The skin is among the most common organs of manifestation for adverse reactions (ADR) and accounts for at least 15% to 20% of all ADRs.4,8 An estimated 636,000 cutaneous ADR-related health care visits occur in the US annually.12 Some patients may be more prone to developing hypersensitivity ADRs and risk factors include the following8: prior drug reaction (inducing drug-specific antibodies), multiple drug therapy or intermittent/repeated use of the same drug (vs continuous therapy), some concurrent illnesses (eg, HIV, Epstein-Barr virus, and CMV), dosage/serum drug level increases (eg, IV vancomycin administration rate), topical route of administration (more immunogenic than subcutaneous > intramuscular > oral > IV), certain genetic factors (eg, certain HLA-B alleles predispose for drug allergies), and certain comorbidities (eg, asthma).
Types of 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 (Fig. e99-6).13 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 (eg, urticaria and angioedema). Severe cutaneous adverse reactions to drugs (SCARs) include Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which are further discussed below. Recently, genetic associations between specific HLA alleles and SCARs have been discovered; this is an area of ongoing research.14
Types of cutaneous drug eruptions. (AGEP, acute generalized exanthematous pustulosis; SJS, Stevens-Johnson’s syndrome; TEN, toxic epidermal necrolysis.) (Adapted from Knowles, S. Drug-Induced Skin Reactions, Table 3, Description of Drug Eruptions. In: Compendium of Therapeutic Choices for Minor Ailments, 2nd ed. Ottawa (ON): Canadian Pharmacists Association; © 2016.)
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. Because this is a delayed hypersensitivity reaction, it is possible that the offending agent is already discontinued (eg, a 10-day antibiotic treatment course) before skin manifestation (eg, on day 12).9 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 (DHS) 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 (DRESS). It is more commonly referred to by the acronym DRESS, although DHS is also used.9
Usual drug culprits include allopurinol, sulfonamides, some anticonvulsants (barbiturates, phenytoin, carbamazepine, and 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 (ie, not dose adjusted for renal impairment).15,16
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. A prodrome of pruritus that suddenly occurs (especially on the scalp, around the mouth, and on palms and soles) may precede the appearance of visible lesions; this is a sign of imminent anaphylaxis.8 Urticaria is characterized by hives, extremely pruritic red raised wheals; angioedema; and mucous membrane swelling. Early symptoms of angioedema of the tongue and larynx include the urge to clear the throat, hoarseness, and throat “tightness.” Urticarial symptoms typically occur within minutes (anaphylactic) to hours (anaphylactoid) (Fig. e99-7). Individual lesions typically last less than 24 h, but new lesions may continually develop.
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.)
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.17 Latex allergy is common in health care workers.18 Aside from latex gloves and medical products, other sources of NRL proteins include rubber insoles of shoes, balloons, inflatable mattresses, and poinsettia plants.
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.12
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.12 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 (Fig. e99-8). Usual drug culprits include tetracyclines, barbiturates, sulfonamides, codeine, phenolphthalein, acetaminophen, and NSAIDs.9
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. (Reproduced with permission from Lapeere H, et al. Chapter 75. Hypomelanoses and Hypermelanoses. In: Goldsmith LA, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 8e. New York, NY:
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.”19 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.19,20 Because of their histologic similarity, in the past SJS and TEN have been considered either distinct disorders or progressions of the same disorder based on the percentage of skin area involved. They are now considered variants of the same disorder but distinct from EM, and these two entities are often discussed together as SJS/TEN.19 Genetic associations between some drug causes of SJS/TEN and HLA alleles have been identified. For example, carbamazepine-induced SJS/TEN is associated with HLA-B*15:02, with this allele being specific for the carbamazepine-induced activation of cytotoxic T cells that release granulysin, a mediator responsible for the epidermal sloughing in SJS/TEN.14
SJS/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.19 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, and 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/TEN anti-infective sulfonamides, phenobarbital, carbamazepine, and lamotrigine. In addition, acetaminophen use is suspected to increase the risk.20 However, cases in children only represented 10% of the population in both studies because the incidence of SJS/TEN increases with age.20
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.12 Usual drug culprits include β-lactam antibiotics, macrolides, and calcium channel blockers.
Other Drug-Induced Skin Reactions
Hyperpigmentation of the skin (Fig. e99-8) may be related to increased melanin (eg, hydantoins), direct deposition (eg, silver, mercury, tetracyclines, and antimalarials), or other mechanisms (some cytotoxic drugs, such as 5-fluorouracil, may cause banding on nails or tracking along veins).
Photosensitivity reactions (Fig. e99-9) 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. (Reproduced with permission from Duncan KO, et al. Chapter 113. Epithelial Precancerous Lesions. In: Goldsmith LA, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 8e. New York, NY: McGraw-Hill; 2012.)
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 (ie, 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 ADR, 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 ADRs unrelated to the normal pharmacologic effects of the drug. Fortunately, unpredictable ADRs (eg, allergic, idiosyncratic, and 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 reaction12 (eg, ampicillin-associated maculopapular skin rash).
The next step is to control symptoms associated with the drug reaction (eg, 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/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, decrease mortality and enhance recovery in patients with SJS or TEN.19,20,21 The use of corticosteroids for SJS/TEN is somewhat controversial; although they may curb disease progression, they may also increase the risk of infection and thus contribute to increased mortality.19 If used, relatively high initial doses followed by rapid tapering as soon as disease progression halts is indicated.19 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 (see Fig. e99-9). For patients with severe reactions (eg, anaphylaxis), information about MedicAlert programs may be appropriate. Genetic predisposition has not been established for most drug-induced reactions, but for SCARs such as SJS/TEN or DRESS, the risk may be higher in first-degree relatives of affected patients.