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ERYTHEMA MULTIFORME

Introduction

Erythema multiforme (EM) is an acute, immune-mediated, mucocutaneous condition characterized by round erythematous papules with concentric color changes that usually develop on the extremities. EM is most commonly caused by the herpes simplex virus (HSV) type I infection and the use of certain medications, and has a wide spectrum of clinical manifestations that may be triggered by hypersensitivity reactions to various antigens. The condition can be either major or minor, with the major form involving mucosal surfaces and the minor form featuring a symmetric red rash with a propensity to involve the extremities.1-4

Pathophysiology

  • EM develops as a consequence of immune-complex mechanisms involving antigen-antibody reactions that target small blood vessels in the skin or mucosa.4
  • Numerous factors have been linked to the development of EM, including infections, medication use, malignancy, autoimmune disease, radiation, immunization, and menstruation. In approximately 90% of cases, the precipitating event relates to infection, with the HSV playing a predominant role in 70-80% of these cases. Both HSV types 1 and 2 can lead to EM, but type 1 is more commonly responsible.2,4,5
  • Another well-recognized infectious agent that has a clearly documented association with EM is Mycoplasma pneumonia. This bacteria appears to have particular importance in the development of EM in children, and is associated with mucositis and more severe systemic symptoms.2
  • Drug-associated EM is reported in less than 10% of cases, and the most common disease-precipitating medications are nonsteroidal anti-inflammatory drugs (NSAIDs), sulfonamides, antiepileptics, and antibiotics.2

Related Anatomy

  • Dermis
  • Epidermis
  • Keratinocytes
  • Antigens
  • Antibodies
  • Cytokines
  • Lymphocytes
  • EM is typically classified as either minor or major:
    • EM minor: typical lesions are symmetrical and have an acral disposition; mucosal involvement is rare, and when present, is light and affects a single mucosa, often the mouth
    • EM major: skin lesions are more extensive; typical target lesions are present and mucosal involvement is severe, affecting at least two different mucosal sites, with the oral mucosa typically affected5

Incidence and Related Conditions

  • Epidemiologic data on EM is scarce and its exact incidence is not known, but is estimated to be <1%.2,6
  • EM typically occurs in adults aged 20-40 years and is slightly more common in women than men at a ratio of 1.5:1.0. It has a reported recurrence rate of 37% and a genetic predisposition to certain Asian ethnic groups.4
  • Stevens-Johnson syndrome (SJS)
  • HSV
  • Toxic epidermal necrolysis

Differential Diagnosis

  • Cutaneous small-vessel vasculitis
  • Fixed drug eruption
  • Hives
  • Paraneoplastic pemphigus
  • Pemphigoids 
  • Polymorphous light eruption
  • Rowell’s syndrome
  • SJS
  • Sweet’s syndrome
  • Uticaria
  • Viral exanthems 
ICD-10 Codes

  • SKIN - COMMON HAND RASHES: ERYTHEMA MULTIFORME

    Diagnostic Guide Name

    SKIN - COMMON HAND RASHES: ERYTHEMA MULTIFORME

    ICD 10 Diagnosis, Single Code, Left Code, Right Code and Bilateral Code

    DIAGNOSISSINGLE CODE ONLYLEFTRIGHTBILATERAL (If Available)
    ERYTHEMA MULTIFORMEL51.9   

    ICD-10 Reference

    Reproduced from the International statistical classification of diseases and related health problems, 10th revision, Fifth edition, 2016. Geneva, World Health Organization, 2016 https://apps.who.int/iris/handle/10665/246208

Symptoms
Flat, round, red target lesions most commonly on palms and soles
Itching
Fever
Fatigue
Joint pain and swelling
Burning sensation
Typical History

A typical patient is a 25-year-old woman who had been infected with the HSV one week prior. Over the course of a 24-hour period, the woman suddenly noticed the eruption of a number of red lesions, which were primarily concentrated on the skin of her palms and soles. During this time she also developed a fever and began to “not feel herself,” which made it difficult for her to complete many daily activities. After a few additional days of similar symptoms, she consulted with a dermatologist for an evaluation.

Positive Tests, Exams or Signs
Work-up Options
Treatment Options
Conservative

Conservative2,4 

  • No specific treatment has yet been identified that predictably alters the clinical course of EM, so interventions primarily target the underlying cause and/or symptomology. In general, treatment should appropriately manage any active viral infection, if present, and any drug suspected of precipitating EM should be promptly discontinued.4
  • EM minor
    • Treatment should be focused on relieving symptoms with topical anti-inflammatory, anesthetic, or analgesic agents. Some treatment options include:
      • Fluocinonide 0.05% or other topical corticosteroid agents applied 2-3 times/day
      • Mouthwash containing equal parts of viscous lidocaine 2%, diphenhydramine (12.5 mg/5 mL), and an aluminum hydroxide and magnesium hydroxide mixture (Maalox) up to 4 times per day
      • Antibiotic therapy if Mycoplasma pneumonia is responsible
      • Oral antihistamines
      • EM major 
        • Systemic corticosteroids
          • May be advised depending on the etiology and severity of the disease
          • Prednisone is most commonly prescribed: 40-60 mg per day and tapered over 2-4 weeks
          • Recurrent EM can be avoided with antiviral or immunosuppressive therapy. Continuous antiviral therapy is effective for the prevention of recurrent HSV-associated EM, and a six-month course of either acyclovir (400 mg twice daily), valacyclovir (500 mg twice daily), or famciclovir (250 mg twice daily) has been suggested.
Operative
  • There do not appear to be any surgical indications for EM.
Complications
  • Patchwork appearance of the skin, with hypopigmented regions and potential hypertrophic scarring
  • Pneumonia/acute respiratory distress syndrome 
  • Dehydration and electrolyte disturbances
  • Gastrointestinal hemorrhage, nephritis, or renal failure
  • Esophagitis
Outcomes
  • The clinical course of an EM episode is variable, and complete healing may take up to 3-6 weeks.4
  • A systematic review of various interventions for EM identified only one relevant randomized controlled trial on the use of acyclovir. The study found that in patients with clinically suspected HSV-related EM, oral acyclovir was superior to placebo in suppressing recurrence.3
Key Educational Points
  • Target lesions are often present and are considered diagnostic. To meet the criteria for a target lesion, three zones of color must be present: 1) a central dark area or blister surrounded by 2) a pale edematous zone surrounded by 3) a peripheral rim of erythema. These lesions can look like insect bites or papular urticaria.1
  • No specific objective markers or criteria are required for an EM diagnosis, so patient history and clinical findings are important.2
  • Biopsies are not usually needed, but if performed, the erythematous plaque will show dermal changes with a lymphohistiocytic perivascular infiltrate and edema in the papillary dermis.1
  • It was once believed that EM represented a spectrum of disorders, including EM major, SJS, and toxic epidermal necrolysis. Recent evidence, however, suggests that EM major and SJS are separate, distinct disorders that manifest with similar mucosal erosions but different cutaneous lesions.2
  • X-ray ay be performed to screen for a pulmonary infection.1
References

New and Cited Articles

  1. Marks JG, Miller JJ. Lookingbill and Marks’ Principles of Dermatology. Fifth Ed. London, New York: Saunders Elsevier; 2013.
  2. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol 2012;51(8):889-902. PMID: 22788803
  3. de Risi-Pugliese T, Sbidian E, Ingen-Housz-Oro S, Le Cleach L. Interventions for erythema multiforme: a systematic review. J Eur Acad Dermatol Venereol 2019;33(5):842-849. PMID: 30680804
  4. Samim F, Auluck A, Zed C, Williams PM. Erythema multiforme: a review of epidemiology, pathogenesis, clinical features, and treatment. Dent Clin North Am 2013;57(4):583-596. PMID: 24034067
  5. Hafsi W, Badri T. Erythema Multiforme. In: StatPearls.Treasure Island (FL) 2019. PMID: 29261983
  6. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol 1983;8(6):763-775. PMID: 6345608
  7. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin.12thEd. Philadelphia, PA. Elsevier, 2016.

Reviews

  1. Paulino L, Hamblin DJ, Osondu N, Amini R. Variants of Erythema Multiforme: A Case Report and Literature Review. Cureus2018;10(10):e3459. PMID: 30564538
  2. de Risi-Pugliese T, Sbidian E, Ingen-Housz-Oro S, Le Cleach L. Interventions for erythema multiforme: a systematic review. J Eur Acad Dermatol Venereol 2019;33(5):842-849. PMID: 30680804
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