Erythema Multiforme
Summary
Erythema multiforme (EM) is an acute, immune-mediated, self-limited skin condition characterised by the appearance of distinctive "target" or "iris" lesions. The classic target lesion has three concentric zones: a central dusky or blistered area, a pale oedematous ring, and an outer erythematous halo. EM most commonly affects young adults and is predominantly triggered by infections, particularly Herpes Simplex Virus (HSV), which accounts for over 70% of recurrent cases. Historically confused with Stevens-Johnson syndrome (SJS), EM is now considered a distinct entity with different aetiology and prognosis. EM minor involves skin only, while EM major includes mucosal involvement at one site. SJS/TEN, by contrast, is predominantly drug-induced with a different lesion morphology and carries much higher morbidity and mortality.
Key Facts
- Definition: Acute immune-mediated reaction with characteristic target lesions
- Incidence: Uncommon; more frequent in young adults (20-40 years)
- Classic lesion: "Target" or "iris" lesion with three zones
- Most common trigger: Herpes Simplex Virus (HSV-1 and HSV-2) — 70%+ of recurrent cases
- Other triggers: Mycoplasma pneumoniae, medications (rare in true EM)
- Distribution: Acral (hands, feet), extensor surfaces; may spread centrally
- Prognosis: Self-limiting; resolves in 2-4 weeks; may recur with HSV reactivation
Clinical Pearls
The True Target Lesion: A classic EM target lesion has THREE distinct zones (central dusky/blister, pale oedematous ring, erythematous halo). Atypical targets (two zones or irregular) suggest SJS/TEN rather than EM.
HSV Precedes EM by 1-2 Weeks: Patients often recall a cold sore or genital lesion 7-14 days before the rash appears. The HSV lesion may have already healed by the time EM develops.
EM vs SJS — Know the Difference: EM is triggered by infection (HSV), has true targets, is acral, and has an excellent prognosis. SJS is triggered by drugs, has atypical targets/macules, is trunk-predominant, and carries significant mortality.
Why This Matters Clinically
Correct diagnosis of EM is essential because management differs significantly from SJS/TEN. Misdiagnosing EM as SJS leads to unnecessary drug withdrawal, overtreatment, and patient anxiety. Conversely, missing SJS in a drug-exposed patient with atypical targets and mucosal involvement can be life-threatening. Recurrent EM can significantly impact quality of life but responds well to suppressive antiviral therapy.
Incidence & Prevalence
- Incidence: Relatively uncommon; estimated at 0.01-1% of the population
- Peak age: 20-40 years (young adults most affected)
- Recurrence: 20-30% of patients experience recurrent episodes
- Seasonal: More common in spring/autumn (HSV reactivation patterns)
Demographics
| Factor | Details |
|---|---|
| Age | Peak incidence 20-40 years; can occur at any age |
| Sex | Slight male predominance in some studies |
| Ethnicity | All ethnic groups |
| Geography | Worldwide distribution |
Risk Factors
Non-Modifiable:
- Prior HSV infection (latent herpes simplex)
- Genetic susceptibility (HLA associations reported)
Modifiable:
| Risk Factor | Association |
|---|---|
| Active HSV infection | Most common trigger |
| Mycoplasma pneumoniae infection | Common trigger in children |
| Medications | Rare in true EM (more associated with SJS/TEN) |
Mechanism
Step 1: Triggering Infection (Usually HSV)
- HSV reactivation (cold sore or genital herpes) typically 1-2 weeks before EM onset
- HSV DNA transported to keratinocytes in distant skin
- Mycoplasma pneumoniae can also trigger via similar immune mechanisms
Step 2: Cell-Mediated Immune Response
- HSV DNA in keratinocytes triggers CD4+ T-helper type 1 (Th1) response
- Interferon-gamma production
- Cytotoxic T cells (CD8+) recruited to skin
Step 3: Keratinocyte Apoptosis
- Cytotoxic T cells induce keratinocyte death via Fas-FasL and perforin/granzyme pathways
- Localised epidermal necrosis creates the central dusky zone of target lesion
- Inflammatory infiltrate causes surrounding oedema and erythema
Step 4: Target Lesion Formation
- Centre: Epidermal necrosis (dusky/blistered)
- Middle ring: Oedema (pale)
- Outer ring: Vasodilation (red)
- Classic three-zone "target" or "iris" appearance
Classification
| Subtype | Features |
|---|---|
| EM Minor | Classic targets; acral distribution; NO mucosal involvement |
| EM Major | Classic targets; acral distribution; mucosal involvement at ONE site (usually oral) |
| EM vs SJS/TEN | See comparison table below |
EM vs SJS/TEN — Critical Differentiation
| Feature | Erythema Multiforme | SJS/TEN |
|---|---|---|
| Main trigger | Infection (HSV, Mycoplasma) | Drugs |
| Target lesion | Typical (3 zones) | Atypical (2 zones or macules) |
| Distribution | Acral (hands, feet, extensors) | Trunk predominant, spreads peripherally |
| Mucosal involvement | 0 (minor) or 1 site (major) | ≥2 mucosal sites |
| Epidermal detachment | Minimal | Extensive (defines TEN) |
| Nikolsky sign | Negative | Positive |
| Mortality | Near zero | SJS 1-10%; TEN 25-35% |
| Recurrence | Common (HSV-related) | Rare |
Symptoms
Typical Presentation:
Associated Symptoms:
Atypical Presentations:
Signs
Skin:
Mucosal (EM Major):
Red Flags
[!CAUTION] Red Flags — Consider SJS/TEN and escalate care if:
- Mucosal involvement at ≥2 anatomical sites (oral, ocular, genital)
- Atypical targets (flat, two-zone) or widespread macules
- Skin tenderness or detachment; positive Nikolsky sign
- Significant systemic toxicity (high fever, malaise)
- Recent drug exposure (1-8 weeks prior)
- Rapid progression involving trunk
Structured Approach
General:
- Vital signs (fever uncommon in uncomplicated EM)
- General appearance (well vs toxic)
Skin Examination:
- Describe lesion morphology: True targets (3 zones) vs atypical (2 zones)
- Record distribution: Acral vs truncal
- Estimate body surface area (BSA) involved
- Check for blistering or skin detachment
- Nikolsky sign (apply lateral pressure to normal-appearing skin)
Mucosal Examination:
- Oral: Lips, buccal mucosa, tongue, palate
- Ocular: Conjunctival injection, erosions
- Genital: Erosions, ulceration
Special Tests
| Test | Technique | Positive Finding | Clinical Significance |
|---|---|---|---|
| Nikolsky sign | Lateral pressure on normal skin | Skin shears off | Positive = SJS/TEN (NOT EM) |
| Target lesion assessment | Visual inspection | 3 distinct zones | Confirms typical EM morphology |
| Mucosal site count | Examine oral, ocular, genital | ≥2 sites involved | Suggests SJS rather than EM |
| HSV PCR (lesion) | Swab if active HSV present | Positive | Confirms HSV trigger |
First-Line (Bedside)
- Clinical diagnosis — Pattern recognition; no specific test for EM
- HSV swab — If active herpetic lesion present at time of EM onset
Laboratory Tests
| Test | Expected Finding | Purpose |
|---|---|---|
| HSV serology (IgG/IgM) | May show recent infection | Identify HSV trigger (often already positive due to prior exposure) |
| HSV PCR (lesion) | Positive if active HSV | Confirm HSV as trigger |
| Mycoplasma serology | IgM positive, rising IgG | If pneumonia symptoms or child |
| FBC | Usually normal | Exclude systemic involvement |
| LFTs/U&Es | Usually normal | Baseline if severe/admitted |
Imaging
Not typically required for EM. CXR if Mycoplasma pneumoniae suspected.
Skin Biopsy (When Diagnosis Uncertain)
| Histopathology | EM | SJS/TEN |
|---|---|---|
| Epidermal necrosis | Minimal, focal | Confluent, full-thickness |
| Interface dermatitis | Present | Present |
| Inflammatory infiltrate | Dense dermal | Sparse |
| Subepidermal clefting | Uncommon | Common |
Management Algorithm
Conservative Management (First-Line for EM Minor)
- Reassurance: Self-limiting condition; resolves in 2-4 weeks
- Symptomatic care: Oral antihistamines for itch; cool compresses
- Wound care: Keep erosions clean; non-adherent dressings
- Oral care (if oral involvement): Antiseptic mouthwash (chlorhexidine); soft diet
Medical Management
| Category | Drug | Dose | Notes |
|---|---|---|---|
| Symptomatic | Antihistamines (cetirizine) | 10mg daily | For pruritus |
| Topical | Moderate-potency corticosteroid | BD application | Inflamed skin lesions |
| Oral analgesic | Paracetamol | Standard dosing | Pain relief |
| Mucosal analgesia | Benzydamine mouthwash | PRN | Oral erosions (EM major) |
| Treat active HSV | Acyclovir | 400mg TDS × 5-7 days | If active HSV lesion present |
Recurrent EM (≥6 episodes per year):
| Drug | Dose | Duration | Notes |
|---|---|---|---|
| Acyclovir | 400mg BD | 6-12 months | Suppressive prophylaxis |
| Valacyclovir | 500mg-1g daily | 6-12 months | Alternative to acyclovir |
Severe EM Major (Controversial):
- Oral corticosteroids sometimes used but evidence is limited
- Prednisolone 0.5-1 mg/kg for short course if significant mucosal involvement
Disposition
- Outpatient: Most EM minor and EM major cases
- Admission: Extensive mucosal involvement with inability to eat/drink; diagnostic uncertainty with SJS/TEN
- Specialist referral: Dermatology if uncertain diagnosis; ophthalmology if ocular involvement
- Follow-up: Review in 2-4 weeks; earlier if worsening
Immediate (Days)
| Complication | Incidence | Presentation | Management |
|---|---|---|---|
| Oral pain limiting intake | 10-20% (EM major) | Dehydration | IV fluids, topical analgesia |
| Secondary bacterial infection | Rare | Crusting, purulence | Topical/oral antibiotics |
Early (Weeks)
- Post-inflammatory hyperpigmentation: Common; resolves over months
- Prolonged oral erosions: May take 4-6 weeks to heal completely
- Symptom recurrence: New HSV reactivation may trigger new EM episode
Late (Months-Years)
- Recurrent EM: 20-30% experience recurrence, often with each HSV reactivation
- Psychological impact: Anxiety about recurrence; impact on quality of life
- Rare scarring: Minimal in EM; more significant scarring seen in SJS/TEN
Natural History
- Self-limiting: Lesions resolve over 2-4 weeks without treatment
- Individual lesions persist for about 7 days then fade
- No mortality in EM minor/major (contrast with SJS/TEN)
Outcomes with Treatment
| Variable | Outcome |
|---|---|
| Resolution time | 2-4 weeks |
| Recurrence rate | 20-30% |
| Response to suppressive antivirals | 80-90% reduction in recurrent EM |
| Mortality | Near zero |
| Scarring | Rare |
Prognostic Factors
Good Prognosis (All EM Cases):
- Self-limiting condition
- Excellent response to symptomatic treatment
- Antivirals highly effective for prevention of recurrence
Factors Associated with Recurrence:
- HSV-1 or HSV-2 seropositivity
- Recurrent oral or genital herpes outbreaks
- Not on suppressive antiviral therapy
Key Guidelines
- British Association of Dermatologists (BAD) — Patient information on erythema multiforme. BAD
- DermNet NZ — Clinical resource on EM. DermNet NZ
- NICE CKS — Erythema multiforme management. NICE CKS
Landmark Studies
Lamoreux et al. (2006) — Comprehensive review of EM
- Established distinction between EM and SJS as separate entities
- Key finding: EM predominantly infection-triggered (HSV); SJS drug-triggered
- Clinical Impact: Changed diagnostic paradigm; EM no longer on SJS/TEN spectrum
Schofield et al. (1993) — Acyclovir for recurrent EM
- Open-label study of continuous acyclovir
- Key finding: Significant reduction in recurrent EM episodes
- Clinical Impact: Established prophylactic acyclovir for recurrent EM
Assier et al. (1995) — HSV as trigger for EM
- Demonstrated HSV DNA in EM skin lesions
- Key finding: HSV polyclonally integrated into keratinocytes in EM
- Clinical Impact: Confirmed HSV as primary EM trigger
Evidence Strength
| Intervention | Level | Key Evidence |
|---|---|---|
| Symptomatic treatment | 4 | Expert consensus |
| Topical corticosteroids | 4 | Expert consensus |
| Suppressive acyclovir (recurrent EM) | 2a | Observational studies |
| Oral corticosteroids | 4 | Limited/controversial evidence |
What is Erythema Multiforme?
Erythema multiforme (EM) is a skin reaction that causes distinctive "target" or "bulls-eye" shaped spots, most commonly on the hands and feet. The spots have a dark or blistered centre, a pale ring around it, and a red outer circle. It is usually triggered by a viral infection, most often the cold sore virus (herpes simplex), which you may have had 1-2 weeks before the rash appeared.
Is it serious?
In most cases, erythema multiforme is not serious and clears up on its own within 2-4 weeks. It is important for a doctor to confirm the diagnosis because there is a different, more serious condition called Stevens-Johnson syndrome (SJS) that can look similar but is caused by medications and requires urgent treatment.
How is it treated?
- Symptomatic relief: Antihistamines and cool compresses can help with itching. Paracetamol for pain.
- Topical creams: Steroid creams may be prescribed for inflamed areas.
- Mouth care: If your mouth is affected, antiseptic mouthwash and a soft diet can help.
- For the cold sore virus: If you have recurrent EM linked to cold sores, taking antiviral medication (like acyclovir) daily can prevent future episodes.
What to expect
- The rash develops over a few days and takes 2-4 weeks to clear completely
- Individual spots may leave temporary darker marks but permanent scarring is rare
- It can come back if you get another cold sore outbreak
When to seek help
See a doctor urgently if:
- You develop blisters inside your mouth, eyes, or genitals at the same time
- The rash is spreading quickly and affecting a large area
- The skin feels tender or is peeling off
- You feel very unwell with a high fever
- You have recently started a new medication
Primary Guidelines
- British Association of Dermatologists. Erythema Multiforme Patient Information Leaflet. 2023. BAD
- Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45-53. PMID: 19815314
Key Literature
- Lamoreux MR, et al. Erythema multiforme. Am Fam Physician. 2006;74(11):1883-1888. PMID: 17168345
- Schofield JK, et al. Recurrent erythema multiforme: clinical features and treatment in a large series of patients. Br J Dermatol. 1993;128(5):542-545. PMID: 8504044
- Assier H, et al. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol. 1995;131(5):539-543. PMID: 7741539
Further Resources
- DermNet NZ Erythema Multiforme: dermnetnz.org/topics/erythema-multiforme
- NHS Erythema Multiforme: nhs.uk/conditions/erythema-multiforme
- British Skin Foundation: britishskinfoundation.org.uk
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. If you have widespread skin lesions with mucosal involvement, seek urgent medical attention to exclude Stevens-Johnson syndrome.