Erythema Multiforme

Why Erythema multiforme major is correct

• Classic three-zone target lesions on acral and extensor surfaces are the hallmark of erythema multiforme
• Herpes simplex virus is the most common trigger, accounting for the majority of cases and typically preceding the eruption by 1-2 weeks
• The designation "major" reflects significant mucosal (here, oral) involvement, distinguishing it from EM minor, which has little or no mucosal involvement
• Acute care is supportive (topical corticosteroids, analgesic mouth rinses, and systemic corticosteroids for severe mucosal disease); antivirals started after the eruption appears do not shorten it, but recurrent HSV-associated EM warrants continuous suppressive acyclovir or valacyclovir

Why the others are wrong

• Fixed drug eruption — produces one or a few round, dusky plaques that recur at the SAME site with re-exposure to a culprit drug, not symmetric acral targets after HSV (confused-with a dusky single lesion)
• Stevens-Johnson syndrome — usually drug-triggered, with flat atypical targets and dusky macules that favor the trunk and face plus epidermal detachment of <10% BSA; raised typical three-zone acral targets after an HSV recurrence, with no culprit drug reported, indicate EM major instead (confusing the two mucosal target eruptions)
• Urticaria with angioedema — transient migratory wheals that resolve within 24 hours without fixed targets or mucosal erosion (anchoring on an acute rash)
• Hand-foot-mouth disease — also places lesions on the palms with painful oral erosions, but it is an enteroviral illness with small oval vesicles on the palms and soles rather than symmetric three-zone targets on the extensor limbs, and it does not follow an HSV recurrence (anchoring on palms plus mouth)

Why CD8+ T-cell–mediated keratinocyte apoptosis at viral antigen deposits is correct

• Erythema multiforme is a delayed-type (type IV) hypersensitivity reaction; here the preceding herpes labialis identifies HSV as the trigger (HSV accounts for >=50% of cases and >70% of recurrent EM).
• HSV DNA fragments are carried to keratinocytes by Langerhans cell precursors, provoking a CD4+ Th1 / IFN-gamma response and CD8+ T-cell–mediated apoptosis of HSV-antigen–bearing keratinocytes — producing the classic acral, three-zone target lesions seen here.

Why the others are wrong

• IgE-mediated mast cell degranulation with transient dermal vascular leak — this is type I hypersensitivity (urticaria/anaphylaxis); it produces transient wheals lasting <24 h, not fixed three-zone target lesions with epidermal injury.
• Immune complex deposition in postcapillary venules with neutrophilic vasculitis — this type III mechanism causes cutaneous small-vessel (leukocytoclastic) vasculitis, including urticarial vasculitis, which produces palpable purpura on dependent sites or burning wheals lasting >24 h that resolve with bruising; it does not produce acral three-zone targets after an HSV outbreak, and EM histology shows interface dermatitis with necrotic keratinocytes rather than fibrinoid necrosis of venules.
• IgG autoantibody attack on desmoglein-3 disrupting keratinocyte adhesion — this is the mechanism of pemphigus vulgaris, an antibody-mediated acantholytic disease causing flaccid bullae and oral erosions with a positive Nikolsky sign, not target lesions.
• Direct cytopathic infection of epidermal keratinocytes by replicating HSV — the preceding cold sore and the HSV DNA detectable in lesions make active skin infection tempting, but EM lesions carry only fragments of viral DNA, not replicating virus, so they are culture-negative and lack viral cytopathic changes; the lag of days after the cold sore and the three-zone targets reflect a T-cell hypersensitivity response.

Additional high-yield points

• Stevens-Johnson syndrome/TEN is the key contrast: a drug-triggered cytotoxic T-cell reaction (granulysin, Fas/Fas-ligand) with flat atypical targets, truncal predominance, and more extensive mucosal involvement, whereas HSV-associated EM has raised, acral, typical targets.