The skin is one of the most common targets for adverse drug reactions.3 Drug eruptions occur in approximately 2% to 5% of inpatients and in more than 1% of outpatients. Several cutaneous reaction patterns account for the majority of clinical presentations occurring in patients with xenobiotic-induced dermatotoxicity (Table 18–2). The following drug reactions will be discussed in detail: urticarial drug reactions, erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), fixed drug eruption, and drug-induced hypersensitivity syndrome.
TABLE 18–2.Xenobiotics Commonly Associated with Various Cutaneous Reaction Patterns ||Download (.pdf) TABLE 18–2. Xenobiotics Commonly Associated with Various Cutaneous Reaction Patterns
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Fixed Drug Eruption
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Urticarial Drug Reactions
Urticarial drug reactions are characterized by transient, pruritic, edematous, pink papules, or wheals that arise in the dermis, which blanch on palpation and are frequently associated with central clearing. At times the urticarial lesions can be targetoid and mimic EM. Approximately 40% of patients with urticaria experience angioedema and anaphylactoid reactions as well.1 The reaction pattern is representative of a type I, or IgE-dependent, immune reaction and commonly occurs as part of clinical anaphylaxis or anaphylactoid (non–IgE-mediated) reactions. Widespread urticaria may occur after systemic absorption of an allergen or after a minimal localized exposure in patients highly sensitized to the allergen. After limited exposure, a localized form of urticaria may occur. Regardless of the specific clinical presentation, the reaction occurs as a result of immunologic recognition of a putative antigen by IgE antibodies, thus triggering the immediate degranulation of mast cells, which are distributed along the dermal blood vessels and nerves. The release of histamine, complements C3a and C5a, and other vasoactive mediators results in extravasation of fluid from dermal capillaries as their endothelial cells contract. This produces the characteristic urticarial lesions described earlier. Activation of the nearby sensory neurons produces pruritus. Nonimmunologically mediated mast cell degranulation producing an identical urticarial syndrome may also occur after exposure to any xenobiotic.14
Historically, it was believed that EM existed on a spectrum with SJS and TEN given overlapping clinical features and morphology; however, these entities have been reclassified on the basis that most cases of EM are believed to be triggered by viral infection (herpes simplex virus most commonly) and most cases of SJS/TEN are triggered by xenobiotics.49 EM is an acute self-limited disease characterized by target-shaped, erythematous macules and patches on the palms and soles, as well as the trunk and extremities (Fig. 18–3). The Nikolsky sign, defined as sloughing of the epidermis when direct pressure is exerted on the skin, is absent. Mucosal involvement is absent or mild in EM minor and severe in EM major. Although less common than viral-induced EM, xenobiotics such as sulfonamides, phenytoin, antihistamines, many antibiotics, rosewood, and urushiol can elicit EM. Differentiating EM from SJS/TEN, which can also present with targetoid lesions, can be difficult, especially in the case of bullous EM, and biopsy may be required.
Erythema multiforme: typical targetoid macules on the palm. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill; 2012. Fig. 39–3.)
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Toxic epidermal necrolysis and SJS (Fig. 18–4) are considered to be related disorders that belong to a spectrum of increasingly severe skin eruptions.43 SJS is defined by less than 10% body surface area epidermal detachment, SJS–TEN overlap is defined by 10% to 30% involvement, and TEN is defined by more than 30% epidermal sloughing. Although on a spectrum, SJS has a mortality rate of 5%, far lower than the approximately 25% to 50% mortality rate for TEN.47,50 TEN is a rare, life-threatening dermatologic emergency whose incidence is estimated at 0.4 to 1.2 cases per 1 million persons, and xenobiotics are causally implicated in 80% to 95% of the cases. More than 220 xenobiotics are implicated in causing TEN. The largest study examining medication triggers of TEN divided these medications into long-term (used for months to years) and short-term ones. Short-term xenobiotics most commonly implicated in the development of TEN included trimethoprim–sulfamethoxazole and other sulfonamide antibiotics followed by cephalosporins, quinolones, and aminopenicillins.51 With chronic medication use, the increased risk largely occurred during the first 2 months of treatment and was greatest for carbamazepine, phenobarbital, phenytoin, valproic acid, oxicam NSAIDs, allopurinol, and corticosteroids.
Toxic epidermal necrolysis. (A) Early eruption. Erythematous dusky red macules (flat atypical target lesions) that progressively coalesce and show epidermal detachment. (B) Advanced eruption. Blisters and epidermal detachment have led to large, confluent erosions. (C) Full-blown epidermal necrolysis characterized by large erosive areas reminiscent of scalding. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill; 2012.)
Classically, the eruption of TEN is painful and occurs within 1 to 3 weeks of the exposure to the implicated xenobiotic(s). The eruption is preceded by malaise, headache, abrupt onset of fever, myalgia, arthralgia, nausea, vomiting, diarrhea, chest pain, or cough. About 1 to 3 days later, signs begin in the mucous membranes, including the eyes, mouth, nose, and genitals in 90% of cases.47 Next a macular erythema develops that subsequently becomes raised and morbilliform on the face, neck, and central trunk, which then progresses to involve the extremities. Individual lesions may appear targetoid because of their dusky centers and progress to bullae in the next 3 to 5 days involving the entire thickness of the epidermis. The nails may be involved becoming necrotic and can slough off. A Nikolsky sign may occur, and although suggestive, is not pathognomonic of TEN because it occurs in a variety of other dermatoses, including pemphigus vulgaris. If the diagnosis is suspected, a punch biopsy should be performed for immediate frozen section and the suspected triggering xenobiotic discontinued immediately. The histopathology typically shows partial or full-thickness epidermal necrosis, with subepidermal bullae with a sparse infiltrate and vacuolization with numerous dyskeratotic keratinocytes along the DEJ adjacent to the necrotic epidermis.
The incidence of TEN is higher in patients with advanced HIV disease.43,59 There is general agreement that the keratinocyte cell death in TEN is the result of apoptosis, which is suggested based on electronic microscopic studies with DNA fragmentation analysis.43 Cytotoxic T lymphocytes are the main effector cells, and experimental evidence points to involvement of the Fas-ligand (FasL) and perforin–granzyme pathways. There are several theories as to the pathogenesis of SJS/TEN. These include that a xenobiotic might induce upregulation of FasL by keratinocytes constitutively expressing Fas, leading to a death receptor–mediated apoptotic pathway; the xenobiotic might interact with major histocompatibility class I–expressing cells, and then drug-specific CD8+ cytotoxic T lymphocytes accumulate within epidermal blisters, releasing perforin and granzyme B that kill keratinocytes; or that the xenobiotic may also trigger the activation of CD8+ T lymphocytes and natural killer (NK) cells, to secrete granulysin, with keratinocyte death not requiring cell contact.42 Serum FasL concentrations are elevated up to 4 days before mucosal involvement in patients with SJS/TEN and may become useful clinically because an early predictor of these severe dermatologic diseases.41 Serum granulysin, a proinflammatory cytolytic enzyme released by CD8+ T lymphocytes found in the blisters of TEN, has been investigated as a potential early predictive marker of SJS/TEN.19 A rapid immunochromatographic test that detects elevated serum granulysin (>10 ng/mL) in 15 minutes has shown promise in a small study in which its sensitivity was noted to be 80% and specificity 95.8% for differentiating SJS/TEN from ordinary exanthematous drug eruptions.19 However, this test is not yet commercially available.
Because immediate removal of the inciting xenobiotic is critical to survival, patients with TEN related to a xenobiotic with a long half-life have a poorer prognosis and should be transferred to a burn or other specialized center for sterile wound care. Risk factors for mortality, such as age, extent of epidermal detachment, and base deficit, have been proposed. In a recent study, only serum bicarbonate concentration less than 20 mEq/L was found to portend hospital death in patients with TEN.64 Porcine xenografts or human skin allografts, including amniotic membrane transplantation, are used and are widely accepted therapies.46 Although corticosteroids are not generally recommended, there is emerging support for the use of intravenous immunoglobulin (IVIG), cyclophosphamide, and cyclosporine.46 A large meta-analysis of 17 studies revealed a trend toward improved mortality with high-dose IVIG in adults and good prognosis in children; however, the authors concluded that there was no significant evidence to support a clinical benefit, so this treatment remains controversial.26 Patients with TEN may develop metabolic abnormalities, sepsis, multiorgan failure, pulmonary emboli, and GI hemorrhages. The major microbes leading to sepsis are Staphylococcus aureus and Pseudomonas aeruginosa. In a patient with SJS/TEN with ophthalmic involvement early ophthalmologic consultation is necessary because blindness is a potential complication.
Mimickers of TEN include SJS, staphylococcal scalded skin syndrome, severe exanthematous drug eruptions, EM major, linear IgA dermatosis, paraneoplastic pemphigus, acute graft-versus-host disease, drug-induced pemphigoid, pemphigus vulgaris, and acute generalized exanthematous pustulosis; however, discussion of some of these entities is beyond the scope of this chapter (Table 18–3).
TABLE 18–3.Differential Diagnosis of Xenobiotic-Induced Blistering (Vesiculobullous) Disorders ||Download (.pdf) TABLE 18–3. Differential Diagnosis of Xenobiotic-Induced Blistering (Vesiculobullous) Disorders
|Disease ||Fever ||Mucositis ||Morphology ||Onset ||Miscellaneous |
|Xenobiotic-induced pemphigoid ||No ||Rare ||Tense bullae (sometimes hemorrhagic) ||Acute ||Diuretics a common cause, especially furosemide, spironolactone; often pruritic |
|Staphylococcal scalded skin syndrome ||Yes ||Absent ||Erythema, skin tenderness, periorificial crusting ||Acute ||Affects children younger than 5 years, adults on dialysis, and those on immunosuppressive therapy |
|Xenobiotic-induced pemphigus ||No ||Usually absent ||Erosions, crusts, patchy erythema (resembles pemphigus foliaceous) ||Gradual ||Commonly caused by penicillamine and other “thiol” drugs; often resolves after inciting agent is discontinued |
|Xenobiotic-triggered pemphigus ||No ||Present ||Mucosal erosions, flaccid bullae ||Gradual ||Caused by “nonthiol” drugs; more likely to persist after discontinuation of drug; may require long-term immunosuppressive therapy |
|Paraneoplastic pemphigus ||No ||Present (usually severe) ||Polymorphous skin lesions, flaccid bullae ||Gradual ||Resistant to treatment; associated with malignancy, especially lymphoma |
|Acute graft-versus-host disease ||Yes ||Present ||Morbilliform rash, bullae and erosions ||Acute ||Closely resembles toxic epidermal necrolysis |
|Acute generalized exanthematous pustulosis ||Yes ||Rare ||Superficial pustules ||Acute ||Self-limiting on discontinuation of drug |
|Xenobiotic-induced linear IgA bullous dermatosis ||No ||Rare ||Tense, subepidermal bullae ||Acute ||Vancomycin is most commonly implicated |
Bullous Reactions (Blistering Reactions)
In addition to SJS and TEN, other bullous cutaneous reactions include drug-induced pseudoporphyria, fixed drug eruption, acute generalized exanthematous pustulosis, phototoxic drug eruptions, and drug-induced autoimmune blistering diseases. Xenobiotic-related cutaneous blistering reactions may be clinically indistinguishable from autoimmune blistering diseases such as pemphigus vulgaris or bullous pemphigoid (Fig. 18–5). Certain topically applied xenobiotics such as the vesicant cantharidin derived from “blister beetles” in the Coleoptera order and Meloidae family are used in the treatment of molluscum and viral warts. In high concentrations, xenobiotics can lead to necrosis of both skin and mucous membranes. Other systemic xenobiotics cause a similar reaction pattern mediated by the production of antibody directed against the cells at the DEJ (Table 18–3).
Pemphigus vulgaris. (A) Flaccid blisters. (B) Oral erosions. (Part A used with permission of Lawrence Lieblich, MD. Part B reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill; 2012.)
A number of medications, many of which contain a “thiol group” such as penicillamine and captopril, can induce either pemphigus resembling pemphigus foliaceus, a superficial blistering disorder in which the blister is at the level of the stratum granulosum, or pemphigus vulgaris, in which blistering occurs above the basal layer of the epidermis (Fig. 18–1). Other xenobiotics, such as furosemide, penicillin, and sulfasalazine, produce tense bullae that resemble bullous pemphigoid. Direct immunofluorescence studies might show epidermal intracellular immunoglobulin deposits at the DEJ. Treatment options include stopping the offending xenobiotic and at times treating with immunosuppressants used to treat bullous pemphigoid and pemphigus vulgaris. The reaction may persist for up to 6 months after the offending xenobiotic is withdrawn.
Fixed drug eruption is another bullous drug eruption that is characterized by well-circumscribed erythematous to dusky violaceous patches that may have central bullae or erosions and develops 1 to 2 weeks after first exposure to the drug. This reaction pattern is so named because reexposure to the xenobiotic causes lesions in the same area but typically within 24 hours of exposures (Fig. 18–6). Typical locations include the acral extremities, genitals, and intertriginous sites, and this process may be confused with TEN if widely confluent as in “generalized fixed drug eruption.” This reaction pattern is generally not life threatening and heals with residual postinflammatory hyperpigmentation. Bullous fixed-drug reactions result from exposure to diverse xenobiotics such as angiotensin-converting enzyme inhibitors and a multitude of antibiotics. As mentioned earlier, EM can have a bullous variant that can also be confused with SJS/TEN.
Fixed drug eruption caused by tetracycline. A well-defined plaque on the knee merging with three satellite lesions. The large plaque exhibits epidermal wrinkling, a sign of incipient blister formation. This was the second such episode after ingestion of a tetracycline. No other lesions were present. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill; 2012.)
“Coma bullae” are tense bullae on normal appearing skin that occur within 48 to 72 hours in comatose patients with sedative–hypnotic overdoses, particularly phenobarbital, or carbon monoxide poisoning. They may also be seen in patients in coma from infectious, neurologic, or metabolic causes. Although these blisters are thought to result predominantly from pressure-induced epidermal necrosis, they occasionally occur in non–pressure-dependent areas, suggesting a systemic mechanism. Histologically, an intraepidermal or subepidermal blister may be observed. There is accompanying eccrine duct and gland necrosis.
Drug-Induced Hypersensitivity Syndrome
The drug hypersensitivity syndrome, also called drug reaction with eosinophilia and systemic symptoms (DRESS), can be severe and potentially life threatening. The skin may be involved with systemic immunologic diseases such that an alteration in the metabolism of certain xenobiotics leads to a hypersensitivity syndrome. The hypersensitivity syndrome is characterized by the triad of fever, skin eruption, and internal organ involvement.31 The frequency has been estimated between one in 1000 to one in 10,000 with anticonvulsants or sulfonamide antibiotic exposures and usually begins within 2 to 6 weeks after the initial exposure. For anticonvulsants, the inability to detoxify arene oxide metabolites has been suggested to be a key factor; after a patient has a documented drug-induced hypersensitivity syndrome to one anticonvulsant, it is important to note that cross-reactivity between phenytoin, carbamazepine, and phenobarbital is well documented, both in vivo and in vitro.45 In the case of sulfonamides, acetylator phenotype and lymphocyte susceptibility to the metabolite hydroxylamine are risk factors for developing drug hypersensitivity syndrome. Further support for the role of genetic predisposition comes from data in Northern European populations in which the presence of the HLA-A*3101 allele significantly increases the risk of developing carbamazepine-induced hypersensitivity syndrome.33 Fever and a cutaneous eruption are the most common symptoms. Accompanying malaise, pharyngitis, and cervical lymphadenopathy may also be present. Atypical lymphocytes and eosinophilia occur initially. The exanthem is initially generalized and morbilliform, and conjunctivitis and angioedema may occur (Fig. 18–7). Later the eruption becomes edematous and facial edema, which is often present, is a hallmark of this syndrome. Half of patients with drug-induced hypersensitivity syndrome will have hepatitis, interstitial nephritis, vasculitis, CNS manifestations (including encephalitis, aseptic meningitis), interstitial pneumonitis, acute respiratory distress syndrome, and autoimmune hypothyroidism. Hepatic involvement can be fulminant and is the most common cause of death associated with this syndrome. Colitis with bloody diarrhea and abdominal pain may occur. In addition to the aromatic anticonvulsants (phenobarbital, carbamazepine, and phenytoin), lamotrigine, allopurinol, sulfonamide antibiotics, dapsone, and the protease inhibitor abacavir have been implicated. Early withdrawal of the offending xenobiotic is crucial, and treatment is generally supportive.40,63 If cardiac or pulmonary involvement is present, systemic corticosteroids are often recommended; however, their benefit on outcome has not been demonstrated, and relapse may occur during tapering, necessitating long-term courses of therapy.
A patient with a hypersensitivity syndrome associated with phenytoin. He has a symmetric, bright red, exanthematous eruption, confluent in some sites. The patient had associated lymphadenopathy. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill; 2012.)
Erythroderma, also known as exfoliative dermatitis, is defined as a generalized redness and scaling of the skin. However, it does not represent one disease entity; rather, it is a severe clinical presentation of a variety of skin diseases, including psoriasis, atopic dermatitis, drug reactions, or cutaneous T-cell lymphoma (CTCL). At times the underlying etiology of erythroderma is never discovered, and this is termed “idiopathic erythroderma.” The importance of this presentation is its association with systemic complications such as hypothermia; peripheral edema; and loss of fluid, electrolytes, and albumin with subsequent tachycardia and cardiac failure. Many xenobiotics can lead to erythroderma (Table 18–2). When ingested, boric acid can cause systemic toxicity in addition to a bright red eruption (“lobster skin”) usually followed within 1 to 3 days by a generalized exfoliation.53
Xenobiotic-induced vasculitis (Fig. 18–8) comprises 10% to 15% of secondary cutaneous vasculitis. It generally occurs from 7 to 21 days after initial exposure to the xenobiotic or 3 days after rechallenge and is considered to be a secondary cause of cutaneous small vessel vasculitis (typically involving dermal postcapillary venules). Many xenobiotics are implicated as triggers of cutaneous vasculitis (Table 18–2).57 Cutaneous vasculitis is characterized by purpuric, nonblanching macules that usually become raised and palpable. The purpura tends to occur predominantly on gravity-dependent areas, including the lower extremities, particularly the feet, ankles, and buttocks. Sometimes the reaction pattern can have edematous purpuric wheals (urticarial vasculitis), hemorrhagic bullae, or ulcerations. The underlying histopathology shows a leukocytoclastic vasculitis, which is characterized by fibrin deposition in the vessel walls. There is a perivascular infiltrate with intact and fragmented neutrophils that appear as black dots, known as “nuclear dust,” and extravasated red blood cells. This reaction pattern may be limited to the skin or may be more serious and involve other organ systems, particularly the kidneys, joints, liver, lungs, and brain. The purpura results from the deposition of circulating immune complexes, which form as a result of a hypersensitivity to a xenobiotic. Treatment consists of withdrawing the putative xenobiotic and systemic corticosteroid therapy if systemic involvement is present. A syndrome of vasculitis, neutropenia, and retiform purpura has been reported as a result of levamisole-adulterated cocaine.13 The earlobe is a common site of purpuric lesions from levamisole, and it is estimated that up to 70% of the cocaine and less than 3% of the heroin supply in the United States contained levamisole.6,60,61
Leukocytoclastic vasculitis in a patient with mixed cryoglobulinemia manifested as palpable purpura and acrocyanosis. The patient had tuberculosis, positive antinuclear antibody, and hepatitis. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill; 2012.)
Purpura is the multifocal extravasation of blood into the skin or mucous membranes (Fig. 18–9). Ecchymoses are therefore considered to be purpuric lesions. Cytotoxic medications that either diffusely suppress the bone marrow or specifically depress platelet counts below 30,000/mm3 predispose to purpuric macules. Xenobiotics that interfere with platelet aggregation, such as aspirin, clopidogrel, ticlopidine, and valproic acid, may cause purpura, as may thrombolytics. Anticoagulants, such as heparin and warfarin, may also result in purpura (Chaps. 22 and 60).
Purpura. Nonblanching red erythematous papules and plaques (palpable purpura) on the legs representing leukocytoclastic vasculitis. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill; 2012.)
Anticoagulant-Induced Skin Necrosis.
Skin necrosis from warfarin, low-molecular-weight heparin, or unfractionated heparin usually begins 3 to 5 days after the initiation of treatment, which corresponds with the expected early decline of protein C function with warfarin (Fig. 18–10). The estimated risk is one in 10,000 persons. It is four times higher in women, especially if they are obese, with peaks in the sixth to seventh decades of life. The necrosis is secondary to thrombus formation in vessels of the dermis and subcutaneous fat. Heparin-induced cutaneous necrosis results from antibodies that bind to complexes of heparin and platelet factor 4 and induce platelet aggregation and consumption. There may be bullae, ecchymosis, ulcers, and massive subcutaneous necrosis, usually in areas of abundant subcutaneous fat, such as the breasts, buttocks, abdomen, thighs, and calves. It may be associated with protein C or S deficiency, anticardiolipin antibody syndrome, and factor V Leiden mutations.44 Treatment involves discontinuing the medication; administration of vitamin K; and, if warfarin induced, switching to heparin. Treatment may include fresh-frozen plasma and protein C. Skin grafting may be necessary if full-thickness necrosis occurs.
Skin necrosis in a patient after 4 days of warfarin therapy. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill; 2012.)
When a xenobiotic comes in contact with the skin, it can result in either an allergic contact dermatitis (20% of cases) or more commonly an irritant contact dermatitis (80% of cases). Contact dermatitis is characterized by inflammation of the skin with spongiosis (intercellular edema) of the epidermis that results from the interaction of a xenobiotic with the skin. Well-demarcated erythematous vesicular or scaly patches or plaques may be noted on areas in direct contact with the xenobiotic while the remaining areas are spared. Bullae may be present.
Allergic contact dermatitis fits into the classic delayed hypersensitivity, or type IV, immunologic reaction. The development of this reaction requires prior sensitization to an allergen, which, in most cases, acts as a hapten by binding with an endogenous molecule that is then presented to an appropriate immunologic T cell. Upon reexposure, the hapten diffuses to the Langerhans cell, is chemically altered, and bound to an HLA-DR, and the complex is expressed on the Langerhans cell surface. This complex interacts with primed T cells either in the skin or lymph nodes, causing the Langerhans cells to make interleukin-1 and the activated T cells to make interleukin-2 and interferon. This subsequently activates the keratinocytes to produce cytokines and eicosanoids that activate mast cells and macrophages, leading to an inflammatory response (Fig. 18–11).30
Contact dermatitis. (1) Causative xenobiotic, typically a hapten of less than 500 Da diffuses through the stratum corneum and binds to receptor on Langerhans cell (LC). (2) The antigen is processed with major histocompatibility complex II (MHC II) receptor site, presented to T-helper lymphocytes, and carried through the lymphatics to regional lymph nodes. (3) There it undergoes the sensitization phase by producing memory, effector, and suppressor T lymphocytes. (4) On reexposure to the same or to a cross-reactive antigen, the LC represents the antigen to T lymphocytes (), which are now sensitized. This initiates an inflammatory process that appears as indurated, scaly patches.
Many allergens are associated with contact dermatitis; a complete list is beyond the scope of this chapter. However, some common xenobiotics are listed in Table 18–2. Among the most common plant-derived sensitizers are urushiol (Toxicodendron species), sesquiterpene lactone (ragweed), and tuliposide A (tulip bulbs). Metals, particularly nickel, are commonly implicated in contact dermatitis and should be considered in patients with erythematous, vesicular or scaly patches or plaques around the umbilicus from nickel buttons on pants, and on the ear lobes from earrings. Several industrial chemicals, such as the thiurams (rubber) and urea formaldehyde resins (plastics), account for the majority of occupational contact dermatitis. Medications, particularly topical medications such as neomycin, commonly cause contact dermatitis. An important allergen that is becoming more frequent is paraphenylenediamine (PPD), a black dye in permanent and semipermanent hair coloring, leather, fur, textiles, industrial rubber products, and black henna tattoos. According to the North American Contact Dermatitis Group, the frequency of sensitization to PPD has been found to be 5.0%.65 Management strategies commonly used are outlined in Table 18–4. A thorough history in addition to patch testing (the gold standard) will often identify the culprit.
TABLE 18–4.Overview of Treatment of Acute Contact Dermatitis ||Download (.pdf) TABLE 18–4. Overview of Treatment of Acute Contact Dermatitis
|Identification of contactant and future avoidance |
|Drying agents, such as topical aluminum sulfate or calcium acetate: if weeping |
|Emollients: lichenified lesions |
|Corticosteroids, topical, rarely systemic: for severe reactions |
|Calcineurin inhibitors (tacrolimus or pimecrolimus) |
|Cyclosporine (oral) |
|Phototherapy, ultraviolet A or B |
Irritant dermatitis, although clinically indistinguishable from direct damage to the skin and does not require prior antigen sensitization. Still, the inflammatory response to the initial mild insult is the cause of the majority of the damage. Irritant xenobiotics include acids, bases, solvents, and detergents, many of which, in their concentrated form or after prolonged exposure, can cause direct cellular injury. The specific site of damage varies with the chemical nature of the xenobiotic. Many xenobiotics can affect the lipid membrane of the keratinocyte, but others can diffuse through the membrane, injuring the lysosomes, mitochondria, or nuclear components. When the cell membrane is injured, phospholipases are activated and affect the release of arachidonic acid and the synthesis of eicosanoids. The second-messenger system is then activated, leading to the expression of genes and the synthesis of various cell surface molecules and cytokines. Interleukin-1 is secreted, which can activate T cells directly and indirectly by stimulation of granulocyte-macrophage colony-stimulating factor production. Treatment is similar to allergic contact dermatitis.
Photosensitivity may be caused by topical or systemic xenobiotics. Nonionizing radiation, particularly to ultraviolet A (UVA) (320–400 nm) and less often to ultraviolet B (UVB) (280–320 nm), are the wavelengths that commonly cause photosensitivity. There are generally two types of xenobiotic-related photosensitivies, phototoxic and photoallergic.39 Phototoxic reactions occur within 24 hours of the first exposure, usually within hours, and are dose related. These reactions result from direct tissue injury caused by UV-induced activation of a phototoxic xenobiotic. The clinical findings include erythema, edema, and vesicles in a light-exposed distribution and resemble a severe sunburn that can last for days to weeks with patients complaining of burning and stinging (Fig. 18–12). A subtype of phototoxic reaction includes phytophotodermatitis in which linear streaks of erythema occur after skin contact with furocoumarins from plants plus exposure to sunlight (Table 18–2). Photoallergic reactions occur less commonly, may occur after even small exposures, and resemble allergic contact dermatitis with lichenoid papules or an eczematous dermatitis on exposed areas and is often pruritic. These are type IV hypersensitivity reactions that develop in response to a xenobiotic that has been altered by absorption of nonionizing radiation, acting as a hapten and eliciting an immune response on first exposure. Only on recurrent exposure do the lesions develop. Studies indicate that benzophenone-3 (oxybenzone), often found in sunscreen, is the most common cause of photoallergic dermatitis.8,16 Other common photoallergens include xenobiotics such as promethazine, NSAIDs, fragrances, and antibacterial agents. Photoallergic reactions can be diagnosed by the use of photopatch tests. Both phototoxic and photoallergic reactions are managed with symptomatic treatment, including topical or, if needed, systemic corticosteroids. Identification and avoidance of the triggering xenobiotic are crucial in addition to avoidance of sun exposure and wearing a broad-spectrum sunscreen (SPF 30 or above) that blocks both UVA and UVB preferably without para-aminobenzoic acid (PABA). PABA is a sensitizing agent to many patients and is rarely included in current sunscreen products.
Phototoxicity associated with a heterocyclic antidepressant. Note the erythema and edema on sun-exposed areas and sparing of sun-protected chest and shaded upper lip and neck. (Photo contributed by Dr. Adrian Tanew. Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw-Hill; 2008.)
A number of environmental xenobiotics are associated with localized or diffuse sclerodermalike reactions. Sclerodermatous refers to a tightened, indurated surface change of the skin that typically occurs on the face, hands, forearms, and trunk and is three times more common in women. This may be accompanied by facial telangiectasias and Raynaud syndrome. Raynaud syndrome consists of skin color changes of white, blue, and red accompanied by intense pain with exposure to cold and can cause acral ulcerations if left untreated. The fibrotic process usually does not remit with removal of the external stimulus, and specific autoantibodies are absent. The association of sclerodermalike reactions with polyvinyl chloride manufacture is likely related to exposure to vinyl chloride monomer. Similar reports of this syndrome are associated with exposure to trichloroethylene and perchloroethylene, which are structurally similar to vinyl chloride. Epoxy resins, silica, and organic solvents have been implicated as environmental causes. The xenobiotics bleomycin, carbidopa, pentazocine, and taxanes are causative.
In Spain, patients exposed to imported rapeseed oil mixed with an aniline denaturant developed widespread cutaneous sclerosis. This became known as the “toxic oil syndrome.” A similar syndrome, after ingestion of contaminated l-tryptophan as a dietary supplement used as a sleeping aid, resulted in the eosinophilia myalgia syndrome, which is characterized by myalgia, paralysis, edema, arthralgias, alopecia, urticaria, mucinous yellow papules, and erythematous plaques.54
Xenobiotics have the potential to cause distinctive patterns of hair loss (Table 18–2). Anagen effluvium, or hair loss during the anagen stage of the growth cycle, is caused by interruption of the rapidly dividing cells of the hair matrix, producing rapid hair loss within 2 to 4 weeks. Telogen effluvium, or toxicity during the resting stage of the cycle, typically produces hair loss 2 to 4 months later and occurs as a side effect of medication or in the setting of systemic disease or altered physiologic states (eg, postpartum). Anagen toxicity is commonly associated with xenobiotic exposures such as to doxorubicin, cyclophosphamide, vincristine, and thallium.56 Many antineoplastics reduce the mitotic activity of the rapidly dividing hair matrix cells, leading to the formation of a thin, easily breakable shaft. Thallium, a toxin classically associated with hair loss, causes alopecia by two mechanisms. Thallium distributes intracellularly, similar to potassium, altering potassium-mediated processes and thereby disrupting protein synthesis. By binding sulfhydryl groups, thallium also inhibits the normal incorporation of cysteine into keratin. Thallium toxicity results in alopecia 1 to 4 weeks after exposure. Within 4 days of exposure, a hair mount observed using light microscopy will demonstrate tapered or bayonet anagen hair with a characteristic bandlike black pigmentation at the base. Seeing this anagen effect can reveal the timing of exposure (Chap. 102). Soluble barium salts, such as barium sulfide, are applied topically as a depilatory to produce localized hair loss. The mechanism of hair loss is undefined.
The nail consists of a horny layer the “nail plate” and four specialized epithelia: proximal nail fold, nail matrix, nailbed, and hyponychium. The nail matrix consists of keratinocytes, melanocytes, Langerhans cells, and Merkel cells.
Nail hyperpigmentation occurs for unclear reasons but may be caused by focal stimulation of melanocytes in the nail matrix leading to melanonychia. The pigment deposition can be longitudinal, diffuse, or perilunar in orientation and typically develops several weeks after chemotherapy.56 Black dark-skinned patients are more commonly affected because of a higher concentration of melanocytes. Cyclophosphamide, doxorubicin, hydroxyurea, zidovudine, and bleomycin are among the most common xenobiotics that cause melanonychia, and the pigmentation generally resolves with cessation of therapy. When approaching a patient with a single streak of longitudinal melanonychia, it is crucial to include nail melanoma in the differential diagnosis.
Nail findings may serve as important clues to xenobiotic exposures that have occurred in the recent past. Matrix keratinization, in a programmed and scheduled pattern, leads to the formation of the nail plate. Certain changes in nails, such as Mees and Beau lines, result from a temporary arrest of the proximal nail matrix proliferation. These lines can be used to predict the timing of a toxic exposure because of the reliability of rate of growth of the nails at approximately 0.1 mm/d. Mees lines, first described in 1919 in the setting of arsenic poisoning, can be used to approximate the date of the insult by the position of growth of the Mees line a patterned leukonychia (not indentation) causing transverse white lines.34 Multiple Mees lines suggest multiple exposures over time. Arsenic, thallium, doxorubicin, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil are examples of xenobiotics that cause Mees lines, but Mees lines may be noted after any period of critical illness such as sepsis or trauma. Beau lines are transverse grooves or indentations more often in the central portion of the nail plate, most commonly caused by trauma (eg, manicures) or dermatologic disease affecting the proximal nailfold. Beau lines present on multiple digits, especially at the same level on each nail, indicate a systemic illness or xenobiotic exposure (Fig. 18–13).
Presence of proximal indented Beau line and distal band of leukonychia caused by cyclophosphamide seen 3 months after bone marrow transplantation. (Reproduced, with permission, from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill; 2012.)