When patients present with dermatologic disorders, a standard approach to assessment should be used. This is especially important for pharmacists, who must decide whether to recommend nonprescription therapies or refer patients to medical practitioners, and to nurse practitioners and physician assistants, who must evaluate symptoms and decide whether a supervising physician or dermatologist should be involved.
Patient History: Questions to Ask
With all skin conditions, including possible drug-induced reactions, a comprehensive patient history is important. These include questioning and physically assessing the patient to obtain the following information:
Signs and Symptoms
Onset. When did the lesions first appear? It is important to distinguish between an acute and a chronic condition.
Progression. Are the lesions improving or worsening or spreading? If lesions are worsening, how quickly are the lesions becoming more severe or widespread?
Timeframe. Did the occurrence of skin lesions correlate temporally with the use of any medications? This may help to distinguish between a drug-induced condition and a disease-related condition.
Location(s) and description of the lesions. Specific details about where the lesions occur and what they look like will help to identify the type of skin condition. For example, plaque psoriasis is usually diagnosed in this manner and not through laboratory means. However, for conditions such as skin cancers,4 a skin biopsy may be needed to establish a definitive histopathologic diagnosis.
Presenting symptoms. Is there pruritus? Are the lesions painful? Pruritus is a common symptom for various skin conditions (e.g., atopic dermatitis, allergic and irritant contact dermatitis, psoriasis, bullous pemphigoid, lichen planus, pityriasis rosea) as well as systemic conditions (e.g., chronic renal failure, hepatobiliary diseases, malignancy, parasitosis) and drug reactions.5
Previous occurrence. Has the patient presented with similar lesions before? If so, that may be extremely helpful in establishing a diagnosis and deciding on a course of treatment.
Severity, area, and extent of skin involvement. If a large area of the body is involved or if signs of severe disease such as skin sloughing or hives (and in some cases, if the face is involved) are present, more urgent treatment may be required, and an immediate referral to a physician would be appropriate if the patient was first seen by another health professional such as a pharmacist. In some cases, a dermatology consult or an emergency hospital admission would be needed.
Signs of a systemic or generalized reaction or disease condition. Is there a fever? If there is any indication that the patient has a systemic disease condition, whether drug induced or disease related, and particularly if the patient is febrile, this generally indicates a more urgent situation requiring immediate medical attention. For example, erythrodermic psoriasis is distinguishable from plaque psoriasis and would require immediate medical care. (See Chap. 78 for details about psoriasis.)
Is the patient using any medication that could potentially cause the observed skin condition? Temporal correlation with medication use is important in evaluating for a potential drug-induced skin reaction. Although possible, drug-induced skin reactions do not generally begin after the offending agent has already been discontinued. However, for some medications it is possible for the patient to have used the offending drug for months to years before a skin reaction occurs.
If the patient had presented with similar skin lesions previously, was the patient taking the same or similar medication(s) at that time? If so, did the skin lesions improve after drug discontinuation?
Is this a disease-related problem, a drug-induced problem, or a food allergy? What other possible diseases or conditions might present in this manner? It is not possible to provide a thorough discussion about differential diagnoses of skin lesions in this chapter. The reader should be aware that there are differential diagnoses for each type of skin lesion. For example, besides drugs (e.g., antimalarials, cyclophosphamide, clofazimine, busulfan, 5-fluorouracil), other causes of hyperpigmentation include Wilson’s disease, malabsorption syndromes, lymphomas, porphyria cutanea tarda, neurofibromatosis, Albright’s syndrome, physical trauma, and others.6 Besides drugs (e.g., aspirin, nonsteroidal antiinflammatory drugs [NSAIDs], penicillins, sulfonamides, opiates), other causes of urticaria include infection (viral, bacterial, fungal, parasitic), insect stings, foods and food additives, cold, pressure, dermatographism, cholinergic stimulation (exercise, hot shower, emotional stress), hereditary C1 inhibitor deficiency, and others.7
As discussed briefly in the following section, the appearance of skin lesions can give some clues as to their causes. Lesions may be categorized as macules (eFig. 23-1), papules (eFig. 23-2), nodules (eFig. 23-3), blisters (eFig. 23-4), or plaque and lichenification (eFig. 23-5).
Macules are circumscribed, flat lesions of any shape or size that differ from surrounding skin because of their color. A. Macules may be the result of hyperpigmentation (a), hypopigmentation, dermal pigmentation (b), vascular abnormalities, capillary dilation (erythema) (c), or purpura (d). B. The clinical appearance of a drug reaction that has produced an eruption consisting of multiple, well-defined red macules of varying size that blanch upon pressure (diascopy) and are thus a result of inflammatory vasodilation. (Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)
Papules are small, solid, elevated lesions that are usually less than 1 cm in diameter. The major portion of a papule projects above the plane of the surrounding skin. A. Papules may result, for example, from metabolic deposits in the dermis (a), from localized dermal cellular infiltrates (b), and from localized hyperplasia of cellular elements in the dermis and epidermis (c). Papules with scaling are referred to as papulosquamous lesions, as in psoriasis (see Chap. 78). B. Clinical examples of papules. The examples are two well-defined and dome-shaped papules of firm consistency and brownish color, which are dermal melanocytic nevi. C. Multiple, well-defined and coalescing papules of varying size are seen. Their violaceous color, glistening surface, and flat tops are characteristic of lichen planus. (Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)
Nodules are palpable, solid, round, or ellipsoidal lesions. Depth of involvement or substantive palpability, rather than diameter, differentiates a nodule from a papule. A. Nodules may extend into the dermis or subcutaneous tissue (a) or be located in the epidermis (b). B. A well-defined, firm nodule with a smooth and glistening surface through which telangiectasia (dilated capillaries) can be seen; there is central crusting indicating tissue breakdown and thus incipient ulceration (nodular basal cell carcinoma). C. Multiple nodules of varying size can be seen (melanoma metastases). (Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)
Vesicles and bullae are the technical terms for blisters. Whereas vesicles are circumscribed lesions that contain fluids, bullae are vesicles that are larger than 0.5 cm in diameter. A. Whereas subcorneal vesicles (a) result from fluid accumulation just below the stratum corneum, spongiotic vesicles (b) result from intercellular edema. B. Multiple translucent subcorneal vesicles are extremely fragile, collapse easily, and thus lead to crusting (arrows). These lesions are staphylococcal impetigo. (Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)
A. Plaque is a mesa-like elevation that occupies a relatively large surface area relative to its height above the skin surface. B. Well-defined, reddish, scaling plaques can coalesce to cover large areas of the back and buttocks, with some regression in the center as is common in psoriasis (see Chap. 78). C. Lichenification, a thickening of the skin and accentuation of skin, can result from repeated rubbing. It develops frequently in patients with atopy and occurs in eczematous dermatitis and other conditions associated with pruritus. Lesions of lichenification are not as well defined as most plaques and often show signs of scratching, such as in excoriations and crusts. (Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18, and Garg Amit, Levin Nikki A, Bernhard Jeffrey D. Structure of Skin Lesions and Fundamentals of Clinical Diagnosis. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest B, Paller AS, Leffell DJ, eds. Fitzpatrick’s Dermatology in General Medicine, 7th ed.).
However, some skin conditions may cause more than one type of lesion. For example, patients with acne vulgaris may present with macules, papules, nodules, or a combination of these. Another example is psoriasis—the most common type is plaque psoriasis noted by discrete, well-defined plaques; however, there are other types of psoriasis such as guttate or erythrodermic with varying lesions. Wheals developing as a result of a drug reaction may present as papules or plaques. In contrast, some skin conditions present with a characteristic lesion. For example, lichenification is a thickening of the skin usually caused by chronic rubbing or scratching and can be seen in patients with chronic pruritus or atopic dermatitis.
Drug-Induced Skin Reactions
Drug-induced skin reactions can be irritant or allergic in origin.
Irritant reactions are localized. Examples include chemical vaginitis, such as those resulting from vaginal douches, spermicides, and imidazoles; and vesication, produced by drug extravasation, as with agents such as anthracyclines.
Allergic reactions depend on inducing an immune response from the host; thus, the reaction may be systemic rather than limited to skin manifestations.
Allergic drug reactions can be classified as exanthematous, urticarial, blistering, or pustular eruptions (eFig. 23-6).8 Skin reactions accompanied by fever are generally more serious systemic disorders. These may be life threatening in some cases, although afebrile skin reactions are not always minor (e.g., urticaria, angioedema).
Types of cutaneous drug eruptions. (SJS, Stevens-Johnson’s syndrome; TEN, toxic epidermal necrolysis; AGEP, acute generalized exanthematous pustulosis.) (Adapted from Knowles S. Drug-induced skin reactions. In: Patient Self-Care (PSC). Ontario, Canada: Canadian Pharmacists Association, 2002.)
Maculopapular skin reaction is an afebrile exanthematous eruption that is considered the most commonly encountered allergic skin reaction. Signs and symptoms of a maculopapular skin rash include erythematous macules and papules that may be pruritic. No fever, blisters, or pustules are present. The lesions usually begin within 7 to 10 days after starting the offending medication and generally resolve within 7 to 14 days after drug discontinuation. However, in a previously sensitized patient, the onset may be earlier (within 2–3 days). The lesions may spread and become confluent. Usual drug culprits include penicillins, cephalosporins, sulfonamides, and some anticonvulsant medications.
Drug hypersensitivity syndrome is an exanthematous eruption accompanied by fever, lymphadenopathy, and multiorgan involvement (including the kidneys, liver, lung, bone marrow, heart, and brain). Signs and symptoms usually begin 1 to 4 weeks after starting the offending drug, and the reaction may be fatal if not promptly treated.
This condition is also known as drug reaction with eosinophilia and systemic symptoms. It is commonly referred to by the acronym DRESS.
Usual drug culprits include allopurinol, sulfonamides, some anticonvulsants (barbiturates, phenytoin, carbamazepine, lamotrigine), and dapsone. For patients taking allopurinol, several factors increase the risk of serious skin reactions: renal impairment, hypertension, and use of thiazide diuretics or excessive allopurinol doses (i.e., not dose adjusted for renal impairment).9,10
Urticaria and angioedema are simple eruptions that are caused by drugs in about 5% to 10% of cases. Other causes include foods (likely the most significant offenders) and physical factors such as cold or pressure, infections, and exposure to latex. The condition may also be idiopathic.
Urticaria has been called the cutaneous manifestation of anaphylaxis. It is an IgE-related (type 1) allergic reaction that may be the first symptom of an emerging anaphylactic reaction. It is characterized by hives, extremely pruritic red raised wheals; angioedema; and mucous membrane swelling. These symptoms typically occur within minutes (anaphylactic) to hours (anaphylactoid) (eFig. 23-7). Individual lesions typically last less than 24 hours, but new lesions may continually develop. Offending drugs include penicillins and related antibiotics, aspirin, sulfonamides, x-ray contrast media, opiates, and others. Latex allergy is linked to the natural rubber latex (NRL) proteins, which bind with human IgE and result in contact urticaria, asthma, and anaphylaxis.11 Aside from latex gloves and medical products, other sources of NRL proteins include rubber insoles of shoes, balloons, inflatable mattresses, and poinsettia plants.
A. Wheals are rounded or flat-topped papules or plaques that are characteristically evanescent, disappearing within hours. An eruption consisting of wheals is termed urticaria and usually itches. B. Wheals may be tiny papules 3 to 4 mm in diameter, as in cholinergic urticaria. C. Alternatively, wheals may present as large, coalescing plaques, as in allergic reactions to penicillin or other drugs or alimentary allergens. (Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)
Serum sickness–like reactions are complex urticarial eruptions presenting with fever, rash (usually urticarial), and arthralgias, usually within 1 to 3 weeks after starting the offending drug. This is not a true serum sickness, and the patient does not have immune complex formation, vasculitis, or renal lesions.8
Fixed drug eruptions are simple eruptions presenting as pruritic, red, raised lesions that may blister. Symptoms can include burning or stinging. Lesions may evolve into plaques.8 These so-called “fixed” drug eruptions recur in the same area each time the offending drug is given. Lesions appear within minutes to days and disappear within days, leaving hyperpigmented skin for months (eFig. 23-8). Usual drug culprits include tetracyclines, barbiturates, sulfonamides, codeine, phenolphthalein, acetaminophen, and NSAIDs.
Hyperpigmentation. This patient exhibits a striking amiodarone-induced, slate-gray pigmentation of the face. The blue color (ceruloderma) is caused by deposition of a brown pigment in the dermis contained in macrophages and endothelial cells. (Reprinted with permission from Ortonne J-P, Bahadoran P, Fitzpatrick TB, et al. Hypomelanoses and hypermelanoses. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:876.)
Stevens-Johnson’s syndrome (SJS) and toxic epidermal necrolysis (TEN) are complex blistering eruptions that, together with erythema multiforme (EM), are known as acute bullous disorders. They are histologically similar and have been considered part of an “EM spectrum of diseases.”12 EM may be considered a dermatologic disorder not associated with a drug reaction, whereas SJS and TEN are immune complex or cell-mediated allergic responses to offending agents, including drugs.12,13 Because of their histologic similarity, SJS and TEN have been considered either distinct disorders or progressions of the same disorder based on the percentage of skin area involved, and these two entities are often discussed together.12
SJS and TEN are rare, severe, and life-threatening conditions with an acute onset (within 7–14 days of drug exposure). Patients present with generalized tender or painful bullous formation with accompanying systemic signs and symptoms, including fever, headache, and respiratory symptoms, that rapidly deteriorate. Lesions show rapid confluence and spread, resulting in extensive epidermal detachment and sloughing.12 This may result in marked loss of fluids; drop in blood pressure; electrolyte imbalances; and secondary infections, including Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus (MRSA). Usual drug culprits include sulfonamides, penicillins, some anticonvulsants (hydantoins, carbamazepine, barbiturates, lamotrigine), NSAIDs, and allopurinol. In children, a pooled analysis using data from two multicenter international case–control studies confirmed the following drug risk factors for SJS and TEN: antiinfective sulfonamides, phenobarbital, carbamazepine, and lamotrigine. In addition, acetaminophen use is suspected to increase the risk.13 However, cases in children only represented 10% of the population in both studies because the incidence of SJS and TEN increases with age.13
Acneiform drug reactions are simple pustular eruptions caused by medications that induce acne (whiteheads or blackheads). The onset is usually about 1 to 3 weeks. Common drug culprits include corticosteroids, androgenic hormones, some anticonvulsants, isoniazid, and lithium. Topical acne treatments can be used to manage symptoms if the offending drug cannot be discontinued or replaced.
Acute generalized exanthematous pustulosis (AGEP) is a complex pustular eruption characterized by acute onset (within days after starting the offending drug), fever, diffuse erythema, and many pustules. About 50% of patients have other cutaneous lesions, and 25% may have mucosal erosions. Generalized desquamation occurs 2 weeks later.8 Usual drug culprits include β-lactam antibiotics, macrolides, and calcium channel blockers.
Other Drug-Induced Skin Reactions
Hyperpigmentation of the skin (eFig. 23-8) may be related to increased melanin (e.g., hydantoins), direct deposition (e.g., silver, mercury, tetracyclines, antimalarials), or other mechanisms (some cytotoxic drugs, such as 5-fluorouracil, may cause banding on nails or tracking along veins).
Photosensitivity reactions (eFig. 23-9) may be phototoxic or photoallergic. Drugs that induce phototoxic reactions absorb UVA light, resulting in skin damage. Severity tends to be proportional to the drug dose. Usual drug culprits include amiodarone, tetracyclines, sulfonamides, psoralens, and coal tar.
Photosensitivity. Severe solar damage of the face revealing both telangiectasias and actinic keratoses at different stages in development, including flat, pink macules and hyperkeratotic papules. (Reprinted with permission from Duncan KO, Leffell DJ. Epithelial precancerous lesions. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:722.)
Drug-induced photoallergic reactions result from UVA transformation of medications into allergens. In this syndrome, skin damage may occasionally spread beyond sun-exposed skin. These reactions require sensitization to the offending drug and are not dose related. Usual drug culprits include sulfonamides, sulfonylureas, thiazides, NSAIDs, chloroquine, and carbamazepine.
Management and Prevention of a Drug-Induced Skin Reaction
The first rule of thumb in managing skin reactions is to remember that not all are drug induced. In clinical practice, a diagnosis of drug-induced skin reaction is often a diagnosis of exclusion (i.e., the diagnosis is reached after other possible diagnoses have been ruled out). Potential foods and other causes have to be thoroughly investigated, and a detailed patient interview is important, as discussed earlier. Consistent with the assessment for any adverse drug reaction, the likelihood of a drug-induced skin reaction should be categorized as probable, possible, or not probable (unlikely). It may not be possible to categorize a drug-induced skin reaction as definite because this requires rechallenge with the potentially offending agent, and this should not be done with most reactions. Reactions are often unpredictable adverse drug reactions unrelated to the normal pharmacologic effects of the drug. Fortunately, unpredictable adverse drug reactions (e.g., allergic, idiosyncratic, carcinogenic) usually affect only a small percentage of patients.
If a drug-induced skin reaction is suspected, the most important treatment in nearly all cases is discontinuing the suspected drug as quickly as possible and avoiding the use of potential cross-sensitizers. In most instances, that is the only specific treatment required. In severe cases, a short course of systemic corticosteroids may be needed. In a few instances, it may be possible to continue the offending drug and “treat through” the reaction8 (e.g., ampicillin-associated maculopapular skin rash).
The next step is to control symptoms associated with the drug reaction (e.g., pruritus). Furthermore, any signs or symptoms of a systemic or generalized reaction may require additional supportive therapies specific to the severity and type of signs and symptoms seen. For high fevers, an antipyretic such as acetaminophen is more appropriate than aspirin or an NSAID because these may exacerbate skin lesions for some reactions. Depending on the type of skin reaction, the affected skin condition may take days to weeks or months to resolve.
For patients with life-threatening SJS or TEN, supportive measures such as maintenance of adequate blood pressure and fluid and electrolyte balance, use of broad-spectrum antibiotics and vancomycin for secondary infections, and IV immunoglobulin (IVIG) may all be appropriate. IVIG has been shown to halt disease progression and enhance recovery for SJS or TEN.12 The use of corticosteroids for SJS or TEN is somewhat controversial; although they may curb disease progression, they may also increase the risk of infection and thus contribute to increased mortality.12 If used, relatively high initial doses followed by rapid tapering as soon as disease progression halts is indicated.12 Refer to the Drug-Induced Skin Reactions case in the Pharmacotherapy Casebook to further explore management.
Patient education should be provided. Advice to the patient should include information about the suspected drug and potential drugs to avoid in the future and which drugs may be used. Potential cross-sensitizers should be identified. For patients with photosensitivity reactions, information should be provided about preventive measures such as the use of sunscreens and sun avoidance (eFig. 23-9). For patients with severe reactions (e.g., anaphylaxis), information about MedicAlert programs may be appropriate. Genetic predisposition has not been established for most drug-induced reactions, but for severe reactions such as SJS or TEN or hypersensitivity syndromes, the risk may be higher in first-degree relatives of affected patients.