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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: Erin X. Wei MD, 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. Prodromal symptoms occasionally can be associated.

Recurrent EM occurs in a subset of patients and has been variably defined as more than 1, more than 2, or more than 6 flares per year.

Persistent EM is uncommon and refers to chronic, continuous presence of EM or outbreaks separated by 15 days or less.

In adults, the primary trigger for EM is herpes simplex virus (HSV), which is estimated to incite about 90% of cases. EM has been reported with other infections including histoplasmosis, Epstein-Barr virus, and, most recently, COVID-19. Medication can also be a trigger. In children, important additional triggers to consider include drugs (particularly penicillin), group A Streptococcus, and Epstein-Barr virus, among other viruses and bacteria. Idiopathic cases have also been seen. 

Typically, all cutaneous lesions appear within 24-72 hours and persist for 1-4 weeks before fading. The eruption recurs on repeated exposure to the inciting agent. 

EM demonstrates classical target lesions, raised atypical target lesions, or both concomitantly on the skin.

The following points should be kept in mind when a diagnosis of EM is being considered:
  • Herpes labialis may typically precede development of EM but may sometimes develop concomitantly or manifest after the onset of EM (In almost half of all cases, herpes labialis precedes EM.)
  • Classical target lesions are well-defined circular lesions that are less than 3 cm in diameter and have 3 distinct color zones and a central zone that has a bulla or crust.
  • Atypical target lesions are palpable, poorly defined, circular lesions that have 2 distinct color zones. Raised atypical targets are a subtype of atypical targets that have a vesicle or bulla centrally.
  • EM is not considered within the same disease spectrum as Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) and confers no risk of progressing to TEN.
  • EM major refers to the presence of significant mucosal involvement in a case of EM, whereas in EM minor, mucosal involvement is absent or minimal.
  • In EM major, painful intraoral and lip erosions eventuate from vesicles or bullae. Secondary crusting, including hemorrhagic crusting, then develops.


L51.9 – Erythema multiforme, unspecified

36715001 – Erythema multiforme

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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 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:

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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:12/19/2022
Last Updated:02/11/2023
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Erythema multiforme - Oral Mucosal Lesion
See also in: Overview,Anogenital
A medical illustration showing key findings of Erythema multiforme (Skin) : Scattered many
Clinical image of Erythema multiforme - imageId=30005. Click to open in gallery.  caption: 'Edematous and erythematous papules and plaques, some with a target-like appearance on the leg.'
Edematous and erythematous papules and plaques, some with a target-like appearance on the leg.
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