Introduction
Background
Erythema multiforme (EM) was initially described in 1866 by Ferdinand von Hebra as an acute self-limited skin disease, symmetrically distributed on the extremities with typical and often recurrent concentric "target" lesions. The term EM minor was proposed later to differentiate the mild cutaneous syndrome from the more severe form, EM major, which involves several mucous membranes.
Target lesion of erythema multiforme. Image courtesy of Chulabhorn Pruksachatkunakorn, MD.
Stevens-Johnson syndrome (SJS) was considered an extreme variant of EM for many years, while toxic epidermal necrolysis (TEN) was considered a different entity. However, in 1993, a group of medical experts proposed a consensus definition and classification of EM, SJS, and TEN based on a photographic atlas and extent of body surface area involvement.1 According to the consensus definition, SJS was separated from the EM spectrum and added to TEN. Essentially SJS and TEN are considered severity variants of a single entity. The two spectra are now divided into (1) EM consisting of erythema minor and major (EMM) and (2) SJS/TEN. The clinical descriptions are as follows:
- EM minor - Typical targets or raised, edematous papules distributed acrally
- EM major - Typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes; epidermal detachment involves less than 10% of total body surface area (TBSA).
- SJS/TEN - Widespread blisters predominant on the trunk and face, presenting with erythematous or pruritic macules and one or more mucous membrane erosions; epidermal detachment is less than 10% TBSA for SJS and 30% or more for TEN.
Pathophysiology
Pathophysiology of EM is not completely understood but appears to involve a hypersensitivity reaction that can be triggered by a variety of stimuli, particularly bacterial, viral, or chemical products.
A recent international prospective study showed that the major cause of EM is herpes virus. It appeared to play a smaller role in SJS/TEN. In fact, recent or recurrent herpes was the principle risk factor for EMM. Drugs were found to be a more common trigger for SJS/TEN.
Histopathologic characteristics include a lymphocytic infiltrate at the dermal-epidermal junction and around dermal blood vessels, dermal edema, epidermal keratinocyte necrosis, and subepidermal bullae formation. Histology and immunochemistry studies have shown that inflammatory infiltrates of EM and SJS/TEN are strikingly different in density and nature. EM has a high density of cell infiltrate rich in T-lymphocytes. By contrast, SJS/TEN is characterized by a cell-poor infiltrate of macrophages and dendrocytes with strong TNF-alpha immunoreactivity. Immune complex deposition is variable and nonspecific. In severe cases, fibrinoid necrosis can occur in the stomach, spleen, trachea, and bronchi.
Frequency
United States
The true incidence of EM is unknown, but it has been estimated to be between 0.01 and 1%. Incidence of SJS and TEN are better characterized and estimated at 0.4-1.2 and 1.2-6 per million person-years, respectively.
International
Similar to US incidence
Mortality/Morbidity
- EM not usually associated with any mortality. Most cases are self-limited and resolve without sequelae in 2-4 weeks.
- SJS has a mortality around 5%.
- TEN has a mortality approximately 30%.
Sex
EM affects males more often than females, with a male-to-female ratio ranging from 3:2 to 2:1. Incidence of SJS and TEN are equal in males and females.
Age
All ages are affected, with a peak incidence in the second through fourth decades of life, 20% occur in children and adolescents. This condition is rare in persons younger than 3 years and older than 50 years. EM occurs more in younger patients, while SJS and TEN occur more in older persons.
Clinical
History
In addition to characterizing skin and mucous membrane lesions of erythema multiforme, a complete history should document recent constitutional symptoms, prior history of herpes simplex infection, and use of prescription and over-the-counter medications.
- Erythema multiforme
- Sudden onset of rapidly progressive, symmetrical, and cutaneous and/or mucocutaneous lesions, with concentric color changes in some or all lesions
- Centripetal spread
- Burning sensation in affected areas
- Pruritus generally absent
- Nonspecific prodromal symptoms suggestive of a viral syndrome in at least 50% of cases, usually 1-14 days before skin lesions develop. Symptoms may include fever, malaise, myalgias, arthralgias, headache, sore throat, cough, nausea, vomiting, and diarrhea.
- SJS/TEN
- Generalized cutaneous and/or mucocutaneous lesions with blisters
- May include symptoms of fever, malaise, myalgias, arthralgias, headache, sore throat, cough, nausea, vomiting, and diarrhea
- Oral pain, which may be severe enough to result in difficulty eating, drinking, or opening the mouth
- Eye pain, edema, and drainage
- Breathing difficulty resulting from tracheobronchial involvement
- Dysuria
Physical
- Erythema multiforme
- Symmetrically distributed, erythematous, expanding macules or papules evolve into classic iris or target lesions, with bright red borders and central petechiae, vesicles, or purpura.
- Lesions may coalesce and become generalized.
- Vesiculobullous lesions develop within preexisting macules, papules, or wheals.
- Rash favors palms and soles, dorsum of the hands, and extensor surfaces of extremities and face.
- Postinflammatory hyperpigmentation or hypopigmentation may occur.
- Eye involvement occurs in 10% of EM cases, mostly bilateral purulent conjunctivitis with increased lacrimation.
- Mucous membrane blistering occurs in about 25% of cases of EM, is usually mild, and typically involves the oral cavity.
- SJS/TEN
- Fever is common.
- Skin findings may be similar to EM but often are more variable and severe. Inflammatory vesiculobullous lesions, often with hemorrhage and necrosis, are typical. Fixed macules and target lesions may be larger and more confluent than in EM.
- Facial edema or central facial involvement
- Mucous membranes are strongly affected, most commonly mouth, lips, and bulbar conjunctivae; less often, anogenital mucosae are affected. Lips may be edematous, bloody, or crusted. A minimum of 2 mucosal surfaces must be involved; 3 mucosal surfaces are involved in about 40% of cases.
- Blisters or epidermal detachment less than 10% BSA for SJS and more than 30% for TEN; the outer layer of the epidermis separates readily from the basal layer with lateral pressure (positive Nikolsky sign).
- Bullae and shallow ulcers resembling aphthous ulcers are common. When bullae rupture, mucosal lesions become deeply erythematous erosions, often covered by gray pseudomembranous exudates.
- Salivation often is increased.
- Nasopharynx, respiratory tract, GI tract, and genitourinary (GU) tract are sometimes affected.
- Genital involvement consists of hemorrhagic, bullous inflammation; urinary retention and phimosis may occur.
- Eye involvement occurs in approximately 85% of cases. These range from hyperemia to extensive pseudomembrane formation. Synechiae between eyelid and conjunctiva often occurs. Keratitis and corneal erosions are less frequent.
Causes
Approximately 50% of cases are idiopathic, with no precipitating factor identified. Many potential triggers have been implicated as possible causes of EM, SJS, and TEN. Most notably causes are infectious agents and drugs. All 3 disorders are linked to drugs with TEN being exclusively attributed to this factor. Infectious causes are more common in children and are implicated more commonly in EM. Herpes simplex infection is the most common cause in young adults and is strongly associated with recurrent EM. The most prevalent bacterial precipitant is Mycoplasma pneumoniae.
- Viral
- Herpes simplex I & II
- Adenovirus
- Coxsackievirus B5
- Echoviruses
- Enteroviruses
- Epstein-Barr
- Hepatitis A
- Hepatitis B
- Measles
- Vaccinia
- Varicella
- Influenza
- Mumps
- Poliovirus
- Bacterial
- Mycoplasma pneumoniae
- Proteus species
- Salmonella species
- Tuberculosis
- Vibrio parahaemolyticus
- Psittacosis
- Catscratch disease
- Brucella species
- Tularemia
- Gonorrhea
- Typhoid fever
- Diphtheria
- Lymphogranuloma venereum
- Cholera
- Yersinia enterocolitica
- Fungal
- Histoplasmosis
- Coccidioides species
- Postvaccination
- Bacille Calmette-Guérin (BCG)
- Oral polio vaccine
- Vaccinia
- Tetanus/diphtheria
- Drugs
- Sulfonamides, including hypoglycemics
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Anticonvulsants
- Barbiturates
- Antituberculous drugs
- Antibiotics
- Pyrazolones
- Phenylbutazone, oxyphenbutazone, and phenazone
- Salicylates
- Malignancy
- Hormonal
- Collagen vascular disease
- Immunologic disorders (sarcoidosis, vasculitides, transient selective C4 deficiency)
- Physical/mechanical factors (tattooing, radiotherapy, cold, sunlight, contactants)
- Risk factors
- Previous history of EM
- Male sex
- Herpes simplex infection
More on Erythema Multiforme |
 Overview: Erythema Multiforme |
| Differential Diagnoses & Workup: Erythema Multiforme |
| Treatment & Medication: Erythema Multiforme |
| Follow-up: Erythema Multiforme |
| Multimedia: Erythema Multiforme |
| References |
| Next Page » |
References
Bastuji-Garin S, Rzany B, Stern RS. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. Jan 1993;129(1):92-6. [Medline].
Assier H, Bastuji-Garin S, Revuz J. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol. May 1995;131(5):539-43. [Medline].
Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schroder W, Roujeau JC. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. Aug 2002;138(8):1019-24. [Medline].
Chapel TA, Chapel J. Erythema multiforme. In: Tintinalli J, et al, eds. Emergency Medicine: A Comprehensive Study Guide. 4th ed. McGraw Hill Text; 1996:1114-1116.
Dore J, Salisbury RE. Morbidity and mortality of mucocutaneous diseases in the pediatric population at a tertiary care center. J Burn Care Res. Nov-Dec 2007;28(6):865-70. [Medline].
Forman R, Koren G, Shear NH. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a review of 10 years' experience. Drug Saf. 2002;25(13):965-72. [Medline].
Fritsch PO, Elias PM. Erythema multiforme and toxic epidermal necrolysis. In: Fitzpatrick TB, et al, eds. Dermatology in General Medicine. 4th ed. McGraw-Hill Professional Publishing; 1993:585-600.
Hazin R, Ibrahimi OA, Hazin MI, Kimyai-Asadi A. Stevens-Johnson syndrome: pathogenesis, diagnosis, and management. Ann Med. 2008;40(2):129-38. [Medline].
Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. Jun 1983;8(6):763-75. [Medline].
Katta R. Taking aim at erythema multiforme. How to spot target lesions and less typical presentations. Postgrad Med. Jan 2000;107(1):87-90. [Medline].
Le Duc M, King MS. Erythema multiforme. In: Dambro M, ed. Griffith's 5 Minute Clinical Consult. Lippincott Williams & Wilkins; 1997:376-377.
Leaute-Labreze C, Lamireau T, Chawki D. Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome. Arch Dis Child. Oct 2000;83(4):347-52. [Medline].
Martinez AE, Atherton DJ. High-dose systemic corticosteroids can arrest recurrences of severe mucocutaneous erythema multiforme. Pediatr Dermatol. Mar-Apr 2000;17(2):87-90. [Medline].
Paquet P, Pierard GE. Erythema multiforme and toxic epidermal necrolysis: a comparative study. Am J Dermatopathol. Apr 1997;19(2):127-32. [Medline].
Power WJ, Ghoraishi M, Merayo-Lloves J. Analysis of the acute ophthalmic manifestations of the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum. Ophthalmology. Nov 1995;102(11):1669-76. [Medline].
Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol. Nov 1997;24(11):726-9. [Medline].
Roujeau JC. The spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis: a clinical classification. J Invest Dermatol. Jun 1994;102(6):28S-30S. [Medline].
Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. Nov 10 1994;331(19):1272-85. [Medline].
Simmons HM. Vesiculobullous eruptions. In: Schwartz GR, et al, eds. Principles and Practice of Emergency Medicine. 3rd ed. Williams & Wilkins; 1992:2315-2320.
Stampien TM, Schwartz RA. Erythema multiforme. Am Fam Physician. Oct 1992;46(4):1171-6. [Medline].
Stern RS. Improving the outcome of patients with toxic epidermal necrolysis and Stevens-Johnson syndrome. Arch Dermatol. Mar 2000;136(3):410-1. [Medline].
Tatnall FM, Schofield JK, Leigh IM. A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol. Feb 1995;132(2):267-70. [Medline].
Villiger RM, von Vigier RO, Ramelli GP, et al. Precipitants in 42 cases of erythema multiforme. Eur J Pediatr. Nov 1999;158(11):929-32. [Medline].
Williams PM, Conklin RJ. Erythema multiforme: a review and contrast from Stevens-Johnson syndrome/toxic epidermal necrolysis. Dent Clin North Am. Jan 2005;49(1):67-76, viii. [Medline].
Further Reading
Keywords
erythema multiforme, erythema multiforme major, erythema multiforme minor, EM major, EM minor, Stevens-Johnson syndrome, acute mucocutaneous hypersensitivity reaction, skin eruption, toxic epidermal necrolysis, TEN, centripetal spread, vesiculobullous lesions, herpessimplex infection, Mycoplasma pneumoniae, drug eruptions
