Basics
Description
- Erythema multiforme (EM) is an acute, self-limited mucocutaneous eruption characterized by distinct targetoid lesions on the skin.
- Although classically defined by the presence of target lesions, at various stages of evolution, EM may appear as erythematous macules, papules, vesicles, or bullae.
- EM is considered an immune-mediated reaction, usually to infectious triggers; numerous additional triggers have been reported in the literature.
- Ranges from relatively mild cutaneous disease (EM minor) to severe forms with significant mucosal involvement (EM major)
- Historically viewed as a spectrum of diseases, most authors now regard EM to be a separate entity from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). SJS and TEN are distinguished from EM by differing patterns of cutaneous involvement, precipitating factors, and prognosis.
Epidemiology
- Predominantly affects healthy young adults but can also affect younger children
- Possible seasonal variation with increased frequency in spring and summer. The more severe form (EM major) has been reported to occur more frequently in winter.
- Recurrences are common.
Etiology
- ~90% of cases are caused by an infectious agent, most commonly herpes simplex virus (HSV) or Mycoplasma pneumoniae.
- <10% of cases are secondary to drug exposure. Common culprits include NSAIDs, sulfonamides, antiepileptics, and antibiotics.
- Reported causes are numerous. Rare precipitants include the following:
- Chemical and physical exposures
- Immunizations
- Autoimmune disease
- Often, the causative factor is not identified.
- HSV is the major cause of recurrent EM.
- M. pneumoniae is associated with more severe bullous skin disease and significant mucosal involvement.
Diagnosis
History
- Prodrome of fever and malaise may precede skin eruption. The prodrome is generally uncommon except in cases of EM major, where symptoms are usually indistinguishable from those of the underlying illness.
- Onset is abrupt with rapid evolution of lesions over the course of 3-5 days.
- Although usually appearing at the same time, mucosal lesions occasionally precede or follow cutaneous lesions by a few days.
- Lesions may be associated with pruritus or burning.
- Elicit careful drug (prescription and OTC) and exposure history, including personal and family history of herpetic lesions.
- Symptoms of HSV, mycoplasma, or other infections may be present.
- Assess for symptoms of mucosal involvement, including dysphagia, dysuria, and ocular symptoms.
Physical Exam
- Early lesions are usually round, well-defined erythematous, edematous papules.
- Classically, some of these will evolve to the characteristic target lesion defined by three zones of concentric color change:
- Dark, dusky center
- Pale, edematous middle zone
- Well-defined erythematous outer border
- The center of well-formed lesions will have signs of necrosis: duskiness, blistering, or erosion.
- Atypical target lesions may also be present, defined by only two zones of color change and/or a poorly defined border.
- Lesions may have multiple morphologies including macules, papules, and vesicles/bullae.
- Distribution is typically symmetric and favors acral sites.
- Oral mucosal involvement (labial and buccal mucosa, vermillion lip) is most common, although any mucosal site may be affected.
- Mucosal involvement usually starts with erythema and edema and progresses to painful erosions with crusting.
Diagnostic Tests & Interpretation
Lab
- Laboratory tests do not establish diagnosis, although they may provide supporting evidence and reveal the underlying cause.
- Eosinophilia may suggest drug as etiology.
- Any lesions suspicious for herpes should be evaluated with culture, direct fluorescent antibody testing (DFA), or polymerase chain reaction (PCR).
- Consider evaluation for Mycoplasma with chest radiograph and cold agglutinins, serology, or PCR.
- Erythrocyte sedimentation rate, white blood cell count, and liver function tests may be elevated in severe EM.
Diagnostic Procedures/Other
Diagnosis of EM can usually be made on clinical grounds. Biopsy is often not required, although it can help confirm diagnosis and exclude other possibilities. Of importance, pathology does not reliably distinguish EM from SJS/TEN and thus differentiation between these entities requires clinical correlation. �
Pathologic Findings
- Necrotic keratinocytes
- Vacuolar basal layer degeneration (liquefactive or hydropic degeneration)
- Subepidermal blistering may be seen in cases of extensive basal layer degeneration.
- Perivascular inflammation in the upper and mid dermis composed mainly of mononuclear cells
- Spongiosis, papillary dermal edema, and exocytosis of lymphocytes may also be seen.
Differential Diagnosis
- SJS/TEN should be considered when a drug is suspected or morphology consists of predominantly macular atypical targets or dusky, ill-defined macules/patches with or without epidermal detachment.
- Urticaria
- Urticaria multiforme
- Vasculitis/urticarial vasculitis
- Fixed drug eruption
- Atypical hand foot and mouth disease
- Pemphigus vulgaris
- Paraneoplastic pemphigus
- Bullous pemphigoid
- Polymorphous light eruption
- Serum sickness reaction
- Systemic lupus erythematosus (Rowell syndrome)
- Sweet syndrome
- Kawasaki disease
- Varicella (chickenpox)
Treatment
General Measures
- Treat the underlying cause (e.g., acyclovir for HSV-related cases) or withdraw the offending agent.
- EM minor
- Care is supportive and symptom-based.
- White petrolatum +/- topical corticosteroids
- Oral antihistamines for pruritus
- EM major
- Skin-directed therapy as above
- White petrolatum and nonstick dressings for bullous lesions
- Pain control
- "Swish and spit"� oral preparations composed of diphenhydramine or viscous lidocaine for painful oral lesions.
- Ophthalmology consultation; consider ENT and urology based on signs and symptoms.
- Avoid aggressive debridement of crust, which can lead to further scarring.
- Monitoring of fluid and electrolyte balance and observation for secondary infection
- The role of systemic steroids is controversial and randomized controlled trials are lacking. Generally thought to be most beneficial when given early in the course of disease. The risks and benefits of corticosteroid therapy must be weighed carefully in the setting of potential infection.
Inpatient Considerations
Admission Criteria
- Severe mucositis with inability to adequately hydrate
- Atypical progression with suspicion for SJS/TEN or other potentially life-threatening process
Ongoing Care
Prognosis
- The course of EM is self-limited. Lesions resolve in 2-4 weeks with postinflammatory pigment alteration. Severe cases of EM may take longer to heal.
- Recurrences may occur and are often associated with HSV. Prophylactic therapy with acyclovir may be considered with frequent episodes.
Complications
- Complications of the triggering/underlying infection may occur in individual cases.
- EM minor generally heals without significant sequelae.
- In EM major, mucosal involvement may lead to sequelae at individual sites: stricture formation of the oral cavity, trachea, esophagus, and urethra. Ophthalmologic consequences include conjunctivitis, corneal erosions, scarring, and rarely, blindness.
- Skin scarring in severe, ulcerated, or secondarily infected sites
Additional Reading
- Auquier-Dunant �A, Mockenhaupt �M, Naldi �L, et al. Correlations between clinical patterns and causes of erythema multiforme major, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002;138(8):1019-1024. �[View Abstract]
- Huff �JC, Weston �WL, Tonnessen �MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. 1983;8(6):763-775. �[View Abstract]
- Riley �M, Jenner �R. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Bet 2. Steroids in children with erythema multiforme. Emerg Med J. 2008;25(9):594-595. �[View Abstract]
- Sokumbi �O, Wetter �DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol. 2012;51(8):889-902. �[View Abstract]
Codes
ICD09
- 695.1 Erythema multiforme, unspecified
- 695.19 Other erythema multiforme
- 695.11 Erythema multiforme minor
- 695.12 Erythema multiforme major
- 695.13 Stevens-Johnson syndrome
- 695.14 Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome
- 695.1 Erythema multiforme
- 695.15 Toxic epidermal necrolysis
ICD10
- L51.9 Erythema multiforme, unspecified
- L51.8 Other erythema multiforme
- L51.0 Nonbullous erythema multiforme
- L51.1 Stevens-Johnson syndrome
- L51 Erythema multiforme
- L51.2 Toxic epidermal necrolysis [Lyell]
- L51.3 Stevens-Johnson synd-tox epdrml necrolysis overlap syndrome
SNOMED
- 36715001 erythema multiforme (disorder)
- 22972008 erythema multiforme, dermal type (disorder)
- 297942002 Drug-induced erythema multiforme (disorder)
- 73442001 Stevens-Johnson syndrome (disorder)