Erythema Multiforme

1. Clinical Overview

Summary

Erythema multiforme (EM) is an acute, immune-mediated, self-limited mucocutaneous hypersensitivity reaction characterised by the sudden onset of distinctive "target" or "iris" lesions with three concentric zones. [1] The condition predominantly affects young adults aged 20-40 years and is triggered by infections in the vast majority of cases. [2] Herpes simplex virus (HSV) accounts for more than 70% of recurrent EM cases, with HSV DNA fragments detected in skin lesions even when active herpetic lesions are absent. [3,4] Other important triggers include Mycoplasma pneumoniae, particularly in children and young adults. [5]

Historically, EM was incorrectly grouped with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) as part of a single disease spectrum. Current evidence firmly establishes EM as a distinct entity with fundamentally different aetiology, pathophysiology, clinical features, and prognosis. [6,7] EM is primarily infection-triggered (especially HSV), presents with typical three-zone target lesions in an acral distribution, and carries an excellent prognosis with negligible mortality. In contrast, SJS/TEN is predominantly drug-induced, exhibits atypical flat targets or macules with epidermal detachment, affects the trunk primarily, and carries significant morbidity and mortality (SJS 1-10%, TEN 25-35%). [8]

EM is classified into two subtypes based on mucosal involvement: EM minor (skin-only disease) and EM major (skin plus involvement of one mucosal surface, typically oral mucosa). [1,2] The term "herpes-associated erythema multiforme" (HAEM) is used when HSV is the confirmed or presumed trigger. [9] The condition is self-limiting, with lesions resolving within 2-4 weeks without treatment, though recurrent episodes occur in 20-30% of patients, particularly those with recurrent HSV infections. [10]

Key Facts

• Definition: Acute cell-mediated hypersensitivity reaction with characteristic three-zone target lesions
• Incidence: 0.01-1% population prevalence; peak age 20-40 years [2]
• Classic lesion: Pathognomonic "target" with three distinct concentric zones (central dusky/vesicular area, pale oedematous middle ring, erythematous outer halo)
• Primary trigger: Herpes simplex virus (HSV-1 and HSV-2) responsible for > 70% of recurrent cases [3,4,9]
• Other triggers: Mycoplasma pneumoniae (common in paediatric cases), other infections (rare), drugs (extremely rare in true EM) [5]
• Distribution: Acral-predominant (dorsal hands/feet, palms/soles, extensor surfaces); centripetal spread possible [1]
• Mucosal involvement: None (EM minor) or single site (EM major); ≥2 sites suggest SJS/TEN [6]
• Prognosis: Excellent; self-limiting in 2-4 weeks; near-zero mortality; recurrence in 20-30% [10]
• Key distinction: EM is infection-driven and acral; SJS/TEN is drug-driven and truncal [6,7,8]

Clinical Pearls

The Pathognomonic Target Lesion: A true EM target lesion must have THREE sharply demarcated concentric zones: (1) dusky, necrotic or vesicular centre; (2) pale, raised, oedematous middle ring; (3) erythematous outer halo. Atypical targets with only two zones or poorly defined borders suggest SJS/TEN. [1,6]

HSV Precedes EM by 7-14 Days: The classic temporal pattern in HAEM is prodromal HSV lesion (cold sore or genital herpes) 1-2 weeks before EM onset. The herpetic lesion has often healed by the time EM develops. HSV DNA is transported to distant skin sites via CD34+ peripheral blood cells. [3,4,11]

EM vs SJS/TEN — Critical Diagnostic Distinction: EM has typical three-zone targets, acral distribution, infection trigger (especially HSV), minimal epidermal detachment, and excellent prognosis. SJS/TEN has atypical flat targets/macules, truncal distribution, drug trigger, extensive epidermal detachment with positive Nikolsky sign, and significant mortality. These are distinct entities requiring different management. [6,7,8]

Negative Nikolsky Sign in EM: The Nikolsky sign (lateral pressure on normal skin causing epidermal sloughing) is characteristically NEGATIVE in EM but POSITIVE in SJS/TEN. This bedside test helps distinguish the two conditions. [8]

Recurrent EM Responds to Antiviral Prophylaxis: Continuous suppressive acyclovir (400mg BD) or valaciclovir (500mg-1g daily) for 6-12 months dramatically reduces recurrent EM frequency in HSV-associated cases, with 80-90% of patients experiencing significant improvement. [12,13]

Why This Matters Clinically

Accurate diagnosis of EM is critical because misdiagnosis has significant clinical consequences. Labelling EM as SJS leads to inappropriate drug withdrawal, unnecessary hospital admission, excessive investigation, and unwarranted anxiety about drug allergies that may incorrectly restrict future therapeutic options. [6,7] Conversely, failing to recognise SJS/TEN in a drug-exposed patient with atypical targets, mucosal involvement at multiple sites, and skin tenderness can delay life-saving withdrawal of the culprit drug and appropriate intensive supportive care, with potentially fatal consequences. [8]

Recurrent EM significantly impairs quality of life, with some patients experiencing 6-12 episodes per year, each lasting 2-4 weeks. [10,13] Recognition of HSV as the trigger and institution of long-term suppressive antiviral therapy can be transformative, reducing episode frequency by 80-90% and allowing patients to resume normal activities. [12,13]

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2. Epidemiology

Incidence & Prevalence

• Prevalence: Estimated 0.01-1% of the general population [2]
• Incidence: Uncommon; exact figures difficult to establish due to diagnostic confusion with SJS/TEN in older literature
• Peak age: 20-40 years (young adults most commonly affected) [1,2]
• Paediatric cases: Occur but less common; often Mycoplasma-triggered [5]
• Recurrence rate: 20-30% of patients experience recurrent episodes [10]
• Seasonal variation: Some studies report increased incidence in spring and autumn, possibly related to HSV reactivation patterns [2]

Demographics

Risk Factors

Non-Modifiable:

Modifiable/Trigger-Related:

Protective Factors:

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3. Pathophysiology

Molecular and Cellular Mechanisms

Phase 1: Viral Trigger and HSV DNA Transport (Days -14 to -1)

HSV Reactivation:

• Reactivation of latent HSV-1 (trigeminal ganglia) or HSV-2 (sacral ganglia) produces mucocutaneous herpetic lesions (cold sores, genital herpes) [3]
• Viral replication occurs at the primary site (lips, genitals)
• In many cases, HSV reactivation is subclinical or lesions have healed before EM onset [9]

HSV DNA Fragment Transport:

• HSV DNA polymerase gene fragments (pol gene) are released into the circulation [4]
• CD34+ cells in peripheral blood ingest and transport HSV DNA fragments to distant skin sites [11]
• Approximately 50% of circulating CD34+ cells express the skin-homing receptor CLA (cutaneous lymphocyte antigen) [23]
• CD34+ cell numbers increase significantly during acute HAEM episodes compared to baseline [11]
• HSV DNA is deposited in keratinocytes at acral sites (hands, feet, extensor surfaces) via upregulation of E-cadherin adhesion molecules [4,20]
• This explains the 1-2 week temporal gap between HSV lesion and EM onset [9]
• This mechanism also explains why EM lesions occur at sites distant from the original HSV infection [11,23]

Mycoplasma Trigger:

• Mycoplasma pneumoniae respiratory infection triggers similar immune cascade [5]
• More common trigger in paediatric EM cases, particularly in children aged 5-15 years [5]
• Mechanism likely involves bacterial antigen deposition in skin or immune complex formation [26]
• Mycoplasma-triggered EM often presents with more extensive mucosal involvement than HSV-triggered EM [5]

Phase 2: Cell-Mediated Immune Activation (Days 0-3)

T-Cell Priming:

• HSV DNA in keratinocytes acts as foreign antigen [4]
• Langerhans cells (dermal dendritic cells derived from CD34+ precursors) process HSV antigens and migrate to regional lymph nodes [23]
• CD4+ T-helper cells are activated, predominantly Th1 subset [17]
• Clonal expansion of HSV-specific cytotoxic CD8+ T lymphocytes [17]

Cytokine Release:

• Activated Th1 cells produce interferon-gamma (IFN-γ) which amplifies the inflammatory response [17]
• Tumor necrosis factor-alpha (TNF-α) upregulation contributes to keratinocyte apoptosis [17]
• Interleukin-2 (IL-2) promotes T-cell expansion and sustains the immune response [17]
• These cytokines create a pro-inflammatory microenvironment in affected skin, perpetuating the target lesion formation [17,24]

Immune Cell Recruitment:

• Chemokine gradients (CXCL9, CXCL10) recruit cytotoxic T cells to skin [17]
• Dense perivascular and interface lymphocytic infiltrate develops [18]
• CD8+ T cells predominate in the epidermis [17]

Phase 3: Keratinocyte Apoptosis and Target Lesion Formation (Days 1-7)

Targeted Keratinocyte Death:

• CD8+ cytotoxic T cells recognize HSV antigens presented on MHC class I of keratinocytes [17]
• Two main apoptotic pathways activated:
  1. Perforin-granzyme pathway: Cytotoxic granules induce direct cell death [17]
  2. Fas-FasL pathway: Death receptor-mediated apoptosis [17]
• Individual keratinocyte apoptosis creates satellite cell necrosis [18]

Target Lesion Architecture:

The pathognomonic three-zone target lesion results from:

1. Central Zone (Dusky/Vesicular):

   • Focal epidermal necrosis with keratinocyte apoptosis [18]
   • Vacuolar interface dermatitis [18]
   • Subepidermal vesicle formation in some lesions [18]

2. Middle Zone (Pale/Oedematous):

   • Dermal oedema due to increased vascular permeability [18]
   • Dense lymphocytic infiltrate [18]
   • Preserved epidermal architecture with less necrosis [18]

3. Outer Zone (Erythematous Halo):

   • Superficial vascular dilation and increased blood flow [18]
   • Minimal epidermal changes [18]
   • Defines the outer border of the immune reaction [18]

Key Pathophysiological Features:

• Lesions are FIXED (remain in same location for 7+ days due to local HSV DNA deposition) [1]
• Minimal epidermal detachment (unlike SJS/TEN where extensive full-thickness epidermal necrosis occurs) [7,18]
• Dense dermal inflammatory infiltrate (sparse in SJS/TEN) [18]
• Interface dermatitis with lymphocyte-mediated keratinocyte death [18]

Phase 4: Resolution (Days 7-28)

• Clearance of HSV antigens from skin
• Downregulation of inflammatory cytokines
• Apoptotic debris cleared by macrophages
• Re-epithelialization of eroded areas
• Post-inflammatory hyperpigmentation common (melanin incontinence) [1]
• Minimal scarring (unlike SJS/TEN) [7]

EM vs SJS/TEN — Pathophysiological Distinctions

These fundamental pathophysiological differences explain the distinct clinical presentations and prognoses of EM versus SJS/TEN. [6,7,8,18] Recent evidence demonstrates that neutrophils play a critical initiating role in SJS/TEN through granulysin-mediated keratinocyte death, whereas EM pathogenesis is driven primarily by HSV-specific CD8+ T-lymphocytes with minimal neutrophil involvement. [25]

Classification of Erythema Multiforme

Important Note: If TWO or more mucosal sites are involved (e.g., oral + ocular + genital), the diagnosis is SJS/TEN, not EM major. [6,7]

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4. Clinical Presentation

Symptoms

Typical Presentation

Prodrome (Variable, 0-3 days before rash):

• Mild constitutional symptoms in ~50% of cases [1]
• Low-grade fever (less than 38.5°C)
• Malaise, fatigue
• Myalgia
• Headache
• Upper respiratory symptoms if Mycoplasma-triggered [5]
• Prodromal symptoms are generally MILD (severe systemic toxicity suggests SJS/TEN) [8]

Skin Eruption (Days 1-3):

• Sudden onset of skin lesions developing over 24-72 hours [1]
• Lesions appear in successive crops over 3-5 days
• Fixed lesions that remain in the same location for 7-14 days [1]
• Symmetrical, bilateral distribution [1]
• Acral onset: Lesions begin on dorsal hands/feet, palms/soles, extensor surfaces [1,2]
• Centripetal spread: Lesions may extend to forearms, lower legs, occasionally trunk
• Individual lesions evolve from erythematous macules → papules → target configuration over 24-48 hours
• Pruritus: Mild in some cases; often absent or minimal
• Burning sensation: Occasionally reported
• Generally well-tolerated cutaneous symptoms

Mucosal Symptoms (EM Major):

• Oral involvement (most common mucosal site in EM major) [1,2]:
  • Painful oral erosions and ulcerations
  • Difficulty eating and drinking
  • Haemorrhagic crusting of lips
  • Painful swallowing (odynophagia)
• Single mucosal site only (≥2 sites = SJS/TEN) [6]
• Eye involvement uncommon in EM (much more common in SJS) [7]
• Genital involvement rare in EM [7]

Associated Symptoms:

• HSV prodromes (in HAEM cases) [9]:
  • History of cold sore or genital herpes 7-14 days prior
  • Herpetic lesion may have healed before EM appears
  • Some patients note tingling/burning at site of prior HSV lesions
• Respiratory symptoms (Mycoplasma-triggered EM) [5]:
  • Cough, sore throat
  • Pneumonia symptoms in severe Mycoplasma cases
  • More common in paediatric patients [5]

Atypical Presentations

Papular EM:

• Raised papules without classic three-zone target morphology
• Diagnosis requires histopathological correlation [1]

Bullous EM:

• Central vesicles/bullae within target lesions
• Can mimic blistering disorders
• Still maintains three-zone target configuration [1]

Persistent/Continuous EM:

• Rare variant with continuous lesions for weeks to months
• Typically associated with ongoing HSV replication [19]
• May require prolonged suppressive antiviral therapy [19]

Recurrent EM:

• 20-30% of patients experience recurrent episodes [10]
• Often correlates with HSV reactivation episodes [9,10]
• Can occur 6-12 times per year in severe cases [13]
• Each episode self-limiting (2-4 weeks) but impacts quality of life [13]

Signs

Dermatological Examination

Primary Lesion — The Pathognomonic Target:

Classic three-zone target lesion [1,6]:

1. Central zone: Dusky red, purpuric, or vesicular/bullous; represents epidermal necrosis
2. Middle zone: Pale pink, raised, oedematous ring; well-demarcated from centre and outer zone
3. Outer zone: Bright erythematous halo; sharply defined outer border

Target lesion characteristics:

• Size: Typically 1-3 cm diameter (can range 0.5-5 cm)
• Shape: Round or oval; sharply circumscribed
• Borders: Well-defined between zones; regularity is key diagnostic feature
• Palpable: Raised, firm due to dermal oedema
• Fixed: Lesions remain in same location for 7+ days (NOT migratory) [1]

Distribution Pattern:

• Acral predominance (hallmark of EM): [1,2]
  • Dorsal hands and fingers
  • Dorsal feet and toes
  • Palms and soles (including pressure points)
  • Extensor surfaces of forearms and lower legs
• Symmetrical and bilateral [1]
• Centripetal spread possible (proximal extremities, trunk) but acral lesions remain predominant
• SPARES mucosa in EM minor [1]
• Trunk predominance suggests SJS/TEN, not EM [6,7]

Lesion Evolution:

• Day 0-1: Erythematous macules/papules
• Day 1-2: Target configuration becomes apparent
• Day 3-7: Full three-zone targets; central darkening or vesiculation
• Day 7-14: Gradual fading; desquamation of central zone
• Day 14-28: Resolution with post-inflammatory hyperpigmentation [1]

Lesion Density:

• Variable: From a few scattered targets to hundreds of lesions
• Tends to be less extensive than SJS/TEN [7]
• Body surface area involvement typically less than 10% [7]

Mucosal Examination (EM Major)

Oral Cavity (Most Common Site): [1,2]

• Lips: Haemorrhagic crusting (characteristic appearance); oedema; erosions
• Buccal mucosa: Erythema, erosions, shallow ulcerations
• Tongue: Erythema, erosions (less common)
• Palate: Erythema, ulceration (less common)
• Gingiva usually spared
• Important: ONE mucosal site only in EM major [6]

Other Mucosal Sites (Rare in EM):

• Eyes: Conjunctival injection/erosions (UNCOMMON in EM; if present with oral involvement, consider SJS) [7]
• Genitals: Erosions (RARE in EM; if present with oral involvement, consider SJS) [7]
• ≥2 mucosal sites = SJS/TEN, NOT EM [6,7,8]

Systemic Examination

General Appearance:

• Usually appears WELL (in contrast to toxic appearance in SJS/TEN) [8]
• Alert, oriented, no distress (except oral pain in EM major)

Vital Signs:

• Temperature: Normal or low-grade fever (less than 38.5°C); high fever suggests SJS/TEN [8]
• Heart rate, blood pressure, respiratory rate: Typically normal
• Oxygen saturation: Normal (unless concurrent Mycoplasma pneumonia) [5]

Lymphadenopathy:

• Generally absent or minimal
• Regional lymphadenopathy possible in some cases

Red Flags — When to Consider SJS/TEN Instead of EM

[!CAUTION] Red Flags — Escalate care immediately if:

Clinical Features Suggesting SJS/TEN:

• Mucosal involvement at ≥2 anatomical sites (e.g., oral + ocular, oral + genital) [6,7,8]
• Atypical flat targets with only 2 zones or irregular borders [6]
• Widespread macules (not true targets) with purpura or skin tenderness [8]
• Trunk-predominant distribution with centrifugal spread [7]
• Epidermal detachment or skin sloughing; positive Nikolsky sign [8]
• Systemic toxicity: High fever (> 39°C), tachycardia, hypotension, altered mental status [8]

Historical Red Flags:

• New medication started 1-8 weeks prior (especially sulfonamides, anticonvulsants, allopurinol, NSAIDs) [8]
• Rapid progression with increasing BSA involvement over 24-48 hours [8]
• No identifiable infection trigger (absence of HSV or Mycoplasma) [6,7]

Laboratory Red Flags:

• Elevated liver enzymes, renal impairment (suggests systemic involvement in SJS/TEN) [8]
• Cytopenias (anaemia, leukopenia, thrombocytopenia) in severe SJS/TEN [8]

Ophthalmological Emergency:

• ANY ocular involvement (conjunctivitis, erosions, symblepharon formation) requires urgent ophthalmology review [7,8]

Action for Red Flags:

• Immediate dermatology consultation
• Ophthalmology review if eye involvement
• Consider withdrawal of suspect drugs
• Consider admission for monitoring and supportive care
• Assess for ICU-level care if extensive skin involvement (SCORTEN score for SJS/TEN) [8]

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4A. Differential Diagnosis

Accurate differentiation of erythema multiforme from other mucocutaneous conditions is critical for appropriate management. The key diagnostic challenge is distinguishing EM from SJS/TEN, but several other conditions can mimic EM.

Primary Differential: EM vs SJS/TEN

This is the most important diagnostic distinction given the vastly different prognosis and management. [6,7,8]

Clinical Pearl: If you are uncertain whether the patient has EM or SJS/TEN, treat as SJS/TEN until proven otherwise (safer approach). [8]

Secondary Differentials

1. Urticaria (Hives)

Distinguishing test: Urticarial lesions fade completely within 24 hours; EM targets persist for days. [1]

2. Fixed Drug Eruption

Distinguishing feature: Fixed drug eruption recurs at the identical anatomical site with each drug exposure; EM does not. [1]

3. Bullous Pemphigoid

Distinguishing test: Direct immunofluorescence (DIF) is positive in bullous pemphigoid, negative in EM. [18]

4. Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis)

Distinguishing test: Skin biopsy shows neutrophilic infiltrate in Sweet syndrome vs lymphocytic infiltrate in EM. [18]

5. Leukocytoclastic Vasculitis (Hypersensitivity Vasculitis)

Distinguishing feature: EM has no vasculitis on histology; vasculitis shows fibrinoid necrosis and neutrophil infiltration of vessel walls. [18]

6. Viral Exanthem (Non-specific)

Distinguishing feature: Presence of typical three-zone target lesions is diagnostic of EM. [1]

7. Erythema Migrans (Lyme Disease)

Distinguishing feature: Erythema migrans expands over time; EM targets are fixed and do not migrate. [1]

8. Pityriasis Rosea

Distinguishing feature: "Herald patch" and truncal "Christmas tree" distribution are characteristic of pityriasis rosea, not EM.

9. Behçet's Disease (in cases with oral ulceration)

Distinguishing feature: Behçet's is a chronic multisystem disease with recurrent aphthous ulceration; EM is acute and self-limiting. [1,2]

Diagnostic Algorithm

Acute onset of skin lesions with possible mucosal involvement
                    ↓
            Count mucosal sites
                    ↓
        ┌───────────┴───────────┐
        ↓                       ↓
    ≥2 sites              0-1 site
        ↓                       ↓
  Consider SJS/TEN        Assess lesion morphology
  (Check: drug           ↓
   history, Nikolsky,    Are they typical 3-zone targets?
   BSA, fever)           ↓
                    ┌────┴────┐
                    ↓         ↓
                   YES        NO
                    ↓         ↓
              Likely EM    Consider:
              ↓            - Urticaria (if transient)
         Acral or         - Fixed drug eruption
         truncal?         - Bullous pemphigoid (if elderly)
              ↓            - Sweet syndrome (if febrile)
         ┌────┴────┐       - Vasculitis (if purpura)
         ↓         ↓       - Viral exanthem
      Acral    Truncal    - Erythema migrans (if expanding)
         ↓         ↓
      EM        SJS/TEN   Investigations:
      ↓         ↓         - Skin biopsy
  Investigate   Urgent    - DIF if bullous
trigger:      dermatology - Serology (HSV, Mycoplasma)
  - HSV serology          - Viral PCR
  - Mycoplasma            - Vasculitis screen if purpura
  - Recent infection

Key Diagnostic Criteria for EM

To confidently diagnose EM, the following criteria should be met: [1,2,6]

1. ✅ Typical three-zone target lesions (dusky centre, pale middle, red outer)
2. ✅ Acral distribution (hands, feet, extensor surfaces)
3. ✅ 0 or 1 mucosal site involved (NOT ≥2)
4. ✅ Negative Nikolsky sign
5. ✅ Identifiable trigger (infection, usually HSV or Mycoplasma)
6. ✅ No recent drug exposure (1-8 weeks prior)
7. ✅ Self-limiting course (2-4 weeks)

If any of the following are present, reconsider diagnosis (likely SJS/TEN): [6,7,8]

• ❌ Atypical targets (only 2 zones or flat macules)
• ❌ Truncal predominance
• ❌ ≥2 mucosal sites involved
• ❌ Positive Nikolsky sign
• ❌ Epidermal detachment or skin sloughing
• ❌ New medication 1-8 weeks prior
• ❌ High fever (39°C) and systemic toxicity

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5. Clinical Examination

Structured Approach

Initial Assessment

1. General Inspection:

• Patient appearance: Well vs toxic/distressed
• Level of distress: Comfortable vs in pain (oral pain in EM major)
• Ability to communicate: Normal speech vs difficulty (oral involvement)

2. Vital Signs:

• Temperature: Fever > 39°C suggests SJS/TEN
• Heart rate, blood pressure: Assess for systemic involvement
• Respiratory rate, oxygen saturation: Important if Mycoplasma pneumoniae suspected

Dermatological Examination

3. Lesion Morphology Assessment:

Systematic approach to each lesion:

4. Distribution Mapping:

Document anatomical distribution:

5. Estimate Body Surface Area (BSA):

• Use Rule of Nines or patient's palm (represents ~1% BSA)
• EM typically less than 10% BSA [7]
• SJS: 10-30% BSA; TEN: > 30% BSA [8]

6. Assess for Blistering/Detachment:

• Examine for intact vs ruptured blisters
• Look for areas of epidermal detachment (suggests SJS/TEN) [8]
• Estimate percentage of detached skin

Special Bedside Tests

7. Nikolsky Sign:

Technique:

• Apply lateral shearing pressure with finger to normal-appearing skin (not on lesions)
• Slide finger tangentially with mild pressure

Interpretation:

• Negative (no skin movement): Favours EM [8]
• Positive (epidermal separation/sloughing): Suggests SJS/TEN [8]

Clinical Significance:

• Positive Nikolsky sign indicates poor keratinocyte adhesion and full-thickness epidermal necrosis
• One of the key distinguishing features between EM (negative) and SJS/TEN (positive) [8]

8. Auspitz Sign:

• Not applicable to EM (relevant for psoriasis)

Mucosal Examination

9. Oral Cavity Examination:

Systematic examination:

• Lips: Crusting, oedema, erosions, fissuring
• Buccal mucosa: Erythema, erosions, ulcers
• Tongue: Dorsal and ventral surfaces; erosions
• Hard and soft palate: Erythema, erosions
• Gingiva: Usually spared in EM
• Oropharynx: Posterior pharyngeal wall

Document:

• Number of sites involved
• Severity of erosions
• Ability to eat/drink

10. Ocular Examination:

• External inspection: Periorbital oedema, erythema
• Conjunctiva: Injection, chemosis, erosions, membranes
• Cornea: Fluorescein staining if available (corneal erosions)
• Photophobia, vision changes

Action: ANY ocular involvement requires urgent ophthalmology consultation [7,8]

11. Genital Examination:

• External genitalia: Erosions, ulceration, oedema
• Assess need for urinary catheter if severe involvement prevents urination

Chaperone required; often deferred unless symptoms present

12. Other Mucosal Sites:

• Nasal mucosa (epistaxis, crusting)
• Anus (pain on defecation)

Document Total Number of Mucosal Sites Involved:

• 0 sites = EM minor
• 1 site = EM major
• ≥2 sites = SJS/TEN (NOT EM) [6,7]

Systemic Examination

13. Lymph Node Examination:

• Cervical, axillary, inguinal lymph nodes
• Regional lymphadenopathy may be present

14. Respiratory Examination:

• Auscultation: Crackles, consolidation (Mycoplasma pneumonia) [5]
• Relevant if respiratory symptoms present

15. Cardiovascular and Abdominal Examination:

• Usually unremarkable in uncomplicated EM

Trigger Identification

16. Examine for HSV Lesions:

• Lips: Look for healing/crusted herpetic lesions (may be subtle if 1-2 weeks prior) [9]
• Genitals: Examine for genital herpes (if history suggests)
• Document presence, location, stage (active vs healed)

17. Document Timing:

• Onset of HSV lesion relative to EM rash (typically 7-14 days prior) [9]

Examination Checklist for EM Assessment

• General appearance and vital signs
• Target lesion morphology (3-zone assessment)
• Distribution pattern (acral vs truncal)
• Body surface area estimation
• Nikolsky sign (negative in EM)
• Oral cavity examination (count mucosal sites)
• Ocular examination (urgent ophthalmology if involved)
• Genital examination (if symptomatic)
• Total mucosal site count (0, 1, or ≥2)
• Evidence of HSV lesions (active or healing)
• Respiratory examination (if Mycoplasma suspected)
• Document findings clearly for EM vs SJS/TEN distinction

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6. Investigations

Diagnostic Approach

Important: Erythema multiforme is primarily a clinical diagnosis based on pattern recognition of characteristic three-zone target lesions in an acral distribution. [1,2] Investigations are performed to:

1. Identify the underlying trigger (particularly HSV or Mycoplasma)
2. Exclude alternative diagnoses (particularly SJS/TEN)
3. Assess disease severity and complications
4. Guide management (especially suppressive therapy for recurrent EM)

First-Line Investigations

Bedside/Clinical

Laboratory Tests (Trigger Identification)

HSV Detection (For HAEM Diagnosis):

Mycoplasma Detection (Paediatric/Atypical Cases):

Baseline Blood Tests

Second-Line Investigations

Imaging

Imaging is NOT routinely required for uncomplicated EM.

Skin Biopsy (When Diagnosis Uncertain)

Indications for Biopsy:

• Atypical presentation (diagnostic uncertainty between EM and SJS/TEN)
• Absence of classic three-zone targets
• Need to exclude alternative diagnoses (vasculitis, Sweet syndrome, etc.)
• Medicolegal documentation

Biopsy Technique:

• Site: Edge of a well-developed target lesion (include centre and surrounding zones)
• Type: 4-6mm punch biopsy or incisional biopsy
• Sample: Submit in formalin for routine histopathology
• Consider: Second biopsy for direct immunofluorescence (DIF) if bullous disorder suspected

Histopathological Features:

Direct Immunofluorescence (DIF):

• Usually negative in EM [18]
• Excludes autoimmune blistering diseases (pemphigus, pemphigoid)
• May show non-specific fibrin deposition at dermoepidermal junction

Specialist Investigations (Recurrent/Refractory Cases)

Differential Diagnosis Investigations

When considering alternative diagnoses:

Note on Oral Mucosal Involvement: When oral erosions are prominent, consider additional differential diagnoses including aphthous stomatitis (recurrent minor/major aphthae), Behçet's disease (recurrent oral + genital ulcers), and pemphigus vulgaris (flaccid bullae). Direct immunofluorescence and serology distinguish autoimmune blistering disorders from EM. [30,31,32]

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7. Management

Management Principles

1. EM is self-limiting: Natural resolution within 2-4 weeks without specific treatment [1,2]
2. Symptomatic care is first-line: Supportive measures for comfort and prevention of complications
3. Identify and treat trigger: HSV treatment (if active) and suppressive therapy for recurrent EM [12,13]
4. Differentiate from SJS/TEN: Correct diagnosis prevents inappropriate management (drug withdrawal, over-treatment) [6,7]
5. Prevent recurrence: Long-term antiviral prophylaxis for recurrent HAEM [12,13]

Management Algorithm

EM Suspected
    ↓
Clinical Assessment
(Target lesions, distribution, mucosal involvement, Nikolsky sign, drug history)
    ↓
    ├─→ ≥2 mucosal sites OR atypical targets OR positive Nikolsky OR drug exposure → Consider SJS/TEN → Urgent dermatology
    ↓
Confirmed EM (typical targets, acral, 0-1 mucosal site, negative Nikolsky)
    ↓
    ├─→ EM Minor (skin only)
    │       ↓
    │   Outpatient Management
    │   - Symptomatic care (antihistamines, topical steroids)
    │   - Reassurance: self-limiting
    │   - Investigate trigger (HSV serology, Mycoplasma if indicated)
    │   - Follow-up 2-4 weeks
    │       ↓
    │   If active HSV: Acyclovir 400mg TDS × 5-7 days
    │   If recurrent EM (≥6 episodes/year): Consider suppressive therapy (acyclovir 400mg BD × 6-12 months)
    │
    └─→ EM Major (1 mucosal site involved)
            ↓
        Assess severity of mucosal involvement
            ↓
        ├─→ Mild (able to eat/drink, no eye involvement)
        │       → Outpatient Management
        │       → Oral care (antiseptic mouthwash, topical analgesia, soft diet)
        │       → Symptomatic care
        │       → Consider short course oral steroids (controversial)
        │
        └─→ Severe (unable to maintain oral intake OR eye involvement)
                → ADMIT
                → IV fluids for hydration
                → Urgent ophthalmology if ocular involvement
                → Topical/systemic analgesia
                → Oral care regimen
                → Consider systemic steroids (short course, controversial)

Conservative Management (First-Line for All EM)

Supportive Care

Symptomatic Relief

For Pruritus/Discomfort:

For Pain:

Topical Therapies

Note: Avoid high-potency topical steroids on face, genitals, or flexures due to skin atrophy risk.

Oral/Mucosal Care (EM Major)

Critical for patients with oral involvement to maintain nutrition and hydration.

Admission Criteria for IV Fluids:

• Inability to maintain oral intake (dehydration risk)
• Weight loss > 5%
• Biochemical evidence of dehydration (elevated urea, creatinine)

Medical Management — Trigger Treatment

Active HSV Infection

If active herpetic lesions (cold sore, genital herpes) are present at time of EM diagnosis:

Evidence: Treatment of active HSV may shorten duration of current EM episode, though data limited. [9] Main benefit is in preventing future episodes (see suppressive therapy below). [12,13]

Mycoplasma Pneumoniae Infection

If respiratory symptoms and confirmed/suspected Mycoplasma:

Evidence: Antibiotics treat Mycoplasma pneumonia but unclear benefit for EM itself (EM still self-limiting). [5]

Medical Management — Recurrent EM Prevention

Indications for Suppressive Antiviral Therapy:

• Recurrent EM with ≥6 episodes per year [13]
• Recurrent EM with significant quality-of-life impairment [13]
• Documented or highly suspected HSV trigger (HAEM) [12,13]

Suppressive Regimens:

Monitoring on Suppressive Therapy:

• Baseline renal function (acyclovir renally excreted)
• Reassess after 6 months: Consider continuing if effective; trial off-treatment if no recurrence
• Monitor for side effects (headache, nausea; rare)

Expected Outcomes:

• Most patients (80-90%) experience dramatic reduction in EM frequency [12,13]
• Some patients become episode-free [13]
• If recurrence occurs despite therapy, consider:
  • Increasing dose (acyclovir 400mg TDS or valaciclovir 1g BD)
  • Confirming HSV as trigger (vs other cause)
  • Checking compliance
  • Assessing for immunosuppression [16]

Systemic Corticosteroids (Controversial)

Indication: Severe EM major with extensive mucosal involvement and significant symptoms.

Evidence: Limited and conflicting data; no RCTs. Some experts use short courses for severe EM major; others avoid due to lack of evidence and theoretical infection worsening. [1,2]

Considerations:

• ✅ Potential benefits: Reduce inflammation, shorten symptom duration, improve mucosal pain
• ❌ Potential harms: Prolong viral shedding (if HSV-triggered), increase infection risk, no clear evidence of benefit
• Consensus: Not routinely recommended; consider only in severe cases with dermatology input [1,2]

IMPORTANT: Do NOT confuse EM management with SJS/TEN management. Corticosteroids are NOT standard of care in SJS/TEN and may worsen outcomes. [8]

Disposition and Follow-Up

Outpatient Management (Most Cases)

Suitable for:

• EM minor (all cases)
• EM major with mild oral involvement and able to maintain hydration

Outpatient plan:

• Symptomatic care (antihistamines, topical steroids, oral care)
• Trigger investigation (HSV serology, Mycoplasma serology if indicated)
• Safety-netting advice (return if worsening, new mucosal sites, systemic symptoms)
• Follow-up in 2-4 weeks (sooner if concerns)

Admission Criteria

Consider admission if:

• Severe oral involvement preventing adequate oral intake (risk of dehydration)
• Diagnostic uncertainty (possible SJS/TEN requiring monitoring)
• Eye involvement (requires ophthalmology input and intensive topical treatment)
• Extensive skin involvement (> 10% BSA; pain management)
• Systemic toxicity (high fever, hypotension, altered mental status — suggests SJS/TEN)
• Social factors (poor support, inability to self-care, patient anxiety)

Inpatient management:

• IV fluids if dehydration/unable to drink (0.9% saline or Hartmann's solution; titrate to urine output ≥0.5ml/kg/hr)
• Regular analgesia (oral/IV); multimodal approach (paracetamol + opioids if severe oral pain)
• Intensive oral care regimen (chlorhexidine, benzydamine, topical lidocaine)
• Ophthalmology review if eye involvement (within 24 hours; risk of corneal scarring)
• Dermatology review for diagnostic confirmation and management optimization
• Monitor for progression (daily skin and mucosal assessment; photograph lesions)
• Nutritional support (dietitian input; high-calorie liquid supplements; NG tube rarely needed) [27]

Specialist Referrals

Follow-Up

2-4 Week Review:

• Assess resolution of skin lesions
• Check for post-inflammatory hyperpigmentation (reassure will fade)
• Review trigger investigation results
• Discuss suppressive therapy if recurrent EM identified
• Reinforce safety-netting (return if recurrence)

6-Month Review (if on suppressive antivirals):

• Assess efficacy (number of recurrences)
• Check renal function
• Decide on continuation vs trial off-treatment
• If effective, consider 12-month total duration then reassess

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8. Complications

Acute Complications (During Episode)

Note: The low complication rate in EM contrasts sharply with SJS/TEN, where severe complications (ocular scarring, sepsis, multi-organ failure) are common. [7,8]

Subacute Complications (Weeks)

Long-Term Complications (Months-Years)

Comparison with SJS/TEN Complications:

EM has a BENIGN complication profile compared to SJS/TEN: [7,8]

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9. Prognosis & Outcomes

Natural History

Acute Episode:

• Onset: Sudden development of target lesions over 24-72 hours [1]
• Progression: New lesions appear in crops over 3-5 days then stop [1]
• Duration: Individual lesions persist for approximately 7 days before fading [1]
• Total episode duration: 2-4 weeks from onset to complete resolution [1,2]
• Resolution pattern: Lesions fade leaving post-inflammatory hyperpigmentation; gradual lightening over weeks to months [1]

Untreated EM:

• Self-limiting in virtually all cases [1,2]
• Spontaneous resolution within 2-4 weeks without specific treatment [1,2]
• No progression to chronic disease
• Excellent prognosis for individual episodes

Outcomes with Treatment

Prognostic Factors

Excellent Prognosis (All EM Patients)

Factors indicating excellent prognosis:

• Self-limiting condition by definition [1,2]
• Near-zero mortality [1,2]
• Minimal long-term sequelae [1]
• Effective preventive therapy available (antivirals for HAEM) [12,13]
• No progression to systemic disease

Factors Associated with Recurrence

Predisposing to recurrent EM:

Protective factors:

• Suppressive antiviral therapy: 80-90% reduction in recurrence [12,13]
• Avoidance of HSV triggers (UV exposure, stress, trauma to lips/genitals) [9]

Long-Term Outcomes

5-Year Outcomes (Observational Data):

Quality of Life:

• Single-episode EM: No long-term QoL impact once resolved [1]
• Recurrent EM (untreated): Significant QoL impairment; work absenteeism; psychological distress [13]
• Recurrent EM (on suppressive therapy): Dramatic QoL improvement; most patients able to resume normal activities [13]

Comparison: EM vs SJS/TEN Prognosis

Critical distinction for patient counselling and prognostication:

Key Message for Patients: EM has an EXCELLENT prognosis with near-zero mortality and minimal long-term complications. This starkly contrasts with SJS/TEN and underscores the importance of accurate diagnosis. [1,2,6,7,8]

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10. Evidence & Guidelines

Key Guidelines

1. British Association of Dermatologists (BAD)

   • Patient information leaflet on erythema multiforme
   • Available: https://www.bad.org.uk/patient-information-leaflets/erythema-multiforme/
   • Summary: Patient-focused guidance on EM diagnosis, triggers, and management

2. DermNet NZ

   • Comprehensive clinical resource on erythema multiforme
   • Available: https://dermnetnz.org/topics/erythema-multiforme
   • Summary: Evidence-based overview for clinicians

3. NICE Clinical Knowledge Summaries (CKS)

   • Erythema multiforme management recommendations
   • Available: https://cks.nice.org.uk
   • Summary: UK primary care management guidance

Landmark Studies and Key Evidence

1. Distinction of EM from SJS/TEN

Bastuji-Garin S, et al. (1993) — Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.

• Arch Dermatol. 1993;129(1):92-96. PMID: 8420497
• Key findings: Established EM as distinct from SJS/TEN based on lesion morphology (typical vs atypical targets), distribution (acral vs truncal), and triggers (infection vs drugs)
• Clinical impact: Revolutionized diagnostic approach; EM no longer part of SJS/TEN spectrum [6]

Assier H, et al. (1995) — 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
• Key findings: EM and SJS are separate entities with different aetiologies; EM predominantly infection-triggered (HSV), SJS drug-triggered
• Clinical impact: Confirmed EM-SJS distinction; changed diagnostic criteria [7]

2. HSV as Primary Trigger

Assier H, et al. (1995) — HSV DNA in EM lesions.

• (As above) PMID: 7741539
• Key findings: HSV DNA fragments detected in skin lesions of EM patients using PCR; establishes HSV as primary trigger [4]

Ono F, et al. (2005) — CD34+ cells in the peripheral blood transport herpes simplex virus DNA fragments to the skin of patients with erythema multiforme (HAEM).

• J Invest Dermatol. 2005;125(6):1276-1281. PMID: 15955097
• Key findings: HSV DNA pol gene fragments transported to distant skin sites via CD34+ peripheral blood cells; explains 1-2 week delay between HSV and EM, and acral distribution [11]
• Clinical impact: Elucidated pathophysiology of HAEM; explains temporal gap and distribution pattern [11]

Aurelian L, et al. (2003) — Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component.

• Dermatol Online J. 2003;9(1):1. PMID: 12639459
• Key findings: HAEM has both viral trigger and autoimmune T-cell response; CD4+ and CD8+ T-cell infiltration
• Clinical impact: Defined immunopathogenesis of HAEM [9]

3. Mycoplasma as Trigger (Paediatric EM)

Amode R, et al. (2018) — Clinical and histologic features of Mycoplasma pneumoniae-related erythema multiforme: A single-center series of 33 cases.

• J Am Acad Dermatol. 2018;79(1):110-117. PMID: 29559400
• Key findings: Mycoplasma pneumoniae is common trigger in paediatric EM; distinct clinical features (more mucosal involvement, younger age, respiratory symptoms)
• Clinical impact: Established Mycoplasma as key differential trigger, especially in children [5]

4. Suppressive Antiviral Therapy

Schofield JK, et al. (1993) — Recurrent erythema multiforme: clinical features and treatment in a large series of patients.

• Br J Dermatol. 1993;128(5):542-545. PMID: 8504044
• Key findings: Continuous acyclovir significantly reduced recurrent EM episodes in open-label study
• Clinical impact: Established prophylactic acyclovir as standard of care for recurrent HAEM [12]

Wetter DA, Davis MD (2010) — Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic.

• J Am Acad Dermatol. 2010;62(1):45-53. PMID: 19815314
• Key findings: 48-patient series; HSV association in majority; continuous acyclovir/valaciclovir reduced recurrence by 80-90%
• Clinical impact: Modern large series confirming efficacy of suppressive antivirals for recurrent EM [13]

5. Comprehensive Reviews

Lerch M, et al. (2018) — Current Perspectives on Erythema Multiforme.

• Clin Rev Allergy Immunol. 2018;54(1):177-184. PMID: 29352387
• Key findings: Comprehensive modern review; EM as distinct entity; HSV main trigger; suppressive antivirals effective
• Clinical impact: Authoritative contemporary review synthesizing evidence [2]

Samim F, et al. (2013) — Erythema multiforme: a review of epidemiology, pathogenesis, clinical features, and treatment.

• Dent Clin North Am. 2013;57(4):583-596. PMID: 24034067
• Key findings: Detailed review of EM epidemiology, pathophysiology, clinical features
• Clinical impact: Accessible comprehensive review for generalists [1]

Kechichian E, Dupin N, Wetter DA (2024) — Erythema multiforme.

• EClinicalMedicine. 2024;77:102878. PMID: 39583748
• Key findings: Most recent authoritative review; confirms EM-SJS distinction; HSV trigger; antiviral prophylaxis
• Clinical impact: Up-to-date evidence synthesis [20]

6. Genetic Susceptibility

Bucciol G, et al. (2021) — Pathogenic TLR3 Variant in a Patient with Recurrent Herpes Simplex Virus 1-Triggered Erythema Multiforme.

• J Clin Immunol. 2021;41(1):96-104. PMID: 33174085
• Key findings: Pathogenic TLR3 mutation identified in patient with severe recurrent HAEM
• Clinical impact: Highlights genetic predisposition in some cases; research area [15]

Evidence Strength Summary

Evidence Levels:

• Level 1: Systematic reviews, meta-analyses, high-quality RCTs
• Level 2 a: Well-designed observational studies (cohort, case-control)
• Level 3: Case series, case reports
• Level 4: Expert consensus, clinical experience

Note: High-level RCT evidence is limited in EM due to self-limiting nature, relative rarity, and ethical challenges of placebo-controlled trials for recurrent disease when effective treatment (antivirals) exists.

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10A. Clinical Vignettes for Examination Preparation

Vignette 1: Classic EM Minor (Easy Difficulty)

Clinical Scenario:
A 28-year-old woman presents to the emergency department with a 2-day history of a rash on her hands and feet. She reports having a cold sore on her lip 10 days ago which has since healed. The rash began suddenly with red spots that have developed a distinctive appearance. She feels generally well with no fever.

Examination:

• Well-appearing, afebrile
• Multiple circular lesions on dorsal hands and feet bilaterally
• Lesions show three concentric zones: dusky centre, pale middle ring, bright red outer halo
• Lesions are raised, firm, and fixed (not migratory)
• No mucosal involvement (oral cavity, eyes, genitals normal)
• Nikolsky sign negative

Questions:

1. What is the most likely diagnosis?
2. What is the pathophysiological mechanism linking the cold sore to the current rash?
3. What initial investigations would you perform?
4. What is the appropriate management?
5. What advice would you give regarding prognosis and recurrence?

Model Answers:

1. Diagnosis: Erythema multiforme minor (EM minor). The three-zone target lesions in acral distribution following HSV infection are pathognomonic for EM. [1,2,20]

2. Pathophysiology: HSV reactivation (cold sore) released viral DNA fragments which were transported by CD34+ cells in peripheral blood to distant skin sites over 1-2 weeks. HSV DNA deposited in keratinocytes acts as foreign antigen, triggering CD8+ T-cell mediated immune response causing the characteristic target lesions. [4,11,23]

3. Investigations: This is a clinical diagnosis. Supportive investigations include HSV serology (IgG/IgM) to confirm prior HSV exposure, HSV PCR if active lesion present. Skin biopsy only if diagnostic uncertainty. [1,3]

4. Management: Reassurance that this is self-limiting (2-4 weeks resolution). Symptomatic care: oral antihistamines for itch, paracetamol for discomfort, emollients. No specific treatment needed for single episode. Outpatient management appropriate. [1,2]

5. Prognosis: Excellent. Near-zero mortality. 70-80% have single episode only. 20-30% experience recurrence. If ≥6 episodes/year, continuous acyclovir 400mg BD reduces recurrence by 80-90%. [10,12,13,28]

Exam Tips: Always count mucosal sites (0 = EM minor, 1 = EM major, ≥2 = SJS). Always check Nikolsky sign (negative in EM). Always ask about recent infections (HSV, Mycoplasma) and medications (drugs suggest SJS).

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Vignette 2: EM vs SJS Diagnostic Challenge (Moderate Difficulty)

Clinical Scenario:
A 35-year-old man presents with a 1-day history of widespread rash and oral ulceration. He started co-trimoxazole for a urinary tract infection 3 weeks ago. He reports feeling unwell with fever (39.2°C), malaise, and severe mouth pain preventing oral intake.

Examination:

• Appears toxic, febrile (39.2°C), tachycardic (110 bpm)
• Widespread erythematous macules with dusky centres on trunk and proximal limbs
• Some lesions have two poorly defined zones; many are flat macules with purpura
• Oral mucosa: extensive erosions on lips, buccal mucosa, and tongue
• Conjunctival injection bilaterally with erosions
• Genital examination: erosions on glans penis
• Nikolsky sign positive on normal-appearing skin
• Estimated body surface area involvement: 20%

Questions:

1. What is the most likely diagnosis and why is EM unlikely?
2. What critical features distinguish this from EM?
3. What is the immediate management priority?
4. What scoring system predicts mortality in this condition?
5. What specialist referrals are required urgently?

Model Answers:

1. Diagnosis: Stevens-Johnson syndrome (SJS). EM is unlikely because: (1) atypical flat targets/macules not typical three-zone targets, (2) truncal distribution not acral, (3) ≥2 mucosal sites involved (oral + ocular + genital), (4) positive Nikolsky sign, (5) recent drug exposure (co-trimoxazole), (6) high fever and systemic toxicity. [6,7,8]

2. Distinguishing features: SJS has drug trigger (EM infection-triggered), atypical targets (EM typical three-zone), truncal distribution (EM acral), ≥2 mucosal sites (EM 0-1), positive Nikolsky (EM negative), systemic toxicity (EM well-appearing), 10-30% BSA (EM less than 10%). Fundamentally different pathophysiology: SJS has granulysin-mediated keratinocyte death initiated by neutrophils; EM has HSV-specific CD8+ T-cell response. [6,7,8,25]

3. Immediate management: (1) STOP co-trimoxazole immediately, (2) admit to burn unit or dermatology ward, (3) IV fluid resuscitation (patient unable to drink), (4) wound care (sterile handling, avoid skin trauma), (5) ophthalmology review within 24h, (6) analgesia (opioids for severe pain), (7) nutritional support, (8) monitor for sepsis. [8]

4. SCORTEN score: Predicts mortality in SJS/TEN based on 7 variables: age greater than 40, malignancy, tachycardia greater than 120, BSA greater than 10%, serum urea greater than 10mmol/L, glucose greater than 14mmol/L, bicarbonate less than 20mmol/L. Score 0-1 = 3.2% mortality; Score ≥5 = 90% mortality. [8]

5. Urgent referrals: (1) Ophthalmology (same day; risk corneal scarring, symblepharon), (2) Dermatology (immediate; confirm diagnosis, guide management), (3) Critical care (consider if extensive BSA or deteriorating; SJS/TEN managed like burns). [7,8]

Exam Tips: In vivas, examiners test EM vs SJS distinction extensively. Know the six key differentiators: trigger, target morphology, distribution, mucosal sites, Nikolsky sign, systemic toxicity. Missing SJS diagnosis is dangerous; if uncertain, treat as SJS until proven otherwise.

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Vignette 3: Recurrent EM and Suppressive Therapy (High Difficulty)

Clinical Scenario:
A 32-year-old woman is referred to dermatology clinic with a 3-year history of recurrent skin eruptions. She experiences target lesions on her hands and feet approximately 8 times per year, each lasting 2-3 weeks. She reports that episodes are often preceded by tingling on her lip, sometimes followed by a small cold sore. The recurrent episodes significantly impact her work as a teacher and cause considerable psychological distress. She has no other medical history and takes no regular medications.

Questions:

1. What is the diagnosis and likely trigger?
2. What investigations would confirm the aetiology?
3. What pathophysiological mechanism explains the recurrence pattern?
4. What treatment options are available for preventing recurrences?
5. What evidence supports the use of suppressive therapy and what are the expected outcomes?

Model Answers:

1. Diagnosis: Recurrent herpes-associated erythema multiforme (HAEM). The temporal association between lip tingling/cold sores and subsequent target lesions 7-14 days later strongly suggests HSV-triggered EM. Frequency of 8 episodes/year indicates severe recurrent disease requiring intervention. [9,10,13]

2. Investigations: HSV serology (IgG) confirms latent HSV infection (seroprevalence ~70% in adults; positive in most HAEM patients). HSV typing (HSV-1 vs HSV-2) identifies whether oral or genital suppression needed. HSV PCR on active cold sore confirms HSV reactivation. Skin biopsy of EM lesion can detect HSV DNA pol gene fragments even without active herpetic lesion. [3,4,9]

3. Pathophysiology: Latent HSV (HSV-1 in trigeminal ganglia in this case) reactivates periodically producing cold sore. HSV DNA fragments released into circulation are ingested by CD34+ cells (50% express CLA skin-homing receptor). CD34+ cells transport viral DNA to keratinocytes at acral sites via E-cadherin upregulation. HSV DNA in keratinocytes triggers delayed hypersensitivity reaction with HSV-specific CD8+ T-cell infiltration and keratinocyte apoptosis, producing target lesions 7-14 days after cold sore. [4,11,20,23]

4. Treatment options: (1) Continuous suppressive antivirals (first-line): Acyclovir 400mg BD or valaciclovir 500mg-1g OD for 6-12 months. (2) Episodic treatment: High-dose acyclovir at first sign of cold sore (800mg 5x/day for 5 days; less effective than continuous suppression). (3) Trigger avoidance: UV protection (SPF lip balm), stress management, avoid lip trauma. (4) Higher-dose or alternative antivirals if standard suppression fails. [12,13,28]

5. Evidence: Level 2a evidence from observational studies shows continuous acyclovir/valaciclovir reduces EM recurrence by 80-90%. Schofield 1993 (open-label study, n=57) showed significant reduction in episode frequency. Wetter 2010 (Mayo Clinic series, n=48) confirmed 80-90% reduction with continuous suppressive therapy. Tatnall 1995 (double-blind placebo-controlled trial, n=22) demonstrated efficacy of continuous acyclovir. Expected outcomes: Most patients (80-90%) experience dramatic reduction in episodes; some become episode-free; quality of life scores improve 60-80%; treatment well-tolerated with minimal side effects (headache, nausea rare); renal function monitoring needed as acyclovir renally excreted. [12,13,28]

Teaching Point: Recurrent HAEM significantly impairs quality of life. Recognition of HSV trigger and institution of long-term suppressive therapy is transformative for patients. After 6-12 months, reassess: if no recurrence, trial off-treatment; if recurrence despite therapy, increase dose or check compliance/immunodeficiency. [13,28]

Exam Tips: In MRCP/FRACP PACES, recurrent EM stations test ability to elicit HSV history, explain pathophysiology, and discuss evidence for suppressive therapy. Examiners expect mention of specific studies (Schofield 1993, Wetter 2010), Level 2a evidence, and 80-90% reduction statistic. Always counsel patients on excellent prognosis with treatment to address psychological impact.

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11. Patient/Layperson Explanation

What is Erythema Multiforme?

Erythema multiforme (EM) is a skin reaction that causes distinctive "target" or "bulls-eye" shaped spots. The spots have a dark or blistered centre, a pale ring around it, and a red outer circle, creating a target-like pattern. These spots most commonly appear on the backs of your hands and feet, and sometimes on your arms and legs.

EM is usually triggered by an infection, most often the cold sore virus (herpes simplex). The cold sore typically appears 1-2 weeks before the skin rash develops. By the time the rash appears, the cold sore may have already healed, which is why you might not always remember having one.

Is it serious?

Good news: Erythema multiforme is not serious in the vast majority of cases. It goes away on its own within 2-4 weeks without treatment, and most people have no long-term problems. It is very different from a more serious condition called Stevens-Johnson syndrome (SJS), which is usually caused by medications and requires urgent hospital treatment.

Important: It's essential for a doctor to confirm the diagnosis because EM and SJS can look somewhat similar at first, but they require very different management.

What causes it?

Common triggers:

• Cold sore virus (herpes simplex): The most common cause, especially in people who get recurrent EM. The virus reactivates (often as a cold sore on the lip or genital herpes), and 1-2 weeks later, the skin rash appears. [3,9]
• Mycoplasma pneumoniae: A type of bacteria that causes chest infections, particularly in children and young adults. [5]
• Other infections: Rarely, other viral infections can trigger EM.

Medications are a very rare cause of true EM. If a medication is involved, it's more likely to be SJS/TEN (the more serious condition). [6,7]

How is it diagnosed?

• Clinical examination: Your doctor will look at the rash and check for the characteristic three-zone target spots.
• Distribution: EM typically affects hands and feet first (called "acral" distribution).
• Mucosal involvement: Your doctor will check your mouth, eyes, and genitals. EM minor affects only the skin. EM major affects the skin plus one area of mucosa (usually the mouth). If two or more mucosal areas are involved, it's likely SJS, not EM. [1,6]
• Blood tests: To check for infections (cold sore virus, Mycoplasma) and rule out other causes. [3,5]

How is it treated?

EM is self-limiting, meaning it gets better on its own. Treatment focuses on making you comfortable while the rash heals:

1. Symptomatic relief:

• Antihistamines (e.g., cetirizine) for itching
• Paracetamol for pain or fever
• Cool compresses on affected skin
• Moisturizing creams for dry skin

2. Topical steroid creams:

• Moderate-strength steroid creams (e.g., betamethasone) can reduce inflammation and discomfort. Apply twice daily to affected areas.

3. Mouth care (if mouth is involved):

• Antiseptic mouthwash (e.g., chlorhexidine) to prevent infection
• Numbing mouthwash (e.g., benzydamine/Difflam) before eating to reduce pain
• Soft diet: Avoid spicy, acidic, or hot foods; stick to soft, bland foods and cold drinks
• Lip care: Apply petroleum jelly (Vaseline) to crusted lips
• Pain relief: Paracetamol or stronger painkillers if needed

4. Treating the underlying trigger:

• If you have an active cold sore, your doctor may prescribe antiviral tablets (e.g., acyclovir 400mg three times daily for 5-7 days). [9]
• If you have a chest infection from Mycoplasma, antibiotics (e.g., azithromycin) may be given. [5]

5. For recurrent EM (6 or more episodes per year):

• Long-term antiviral tablets (acyclovir 400mg twice daily or valaciclovir 500mg-1g daily) can prevent future episodes. Studies show this reduces recurrence by 80-90%. [12,13]
• You typically take these for 6-12 months, then reassess.

What to expect

Timeline:

• Days 1-3: Rash develops suddenly; target spots appear on hands and feet
• Days 3-7: New spots may continue to appear; existing spots reach full development
• Days 7-14: Spots begin to fade; some peeling and darkening of skin
• Weeks 2-4: Gradual resolution; temporary darker marks where spots were (post-inflammatory hyperpigmentation)
• Months 1-6: Dark marks gradually fade

Will it scar?

• Scarring is rare in EM. Most people are left with temporary darker marks that fade over several months. [1]

Will it come back?

• About 20-30% of people experience recurrent episodes, especially if triggered by cold sores. [10]
• If you get 6 or more episodes per year, long-term antiviral tablets can dramatically reduce recurrences. [12,13]

When to seek urgent help

See a doctor urgently or go to A&E if:

• You develop blisters or sores in your mouth, eyes, AND genitals at the same time (suggests SJS, not EM)
• Your skin is peeling off or feels very tender
• You have a high fever (above 39°C) and feel very unwell
• The rash is spreading rapidly and covering large areas of your body
• You have eye pain, redness, or vision changes (urgent ophthalmology needed)
• You cannot eat or drink due to mouth pain (risk of dehydration)
• You have recently started a new medication (in the past 1-8 weeks)

Living with recurrent EM

If you have recurrent EM triggered by cold sores:

Prevention strategies:

• Avoid cold sore triggers: Excessive sun exposure (use lip balm with SPF), stress, trauma to lips
• Recognize early signs: Tingling at usual cold sore site; start antiviral treatment early
• Long-term suppressive therapy: Daily antiviral tablets (acyclovir or valaciclovir) can prevent both cold sores and EM episodes [12,13]

Emotional support:

• Recurrent EM can be frustrating and impact quality of life
• Knowing there is effective treatment (suppressive antivirals) is reassuring
• Most patients on suppressive therapy experience dramatic improvement [13]

Key Takeaways

✅ EM is a self-limiting skin reaction usually triggered by the cold sore virus
✅ It is NOT serious and has an excellent prognosis (near-zero mortality) [1,2]
✅ Characteristic target-shaped spots on hands and feet
✅ Treatment is symptomatic (antihistamines, steroid creams, mouth care)
✅ Recurrent EM can be prevented with long-term antiviral tablets [12,13]
✅ EM is very different from Stevens-Johnson syndrome (SJS), which is more serious
✅ See a doctor urgently if you have involvement of 2+ mucosal sites, skin peeling, or severe symptoms

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12. References

Primary Literature

1. Samim F, Auluck A, Zed C, Williams PM. Erythema multiforme: a review of epidemiology, pathogenesis, clinical features, and treatment. Dent Clin North Am. 2013;57(4):583-596. doi:10.1016/j.cden.2013.07.001

2. Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Current Perspectives on Erythema Multiforme. Clin Rev Allergy Immunol. 2018;54(1):177-184. doi:10.1007/s12016-018-8667-7

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Guidelines and Resources

• British Association of Dermatologists. Erythema Multiforme Patient Information Leaflet. 2023. Available at: https://www.bad.org.uk/patient-information-leaflets/erythema-multiforme/

• DermNet NZ. Erythema Multiforme. Available at: https://dermnetnz.org/topics/erythema-multiforme

• NICE Clinical Knowledge Summaries. Erythema Multiforme. Available at: https://cks.nice.org.uk

• NHS. Erythema Multiforme. Available at: https://www.nhs.uk/conditions/erythema-multiforme/

• British Skin Foundation. Erythema Multiforme Information. Available at: https://www.britishskinfoundation.org.uk

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference only. This information does not replace professional medical advice, diagnosis, or treatment. If you develop widespread skin lesions with mucosal involvement, skin detachment, or systemic symptoms, seek urgent medical attention to exclude Stevens-Johnson syndrome or toxic epidermal necrolysis, which require immediate specialist care.