History

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.

Subacute cutaneous lupus erythematosus exacerbated by terbinafine. Courtesy of Jeffrey P. Callen.

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Pseudoporphyria.

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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.^[33]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,^[34]but calcium channel blockers, ACE inhibitors, griseofulvin, and terbinafine^[35]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.

Physical Examination

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,^[36] 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.

Complications

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).

Differential Diagnoses

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Phototoxic reaction.
Photoallergic reaction.
Pseudoporphyria.
Subacute cutaneous lupus erythematosus exacerbated by terbinafine. Courtesy of Jeffrey P. Callen.

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Table 1. Common Photosensitizing Medications

Class	Medication	Photo-toxic Reaction	Photo-allergic Reaction	Lichenoid Reaction	Pseudo-porphyria	Subacute Cutaneous Lupus Erythematosus
Antibiotics	Tetracyclines (doxycycline, tetracycline)	Yes	No	Yes	Yes	No
	Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin)^[10]	Yes	No	No	No	No
	Sulfonamides	Yes	No	No	No	No
Nonsteroidal anti-inflammatory drugs^[11]	Ibuprofen	Yes	No	Yes	No	No
	Ketoprofen^[12]	Yes	Yes	No	No	No
	Naproxen^[13]	Yes	No	Yes	Yes	No
	Celecoxib^[14]	No	Yes	No	Yes	No
Diuretics	Furosemide	Yes	No	No	Yes	No
	Bumetanide	No	No	No	Yes	No
	Hydro-chlorothiazide	Yes	No	No	No	Yes
Retinoid	Isotretinoin	Yes	No	No	No	No
Retinoid	Acitretin	Yes	No	No	No	No
Hypoglycemics	Sulfonylureas (glipizide, glyburide)^[10]	No	Yes	Yes	Yes	No
HMG-CoA* reductase inhibitors	Statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin)^[15]	Yes	Yes	Yes	Yes	No
Epidermal growth factor receptor inhibitors	Cetuximab, panitumumab, erlotinib, gefitinib, lapatinib, vandetanib^[16]	Yes	Yes	Yes	Yes	No
BRAF inhibitors	Vemurafenib,^{[6, 7, 8, 17]}sorafenib	Yes	No	No	No	Yes
Photodynamic therapy prophoto-sensitizers	5-Aminolevulinic acid^[18]	Yes	No	No	No	No
	Methyl-5-aminolevulinic acid	Yes	No	No	No	No
	Verteporfin^[19]	Yes	No	No	No	No
	Photofrin^[20]	Yes	No	No	No	No
Neuroleptic drugs^[21]	Phenothiazines (chlorpromazine, fluphenazine, perazine, perphenazine, thioridazine)^[22]	Yes	Yes	Yes	No	No
Neuroleptic drugs^[21]	Thioxanthenes (chlorprothixene, thiothixene)	Yes	No	No	No	No
Antifungals	Terbinafine	No	No	No	No	Yes
	Itraconazole	Yes	Yes	No	No	No
	Voriconazole^{[23, 24, 25, 26]}	Yes	No	No	Yes	No
	Griseofulvin	Yes	Yes	No	No	Yes
Other drugs	Para-aminobenzoic acid	Yes	Yes	No	No	No
	5-Fluorouracil	Yes	Yes	Yes	Yes	No
	Paclitaxel^{[11, 27]}	Yes	No	No	No	Yes
	Amiodarone	Yes	No	No	Yes	No
	Diltiazem	Yes	No	No	No	Yes
	Quinidine	Yes	Yes	Yes	No	No
	Hydroxychloroquine	No	No	Yes	No	No
	Coal tar	Yes	No	No	No	No
	Enalapril	No	No	No	No	Yes
	Dapsone	No	Yes	Yes	Yes	No
	Oral contraceptives^{[28, 29]}	No	Yes	No	Yes	No
Sunscreens^[30]	Para-aminobenzoic acid	No	Yes	No	No	No
	Cinnamates	No	Yes	No	No	No
	Benzophenones	No	Yes	No	No	No
	Salicylates	No	Yes	No	No	No
Fragrances	Musk ambrette	No	Yes	No	No	No
Fragrances	6-Methylcoumarin	No	Yes	No	No	No
*3-Hydroxy-3-methylglutaryl coenzyme A.

Table 2. Distinguishing Characteristics of Phototoxic and Photoallergic Reactions

Feature	Phototoxic Reaction	Photoallergic Reaction
Incidence	High	Low
Amount of agent required for photosensitivity	Large	Small
Onset of reaction after exposure to agent and light	Minutes to hours	24-72 hours
More than one exposure to agent required	No	Yes
Distribution	Sun-exposed skin only	Sun-exposed skin, may spread to unexposed areas
Clinical characteristics	Exaggerated sunburn	Dermatitis
Immunologically mediated	No	Yes; Type IV

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Author

Alexandra Y Zhang, MD Staff Physician, Dermatology and Plastic Institute, Cleveland Clinic Foundation

Alexandra Y Zhang, MD is a member of the following medical societies: American Academy of Dermatology, Women's Dermatologic Society, Dermatology 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

Craig A Elmets, MD is a member of the following medical societies: American Academy of Dermatology, American Association of Immunologists, American College of Physicians, American Federation for Medical Research, Society for Investigative Dermatology

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 Editor Board

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

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Military Dermatologists, Phi Beta Kappa, Texas Dermatological Society

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, American College of Rheumatology

Disclosure: Received income in an amount equal to or greater than $250 from: Biogen US (Adjudicator for study entry cutaneous lupus erythematosus); Priovant (Adjudicator for entry into a dermatomyositis study); IQVIA (Serono - adjudicator for a study of cutaneous LE) <br/>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 these trust accounts for: Stocks held in various trust accounts: Allergen; Amgen; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble;; Celgene; Gilead; CVS; Walgreens; Bristol-Myers Squibb.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Abdul-Ghani Kibbi, MD, FACP Professor and Chair, Department of Dermatology, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.