15 Adverse Cutaneous Drug Reactions

Adverse drug reactions (ADRs) can mimic a wide range of dermatoses with morphologies that include morbilliform, urticarial, papulosquamous, pustular, and bullous lesions; thus, drug hypersensitivity may have replaced syphilis as the "great imitator" of disease.^[1-3] The overall incidence of ADRs, mainly adverse cutaneous reactions (CARs), is an estimated 2%-7% of hospital inpatients^[4-8] and about 2% of outpatients.^[4] The incidence of CARs due to semisynthetic penicillins, trimethoprim/sulfamethoxazole (TMP-SMX), and many anticonvulsants is about 3%-7%.^[4] Patients infected with human immunodeficiency virus (HIV) may also be at increased risk.^[5,8]

For each patient with a suspected ADR, obtain a detailed history of all medications taken over the last several months, including over-the-counter (OTC) and herbal remedies.^[1] The diagnosis for CARs is typically made on the basis of a careful history and the appearance of the skin findings. The image shows an individual with Stevens-Johnson syndrome (SJS), a severe drug-induced bullous reaction that can lead to significant morbidity/mortality.

Image courtesy of Medscape/David F Butler, MD.

Acute Generalized Exanthematous Pustulosis
Acute generalized exanthematous pustulosis (AGEP) is a diffuse scarlatiniform rash with numerous 1- to 5-mm pustules that typically develops 1-5 days after starting a medication, most commonly antibiotics.^[9] Patients may report pruritic or burning painful eruptions with fever, malaise, and prostration. Facial swelling is followed by the eruption of pinpoint pustules, commonly involving the forehead (shown) and medial cheeks. Purpura, and bullous coalescing or targetoid lesions may occur. Mucosal involvement is common. Complete blood counts (CBCs) reveal neutrophilia and occasional eosinophilia.^[9-11] The prognosis is good and, in most situations, the removal of the offending drug will cause the eruptions to dry up and desquamate within 2 weeks.

It is important to differentiate this eruption from generalized pustular psoriasis, which has a more guarded prognosis. The acute onset as well as the lack of a history of psoriasis or other stigmata are helpful differentiating features.

Image courtesy of Dirk Elston, MD.

Fixed Drug Eruption
Fixed drug eruption (FDE) is characterized by sharply demarcated erythematous macules.^[11,12] The rash presents with symptoms of pruritus, burning, and fever that typically develop within 6-48 hours of drug administration. Many drugs may be responsible, but the most commonly identified ones are aspirin, barbiturates, cotrimoxazole, phenolphthalein, feprazone, sulfonamides, and tetracycline.^[12] Aspirin most commonly causes lesions in the trunk and limbs, whereas tetracyclines cause lesions in the genitalia. Less pigment is noted when the eruption follows acetaminophen ingestion.

The prognosis is good with removal of the offending drug.^[12] Patch or oral provocation testing may be used to implicate a specific medication. Rarely, the macules may develop into vesicles and bullae, leading to a more severe reaction. Repeated ingestion can give rise to widespread lesions, termed generalized bullous FDE.

Image courtesy of Dirk Elston, MD.

Drug-Induced Pemphigus
Drug-induced pemphigus is characterized by superficial bullae that may develop days or months after ingesting an offending agent. The lesions rupture easily, leaving behind painful erosions.^[13,14] Patients may report itching; if the oral mucosa is involved, then hoarseness, dysphagia, and halitosis may develop. The lesions are flaccid with a positive Nikolsky sign, in which the top layers of the skin separate from the lower layers when rubbed in a sliding motion.^[13] Biopsies typically show acantholysis in the granular layer,^[14] antinuclear antibodies may be found on laboratory examination,^[13] and direct immunofluorescence demonstrates an intercellular pattern.^[13]

The prognosis is typically good after removal of the offending agent, but resolution is slow. Thiol-containing molecules are the most common agents implicated.^[13,14]

Image courtesy of Medscape/David F Butler, MD.

Drug-Induced Pemphigoid
Drug-induced pemphigoid is characterized by tense bullae that may develop after oral or topical drug administration (most often sulfa drugs, especially furosemide).^[13-15] Denuded areas remain after bullae rupture but usually heal spontaneously. Pruritus is the most common complaint.^[15] If the epiglottis is involved, then acute airway obstruction may develop. The lesions are Nikolsky sign positive and may be found overlying normal skin or have an erythematous base (shown) at any body site. Erythematous patches, urticarial plaques (shown), and targetoid lesions may also be noted. Eosinophilia and elevated soluble interleukin-2 receptors may be found on laboratory studies.^[15]

The overall prognosis is excellent after drug discontinuation, but persistent lesions may develop.^[14]

Image courtesy of Medscape/David F Butler, MD.

Cicatricial pemphigoid is a subset of drug-induced pemphigoid characterized by scarring.^[16] It typically involves the mucous membranes of the eyes (shown), pharynx, genitalia, and anus, with the development of adhesions, strictures, and loss of function.

Cicatricial pemphigoid shows a small tendency for remission.^[16] In severe cases, scarring and blindness may occur if there is ocular involvement. Biopsies show a subepidermal bulla^[16,17] with eosinophils and often neutrophils.^[17]

Image of cicatricial pemphigoid with symblepharon, demonstrated by the tethering of the lower lid to the cornea, courtesy of Medscape/Anatoli Freiman, MD, FRCPC, DABD.

Drug-Induced Linear IgA Bullous Dermatosis
Drug-induced linear immunoglobulin (Ig) A bullous dermatosis (LABD) has a protean manifestation,^[17,18] typically 1-2 weeks after ingestion of an offending agent.^[13] Common presentations of lesions include urticated plaques, papulovesicles similar to dermatitis herpetiformis, targetoid lesions similar to erythema multiforme, and bullae similar to bullous pemphigoid. In adults, the lesions are most commonly found on the trunk and limbs; in children, they are most commonly seen in the lower abdomen and anogenital areas (shown).^[17,18] Patients may report severe burning pain and pruritus.^[17,18]

The most common cause is vancomycin^[13,14,18]; other identified responsible drugs include captopril, diclofenac, somatostatin, lithium, phenytoin, amiodarone, cefamandole, amoxicillin, and ampicillin-sulbactam.^[17,18] Patients at risk are usually seriously ill, but the prognosis is typically excellent after removal of the causative agent. A biopsy demonstrates a subepidermal bulla.^[13,17]

Image courtesy of Medscape.

Drug-Induced Pseudoporphyria
Drug-induced pseudoporphyria is a distinct entity from porphyria cutanea tarda (PCT). It does not have any underlying abnormality in heme biosynthesis, and urine and serum porphyrins are normal. Note also that the rash of drug-induced pseudoporphyria may be precipitated or triggered by furosemide, nabumetone, nalidixic acid, naproxen, oxaprozin, tetracycline, and voriconazole,^[17] whereas in true PCT, estrogen and alcohol are triggers.^[13] Patients typically develop tense blisters, erosions, and milia, particularly on the dorsum of the hands (shown) and forearms; they may also report photosensitivity, skin fragility, and hand and forearm blistering.^[13]

The prognosis is typically excellent after removal of the offending agent in both drug-induced porphyria and PCT.

Image courtesy of Medscape/David F Butler, MD.

Erythema Multiforme Minor
Erythema multiforme (EM) minor is related to EM major (SJS) and toxic epidermal necrolysis (TEN). The classic "iris" or target lesions are sharply marginated erythematous annular macules or patches that become raised (shown); they have a central dusky area that may form a tense bulla, then an edematous pale ring, and then an erythematous ring.^[19] Prodromal symptoms are usually absent,^[19,20] or they may be mild and suggestive of an upper respiratory infection (eg, coryza, cough, pharyngitis).^[20] Within 7-10 days, skin lesions begin to develop acrally and symmetrically on the hands (shown), feet, and distal extremities, becoming progressively darker with surrounding erythema; oral involvement is less common.^{[11,17,19,20]}

Although herpes simplex virus is the most common etiology, EM minor may also be caused by drug ingestion, commonly sulfa drugs.^{[11,17,19,20]} Lesions typically subside within 2-3 weeks without scarring, but recurrence is common.

Image courtesy of Medscape/David F Butler, MD.

Erythema Major/Stevens-Johnson Syndrome
Erythema major, or SJS, is much more severe than EM minor. The rash presents with prodromal symptoms of high fever, asthenia, muscular pains, diarrhea, vomiting, arthralgias, and pharyngitis.^[20] Large, confluent, irregularly shaped, coalescing lesions involve the trunk (shown) and two or more mucosal sites (oral, ocular, genital) (<10% body surface [BSA]).^{[10,11,17,19-21]} Medications associated with this rash include antibiotics, nonsteroidal anti-inflammatory agents (NSAIDs), antihypertensives, anticonvulsants, and allopurinol.^{[10,11,17,19-21]}

Patients are typically treated in intensive care [ICU] or burn units, primarily with removal of the offending agent, aggressive fluid and electrolyte replacement, nutritional support, and infection prophylaxis. The roles of corticosteroids and intravenous Ig in erythema major/SJS are controversial.^{[10,11,17,19-21]} Overall mortality is about 5%-15%,^{[10,11,20,21]} and survivors usually have extensive morbidity related to cicatrization of conjunctival erosions.

Image courtesy of Medscape/David F Butler, MD.

Toxic Epidermal Necrolysis
TENS is a severe drug eruption that shares many characteristics with erythema major/SJS, differing mainly in its distribution (>30% BSA) and mortality rate (30%-40%).^{[10,11,17,19-21]} The TENS rash presents with diffuse skin tenderness and erythema that resembles a severe sunburn, typically beginning on the face and spreading downward, with sparing of the scalp. Extension continues for 2-3 days with characteristic sheetlike separation of the epidermis (shown). Flaccid bullae that are Nikolsky sign positive may occur. Implicated medications include antibiotics, NSAIDs, antihypertensives, anticonvulsants, and allopurinol. Electrolyte abnormalities and hypoalbuminemia may develop.^{[10,11,17,19-21]}

Treatment involves removal of the offending agent, fluid and electrolyte replacement, and nutritional support in an ICU or burn unit. The role of agents such as intravenous Ig and cyclosporine is controversial, as data are mixed, and large randomized controlled studies are lacking.^{[10,11,17,19-21]}

Image courtesy of Dirk Elston, MD.

Drug-Induced Dyspigmentation
Drug-induced dyspigmentation is a common problem for certain classes of medications (eg, antimalarials, chemotherapeutic agents, heavy metals, psychotropics, tetracyclines)^[22] and with amiodarone and azidothymidine. It is caused by either direct drug or drug metabolite deposition, enhanced melanin production, or drug-induced postinflammatory skin changes^[22,23] and may result in significant patient discomfort. Different medications will have different distributions.

A patchy distribution, enhanced by sun exposure, is common with amiodarone (shown), chemotherapeutics, and gold. Uniform generalized changes are most common with minocycline. Discoloration of scars is found with hydroxyurea, and changes at the site of drug administration are common with iron, silver, or topical hydroquinone. Drug discontinuation or dose reduction is typically sufficient to resolve skin changes.

Image courtesy of Medscape/David F Butler, MD.

Erythema Nodosum
Erythema nodosum is an acute nodular erythematous eruption caused by infections, autoimmune disorders, and malignancy, among other conditions.^{[11,14,17,24]} When drug induced (eg, sulfonamides, halides, gold, sulfonylureas, oral contraceptive pills), it is the result of a delayed hypersensitivity reaction. Patients may report a flulike prodrome with fever and generalized aches.^[14,24] Subsequently, a painful rash develops, typically beginning as 2- to 6-cm red tender nodules with poorly defined borders on the extensor aspects of the lower extremities (shown).^{[11,14,17,24]} The rash generally lasts for 2 weeks, but new lesions may continually appear. In the first week, the lesions become tense, hard, and painful; over the second week, the lesions do not suppurate or become ulcerated.^[17]

Symptomatic relief can typically be achieved with NSAIDs, and removal of the offending agent is usually sufficient for complete resolution.

Images courtesy of Medscape (left) and Medscape/Jonathan E Blume, MD (right).

Leukocytoclastic Vasculitis
Leukocytoclastic vasculitis, also known as hypersensitivity vasculitis, hypersensitivity angiitis, and cutaneous vasculitis, is a small-vessel vasculitis that manifests in the skin, joints, gastrointestinal tract, or kidneys.^{[13,14,25,26]} Patients may be asymptomatic or report itching, burning, or pain. Palpable purpura (typically round, 1-3 mm) is one of the most frequently seen drug-induced skin reactions in clinical practice and the most common cutaneous manifestation of leukocytoclastic vasculitis.^{[13,14,25,26]} These lesions may coalesce to form plaques (shown) or ulcerate, and they are most often found on the legs.^[14] Causative agents include antibiotics, particularly beta-lactams; NSAIDs; and diuretics.^[13,14,24]

Removal of the offending drug will typically cause lesions to disappear in up to 2 weeks. Elevation of dependent areas or the use of compressive stockings may be helpful, and prednisone may be required to treat active renal vasculitis.

Image courtesy of Dirk Elston, MD.

Serum Sickness
Serum sickness is a type III hypersensitivity reaction mediated by the deposition of immune complexes in small vessels, activation of complement, and recruitment of granulocytes.^[10,27] It typically develops 1-2 weeks after exposure to a foreign antigen^[27] in a naive individual; after subsequent exposure, it can develop much faster.^[10] The rash typically begins with erythema on the sides of fingers, hands, and toes, which then progresses to a widespread morbilliform or urticarial (shown) rash. Patients typically also report a triad of fever, myalgia, and lymphadenopathy.^[10,27]

The drugs most commonly responsible are those that contain the proteins of other species (eg, antitoxins, antivenins), as well as antibiotics, including cephalosporins, ciprofloxacin, griseofulvin, lincomycin, metronidazole, penicillins, streptomycin, sulfonamides, and tetracyclines. Laboratory results will typically show leukopenia or mild leukocytosis, an elevated erythrocyte sedimentation rate, an IgG spike, proteinuria/hematuria, and decreased complement levels.^[10,27] Withdrawal of the offending agent and symptomatic relief with anti-inflammatories and antihistamines are the mainstays of treatment.

Image courtesy of Medscape.

Drug-Induced Lupus Erythematosus
Drug-induced lupus erythematosus (DILE) is an autoimmune process that is a similar, yet distinct, clinical entity to lupus erythematosus.^[14,28] DILE may be difficult to differentiate from lupus erythematosus, as no specific criteria establish the diagnosis of DILE and both share similar manifestations. Thus, DILE is usually a diagnosis of exclusion. Patients may report arthralgias, lymphadenopathy, rash, and fevers. The rash develops months to years after exposure to certain medications (eg, hydralazine, procainamide, quinidine, isoniazid, diltiazem, minocycline).^[14,28] The cutaneous findings may include mucosal ulcers, alopecia, discoid plaques, photosensitivity, purpura, erythema nodosum, and erythematous papules typically in sun-exposed areas (shown).

Discontinuation of the medication usually leads to symptomatic resolution in several weeks, but residual antibodies may persist for extended time periods.^[14,28] In severe cases, low doses of systemic corticosteroids may be helpful. In rare cases, patients may die from renal involvement or experience severe serositis.

Image courtesy of Medscape.

Drug Reaction with Eosinophilia and Systemic Symptoms
Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), also called drug hypersensitivity syndrome or drug-induced hypersensitivity syndrome (DIHS), is a life-threatening drug reaction that occurs up to 8 weeks after ingestion of certain medications.^[17,29] Anticonvulsant agents produce the classic triad of fever, generalized exanthem, and multiorgan failure, but many other drugs can also cause DRESS, including antitubercular agents, calcium channel blockers, NSAIDs, carbamazepine, and sulfonamides.^[17,29] Dapsone is less likely to produce eosinophilia, allopurinol is more likely to produce renal involvement, and minocycline can produce a lupuslike reaction with prominent pulmonary and cardiac involvement.

Patients may die from hepatic necrosis if the offending drug is not stopped, adequate doses of corticosteroids not given, and supportive care not administered.^[29] The image shows peripheral eosinophilia in a patient with DRESS syndrome who presented with a morbilliform rash, facial edema, malaise, and lymphadenopathy while taking an anticonvulsant agent.

Image courtesy of Dirk Elston, MD.