Erythema multiforme in AdultSee also in: Anogenital,Oral Mucosal Lesion
Alerts and Notices
SynopsisErythema 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. 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.
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.)
- Although a strong association exists with HSV and EM, a direct immunofluorescence test or viral culture for HSV will be negative in EM lesions.
- 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 can demonstrate classical target lesions, raised atypical target lesions, or both concomitantly.
- 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.
L51.9 – Erythema multiforme, unspecified
36715001 – Erythema multiforme
Differential Diagnosis & Pitfalls
- Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) – Histologic features may not differentiate EM from SJS/TEN. Clinically, however, look for irregularly shaped, dusky red macular or patch-like lesions on the trunk, face, and palms / soles. A positive Nikolsky sign can be found; there is mucosal involvement, including the eyes, lips, mouth, and genitalia. Look for hemorrhagic crusts, bullae, and denudation in these areas. Systemic symptoms are commonly present but not invariable. Lesions are more pronounced on the trunk than on the extremities. 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. Cutaneous lesions do not erode or desquamate as seen in SJS/TEN. (Note: Erosion is seen in the genital and perianal skin, which are considered akin to mucosal surfaces.) Nikolsky sign is negative. Acute and convalescent mycoplasma titers may be employed to help establish this diagnosis in the correct clinical scenario.
- Generalized fixed drug eruption – Look for erythematous plaques that develop on the lips, face, distal extremities, and genitalia 1-2 weeks after medication ingestions. Oral mucosa can be involved. Histology will differentiate fixed drug eruption from EM.
- Urticaria multiforme – New lesions appear daily; lesions are transient and last less than 24 hours; associated with edema of lips, face, hands, and feet. No evidence of epidermal damage in the center of urticarial lesions. Subcutaneous epinephrine injections will clear urticarial lesions but not EM lesions.
- Erythema annulare centrifugum (EAC) – Erythematous, annular patches and plaques that are idiopathic in nature; can last from days to months, there are no systemic symptoms, and lesions commonly appear on hips and thighs. Biopsy will differentiate EAC and EM.
- Lichen planus – Very pruritic, sometimes associated with hepatitis C. Biopsy will differentiate EM from lichen planus.
- SCLE – Antinuclear antibodies (ANA) will be positive in the majority of lupus patients. SCLE is characterized by annular plaques with raised borders and central clearing or papulosquamous lesions that are restricted to sun-exposed skin.
- Secondary syphilis – Scattered scaling papules and plaques; check rapid plasma reagin (RPR), and check for history of primary chancre and systemic symptoms.
- Leukocytoclastic vasculitis (LCV) – Palpable purpura is the most common finding, consisting of nonblanching 1-3 mm, violaceous, round papules, characteristically involving the lower extremities. Biopsy will differentiate fixed LCV from EM.
- Arthropod bites – Haphazard distribution of erythematous papules.
- Viral exanthem
- Erythema nodosum
- Cocaine levamisole toxicity
- Kawasaki disease
- Autoimmune progesterone dermatitis
- Paraneoplastic pemphigus
Drug Reaction DataBelow 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.
Patient Information for Erythema multiforme in Adult
OverviewErythema multiforme is an inflammatory skin reaction that occurs in response to medication, infection, or illness. There are two types of erythema multiforme: erythema multiforme minor and erythema multiforme major. Erythema multiforme major has systemic symptoms such as fever and joint pain.
Who’s At RiskErythema multiforme often occurs as a drug reaction in response to barbiturates, penicillins, phenytoin, and sulfonamides. It can also develop after contracting herpes simplex virus or a mycoplasma infection.
Signs & SymptomsSymptoms of erythema multiforme include:
- Itchy skin
- Joint aches
- Sore, abnormal skin lesions
Self-Care GuidelinesMeasures can be taken to manage symptoms:
- Use moist compresses on the skin
- Take pain medication such as ibuprofen (Advil) or acetaminophen (Tylenol)
- Keep clean and maintain distance from others to prevent secondary infections
When to Seek Medical CareSeek medical care if you suspect you may have erythema multiforme or if symptoms get worse.
TreatmentsYour health care provider may tell you to stop taking any medication that could be causing erythema multiforme.
For mild symptoms, the following treatments may be given:
- Antihistamines to stop itching
- Oral antiviral medicine if herpes simplex is causing the problem
- Pain medication
- Topical anesthetics to reduce pain, especially if reaction is in your mouth
For more severe symptoms, your health care provider may prescribe:
- Antibiotics for skin infections
- Corticosteroids to reduce inflammation
Erythema multiforme in AdultSee also in: Anogenital,Oral Mucosal Lesion