Miscellaneous Inflammatory Diseases of the Skin and Cutaneous Drug Reactions

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[edit] Miscellaneous Inflammatory Diseases of the Skin and Cutaneous Drug Reactions

James C. Shaw

[edit] URTICARIA

[edit] Epidemiology

Urticaria (hives) occurs at any age without preference to genetic population, age, or sex. Up to 20% of the population is affected at some time with urticaria. The majority of cases are acute and self-limited. A small number persist beyond 6 weeks and are termed chronic urticaria. Multiple causative factors exist (Box 95-1).

[edit] Autoantibodies.

Recently, autoantibodies to IgE receptors on mast cells have been demonstrated in patients with chronic idiopathic urticaria. Up to one-third to one-half of patients with chronic urticaria have demonstrated such autoantibodies.^[1] This information may help to explain the large group of patients with no known trigger factor identified.

[edit] Pathophysiology

Urticaria occurs when cutaneous mast cells release histamine and other inflammatory mediators into the dermis, causing capillary fluid leakage, inflammatory cell infiltrate, and stimulation of sensory nerves. The results are pruritic raised lesions observed clinically.

Immunologically induced urticaria is most commonly a type 1 IgE-mediated process in which circulating antigens bind with IgE receptors at the cell membrane and trigger the enzyme-activated degranulation. In up to half of patients with chronic idiopathic urticaria, there are circulating autoantibodies against the high affinity IgE receptor, or IgE, or both. Less commonly, immune complexes cause urticaria through the activation of complement. In nonimmunologically induced urticaria, the same enzymatic cellular response is induced by certain pharmacologic or physical stimuli such as morphine, strawberries, or vibration.

[edit] Patient Evaluation

[edit] History.

The diagnosis of urticaria is usually evident after a brief history and examination. The history of pruritic wheals lasting up to several hours is typical. The pruritus can be intense. A history of a swollen tongue or lips and epigastric discomfort can imply gastrointestinal involvement, and the presence of wheezing or pharyngeal swelling suggests an anaphylactic reaction. Obtaining a detailed history is an essential part of determining the cause of the urticaria.Box 95-2 lists some important points to consider when taking a history.

[edit] Physical Examination.

Sharply demarcated raised areas of erythema with variable size and shape (circular, annular, serpiginous), ranging in size from 0.5 cm papules to 20 cm plaques are typical (see Plate 4 ). Central clearing is common. Any area of the body can be involved. A complete examination may be needed to identify possible causes such as infection and internal disease.

[edit] Diagnosis

[edit] Diagnostic Procedures.

Biopsy can be confirmatory and can be useful in excluding the presence of vasculitis, erythema multiforme, or drug reactions.

[edit] Laboratory Evaluation.

Laboratory evaluation is helpful in those cases where the history or physical examination suggest an association with other disease. Tests can include complete blood count, serum chemistries, urinalysis, and antinuclear antibodies.

[edit] Management.

If a cause can be identified and eliminated, pharmacologic treatment of the urticaria may not be required. Frequently the cause cannot be identified and management consists of controlling the development of new lesions and reducing symptoms. Antihistamines control the majority of patients with acute and chronic urticaria. Antihistamines competitively block histamine receptors, but do not prevent mast cell release of inflammatory mediators. They are therefore most effective when administered continuously as a preventive therapy. Combinations of antihistamines may be necessary to suppress the development of urticaria. The H₁ blockers diphenhydramine and hydroxyzine are commonly used in doses ranging from 25 mg to 100 mg every 8 hours as tolerated by sedation. The nonsedating H₁ blockers (cetirizine, loratidine, fexofenadine) can be useful during the day in patients who are intolerant of the sedation. The tricyclic antidepressant doxepin is a potent H₁ blocker that can be used in difficult cases. Because of sedation, doxepin is best administered at night. Evidence for the addition of H₂ blockers (cimetidine, ranitidine) is lacking, and these drugs should not be considered unless maximal use of H₁ blockers has failed.

Systemic corticosteroids can be tried in recalcitrant cases to suppress autoantibody formation. Although many cases ultimately resolve spontaneously without a proved cause, a systematic elimination of some ingested substances can be helpful (Box 95-3).

[edit] ERYTHEMA MULTIFORME

Erythema multiforme is an acute self-limited disease of skin and mucous membranes that consists of characteristic clinical lesions and histopathology. The severity of erythema multiforme is variable, ranging from mild cases with few lesions to a widespread vesiculobullous form (Stevens-Johnson syndrome), which is discussed later in this chapter.

[edit] Epidemiology

The true incidence of erythema multiforme is not known. Estimates range from 1 in 1000 to 1 in 10,000 persons. It is generally a disease of children, adolescents, and young adults.

[edit] Etiology

Infections and medications are the most common causes of erythema multiforme. The most common association is with either recurrent Herpes Simplex virus (HSV) infection^[2] or mycoplasmal pneumonia.Boxes 95-4 and 95-5 list the infections and drugs that can cause erythema multiforme.

[edit] Pathophysiology

An immunologic mechanism of disease has been postulated as the cause of erythema multiforme. This is supported by the frequent association with the administration of medications and with some infections plus the finding of immune complexes containing herpesvirus DNA around the microvasculature of involved skin.

[edit] Patient Evaluation

[edit] History.

Patients usually report a rapid onset of lesions that may follow a short prodrome of malaise. The hands and feet are commonly involved in early stages. Mouth tenderness is common if there is mucosal involvement.A detailed history of recent illnesses, medications, and infections, including a past history of herpetic infection, is essential to identifying the cause.

[edit] Physical Examination.

The classic lesions of erythema multiforme are raised circular erythematous lesions, 0.5 cm to 3 cm in diameter. Central epidermal pallor with surrounding erythema produces the “target” or “iris” lesions that are described ( Plate 90 ). The central dusky gray pallor is caused by epidermal necrosis and can be mistaken for pustule formation. Mucosal lesions erode easily, presenting as shallow ulcerations. Although the distribution of erythema of erythema multiforme can be widespread, the distal extremities, including palms and plantar surfaces, are most commonly involved.

[edit] Diagnosis

[edit] Diagnostic Procedures.

Biopsy shows a lymphocytic infiltrate at the dermal-epidermal junction with a characteristic vacuolization of epidermal cells and necrotic keratinocytes within the epidermis. Blood studies may show a slight leukocytosis and elevation of the erythrocyte sedimentation rate. However, no consistent laboratory abnormalities are associated with erythema multiforme. The differential diagnosis of erythema multiforme can include other annular eruptions, such as urticaria and other figurate erythemas, and in the mouth, herpesvirus infection and blistering diseases in the pemphigus group.

[edit] Management.

Erythema multiforme is usually self-limited without treatment. Identification and treatment of any underlying illness may prevent recurrent episodes. In cases without an obvious trigger, the use of empiric treatment to suppress HSV infection has been shown to be effective in a majority of patients.^[3] Analgesics may be necessary in some cases. The use of systemic corticosteroids is controversial but may be helpful early in the disease.

[edit] STEVENS-JOHNSON SYNDROME

A widespread vesiculobullous form of erythema multiforme with involvement of mucosal surfaces is called Stevens-Johnson syndrome. The two diseases have been thought to represent variations of the same pathophysiologic mechanism. A recent review suggests that on the basis of different trigger factors Stevens-Johnson syndrome may be a different disease process than erythema multiforme.^[4]

[edit] Etiology

The causes of both erythema multiforme and Stevens- Johnson syndrome are similar (see Box 95-5). Radiation therapy and particularly cranial x-ray therapy, in association with the administration of antiseizure medications, appears to be associated with an increased incidence of erythema multiforme and Stevens-Johnson syndrome.

[edit] Patient Evaluation

[edit] History.

A rapid onset of skin and mucosal lesions associated with variable symptoms of malaise and fever are typical in Stevens-Johnson syndrome. Pain or burning in the conjunctivae and mouth are common early symptoms that may at first suggest an infectious etiology until more skin involvement is apparent. A detailed history of underlying diseases and exposure to medications is essential.

[edit] Physical Examination.

The extensive distribution and severity of the lesions are what distinguish Stevens-Johnson syndrome from erythema multiforme. Erosive changes on the lips, mouth, conjunctivae, anogenital area, and ears are typical ( Plate 91 ). Intact vesicles and bullae are uncommon in these areas. Cutaneous lesions may involve the entire skin surface. Individual lesions may be characteristic circular lesions of erythema multiforme, but it is more common to find large confluent areas of dusky erythematous skin, with occasional flaccid vesicles, bullae, and erosions. The lesions are usually tender to touch.

[edit] Diagnosis

[edit] Diagnostic Procedures.

Biopsy is frequently helpful in confirming the diagnosis. Histologic features are those of erythema multiforme. Viral cultures of intact vesicular lesions or mucosal erosions may be indicated to exclude herpesvirus infection.

[edit] Differential Diagnosis.

Stevens-Johnson syndrome should be differentiated from staphylococcal scalded skin syndrome, vesicular viral exanthems, Kawasaki's disease, toxic shock syndrome, and paraneoplastic pemphigus. The presence of the classic circular “target” or “iris” lesions plusthe erosive changes on the mucous membranes should allow for making the correct diagnosis.

[edit] Management.

While supportive treatment is essential, recent evidence supports the early use of high doses of corticosteroids. Control of pain and treatment of secondary infection may require narcotic analgesics and antibiotics. Patients with large areas of denuded skin need fluid and electrolyte management. Liquid diet or intravenous nutrition may be required when mouth lesions prevent intake by mouth. Eroded areas of skin should be cleansed gently and kept covered with occlusive compresses to prevent drying. Mucosal lesions should be kept moist by frequent application of antibacterial ointments or other protective agents.

The use of systemic corticosteroids has been controversial. Early studies demonstrated delayed healing and higher incidence of complications when steroids are used. More recent studies have demonstrated clear benefit when high doses of corticosteroids are used early in the disease course.^[5]

[edit] TOXIC EPIDERMAL NECROLYSIS

The widespread blistering disease called toxic epidermal necrolysis (TEN), or Lyell's syndrome, has many similarities to Stevens-Johnson syndrome and many consider the two to be variations of the same disease. Most authors agree that TEN and Stevens-Johnson syndrome are differentiated on the basis of the percentage of total body surface area involved, with TEN having greater than 30% to 40% involvement. Histologic differences between the two diseases suggest different mechanisms of disease.

[edit] Etiology

Clinical evidence points to drugs as the main cause of TEN. The list of drugs associated with TEN is similar to that associated with Stevens-Johnson syndrome, with anticonvulsants, nonsteroidal antiinflammatory agents and antibiotics being most commonly involved (see Box 95-5). Immunizations, some viral infections, and graft-vs.-host disease have also been implicated.

[edit] Pathophysiology

The pathophysiology of TEN is not known but most evidence supports an immune-mediated process. A genetic predisposition is suggested by the increased incidence of HLA B12 in patients with TEN. An interaction between the normally expressed Fas receptor and Fas ligand on keratinocytes has been recently demonstrated in TEN, with blockade of this interaction resulting in disease improvement.^[6]

[edit] Patient Evaluation

[edit] History.

The prodrome in TEN is similar to that of Stevens-Johnson syndrome, with two or three days of fever and malaise. The history of a new drug taken within one to three weeks before the onset of the illness is strong evidence of a causal relationship.

[edit] Physical Examination.

Extensive epidermal sloughing along with severe mucosal changes are characteristic of TEN ( Plate 92 ). The mucosal changes, which are present in over 90% of cases, frequently precede the skin involvement. The percentage of skin surface involvement can range from 40% up to 100%. The full-thickness epidermal detachment leaves painful areas of denuded dermis. Primary target lesions can also be seen occasionally.

[edit] Complications.

Complications contribute to the mortality rate in TEN that ranges between 25% and 70%. Sepsis is the main cause of death. Gastrointestinal hemorrhage, hypovolemia, and pulmonary edema have also contributed to mortality. Ocular complications include conjunctival scarring, corneal ulceration, and photophobia. Cutaneous complications include alopecia, loss of nails, pigmentary changes, and hypertrophic scarring with contractures.^[6]

[edit] Diagnosis

[edit] Diagnostic Procedures.

Biopsy can be helpful in differentiating between TEN and a less severe form of drug eruption. Epidermal separation with scant dermal infiltrate and characteristic necrotic keratinocytes is suggestive of TEN.

[edit] Differential Diagnosis.

Staphylococcal scalded skin syndrome in children is the main differential diagnosis to consider. Bullous graft vs. host disease can mimic TEN.

[edit] Management

[edit] Nonpharmacologic Therapy.

A burn center provides the best environment for the treatment of TEN. The skills and materials needed to treat TEN are similar to those used in burn care, including xenografts, temperature control, and nutritional management. Treatment consists of supportive measures designed to prevent complications and allow healing of all affected tissue. A successful approach requires the help of the surgical team, intensivist or internist, ophthalmologist, physical therapist, and expert nursing staff.

[edit] Pharmacologic Treatment.

Although there are no established treatments of TEN, recent work with intravenous immune globulin (IVIG) is promising. IVIG is thought to block the interaction between Fas receptor and Fas ligand to prevent keratinocyte death and was successfully used in a pilot study of 10 patients with TEN, in whom the disease reversed rapidly and all patients recovered.^[6]

[edit] ERYTHEMA NODOSUM

Erythema nodosum (EN) is the most common of a group of diseases under the heading of `panniculitis'.

[edit] Epidemiology

EN occurs mostly in young adults, with women affected more than men in a ratio of approximately 3-6:1. Since EN is considered an immunologic response to a variety of antigenic stimuli, prevalence rates vary on the basis of regional antigen exposures. Overall prevalence rates are in the range of 1:1000/year.

[edit] Pathophysiology

EN is thought to be a hypersensitivity reaction, but the exact type has not been determined. The immunologic reaction is centered in the subcutaneous fat. Numerous causes of EN have been reported including infections with bacteria, viruses, fungi, and parasites, medications (especially oral contraceptives), sarcoidosis, inflammatory bowel disease, malignancies, and collagen vascular diseases. A recent studyfrom France demonstrated predominance of streptococcal infections and sarcoidosis in patients with EN.^[7]

[edit] Patient Evaluation

[edit] History.

A prodrome that can include malaise, low grade fever, or arthralgias can be reported in the majority of patients with EN. This is followed in several days by characteristic tender lesions usually on extensor legs. A complete history looking for underlying disease, medications, and infections is essential.

[edit] Physical Examination.

Tender erythematous, smooth-topped, subcutaneous nodules present on extensor surfaces are characteristic ( Plate 93 ). Pretibial location is most common, but lesions may be present on upper extremities and trunk.

[edit] Diagnosis

[edit] Diagnostic Procedures.

A biopsy that includes involved subcutaneous fat is usually helpful, although the histologic findings are not pathognomonic. Other diagnostic evaluation is based on evidence from the history and physical examination and may include blood studies, chest x-ray, and cultures for bacterial or viral infection.

[edit] Differential Diagnosis.

The main differential diagnosis in EN is nodular vasculitis, sometimes called erythema induratum, which is associated with prior infection with Mycobacterium tuberculosis. Occasionally, it is difficult to differentiate between these two.

[edit] Management

[edit] Nonpharmacologic Therapy.

The disease is usually self-limited; thus identification and treatment of underlying disease or offending medication is most important. Bed rest with leg elevation is a time-honored treatment usually combined with pharmacologic treatment.

[edit] Pharmacologic Treatment.

Nonsteroidal antiinflammatory drugs (NSAIDs) are the treatment of choice, in conjunction with bed rest. In some cases, systemic corticosteroids (approximately 40 mg/day) for 1 or 2 weeks may be needed.

[edit] GRANULOMA ANNULARE

Granuloma annulare (GA) is an uncommon inflammatory skin disease that has a characteristic clinical presentation. The cause of GA is not known.

[edit] Epidemiology

Two forms of GA are seen most often. The localized form is most common and is a disease of men and women usually under age 50. A generalized form is seen between the ages of 40 and 70. Some studies have suggested an association between GA, especially the generalized form, and diabetes mellitus.

[edit] Pathophysiology

The pathophysiology of GA is not well understood. The presence of histiocytes and mucin in the dermis suggests an interaction between immune mediators and dermal fibroblasts.

[edit] Patient Evaluation

[edit] History.

A rapid onset of one or more areas of pruritus, commonly on the hands, feet, or elbows, is typical. Usually there are no identifiable trigger factors.

[edit] Physical Examination.

GA has a characteristic color and shape ( Plate 94 ). The color is a red-brown, reflecting histiocytes in the dermis. This color is similar to other granulomatous (histiocytic) diseases including sarcoidosis and leprosy. The shape is usually one or more annular ring of confluent papules. Individual papules may or may not be evident. The size of the annular ring can vary from 1 to 10 cm diameter. The center of the rings is usually clear, and there are usually no epidermal changes such as scaling or crust.

[edit] Diagnosis

[edit] Diagnostic Procedures.

A biopsy is usually diagnostic. The presence of histiocytes in a palisaded array surrounding dermis with increased mucin is typical.

[edit] Differential Diagnosis.

Other granulomatous diseases should be considered, such as sarcoidosis, leprosy, and other mycobacterial diseases, and necrobiosis lipoidica.

[edit] Management.

Although not life-threatening, this disease causes pruritus that can be severe, especially in the generalized form. Topical, intralesional, and systemic corticosteroids are the usual treatments. Dapsone and niacinamide have been used in the generalized form.

[edit] DRUG REACTIONS

Cutaneous reactions to drugs are common, can mimic virtually all forms of skin conditions, and should be in the differential diagnosis in all patients presenting with skin complaints.

[edit] Epidemiology

Drug rashes account for 2% of skin reactions in the hospital setting. They can affect all ages. Those most commonly associated with adverse reactions are antibiotics and nonsteroidal anti-inflammatory agents.^[8]

[edit] Pathophysiology

The cellular mechanisms of cutaneous drug reactions are largely unknown. Only about 25% of drug reactions have a clearly identified immunologic cause, i.e., one of the four types of hypersensitivity reactions. The mechanisms of nonimmunologic-mediated drug reactions include toxic overdose, idiosyncratic, drug interactions, and pharmacologic side effects. The mechanisms involved are urticaria, Stevens-Johnson syndrome, and EN, all of which are commonly drug induced and discussed earlier in this chapter.

[edit] Patient Evaluation

[edit] History.

The onset of a drug eruption is usually 5 to 10 days after the initiation of the drug or 2 days after reexposure in a sensitized patient. Drugs that are chemically related can cross-react (thiazides and sulfonylureas). All ingested chemicals are suspected, including vitamins, herbs, other over-the-counter preparations, recreational drugs, and food additives. When multiple drugs are being used, carefully noting the dates of administration and doses of each drug may be useful.Knowledge of which drugs are most likely to cause a rash is also crucial^[9](Box 95-6).

[edit] Physical Examination

[edit] Common Types of Drug Reactions.

Morbilliform (exanthematous, toxic erythema, maculopapular) eruptions are the most common of all drug rashes ( Plate 95 ). These eruptions often begin on the trunk and evolve onto the extremities. Pruritus is common, and mild fever can occur. Both usually begin within the first 2 weeks after a variety of drugs are taken and clear within 2 to 3 weeks after the drug is withdrawn. Fortunately, these are not associated with organ damage.

Lichen planus-like drug eruptions (lichenoid drug reaction) resemble lichen planus, with pruritic violaceous papules and plaques ( Plate 96 ). Gold and antimalarials are the most common culprit drugs (see Box 95-6).

Fixed drug eruptions ( Plate 97 ) are frequently misdiagnosed because of their unique presentation. One or several circular areas of violaceous erythema that may become bullous, followed by healing that leaves postinflammatory hyperpigmentation is the usual presentation. The samepresentation recurs every time the offending drug is ingested. A common site of involvement is the penis. In addition to common offenders, such as tetracycline and sulfa drugs, over-the-counter drugs such as pseudoephedrine and phenolphthalein found in some wines may cause this reaction.

Photosensitivity induced by drugs occurs by two main mechanisms: phototoxicity and photoallergic reactions. Phototoxicity can occur after the first exposure to the drug and results in cellular damage resembling a sunburn. Tetracyclines, thiazides, sulfonylureas, and NSAIDs are the usual causes of phototoxic reactions. Photoallergic drug reactions require sensitization and repeated exposure and are usually manifested by an eczematous pruritic eruption. Common causes of photoallergic reactions include chlorpromazine, promethazine, and topical sunscreen agents PABA, benzophenone, and cinnamates.

Drug-induced pigmentation can be caused by several drugs, either as a chemical pigment deposition or by stimulation of melanogenesis. Minocycline pigmentation is a blue-gray-black pigment deposit, commonly in scars but can be widespread ( Plate 98 ). Antimalarial pigmentation is also from a deposit of chemical pigment. Bleomycin causes an unusual streaked pigmentation that suggests prior scratching on the skin. Nail pigmentation can be seen with nucleoside antiretroviral drugs.

[edit] Diagnosis

[edit] Laboratory Studies/Diagnostic Procedures.

No laboratory tests can diagnose a drug eruption or identify a specific drug. Skin biopsy can help to identify the specific clinical form of the skin rash, but not whether a drug is the etiology. Skin tests for penicillin are only of use for predicting immediate hypersensitivity reactions such as hives and anaphylaxis. Rechallenging with the suspected agent is potentially dangerous.

[edit] Differential Diagnosis.

Viral exanthems, scarlet fever, Kawasaki disease, and exfoliative erythroderma can resemble drug eruptions. Viral exanthems are associated with enanthems, fever, and other viral symptoms. Exfoliative erythroderma also can be due to drugs, psoriasis, eczema, or cutaneous T-cell lymphoma.

[edit] Management

[edit] Nonpharmacologic Therapy.

Ideally, a nonpharmacologic approach, discontinuing the offending drug, clears the skin rash. When the patient is on multiple drugs, a drug should be withdrawn or switched when possible. Most cutaneous drug reactions remit within 2 to 3 weeks after the drug is stopped. Some drug reactions are serious, such as TEN, vasculitis, erythema multiforme, and exfoliative erythroderma and take a longer period to resolve.

[edit] Pharmacologic Treatment.

Judicious use of antipruritics, antihistamines, and occasionally systemic corticosteroids is helpful. Treatment of life-threatening drug eruptions is discussed in Chapter 86 .

[edit] REFERENCES