Erythema multiforme (EM) is one of those Step 1 dermatology topics that looks “easy” until you miss the one detail that separates it from Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). If you can recognize true target lesions, connect EM to HSV, and remember the mucosal involvement rules, you’ll pick up a lot of points quickly.
Where Erythema Multiforme Fits (Big Picture)
EM is an acute, immune-mediated skin reaction classically triggered by infections—most importantly herpes simplex virus (HSV). It lives on the spectrum of “targetoid eruptions,” but EM is distinct from SJS/TEN in both typical cause and severity.
High-yield separation:
- EM: usually HSV (sometimes Mycoplasma pneumoniae), target lesions, limited epidermal detachment
- SJS/TEN: often medications, prominent mucosal erosions, significant epidermal necrosis/detachment
Definition (Step-Style)
Erythema multiforme is an acute hypersensitivity reaction characterized by target lesions (a.k.a. iris lesions), usually on the extremities, often triggered by HSV.
EM Minor vs EM Major
This is a common testing angle.
| Feature | EM Minor | EM Major |
|---|---|---|
| Typical trigger | HSV | HSV or Mycoplasma |
| Skin | Target lesions | Target lesions |
| Mucosal involvement | Absent or minimal | Present (≥1 mucosal site) |
| Desquamation / detachment | Minimal | Still limited (contrast with SJS/TEN) |
| Severity | Mild | More severe but not SJS/TEN |
Key exam line: EM can have mucosal involvement (EM major) but does not have the extensive skin detachment typical of SJS/TEN.
Pathophysiology (What’s Actually Happening)
EM is driven by a cell-mediated immune response:
- Type IV hypersensitivity (T-cell mediated)
- Cytotoxic T cells target keratinocytes presenting antigens (often HSV-related antigens)
- Results in interface dermatitis and keratinocyte apoptosis
Why HSV matters (classic association):
- HSV reactivation can lead to viral antigen deposition in skin → immune response → EM flare.
Board-style pearl: EM is typically infection-associated, while SJS/TEN is classically drug-associated (though Mycoplasma can complicate the picture).
Classic Clinical Presentation
Lesion Morphology: “Target Lesions”
True EM target lesions have 3 zones:
- Central dusky area (can blister/crust)
- Paler edematous ring
- Peripheral erythematous ring
Distribution:
- Often acral (hands/feet), extensor surfaces
- Can spread centripetally (toward trunk) but tends to favor extremities
Symptoms
- Can have mild prodrome (malaise, low-grade fever), especially with EM major
- Pain/burning may occur, particularly with mucosal involvement
Mucosal Involvement (when present)
- More consistent with EM major
- Oral erosions, lip crusting; can involve eyes/genitals
High-Yield Triggers & Associations
Most important
- HSV-1/HSV-2 (most classic; recurrent EM often follows HSV outbreaks)
Also high-yield
- Mycoplasma pneumoniae (more likely to be associated with mucositis; can resemble SJS spectrum clinically—test writers like this nuance)
Drugs?
- Drugs are more classic for SJS/TEN, but can occasionally be implicated in EM. On Step 1, if the vignette screams “drug + mucosal erosions + skin sloughing,” choose SJS/TEN, not EM.
Diagnosis (How It’s Tested)
Step 1/2: Clinical diagnosis is usually enough
You’ll most often diagnose EM based on:
- Target lesions
- Acral/extensor distribution
- Preceding HSV outbreak or respiratory infection
When biopsy shows up (interface dermatitis)
Histology can demonstrate:
- Necrotic keratinocytes (apoptosis)
- Interface dermatitis with lymphocytic infiltrate
Practical test clue: If the stem includes “classic target lesions” you usually don’t need labs. If it includes large areas of epidermal detachment or positive Nikolsky sign, think SJS/TEN instead.
Differential Diagnosis (Don’t Get Tricked)
EM vs Urticaria
- Urticaria: transient wheals, migrate, typically <24 hours per lesion
- EM: fixed lesions, classic target morphology
EM vs SJS/TEN (extremely high yield)
| Feature | EM | SJS/TEN |
|---|---|---|
| Typical trigger | HSV, Mycoplasma | Medications (e.g., sulfa drugs, anticonvulsants, allopurinol, NSAIDs) |
| Lesions | Target lesions (often well-formed) | Atypical targets, widespread dusky macules |
| Mucosa | None/minimal (minor) or present (major) | Prominent, severe |
| Nikolsky sign | Usually negative | Often positive |
| Epidermal detachment | Minimal | Significant (esp. TEN) |
EM vs Bullous Pemphigoid / Pemphigus Vulgaris
- Pemphigus vulgaris: flaccid bullae + mucosal involvement + positive Nikolsky
- Bullous pemphigoid: tense bullae, usually older patients, typically negative Nikolsky
- EM: target lesions ± limited blistering; different distribution and story (HSV trigger)
Treatment (Step-Relevant Approach)
General management
- Supportive care (the mainstay for uncomplicated EM)
- Topical corticosteroids for symptomatic relief
- Oral antihistamines for pruritus
- Pain control as needed
- Hydration and wound care if mucosal involvement affects intake
Treat the trigger
- If associated with HSV:
- Acyclovir/valacyclovir can be used (especially if active HSV infection)
- For recurrent HSV-associated EM, suppressive antiviral therapy may reduce recurrences (high-yield association)
When to escalate care
- Significant mucosal disease (EM major) may require:
- More intensive supportive care
- Ophthalmology evaluation if ocular involvement is suspected (prevent scarring/complications)
Exam caution: If the vignette suggests SJS/TEN, management shifts toward burn-unit level supportive care and stopping the offending drug.
“First Aid”-Style Cross-References (How to File It Mentally)
While editions vary, EM is typically grouped in First Aid under Dermatologic disorders / Hypersensitivity skin reactions, often near:
- Erythema multiforme: target lesions, HSV association
- SJS/TEN: medication-associated epidermal necrosis, mucosal involvement, Nikolsky sign
- Pemphigus vulgaris vs bullous pemphigoid: blistering disorders with DIF patterns (a common nearby comparison)
How to remember placement: EM is the “HSV target lesion” anchor that helps you distinguish benign-ish immune eruptions from life-threatening epidermal necrolysis (SJS/TEN).
High-Yield Rapid Review (Exam-Day Bullets)
- EM = type IV hypersensitivity, classically triggered by HSV
- Target lesions with 3 zones are the giveaway
- Often acral/extensor distribution
- EM minor: minimal/no mucosal involvement
- EM major: mucosal involvement, but not the extensive detachment seen in SJS/TEN
- SJS/TEN more likely with drugs + positive Nikolsky + widespread epidermal necrosis
- Treatment is primarily supportive; consider antivirals for HSV-associated/recurrent EM