- Erythema multiforme (EM) is an uncommon, self-limiting, immune-mediated, mucocutaneous disease.
- Approximately 90% of cases are triggered by infectious agents (herpes simplex virus [HSV]-1 or -2 up to 50%), or less commonly, by drugs and vaccinations (1),(2).
- Characteristic skin lesions are acrally distributed, distinct, targetoid papules with concentric color variation (three zones), occasionally accompanied by oral, genital, or ocular mucosal involvement (1),(3),(4).
- EM needs to be differentiated from Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are characterized by truncal, flat lesions with or without blisters which can result in significant mortality (2),(3).
- There are no universal diagnostic criteria, but clinical history, clinical examination, skin biopsy, laboratory studies, and special consideration of persistent EM are all helpful in making a diagnosis (1).
- Treatment focuses on supportive care in addition to treating the underlying etiology and discontinuing causative agents (2).
- There are two subtypes of EM: erythema multiforme minor (EMm), which involves ≤1 mucosal site, and erythema multiforme major (EMM), which involves ≥2 mucosal sites (4).
- EMM is now separate from SJS and TEN. Skin lesions that are predominantly truncal, flat (macular, nonpalpable), and atypical (less sharply demarcated with only two concentric zones) with or without blisters are more suggestive of SJS or TEN (2),(3).
- Recurrent EM is defined as ≥3 episodes but has a mean number of 6 episodes per year and a mean duration of 6 to 10 years.
Annual U.S. incidence is estimated at <1% (2).
Etiology and Pathophysiology
- Etiology (1),(2),(4)
- Viral infections: HSV-1 and -2 (most common etiology), Epstein-Barr, hepatitis C, coxsackievirus, echovirus, varicella, mumps, poliovirus, cytomegalovirus, HIV, molluscum contagiosum
- Bacterial infections: Mycoplasma pneumoniae (2nd most common etiology), Treponema pallidum, Mycobacterium tuberculosis, and Gardnerella vaginalis
- Drugs: NSAIDs, anti-epileptics, antibiotics (penicillin, sulfonamides, erythromycin, nitrofurantoin, tetracyclines), statin, TNF-α inhibitors, and barbiturates
- Vaccines: stronger association with HPV, MMR, and small pox vaccines, but also associated with hepatitis B, meningococcal, pneumococcal, varicella, influenza, diphtheria-pertussis-tetanus, and Haemophilus influenzae
- Occupational exposures: herbicides (alachlor and butachlor), iodoacetonitrile, heavy metals
- Radiation therapy
- Premenstrual hormone changes
- Malignancy (e.g., lymphoma)
- Inflammatory bowel disease
- Pathogenesis of EM (1)
- In HSV-associated EM, peripheral mononuclear cells that phagocytose the virus transport fragmented HSV DNA to keratinocytes. Within the keratinocytes, the HSV DNA polymerase gene (pol) leads to a TH-1 mediated immune response. Activation of the HSV-specific CD4+ TH-1 cells then produces cytokines such as interferon (IFN)-γ and triggers an inflammatory cascade, which leads to the mucocutaneous findings.
- Development of EM from other inciting factors such as drugs and vaccinations is not completely understood, but it appears that the pathway involves tumor necrosis factor (TNF)-α, perforin, and granzyme B rather than IFN-γ.
- Previous history of EM
- Age 20 to 40
- Use of causative agents or infection with causative pathogens
Commonly Associated Conditions
See “Etiology and Pathophysiology” earlier.
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Domino, Frank J., et al., editors. "Erythema Multiforme." 5-Minute Clinical Consult, 27th ed., Wolters Kluwer, 2020. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116217/all/Erythema_Multiforme.
Erythema Multiforme. In: Domino FJF, Baldor RAR, Golding JJ, et al, eds. 5-Minute Clinical Consult. Wolters Kluwer; 2020. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116217/all/Erythema_Multiforme. Accessed June 1, 2023.
Erythema Multiforme. (2020). In Domino, F. J., Baldor, R. A., Golding, J., & Stephens, M. B. (Eds.), 5-Minute Clinical Consult (27th ed.). Wolters Kluwer. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116217/all/Erythema_Multiforme
Erythema Multiforme [Internet]. In: Domino FJF, Baldor RAR, Golding JJ, Stephens MBM, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2020. [cited 2023 June 01]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116217/all/Erythema_Multiforme.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Erythema Multiforme ID - 116217 ED - Domino,Frank J, ED - Baldor,Robert A, ED - Golding,Jeremy, ED - Stephens,Mark B, BT - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116217/all/Erythema_Multiforme PB - Wolters Kluwer ET - 27 DB - Medicine Central DP - Unbound Medicine ER -