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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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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