eMedicine Specialties > Infectious Diseases > Skin and Soft-Tissue Infections

Erythema Multiforme (Stevens-Johnson Syndrome)

Author: Don R Revis Jr, MD, Consulting Staff, Department of Surgery, Division of Plastic and Reconstructive Surgery, University of Florida College of Medicine
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Updated: Aug 5, 2009

Introduction

Background

Erythema multiforme (also known as Stevens-Johnson syndrome [SJS]) and toxic epidermal necrolysis (TEN) are often confused in the medical literature.

In 1860, Ferdinand von Hebra initially described erythema multiforme as an acute, self-limited condition with characteristic red papular skin lesions.¹ The papules evolve into pathognomonic target lesions or iris lesions that appear within a 72-hour period and begin on the extremities. Lesions remain in a fixed location for at least 7 days and then begin to heal. Precipitating factors include herpes simplex virus (HSV), Epstein-Barr virus, and histoplasmosis. Because this condition may be related to a persistent antigenic stimulus, recurrence is the rule rather than the exception, with most affected individuals experiencing 1-2 recurrences per year. Erythema multiforme is typically a benign, self-limited disorder.

SJS is a mucocutaneous disorder. It was first described by Stevens and Johnson in 1922 as febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption.² Lesions typically begin on the face and trunk. They are flat, atypical lesions, described as irregular purpuric macules with occasional blistering. Most patients also have extensive mucosal involvement. More than 50% of all cases are attributed to medications. This is a more serious illness and is potentially life threatening.

The confusion between these two separate clinical entities began in 1950, when Thomas coined the terms erythema multiforme minor and erythema multiforme major to describe conditions he encountered.

• Erythema multiforme minor was applied to patients with the illness originally described by von Hebra as erythema multiforme.
• Erythema multiforme major was applied to patients who also displayed oral mucosal involvement, similar to that described by Stevens and Johnson.

Up to 50% of patients with HSV-associated erythema multiforme have been found to have oral ulcers. However, this is now recognized as a variant of erythema multiforme, rather than SJS. Because SJS and erythema multiforme have different precipitating factors and different clinical patterns, the terms erythema multiforme major and erythema multiforme minor should no longer be used.

• Erythema multiforme with mucosal involvement is now termed bullous erythema multiforme.
• SJS is recognized as a separate clinical entity.

Lyell first described TEN in 1956.³ His original description made no reference to the work of Stevens and Johnson. The distinction between SJS and TEN is not clear. In fact, these conditions probably represent differing severities of the same disease process.

SJS and TEN have similar precipitating factors, identical histopathologic lesions, and similar clinical patterns. By current convention, the following terminology is used:

• The term SJS is used when the disease involves less than 10% of the total body surface area.
• TEN is used when the disease involves more than 30% of the body surface area.
• Patients whose disease involves 10-30% of their body surface area are said to have SJS/TEN overlap. Mortality increases as the percentage of involved body surface increases, making TEN the more severe of the skin reactions.

This article explores SJS in greater detail.

Pathophysiology

The pathophysiology of SJS is not completely understood. The disease process is probably immunologically mediated and often involves an abnormal metabolism of the responsible drug. The keratinocyte is the ultimate target of this disease process with keratinocyte necrosis being the earliest pathological finding.

Patients frequently display an altered metabolism of the responsible drug, and are considered to be slow acetylators, both genotypically and phenotypically. This means that an increased proportion of drug metabolism is directed toward the alternative pathway of oxidation by the cytochrome P-450 system, resulting in increased production of reactive and potentially toxic metabolites. Affected individuals have a defect in the ability to detoxify these reactive metabolites, which may then behave as haptens by binding covalently to proteins on the surface of epithelial cells. This may then induce the immune response, leading to the severe skin reaction.

Cell-mediated immunity appears to be responsible for the destruction of epithelial cells observed in SJS. Early in the disease process, the epidermis becomes infiltrated with CD8 T lymphocytes and macrophages, while the dermis displays a slight influx of CD4 lymphocytes. These immunologically active cells are not present in sufficient numbers to be directly responsible for epithelial cell death. Instead, they release diffusable cytokines, which mediate the inflammatory reaction and resultant apoptosis of epithelial cells. In some patients, circulating T cells transiently demonstrate (for <30 d) a TH1 cytokine response (interferon gamma, tumor necrosis factor [TNF] alpha, interleukin 2). Results of immunohistochemical analysis have also shown lesion blister fluid to contain TNF, an important proinflammatory cytokine.

Other evidence supports the hypothesis that SJS is the result of cell-mediated immune reactions. Individuals possessing HLA-B12 are 3 times more likely to develop this disorder. The classic timing for a primary cell-mediated immune reaction is 9-14 days after the initiation of the offending drug. In recurrent exposure, the reaction occurs within several hours to 1-2 days, which is consistent with the timing of a secondary cell-mediated immune response.

Frequency

International

Frequency is estimated at approximately 1.2-6 cases per million individuals per year. The following medical conditions seem to predispose individuals to a higher risk of developing the disorder: HIV infection, corticosteroid exposure, bone marrow transplant, systemic lupus erythematosus, graft versus host disease, and inflammatory bowel disease. Individuals undergoing radiation, chemotherapy, or neurosurgery for brain tumors are also at higher risk.

For more information on inflammatory bowl disease, see Medscape's Inflammatory Bowel Disease Resource Center.

Mortality/Morbidity

• The mortality rate is approximately 5% and is directly proportional to the total body surface area of sloughed epithelium. Sepsis secondary to loss of the cutaneous barrier is the principle cause of death.
  
  

  

  Note extensive sloughing of epidermis in a patient with Stevens-Johnson syndrome. Courtesy of David F. Butler, MD.

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  Note extensive sloughing of epidermis in a patient with Stevens-Johnson syndrome. Courtesy of David F. Butler, MD.

• Advanced age, visceral involvement, increased serum urea nitrogen level, and prior bone marrow transplant are poor prognostic factors. Surprisingly, although the incidence is increased among individuals with HIV (approaching 1 case per 1000 individuals per year), they do not appear to have a higher mortality rate.

Race

• SJS occurs throughout the world in all racial or ethnic groups exposed to medications.

Sex

• Before the HIV epidemic among young males, there was a slight female predominance of this disease.
• Incidence is now approximately equal between the sexes.

Age

• All age groups are susceptible.
• The median age is approximately 48 years.
• Elderly individuals have an increased incidence and severity of disease.

Clinical

History

Patient history may include the presence of an influenzalike prodrome consisting of fever, cough, and malaise.

• Ten to 30% of patients relate this history.
• Patients may also present with mucocutaneous eruptions with the following characteristics:
  • The classic time course of development
  • Lesions that are usually symmetrical and that extend from the face and torso to the trunk and proximal extremities
  • Difficulty eating or drinking secondary to oral ulceration
  • Painful micturition secondary to genitourinary tract ulceration
  • Photophobia, burning eyes, or visual impairment secondary to ocular ulceration
  • Profuse diarrhea secondary to gastrointestinal tract ulceration
  • Shortness of breath or difficulty in breathing secondary to tracheobronchial epithelial involvement
• Obtain a history of all medications, with particular attention to those started in the previous 2 months.
• Obtain a history of recent or current HSV or Mycoplasma pneumoniae infection, which may cause erythema multiforme.
• Patients may have a history of anxiety.

Physical

• Discrete, irregular, flat, dark red, purpuric macules
  • Macules begin as symmetrically distributed lesions over the face and trunk.
  • Over the course of a few hours or days, the lesions rapidly progress to involve the abdomen, back, and proximal extremities.
  • By definition, lesions cover less than 10% of total body surface area.
  • The center of each lesion may reveal a blister or a denuded, red, oozing dermis.
• Mucous membrane involvement is noted in 90% of patients. The most common sites in order of frequency are the oropharynx, conjunctivae, genitalia, anus, tracheobronchial tree, esophagus, and bowel.
• Hyperventilation and mild hypoxia may result from anxiety or tracheobronchial involvement.
• Mild temperature elevation is usually noted.
• Dehydration may range from mild to massive as a result of the following factors:
  • Evaporation through open skin lesions
  • Poor oral intake secondary to oropharyngeal mucous membrane involvement
  • Profuse diarrhea from involvement of bowel mucosa
  • Increased insensible losses secondary to elevated core body temperature

Causes

• More than 50% of cases are related to medication use, but no test reliably proves the link between a single case and a specific drug.
• Over 100 different drugs have been implicated in numerous case reports.  
  • Sulfonamides are generally considered the most common cause, accounting for 30% of all cases. These include the following agents:
    • Sulfadoxine and pyrimethamine (Fansidar-R)
    • Sulfadiazine
    • Sulfadoxine
    • Sulfasalazine
    • Trimethoprim-sulfamethoxazole
  • The second most commonly involved agents are the anticonvulsants.  
    • Carbamazepine
    • Phenobarbital
    • Phenytoin
  • The following medications are also implicated in the evolution of Stevens-Johnson syndrome (SJS):  
    • Acetaminophen
    • Allopurinol
    • Aminopenicillins
    • Amithiozone
    • Amoxapine
    • Barbiturates
    • Cephalosporins
    • Chlormezanone
    • Clobazam
    • Diclofenac
    • Fluvoxamine
    • Hydantoins
    • Imidazole antifungals
    • Indapamide
    • Lamotrigine
    • Macrolides
    • Mianserin
    • Oxicam nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, piroxicam, tenoxicam)
    • Propionic NSAIDs
    • Propranolol
    • Pyrazolone derivatives (eg, dipyrone)
    • Quinolones
    • Salicylates
    • Sertraline
    • Tetracycline
    • Tiapride
    • Trazodone
    • Valproic acid
• Following the institution of a new drug regimen, the mean time of onset of clinical disease is 9-14 days. The highest risk occurs during the first 2 months following the initiation of a new medication.
• The second most common cause of SJS is infectious agents, with numerous agents being implicated.
• The following infectious diseases have also been reported to cause this disorder:  
  • Adenoviruses
  • Calmette-Guérin virus
  • Deep fungal infections
  • Enterobacter
  • Enteroviruses
  • HSV
  • Influenza
  • Measles
  • Mumps
  • Mycobacterium tuberculosis
  • M pneumoniae
  • Streptococcus pneumoniae
  • Syphilis
  • Typhoid fever

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