Chapter 177. Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis

A 14-year-old boy presents to the emergency department with a 1-day history of fever associated with lip swelling and peeling (Figure 177-1A). Within 48 hours he developed involvement of his ocular (Figure 177-1B) and urethral mucosa along with an erythematous papular rash on his trunk that spread to his extremities. In Figure 177-1C target lesions can be seen on the back. He was diagnosed with Stevens-Johnson syndrome and admitted to the hospital.

Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are skin disorders thought to be types of hypersensitivity reactions (undesirable reactions produced by a normal immune system in a presensitized host) that occur in response to medication, infection, or illness. Both SJS and TEN are severe cutaneous reactions thought to describe the same disorder, only differing in severity (TEN more severe); however, there is debate as to whether these three fall into a spectrum of disease that includes EM.

• EM has also been called EM minor.
• SJS has been called EM major in the past but it is now thought to be a distinct entity different from all types of EM.
• TEN is also known as Lyell syndrome.

• The incidence of EM has been estimated to range from 1 in 1000 persons to 1 in 10,000 persons.1 The true incidence of the disease is unknown.1
• SJS and TEN are rare severe cutaneous reactions often caused by drugs. Reports of incidence vary from 1.2 to 6 per 1 million for SJS and from 0.4 to 1.2 per 1 million for TEN.2-4
• EM most commonly occurs between the ages of 10 and 30 years, with 20% of cases occurring in children and adolescents.5
• With respect to EM, males are affected slightly more often than females.5

Numerous factors have been identified as causative agents for EM:

• Herpes simplex virus (HSV) I and HSV II are the most common causative agents, having been implicated in at least 60% of the cases (Figure 177-2).6,7
• The virus has been found in circulating blood,8 as well as on skin biopsy of patients with EM minor.6

For SJS and TEN, the majority of cases are drug induced.

• Drugs most commonly known to cause SJS and TEN are sulfonamide antibiotics, allopurinol, NSAIDs, amine antiepileptic drugs (phenytoin and carbamazepine), and lamotrigine.9
• Mycoplasma pneumoniae has been identified as the most common infectious cause for SJS.7

Other less-common causative agents for EM, SJS, and TEN include:

• Infectious agents such as Mycobacterium tuberculosis, group A streptococci, hepatitis B, Epstein Barr virus, Francisella tularensis, Yersinia, enteroviruses, Histoplasma, Coccidioides.1
• Neoplastic processes, such as leukemia and lymphoma.1
• Antibiotics, such as penicillin, isoniazid, tetracyclines, cephalosporins, and quinolones.
• Anticonvulsants, such as phenobarbital and valproic acid.1,7
• Other drugs, including captopril, etoposide, aspirin, and allopurinol.
• Immunizations, such as Calmette-Guérin bacillus, diphtheria-tetanus toxoid, hepatitis B, measles-mumps-rubella, and poliomyelitis.6
• Other agents or triggers, including radiation therapy, sunlight, pregnancy, connective tissue disease, and menstruation.1

Although the pathogenesis of EM, SJS, and TEN remains unknown, recent studies show that it may be as a result of a host-specific cell-mediated immune response to an antigenic stimulus that activates cytotoxic T-cells and results in damage to keratinocytes.6,9

• The epidermal detachment (skin peeling) seen in SJS and TEN appears to result from epidermal necrosis in the absence of substantial dermal inflammation.

• Recent evidence shows individuals with certain human leukocyte antigen (HLA) alleles may be predisposed to developing SJS/TEN when taking certain drugs.2
• Certain diseases, such as HIV/AIDS (Figure 177-3), malignancy, or autoimmune disease, also predispose individuals to SJS/TEN.2,10

Clinical Features

In all of these conditions, there is a rapid onset of skin lesions. EM is a disease in which patients present with the following lesions:

• Classic lesions begin as red macules and expand centrifugally to become target-like papules or plaques with an erythematous outer border and central clearing (iris or bull's-eye lesions) (Figures 177-4, 177-5, 177-6, and 177-7). Target lesions, although characteristic, are not necessary to make the diagnosis. The center of the lesions should have some epidermal disruption, such as vesicles or erosions.
• Lesions can coalesce and form larger lesions up to 2 cm in diameter with centers that can become dusky purple or necrotic.
• Unlike urticarial lesions, the lesions of EM do not appear and fade; once they appear they remain fixed in place until healing occurs many days to weeks later.
• Patients are usually asymptomatic, although a burning sensation or pruritus may be present.
• Lesions typically resolve without any permanent sequelae within 2 weeks.
• Recurrent outbreaks are often associated with HSV infection (Figure 177-2).6,7

In both SJS and TEN, patients may have blisters that develop on dusky or purpuric macules. SJS is diagnosed when less than 10% of the body surface area is involved, SJS/TEN overlap when 10% to 30% is involved, and TEN when greater than 30% is involved.

• Lesions may become more widespread and rapidly progress to form areas of central necrosis, bullae, and areas of denudation (Figure 177-1).
• Fever higher than 39°C (102.2°F) is often present.
• In addition to skin involvement, there is involvement of at least 2 mucosal surfaces, such as the eyes, oral cavity, upper airway, esophagus, GI tract, or the anogenital mucosa (Figures 177-1 and 177-3).
• New lesions occur in crops and may take 4 to 6 weeks to heal.
• Large areas of epidermal detachment occur (Figures 177-8, 177-9, and 177-10).
• Severe pain can occur from mucosal ulcerations but skin tenderness is minimal.
• Skin erosions lead to increased insensible blood and fluid losses, as well as an increased risk of bacterial superinfection and sepsis.
• These patients are at high risk for ocular complications that may lead to blindness. Additional risks include bronchitis, pneumonitis, myocarditis, hepatitis, enterocolitis, polyarthritis, hematuria, and acute tubular necrosis.

Typical Distribution

• The distribution of the rash in EM can be widespread.
• The distal extremities, including the palms and soles, are most commonly involved.
• Extensor surfaces are favored.
• Oral lesions may be present, especially in SJS (Figures 177-1 and 177-3).
• Severe lesions with exfoliation and extensive mucosal lesions occur in SJS and TEN (Figures 177-8, 177-9, and 177-10).

Laboratory and Imaging

• There are no consistent laboratory findings with these conditions. The diagnosis is usually made based on clinical findings.
• Routine blood work may show leukocytosis, elevated liver transaminases, and an elevated erythrocyte sedimentation rate.
• In TEN, leukopenia may occur.

Biopsy

• A cutaneous punch biopsy can be performed to confirm the diagnosis or to rule out other diseases.
• Histologic findings of EM will show a lymphocytic infiltrate at the dermal-epidermal junction. There is a characteristic vacuolization of the epidermal cells and necrotic keratinocytes within the epidermis.1

• Bullous pemphigoid—Can be either subacute or acute with tense widespread blisters that can occur after persistent urticaria; mucosal involvement is rare. Significant pruritus can be present. As with EM, SJS, and TEN, bullous pemphigoid can occur after certain exposures such as UV radiation, or certain drugs (Chapter 184, Bullous Pemphigoid).
• Urticaria—A skin reaction characterized by red wheals that are usually pruritic. Unlike EM, individual lesions rarely last more than 24 hours (Chapter 150, Urticaria and Angioedema).
• Kawasaki disease—Fever persists at least 5 days and there must be at least four of the following features11:
  • Changes in extremities—Acute: erythema of palms, soles; edema of hands and feet; or subacute: periungual peeling of fingers and toes in weeks 2 and 3.
  • Polymorphous exanthem.
  • Bilateral bulbar conjunctival injection without exudate.
  • Changes in lips and oral cavity—Erythema, lips cracking, strawberry tongue (see Chapter 34, Scarlet Fever and Strawberry Tongue), diffuse injection of oral and pharyngeal mucosae.
  • Cervical lymphadenopathy (>1.5 cm diameter), usually unilateral.
• Cutaneous vasculitis—Also caused by a hypersensitivity reaction, lesions are palpable papules or purpura. Blisters, hives, and necrotic ulcers can occur on the skin. Lesions are usually located on the legs, trunk, and buttocks (see Chapter 179, Vasculitis).
• Erythema annulare centrifugum—A hypersensitivity reaction caused by a variety of agents. Lesions look similar with erythematous papules of a few to several centimeters that enlarge and clear centrally and may be vesicular. Lesions tend to appear on the legs and thighs, but may occur on upper extremities, trunk, and face; palms and soles are spared (see Chapter 206, Erythema Annulare Centrifugum).
• Staphylococcal scalded skin syndrome—Rash may also follow a prodrome of malaise and fever but is macular, brightly erythematous, and initially involves the face, neck, axilla, and groin. Skin is markedly tender. Like SJS and TEN, large areas of the epidermis peel away. Unlike TEN, the site of the staphylococcal infection is usually extracutaneous (e.g., otitis media, pharyngitis) and not the skin lesions themselves (Chapter 116, Impetigo).

EM:

• The treatment is mainly supportive. Symptomatic relief may be provided with topical emollients, systemic antihistamines, and acetaminophen. These do not, however, alter the course of the illness.
• The use of corticosteroids has not been well studied, but is thought to prolong the course or increase the frequency of recurrences in HSV-associated cases.7
• Prophylactic acyclovir has been used to control recurrent HSV-associated EM with some success.7

SJS and TEN:

• Treatment again, is mainly supportive and may require intensive care or placement in a burn unit. Early diagnosis is imperative so that triggering agents can be discontinued.
• Oral lesions can be managed with mouthwashes and glycerin swabs.
• Skin lesions should be cleansed with saline or Burow solution (aluminum acetate in water).
• IV fluids should be given to replace insensible losses.
• Daily examinations for secondary infections should occur and systemic antibiotics should be started as needed.
• Consultation with an ophthalmologist is important because of the high risk of ocular sequelae.
• Pharmacologic therapy is widely debated in the literature. Evidence suggests that intravenous immunoglobulin (IVIG) at doses of 2 to 3 g/kg can help shorten the course and improve outcome if started early in the course of the disease.12
• Systemic corticosteroids have been the mainstay of treatment for SJS/TEN. Recent evidence, however, suggests there may be an increase in morbidity and mortality when used for TEN.12
• Other agents that have been tried with limited success include thalidomide, tumor necrosis factor (TNF)-α inhibitors, cyclophosphamide, cyclosporine, and plasmapheresis.

Screening populations known to carry HLA alleles prior to starting medications with higher risks for SJS/TEN has been suggested by some researchers.2

• EM usually resolves spontaneously within 1 to 2 weeks.
• Recurrence of EM is common, especially when preceded by HSV infection.
• Prognosis is poorer for patients with SJS and TEN if they are older, have a large percentage of body surface area involved, or have intestinal or pulmonary involvement.
• Mortality for SJS/TEN can be predicted based on the severity of illness score for TEN.13 One point is given for each of the following: serum blood urea nitrogen greater than 10 mmol/L; serum bicarbonate less than 20 mmol/L; serum glucose greater than 14 mmol/L; age older than 40 years; malignancy present; heart rate greater than 120 beats per minute; percentage of body surface area involved greater than 10%. Scores of 0 to 1 are associated with a mortality rate of 3.2% whereas scores of 5 or higher are associated with a mortality rate of 90%.
• For patients with SJS, mortality rates have been reported of 5% to 10% and up to 30% for TEN.9,14

• For uncomplicated cases, no specific follow-up is needed.
• For patients with EM major and any of the complications listed above, follow-up should be arranged with the appropriate specialist.

• If an offending drug is found to be the cause, it should be discontinued immediately.
• Patients with HSV-associated EM should be made aware of the risk of recurrence.

Patient Resource

• Erythema multiforme—http://www.nlm.nih.gov/medlineplus/ency/article/000851.htm.

Provider Resources

• Medscape. Erythema Multiforme—http://emedicine.medscape.com/article/1122915.
• Medscape. Stevens-Johnson Syndrome—http://emedicine.medscape.com/article/1197450.