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Pathogenesis, clinical features, and diagnosis of erythema multiforme

Author
David A Wetter, MD
Section Editor
Jeffrey Callen, MD, FACP, FAAD
Deputy Editor
Abena O Ofori, MD

INTRODUCTION

Erythema multiforme (EM) is an acute, immune-mediated condition characterized by the appearance of distinctive target-like lesions on the skin. These lesions are often accompanied by erosions or bullae involving the oral, genital, and/or ocular mucosae. Erythema multiforme major is the term used to describe EM with mucosal involvement; erythema multiforme minor refers to EM without mucosal disease.

A variety of factors have been implicated in the pathogenesis of EM. The disorder is most commonly induced by infection, with herpes simplex virus being the most frequent precipitator. The clinical course of EM is usually self-limited, resolving within weeks without significant sequelae. However, in a minority of cases, the disease recurs frequently over the course of years.

Similarities in clinical and histopathologic findings have led to controversy over the distinction between EM and Stevens-Johnson syndrome (SJS), an often drug-induced disorder that may present with cutaneous targetoid lesions and mucosal erosions. However, there is suggestive evidence that EM with mucous membrane involvement and SJS are different diseases with distinct causes [1]. The term erythema multiforme major should not be used to refer to SJS.  

The epidemiology, pathogenesis, clinical features, evaluation, and diagnosis of acute and recurrent EM will be reviewed here. The treatment of EM and similar issues related to SJS are discussed separately. (See "Treatment of erythema multiforme" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

EPIDEMIOLOGY

The annual incidence of erythema multiforme (EM) is unknown, although it is estimated to be far less than 1 percent [2]. EM most frequently occurs in young adults between the ages of 20 and 40 and exhibits a slight male predominance. Children and older adults can also be affected [2,3].

                     

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Literature review current through: Nov 2016. | This topic last updated: Tue Nov 15 00:00:00 GMT 2016.
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References
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  1. Assier H, Bastuji-Garin S, Revuz J, Roujeau JC. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol 1995; 131:539.
  2. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol 1983; 8:763.
  3. Huff JC. Erythema multiforme. Dermatol Clin 1985; 3:141.
  4. French LE, Prins C. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. In: Dermatology, Bolognia JL, Jorizzo JL, Rapini RP (Eds), Elsevier Limited, 2008. p.287.
  5. Weston WL, Brice SL, Jester JD, et al. Herpes simplex virus in childhood erythema multiforme. Pediatrics 1992; 89:32.
  6. Weston WL. Herpes-associated erythema multiforme. J Invest Dermatol 2005; 124:xv.
  7. Schalock PC, Dinulos JG, Pace N, et al. Erythema multiforme due to Mycoplasma pneumoniae infection in two children. Pediatr Dermatol 2006; 23:546.
  8. Keller N, Gilad O, Marom D, et al. Nonbullous Erythema Multiforme in Hospitalized Children: A 10-Year Survey. Pediatr Dermatol 2015; 32:701.
  9. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993; 129:92.
  10. Roujeau JC. Re-evaluation of 'drug-induced' erythema multiforme in the medical literature. Br J Dermatol 2016; 175:650.
  11. Brice SL, Krzemien D, Weston WL, Huff JC. Detection of herpes simplex virus DNA in cutaneous lesions of erythema multiforme. J Invest Dermatol 1989; 93:183.
  12. Brice SL, Leahy MA, Ong L, et al. Examination of non-involved skin, previously involved skin, and peripheral blood for herpes simplex virus DNA in patients with recurrent herpes-associated erythema multiforme. J Cutan Pathol 1994; 21:408.
  13. Miura S, Smith CC, Burnett JW, Aurelian L. Detection of viral DNA within skin of healed recurrent herpes simplex infection and erythema multiforme lesions. J Invest Dermatol 1992; 98:68.
  14. Ng PP, Sun YJ, Tan HH, Tan SH. Detection of herpes simplex virus genomic DNA in various subsets of Erythema multiforme by polymerase chain reaction. Dermatology 2003; 207:349.
  15. Darragh TM, Egbert BM, Berger TG, Yen TS. Identification of herpes simplex virus DNA in lesions of erythema multiforme by the polymerase chain reaction. J Am Acad Dermatol 1991; 24:23.
  16. Aslanzadeh J, Helm KF, Espy MJ, et al. Detection of HSV-specific DNA in biopsy tissue of patients with erythema multiforme by polymerase chain reaction. Br J Dermatol 1992; 126:19.
  17. Ono F, Sharma BK, Smith CC, et al. CD34+ cells in the peripheral blood transport herpes simplex virus DNA fragments to the skin of patients with erythema multiforme (HAEM). J Invest Dermatol 2005; 124:1215.
  18. Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component. Dermatol Online J 2003; 9:1.
  19. Ahdout J, Haley JC, Chiu MW. Erythema multiforme during anti-tumor necrosis factor treatment for plaque psoriasis. J Am Acad Dermatol 2010; 62:874.
  20. Schofield JK, Tatnall FM, Leigh IM. Recurrent erythema multiforme: clinical features and treatment in a large series of patients. Br J Dermatol 1993; 128:542.
  21. Khalil I, Lepage V, Douay C, et al. HLA DQB1*0301 allele is involved in the susceptibility to erythema multiforme. J Invest Dermatol 1991; 97:697.
  22. Schofield JK, Tatnall FM, Brown J, et al. Recurrent erythema multiforme: tissue typing in a large series of patients. Br J Dermatol 1994; 131:532.
  23. Roujeau JC. Erythema multiforme. In: Fitzpatrick's Dermatology in General Medicine, Wolff K, Goldsmith LA, Katz SI, et al (Eds), McGraw-Hill Companies, Inc, 2008. p.343.
  24. Bean SF, Quezada RK. Recurrent oral erythema multiforme. Clinical experience with 11 patients. JAMA 1983; 249:2810.
  25. Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol 2010; 62:45.
  26. Farthing PM, Maragou P, Coates M, et al. Characteristics of the oral lesions in patients with cutaneous recurrent erythema multiforme. J Oral Pathol Med 1995; 24:9.
  27. Ayangco L, Rogers RS 3rd. Oral manifestations of erythema multiforme. Dermatol Clin 2003; 21:195.
  28. Rogers RS 3rd. Pseudo-Behçet's disease. Dermatol Clin 2003; 21:49.
  29. Celentano A, Tovaru S, Yap T, et al. Oral erythema multiforme: trends and clinical findings of a large retrospective European case series. Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 120:707.
  30. Huff JC, Weston WL. Recurrent erythema multiforme. Medicine (Baltimore) 1989; 68:133.
  31. Leigh IM, Mowbray JF, Levene GM, Sutherland S. Recurrent and continuous erythema multiforme--a clinical and immunological study. Clin Exp Dermatol 1985; 10:58.
  32. Lewis MA, Lamey PJ, Forsyth A, Gall J. Recurrent erythema multiforme: a possible role of foodstuffs. Br Dent J 1989; 166:371.
  33. Grosber M, Alexandre M, Poszepczynska-Guigné E, et al. Recurrent erythema multiforme in association with recurrent Mycoplasma pneumoniae infections. J Am Acad Dermatol 2007; 56:S118.
  34. Dumas V, Thieulent N, Souillet AL, et al. Recurrent erythema multiforme and chronic hepatitis C: efficacy of interferon alpha. Br J Dermatol 2000; 142:1248.
  35. Geraminejad P, Walling HW, Voigt MD, Stone MS. Severe erythema multiforme responding to interferon alfa. J Am Acad Dermatol 2006; 54:S18.
  36. Fraser-Andrews EA, Morris-Jones R, Novakovic L, Hawk JL. Erythema multiforme following polymorphic light eruption: a report of two cases. Clin Exp Dermatol 2005; 30:232.
  37. Drago F, Parodi A, Rebora A. Persistent erythema multiforme: report of two new cases and review of literature. J Am Acad Dermatol 1995; 33:366.
  38. Pavlović MD, Karadaglić DM, Kandolf LO, Mijusković ZP. Persistent erythema multiforme: a report of three cases. J Eur Acad Dermatol Venereol 2001; 15:54.
  39. Chen CW, Tsai TF, Chen YF, Hung CM. Persistent erythema multiforme treated with thalidomide. Am J Clin Dermatol 2008; 9:123.
  40. Wanner M, Pol-Rodriguez M, Hinds G, et al. Persistent erythema multiforme and CMV infection. J Drugs Dermatol 2007; 6:333.
  41. Howland WW, Golitz LE, Weston WL, Huff JC. Erythema multiforme: clinical, histopathologic, and immunologic study. J Am Acad Dermatol 1984; 10:438.
  42. Ackerman AB, Penneys NS, Clark WH. Erythema multiforme exudativum: distinctive pathological process. Br J Dermatol 1971; 84:554.
  43. McKee PH. Lichenoid and interface dermatoses. In: Pathology of the skin with clinical correlations, McKee PH, Calonje E, Granter SR (Eds), Elsevier Limited, Philadelphia, PA 2005. p.237.
  44. Weston JA, Weston WL. The overdiagnosis of erythema multiforme. Pediatrics 1992; 89:802.
  45. Mathur AN, Mathes EF. Urticaria mimickers in children. Dermatol Ther 2013; 26:467.
  46. Emer JJ, Bernardo SG, Kovalerchik O, Ahmad M. Urticaria multiforme. J Clin Aesthet Dermatol 2013; 6:34.
  47. Zeitouni NC, Funaro D, Cloutier RA, et al. Redefining Rowell's syndrome. Br J Dermatol 2000; 142:343.
  48. Lee A, Batra P, Furer V, et al. Rowell syndrome (systemic lupus erythematosus + erythema multiforme). Dermatol Online J 2009; 15:1.
  49. Wolf P, Soyer HP, Fink-Puches R, et al. Recurrent post-herpetic erythema multiforme mimicking polymorphic light and juvenile spring eruption: report of two cases in young boys. Br J Dermatol 1994; 131:364.
  50. Pérez-Carmona L, Vaño-Galvan S, Carrillo-Gijón R, Jaén-Olasolo P. Photosensitive erythema multiforme presenting as juvenile spring eruption. Photodermatol Photoimmunol Photomed 2010; 26:53.
  51. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol 2012; 51:889.
  52. Hughey LC. Approach to the hospitalized patient with targetoid lesions. Dermatol Ther 2011; 24:196.