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Last updated: September 12, 2023
Keywords #
Erythema multiforme
Herpes virus simplex
Diagnosis #
Erythema multiforme (EM) is an immune-mediated reaction that is characterized by the abrupt appearance of targetoid skin lesions. These lesions often present concurrently with mucosal erosions or bullae. If mucosal involvement is severe and associated systemic symptoms such as fever and arthralgias are present, the disease is classified as erythema multiforme major. Erythema multiforme minor is EM with mild to no mucosal involvement and no associated systemic symptoms.[1]
Historically, due to mucosal involvement, erythema multiforme major was placed on a continuum with Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). It is now known, however, that erythema multiforme major does not progress to SJS or TEN, and is therefore now classified as a distinct entity.[2]
EM is proposed to result from a cell-mediated immune reaction. Many factors have been implicated in the pathogenesis of EM, but 90% of cases are attributed to infection, particularly by the herpes simplex virus (HSV).[1] Of note, herpes-associated EM has shown an association with the HLA-DQB1*0301 allele, suggesting that EM may be influenced by genetic susceptibility.[3] Other less common precipitating factors of EM include drugs such as sulfonamides and NSAIDs, immunologic disease, food additives including benzoates and nitrobenzene, and chemicals such as terpenes.[1]
Key Concepts #
- Erythema multiforme is characterized by targetoid skin lesions and can be associated with mild to severe mucosal involvement.
- The vast majority of cases of erythema multiforme are secondary to infection, most notably herpes simplex virus.
- Lesions are characteristically self-limited and clear within 2-3 weeks. Recurrences are uncommon, but possible.
Epidemiology #
The annual incidence of EM is estimated to be less than 1%, though the exact number is unknown. It occurs most commonly in young adults with a slight male predominance.[1]
Clinical Features #
- The typical lesion of EM is a circular macule or papule less than 3 cm in diameter with concentric rings that produce three distinct color zones: (1) central darkening surrounded by (2) a pale edematous zone that is (3) rimmed by erythema.
- The central zone typically has a bulla or crust. This is referred to as a “typical target.”
- In comparison, atypical lesions are ill-defined and only have 2 distinct color zones.
- As the name multiforme suggests, the rash can be polymorphic. In classic EM, lesions tend to be symmetrically distributed with a predilection for the extremities and the face.
- The lesions can be asymptomatic or associated with burning pain or itching.[4,5]
- Prodromal symptoms such as fever, malaise, and arthralgias can precede the appearance of cutaneous lesions.[1]
- The mucosal involvement seen in erythema multiforme major is characterized by superficial, painful erosions, bullae, and erythema. Mucosal lesions usually present simultaneously with cutaneous lesions, however, there have been cases where mucosal involvement either preceded the rash or began several days afterwards.
- Lesions most commonly occur on the oral mucosa, though the ocular, genital, upper respiratory, and pharyngeal mucosa can also be involved.[5]
- Preceding or concurrent lesions of orolabial or cutaneous herpes simplex may also be present.
Differential Diagnoses #
- Mycoplasma pneumonia-induced rash and mucositis (MIRM)
- SJS/TEN
- Urticaria
- Viral exanthema/enanthem
- Fixed drug eruption
- Secondary syphilis
- Autoimmune blistering disorders
- Vasculitis
- Rowell syndrome
- Lichen planus.
Diagnostic Workup #
As EM has a very distinct presentation, diagnosis is usually clinical and often does not require a biopsy. If a skin biopsy is performed, histopathology typically reveals a superficial lymphohistiocytic infiltrate and epidermal changes ranging from individual cell to full-thickness necrosis.[4] The findings of direct immunofluorescence (DIF) in EM are usually nonspecific.[5]
Other tests can help elucidate the cause of EM, such as a viral culture, PCR, or Tzank smear for herpes simplex.
Treatment #
Erythema multiforme is a self-limiting cutaneous disease. In the minor form of the disease, lesions tend to resolve within 2 to 3 weeks, but lesions from the major subtype may take up to 6 weeks to clear.[4]
Although there is a paucity of evidence to suggest that medical therapy can alter the course of cutaneous presentation of EM, it is appropriate to treat any precipitating infection (ie. valacyclovir for herpes simplex). For patients with frequently recurring disease, maintenance antiviral therapy may help prevent future episodes.[6]
Patients with severe disease (such as significant mucosal involvement) are frequently treated with systemic corticosteroids. Milder mucosal lesions can be treated with viscous lidocaine for symptomatic relief and with topical steroids such as clobetasol, fluocinonide, or dexamethasone solution.[4]
Slide Viewer #
https://utahderm.med.utah.edu/image-viewer/References #
- Samim F, Auluck A, Zed C, Williams PM. Erythema Multiforme: A Review of Epidemiology, Pathogenesis, Clinical Features, and Treatment. Dental Clinics of North America. 2013;57(4):583-596.
- Assier H, Bastuji-Garin S, Revuz J, Roujeau J-C. Erythema Multiforme With Mucous Membrane Involvement and Stevens-Johnson Syndrome Are Clinically Different Disorders With Distinct Causes. Archives of Dermatology. 1995;131(5):539-543.
- Khalil I, Lepage V, Douay C, et al. HLA DQB1*0301 Allele is Involved in the Susceptibility to Erythema Multiforme. Journal of Investigative Dermatology. 1991;97(4):697-700.
- James G Marks JJM. Erythema Multiforme. In: Lookingbill and Marks’ Principles of Dermatology. Elsevier; 2019:225-229.
- Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. International Journal of Dermatology. 2012;51(8):889-902.
- Wetter DA. Erythema multiforme: Pathogenesis, clinical features, and diagnosis. 2019; https://www.uptodate.com/contents/erythema-multiforme-pathogenesis-clinical-features-and-diagnosis. Accessed Feb 26, 2020.
