Erythema Multiforme


Historical Terminologic Controversy

  • 1866: Erythema Multiforme (EM) was first described by Ferdinand von Hebra
    • Definition: “multiforme” refers to various skin manifestations (although most patients have similar lesions at a specific point in time, morphology of lesions may vary between patients and may evolve over time in a single patient)
    • Epidemiology: association with Herpes Simplex Virus (HSV)
    • Clinical Features: acral (peripheral) skin lesion, consisting of target lesions, edematous papules, and/or plaques without mucosal involvement
  • 1922: Stevens-Johnson Syndrome (SJS) was described a pediatric febrile mucocutaneous disorder with febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption
  • 1948: first description of Toxic Epidermal Necrolysis (TEN)
  • 1950: Thomas proposed the subclassification of EM
    • Erythema Multiforme Minor: acute, self-limited condition with characteristic red papular skin lesions
    • Erythema Multiforme Major: applied to patients who also displayed oral mucosal involvement
      • Note: this subset included patients with SJS/TEN (and some Dermatologists confusingly use this term and SJS/TEN interchangeably)
  • Current State of Understanding
    • Strong association between HSV and EM
    • SJS is more commonly associated with exogenous agents (such as drugs)
    • Studies of IL-13 and other cytokines suggest that SJS and TEN are related, while EM is a distinct disorder

Current Classification Schema (Based on 1993 Classification)

  • Erythema Multiforme Minor
    • Etiology
    • Clinical
      • Typical targets or raised, edematous papules distributed acrally (peripherally)
      • Absence of mucosal involvement
  • Erythema Multiforme Major
    • Etiology
      • Typically due to HSV, Mycoplasma Pneumoniae, and drugs
    • Clinical
      • Typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes
      • Epidermal detachment involves <10% of total body surface area
      • Commonly involves mucosal membranes (oral, nasal, ocular, genital)
      • Hemorrhagic crusting of lips (also may be seen in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, HSV, Pemphigus Vulgaris, and Paraneoplastic Pemphigus)
  • Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (see Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis, [[Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis]])
    • Widespread blisters predominantly on trunk and face, erythematous or pruritic macules, and one or more mucous membrane erosions
      • Stevens-Johnson Syndrome: epidermal detachment is <10% of body surface area
      • Toxic Epidermal Necrolysis: epidermal detachment is >30% of body surface area

General Epidemiological Features

  • Annual Incidence: <1%
  • Age: peak incidence in age 20-40 group, although children and older adults can be affected
  • Sex: slight male predominance
  • Genetic Risk Factors
    • HLA-DQB1*0301: present in 66% of EM patients (vs 31% of controls) -> strongest association is with patients with HSV-associated EM
    • HLA-Aw33: controversial association
    • HLA-DRw53
    • HLA-B15(62)
    • HLA-B35
    • HLA-DQ3: controversial association


Autoimmune Disease

  • xxx

Infection (90% of Cases)

  • Adenovirus (see Adenovirus, [[Adenovirus]])
  • Chlamydia Psittaci (see Psittacosis, [[Psittacosis]])
  • Coxsackie Virus (see Coxsackie Virus, [[Coxsackie Virus]])
  • Cytomegalovirus (CMV) (CMV) (see Cytomegalovirus, [[Cytomegalovirus]])
  • Dermatophytosis
  • Epstein-Barr Virus (EBV) (see Epstein-Barr Virus, [[Epstein-Barr Virus]])
  • Hepatitis C Virus (HCV) (see Hepatitis C Virus, [[Hepatitis C Virus]])
  • Herpes Simplex Virus-1 (HSV-1)/Herpes Simplex Virus-2 (HSV-2) (see Herpes Simplex Virus, [[Herpes Simplex Virus]])
    • Most common infectious etiology (although EM only occurs in a small percentage of patients with HSV and does not always recur with HSV outbreaks)
    • EM may occur after asymptomatic subclinical HSV outbreaks
    • EM usually occurs 2 to 17 days (mean interval: 8 days) after the initial viral eruption
  • Histoplasmosis (see Histoplasmosis, [[Histoplasmosis]])
  • Human Immunodeficiency Virus (HIV) (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
  • Influenza Virus (see Influenza Virus, [[Influenza Virus]])
  • Mycoplasma Pneumoniae (see Mycoplasma Pneumoniae, [[Mycoplasma Pneumoniae]]): particularly in children
  • Parapoxvirus
  • Parvovirus B19 (see Parvovirus B19, [[Parvovirus B19]])
  • Salmonella (see Salmonella, [[Salmonella]])
  • Tuberculosis (see Tuberculosis, [[Tuberculosis]])
  • Varicella-Zoster Virus (VZV) (see Varicella-Zoster Virus, [[Varicella-Zoster Virus]])


  • xxx

Drugs (<10% of Cases)


  • Diphtheria-Tetanus Vaccine
  • Hepatitis B Vaccine
  • Measles-Mumps-Rubella (MMR) Vaccine
  • Smallpox Virus Vaccine



  • Herpes Simplex Virus-Associated Cases
    • Cell-mediated immune response against HSV antigens deposited in lesional skin (HSV DNA can detected in skin biopsy specimens from EM patients)


  • Elevated ESR
  • Leukocytosis
  • Elevated LFT’s
  • Skin Biopsy: basal cell vacuolar degeneration, scattered necrotic keratinocytes, and lymphocyte exocytosis
    • Dense superficial dermal lymphohistiocytic infiltrate around blood vessels and the dermoepidermal junction
    • Papillary dermal edema and red blood cell extravasation may be evident (especially in early lesions)
    • Subepidermal clefting and vesiculation (due to extensive basal cell vacuolar degeneration) are present in some specimens
    • Biopsy of Mucosal Lesions: similar histologic features to those of cutaneous lesions
      • More prominent spongiosis and intracellular edema and vesiculation may be present
    • Choice of Biopsy Site: may influence histopathology
      • While specimens from the dusky central portions of lesions may reveal subepidermal separation with necrotic keratinocytes, biopsies from the peripheral portions often show predominantly dermal changes, such as papillary dermal edema, vascular dilation, and a perivascular mononuclear cell infiltrate
    • Direct Immunofluorescence: usually non-specific (although one study found granular deposits of C3 and IgM at the dermoepidermal junction and around superficial dermal blood vessels, fibrin around dermal blood vessels and in a band-like distribution at the dermoepidermal junction in regions of necrosis or blister formation)
      • Direct and indirect immunofluorescence aid in the exlclusion of Bullous Pemphigoid and Paraneoplastic Pemphigus
    • Lack of Neutrophilic Infiltrate: aids in the exclusion of Sweet’s syndrome


Prodromal Syndrome

  • Including fever/malaise/myalgias
  • Uncommon in mild EM, but may be seen in cases with mucosal involvement

Dermatologic Manifestations

  • Skin Lesions
    • Lesions often begin as round erythematous papules, which evolve into acrally (peripherally)-distributed target lesions on extensor surfaces of extremities -> spread centripetally
      • Lesions usually appear over 3-5 days and resolve within 2 weeks
      • Post-inflamatory hyperpigmentation may occur in some patients with dark skin (but scarring is usually not seen)
    • Target Lesions (see Vesicular-Bullous Skin Lesions, [[Vesicular-Bullous Skin Lesions]])
      • Note: target lesions are not necessary to make the diagnosis of EM
      • Typical Target Lesions (3 components): dusky central area or blister, dark red inflammatory zone surrounded by a pale ring of erythema, and an outer erythematous halo
      • Atypical Target Lesions: raised edematous lesions with two zones of color change and poorly defined border
    • Face/neck/palms/soles/trunk may also be involved
    • Lesions may cluster on elbows and knees
    • Lesions may occur at sites of trauma or sunburn
    • Erythema and swelling of nail folds may occur
    • Most lesions are asymptomatic, but some patients experience pruritus or burning
    • Limited Extent of Skin Detachment
  • Hemorrhagic Crusting of Lips: also may be seen in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, Herpes-Simplex Virus, Pemphigus Vulgaris, and Paraneoplastic Pemphigus)
  • Mucosal Involvement (component of Erythema Multiforme Major): mucous membrane involvement usually occurs in association with skin lesions (however, there have been cases reported with isolated mucous membrane involvement)
    • Oral Lesions (common mucosal site, can be present in up to 70% of EM cases)
      • May onvolve vermilion lip, buccal mucosa, labial mucosa, non-attached gingiva, and tongue
      • Mucosal Erythema, Painful Erosions, or Bullae
    • Sore Throat/Pharyngeal/Upper Respiratory Tract Lesions (infrequent)
    • Ocular Lesions (17% of cases)
      • Conjunctivitis
      • Keratitis
      • Conjunctival Scarring
      • Visual Impairment
    • Genital Lesions (25% of cases)
    • Esophageal Lesions: esophagitis

Other Manifestations

  • Fever: may precede or accompany skin eruption
  • Malaise: may precede or accompany skin eruption
  • Myalgias: may precede or accompany skin eruption
  • Sore Throat: may precede or accompany skin eruption
  • Cough: may precede or accompany skin eruption

Persistent Erythema Multiforme

  • Definition: uninterrupted occurrence of typical and atypical EM lesions (may occur for as long as a year without treatment)
  • Etiology
  • Diagnosis: Laboratory abnormalities including hypocomplementemia and circulating immune complexes also can occur, but are not found in all affected patients
  • Clinical: widespread papulonecrotic or bullous lesions
    • Mucosal Lesions: variable

Recurrent Erythema Multiforme

  • Epidemiology
    • A subset of patients experience recurrent episodes of EM
    • Average Frequency of Recurrence: 6 episodes per year
    • Mean Duration of Disease: 6 to 10 years
  • Etiology
    • Benzoic Acid Ingestion: used as a preservative
    • Complex Aphthosis
    • Herpes Simplex Virus (61-100% of cases) (see Herpes Simplex Virus, [[Herpes Simplex Virus]])
    • Mycoplasma Pneumoniae (see Mycoplasma Pneumoniae, [[Mycoplasma Pneumoniae]])
    • Hepatitis C (see Hepatitis C Virus, [[Hepatitis C Virus]])
    • Idiopathic (up to 60% of cases)
    • Menstruation
    • Polymorphic Light Eruption
    • Vulvovaginal Candidiasis


Acute Erythema Multiforme

  • Discontinue Drug: if necessary
  • Supportive Care: as necessary
    • Opthalmologist Consultation: necessary for ocular involvement
  • Treatment of Underlying HSV (if present): does not affect the clinical course of EM
  • Intravenous Immunoglobulin (IVIG)
    • xxx
  • Corticosteroids: prednisone 40-60 m/day
    • Probably only indicated (in short-course) for severe and debilitating EM with mucosal involvement -> tapered over 2-4 wks
    • With oral involvement, there is some concern that steroids may increase the risk for disease chronicity and prolong the duration of attacks

Recurrent Erythema Multiforme

  • Prophylactic Systemic Acyclovir (or Valacyclovir/Famciclovir): indicated for patients with defined HSV-associated EM and >6 episodes per year
  • Azathioprine
  • Mycophenolate Mofetil
  • Dapsone
  • Intramuscular Immunoglobulin G
  • Hydroxychloroquine
  • Cyclosporine-A
  • Thalidomide
  • Interferon-Alpha: in cases secondary to hepatitis C virus infection)
  • Cimetidine


  • Skin lesions usually resolve over 2-4 wks, but may be recurrent (especially in HSV-associated cases)
  • Adverse Prognostic Features in Recurrent EM
    • Inability to identify a specific cause
    • Lack of improvement with continuous antiviral therapy
    • Severe oral involvement
    • Almost continuous use of glucocorticoid therapy for more than one year
    • History of use of two or more immunosuppressive agents


  • Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. Jan 1993;129(1):92-6
  • A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol. 1995;132(2):267
  • Characteristics of the oral lesions in patients with cutaneous recurrent erythema multiforme. Oral Pathol Med. 1995;24(1):9