Autoimmune Blistering Disorders
Primary bullous dermatoses associated with autoantibodies to various components of the epidermis and underlying basement membrane zone of the skin (1) include bullous pemphigoid, pemphigus vulgaris, bullous lupus erythematosus, acquired epidermolysis bullosa acquisita, linear immunoglobulin A (IgA) bullous dermatosis, vancomycin and other drug-induced linear IgA dermatoses, and paraneoplastic pemphigus. Patients with these conditions have flaccid to tense bullae, with or without an erythematous, urticarial base, distributed in a localized or generalized fashion on the skin and mucosal surfaces. Because some of these disorders may be associated with significant morbidity and mortality, patients suspected of having an autoimmune blistering disorder should undergo skin biopsy for routine histologic and special staining (direct immunofluorescence to identify the site of deposited immunoglobulin within the epidermis). Particularly in the treatment of pemphigus vulgaris, very aggressive therapies, including prednisone, cytotoxic agents, and plasmapheresis, may be required (2). The various patterns of these disorders are as follows.
Bullous pemphigoid typically includes mild asymptomatic oral involvement and tense skin blisters on an urticarial base; affected patients are usually older than age 60. Herpes gestationis is similar to bullous pemphigoid, but it occurs in association with pregnancy. Pemphigus vulgaris is associated with extensive oral lesions and flaccid cutaneous blisters that exhibit a positive Nikolsky sign in which pressure applied to a blister causes the blister to enlarge by spreading outward into the adjacent skin.
Bullous diseases associated with systemic disease or medications include paraneoplastic pemphigus, bullous lupus erythematosus, and drug-induced linear IgA derma-tosis. Paraneoplastic pemphigus (PNP) (3), like pemphigus
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vulgaris, is associated with extensive oral lesions but, unlike pemphigus vulgaris, cutaneous lesions are variable and may include bullous pemphigoid-like lesions with tense vesiculobullae, erythema multiforme-like lesions with targetoid “bulls eye” lesions, and lichen planus-like lesions with violaceous flat topped papules and plaques, usually with an upper body predominance. A recent review has summarized the malignancies and frequencies thereof associated with PNP: over 80% of neoplasms are hematologic-related malignancies and include non-Hodgkins lymphoma (39%), chronic lymphocytic leukemia (18%), Castleman disease (18%); associated nonhematologic associated malignancies include epithelial-origin-carcinoma (9%), mesenchymal origin-sarcoma (6%), and melanoma (<1%) (4). Bullous lupus erythematosus occurs in the setting of systemic lupus erythematosus; lesions may resemble those seen in bullous pemphigoid with vesiculobullous lesions on an urticarial base or may appear more erythema multiforme-like with targetoid, hemorrhagic blisters. Vancomycin and other drug-induced linear IgA dermatoses appear similar to bullous pemphigoid. The eruption typically clears within weeks of withdrawal of the inciting drug, however occasionally the eruption persists, thereby defining idiopathic linear IgA disease, unmasked by a drug. In general, one will want to consult with a dermatologist if there is any doubt about the diagnosis or treatment of a patient suspected of having a form of autoimmune blistering disorder.
Photosensitivity
Photosensitivity is an abnormal response to natural sunlight or artificial ultraviolet (UV) radiation or visible light. It manifests as a diffuse macular erythema (phototoxic reaction) or a papular or papulovesicular erythema (e.g., photoallergic reaction) on the exposed surfaces. The phototoxic or sunburn-like reaction is caused by phototoxic drugs such as sulfonamides, quinolones, doxycycline, phenothiazines, nonsteroidal anti-inflammatory drugs (NSAIDs), porphyrin precursors, and psoralens. Just like a sunburn, it is either asymptomatic or painful. This is a nonimmunologic toxic reaction that occurs in any patient who has a sufficiently high serum level of a photoactivated drug and sufficient UVA (wavelength from 320 to 400 mm) radiation exposure. Besides the usual summer sunlight, other significant UVA exposures should be remembered: wintertime sunlight, most intense on highly reflective snow covered high altitude places like ski slopes, sunlight passing through car windows (unlike UVB, spanning wavelengths from 290 to 320 mm, longer wavelength UVA does pass through glass), and tanning salon sessions. Although any of these drugs may cause severe phototoxicity, the most frightening reaction and outcome results when psoralen is taken before tanning salon or natural sunlight exposure. Indeed, death from burns has occurred with tanning salon exposure after taking psoralen. Patients may unknowingly receive a severe phototoxic reaction if they take any of these drugs and attend a tanning salon session or sun bathe.
Sun-exposed site pruritic, papular, or papulovesicular erythema may represent a drug-induced photoallergic eruption, polymorphous light eruption, or cutaneous lupus erythematosus. The drug-induced photoallergic eruption is a cell-mediated immune reaction that is most often caused by thiazides, NSAIDs, sulfonamides and sulfonylureas, oral contraceptives, and quinidine. Polymorphous light eruption is a common idiopathic disorder in which patients develop a pruritic papular eruption on the extensor surface of the arms and other sun-exposed sites, typically sparing the chronically sun-exposed (“hardened”) face. The eruption typically occurs with each of the first several beach, pool, or picnic sun exposures in the late spring or summer months. After these two or three exposure-associated rashes, patients usually become hardened on the sites of the prior eruption, showing a tan, and have no further problems until the next spring or summer. When the diagnosis of photoallergic drug eruption or polymorphous light eruption cannot be made based on the patient's appearance and clinical course (photoallergy should resolve with drug withdrawal and polymorphous light eruption should resolve with continued sun exposure), further evaluation for possible lupus erythematosus, including skin biopsy, should be done. A dermatologist should be consulted if there is doubt about the diag-nosis.
In all patients with photosensitive disorders, appropriate protective sun-blocking clothing and high sun protection factor (e.g., sun protection factor [SPF] 30) sunscreens should be used. These eruptions are caused primarily by UVA radiation in the case of drug eruptions and UVB and UVA radiation in the case of polymorphous light eruption and lupus erythematosus. UVA passes through window glass and patients who are photosensitive or on photosensitizing drugs should be made aware to avoid sunlight received through glass.
Sunscreens and Sunblocks
Sunscreens or sunblocks and physical protection should be recommended not only for people with photosensitivity, but also for all individuals receiving significant ultraviolet radiation exposure, regardless of whether it is “sunny or overcast.” Albeit undesirable, when sunburn does occur, it serves as a great reminder to use protection in the future. Sunburn is not reversible, thus treatment is palliative (oral analgesics, tepid water baths, and appropriate hydration); corticosteroids have no effect on sunburn. Suntanning should be discouraged not only because it may cause sunburn, “liver spots” (solar lentigos), leathery skin
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and wrinkling, but, most impotantly because both UVB and UVA are known carcinogens which cause skin cancer.
Although there have been conflicting reports about a possible causative association between sunscreen use and melanoma, a meta-analysis of studies identified through a MEDLINE search of publications between the years 1966 and 2003, which examined sunscreen use prior to the development of melanoma, found no association between sunscreen use and melanoma. Although this analysis did not find a protective effect of sunscreen use, the authors commented that this lack of an association may have been because of the fact that the studies analyzed may have failed to control for significant confounders (5). Regardless, we can assure patients that sunscreens may be used safely in combination with appropriate physical protection (clothing, hats, sunglasses, umbrellas) and minimization of exposure during of peak UV radiation (UVR) hours surrounding noontime.
Sunscreens contain chemicals that absorb UVR. Adverse reactions to any sunscreen may occur. These chemicals are altered by radiation, and this is believed to be the cause of burning and stinging that may occur with higher SPF sunscreens, particularly when used on the face. Such reactions are most common in fair-skinned women especially if also using α-hydroxy acid or retinoic acid-based (e.g., Renova, Retin-A) facial creams. The alternative to sunscreens for people who experience either stinging or true allergic reactions are sunblocks. These block rather than absorb UVR and include plain zinc oxide (visibly white) and micronized zinc oxide and titanium dioxide (translucent when applied). Sunblocks tend to be less cosmetically acceptable because they have a chalky feel; however, they effectively block both UVB and UVA.
Sunscreens and sunblocks are given an SPF rating, which is the ratio of time needed for UV-radiation to cause minimal erythema (redness) when using versus not using the sunscreen. In the laboratory, an SPF of 15 screens 92% of UVB, and an SPF of 30 screens 96% of UVB. However, most sunscreen users apply significantly less than 50% of the amount of lotion needed for this protection, turning an SPF 30 product effectively into an SPF 15 product, at best. For this reason, it is best to recommend an SPF 30 sunscreen. Finally, because some people may ordinarily obtain some or all of their vitamin D from the sun instead of through their daily diet or by taking supplemental vitamins, the recommendation for sunscreens and sun avoidance should also include a recommendation for adequate daily vitamin D ingestion (see Chapter 103).
Drug Eruptions
Numerous prescription and nonprescription medications may cause a wide array of cutaneous abnormalities and aggravate pre-existing dermatoses (Table 118.1). It has been estimated that in hospitalized patients, 1% to 3% have adverse cutaneous drug reactions and 2% of these reactions are severe, being associated with significant morbidity and potential mortality (6,7). A systematic review of the MEDLINE database from 1966 to 2000 identified nine large studies containing primary data on the rates of cutaneous reactions to drugs. Analysis of these studies revealed “remarkable agreement” between the studies on reaction rates to drugs, with antibiotics causing most reactions (8). Although this is a large body of data, one might question the accuracy of diagnoses of drug reactions when not systematically confirmed. An interesting addition to this data is a prospective survey of cutaneous drug reactions occurring in a single hospital in Paris, France over a 6-month period. In this study, criteria for diagnosis were quite strict; patients were examined by a dermatologist and a group of dermatologists and pharmacologists evaluated “the drug imputability and preventability” after reviewing the patient's history, timing of medications, and appearance and timing of the eruption. The calculated prevalence of cutaneous drug reactions in these hospitalized patients was 3.6 per 1000, significantly less than the above stated rates of “1% to 3%.” Similar to past studies, the majority of the eruptions were attributable to antibiotics (mostly penicillins). Fifteen percent of reactions were judged to be preventable. Interestingly, 31% of the patients with reactions had a history of a prior immunologic reaction to a drug, suggesting a possible genetic susceptibility for drug reactions. It should be noted that in these patients diagnosed with reactions, imputability was “definitive” in only 44% and “probable” in the remaining 56%, thereby highlighting the difficulty in defining rates of drug reactions even when systematic evaluation is performed (9). Excluding urticaria (Coombs and Type I immunologic reaction) and vasculitis (Type III immunologic reaction), cutaneous drug reactions are considered “delayed hypersensitivity reactions” (Type IV immunologic reactions), mediated by activated T cells with activation of different T-cell subsets leading to varied reactions, including exanthems (e.g., macular and papular exanthem), eczema (e.g., systemic allergic contact dermatitis), bullous reactions (e.g., bullous fixed drug eruption, erythema multiforme, toxic epidermal necrolysis, linear IgA bullous drug eruption), and pustular eruptions (pustular exanthem) (10).
Urticaria
Chapter 1 discusses urticaria.
Exanthems
The most commonly seen acute drug-induced eruption is a pruritic exanthem. This is usually macular and papular (morbilliform) but may be a purely macular erythema, exfoliative erythroderma, or scarlatiniform eruption.
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Although innumerable drugs may cause this eruption, the most commonly implicated drugs include penicillins and semisynthetic penicillins, cephalosporins, sulfonamides, quinidine, cimetidine, allopurinol, carbamazepine, phenytoin, isoniazid, and nitrofurantoin.
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TABLE 118.1 Adverse Cutaneous Drug Reactions and Some Common Causative Drugs |
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Although data suggest that patient-reported history regarding drug allergy, particularly penicillin allergy, may be incorrect (11), it should always be presumed to be accurate, and if the decision is made to administer the drug, a reaction must be anticipated. When the question of possible immediate reaction (IgE, anaphylaxis) to penicillins and cephalosporins arises, testing may be done to confirm or exclude an IgE mediated allergy (see Chapter 30). Unfortunately, such testing is not available for other drugs or for other types of immune reactions.
Eruptions may begin at any time but usually occur at one of two periods of drug administration: after 2 to 3 days or after 9 to 10 days. The early form is seen in patients who have previously been sensitized to the drug. With this prior sensitization, an exanthem may or may not have occurred, depending on the timing of sensitization and how soon the drug was stopped. The more delayed reaction occurring 9 to 10 days after drug initiation occurs in patients not previously sensitized to the drug. Systemic manifestations of drug sensitivity are absent. In contrast, when visceral hypersensitivity occurs (i.e., “drug hypersensitivity syndrome” or drug rash with eosinophilia and systemic symptoms [DRESS]), onset is usually 2 to 8 weeks after initiation of the offending drug, however, onset may be more delayed (e.g., as seen in minocycline hypersensivity syndrome). Eosinophilia occurs in combination with variable organ involvement, which may include the lymph nodes, kidneys, liver, spleen, lungs, gastro-intestinal tract, pancreas, heart, thyroid gland, peripheral nerves, parotid and salivary glands, and bone marrow. Hypersensivity syndromes are most commonly due to anticonvulsants (phenytoin, phenobarbital, carbamazepine, lamotrigine), allopurinol, isoniazid, and minocycline, but have also been reported with several drugs (e.g., ter-binafine, sulfasalazine, hydrochlorothiazide, cyclosporine, nevirapine) (10,12,13). Rarely, an exanthem may be complicated by the subsequent development of yet another immunologic reaction, e.g., toxic epidermal necrolysis (see Toxic Epidermal Necrolysis below).
With uncomplicated nonbullous cutaneous eruptions, the suspected causative drug should be stopped if possible,
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and topical treatment begun to reduce pruritus. Such treatment includes frequent application of bland, topical, over-the-counter preparations containing menthol or phenol such as Sarna or Sarna HC (with 1% hydrocortisone) lotion or Aveeno Anti-Itch cream. In contrast, systemic drug hypersensitivity syndromes require immediate intervention with prompt discontinuation of all suspected drugs and close observation (7).
Erythema Multiforme
Erythema multiforme is a mucocutaneous hypersensitivity syndrome caused most commonly by a drug or infection. It is divided into erythema multiforme minor and erythema multiforme major, depending on whether it affects one or more than one mucosal surface, respectively (7,14). Although the pathogenesis of erythema multiforme is unknown, it is believed that an infection or a drug leads to a cell-mediated cytotoxic reaction in the epidermis.
Erythema multiforme major, which accounts for approximately 20% of cases of erythema multiforme, may cause morbidity and even mortality. It is associated with drugs more often than erythema multiforme minor, but similar infections may cause both forms. Patients usually have a prodrome of malaise, myalgia, fever, and sometimes upper respiratory symptoms. The eruption develops rapidly, is generally widespread, and involves at least two mucosal surfaces, usually the conjunctiva and the oral mucosa. Cutaneous lesions evolve quickly from macules into target-like plaques with dusky centers (Fig. 118.1, Color Plate section), often surmounted by blisters and often confluent over large areas. Usually, the lips are covered with hemorrhagic crusts and the mucosa shows diffuse pseudomembranous denudation, and the eyes show conjunctival injection, erosions, or exudate. Less often the nasal, genital, esophageal, and, rarely, the respiratory mucosae are involved.
The most common and significant acute complication of erythema multiforme major is secondary bacterial infection and sepsis; the most devastating long-term complication is ocular scarring and vision loss. Patients with erythema multiforme major must be hospitalized and, depending on the extent of disease, may benefit from care in a burn unit. Ophthalmologic consultation should be obtained immediately.
Erythema multiforme minor causes 80% of all cases of erythema multiforme. It is seen in patients of all ages but is more common in patients who are between the ages of 20 and 40 years. Most cases of erythema multiforme minor are caused by a preceding herpes simplex virus infection. Most patients with recurrent erythema multiforme minor, even those without a history of HSV infection, have detectable HSV deoxyribonucleic acid (DNA) in the lesions. Causes of erythema multiforme minor other than herpes simplex infection include other viral infections, Mycoplasma pneumoniae, other bacterial infections, and drugs (most commonly sulfonamides, penicillins, NSAIDs, and anticonvulsants).
Erythema multiforme minor begins with asymptomatic to tender erythematous to violaceous macules that evolve into papules with an expanding border, leaving a nonblanchable, dusky, slightly depressed center, creating an iris or target lesion. Lesions may coalesce into plaques or become bullous (bullous erythema multiforme). The eruption favors the palms and soles, dorsal hands and feet, and knees and elbows, but may be widely distributed. Approximately 20% of patients have mucosal lesions with mild to extensive flaccid bullae and deep erosions of the lips, buccal mucosa, and gingiva. Erythema multiforme is occasionally limited to the mouth without cutaneous lesions. Patients may have associated fever and malaise. If the diagnosis cannot be made on clinical grounds, skin biopsy should be done and will show necrotic keratinocytes, epidermal and dermal edema, and a mononuclear cell infiltrate. The treatment of erythema multiforme minor involves identification of the causative drug or infection and withdrawal of any suspected offending drug. Although necessary, treatment of a causative infection does not change the course of the erythema multiforme. For symptomatic relief, the oral lesions may be treated with an oral suspension containing diphenhydramine and antacid (e.g., Benadryl Elixir and Maalox in equal parts; swish for 1 minute and expectorate, four to six times per day) or sucralfate (e.g., Carafate 16 g [16 tabs] in 60 mL water; add to 180 mL 70% sorbitol; paint on erosions with finger as needed) in combination with 3% hydrogen peroxide washes (swish for 15 seconds and expectorate or swab with dental sponge four to six times per day). Topical anesthetics (Xylocaine gel) may be applied to individual painful lesions before meals. The use of systemic corticosteroids is controversial, and consultation with a dermatologist is recommended. One should note that if used, corticosteroid therapy should be given early in the course of the disease. If given after the eruption has fully evolved, one would not be expected to alter the severity of erythema multiforme and use of corticosteroids may increase the risk of secondary infection and even impair healing. In cases of recurrent erythema multiforme minor triggered by HSV, prophylactic acyclovir should be given to prevent HSV re-currences.
Toxic Epidermal Necrolysis
Toxic epidermal necrolysis (TEN), fortunately uncommon, is associated with a 25% to more than 40% mortality rate. Because it has many features in common with erythema multiforme major, these reactions are believed to represent a continuum of one disease. TEN is most often caused by drugs, especially sulfonamides, anticonvulsants, NSAIDs, allopurinol, colchicine, cephalosporins, quinolones, and aminopenicillins (14).
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Similar to a sunburn, TEN typically begins with a diffuse painful erythema, often first noted on the trunk. Rapidly, patchy, and then coalescing areas of dusky epidermal necrosis and skin sloughing develop. Oral and ocular manifestations are similar to the changes seen in erythema multiforme major. Although the diagnosis is made presumptively and appropriate management initiated, biopsy should be done to confirm the diagnosis if there is any question. Routine histopathology reveals epidermal necrosis with sloughing of the epidermis from the dermis and a sparse mononuclear perivascular dermal infiltrate.
Patients with TEN are critically ill and may develop a number of associated problems, including cytopenias, hepatitis, hypoalbuminemia, hypophosphatemia, prerenal azotemia, disseminated intravascular coagulation, and pancreatitis (7). These patients should urgently be admitted to a hospital and for intensive care, ideally in a burn unit. Urgent consultation with a burn unit or medical intensivist, a dermatologist or plastic surgeon, and an ophthalmologist should be obtained. Debate is ongoing as to whether high-dose intravenous immunoglobulin (IVIG) therapy is useful in patients with TEN, as some retrospective analyses have demonstrated reduced mortality rates while others have not (15,16). In a recent “negative” retrospective analysis of 16 patients treated with IVIG and 16 not so treated, mortality rates were 25% and 38%, respectively, but this appreciable difference in mortality did not reach “statistical significance” as the number of patients studied was small. Unfortunately, or fortunately, large studies of TEN patients are common because of the relative rarity of TEN (16). Until randomized, double-blind placebo controlled studies are available, some treatment centers have begun administering IVIG to patients with TEN, as the natural history of this disorder is associated with such a high mortality rate and the risk of IVIG therapy is low. Regardless of treatment, mortality is most often the result of sepsis, whereas chronic morbidity in survivors is most often caused by cutaneous and ocular scarring, with the latter potentially leading to severe vision loss.
Nonspecific Eruptions Secondary to Drugs
Toxicity in the Elderly
Drug toxicity is an important cause of cutaneous eruptions in patients with declining renal or hepatic function, particularly when they are on multiple drugs that compete for hepatic metabolism or renal secretion. Such situations are typical of the elderly, who are most at risk for drug reactions in general (see Chapter 12).
Toxic drug eruptions may occur at any time while the patient is taking a drug. When an eruption occurs months or even years after the start of a drug, a toxic drug reaction is often not considered. Such instances of toxicity after many months of drug administration may result in pruritus with an associated or resultant dermatitis and possibly exacerbation of previously existing skin diseases (e.g., psoriasis, atopic dermatitis). Drug withdrawal in this situation usually leads to a slow improvement over several weeks. Toxic drug reactions should be considered in patients complaining of new, usually symmetric, dermatoses or exacerbation of previously stable skin conditions, even if a patient has been on a drug for months or years. Whenever possible, such drugs should be eliminated or reduced in dosage (17, 18, 19).
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.