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Erythema multiforme - Oral Mucosal Lesion
See also in: Overview,Anogenital
Other Resources UpToDate PubMed

Erythema multiforme - Oral Mucosal Lesion

See also in: Overview,Anogenital
Contributors: Susan Burgin MD, Belinda Tan MD, PhD, Carl Allen DDS, MSD, Sook-Bin Woo MS, DMD, MMSc
Other Resources UpToDate PubMed


Erythema multiforme (EM) is a self-limited hypersensitivity reaction of the skin and mucous membranes characterized by the acute onset of fixed lesions of concentric color change (target lesions). Two subtypes exist: EM major and EM minor. Key differences between the EM subtypes include mucosal involvement and systemic symptoms such as fever, arthralgias, and asthenias seen in the major subtype.

In the past, the conditions EM, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) were considered a continuum, but it is now recognized that EM does not progress to TEN. Therefore, EM is now considered a distinct hypersensitivity eruption, which can be distinguished from SJS/TEN based on the presence of target lesions, papular (rather than macular) atypical target lesions, and an acral distribution.

In adults, the primary trigger for EM is herpes simplex virus (HSV), which is estimated to incite about 90% of cases. In children, important additional triggers to consider include drugs (particularly penicillin), group A Streptococcus, and Epstein-Barr virus among other viruses and bacteria.

Typically, all cutaneous lesions appear within 24-72 hours and persist for 2 weeks before fading. The eruption recurs on repeated exposure to the inciting agent. While HSV is the most common etiology associated with recurrent EM, several viruses have been associated as triggers, too.

EM demonstrates classical target lesions, raised atypical target lesions, or both concomitantly on the skin. In EM minor, little or no mucosal involvement is seen. In EM major, significant mucositis is seen. Painful intraoral and lip erosions eventuate from vesicles or bullae. Secondary crusting, including hemorrhagic crusting, then develops.


L51.9 – Erythema multiforme, unspecified

22972008 – Erythema multiforme, dermal type

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

  • Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) – Clinically, look for irregularly shaped, dusky red necrotic macules on the trunk, face, and palms / soles. A positive Nikolsky sign can be found. Oral involvement in SJS/TEN parallels that of EM; there is mucosal involvement, including the eyes, lips, mouth, and genitalia. Look for hemorrhagic crusts and intraoral erosions. Precipitating factors are usually medications.
  • Reactive infectious mucocutaneous eruption (RIME) – Usually occurs secondary to mycoplasma infection (as evidenced by clinical pneumonia, imaging studies, and/or mycoplasma serologies) although Chlamydia pneumoniae, human parainfluenza virus 2, rhinovirus, adenovirus, enterovirus, human metapneumovirus, and influenza B virus have more recently been recognized to cause a similar clinical picture. There is pronounced oral and ocular mucositis with absent, spare, or mild cutaneous involvement. Cutaneous lesions are most often tense vesiculobullae. Target or targetoid lesions may be present. Nikolsky sign is negative. Acute and convalescent mycoplasma titers may be employed to help to establish this diagnosis in the correct clinical scenario.
  • Fixed drug eruption – May involve the lips. Has a characteristic round shape.
  • Herpes simplex virus
  • Lichen planus – Whitish reticulated plaques may be seen on the lips and oral mucosa. Erosive intraoral forms are less frequently seen.
  • Pemphigus vulgaris – Lips are usually spared.
  • Mucous membrane pemphigoid – This condition mostly affects the mucosa and almost always the gingiva, although other sites may be involved.
  • Bullous pemphigoid – Intraoral erosions may be seen.
  • Epidermolysis bullosa acquisita – Intraoral vesicles or bullae and ulcers occur in a minority of patients.
  • Aphthous stomatitis
  • Kawasaki disease
  • Autoimmune progesterone dermatitis
  • Paraneoplastic pemphigus
Differential diagnosis of hemorrhagic crusting of both lips:

Best Tests

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Management Pearls

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Drug Reaction Data

Below is a list of drugs with literature evidence indicating an adverse association with this diagnosis. The list is continually updated through ongoing research and new medication approvals. Click on Citations to sort by number of citations or click on Medication to sort the medications alphabetically.

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Last Reviewed:12/04/2016
Last Updated:02/16/2022
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Erythema multiforme - Oral Mucosal Lesion
See also in: Overview,Anogenital
Erythema multiforme : Bullae, Painful skin lesions, Palms and soles, Scattered many, Smooth plaque, Tense vesicles
Clinical image of Erythema multiforme
Copyright © 2022 VisualDx®. All rights reserved.