Erythema Multiforme
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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Risk factors
- Herpes simplex virus (HSV-1 > HSV-2) — implicated in ≥50% of cases and >70% of recurrent EM
- Mycoplasma pneumoniae — especially in children and adolescents
- Other infections: EBV, CMV, hepatitis viruses, parvovirus B19, COVID-19, fungi, parasites
- 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
- Pemphigus vulgaris — Painful oral erosions, flaccid bullae, positive Nikolsky; DIF positive
- Sweet syndrome — Painful red plaques with neutrophilic infiltrate, fever, leukocytosis; associated with malignancy or infection
- Vasculitis (small vessel) — Palpable purpura on lower extremities; biopsy
- Rowell syndrome (SLE) — EM-like lesions + SLE features + anti-La (SSB) positivity
Diagnostic workup
Diagnostic criteria
Clinical: typical target lesions in acral distribution ± mucosal involvement; biopsy if atypical.
Labs
- Clinical diagnosis — characteristic morphology and distribution
- Skin biopsy if atypical: interface dermatitis with apoptotic keratinocytes, lymphocytic infiltrate (less full-thickness necrosis than SJS/TEN)
- HSV PCR or culture of any vesicles; serology
- Mycoplasma pneumoniae PCR, IgM, cold agglutinins; chest X-ray if respiratory symptoms
- CBC, CMP, ESR to exclude systemic illness
- 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 |
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
- Refractory: dapsone, antimalarials, mycophenolate, azathioprine
EM major (severe mucosal)
- 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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