Hartnup disease

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely prescribed by primary care physicians for the past two decades. Some NSAIDs, including ibuprofen and naproxen, are available in over-the-counter preparations. With the increased use of NSAIDs, cutaneous reactions have been reported more frequently. Although reactions to NSAIDs vary widely, photosensitivity reactions are relatively common. This article reviews photosensitivity reactions and presents a case report of photosensitivity induced by the use of piroxicam (Feldene).

Definitions

PHOTOSENSITIVITY

Photosensitivity is a broad term used to describe abnormal or adverse reactions to light energy, either sunlight or filtered or artificial light at wavelengths of 280 to 400 nm. Photosensitivity includes common phototoxic responses as well as uncommon photoallergic reactions.(1) A comparison of phototoxic and photoallergic reactions is given in Table 1.

TABLE 1 Comparison of Phototoxic and Photoallergic Reactions

Reaction

Phototoxic reactions

Mechanism of action

Nonimmunologic

Rash onset after exposure

30 minutes to hours

Clinical presentation

Erythema, pain, edema

Histology

Dyskeratosis, epidermal necrosis

Treatment

Burn care

Reaction

Photoallergic reactions

Mechanism of action

Immunologic

Rash onset after exposure

1 to 14 days

Clinical presentation

Papulovesicular eruption, pruritus, eczematous dermatitis

Histology

Epidermal spongiosis, perivascular infiltrates

Treatment

Antihistamines, systemic corticosteroids

PHOTOTOXICITY

Phototoxicity is a nonimmunologic phenomenon that resembles a sunburn. It occurs when a potentiating agent of solar energy (Table 2) is taken internally or applied topically before exposure to sunlight. Thirty minutes to several hours after exposure, erythema, pain and sometimes frank blistering develop. The most important clinical clue is that these findings occur only on the areas of the skin exposed to sunlight.(2) Clinical improvement typically occurs within 48 to 96 hours. Histologically, phototoxicity is characterized by dermal edema, dyskeratosis and necrosis of the keratinocytes.(1)(3)

TABLE 2 Common Photosensitizing Agents and Reactions

NSAIDs = nonsteroidal anti-inflammatory drugs.

Adapted from The guide to drug eruptions. Norwood, N.J.: American Overseas Book Co., 1987:32. Used with permission.

PHOTOALLERGY

Photoallergy involves an immunologic mechanism and can be elicited only in a small number of persons who have been sensitized by previous exposure to the photosensitizing agent and at the same time to light. The photosensitizing agent can be a topical agent (as in photoallergic contact dermatitis) or a systemic agent (as in photoallergic dermatitis).(1)(4)(5) The presumed mechanism is that of a type IV cell-mediated hypersensitivity response, the type seen in simple contact allergic dermatitis.

The initial eruption occurs one to 14 days after the initial exposure. The eruption is a papulovesicular eczematous dermatitis occurring chiefly on the areas exposed to light. Severe photoallergic rashes, however, may extend beyond these areas. Subsequent reactions typically occur with exposure to both the photosensitizing agent and to light, but reactions also can occur with exposure to light alone in patients with persistent light reactivity.(1)(2)(6) The histopathologic findings of this type of dermatitis are similar to the histopathologic findings of contact dermatitis. Epidermal spongiosis and, occasionally, acanthosis are present. A perivascular lymphocytic infiltrate with varying numbers of eosinophils is present in the dermis.(1)(3)

Illustrative Case

A 42-year-old woman was treated with piroxicam, 20 mg daily, for foot pain. Three days after piroxicam therapy was started, a pruritic rash developed on the patient's face, arms and neck. She had no history of eczema or photosensitivity and had previously taken NSAIDs such as ibuprofen without problems. She had not used any topical medications or sunscreens and did not report recent prolonged sun exposure.

Physical examination revealed eczematous papules and plaques on the patient's face, neck and arms and in a V-shaped distribution on her upper anterior chest. In addition, multiple vesicles were present on the dorsum of her hands (Figures 1 and 2). The affected areas were typically exposed to the sun.

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The piroxicam was stopped, and the patient was treated with benadryl and a topical corticosteroid cream; she was instructed to avoid sun exposure. Eight days later, the rash on the patient's face and hands had worsened. She was then treated with prednisone, 60 mg per day, which was tapered over three weeks. Her symptoms subsequently resolved completely.

Histologic examination of a skin biopsy specimen revealed spongiosis in the epidermis and a superficial dermal perivascular lymphocytic infiltrate (Figure 3). These findings, along with the clinical clues, were consistent with a diagnosis of photoallergy.

[ILLUSTRATION OMITTED]

Discussion

PATHOPHYSIOLOGY

The mechanism of piroxicam-induced photosensitivity is controversial.(7)(8) The active agent may be piroxicam itself or metabolites produced by a photochemical reaction. Studies performed in vivo and in vitro have produced varying data and conclusions.(7)(9) Mechanisms of both photoallergic and phototoxic reactions have been supported.(6)(7)(9) A confounding factor in the studies may be the cross-reactivity of piroxicam with thimerosal (a preservative in some eyedrops and cosmetics) found on photopatch testing.(10) In one study by the American Academy of Dermatology,(11) NSAIDs were implicated in 13 percent of all adverse cutaneous reactions reported, and of NSAIDs, piroxicam caused the highest number of reactions.

DIAGNOSIS

A photosensitivity reaction should be suspected when a rash develops primarily on sun-exposed areas of the skin, specifically the face, neck, lower arms, dorsal surfaces of the hands or on the upper chest. Sharp demarcations at sleeve levels and sparing of the submental area are helpful clues. Phototoxic reactions are typically distinguished by pain, erythema and complete sparing of areas of skin kept covered.

The differential diagnosis of a photoallergic reaction includes the metabolic and idiopathic photodermatoses as well as diseases aggravated by sunlight (Table 3). Pellagra and Hartnup disease, which are characterized by a cellular deficiency of niacin, have eruptions that can be indistinguishable from a photoallergic reaction. They both, however, also have gastrointestinal and neurologic abnormalities. Hartnup disease also is distinguished by aminoaciduria and onset in childhood. Bloom syndrome, Cockayne's syndrome and Rothmund-Thomson syndrome, as well as xeroderma pigmentosum, begin in early childhood or infancy and do not abate.(2)(12)

TABLE 3 Classification of Photodermatoses

Adapted from Rook A, et al., eds. Textbook of dermatology. 4th ed. Boston: Blackwell Scientific, 1986:512-5. Used with permission.

Patients with systemic lupus erythematosus or dermatomyositis usually have fever, arthritis or weakness, as well as involvement of other organs. Rashes related to these disorders, although photodistributed, are characterized by poikiloderma (hyperpigmentation and hypopigmentation, cutaneous atrophy and telangiectasia).(12) The skin findings of the porphyrias are noninflammatory blisters and scarring. Airborne pollens or other airborne allergens such as smoke from burning poison ivy also can cause dermatitis in a photocutaneous distribution.

TREATMENT

Management of phototoxic and photoallergic conditions differs significantly. Intervention for phototoxic reactions includes routine burn care and avoidance of agents that can cause phototoxicity. Antihistamines and corticosteroids, both systemic and topical, are ineffective.(2)(13) NSAIDs can, to some degree, suppress erythema induced by ultraviolet B rays.(12)(13)

For acute photoallergic reactions, sun avoidance and discontinuation of the photosensitizing agent are often sufficient. Topical corticosteroids and antihistamines provide minimal symptomatic relief of itching. For highly symptomatic cases, prednisone, starting at 1 mg per kg per day and tapering over three weeks, is very effective. Patients who persistently react to light may require treatment with psoralen followed by ultraviolet A (PUVA) or azathioprine (Imuran). Phototesting may help these individuals avoid the wavelengths to which they are sensitive.(3)(14)(15) Sunscreens typically block ultraviolet B and, to a lesser degree, ultraviolet A. New formulations of titanium have become much more cosmetically acceptable. These agents block ultraviolet A, ultraviolet B and visible radiation. Treatments such as chloroquine, hydroxy-chloroquine and beta carotene offer little or no benefit.(12)

Final Comment

Cutaneous photosensitivity reactions must be considered when a patient presents with a rash primarily involving sun-exposed areas of the skin. Knowledge of the different mechanisms for these reactions is necessary to make the correct diagnosis and institute appropriate therapy.

The authors thank Carl Minami, CAPT, MC, USA, for supplying the photomicrograph and Jeffrey C. Kuhlman, LCDR, MC, USNR, for referring this patient to us and obtaining the clinical photographs.

REFERENCES

(1.)Epstein JH. Photoallergy. A review. Arch Dermatol 1972; 106:741-8.

(2.)Arnold HL Jr, Odom RB, James WD, eds. Diseases of the skin: clinical dermatology. 8th ed. Philadelphia: Saunders, 1990:34-8.

(3.)Halasz CL. Photosensitivity to the nonsteroidal anti-inflammatory drug piroxicam. Cutis 1987; 39:37-9.

(4.)DeLeo VA, Suarez SM, Maso MJ. Photoallergic contact dermatitis. Results of photopatch testing in New York, 1985 to 1990. Arch Dermatol 1992; 128:1513-8.

(5.)Toback AC, Anders JE. Phototoxicity from systemic agents. Dermatol Clin 1986; 4(2):223-30.

(6.)Kaidbey KH, Messenger JL. The clinical spectrum of the persistent light reactor. Arch Dermatol 1984; 120:1441-8.

(7.)Kochevar IE, Morison WL, Lamm JL, McAuliffe DJ, Western A, Hood AF. Possible mechanism of piroxicam-induced photosensitivity. Arch Dermatol 1986; 122:1283-7.

(8.)Serrano G, Fortea JM, Latasa JM, SanMartin O, Bonillo J, Miranda MA. Oxicam-induced photosensitivity. Patch and photopatch testing studies with tenoxicam and piroxicam photoproducts in normal subjects and in piroxicam-droxicam photosensitive patients. J Am Acad Dermatol 1992; 26:545-8.

(9.)Serrano G, Bonillo J, Aliaga A, Gargallo E, Pelufo C. Piroxicam-induced photosensitivity. In vivo and in vitro studies of its photosensitizing potential. J Am Acad Dermatol 1984; 11:113-20.

(10.)McKerrow KJ, Greig DE. Piroxicam-induced photosensitive dermatitis. J Am Acad Dermatol 1986; 15:1237-41.

(11.)Stern RS, Bigby M. An expanded profile of cutaneous reactions to nonsteroidal anti-inflammatory drugs. Reports to a specialty-based system for spontaneous reporting of adverse reactions to drugs. JAMA 1984; 252:1433-7.

(12.)Rook A, et al., eds. Textbook of dermatology. 4th ed. Boston: Blackwell Scientific, 1986:512-5.

(13.)Greenwald JS, Parrish JA, Jaenicke KF, Anderson RR. Failure of systemically administered corticosteroids to suppress UVB-induced delayed erythema. J Am Acad Dermatol 1981; 5:197-202.

(14.)Yokel BK, Hood AF, Morison WL. Management of chronic photosensitive eczema. Arch Dermatol 1990; 126:1283-5.

(15.)Lim HW, Buchness MR, Ashinoff R, Soter NA. Chronic actinic dermatitis. Study of the spectrum of chronic photosensitivity in 12 patients. Arch Dermatol 1990; 126:317-23.

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