Erythema exsudativum multiforme

Ferdinand v. Hebra 1860

Erythema multiforme, EM, EEM, erythema multiforme of Hebra, cocard erythema, disk rose.

Acute, usually self-limiting, polyaetiological disease characterised by "target-like lesions".

• Division:
  • Minor form: no mucosal involvement.
  • Major form: with mucosal involvement (up to 70% of patients).

• Incidence: unknown, but estimated well below 1% per annum.
• Peak incidence: 20- 40 yrs.
• M > F

• Possible triggers (combinations also possible)
• Infections
  • approx. 90% of all triggers
  • Viral
    • Herpes simplex virus (HSV) type I (most common trigger)
    • HSV type II
    • Orf virus
    • Parapox virus
    • Varicella zoster virus
    • Epstein-Barr virus
    • Parvovirus B19
    • Adenovirus
    • Cytomegalovirus
    • Coxsackie virus
    • Hepatitis B or C- virus
    • HI virus
  • Bacteria
    • Mycoplasma pneumoniae (frequent trigger, especially in children)
    • Chlamydophila psittaci
    • Salmonella
  • Mycobacteria
    • Mycobacterium tuberculosis
  • Mycoses
    • Histoplasma capsulatum
    • Dermatophytes
  • Medicines (< 10%)
    • NSAIDs
    • Sulfonamides
    • Antiepileptics
    • Antibiotics
  • Neoplasia
  • Autoimmune diseases
  • Vaccinations
  • UV-radiation (sunburn)
  • Trauma
  • Sarcoidosis
  • Menstruation
  • Possible genetic predisposition: HLA-DQw3, DRw53, AW33, HLA-DQB1*0301, B15(62), B35, and DQ3.
  • HSV infection causes cellular immune responses against viral antigens localised in the skin.

• Localisation
  • Mostly symmetrical on the extensor sides of the extremities. Spread is centripetal. Face, trunk, palmoplantar, elbows as well as mucous membranes may be affected.
• After an incubation period of 2-3 days, the first skin changes usually appear. In some cases, however, there may be up to 17 days between contact with the trigger and the first appearance of efflorescences.

• Facultative prodromal symptoms may occur:
• ↓ AZ, fever, myalgias
• Cough in M. pneumoniae infection

• There are usually erythematous, often pruritic or burning papules in the above-mentioned localisations, which in the course of time change exanthematously into coquette- and disc-shaped plaques with a characteristic central vesicle. A linear arrangement may be detectable (Köbner phenomenon)
• The area of the mucous membranes shows enanthema, painful erosions or vesicles. Usually only the oral cavity is affected, but in a few cases it can lead to involvement of the pharynx and the upper respiratory organs.
• In most cases, only the oral mucosa is affected. Involvement of the genital mucosa occurs in approx. 25%, ocular involvement in approx. 17%.

• Anamense (infections?, herpes simplex?, cough?, medication?)
• Clinic
• Lab:
  • Nonspecific
  • Optional: ↑BSG, leukocytosis, ↑ transaminases, HSV serology pos.
• U status
  • Mycoplasma pneumoniae
• Biopsy
  • Dermatopathology
  • Direct immunofluorescence

• Scarless healing, but in some cases with hyperpigmentation, within 2 weeks.
• Very few patients suffer recurrences, some up to 6x per year. The average duration of recurrences is 6-10 years.

1. Aslanzadeh J, Helm KF, Espy MJ, Muller SA , Smith TF. Detection of HSV-specific DNA in biopsy tissue of patients with erythema multiforme by polymerase chain reaction. Br J Dermatol 1992;126:19-23.
2. Assier H. Erythema Multiforme With Mucous Membrane Involvement and Stevens-Johnson Syndrome Are Clinically Different Disorders-Reply. Arch Dermatol 1996;132:711.
3. Atzori L, Pau M , Aste M. Erythema multiforme ID reaction in atypical dermatophytosis: a case report. Journal of the European Academy of Dermatology and Venereology 2003;17:699-701.
4. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schröder W , Roujeau J-C. Correlations Between Clinical Patterns and Causes of Erythema Multiforme Majus, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis. Arch Dermatol 2002;138.
5. Bastuji-Garin S. Clinical Classification of Cases of Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, and Erythema Multiforme. Arch Dermatol 1993;129:92.
6. Batalla A, Alvarez-Arguelles ME, Gonzalez-Martinez MB , Curto JR. [Milker's nodule complicated with erythema multiforme]. Med Clin (Barc) 2013;141:e5.
7. Brice SL, Leahy MA, Ong L, Krecji S, Stockert SS, Clark Huff J 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;21:408-12.
8. Clark Huff J , Weston WL. Isomorphic phenomenon in erythema multiforme. Clin Exp Dermatol 1983;8:409-13.
9. Côté B. Clinicopathologic Correlation in Erythema Multiforme and Stevens-Johnson Syndrome. Arch Dermatol 1995;131:1268.
10. Darragh TM, Egbert BM, Berger TG , Benedict Yen TS. Identification of herpes simplex virus DNA in lesions of erythema multiforme by the polymerase chain reaction. Journal of the American Academy of Dermatology 1991;24:23-6.
11. Dikiand WJ, Oranje AP, Stoiz E , Joost T. Erythema Multiforme in Childhood and Early Infancy. Pediatric Dermatology 1986;3:135-9.
12. Farthing PM, Maragou P, Coates M, Tatnall F, Leigh IM , Williams DM. Characteristics of the oral lesions in patients with cutaneous recurrent erythema multiforme. J Oral Pathol Med 1995;24:9-13.
13. Howland WW, Golttz LE, Weston WL , Huff JC. Erythema multiforme: Clinical, histopathologic, and immunologic study. Journal of the American Academy of Dermatology 1984;10:438-46.
14. Huff JC. Erythema multiforme. Dermatol Clin 1985;3:141-52.
15. Huff JC , Weston WL. Recurrent Erythema Multiforme. Medicine 1989;68:133-40.
16. Johnston GA, Ghura HS, Carter E , Graham-Brown RAC. Neonatal erythema multiforme major. Clin Exp Dermatol 2002;27:661-4.
17. Khalil I, Lepage V, Douay C, Morin L, Al-Daccak R, Wallach D et al. HLA DQB1*0301 Allele is Involved in the Susceptibility to Erythema Multiforme. Journal of Investigative Dermatology 1991;97:697-700.
18. Kokuba, Imafuku, Huang, Aurelian , Burnett. Erythema multiforme lesions are associated with expression of a herpes simplex virus (HSV) gene and qualitative alterations in the HSV-specific T-cell response. Br J Dermatol 1998;138:952-64.
19. Kokuba H, Aurelian L , Burnett J. Herpes Simplex Virus Associated Erythema Multiforme (HAEM) is Mechanistically Distinct from Drug-Induced Erythema Multiforme: Interferon-γ is Expressed in HAEM Lesions and Tumor Necrosis Factor-α in Drug-Induced Erythema Multiforme Lesions. Journal of Investigative Dermatology 1999;113:808-15.
20. Lepage V, Douay C, Mallet C, Binet O, Lemarchand F, Wallach D et al. Erythema multiforme is associated to HLA-Aw33 and DRw53. Tissue Antigens 1988;32:170-5.
21. Martinez AE , Atherton DJ. High-Dose Systemic Corticosteroids Can Arrest Recurrences of Severe Mucocutaneous Erythema Multiforme. Pediatric Dermatology 2000;17:87-90.
22. Ono F, Sharma BK, Smith CC, Burnett JW , Aurelian L. CD34+ Cells in the Peripheral Blood Transport Herpes Simplex Virus DNA Fragments to the Skin of Patients with Erythema Multiforme (HAEM). Journal of Investigative Dermatology 2005;124:1215-24.
23. Rzany B, Hering O, Mockenhaupt M, Schroder W, Goerttler E, Ring J et al. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol 1996;135:6-11.
24. Rzany B, Mockenhaupt M, Baur S, Schröder W, Stocker U, Mueller J et al. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990–1992): Structure and results of a population-based registry. Journal of Clinical Epidemiology 1996;49:769-73.
25. Salim A , Young E. Erythema multiforme associated with Trichophyton mentagrophytes infection. Journal of the European Academy of Dermatology and Venereology 2002;16:645-6.
26. Schalock PC, Brennick JB , Dinulos JGH. Mycoplasma pneumoniae infection associated with bullous erythema multiforme. Journal of the American Academy of Dermatology 2005;52:705-6.
27. Schalock PC, Dinulos JG, Pace N, Schwarzenberger K , Wenger JK. Erythema multiforme due to Mycoplasma pneumoniae infection in two children. Pediatr Dermatol 2006;23:546-55.
28. Schofield JK, Tatnall FM , Leigh IM. Recurrent erythema multiforme: clinical features and treatment in a large series of patients. Br J Dermatol 1993;128:542-5.
29. Tatnall FM, Schofield JK , Leigh IM. A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. British Journal of Dermatology 2006;132:267-70.
30. Werchniak AE , Schwarzenberger K. Poison ivy: An underreported cause of erythema multiforme. Journal of the American Academy of Dermatology 2004;51:S159-S60.
31. Weston WL. What Is Erythema Multiforme? Pediatric Annals 1996;25:106-9.
32. Weston WL. Herpes Simplex Virus–Associated Erythema Multiforme in Prepubertal Children. Arch Pediatr Adolesc Med 1997;151:1014.
33. Weston WL. Herpes-Associated Erythema Multiforme. Journal of Investigative Dermatology 2005;124:xv-xvi.
34. Weston WL. Herpes-associated erythema multiforme. J Invest Dermatol 2005;124:xv-xvi.
35. Weston WL , Brice SL. Atypical forms of herpes simplex–associated erythema multiforme. Journal of the American Academy of Dermatology 1998;39:124-6.
36. Weston WL, Brice SL, Jester JD, Lane AT, Stockert S , Huff JC. Herpes simplex virus in childhood erythema multiforme. Pediatrics 1992;89:32-4.
37. 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;62:45-53.
38. Wetter DA , Davis MDP. Recurrent erythema multiforme: Clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. Journal of the American Academy of Dermatology 2010;62:45-53.
39. Wolf P, Soyer HP, Fink-Puches R, Huff JC , Kerl H. Recurrent post-herpetic erythema multiforme mimicking polymorphic light and juvenile spring eruption: report of two cases in young boys. Br J Dermatol 1994;131:364-7.
40. Lebwohl, Mark. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. Elsevier, 2014. Print.