INFLAMMATORY AND IMMUNE-MEDIATED SKIN DISORDERS

Erythema Multiforme (EM)

Classification: Acute interface dermatitis characterized by rapidly developing target-like lesions and a spectrum from limited skin disease to prominent mucosal involvement (Pincus & McCalmont, 2019).

Key diagnostic discriminator: The prototypical lesion begins as a red macule or thin papule, expands centrifugally, and develops a dusky or necrotic center. Lesions arise in crops, usually beginning on acral surfaces (Pincus & McCalmont, 2019).

Clinical priority: Prominent mucosal disease or widespread cutaneous involvement may be severe. Medication-associated SJS/TEN is classified separately and produces extensive skin and mucosal necrosis (Pincus & McCalmont, 2019).

Etiology and risk factors

  • Infection precipitates most cases, with herpes simplex virus type 1 the predominant identified trigger. Other infections, medications, and vaccinations may trigger erythema multiforme. Mycoplasma pneumoniae-associated mucocutaneous disease is now generally classified separately as reactive infectious mucocutaneous eruption (RIME) (King, 2022).
  • HSV-associated episodes may recur. Viral DNA and a cytotoxic immune response have been demonstrated in lesional skin in some affected patients (Pincus & McCalmont, 2019).

Pathophysiology

  • Erythema multiforme is a vacuolar interface dermatitis in which a relatively sparse inflammatory infiltrate accompanies injury and necrosis of basal keratinocytes (Pincus & McCalmont, 2019).
  • CD4 and CD8 lymphocytes are present in the dermal infiltrate, and epidermal CD8 cytotoxic cells lie near damaged keratinocytes. Cytotoxicity and cytokines contribute to epidermal injury (Pincus & McCalmont, 2019).
  • Differences in the intensity of inflammation and necrosis across a lesion produce its target-like appearance (Pincus & McCalmont, 2019).

Clinical manifestations

  • Lesions develop rapidly in crops, initially on acral surfaces, and may spread proximally to the trunk and face. The characteristic lesion has an erythematous outer area and a dusky or necrotic center (Pincus & McCalmont, 2019).
  • Mucosal erosions or ulcers occur in a minority of cases and can occasionally be the only presenting feature (Pincus & McCalmont, 2019).
  • EM minor is confined to the skin or includes limited mucosal involvement. EM major includes prominent involvement of at least two of the oral, anogenital, and conjunctival sites (Pincus & McCalmont, 2019).

Findings that argue against or redirect

  • Transient wheals favor urticaria rather than erythema multiforme. EM lesions are target-like and remain fixed long enough to evolve centrally (Gohara et al., 2012; Pincus & McCalmont, 2019).
  • Widespread medication-associated skin and mucosal necrosis redirects toward SJS/TEN, which is classified separately from erythema multiforme (Gohara et al., 2012; Pincus & McCalmont, 2019).
  • A dense lichenoid infiltrate and the clinical pattern of lichen planus redirect away from the sparse vacuolar interface pattern of erythema multiforme (Gohara et al., 2012; Pincus & McCalmont, 2019).

Diagnostic evaluation

  • Diagnosis is based primarily on the target-like morphology, rapid development in crops, acral distribution, mucosal involvement, and a history of herpes infection or medication exposure (Gohara et al., 2012; Pincus & McCalmont, 2019).
  • Histopathologic evaluation can support the diagnosis by demonstrating vacuolar interface change and necrotic keratinocytes. Diagnosis depends on clinicopathologic correlation rather than a single definitive test (Gohara et al., 2012; Pincus & McCalmont, 2019).

Expected diagnostic and laboratory findings

  • Histology shows vacuolated and necrotic basal keratinocytes with a relatively sparse inflammatory infiltrate. CD8 cytotoxic lymphocytes may be present within the epidermis (Pincus & McCalmont, 2019).
  • Near-complete epidermal necrosis may occur in the dusky center of a target lesion, while inflammation and vacuolization are less intense at the periphery (Pincus & McCalmont, 2019).

Differential diagnosis

  • Urticaria: transient wheals without persistent necrotic centers (Gohara et al., 2012; Pincus & McCalmont, 2019).
  • SJS/TEN: a separate, usually medication-associated spectrum with extensive skin and mucosal necrosis (Gohara et al., 2012; Pincus & McCalmont, 2019).
  • Lichen planus: a lichenoid interface dermatitis with a denser band-like infiltrate and a different clinical morphology (Gohara et al., 2012; Pincus & McCalmont, 2019).

Treatment and management

  • Many episodes are brief and self-limited. Mild cutaneous symptoms can be managed with oral antihistamines and topical corticosteroids; mild painful mucosal disease may benefit from antiseptic or local-anesthetic mouth rinses (King, 2022).
  • Treat the precipitating infection when indicated and discontinue a suspected causative medication. Antiviral therapy does not substantially alter an established single HSV-associated episode (King, 2022).
  • Ocular involvement requires ophthalmology evaluation. Severe mucosal disease may require hospital admission to support hydration, nutrition, and pain control (King, 2022).
  • Continuous oral antiviral prophylaxis, commonly acyclovir, may reduce recurrent erythema multiforme, including recurrent disease without a clearly identified trigger (King, 2022).

Additional complications and red flags

  • Repetitive or generalized attacks can be disabling and, in severe cases, life-threatening (Pincus & McCalmont, 2019).
  • Prominent mucositis can substantially increase disease severity (Pincus & McCalmont, 2019).

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References

Gohara, M. A., Schaffer, J. V., Abbasi, N. R., Kingsley, M. M., Sheehan, J. M., & Arndt, K. A. (2012). Inflammatory dermatoses (rashes). In M. C. Henderson, L. M. Tierney, Jr., & G. W. Smetana (Eds.), The patient history: An evidence-based approach to differential diagnosis (2nd ed.). McGraw-Hill.

King, C. (2022, February). Erythema multiforme. DermNet. https://dermnetnz.org/topics/erythema-multiforme

Pincus, L. B., & McCalmont, T. H. (2019). Diseases of the skin. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). McGraw-Hill Education.