Erythema Multiforme

1. Pathophysiology
   1. Self limited mucocutaneous reaction
   2. Hypersensitivity Reaction to various antigens
2. 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
3. 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 Pox vaccine)
      10. Candesartan (Atacand)
      11. Metformin (Glucophage)
      12. Adalimumab (Humira)
      13. Bupropion (Wellbutrin)
      14. Ciprofloxacin
   5. Pregnancy
   6. Food Allergy
   7. Neoplasm
4. Epidemiology
   1. Age: Peaks age 20-30 (20% of cases under age 18)
   2. Gender: Males affected more often than females
5. Symptoms
   1. Rash develops after prodrome
   2. Mild prodrome for 7-10 days may be present
      1. Malaise
      2. Fever
      3. Headache
      4. Rhinorrhea
      5. Cough
6. Signs
   1. Distinctive Target or Iris skin lesion
      1. Starts as erythematous Macule that becomes raised
      2. Distribution: Symmetrical involvement
         1. Onset on distal extremities (often dorsal hands)
         2. Progress proximally (often extensor surfaces)
         3. Oral Mucosal involvement may be present
      3. Develops concentrically into target lesion by day 2
         1. Center: Dusky erythema or Vesicle
         2. Middle: Pale edematous ring
         3. Outer: Dark band of erythema
      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
7. 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
8. 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. 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
   10. Mucocutaneous lesions
       1. Cicatricial Pemphigoid
       2. Pemphigus Vulgaris
       3. Lichen Planus
       4. Aphthous Ulcer
       5. Acute Herpetic Mucositis
9. 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)
      4. Oral Lesions
         1. Saline mouth rinses
   3. Moderate Erythema Multiforme Minor
      1. Oral Acyclovir
      2. Prednisone (controversial)
         1. Dose: 40-80 mg PO daily for 1-2 weeks, then taper
   4. 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
10. 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
11. References
    1. Lamoreux (2006) Am Fam Physician 74:1883-8
    2. Leaute-Labreze (2000) Arch Dis Child 83:347-52
    3. Williams (2005) Dent Clin North Am 49:67-76