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Erythema Multiforme

Aka: Erythema Multiforme, Erythema Multiforme Minor

I. Pathophysiology

  1. Self limited mucocutaneous reaction
  2. Type IV Hypersensitivity Reaction (T Lymphocyte mediated) to various antigens

II. Types

  1. Erythema Multiforme Minor
    1. Now known simply as Erythema Multiforme
    2. Other forms below are distinct entities
  2. Erythema Multiforme Major (Stevens Johnson Syndrome)
    1. Previously thought to be along same spectrum as minor
    2. Now thought to be distinct entity
    3. May include Toxic Epidermal Necrolysis

III. Causes

  1. Idiopathic (50%)
  2. Herpes Simplex Virus (>50%)
    1. Occurs 10 days after acute eruption
    2. HSV may be cause even without active lesions
  3. Other infections
    1. Mycoplasma pneumoniae
    2. Varicella Zoster Virus
    3. Hepatitis C
    4. Cytomegalovirus
    5. Human Immunodeficiency Virus
  4. Drug sensitivity (1-3 weeks after intake)
    1. Sulfonamides (e.g. Septra)
    2. Penicillins
    3. Hydantoins (e.g. Dilantin)
    4. Phenothiazines
    5. Phenobarbitals
    6. NSAIDs (esp. Ibuprofen)
    7. Bextra (FDA black box warning)
    8. Allopurinol
    9. Vaccines (Td, Hepatitis B Vaccine, Small PoxVaccine)
    10. Candesartan (Atacand)
    11. Metformin (Glucophage)
    12. Adalimumab (Humira)
    13. Bupropion (Wellbutrin)
    14. Ciprofloxacin
  5. Pregnancy
  6. Food Allergy
  7. Neoplasm

IV. Epidemiology

  1. Age: Peaks age 20-40 (20% of cases under age 18)
  2. Gender: Males affected more often than females

V. Symptoms

  1. Rash develops 3-5 days after prodrome
  2. Mild prodrome for 7-10 days may be present
    1. Malaise
    2. Fever
    3. Headache
    4. Rhinorrhea
    5. Cough

VI. Signs

  1. Distinctive Target or Iris skin lesion
    1. Starts as a dull erythematous Macule that becomes raised
    2. Centripetal spread (extremities to trunk) into target lesion by day 2
      1. Center: Dusky erythema or Vesicle
      2. Middle: Pale edematous ring
      3. Outer: Dark band of erythema
    3. Distribution: Symmetrical involvement
      1. Onset on distal extremities (often dorsal hands, as well as palms and soles)
      2. Progress proximally (often extensor surfaces)
      3. Features absent in Erythema Multiforme Minor (contrast with EM Major and TEN)
        1. Oral Mucosal involvement is absent in Erythema Multiforme Minor
        2. Nikolsky Sign is absent in Erythema Multiforme Minor
        3. Non-toxic patient appearance
    4. Progresses
      1. Central necrosis
      2. Some lesions may coalesce into annular Plaques
    5. Healing
      1. Scarring
      2. Postinflammatory Hyperpigmentation
  2. Alternative presentations
    1. Non-transient Urticarial Plaques
    2. Vesicles or bullae form in prior Macule or wheal

VII. Labs: None are necessary (use for differential diagnosis)

  1. Complete Blood Count
  2. Skin Biopsy (if diagnosis unclear)
  3. Evaluate underlying etiology
    1. Herpes Simplex Virus
      1. Tzanck Preparation of skin lesion
    2. Mycoplasma pneumoniae
      1. Complement fixation
      2. Cold agglutinins
      3. Chest XRay

VIII. Differential Diagnosis

  1. Severe illnesses with Erythema Multiforme type lesions
    1. Erythema Multiforme Major (Stevens Johnson Syndrome)
    2. Toxic Epidermal Necrolysis
  2. Chronic Urticaria
    1. Urticarial lesions persist <24 hours, then migrate
  3. Serum Sickness
  4. Figurate erythema
  5. Toxic erythema
    1. Viral infection
    2. Drug exposure
  6. Graft versus host disease
  7. Necrotizing Vasculitis
  8. Systemic Lupus Erythematosus
  9. Erythema Nodosum
  10. Vesiculobullous lesions
    1. Bullous Pemphigoid
    2. Pemphigus Vulgaris
    3. Impetigo
    4. Toxic Epidermal Necrolysis
    5. Dermatitis Herpetiformis
    6. Behcet's Syndrome
    7. Reiter's Syndrome
  11. Mucocutaneous lesions
    1. Cicatricial Pemphigoid
    2. Pemphigus Vulgaris
    3. Lichen Planus
    4. Aphthous Ulcer
    5. Acute Herpetic Mucositis

IX. Management

  1. Elimination of precipitating factors
    1. Herpes Simplex Virus
    2. Mycoplasma pneumoniae
    3. Suspected drug or food item
  2. Mild Involvement: Supportive care
    1. Analgesics
    2. Oral Antihistamines
    3. Skin lesions
      1. Wet Dressings or soaks
      2. Topical Corticosteroids (questionable efficacy)
  3. Moderate Erythema Multiforme Minor
    1. Oral Acyclovir
    2. Prednisone (controversial, not typically recommended)
      1. Dose: 40-80 mg PO daily for 1-2 weeks, then taper
    3. Oral Lesions (Erythema Multiforme Major)
      1. Saline mouth rinses
  4. Home Precautions
    1. Return for fever, new systemic symptoms, large bullae or Oral Lesions
  5. Recurrent Erythema Multiforme Minor
    1. Systemic antivirals
      1. Continue until lesion-free for 4 months
        1. Then taper dose gradually
      2. First-line
        1. Acyclovir 400 mg PO bid
      3. Second-line if Acyclovir ineffective
        1. Valacyclovir 500-1000 mg PO daily
        2. Famciclovir 125 to 250 mg PO daily
    2. Other agents in refractory cases
      1. Prescribed by Dermatology
      2. Agents (high rate of adverse effects)
        1. Dapsone
        2. Hydroxychloroquine
        3. Azathoprine
        4. Cyclosporine
        5. Thalidomide

X. Course

  1. New lesions occur over 3-5 days
  2. Lesions persist for 1-2 weeks (non-migratory)
    1. Contrast with Urticaria that last <24 hours
  3. Resolves spontaneously in 3-5 weeks
  4. May recur multiple times in one year

XI. References

  1. Long (2016) Crit Dec Emerg Med 30(7):3-10
  2. Lamoreux (2006) Am Fam Physician 74:1883-8 [PubMed]
  3. Leaute-Labreze (2000) Arch Dis Child 83:347-52 [PubMed]
  4. Williams (2005) Dent Clin North Am 49:67-76 [PubMed]

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Ontology: Erythema Multiforme (C0014742)

Definition (NCI_CTCAE) A disorder characterized by target lesions (a pink-red ring around a pale center).
Definition (NCI) A hypersensitivity reaction characterized by the sudden appearance of symmetrical cutaneous and mucocutaneous macular or papular lesions which evolve into lesions with bright red borders (target lesions). The lesions usually appear in the hands, feet, extremities, and face. Symptoms include fever, malaise, sore throat, cough, vomiting, diarrhea, arthralgia, and myalgia. Causes include infections (most commonly herpes simplex virus), drugs (e.g., sulfonamides, anticonvulsants, and antibiotics), malignancies, and collagen vascular disorders.
Definition (MSH) A skin and mucous membrane disease characterized by an eruption of macules, papules, nodules, vesicles, and/or bullae with characteristic "bull's-eye" lesions usually occurring on the dorsal aspect of the hands and forearms.
Definition (CSP) skin and mucous membrane disease characterized by an eruption of macules, papules, nodules, vesicles, and/or bullae with characteristic bull's-eye lesions usually occurring on the dorsal aspect of the hands and forearms.
Concepts Disease or Syndrome (T047)
MSH D004892
ICD9 695.10, 695.1
ICD10 L51 , L51.9
SnomedCT 36715001, 200919006, 156362004, 200928007, 267848009
English ERYTHEMA MULTIFORME, Erythema multiforme, unspecified, erythema multiforme, erythema multiforme (diagnosis), Erythema multiforme NOS, Erythema Multiforme [Disease/Finding], erythema polymorphe, multiforme erythema, Erythema;multiforme, erythema multiformes, Target lesion, Multiforme - erythema, Erythema multiforme NOS (disorder), Erythaema polymorphe, Erythema polymorphe, Erythema multiforme, EM - Erythema multiforme, Erythema multiforme (disorder), erythema; multiforme, multiforme; erythema, Erythema multiforme, NOS, Erythema Multiforme
Portuguese ERITEMA MULTIFORME, Eritema polimorfo, Eritema multiforme, Eritema Multiforme
Spanish ERITEMA MULTIFORME, Eritema poliforme, Eritema polimórfico, eritema multiforme, SAI (trastorno), eritema multiforme, SAI, eritema multiforme, eritema polimorfo (trastorno), eritema polimorfo, Eritema multiforme, Eritema Multiforme
Italian Eritema multiforme o polimorfo, Eritema polimorfo, Eritema essudativo polimorfo
Dutch polymorf erytheem, erytheem, polymorf, erytheem; multiforme, multiforme; erytheem, Erythema exsudativum multiforme, niet gespecificeerd, erythema multiforme, Erythema exsudativum multiforme, Erythema multiforme
German Polymorphes Erythem, Erythaema polymorphe, ERYTHEMA MULTIFORME, Erythema exsudativum multiforme, nicht naeher bezeichnet, Erythema multiforme, Erythema exsudativum multiforme
Japanese 多形紅斑, ﾀｹｲｺｳﾊ�
Swedish Erythema multiforme
Czech erythema multiforme, Erythema multiforme, Polymorfní erytém
Finnish Monimuotoinen punavihoittuma
Russian ERITEMA MNOGOFORMNAIA EKSSUDATIVNAIA, ЭРИТЕМ� М�ОГОФОРМ��Я ЭКССУД�ТИВ��Я
French ERYTHEME POLYMORPHE, Erythème polymorphe, Érythème multiforme, Érythème exsudatif multiforme, Érythème polymorphe
Korean �세불명� 다형�반, 다형�반
Croatian POLIMORFNI ERITEM, ERITEM, MULTIFORMNI
Polish Rumień wielopostaciowy
Hungarian Polymorph erythema, erythema, polymorph, Erythema multiforme
Norwegian Erythema multiforme
Derived from the NIH UMLS (Unified Medical Language System)

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