Drug-induced photosensitivity refers to the development of cutaneous disease as a result of the combined effects of a chemical and light.[1] Exposure to either the chemical or the light alone is not sufficient to induce the disease; however, when photoactivation of the chemical occurs, one or more cutaneous manifestations may arise. These include phototoxic and photoallergic reactions, a planus lichenoides reaction, pseudoporphyria, and subacute cutaneous lupus erythematosus. Photosensitivity reactions may result from systemic medications and topically applied compounds (see Table 1 below).
UV-A–associated phototoxicity is also common with vemurafenib,[2, 3, 4] with reduced UV-A minimal erythema dose in 94% of those tested.[2]
Wavelengths within the UV-A (320-400 nm) range and, for certain compounds, within the visible range, are more likely to cause drug-induced photosensitivity reactions, although occasionally UV-B (290-320 nm) can also be responsible for such effects. UV-B wavelengths are most efficient at causing sunburn and nonmelanoma skin cancer. In patients who present with photosensitivity, it is often difficult to differentiate phototoxic from photoallergic reactions. However, they have a number of distinguishing characteristics (see Table 2 below).
Table 1. Common Photosensitizing Medications
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Phototoxic reactions occur because of the damaging effects of light-activated compounds on cell membranes and, in some instances, DNA. By contrast, photoallergic reactions are cell-mediated immune responses to a light-activated compound. Phototoxic reactions develop in most individuals if they are exposed to sufficient amounts of light and drug. Typically, they appear as an exaggerated sunburn response, as shown in the image below.
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Phototoxic reaction.
Photoallergic reactions resemble allergic contact dermatitis, with a distribution limited to sun-exposed areas of the body. However, when the reactions are severe or prolonged, they may extend into covered areas of skin.
Table 2. Distinguishing Characteristics of Phototoxic and Photoallergic Reactions
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Photoallergic reactions develop in only a minority of individuals exposed to the compound and light; they are less prevalent than phototoxic skin reactions. The amount of drug required to elicit photoallergic reactions is considerably smaller than that required for phototoxic reactions. Moreover, photoallergic reactions, as shown in the image below, are a form of cell-mediated immunity; their onset often is delayed by as long as 24-72 hours after exposure to the drug and light. By contrast, phototoxic responses often occur within minutes or hours of light exposure.
Phototoxic reactions result from direct damage to tissue caused by a photoactivated compound. Many compounds have the potential to cause phototoxicity. Most have at least one resonating double bond or an aromatic ring that can absorb radiant energy. Most compounds are activated by wavelengths within the UV-A (320-400 nm) range, although some compounds have a peak absorption within the UV-B or visible range.
In most instances, photoactivation of a compound results in the excitation of electrons from the stable singlet state to an excited triplet state. As excited-state electrons return to a more stable configuration, they transfer their energy to oxygen, leading to the formation of reactive oxygen intermediates. Reactive oxygen intermediates such as an oxygen singlet, superoxide anion, and hydrogen peroxide damage cell membranes and DNA. Signal transduction pathways that lead to the production of proinflammatory cytokines and arachidonic acid metabolites are also activated. The result is an inflammatory response that has the clinical appearance of an exaggerated sunburn reaction.
The exception to this mechanism of drug-induced phototoxicity is psoralen-induced phototoxicity. Psoralens intercalate within DNA, forming monofunctional adducts. Exposure to UV-A radiation produces bifunctional adducts within DNA. Exactly how bifunctional adducts cause photosensitivity is unknown.
Photoallergic reactions
Photoallergic reactions are cell-mediated immune responses in which the antigen is a light-activated drug. Photoactivation results in the development of a metabolite that can bind to protein carriers in the skin to form a complete antigen. The reaction then proceeds exactly as other cell-mediated immune responses do. Specifically, Langerhans cells and other antigen-presenting cells take up the antigen and then migrate to regional lymph nodes. In those locations, the Langerhans cells present the photoallergen to T lymphocytes that express antigen-specific receptors. The T cells become activated and proliferate, and they return to the site of photoallergen deposition. In the skin, the T cells orchestrate an inflammatory response that usually has an eczematous morphology if the photoallergen is applied topically or the characteristics of a drug eruption if the photoallergen is administered systemically.
Most phototoxic reactions result from the systemic administration of drugs. Photoallergic reactions can be caused by either topical or systemic administration of the chemical. Compounds that commonly cause phototoxic and/or photoallergic reactions are listed in Table 1 in Background.
The incidence of drug-induced photosensitivity in the United States is uncertain. Phototoxic reactions are considerably more common than photoallergic reactions.
International
The incidence of drug-induced photosensitivity is unknown.
Race
The racial incidence of drug-induced photosensitivity reactions is unknown. Photosensitivity reactions can occur in races with heavily pigmented skin.
Sex
Men are more likely to have photoallergic reactions than women.
Age
Drug-induced photosensitivity reactions can occur in persons of any age.
In most patients, the prognosis is excellent once the offending agent is removed. However, complete resolution of the photosensitivity may take several weeks to months with some compounds. Occasionally, patients have persistent light reactivity for which the prospects for resolution are poor.
Drug-induced photosensitivity is associated with death only in rare individuals who are exposed to large amounts of sunlight after taking large doses of psoralens. Although mortality is rare, drug-induced photosensitivity can cause significant morbidity in some individuals, who must severely limit their exposure to natural or artificial light.
Voriconazole photosensitivity is associated with a risk of skin cancer.[26, 27] The changes that occur with long-term exposure resemble accelerated photo-aging. Acute photosensitivity occurs in 1–2% or more of patients taking voriconazole for more than 12 weeks. It appears to be UV-A induced, but it is not strictly dose-dependent. Cheilitis and facial erythema are typical initial manifestations.
Patients need to be counseled regarding the possible photosensitizing properties of both prescription and nonprescription medications. Most often, appropriate sun protection measures prevent drug-induced photosensitivity reactions.
For patient education resources, see the Burns Center, as well as Sunburn.
Patients with drug-induced photosensitivity often, but not always, note intolerance to sunlight. While most individuals can tolerate minutes or hours of sun exposure, patients with drug-induced photosensitivity exhibit skin lesions of one type or another. In most cases, a sunburn response or dermatitis occurs. Drug-induced photosensitivity reactions may result in phototoxicity, photoallergy, lichenoid reactions, subacute cutaneous lupus erythematosus (SCLE), or pseudoporphyria, as shown in the images below, respectively.
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Subacute cutaneous lupus erythematosus exacerbated by terbinafine. Courtesy of Jeffrey P. Callen.
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Pseudoporphyria.
Pseudoporphyria may occur with some medications, the most common of which is naproxen. Pseudoporphyria is characterized by a bullous reaction that clinically and histologically resembles porphyria cutanea tarda. The hypertrichosis and sclerodermoid changes typically seen in porphyria cutanea tarda are not seen in pseudoporphyria. The results of porphyrin studies are normal.
Lichenoid reactions that occur in a photodistribution are often difficult to distinguish from idiopathic lichen planus.[28] These reactions are characterized by violaceous or erythematous papules and plaques that sometimes have Wickham striae. Hydrochlorothiazide, hydroxychloroquine, and captopril are known causes of drug-induced lichenoid reactions.
Drug-induced photosensitivity reactions also may include lupuslike reactions. Drug-induced reactions usually resemble SCLE because of their scaling, annular, and psoriasiform characteristics. Hydrochlorothiazide is the drug most frequently associated with this reaction,[29] but calcium channel blockers, ACE inhibitors, griseofulvin, and terbinafine[30] are other agents that have been implicated. The rate of reaction is low for any of these agents. Hydrochlorothiazide is commonly used in many combined antihypertensive agents. Patients with drug-induced reactions commonly have anti-Ro (SS-A) antibodies.
As photodynamic therapy (PDT) becomes a more popular treatment modality for actinic keratoses and nonmelanoma skin cancer, recognition of PDT photosensitizer–induced phototoxicity is important. 5-Aminolevulinic acid or methyl 5-aminolevulinic acid is applied topically, followed by the use of a blue (410-420 nm) or red light (570-670 nm) PDT illuminator. 5-Aminolevulinic acid is a prodrug that enters the heme biosynthetic pathway and is metabolized intracellularly to form the photosensitizing molecule protoporphyrin IX (PpIX). Light activates PpIX to generate free radicals and cytotoxic reactive oxygen species that may cause destruction of malignant and nonmalignant hyperproliferative tissue. Common adverse effects include mild-to-moderate local phototoxic reactions that usually resolve in several days.
Discriminating between photosensitivity diseases and heat-related exacerbation of skin diseases may be difficult for the patient. Clarify this issue in the history. Assess symptoms of other diseases that are known to cause photosensitivity and determine if a family history of photosensitivity exists.
Establishing whether the photosensitivity can be elicited with exposure to sunlight through window glass may provide information about the wavelengths of light that cause the response. UV-B light does not penetrate window glass, whereas UV-A light and visible light do.
In most patients, the findings of the physical examination suggest a photosensitivity reaction. Specifically, inquire about intolerance to the sun. Ask patients who report photosensitivity about the medications they are taking and the products they are applying to the skin (see Table 1 in Background). Sunscreens; fragrances; and, occasionally, antibacterial soaps may cause photoallergic reactions when applied to the skin.
Both phototoxic and photoallergic reactions occur in sun-exposed areas of skin, including the face, V of the neck, and dorsa of the hands and forearms. The hair-bearing scalp, postauricular and periorbital areas, and submental portion of the chin are usually spared. A widespread eruption suggests exposure to a systemic photosensitizer, whereas a localized eruption indicates a reaction to a locally applied topical photosensitizer.
Phototoxic reactions in skin
Acute phototoxicity often begins as an exaggerated sunburn reaction with erythema and edema that occurs within minutes to hours of light exposure. Vesicles and bullae may develop with severe reactions. The lesions often heal with hyperpigmentation, which resolves in a matter of weeks to months. Chronic phototoxicity may also appear as an exaggerated sunburn reaction. However, lichenification often develops because of repeated rubbing and scratching of the photosensitive area. Thus, distinguishing phototoxic reactions from photoallergic reactions strictly based on physical appearance of the lesions may be difficult.
Other less common skin manifestations of phototoxicity include pigmentary changes. A blue-gray pigmentation is associated with several agents, including amiodarone, chlorpromazine, and some tricyclic antidepressants. Reactions to psoralen-containing botanicals (phytophotodermatitis) and drugs may resolve, with a brownish discoloration. Frequently, the pigmentary change is preceded by a typical sunburn reaction. If the reaction is not severe, some patients may not notice the erythema.
Photosensitizing drugs may also cause a lichen planus–like eruption in sun-exposed areas. Drugs likely to cause this type of reaction include demeclocycline, hydrochlorothiazide, enalapril, quinine, quinidine, chloroquine, and hydroxychloroquine.
Pseudoporphyria, which involves porphyria cutanea tarda–like changes of skin fragility and subepidermal blisters on the dorsa of hands, may occur after exposure to naproxen, nalidixic acid, tetracycline, sulfonylureas, furosemide, dapsone, amiodarone, bumetanide, and pyridoxine. Frequent use of sun-tanning beds and chronic renal failure are other predisposing factors.
Phototoxic reactions in nails
Photo-onycholysis, or separation of the distal nail plate from the nail bed, is another manifestation of phototoxicity. Photo-onycholysis has been reported with the use of many systemic medications, including tetracycline, psoralen, chloramphenicol, fluoroquinolones, oral contraceptives, quinine, voriconazole,[31] and mercaptopurine. Photo-onycholysis may be the only manifestation of phototoxicity in individuals with heavily pigmented skin.
Photoallergic reactions in skin
Photoallergic reactions typically develop in sensitized individuals 24-48 hours after exposure. The reaction usually manifests as a pruritic eczematous eruption. Erythema and vesiculation are present in the acute phase. More chronic exposure results in erythema, lichenification, and scaling. Hyperpigmentation does not occur in photoallergic reactions.
Chronic cutaneous effects of repeated phototoxic injury have been evaluated only with psoralen-containing compounds. Premature aging of the skin, lentigines, and skin cancer are common. With respect to skin cancer, increases in the incidence of squamous cell carcinoma are greater than those of basal cell carcinoma. The incidence of melanoma may also increase over time. The effects of chronic exposure to virtually all other photosensitizing compounds are unknown.
Persistent light reactivity is a form of chronic actinic dermatitis that occurs in patients with photoallergic contact dermatitis. In patients with persistent light reactivity, photosensitivity persists for months or years after the offending agent is eliminated. The disease may involve all sun-exposed areas and spread to covered areas of skin. Initially, persistent light reactivity is misdiagnosed as atopic dermatitis or a lichenoid drug reaction. The photosensitivity can be incapacitating because the patients are sensitive to light not only in the UV-A range but also in both the UV-B and visible ranges. Some patients confine themselves to darkened rooms because of their severe photosensitivity. Although systemic drugs (eg, thiazides, quinidine) have been implicated as causes of persistent light reactivity, sunscreens, halogenated salicylanilides and musk ambrette are the most frequent causes. The treatment of persistent light reactivity involves the avoidance of contact with exacerbating agents and photoallergens. Emollients, topical steroids, systemic steroids, and (at times) hydroxychloroquine. Paradoxically, psoralen UV-A (PUVA) and narrow band UV-B have been used, although relapse is common. Patients who show no signs of improvement may require the use of immunosuppressive agents (eg, azathioprine, cyclosporine).
To exclude porphyria cutanea tarda, assess urine porphyrin levels, which are elevated in porphyria cutanea tarda and within the normal range in pseudoporphyria and drug-induced photosensitivity. Determine antinuclear antibody (ANA) and anti-Ro (SS-A) antibody levels.
Photopatch testing is an important tool in the diagnosis of photoallergic contact dermatitis. Suspected photoallergens are applied to the back in 2 sets. One set is removed after 24 hours and irradiated with 5-10 J/cm2 UV-A. Both sets of patch tests are evaluated for a positive reaction after 48 hours. Erythema, edema, and/or vesiculation at an irradiated site indicate a positive reaction. A positive reaction at both sites is interpreted as an allergic contact dermatitis. A positive reaction at the unirradiated site with a stronger one at the irradiated site should be interpreted as both allergic dermatitis and photoallergic contact dermatitis reaction to the same compound.
Phototesting with UV-A; UV-B; and, sometimes, visible light is helpful in diagnosing photosensitivity disorders. This test is performed by treating small areas of skin on the back or inner aspect of the forearms with gradually increasing doses of light. The minimum dose of light required to produce uniform erythema over the entire irradiated site after 24 hours is called the minimum erythema dose (MED). Patients with phototoxic reactions have a reduced MED to UV-A or, in some instances UV-B.
In acute phototoxic reactions, necrotic keratinocytes are observed. If the reaction is severe, the necrosis is panepidermal. In addition, epidermal spongiosis with dermal edema and a mixed infiltrate consisting of lymphocytes, macrophages, and neutrophils may be present. Blue-gray pigmentation associated with phototoxic reactions results from increased melanin in the dermis or deposition of the drug or its metabolites within the skin.
The histologic features of a lichen planus–like phototoxic reaction are essentially indistinguishable from idiopathic lichen planus. However, increased amounts of spongiosis and necrotic keratinocytes may be present.
The histologic features of a subacute cutaneous lupus erythematosus (SCLE) – like reaction reveal an interface dermatitis that is indistinguishable from non–drug-induced SCLE. Like porphyria cutanea tarda, pseudoporphyria causes a subepidermal blister at the level of the lamina lucida. A characteristic feature of both pseudoporphyria and porphyria cutanea tarda is festooning, which refers to the irregular configuration of the dermal papillae in the floor of the bulla.
Photoallergic reactions are histologically similar to contact dermatitis. Epidermal spongiosis with a dermal lymphocytic infiltrate is a prominent feature. However, the presence of necrotic keratinocytes is suggestive of photoallergy rather than allergic contact dermatitis.
The mainstays of treatment of drug-induced photosensitivity include identification and avoidance of the causative agent, the use of sun protection, and the institution of measures for symptomatic relief.
Topical corticosteroids and cool compresses may alleviate drug-induced photosensitivity. The use of systemic corticosteroids should be reserved for the most severe cases.
If sunscreens are not the cause of the photosensitivity, they should be used liberally. The sun protection factor (SPF) may not be a reliable indicator of protection against drug-induced photosensitivity. The SPF refers to the degree of protection against sunlight-induced sunburn, primarily that caused by UV-B. Most drug-induced photosensitivity reactions are caused by wavelengths within the UV-A range. Therefore, sunscreens that absorb UV-A should be prescribed. Sunscreens that contain avobenzone (Parsol 1789), titanium dioxide, and zinc oxide are more effective in blocking out UV-A radiation than sunscreens that contain other ingredients.
Patients who experience drug-induced photosensitivity should identify and avoid the causative agent. Patients should use a sunscreen if it is not the offending agent. Sun protection often prevents photosensitivity reactions.
The goal of pharmacotherapy for drug-induced photosensitivity is to reduce morbidity and to prevent complications. Broad-spectrum sunscreens with coverage in the UV-A and UV-B ranges are recommended. Sunscreens containing avobenzone (Parsol 1789) absorb light in the UV-A range. Physical sunscreen agents, such as titanium dioxide and zinc oxide, have full UV spectrum protection. Note that some individuals are allergic to some chemical sunscreens that are sensitizers and may induce contact dermatitis and/or photoallergy.
Clinical Context:
Betamethasone topical is used for the treatment of inflammatory dermatoses responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.
Clinical Context:
Hydrocortisone valerate is an adrenocorticosteroid derivative suitable for application to skin or external mucous membranes. It has mineralocorticoid and glucocorticoid effects that result in anti-inflammatory activity.
Clinical Context:
Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. Potent class I and II topical steroids may be used. Less potent topical steroids such as hydrocortisone valerate, desonide, or fluticasone may be used twice a day in children to decrease risk of systemic absorption.
What is drug-induced photosensitivity?What is the pathophysiology of phototoxicity in drug-induced photosensitivity?What is the pathophysiology of photoallergic reactions in drug-induced photosensitivity?What causes drug-induced photosensitivity?What is the incidence of drug-induced photosensitivity in the US?What is the global incidence of drug-induced photosensitivity?What are the racial predilections of drug-induced photosensitivity?What are the sexual predilections in the prevalence of drug-induced photosensitivity?Which age groups have the highest risk for drug-induced photosensitivity?What is the prognosis of drug-induced photosensitivity?What should be included in patient education about drug-induced photosensitivity?Which clinical history findings are characteristic of drug-induced photosensitivity?What is the role of photodynamic therapy (PDT) in drug-induced photosensitivity?How is drug-induced photosensitivity differentiated for other conditions of photosensitivity?Where do phototoxic and photoallergic reactions typically occur in drug-induced photosensitivity?Which physical findings are characteristic of phototoxic reactions in drug-induced photosensitivity?Which physical findings are characteristic of photo-onycholysis in drug-induced photosensitivity?Which physical findings are characteristic of photoallergic reactions in drug-induced photosensitivity?What are possible complications of drug-induced photosensitivity?What are the differential diagnoses for Drug-Induced Photosensitivity?What is the role of lab testing in the diagnosis of drug-induced photosensitivity?What is the role of photopatch testing in the diagnosis of drug-induced photosensitivity?What is the role of phototesting in the diagnosis of drug-induced photosensitivity?Which histologic findings are characteristic of drug-induced photosensitivity?How is drug-induced photosensitivity treated?How is drug-induced photosensitivity prevented?What is the goal of drug treatment for drug-induced photosensitivity?Which medications in the drug class Corticosteroids are used in the treatment of Drug-Induced Photosensitivity?
Alexandra Y Zhang, MD, Staff Physician, Dermatology and Plastic Institute, Cleveland Clinic Foundation
Disclosure: Nothing to disclose.
Coauthor(s)
Craig A Elmets, MD, Professor and Chair, Department of Dermatology, Director, Chemoprevention Program Director, Comprehensive Cancer Center, UAB Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: University of Alabama at Birmingham; University of Alabama Health Services Foundation<br/>Serve(d) as a speaker or a member of a speakers bureau for: Ferndale Laboratories<br/>Received research grant from: NIH, Veterans Administration, California Grape Assn<br/>Received consulting fee from Astellas for review panel membership; Received salary from Massachusetts Medical Society for employment; Received salary from UpToDate for employment. for: Astellas.
Specialty Editors
David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic
Disclosure: Nothing to disclose.
Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine
Disclosure: Received honoraria from UpToDate for author/editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Allergen; Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.
Chief Editor
Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Abdul-Ghani Kibbi, MD, Professor and Chair, Department of Dermatology, American University of Beirut Medical Center, Lebanon
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