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P&S Medical Review: Nov 1993, Vol.1, No.1
Cutaneous Drug Eruptions
Nicholas A. Orfan, M.D. and William W. Stocker, M.D.
Divisions of Allergy & Immunology and Dermatology
The Mary Imogene Bassett Hospital, Cooperstown, NY
CUTANEOUS drug eruptions are the most frequent type of adverse drug reactions and the overwhelming majority of these reactions are thought to be allergic in origin. The Boston Collaborative Drug Surveillance Program revealed data indicating that 2 to 3 percent of medical inpatients experience cutaneous eruptions to prescribed medications.[1] These figures would probably be comparable in an outpatient population. Categories of drugs most commonly implicated are antimicrobial agents, non-steroidal anti-inflammatory drugs and anticonvulsants.[2] However, all drugs are suspect in the setting of cutaneous eruptions. Early recognition and management of drug related cutaneous reactions are important to prevent serious sequelae of drug hypersensitivity.
Morbilliform rash is the most common cutaneous drug eruption, and is characterized by a measles-like viral exanthem. Morbilliform reactions usually start in dependent areas and then become generalized. They usually begin 2 to 10 days after initiation of the drug, but can occur up to 14 days after a drug is stopped. The immunologic mechanism involved in this type of rash is not known. Morbilliform rash is frequently related to antimicrobial therapy. For example, morbilliform rash is seen with high frequency in patients with Epstein-Barr virus or cytomegalovirus mononucleosis treated with ampicillin and in patients with human immunodeficiency virus (HIV) infection who are treated with sulfa drugs.[3] Sometimes a fever, leukemoid reaction, interstitial nephritis, or elevation of serum transaminase indicative of hepatocellular inflammation may accompany this type of rash. Treatment includes discontinuation of the suspected agent, topical or systemic antipruritic therapy, and a two week course of systemic corticosteroid therapy if the reaction is severe. Most morbilliform rashes resolve with some degree of superficial skin desquamation.
Urticaria, which may be associated with angioedema, can occur as a result of drug therapy and will present as evanescent, raised, red, pruritic, well demarcated lesions which disappear without residual scarring or hyperpigmentation. Urticaria related to drugs may occur due to type I IgE-mediated reactions or type III (serum-sickness) immune complex reactions with complement activation and production of anaphylatoxins (c3a, c5a).[4] Urticaria due to a type I reaction may be accompanied by anaphylactic signs and symptoms including wheezing, gastrointestinal cramping, and hypotension. Urticaria due to type III reactions may be accompanied by serum sickness including fever, arthritis, nephritis, and lymphadenopathy. Urticaria may also result from sensitivity to aspirin and other non-steroidal anti-inflammatory agents due to unclear mechanisms.[5] Certain agents such as opiates or radiocontrast media may have direct effects on mast cell membranes inducing degranulation with release of mast cell mediators such as histamine which result in urticaria. Treatment of urticarial drug reactions includes cessation of the offending drug, institution of systemic antihistamine therapy, and the use of corticosteroids if urticaria is severe and unresponsive to antihistamines or if signs of serum sickness are present.
Erythema multiforme minor is a cutaneous eruption which may initially resemble urticaria. The lesions are red, raised, well demarcated plaques which will persist for several days to weeks. The plaques often develop a dusky center producing the classic `target' lesion. Palms, soles, and extensor surfaces are usually involved. Bullae may develop. Erythema multiforme has commonly been attributed to drug therapy with sulfa agents, anticonvulsants such as phenytoin, and non-steroidal anti-inflammatory agents.[6] When erythema multiforme is severe, extensive, and accompanied by mucosal inflammation and sloughing in a toxic appearing patient with a high fever, a diagnosis of Stevens-Johnson syndrome (erythema multiforme major) is made. Stevens-Johnson syndrome is a potentially life threatening condition in which patients may suffer complications similar to those seen in burn patients. Therapy must be supportive including good hydration and local skin, mucosal, and ophthalmic care. The use of corticosteroids in the treatment of Stevens-Johnson syndrome is still debated. A retrospective study in a pediatric population showed no survival benefit from corticosteroid therapy,[7] but a recent retrospective review of corticosteroid treatment in early Stevens-Johnson syndrome demonstrated zero mortality.8 The underlying immunologic mechanism responsible for erythema multiforme and Stevens-Johnson syndrome is not understood but does not appear to be an immune complex mechanism.
Toxic epidermal necrolysis (TEN) shares certain features with Stevens-Johnson syndrome such as the types of causative drugs, fever, mucosal membrane involvement and full thickness epidermal sloughing.[9] TEN may be considered an extreme form of Stevens- Johnson characterized by the acute onset of a diffuse erythroderma (usually within 48 hours of starting a drug) with the subsequent development of vesicles that coalesce to form large bullae. These bullae will then rupture and skin will tend to peel off in sheets leaving large denuded areas. TEN is associated with a poorer prognosis than Stevens-Johnson syndrome (especially in older patients) with about a 30 percent mortality. Ideally, TEN should be treated in a burn unit.
Leukocytoclastic vasculitis (LV) is a hypersensitivity reaction characterized by neutrophilic inflammation of blood vessels in the skin. Sometimes, a specific drug can be implicated as the causative agent. Drugs most commonly implicated include antibiotics, diuretics, and anticonvulsants. Leukocytoclastic vasculitis may be associated with systemic disease such as connective tissue diseases, systemic vasculitis, cryoglobulinemia, or certain infections such as hepatitis B virus[10] and appropriate evaluation should be undertaken to rule out these entities. Leukocytoclastic vasculitis is sometimes part of the clinical picture seen with drug-induced serum sickness. The most common presentation of this cutaneous hypersensitivity response is palpable purpura of dependent areas, but nodules, ulcers and urticaria may also be seen in cutaneous vasculitis. Skin biopsies are essential to confirm the diagnosis and will reveal neutrophilic infiltration with necrosis of blood vessel walls and nuclear `dust.' There is good evidence that leukocytoclastic vasculitis is caused by immune complex deposition in the small vessels of the skin. Biopsy specimens can be tested for the presence of immunoglobulin and complement. Treatment of this drug related cutaneous eruption includes removing the offending drug, keeping the legs in a non-dependent position, and potent topical corticosteroids. Most patients with LV do not seem to benefit from antihistamine therapy. Cases of LV often resolve without additional therapy. For severe cutaneous disease or systemic involvement, systemic corticosteroid therapy is indicated and should be tapered gradually over weeks.
Allergic contact dermatitis may be seen with various topical therapeutic agents including neomycin, benzocaine and diphenhydramine.[11] The skin eruption seen is characterized by asymmetrically distributed, erythematous, pruritic papules and vesicles (acute eczematous dermatitis). The skin reaction appears in 24 to 72 hours after exposure in previously sensitized patients. Allergic contact dermatitis to topical medication is a type IV, T cell mediated response also known as delayed type hypersensitivity. The offending drug may be identified by clinical history but patch testing is required to identify the antigen. For example, ethylene diamine is a stabilizer present in various topical agents. Allergic contact sensitivity to ethylene diamine can be established by patch testing and the allergic patient should be educated to avoid further contact with this agent. Allergic contact dermatitis must be distinguished from non-immunologic irritant dermatitis which may be seen with repeated exposure to solvents or detergents.
Systemic administration of agents identical to or cross- allergenic with topical agents to which the patient has been previously sensitized may induce a generalized systemic contact dermatitis manifesting as a flare of previously involved skin or as a generalized skin eruption.[12] For example, a patient sensitized to topical diphenhydramine may develop a rash after receiving diphenhydramine orally or intravenously. Similarly, a patient sensitized to topical neomycin may experience a systemic skin eruption when receiving intravenous gentamicin, a cross- allergenic aminoglycoside. The skin eruption is usually papular or vesicular but may be urticarial or erythema multiforme-like. The mechanism of these systemic reactions is not clear.
When allergic contact dermatitis to a therapeutic agent occurs, discontinuation of the offending drug is frequently not enough to prevent a prolonged rash (3 to 4 weeks) which may continue to worsen before improving. In order to modify the course of this cutaneous eruption, suppression of delayed type hypersensitivity is needed and must be continued for a period of at least two weeks. Topical versus systemic glucocorticoid therapy may be chosen depending on the distribution and severity of the rash.
A less common type of drug induced cutaneous eruption is the fixed drug eruption.[13] A solitary erythematous macule will appear during treatment with agents such as tetracycline, phenophthalein (laxative), or non-steroidal anti-inflammatory agents as well as other drugs. The macule is pruritic and will evolve into a raised plaque or even a blister. Plaques are usually 2 to 4 cm in diameter. Skin biopsy is helpful in making the diagnosis. Lesions occur in descending order of frequency on the oral or genital mucosa, the face, and the extremities. After withdrawal of the drug, the lesion resolves leaving a hyperpigmented area of skin. If the drug is reintroduced the fixed drug eruption will recur at the same location. The mechanism of fixed drug eruption is not known. Topical corticosteroids may render the eruption somewhat less intense and speed resolution after discontinuation of the initiating drug.
Certain cutaneous drug eruptions occurring only on sun exposed skin are called photosensitive drug reactions. Depending on the type of photosensitizing drug, either a phototoxic or a photoallergic rash will occur.[14] A phototoxic drug reaction (seen with sulfonamides, tetracyclines, and psoralens) involves absorption of ultraviolet radiation and the release of energy causing damage to epidermal cells. Clinically, this usually manifests as an exaggerated sunburn but almost any morphology can occur including bullous eruptions and hyperpigmentation.
A photoallergic drug reaction (seen with griseofulvin, thiazides, and chlorpromazine) occurs when ultraviolet energy causes the drug hapten to bind to native protein on epidermal cells, thereby creating a complete antigen that sensitizes nearby lymphocytes. This manifests as a pruritic eczematous eruption on sun exposed areas. After cessation of the drug, re-exposure to sunlight may cause a recurrence of the rash in the case of photoallergic but not phototoxic cutaneous eruptions.
When patients experience drug-induced cutaneous eruptions every effort should be made to determine, either by clinical assessment or histopathology, the immunopathologic mechanism involved. In certain types of cutaneous eruptions immune mechanisms remain obscure. Clear documentation in the medical record will help ensure that other caretakers prescribing medications will be aware of the patient's hypersensitivity to a particular drug. Alternative medications with adequate therapeutic effect and no cross- allergenicity with the offending drug must be sought. In patients with a history of Stevens-Johnson syndrome, TEN, or other potentially fatal skin eruptions for which no effective desensitization or premedication is available, rechallenge with the responsible drug should never be attempted. A single dose of the drug may cause a fatal recurrence. For patients requiring a particular medication which previously caused severe urticaria and angioedema characteristic of an anaphylactic response, rechallenge may be attempted. This can be accomplished either with the use of prophylactic medication as with radiocontrast media or by desensitization as with insulin or beta-lactam antibiotics.[15] Desensitization in the case of beta-lactam antibiotics may be performed by an oral or parenteral route and published protocols exist for both.[15] Patients with a prior history of drug-induced morbilliform rash with or without fever have been successfully rechallenged with the offending drug, usually by graded oral challenge. Generally, the more gradual the rechallenge dose schedule, the greater the chance of success. Rechallenge in this setting is appropriate if the patient will derive clear therapeutic benefit from a drug for which there is no substitute. Close monitoring is obviously vital during such a rechallenge procedure.
In certain clinical situations, cutaneous drug eruptions may develop when continued therapy with the responsible drug is essential to the welfare of the patient. As long as the cutaneous drug eruption itself is not life-threatening, the clinician may choose to `treat through the rash,' sometimes by adding medications that suppress the hypersensitivity response. For example, in a patient being treated with penicillin for pneumococcal meningitis who develops urticaria after two days of therapy with no overt sign of anaphylaxis, an antihistamine may be prescribed and penicillin therapy continued. Often, the urticaria will subside. An HIV- infected patient being treated with sulfadiazine for central nervous system toxoplasmosis who develops a morbilliform rash may be treated with moderate dose prednisone to suppress a hypersensitivity response to the sulfa agent until the treatment course is complete.[16] The prednisone is then gradually tapered over 2 to 3 weeks.
Cutaneous drug eruptions vary in their appearance, rapidity of onset, severity, potential sequelae, and underlying immunopathologic mechanism. Certain classes of drugs such as antibiotics and anticonvulsants are most often implicated. Characteristic types of cutaneous eruptions (e.g., fixed drug eruption, photoallergic reaction) are associated with specific drugs. The clinician must bear in mind, however, that any drug can cause any reaction. When a cutaneous drug eruption is suspected, the causative drug must be identified and withdrawn. Depending on the nature of the drug eruption, symptomatic treatment may be accompanied by local skin care and, if indicated, immunomodulating therapy with corticosteroids to reduce the severity of the skin reaction and ameliorate the clinical course. In rare instances in which therapy is deemed essential and no alternative therapeutic agent is available, an offending drug may be continued or reintroduced using previously published protocols.
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Gordin FM, Simon GL, Wofsy CB, et al. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1984;100:495-9.
Kaplan AP. Urticaria and angioedema. In: Middleton E, Reed CE, Ellis EF, et al., eds. Allergy: Principles and Practice. 4th ed. St. Louis: Mosby, 1993:1553-80.
Stevenson DD. Diagnosis, prevention, and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol 1984;74:617-22.
Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: A critical reveiw of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol 1983;8:763-75.
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Fritsch PO, Elias PM. Erythema multiforme and toxic epidermal necrolysis. In: Fitzpatrick TB, Eisen ZA, Wolff K, et al., eds. Dermatology in General Medicine. 4th ed. New York: McGraw-Hill, 1993:596-8.
Leavitt RY. Cutaneous vasculitis. In: Lichtenstein, Fauci, eds. Current Therapy in Allergy, Immunology and Rheumatology. 4th ed. St. Louis: Mosby, 1992:216-7.
Storrs FJ. Contact dermatitis caused by drugs. Immunology and Allergy Clinics of North America 1991;11:509-23.
Menne T, Veien NK, Maibach HI. Systemic contact-type dermatitis due to drugs. Seminars in Dermatology 1989;8:144-8.
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Harber LC, Baer RL. Pathogenic mechanisms of drug-induced photosensitivity. J Invest Dermatol 1972;58:327-42.
Patterson R, DeSwarte RD, Greenberger PA, Grammer LC. Drug allergy and protocols for management of drug allergies. N Engl Reg Allergy Proc 1986;7:325-42.
Greenberger PA, Patterson R. Management of drug allergy in patients with acquired immunodeficiency syndrome. J Allergy Clin Immunol 1987;79:484-8.