AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Acknowledgments
• Multimedia
• References

Background

Erythema multiforme (EM) is an acute self-limited eruption characterized by a distinctive clinical eruption, the hallmark of which is the iris or target lesion. EM may present within a wide spectrum of severity. EM minor represents a localized eruption of the skin with mild or no mucosal involvement, corresponding to the initial description of von Hebra. EM major and Stevens-Johnson syndrome (SJS) are more severe mucosal and skin diseases and are potentially life-threatening disorders.

Recently, international collaborators have suggested that EM and SJS could be separated as 2 distinct clinical disorders with similar mucosal reactions but different patterns of cutaneous lesions. The clinical pictures are as follows:

• Mucosal erosions plus typical or raised atypical targets and epidermal detachment involving less than 10% of the body surface. The lesions are usually located on the extremities and/or the face. This characterizes herpes-induced EM major.
• Mucosal erosions plus widespread distribution of flat atypical targets or purpuric macules and epidermal detachment involving less than 10% of the body surface. The lesions may be present on the trunk, the face, and the extremities. These are characteristic findings of drug-induced SJS.

Pathophysiology

The pathophysiology of EM is still not completely understood; however, herpes-associated EM (HAEM) appears to represent the result of a cell-mediated immune reaction associated with herpes simplex virus (HSV) antigen. The immunologic reaction affects HSV-expressing keratinocytes. Cytotoxic effector cells, CD8⁺ T lymphocytes in the epidermis, induce apoptosis of scattered keratinocytes and lead to satellite cell necrosis. Neighboring epidermal cells are human leukocyte antigen DR (HLA-DR) positive. A relationship exists between human leukocyte antigen (HLA) types A33, B35, B62 (B15), DR4, DQB1*0301, DQ3, and DR53 and recurrent EM. HLA-DQ3 has been proven to be especially related to recurrent EM, and it may be a helpful marker for distinguishing HAEM from other diseases with EM-like lesions.

Frequency

United States

The exact incidence of EM is unknown; as many as 1% of dermatologic outpatient visits are for EM.

Mortality/Morbidity

Most cases of EM minor subside completely within 2-3 weeks without any complications. The mortality rate of EM major is reportedly less than 5%, and clearing requires a longer time than EM minor. EM major usually takes 3-6 weeks to heal.

Sex

Males are slightly more often affected than females.

Age

The highest incidence is in the second to fourth decades of life, with 20% of cases occurring in children and adolescents. Although it is extremely rare during the neonatal period, a 1-day-old newborn with early congenital syphilis has been reported with targetoid lesions.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Acknowledgments
• Multimedia
• References

History

• The prodromal symptoms are mild or absent in EM minor and may present as a mild nonspecific upper respiratory infection. The abrupt onset of a rash usually occurs within 3 days, starting on the extremities symmetrically with centripetal spreading.
• In EM major, 50% of patients have nonspecific prodromes, including moderate fever, general discomfort, cough, sore throat, vomiting, chest pain, and diarrhea. These symptoms are usually present for 1-14 days preceding the eruption. The lesions begin on the acral areas and spread similarly to the distribution of EM minor.
• Prominent mucosal involvement may occur in EM major. Erosions of the oral mucosa may result in difficulty in eating, in drinking, and in opening the mouth. Eye involvement may cause lacrimation and photophobia. Genital lesions are painful and may result in urinary retention.
• Skin tenderness is absent with an occasional mild burning sensation and itching.
• A localized form of EM has been reported at the site of marrow aspiration.
• One half of children who are affected have a history of herpes labialis or herpes genitalis. While the onset usually precedes EM by 3-14 days, it may still be present at the onset of EM. HAEM can be precipitated by exposure to the sun.

Physical

The hallmark of EM is a target lesion with variable mucous membrane involvement.

• Skin lesion
• • The initial lesion is a dull red macule or urticarial plaque expanding slightly to a maximum of 2 cm over 24-48 hours. In the center, a small papule, vesicle, or bulla develops, flattens, and then may clear. The intermediate ring develops and becomes raised, pale, and edematous. The periphery gradually changes to become cyanotic or violaceous and forms a typical concentric target lesion (see Media file 1).
  • Some lesions are atypical targets that consist of only 2 concentric rings.
  • Polycyclic or arcuate lesions may occur (see Media file 2).
  • The Koebner phenomenon may be observed.
  • The Nikolsky sign is negative.
• Skin distribution
• • The lesions appear predominantly on the extensor surfaces of the symmetrical acral extremities and spread centripetally.
  • The palms, the neck, and the face are frequently involved. Lesions of the soles and flexural aspects of the extremities are less frequent.
  • A zosteriform distribution has been observed.
• Mucosal lesions
• • Mucosal involvement is present in as many as 70% of patients with EM. The degree is usually mild with limitation to one mucosal surface.
  • Oral lesions are the most common, with the lips, the palate, and the gingiva often affected. More severe erosions of at least 2 mucosal surfaces are seen in EM major and are characterized by a hemorrhagic crusting of the lips and ulceration of the nonkeratinized mucosa (see Media file 3).
  • Extensive painful mucosal involvement with few or no skin lesions may be seen.
  • Eye involvement is usually mild and may present as red conjunctivae, chemosis, and lacrimation.
  • The genital areas may have painful, hemorrhagic bullae and erosions.
  • Mucosal lesions usually heal without sequelae. The mucosal involvement in SJS is more severe and extensive than in EM major.
• Other systemic involvement: Generalized lymphadenopathy often accompanies EM major.

Causes

Many suspected etiologic factors have been reported to cause EM (and many were published at a time when a distinction between EM major and SJS was not made). They are listed below. EM and SJS are both caused by drugs, but infectious agents are considered to be the major cause of EM. EM minor is regarded as commonly being triggered by HSV; many instances of idiopathic EM minor may be precipitated by subclinical HSV infection. Among the other infections, Mycoplasma infection appears to be a common cause. Drugs are reported in many documented cases of SJS and EM major. Sulfa drugs are the most common triggers. A slow acetylator genotype is a risk factor for sulfonamide-induced SJS. Prophylactic anticonvulsants after surgery for a brain tumor combined with cranial irradiation may result in life-threatening SJS.

• Infections
• • Bacterial - BCG vaccination, borreliosis, catscratch disease, diphtheria, hemolytic streptococci, legionellosis, leprosy, Neisseria meningitidis, Mycobacterium avium complex, pneumococcus, Proteus species, Pseudomonas species, Salmonella species, Staphylococcus species, Treponema pallidum, tuberculosis, tularemia, Vibrio parahaemolyticus, Vincent disease, Yersinia species, rickettsial infections, Mycoplasma pneumoniae
  • Chlamydial - Lymphogranuloma venereum, psittacosis
  • Fungal - Coccidioidomycosis, dermatophytosis, histoplasmosis
  • Parasitic - Trichomonas species, Toxoplasma gondii
  • Viral - Adenovirus, coxsackievirus B5, cytomegalovirus, echoviruses, enterovirus, Epstein-Barr virus, hepatitis A, hepatitis B, hepatitis C, herpes simplex, influenza, measles, mumps, paravaccinia, parvovirus B19, poliomyelitis, vaccinia, varicella-zoster, variola
  • Virus-Drug interaction – Cytomegalovirus infection–Terbinafine, Epstein-Barr virus infection-Amoxicillin
• Drugs
• • Antibiotics - Penicillin, ampicillin, tetracyclines, amoxicillin, cefotaxime, cefaclor, cephalexin, ciprofloxacin, erythromycin, minocycline, sulfonamides, trimethoprim-sulfamethoxazole, vancomycin
  • Anticonvulsants - Barbiturates, carbamazepine, hydantoin, phenytoin, valproic acid
  • Antipyretics - Analgesics, especially aspirin
  • Antituberculoids - Rifampicin, isoniazid, thiacetazone, pyrazinamide
  • Others - Acarbose, albendazole, allopurinol, arsenic, bromofluorene, chinine, cimetidine, clofibrate, corticosteroids, diclofenac, didanosine, dideoxycytidine, diphosphonate, estrogen, etretinate, fluconazole, griseofulvin, gabapentin, granulocyte-macrophage colony-stimulating factor, hydralazine, indapamide, indinavir, lamotrigine, methazolamide, mefloquine, methotrexate, meprobamate, mercurials, minoxidil, nifedipine, nevirapine, nitrogen mustard, nystatin, nonsteroidal anti-inflammatory drugs (NSAIDs), phenolphthalein, piroxicam, pyritinol, progesterone, potassium iodide, sulindac, suramin, saquinavir, thiabendazole, thiouracil, terbinafine, theophylline, verapamil
• Contactants - Ammoniated mercury, budesonide, bufexamac, capsicum, chloromethylnaphthalene, desoximetasone, dinitrochlorobenzene (DNCB), disperse blue 124, diphenylcyclopropenone, fire sponge (Tedania ignis), herbal medicines (eg, Alpinia galanga), isopropyl-p-phenylenediamine of rubber, nickel, nitrogen mustard, oxybenzone, phenylbutazone, poison ivy, proflavin, resin, rosewood, triamcinolone acetonide
• Flavorings and preservatives – Benzoic acid, cinnamon
• Immunologic disorders - Transient selective C4 deficiency of infancy
• Mechanical factors - Tattooing
• Foods - Salmon berries, margarine
• Physical factors - Radiotherapy, cold, sunlight
• Others - Collagen diseases, vasculitides, non-Hodgkin lymphoma, leukemia, multiple myeloma, myeloid metaplasia, polycythemia

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Disseminated lesions of contact dermatitis
Figurate erythema
Fixed drug eruption
Herpes gestationis
Lupus erythematosus
Urticaria
Primary herpetic gingivostomatitis
Major oral aphthae

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Acknowledgments
• Multimedia
• References

Lab Studies

• Complete blood cell count; electrolyte levels; BUN determination; erythrocyte sedimentation rate (ESR); liver function tests; and cultures from blood, sputum, and erosive areas are indicated in severe cases of EM major. In severe cases, elevated ESR, moderate leukocytosis, and mildly elevated liver transaminase levels may be found.
• Specific HSV antigens have been detected within keratinocytes by immunofluorescence study. The HSV DNA has been identified primarily within the keratinocytes by polymerase chain reaction amplification.

Procedures

• A histopathologic examination of a cutaneous punch biopsy should be performed to confirm the diagnosis and to rule out the other differential diagnoses.

Histologic Findings

The early lesion of EM is characterized by infiltration of lymphocytes at the dermal-epidermal interface with accompanying exocytosis and spongiosis in the epidermis. Individual eosinophilic necrotic keratinocytes may be scattered and surrounded by lymphocytes (satellite cell necrosis). The dermal changes include edematous papillary dermis, ectatic and swollen endothelial cells of the vessels, and extravasation of the red blood cells.

As lesions progress, partial-to-full-thickness epidermal necrosis, intraepidermal vesiculation, subepidermal blisters due to spongiosis, ballooning, vacuolar degeneration of the junctional zone, and severe papillary edema occur. Lymphohistiocytes (CD4⁺ more than CD8⁺ T lymphocytes) with a few neutrophils and occasional eosinophils comprise the dermal inflammatory infiltrate. Recently, an observation revealed that acrosyringeal keratinocyte necrosis and dermal inflammation containing eosinophils may occur in drug-related cases.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Acknowledgments
• Multimedia
• References

Medical Care

Identification of the cause should be made if possible. If a drug is suspected, it must be withdrawn. Infections should be appropriately treated after cultures and/or serologic tests have been performed.

• For all forms of EM, symptomatic treatment, including oral antihistamines, analgesics, local skin care, and soothing mouthwashes, is of great importance. Topical steroids may be considered.
• A liquid diet and intravenous fluid therapy may be necessary. Oral antacids may be helpful for discrete oral ulcers.
• Electrolytes and nutritional support should be started as soon as possible.
• The use of liquid antiseptics, such as 0.05% chlorhexidine, during bathing is preferable. Topical treatment, including that for genital involvement, may be performed with a gauze dressing or a hydrocolloid. Local supportive care for eye involvement is important and includes topical lubricants for dry eyes, sweeping of conjunctival fornices, and removal of fresh adhesions.
• Systemic corticosteroids are controversial, and some believe they may predispose to complications. Beneficial effects of hemodialysis, plasmapheresis, cyclosporin, immunoglobulin, levamisole, thalidomide, dapsone, and cyclophosphamide have been documented in case reports.

Consultations

• Obtain a dermatologic consultation for diagnosis and management.
• Consult an internal medicine specialist or a pediatric specialist for evaluation of the underlying causes of disorders and systemic sequelae.
• Obtain an early ophthalmologic consultation for evaluation and management of ocular involvement.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• EM major may require hospitalization for the treatment of complications and sequelae.

In/Out Patient Meds

• Prophylaxis for recurrence of HAEM should be considered in patients with more than 5 attacks per year.
• • Low-dose acyclovir (200 mg qd to 400 mg bid) can be effective for recurrence of HAEM, even in subclinical HSV infection. In children, the dosage of 10 mg/kg/d may be considered.
  • Prophylaxis may be required for 6-12 months or longer.
  • If unresponsive, continuous therapy of valacyclovir (500 mg bid) has been reported to be effective.
• Alternative treatments of EM include dapsone, antimalarials, azathioprine, cimetidine, and thalidomide.

Transfer

• The most severe cases should be managed in intensive care or burn units.

Deterrence/Prevention

• Sulfonamide-containing ointments should be avoided.

Complications

• Most patients have an uncomplicated course, with the exception of hosts who are immunocompromised and those with secondary bacterial infections of the skin or the mucosa.
• Severe oral involvement may be accompanied by difficulty in consuming food and fluid and can result in dehydration.
• Ocular complications may manifest as purulent conjunctivitis, dry eyes, anterior uveitis, panophthalmitis, scarring of the conjunctivae, symblepharon, and blindness.
• Vaginal and urethral lesions are infrequent. The erosions may cause urinary retention and phimosis. Hematocolpos is the result of genital lesions in teenage females. Severe scarring of the genitourinary tract may cause vaginal and urethral stenosis.

Prognosis

• In EM minor, the lesions ultimately subside within 2-3 weeks without scarring. The recurrence of EM minor is common and mostly preceded by apparent or subclinical HSV infection.
• EM major has a mortality rate of less than 5%. It usually takes a more protracted course than EM minor; clearing may require 3-6 weeks. Skin lesions usually heal with hyperpigmentation and/or hypopigmentation. Scarring is usually absent, except after secondary infection.
• Recently, 2 additional rare clinical forms of EM have been reported, one that is associated with a prolonged course, another that is resistant to conventional treatment; they are termed continuous EM and persistent EM. Continuous EM manifests as a prolonged course with overlapping attacks and may be associated with systemic administration of glucocorticoids. Persistent EM manifests as a protracted clinical course over months and is commonly associated with atypical skin lesions. It has been reported in association with inflammatory bowel disease, occult renal carcinoma, persistent or reactivated Epstein-Barr virus infection, and HSV infection.
• Healing of the mucosal areas is usually complete. Scars and strictures of the esophageal, urethral, vaginal, and anal mucosa rarely occur.
• Severe eye complications may result in permanent blindness.

Patient Education

• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Life-Threatening Skin Rashes.

ACKNOWLEDGMENTS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor, Lawrence A Schachner, MD, to the development and writing of this article.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Acknowledgments
• Multimedia
• References

Media file 1:  Target lesion of erythema multiforme.
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Media type:  Photo

Media file 2:  Raised atypical targets and arcuate lesions.
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Media type:  Photo

Media file 3:  Hemorrhagic crusts on the lips.
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Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Acknowledgments
• Multimedia
• References

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Article Last Updated: Mar 7, 2007