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Erythema Multiforme

BASICS

DESCRIPTION

  • Immune-mediated, self-limited mucocutaneous disorder.
  • Characteristic acral, targetoid papules with three concentric zones (central necrosis, dark red zone, pale outer ring).
  • Two subtypes:
  • EM minor (EMm): ≀1 mucosal site involved.
  • EM major (EMM): β‰₯2 mucosal sites involved, distinct from Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).
  • Recurrent EM defined as β‰₯3 episodes; average 6 episodes/year lasting 6-10 years.

EPIDEMIOLOGY

  • Incidence <1% annually in the U.S.
  • Affects primarily young adults aged 20-40 years.
  • Slight female predominance.
  • No racial predilection.

ETIOLOGY AND PATHOPHYSIOLOGY

  • Infectious triggers (~90%):
  • HSV-1 (most common), HSV-2
  • Mycoplasma pneumoniae (second most common)
  • Other viruses: EBV, hepatitis C, coxsackievirus, CMV, HIV, COVID-19, etc.
  • Drug triggers: NSAIDs, antibiotics, anticonvulsants, statins, TNF-Ξ± inhibitors, barbiturates.
  • Vaccines: HPV, MMR, smallpox, hepatitis B, influenza, diphtheria-pertussis-tetanus, COVID-19, etc.

  • Other causes: occupational exposures, radiation, hormone changes, malignancy, IBD.

  • Pathogenesis:

  • HSV DNA fragments transported to keratinocytes β†’ TH1 cell activation β†’ IFN-Ξ³ release β†’ inflammation.

  • Drug/vaccine induced involves TNF-Ξ±, perforin, granzyme B pathways.

  • Genetics:

  • HLA-DQB1*0301 allele associated with HSV-associated EM.
  • Recurrent EM linked to HLA-B35, B62, DR53 alleles.

RISK FACTORS

  • Prior EM episodes.
  • Age 20-40 years.
  • Exposure to causative infections, drugs, or vaccines.

GENERAL PREVENTION

  • Avoid known causative agents.
  • HSV-related recurrent EM may benefit from antiviral prophylaxis (acyclovir, valacyclovir, famciclovir).

DIAGNOSIS

HISTORY

  • Acute, episodic, self-limited course.
  • Prodromal symptoms typically absent, except with mucosal involvement.
  • Recent history of HSV infection or respiratory symptoms suggestive of Mycoplasma pneumoniae.
  • Medication or vaccination history.
  • Exposure to occupational toxins or radiation.

PHYSICAL EXAM

  • Typical skin lesions: targetoid papules with three concentric zones:
  • Central epidermal necrosis (dusky or blistered)
  • Dark red inflammatory zone
  • Outer pale edematous ring
  • Lesions distributed acrally, symmetrically on extensor surfaces.
  • Mucosal involvement:
  • EMm: minimal, usually oral mucosa.
  • EMM: β‰₯2 mucosal sites including eyes (conjunctivitis, keratitis), mouth (stomatitis, cheilitis), genital tract.

DIFFERENTIAL DIAGNOSIS

  • Stevens-Johnson syndrome (SJS): truncal, flat, atypical lesions, blisters, mucosal involvement β‰₯2 sites, systemic symptoms, positive Nikolsky sign, mortality ~10%.
  • Toxic epidermal necrolysis (TEN): extensive skin detachment >30%, mortality up to 50%.
  • Urticaria, fixed drug eruption, bullous pemphigoid, Sweet syndrome, lupus erythematosus, herpes gestationis, etc.

DIAGNOSTIC TESTS

  • Clinical diagnosis primarily.
  • Supportive tests:
  • HSV serology, skin biopsy with immunofluorescence, PCR, viral culture, Tzanck smear for HSV.
  • Mycoplasma pneumoniae: serology, chest X-ray, PCR.
  • Autoimmune markers if Rowell syndrome suspected.
  • Histopathology: spongiosis, necrotic keratinocytes, lymphocytic infiltrate at dermo-epidermal junction.
  • DIF and IIF mostly negative or nonspecific.

TREATMENT

GENERAL MEASURES

  • Supportive care.
  • Identify and discontinue offending drugs.
  • Treat underlying infections.

MEDICATION

Acute EM

  • Discontinue causative agents.
  • Treat Mycoplasma pneumoniae infection if present.
  • HSV-induced EM: antivirals have no proven effect on acute mild EM course.
  • Mild cutaneous lesions:
  • Medium-potency topical steroids on trunk/extremities.
  • Low-potency topical steroids on face/intertriginous areas.
  • Oral antihistamines for pruritus.

Mucosal Involvement

  • Ocular: urgent ophthalmology consult; use nonpreserved dexamethasone 0.1% and lubricants.
  • Oral:
  • High-potency topical corticosteroid gel (fluocinonide 0.05%).
  • Lidocaine/antacid/diphenhydramine mouthwash for symptomatic relief.
  • Severe mucosal disease may require hospitalization for hydration, nutrition, pain control.
  • Systemic corticosteroids may be used in severe cases (prednisone 40-60 mg daily tapered over weeks), but evidence limited.

Recurrent EM

  • First-line: antiviral prophylaxis for HSV-associated and idiopathic recurrent EM (β‰₯6 months):
  • Acyclovir 400 mg BID, valacyclovir 500 mg BID, famciclovir 250 mg BID.
  • Second-line options: dapsone, azathioprine, mycophenolate mofetil, thalidomide, tacrolimus ointment, hydroxychloroquine, levamisole.
  • Levamisole requires dose titration and monitoring due to risk of agranulocytosis.

ISSUES FOR REFERRAL

  • Autoimmune diseases, recurrent HSV infections, possible malignancy.

ADMISSION/INPATIENT CONSIDERATIONS

  • Most cases outpatient.
  • Hospitalize if severe oral lesions impair oral intake requiring hydration, electrolyte replacement, nutrition, pain control.

ONGOING CARE

  • Self-limiting disease; rare complications; no mortality.

PATIENT EDUCATION

  • Avoid identified triggers.

PROGNOSIS

  • Lesions evolve over 1-2 weeks, resolve in 2-6 weeks without scarring typically.
  • May cause postinflammatory hyper/hypopigmentation.

COMPLICATIONS

  • Secondary infection, scarring, ocular damage.

REFERENCES

  1. Trayes KP, Love G, Studdiford JS. Erythema multiforme: recognition and management. Am Fam Physician. 2019;100(2):82-88.
  2. de Risi-Pugliese T, Sbidian E, Ingen-Housz-Oro S, et al. Interventions for erythema multiforme: a systematic review. J Eur Acad Dermatol Venereol. 2019;33(5):842-849.

CODES

  • ICD10 L51.0 Nonbullous erythema multiforme
  • ICD10 L51.1 Stevens-Johnson syndrome
  • ICD10 L51.3 Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome

CLINICAL PEARLS

  • EM diagnosis is clinical; typical targetoid lesions have three zones ("iris" lesions).
  • Lesions are symmetric and acrally distributed.
  • HSV-associated recurrent EM may respond to antiviral prophylaxis.
  • Differentiation from SJS/TEN is critical due to severity and prognosis differences.