| Photosensitivity = التحسس الضيائي |
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ACUTE
PHOTOTOXICITY Acute phototoxicity usually occurs within hours of exposure to the phototoxic agent and UV radiation. Symptoms are drug-dose and UV-dose dependent, but at sufficient doses, the patient complains of a burning and stinging sensation on exposed areas, such as forehead, nose, V area of the neck, and dorsa of the hands. Erythema and edema may appear within hours of exposure; in severe cases, vesicles and bullae may develop. Protected areas, such as nasolabial folds, postauricular and submental areas, and areas covered by clothing, are spared . A notable exception to these kinetics is psoralen-induced phototoxicity, in which often the acute response first appears after 24 hours, and peaks at 48 to 72 hours, which is the rationale for administering psoralen plus UVA (PUVA) photochemotherapy doses 48 to 72 hours apart. The phototoxic response usually resolves with a varying degree of hyperpigmentation, which may last for months. At lower drug/UV doses, gradual tanning only, without preceding sunburn-like reaction, can be seen.
PHOTO-ONYCHOLYSIS
Separation of the distal nail from the nail bed is a manifestation of acute phototoxicity, with the nail plate serving as a lens to focus UV energy on the nail bed. It has been reported with doxycycline and other tetracyclines, fluoroquinolones, psoralens, benoxaprofen, clorazepate dipotassium, and quinine
SLATE-GRAY PIGMENTATION
Blue-gray pigmentation on sun-exposed areas has been associated with exposure to several agents. One percent to 10 percent of patients taking amiodarone develop this side effect . Chlorpromazine can induce a similar change. The tricyclic antidepressants imipramine and, less commonly, desipramine have also been reported to cause slate-gray pigmentation. A drug metabolite-melanin complex has been postulated to be the cause of this alteration. Chronic exposure to diltiazem, a benzothiazepine calcium channel blocker, has resulted in photodistributed, reticulated, slate-gray pigmentation . Pigmentary incontinence and melanosome complexes are the prominent histologic and electron microscopic findings. Slate-gray pigmentation seen in argyria involves the nail lunulae, mucous membranes, and sclerae. A photochemical reaction in which silver granules are deposited in the dermis results in these pigmentary alterations. LICHENOID ERUPTION Lichenoid eruption has been reported but is controversial. PSEUDOPORPHYRIA The development of porphyria cutanea tarda-like cutaneous changes of skin fragility, vesicles, and sub-epidermal blisters is associated with
PHOTODISTRIBUTED TELANGIECTASIA
Telangiectasia on sun-exposed areas has been reported with calcium channel blockers, including nifedipine, amlodipine, felodipine, and diltiazem, and with the antibiotic cefotaxime. In some of these patients, provocation with UVA resulted in the development of telangiectasia.
PERSISTENCE OF
PHOTOSENSITIVITY AND
EVOLUTION TO CHRONIC ACTINIC
DERMATITIS
Although phototoxicity usually resolves after discontinuation of the causative agent, there are reports of persistence of photosensitivity for many years after the cessation of exposure, which results in the development of chronic actinic dermatitis (see Photoallergy). This has been reported most often with dexamethahexachlorine, an ingredient previously found in some spas, but also with thiazides, quinidine, quinine, and amiodarone.
CHRONIC EFFECTS
Cutaneous effects of long-term, repeated phototoxic tissue injury are best exemplified by the manifestations in patients who have received long-term PUVA photochemotherapy, which is known to affect DNA. These effects include premature aging of the skin, lentigines, squamous cell and basal cell carcinomas, and melanoma. These are discussed in greater detail in Chap. Phototoxic Agents
TOPICAL AGENTS
Table 91-2 lists the major topical phototoxic agents. Therapeutic or occupational exposures to these agents are the common route of contact. The action spectrum is in the UVA or visible light range . Furocoumarins.
Topical exposures to furocoumarins may occur in individuals in certain occupations (bartenders, salad chefs, gardeners) and in patients receiving topical photochemotherapy with psoralens. Such exposures were reported in the past among users of tanning preparations or perfumes containing 5-methoxypsoralen (bergapten), but these preparations have been withdrawn from the market.
Tar.
Crude coal tar used in dermatologic therapy is the product of the destructive distillation of coal. It is a complex mixture of over 10,000 compounds, including many phototoxic polyaromatic hydrocarbons that produce a burning and stinging sensation on exposure to UVA (“tar smarts”). Occupational exposure to tar is associated with increased risk of non-melanoma skin cancers, in addition to phototoxicity, although the carcinogenicity of coal tar used in dermatologic therapy remains controversial.
SYSTEMIC AGENTS
Table 91-3 lists the major systemic phototoxic agents.25-53 They commonly produce an exaggerated sunburn reaction but like most phototoxins may also induce an eczematous photoallergic response in a small percentage of users, especially after topical exposure. As a rule, the action spectra are in the UVA range; exceptions include the sulfonamides and ranitidine, whose action spectra are in the UVB range, and the porphyrins, fluorescein, and other dyes, whose action spectra are in the visible light range. Histopathology
Acute phototoxicity is characterized by individual necrotic keratinocytes and, in severe cases, epidermal necrosis . There may be epidermal spongiosis, dermal edema, and a mild infiltrate consisting of neutrophils, lymphocytes, and macrophages. Slate-gray pigmentation is associated with increased dermal melanin and dermal deposits of the drug or its metabolite. Histologic features of lichenoid eruptions are similar to those of idiopathic lichen planus; however, there may be a greater degree of spongiosis and dermal eosinophilic and plasma cell infiltrates, and a larger number of necrotic keratinocytes and cytoid bodies. In pseudoporphyria, as in porphyria cutanea tarda, there is dermal-epidermal separation at the lamina lucida and deposits of immunoglobulins at the dermal-epidermal junction and surrounding blood vessel walls.
Management Identification and avoidance of the causative phototoxic agent are the most important steps in management. Beyond this, sun avoidance is essential. Because the action spectrum for most agents is in the UVA range, high sun protection factor, broad-spectrum sunscreens containing efficient UVA filters should be used . Acute phototoxicity can be managed with topical corticosteroids and compresses; systemic corticosteroids should be reserved for only the most severely affected patients. Management of patients with slate-gray pigmentation, lichenoid eruption, pseudoporphyria, and photodistributed telangiectasia is symptomatic only, and patients should be advised that it will take months after the discontinuation of the offending agent for the condition to resolve. Patients with nonsteroidal anti-inflammatory drug (NSAID)-induced pseudoporphyria who require NSAIDs should be switched to a different class of agents or to those that are less photosensitizing, such as indomethacin or sulindac. ▪ PHOTOALLERGY Pathophysiology Photoallergy is a type IV delayed hypersensitivity response requiring the presence of both photoallergen and the activating wavelengths of radiation, which for most agents are in the UVA range.
Once the complete antigen is formed, the mechanism of photoallergy is identical to that of contact allergy. The antigen is taken up and processed by Langerhans cells, which then migrate to regional lymph nodes to present the antigen to T lymphocytes. Cutaneous lesions develop when the activated T lymphocytes circulate to the exposed site to initiate an inflammatory response.
Clinical Manifestations
In sensitized individuals, exposure to the photoallergen and sunlight results in the development of a pruritic, eczematous eruption within 24 to 48 hours after exposure. Although the morphology is clinically indistinguishable from that of allergic contact dermatitis, the distribution of the eruption in photoallergy is predominantly confined to sun-exposed areas; however, in severe cases it may spread to the covered areas, albeit at a lower intensity. Unlike the lesions in phototoxicity, those in photoallergy usually resolve without significant post-inflammatory hyperpigmentation. Lichenoid eruption has also been reported. Currently, in the United States, United Kingdom, and France, UV filters in sunscreen products (especially benzophenone-3) are the most common cause of photoallergy, whereas NSAIDs are the leading topical photoallergens in Germany, Austria, and Switzerland As with phototoxicity, persistence of photosensitivity and evolution to chronic actinic dermatitis have been reported after exposure to photoallergens, including halogenated salicylanilides, musk ambrette, ketoprofen, dioxopromethazine, olaquindox, and quinidine. The mechanism is not completely understood. One possible explanation is that UV radiation alters the carrier protein that originally binds the photoallergen; this results in the formation of a neoantigen that stimulates the immune system over the long term. This hypothesis is supported by the observation that the histidine moiety in albumin can undergo oxidation in the presence of salicylanilide, which binds to albumin.
Photoallergens
TOPICAL AGENTS Topical exposure is the most common route of sensitization to photoallergens.59 Table 91-4 lists the common groups of photoallergens. SYSTEMIC AGENTS Photoallergy caused by systemic agents is much less frequent than that induced by topical agents. All but one of these photoallergenic agents (pyridoxine) are also phototoxic and have been discussed previously in this chapter .
Histopathology
The histologic features of photoallergy are similar to those of allergic contact dermatitis. There is epidermal spongiosis associated with infiltrate of mononuclear cells in the dermis . Management Management is identical to that of phototoxicity: identification and avoidance of the photoallergen, sun-protective measures, and symptomatic therapy. ▪ EVALUATION OF PATIENTS WITH PHOTOTOXICITY AND PHOTOALLERGY The evaluation of patients with phototoxicity and photoallergy is similar to the evaluation of patients with other photosensitivity disorders and is described in greater detail in Chap. 90. A history of exposure to known photosensitizers is most important. It is also helpful to ascertain whether window glass-filtered sunlight can induce the cutaneous eruption, because UVB and UVA2 (320 to 340 nm) are filtered out by window glass. Distribution of the cutaneous eruption is a helpful clue to the type of photosensitizer responsible. Widespread eruption suggests systemic photosensitizers, whereas topical photosensitizers produce lesions only in areas that have been exposed to both sensitizers and radiation. Vesicular and bullous eruptions are most commonly associated with phototoxicity, whereas eczematous eruptions suggest photoallergy; usually, the former is associated with a burning sensation, the latter with pruritus. Skin biopsy findings may also be helpful in differentiating these two conditions: necrotic keratinocytes are commonly seen in phototoxicity, whereas spongiotic dermatitis is associated with photoallergy . Phototests and photopatch tests are an integral part of the evaluation of photosensitivity. Approximately 10 percent of patients who undergo photopatch testing have clinically relevant positive results, which leads to the diagnosis of photoallergic contact dermatitis. The procedures for phototesting and photopatch testing are generally as follows, although there are variations in testing methods.62 On day 1, exposure to UVB and UVA to determine minimal erythema dose (MED) is carried out, and duplicate sets of photoallergens are applied symmetrically to another site on the back and covered by an opaque tape. On day 2, the MEDs are determined. One of the duplicate set of photoallergens is exposed to 10 J/cm2 of UVA or 50 percent of the MED to UVA, whichever is lower. After irradiation, the exposed site is covered again with an opaque tape. On day 3, both irradiated and nonirradiated test sites are uncovered, and the reactions are
▪ DIFFERENTIAL DIAGNOSIS OF
PHOTOTOXICITY AND
PHOTOALLERGY
Airborne allergic contact dermatitis is characterized by involvement of skinfolds on exposed areas, such as the nasolabial folds, and the eyelids that receive minimal direct sunlight. It also involves exposed areas that are relatively sun protected, such as the postauricular areas and area under the chin. Allergic contact dermatitis and irritant contact dermatitis occur in both sun-exposed and in sun-protected areas. Other photodermatoses can be differentiated from phototoxicity and photoallergy by their characteristic time course and morphology and lack of a compatible exposure history. Polymorphous light eruption manifests itself within a few hours of sun exposure as pruritic papules, plaques, and, uncommonly, vesicles on sun-exposed sites and resolves in a few days. Chronic actinic dermatitis presents as chronically lichenified plaques on sun-exposed areas. Lesions of solar urticaria appear within minutes of sun exposure as mildly pruritic urticaria and resolve within a few hours. ▪ OTHER EXOGENOUS AGENT- INDUCED PHOTODERMATOSES AND PHOTO-EXACERBATED DERMATOSES Porphyria Cutanea Tarda Ingestion of wheat treated with hexachlorobenzene (HCB) as a preservative resulted in an outbreak of a porphyria cutanea tarda-like syndrome in Turkey in the 1950s.63 Inhibition of the enzyme uroporphyrinogen decarboxylase by HCB was thought to be responsible for the clinical manifestations. However, a study of adults highly exposed to HCB in Catalonia, Spain, did not show any increase in prevalence of porphyria cutanea tarda or increased urinary concentrations of porphyrins.64 Lupus Erythematosus Although many medications are associated with drug-induced lupus erythematosus, the association has been best established for procainamide, hydralazine, and minocycline.65 Arthralgia and systemic symptoms are common; photosensitivity is a rare manifestation. Most patients have antibodies to histones. Individuals whose hepatic N-acetyltransferase system expresses a “slow acetylator” phenotype or who are positive for human leukocyte antigen DR4 are most susceptible.
Pellagra
Skin changes of pellagra (from the Italian pelle agra, “rough skin”) are associated with isoniazid, 6-mercaptopurine, 5-fluorouracil, chloramphenicol, sulfapyridine, anticonvulsants, and antide-pressants.66,67 The pathogenesis of drug-induced pellagra probably is related to the inhibition of conversion of niacin to nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate.
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