Acute self-limited immune-mediated mucocutaneous reaction with target lesions; most often triggered by HSV.
Also known as: erythema multiforme, EM, EM minor, EM major, target lesions
Overview
An acute, self-limited, immune-mediated mucocutaneous reaction characterized by typical 'target' (iris) lesions on extensor extremities and palms/soles. EM minor lacks significant mucosal involvement; EM major involves ≥1 mucous membrane.
Epidemiology
Peak ages 20-40; rare in children <5 and adults >50. Slight male predominance. Recurrent EM affects ~25% of patients, usually HSV-driven.
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Question 1DermatologyMedium
A 28-year-old woman develops symmetric, targetoid skin lesions with three concentric color zones on her palms and the extensor surfaces of her arms and legs, along with painful erosions of the oral mucosa. Ten days earlier she had a recurrent cold sore on her lip from herpes simplex virus type 1. Which of the following is the most likely diagnosis?
AFixed drug eruption
BBullous impetigo
CUrticaria with angioedema
DErythema multiforme major
Reveal answer & full explanation
Correct answer: D — Erythema multiforme major
AFixed drug eruption
BBullous impetigo
CUrticaria with angioedema
DErythema multiforme major✓
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 spares mucosa
HSV-associated EM is managed with antiviral therapy, and recurrent disease warrants suppressive acyclovir
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)
Bullous impetigo — a staphylococcal infection with flaccid bullae and honey-colored crust, lacking target morphology or mucosal erosions (buzzword-matching skin blistering)
Urticaria with angioedema — transient migratory wheals that resolve within 24 hours without fixed targets or mucosal erosion (anchoring on an acute rash)
Question 2DermatologyMedium
A 28-year-old man presents with a 3-day history of a non-painful rash. Ten days earlier he had a cold sore on his lip that has since crusted over. Examination shows symmetric, raised lesions on the dorsal hands, forearms, palms, and soles; each lesion has three concentric zones — a dusky central area, a pale edematous ring, and an outer red halo. There is a single small erosion on the buccal mucosa. He takes no medications. A diagnosis of erythema multiforme is made. Which of the following best explains the findings?
AIgE-mediated mast cell degranulation with transient dermal vascular leak
BCD8+ T-cell–mediated keratinocyte apoptosis at viral antigen deposits
CFas/Fas-ligand–mediated keratinocyte apoptosis from a reactive drug metabolite
DIgG autoantibody attack on desmoglein-3 disrupting keratinocyte adhesion
Reveal answer & full explanation
Correct answer: B — CD8+ T-cell–mediated keratinocyte apoptosis at viral antigen deposits
AIgE-mediated mast cell degranulation with transient dermal vascular leak
BCD8+ T-cell–mediated keratinocyte apoptosis at viral antigen deposits✓
CFas/Fas-ligand–mediated keratinocyte apoptosis from a reactive drug metabolite
DIgG autoantibody attack on desmoglein-3 disrupting keratinocyte adhesion
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
Fas/Fas-ligand–mediated keratinocyte apoptosis from a reactive drug metabolite — this is the mechanism of Stevens-Johnson syndrome / TEN, which is drug-induced with diffuse flat atypical targets and truncal predominance; this patient is on no drugs and has true three-zone acral targets following an HSV outbreak.
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.
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.
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Drugs: rare cause of true EM (more often cause SJS/TEN) — NSAIDs, sulfonamides, antiepileptics
Autoimmune disease: SLE, IBD, sarcoidosis (rare)
Vaccines (rare)
Pathophysiology
Delayed-type hypersensitivity (type IV) reaction with CD8+ T-cell mediated keratinocyte apoptosis at sites of HSV antigen deposition. HSV DNA fragments (especially the pol gene) are transported to keratinocytes by CD34+ Langerhans cell precursors, triggering CD4+ Th1 response → IFN-γ → keratinocyte injury. EM is now considered immunopathogenically distinct from SJS/TEN (which is drug-induced, more diffuse Fas/FasL-mediated apoptosis).
Clinical presentation
Symptoms
Prodrome may be absent (EM minor) or mild (low-grade fever, malaise)
Burning or pruritus of lesions
Oral pain, dysphagia (EM major)
Recurrent HSV often precedes outbreak by 7-10 days
Signs / physical exam
Typical target ('iris') lesion: 3 concentric zones — central dusky/dark purple or vesicular zone, middle pale edematous ring, outer erythematous halo
Atypical target: 2 zones (raised palpable lesion with single ring)
Distribution: acral and symmetric — extensor surfaces of hands, forearms, feet, knees, elbows, face; palms and soles characteristically involved
Koebner phenomenon at sites of trauma
EM minor: skin only or single mucosal site (oral)
EM major: ≥1 mucous membrane (oral, ocular, genital) with erosions/crusts; lips classically with hemorrhagic crusts
Lesions appear over 3-5 days, persist for 1-2 weeks, resolve over 2-4 weeks; recurrent episodes lasting weeks
Classic findings
Acral and symmetric distribution of true 3-zone target lesions involving palms and soles, often preceded by HSV outbreak.
Differential diagnosis
Stevens-Johnson syndrome / TEN — Drug-induced, prodrome of fever/malaise, widespread atypical FLAT targets, mucosal involvement severe, BSA detachment <10% (SJS) to >30% (TEN); NOT acral predominance
Urticaria multiforme — Polycyclic urticarial plaques with central clearing in children — lesions transient (<24 h), no true epidermal detachment; resolves quickly with antihistamines
Fixed drug eruption — Single or few round dusky plaques recurring in same location after drug exposure
Bullous pemphigoid — Tense bullae on urticarial base in elderly; DIF positive
Review medications (consider SJS/TEN if recent new drug)
Imaging
Chest X-ray if Mycoplasma suspected
Diagnostic algorithm
Feature
EM Minor
EM Major
SJS / TEN
Trigger
HSV most common
HSV, Mycoplasma
Drugs (>80%)
Lesions
Typical 3-zone targets
Typical targets + bullae
Atypical flat targets, dusky macules
Distribution
Acral (extensors, palms/soles)
Acral with some truncal
Truncal predominant
Mucosa
Absent or single site
≥1 mucosa
≥2 mucosae, severe
Detachment
None
Minimal (<10% if any)
<10% SJS / 10-30% overlap / >30% TEN
Treatment
Symptomatic, treat trigger
Treat trigger, ± systemic steroids
Stop drug, supportive ICU/burn unit care
Distinguishing erythema multiforme from SJS/TEN.
Treatment
First-line
Identify and treat trigger: oral acyclovir 400 mg 5x/day or valacyclovir 1 g TID × 7 days if active HSV; azithromycin 500 mg day 1 then 250 mg × 4 days for Mycoplasma
Symptomatic care: oral antihistamines for pruritus, topical corticosteroids for skin lesions, magic mouthwash (viscous lidocaine, diphenhydramine, antacid) for oral erosions
Hydration, soft diet, attention to nutrition
Discontinue any potentially offending drugs (if drug-induced EM rather than infectious)
EM is self-limited — most cases resolve in 2-4 weeks without treatment
Recurrent EM (HSV-driven)
Chronic suppressive antiviral: acyclovir 400 mg BID, valacyclovir 500-1000 mg daily, or famciclovir 250 mg BID — for at least 6-12 months
Effective in 80-90% of HSV-associated recurrent EM
Ophthalmology, urology/gynecology consultation as needed
Hospitalization for dysphagia, dehydration, or severe pain
Short course systemic corticosteroids (controversial) — prednisone 0.5-1 mg/kg/day tapered over 1-3 weeks for severe cases
Treat underlying infection aggressively
Second-line / adjunct
Cyclosporine, dapsone, hydroxychloroquine, IVIG for recurrent steroid-dependent or refractory cases
Avoid prophylactic systemic steroids — efficacy unproven and may prolong recovery in some studies
Complications
Mucosal scarring (rare in EM, more common in SJS/TEN)
Secondary bacterial infection of erosions
Conjunctival inflammation, rare ocular sequelae
Recurrent episodes affecting quality of life
Misdiagnosis as SJS/TEN leading to unnecessary aggressive therapy
PANCE pearls
True target lesions have THREE distinct zones; SJS/TEN lesions are typically atypical with two zones or flat dusky macules.
EM is acral and centripetal; SJS/TEN is truncal and centrifugal.
Recurrent EM is HSV-driven in the vast majority — long-term suppressive antivirals are highly effective.
Mycoplasma-induced rash and mucositis (MIRM) in children was previously classified as EM but is now considered a distinct entity with mucositis predominating over skin lesions.
Drugs more often cause SJS/TEN than true EM — re-examine the diagnosis if onset followed a new drug.
References
AAD 2019 — Clinical Features and Management of Erythema Multiforme (AAD review series)
Trayes 2019 — Erythema Multiforme: Recognition and Management (Trayes et al., Am Fam Physician 2019)
Sokumbi 2012 — Clinical Features, Diagnosis, and Treatment of Erythema Multiforme (Sokumbi and Wetter, Int J Dermatol 2012)
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