Chapter 92. Abnormal Responses to Ultraviolet Radiation: Photosensitivity Induced by Exogenous Agents

Photosensitivity may be caused by exogenous or endogenous agents. It occurs when a compound, classically one with unsaturated double bonds in a six-carbon ring, absorbs radiation energy in its action spectrum, usually ultraviolet A (UVA) wavelengths. Exogenous photosensitizers can be agents administered systemically or applied topically. Well-characterized examples of photosensitivity induced by endogenous photosensitizers are the cutaneous porphyrias, which are associated with enzymatic defects in heme biosynthetic pathways that result in elevated levels of porphyrins, known phototoxic agents (see Chapter 132).

Photosensitivity induced by exogenous agents can be divided into phototoxicity and photoallergy. Phototoxicity is the result of direct tissue injury caused by the phototoxic agent and radiation. It can occur in all individuals exposed to adequate doses of the agent and the activating wavelengths of radiation (Table 92-1). In contrast, photoallergy is a type IV delayed hypersensitivity response to a molecule that has been modified by absorption of photons. It has a sensitization phase, occurs only in sensitized individuals, and requires only a minimal concentration of the photoallergen (see Table 92-1).

Over 350 medications in the United States have been reported to cause photosensitivity.1 Only a small number of them, however, induce reactions frequently or have been well studied (Tables 92-2, 92-3, 92-4, and 92-5). In evaluations performed at photodermatology centers in New York City, Melbourne, Singapore, and Detroit, photosensitivity induced by a systemic drug was documented in 5% to 15% of the referred patients.2–5 In studies performed in the United States, United Kingdom, Europe, and Australia, the percentage of photopatch-tested patients who had clinically relevant reactions leading to a diagnosis of photoallergic contact dermatitis ranged from 1.4% to 12.0%, with the value in most series being around 10%.2,5–11

Pathophysiology

Several pathways eventuate in the development of phototoxic tissue damage, and for many phototoxic agents more than one pathway is responsible.

Photodynamic Processes

On absorption of radiation energy by the photosensitizer (P) at its ground state, formation of an excited (usually triplet) state (3P) molecule occurs. The excited state molecule may then participate in oxygen-dependent processes (i.e., photodynamic processes) via two major pathways, type I and type II reactions, both of which result in cytotoxic injury.12

The type I reaction involves transfer of an electron or a hydrogen atom to the excited state photosensitizer (3P), which results in the formation of free radicals [Eq. (92-1)]. These may then participate in an oxidation–reduction reaction that results in peroxide formation and subsequent cell damage [Eqs. (92-2) and (92-3)].

Alternatively, interaction of 3P with ground state oxygen could result in the formation of superoxide anion (O2−.), which, in turn, can be converted into highly reactive and cytotoxic hydroxyl radicals (OH·).

The type II reaction is also known as an energy transfer process. Transfer of energy to ground state oxygen results in the formation of singlet oxygen (1O2), which is highly reactive and has a lifetime of 50 ns [Eq. (92-4)]:

Cytotoxic injury occurs upon singlet oxygen-induced oxidation of amino acids and unsaturated fatty acids; interaction with the latter results in the formation of hydroperoxides, which initiate lipid and protein oxidation.

Phototoxicities induced by porphyrins,12 quinolones,13 nonsteroidal anti-inflammatory agents, tetracyclines, amitriptyline, imipramine, sulfonylureas, hydrochlorothiazide, furosemide, and chlorpromazine14 are examples of photodynamic phototoxic reactions.

Generation of Photoproducts

Exposure to radiation may result in the generation of stable photoproducts that are responsible for tissue injury. Phototoxic products have been demonstrated on irradiation of phenothiazines, chlorpromazine, tetracyclines, quinolones, and nonsteroidal anti-inflammatory agents.15

Binding to Substrate

Another mechanism of phototoxicity is radiation-mediated binding of the photosensitizer to its biologic substrate. A photoaddition reaction occurs when the excited state molecule covalently binds to a ground state molecule. An example is the covalent binding of 8-methoxypsoralen to pyrimidine bases of the DNA molecules, which results in the formation of a cross-link between the DNA strands.

Inflammatory Mediators

Mediators of inflammation and inflammatory cells participate in phototoxic tissue injury. Biologically active products of complement activation, mast cell-derived mediators, eicosanoids, proteases, and polymorphonuclear leukocytes contribute to the development of phototoxicity induced by porphyrins, demeclocycline, and chlorpromazine.16

Apoptosis

Photodynamic therapy (PDT) involves the use of a photosensitizer and electromagnetic radiation in the presence of oxygen to treat premalignant and malignant skin conditions. In addition to generating reactive oxygen species, which results in cytotoxicity, PDT also is a potent inducer of apoptosis.12

Clinical Manifestations

Acute Phototoxicity

(See Table 92-1.)

Acute phototoxicity occurs within hours of exposure to the phototoxic agent and UV radiation. Symptoms are drug-dose and UV-dose dependent—usually asymptomatic, 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 (Fig. 92-1). Erythema and edema may appear within hours of exposure; in severe cases, vesicles and bullae may develop accompanied by pruritus. 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 48–72 hours, which is the rationale for administering psoralen plus UVA (PUVA) photochemotherapy doses 48–72 hours apart. The phototoxic response 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, usually painful, 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, olanzapine, aripiprazole, indapamide, and quinine (Fig. 92-2).17

Slate-Gray Pigmentation

Asymptomatic blue–gray pigmentation on sun-exposed areas has been associated with exposure to several agents.18,19 One percent to ten percent of patients taking amiodarone develop this side effect (Fig. 92-1). Chlorpromazine and clozapine 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. Minocycline can induce blue–gray pigmentation on the face (Fig. 92-3), frequently on sites of acne scars, although similar pigmentation on forearms and shins can also occur. Chronic exposure to diltiazem, a benzothiazepine calcium channel blocker, has resulted in photodistributed, reticulated, slate-gray pigmentation. 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 as a form of phototoxicity, but is controversial.

Pseudoporphyria

The development of porphyria cutanea tarda-like cutaneous changes of skin fragility, vesicles, and subepidermal blisters is associated with several phototoxic agents (Fig. 92-4). Although histologic and immunofluorescence findings are similar to those of porphyria cutanea tarda, the porphyrin profile is normal or in the upper range of normal in these patients. Naproxen is the most commonly reported causative agent. Other drugs incriminated include amiodarone, β-lactam antibiotics, celecoxib, ciprofloxacin, cyclosporine, diflunisal, etretinate, furosemide, imatinib, nabumetone, nalidixic acid, narrowband UVB, oral contraceptives, oxaprozin, ketoprofen, mefenamic acid, the tetracyclines, tiaprofenic acid, torsemide, and voriconazole.20,21

Accelerated Photo-Induced Changes

This has been uniquely described with voriconazole, a broad spectrum antifungal agent. Immunosuppressed patients receiving voriconazole for >12 weeks can develop photosensitivity, pseudoporphyria, photoaging, lentigines, premature dermatoheliosis; in addition, squamous cell carcinoma and melanoma have been described in this group of patients who were on voriconazole for >12 months.21

Photodistributed Telangiectasia

Telangiectasia on sun-exposed areas has been reported with calcium channel blockers, including nifedipine, amlodipine, felodipine, and diltiazem, with the antibiotic cefotaxime, and with antidepressant venlafaxine. In some of these patients, provocation with UVA resulted in the development of telangiectasia.22

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 (Fig. 92-5). The condition presents with pruritus and lichenification and excoriation on sun-exposed sites; it has been reported with thiazides, quinidine, quinine, and amiodarone.23

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 Chapter 238.

Phototoxic Agents

Topical Agents

Table 92-2 lists the major topical phototoxic and photosensitizing agents. It should be noted that fluorouracil and retinoids induce exaggerated UV response due to their irritant effect on the skin. Therapeutic or occupational exposures to these agents are the common route of contact.

Furocoumarins

Topical exposures to furocoumarins may occur in individuals in certain occupations (bartenders, salad chefs, gardeners) and in patients receiving topical photochemotherapy with psoralens.

Tar

Crude coal tar, although no longer commonly used in dermatologic therapy, is well documented to produce a burning and stinging sensation on exposure to UVA (“tar smarts”). In addition to phototoxicity, occupational exposure to tar is associated with increased risk of nonmelanoma skin cancers.

Systemic Agents

Table 92-3 lists the major systemic phototoxic agents.24–28 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; notable exceptions are 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 (see Table 92-1). 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.18,19 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.20,21

Management

Identification and avoidance of the causative phototoxic agent are the most important steps in management. Beyond this or if the agent cannot be removed, 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 (see Chapter 223). 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-induced (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.29

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.30 After the absorption of UV energy, a photoallergen may be converted to an excited state molecule, which subsequently reverts to ground state by releasing the energy. In this process, the molecule may conjugate with a carrier protein to form a complete antigen. This is thought to be the mechanism of photoallergy induced by halogenated salicylanilides, chlorpromazine, and para-aminobenzoic acid (PABA). Alternatively, a photoallergen may form a stable photoproduct on exposure to radiation, which in turn may conjugate with a carrier protein to form a complete antigen. Sulfanilamide and chlorpromazine have both been shown to participate in this reaction.

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 (see Table 92-1). 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 in fair-skinned individuals, those in photoallergy usually resolve without significant postinflammatory hyperpigmentation. Lichenoid eruption has also been reported.

Currently, in the United States, United Kingdom, and France, UV filters in sunscreen products (especially benzophenone-3) and antimicrobial agents are the most common cause of photoallergy, whereas NSAIDs are the leading topical photoallergens in Europe.10,11,30–32 Although there have been reports of systemic agents inducing a photoallergic response, the evidence of such response remains unclear.30

As with phototoxicity, persistence of photosensitivity and evolution to chronic actinic dermatitis (see Chapter 91) have been reported after exposure to photoallergens, including chlorpromazine, dioxopromethazine, halogenated salicylanilides, ketoprofen, musk ambrette, olaquindox, and quinidine.33,34 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.30,35 Table 92-4 lists the common groups of photoallergens.

Systemic Agents

Photoallergy caused by systemic agents is much less frequent, and not as well documented, 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 (see Section “Systemic Agents” under Section “Phototoxic Agents” and Table 92-3).

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 (see Table 92-1).

Management

Management is identical to that of phototoxicity: identification and avoidance of the photoallergen, sun-protective measures, and symptomatic therapy.

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 Chapter. 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 is 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 strongly 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 (see Table 92-1).

Phototests and photopatch tests are an integral part of the evaluation of photosensitivity when history and physical examination alone are insufficient to determine the responsible agent. Approximately 10% of patients who undergo photopatch testing have clinically relevant positive results, which leads to the diagnosis of photoallergic contact dermatitis.2,11

The procedures for phototesting and photopatch testing are generally as follows, although there are variations in testing methods.5,10 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% 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 graded. On day 5 or day 8, the irradiated and nonirradiated sites are evaluated for delayed reactions. Reaction only at an irradiated site indicates photoallergy. Reaction of equal intensity at both irradiated and covered sites indicates allergic contact dermatitis. Reaction at both sites, but with higher intensity at the irradiated site, signifies both photoallergy and allergic contact dermatitis. Well-defined erythema that resolves promptly indicates an irritant dermatitis.

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 at sites of contact, 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.

Porphyria Cutanea Tarda

(See Chapter 132)

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.36 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, and of children from the same area, did not show any increase in prevalence of porphyria cutanea tarda or increased urinary concentrations of porphyrins.37

Lupus Erythematosus

(See Chapter 155)

Drug-induced systemic lupus erythematosus present with purpura, erythema nodosum, urticarial and necrotizing vasculitis, and/or photosensitivity. It is most commonly associated with exposure to hydralazine, procainamide, isoniazid, and minocycline; antinuclear antibody (ANA) test is positive and antihistone antibodies are characteristically present.38

Drug-induced subacute cutaneous lupus erythematosus (SCLE) presents with similar cutaneous lesions as idiopathic SCLE, although blisters and targetoid lesions may occur, and lower extremities may be involved. Antinuclear antibody and anti-Ro/SSA antibodies are frequently present, while antihistone antibodies are usually absent. Drugs associated with this condition include calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine and tumor necrosis factor(TNF)-α antagonists.38

Drug-induced discoid lupus erythematosus is very rare; it has been reported with exposure to fluorouracil and TNF-α antagonists.

Identification and avoidance of the precipitating agent is the treatment of drug-induced lupus erythematosus.