Chapter 056. Cutaneous Drug Reactions (Part 7) FIXED DRUG ERUPTIONS These reactions are characterized by one or more sharply demarcated, erythematous lesions, sometimes leading to a blister. Hyperpigmentation results after resolution of the acute inflammation. With rechallenge, the lesion recurs in the same (i.e., fixed) location. Lesions often involve the lips, hands, legs, face, genitalia, and oral mucosa and cause a burning sensation. Most patients have multiple lesions. Fixed drug eruptions have been associated with phenolphthalein, sulfonamides, cyclines, dipyrone, NSAIDs, and barbiturates. Patch testing has been used in Europe to help establish the etiology. Immune Cutaneous Reactions: Severe VASCULITIS Cutaneous necrotizing vasculitis often presents as palpable purpuric lesions that may be generalized or limited to the lower extremities or other dependent areas (Chap. 319). Urticarial lesions, ulcers, and hemorrhagic blisters also occur. Vasculitis may involve other organs, including the liver, kidney, brain, and joints. Drugs are an infrequent cause of vasculitis. Infection and collagen vascular disease are responsible for the majority of cases. Propylthiouracil induces a cutaneous vasculitis that is accompanied by leukopenia and splenomegaly. Direct immunofluorescent changes in these lesions suggest immune-complex deposition. Drugs implicated in vasculitis include allopurinol, thiazides, sulfonamides, other antimicrobials, and several NSAIDs. The presence of eosinophils in the perivascular infiltrate of skin biopsy may indicate a higher probability of a drug etiology. PUSTULAR ERUPTIONS AGEP is a rare reaction pattern, often associated with exposure to drugs. Usually beginning on the face or intertriginous areas, small nonfollicular pustules overlying erythematous and edematous skin may coalesce and lead to superficial ulceration. Differentiating this eruption from TEN in its initial stages may be difficult. A skin biopsy is important and shows scattered pustules in the upper part of the epidermis instead of the full-thickness necrosis that characterizes TEN. Fever is present with elevated neutrophil counts, and sepsis is often suspected. Acute pustular psoriasis is the principal differential diagnostic consideration. AGEP often begins within a few days of initiating drug treatment, most notably antibiotics. For other associated drugs, diltiazem, chloroquine, hydroxychloroquine or terbinafine, AGEP begins later: 7–14 days after initiation of treatment. HYPERSENSITIVITY SYNDROME Initially described with phenytoin, hypersensitivity syndrome—a multiorgan drug-induced reaction—is also known as DRESS and drug-induced hypersensitivity syndrome (DIHS). It presents as a widespread erythematous eruption that may become purpuric or lichenoid and is accompanied by many of the following features: fever, facial and periorbital edema, tender generalized lymphadenopathy, leukocytosis (often with atypical lymphocytes and eosinophils), hepatitis, and sometimes nephritis or pneumonitis. The cutaneous reaction usually begins 2–8 weeks after the drug is started and lasts longer than mild eruptions after drug cessation. Symptoms may persist for several weeks, especially hepatitis. The eruption recurs with rechallenge, and cross-reactions among aromatic anticonvulsants, including phenytoin, carbamazepine, and barbiturates, are frequent. Other drugs causing this syndrome include lamotrigine, minocycline, dapsone, allopurinol, and sulfonamides, as well as abacavir and zalcitabine in HIV-infected patients. Reactivation of herpes viruses, especially of herpes virus 6, has been reported to be frequent in this syndrome. The role of virus infection is still unclear; it may contribute to long-lasting manifestations such as hepatitis or encephalitis. Mortality as high as 10% has been reported. In life- threatening situations such as pneumonitis or nephritis, systemic glucocorticoids (prednisone, 0.5–1.0 mg/kg) seem to reduce symptoms. Topical high-potency glucocorticoids may also be helpful. In all cases, rapid withdrawal of the suspected drug is required. STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS SJS and TEN are terms that, most believe, describe the same usually drug- induced disorder, which is characterized by blisters and epidermal detachment resulting from epidermal necrosis in the absence of substantial dermal inflammation. The term SJS is now used to describe cases with blisters developing on dusky or purpuric macules in which total body surface area blistering and eventual detachment is <10%. The term SJS/TEN is used to describe cases with 10–30% detachment, and TEN is used to describe cases with >30% detachment. Erythema multiforme major is now considered by most to be different from SJS, characterized by typical "target" lesions and resulting from a reaction to infection, most commonly from herpes simplex virus. Patients with SJS, SJS/TEN, or TEN initially present with acute symptoms, painful skin lesions, fever >39°C (102.2°F), sore throat, and visual impairment resulting from mucous membrane and ocular lesions. Intestinal and pulmonary involvements are associated with a poor prognosis, as are a greater extent of epidermal detachment and older age. About 10% and 30% of SJS- and TEN- affected persons die from their disease, respectively. Drugs that most commonly cause SJS or TEN are anti-infectious sulfonamides, nevirapine, allopurinol, lamotrigine, aromatic anticonvulsants, and oxicam NSAIDs. At this time SJS or TEN have no treatment of proven efficacy. The best results come from early diagnosis, immediate discontinuation of any suspected drug, and supportive therapy, paying close attention to ocular complications, often in burn units or intensive care units. . Chapter 056. Cutaneous Drug Reactions (Part 7) FIXED DRUG ERUPTIONS These reactions are characterized by one or more sharply demarcated,. Patch testing has been used in Europe to help establish the etiology. Immune Cutaneous Reactions: Severe VASCULITIS Cutaneous necrotizing vasculitis often presents as palpable purpuric lesions. sometimes nephritis or pneumonitis. The cutaneous reaction usually begins 2–8 weeks after the drug is started and lasts longer than mild eruptions after drug cessation. Symptoms may persist for