatelli M, Charalampidis S, Novakovic LB, et al. Photodermatoses with onset in the elderly. Br J Dermatol. 2009;161:69-77. 7. Lehmann P. Diagnostic approach to photodermatoses. J Dtsch Dermatol Ges. 2006;4:965-975. 8. Lim HW. Abnormal responses to ultraviolet radiation: photosensitivity induced by exogenous agents. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, editors. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw Hill; 2012:1066-1074. 9. Siani AM, Casale GR, Sisto R, et al. Short-term UV exposure of sunbathers at a Mediterranean Sea site. Photochem Photobiol. 2009;85:171-177. 10. Lehmann P. Sun exposed skin disease. Clin Dermatol. 2011;29: 180-188. 11. Cowen EW, Nguyen JC, Miller DD, et al. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol. 2010;62:31-37. 12. Kar HK, Langar S, Arora TC, et al. Occurrence of plant sensitivity among patients of photodermatoses: a control-matched study of 156 cases from New Delhi. Indian J Dermatol Venereol Leprol. 2009;75: 483-487. 13. Balagula Y, Newman SB, Lacouture ME. Photodermatosis associated with eculizumab (Soliris): a novel monoclonal antibody directed against the complement protein C5. Am J Hematol. 2010;85:392-393. 14. Kerr A, Ferguson J. Photoallergic contact dermatits. Photodermatol Photoimmunol Photomed. 2010;26:56-65. 15. Bylaite M, Grigaitiene J, Lapinskaite GS. Photodermatoses: classification, evaluation and management. Br J Dermatol. 2009;161:61-68. 16. Fourtanier A, Moyal D, Seite S. UVA filters in sun-protection products: regulatory and biological aspects. Photochem Photobiol Sci. 2012;11: 81-89. 17. Deleo V. Sunscreen use in photodermatoses. Dermatol Clin. 2006;24: 27-33. 18. Medeiros VL, Lim HW. Sunscreens in the management of photodermatoses. Skin Therapy Lett. 2010;15:1-3. 19. Victor FC, Cohen DE, Soter NA. A 20-year analysis of previous and emerging allergens that elicit photoallergic contact dermatitis. J Am Acad Dermatol. 2010;62:605-610. 20. Kerr HA, Lim HW. Photodermatoses in African Americans: a retrospective analysis of 135 patients over a 7-year period. J Am Acad Dermatol. 2007;57:638-643.
