Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous reaction characterized by classic raised target lesions with three concentric zones, predominantly affecting the extremities (acral distribution). It is most commonly triggered by herpes simplex virus (HSV) infection, followed by Mycoplasma pneumoniae and drugs. Prevalence is estimated at 0.01–1%, with a predilection for young adults and a female preponderance. [1-2]
The following figure illustrates the classic target lesions of EM compared with Stevens-Johnson syndrome and toxic epidermal necrolysis:
1. History
- Onset and timing: Acute onset of skin lesions, often 1–2 weeks after a triggering event (HSV outbreak, URI, new medication) [1-2]
- Prodrome: Fatigue, malaise, myalgia may precede skin/mucosal lesions by ~1 week in severe cases [1]
- Symptom characterization: Burning or pruritus at lesion sites; pain if mucosal involvement
- Key HPI questions:
- Recent cold sore or genital herpes outbreak?
- New medications in the past 1–3 weeks (especially antibiotics, anticonvulsants, allopurinol, NSAIDs)?
- Recent upper respiratory infection, cough, or fever (Mycoplasma)?
- Recent vaccination or immunotherapy?
- Prior episodes of similar rash (recurrent EM)?
- Important negatives: Absence of diffuse skin sloughing, absence of widespread purpuric macules, no systemic toxicity [2][4]
2. Alarm Features
- Widespread confluent blistering or epidermal detachment → concern for SJS/TEN [5]
- Nikolsky sign positive (epidermal separation with lateral pressure)
- Extensive mucosal involvement (≥2 mucosal sites with severe erosions) → EM major vs. SJS [1][6]
- Inability to eat/drink due to oral pain → risk of dehydration
- Ocular involvement: Conjunctival injection, pseudomembrane formation → urgent ophthalmology consult
- Respiratory symptoms (cough, dyspnea) → Mycoplasma-associated EM with possible pneumonia [1]
- Hemodynamic instability, high fever, or signs of sepsis
- Rapidly progressive lesions with >10% BSA detachment → SJS/TEN overlap [5]
3. Medications
Common triggers (discontinue if suspected)
- Sulfonamide antibiotics, penicillins, cephalosporins
- Anticonvulsants: phenytoin, phenobarbital, valproic acid
- Allopurinol, NSAIDs (acetylsalicylic acid)
- TNF-α inhibitors (adalimumab, infliximab, etanercept)
- Tetracyclines, nitrofurantoin, erythromycin
- Statins, imiquimod [7]
Treatments
- Mild EM minor: Topical corticosteroids, oral antihistamines for symptomatic relief [2]
- HSV-associated recurrent EM: Continuous oral acyclovir 400 mg BID or valacyclovir 500 mg BID prophylaxis [7-8]
- Severe mucosal EM: Analgesics (including opioids), antiseptic mouthwashes (chlorhexidine + lidocaine + nystatin + bicarbonate q4h), lidocaine gel before meals [1]
- Systemic corticosteroids: Debated; prednisone 0.5–1 mg/kg/day with taper over 10–15 days used in some severe cases, but evidence is limited [1][8]
- Refractory/recurrent EM: Dapsone, thalidomide, or IVIG in steroid-recalcitrant cases [9-10]
Cautions
- Systemic corticosteroids in children with SJS associated with increased complications (infection, GI bleeding, prolonged hospitalization) [8]
- Topical acyclovir does NOT prevent recurrent EM episodes — must use systemic antiviral [7]
4. Diet
- Acute phase with oral involvement: Soft, bland, cool foods; avoid acidic, spicy, or hot foods
- Hydration is critical — monitor oral intake closely; if severely impaired, consider NG tube feeding or IV fluids [1]
- No specific long-term dietary triggers are established for EM
5. Review of Systems
- Skin: New lesions, blistering, skin tenderness, pruritus
- HEENT: Oral pain, dysphagia, eye redness/pain/discharge, nasal crusting
- Respiratory: Cough, dyspnea (Mycoplasma pneumonia) [1]
- GU: Genital lesions, dysuria (genital mucosal involvement; recent HSV outbreak)
- GI: Odynophagia, decreased oral intake, esophageal involvement [1]
- Constitutional: Fever, malaise, myalgia, arthralgias
6. Collateral History and Family History
- History of recurrent HSV (oral or genital) — present in up to 71% of EM cases [8]
- Medication reconciliation with pharmacy records — identify new drugs in past 1–3 weeks
- Vaccination history — recent immunizations can trigger EM, especially in infants [11]
- Family history: No strong hereditary pattern, though some genetic susceptibility to HSV-triggered EM has been suggested
- Social context: Immunosuppression (HIV status), sexual history (HSV exposure)
7. Risk Factors
- Recurrent HSV infection — the single most important risk factor [2][6]
- Young adult age (20–40 years) [1]
- Female sex (slight preponderance) [1]
- Mycoplasma pneumoniae infection — especially in children and during winter months [1]
- Recent drug exposure (sulfonamides, anticonvulsants, allopurinol) [7]
- Immunosuppression (HIV, malignancy)
- Recent vaccination — particularly in infants [11]
8. Differential Diagnosis
- Stevens-Johnson syndrome (SJS): Widespread purpuric macules with blisters, >1 mucosal site, predominantly drug-triggered, atypical flat target lesions — distinct from EM's raised true targets [3][5]
- Urticaria: Lesions are transient (<24 hours), migratory, and pruritic vs. EM lesions fixed ≥7 days [2][4]
- Fixed drug eruption: Recurrent well-demarcated round plaques at same site with drug re-exposure
- Bullous pemphigoid: Tense blisters on urticarial base, older patients, positive DIF
- Cutaneous small-vessel vasculitis: Palpable purpura, non-blanching
- Sweet syndrome: Tender erythematous plaques, neutrophilic infiltrate, fever
- Tinea corporis: Annular scaling plaques, KOH positive
- Lupus erythematosus (Rowell syndrome): EM-like lesions with ANA positivity
- Polymorphous light eruption: Photodistributed papulovesicles
- Behçet disease: Recurrent oral/genital ulcers, pathergy [6][12]
9. Past Medical History
- Prior EM episodes — recurrent EM occurs in ~14% of pediatric cases, commonly HSV-linked [11]
- History of HSV-1 or HSV-2 infection
- History of Mycoplasma pneumoniae infection
- Autoimmune conditions (SLE, inflammatory bowel disease)
- HIV status — associated with more severe and recurrent EM
- Medication allergy history — prior drug reactions
10. Physical Exam
Vital signs: Fever may be present (especially Mycoplasma-associated EM); tachycardia if dehydrated
Skin
- Classic target lesions: Three concentric zones — central dusky/bullous area, surrounding pale edematous ring, outer erythematous ring [1][6]
- Distribution: Symmetric, acral predominant (dorsal hands, palms, soles, extensor surfaces), spreading centripetally [2]
- Mycoplasma-associated EM: More truncal, purpuric macules to vesicles/bullae [1]
- Nikolsky sign: Should be negative in EM (positive suggests SJS/TEN)
Mucosal exam (examine ALL mucosal surfaces)
- Oral: Erosions, hemorrhagic crusting of lips, painful ulcers [1]
- Ocular: Conjunctival injection, pseudomembranes, corneal erosions
- Genital/anal: Erosions, ulcers [1]
Pulmonary: Auscultate for crackles (Mycoplasma pneumonia) [1]
11. Lab Studies
- Routine labs are often unnecessary in mild EM minor
- If severe or diagnostic uncertainty:
- CBC, CMP (assess hydration, renal function, electrolytes)
- ESR/CRP (nonspecific inflammation)
- HSV workup: Tzanck smear, HSV PCR, or viral culture from suspicious vesicular lesions [1]
- Mycoplasma testing: IgM antibodies, throat swab PCR, chest radiograph [1]
- Skin biopsy: Interface dermatitis with necrotic keratinocytes, lymphocytic infiltrate — helps differentiate from SJS and other mimics [6-7]
- Direct immunofluorescence (DIF): To exclude autoimmune blistering diseases (bullous pemphigoid, pemphigus)
12. Imaging
- Chest X-ray: Indicated in all severe EM cases to evaluate for Mycoplasma pneumonia (infiltrates may be present even without respiratory symptoms) [1]
- CT chest: Rarely needed; consider if CXR equivocal with respiratory symptoms
- Imaging is unnecessary in straightforward mild EM minor
13. Special Tests
- Skin biopsy with H&E: Confirms diagnosis — shows vacuolar interface dermatitis, necrotic keratinocytes, perivascular lymphocytic infiltrate [7]
- DIF: Negative (helps exclude lupus, pemphigoid, pemphigus)
- HSV PCR of lesional skin: Can detect HSV DNA polymerase gene (pol) in EM lesions even without active herpes [6]
- SCORTEN: Use for SJS/TEN if diagnostic uncertainty exists regarding severity — not validated for EM specifically [5]
- Patch testing: May be considered if drug trigger suspected but unclear
14. ECG
- Not routinely indicated in EM
- Consider ECG if systemic toxicity, hemodynamic instability, or electrolyte derangements from poor oral intake
- Myocarditis is an exceedingly rare complication of Mycoplasma infection — ECG if chest pain or dyspnea present
15. Assessment
Classification
- EM minor: Cutaneous target lesions only, ≤1 mucosal site involved (usually oral), predominantly acral [6-7]
- EM major: Cutaneous lesions + ≥2 mucosal sites involved (oral, ocular, genital, anal) [1][13]
- MIRM/RIME (Mycoplasma-induced rash and mucositis): Severe mucositis with variable skin involvement, younger patients, better prognosis than SJS [1]
Typical course: Self-limited, resolving in 2–4 weeks without scarring (cutaneous lesions). Mucosal lesions may take longer. Recurrence in ~30–40% of HSV-associated cases. [2][6]
Complications: Dehydration from poor oral intake, secondary bacterial infection of skin lesions, ocular sequelae (symblepharon, corneal scarring), post-inflammatory hyperpigmentation, esophageal stricture (rare). [1]
16. Treatment Plan
EM Minor (mild, cutaneous only)
- Supportive care: topical corticosteroids (triamcinolone 0.1% cream), oral antihistamines (cetirizine, diphenhydramine) [2][4]
- Wound care: moisturizing ointment (petrolatum) BID to skin lesions [1]
- Treat underlying HSV if active: acyclovir 400 mg PO TID × 5–10 days or valacyclovir 1 g PO BID × 5–10 days
EM Major (mucosal involvement)
- Analgesics: acetaminophen, NSAIDs; opioids for severe pain [1]
- Oral care: chlorhexidine/lidocaine/nystatin/bicarbonate mouthwash q4h; lidocaine gel before meals [1]
- Ocular care: preservative-free artificial tears, vitamin A ointment; ophthalmology consult [1]
- Genital care: petrolatum to erosions [1]
- IV fluids if unable to maintain oral intake
- Consider systemic corticosteroids (prednisone 0.5–1 mg/kg/day, taper over 10–15 days) in severe cases — evidence remains debated [1][8]
- IVIG may be considered in steroid-recalcitrant severe EM major [9]
Recurrent EM (≥6 episodes/year or severe recurrences)
- Continuous antiviral prophylaxis: acyclovir 400 mg PO BID or valacyclovir 500 mg PO BID for ≥6 months [8][10][14]
- If antiviral-refractory: add dapsone (check G6PD first) [10]
- If dapsone-intolerant: thalidomide (with strict pregnancy precautions) [10][15]
- Emerging options: apremilast, JAK inhibitors [7]
17. Disposition
Discharge (most EM minor cases)
- Mild cutaneous disease, no mucosal involvement or minimal oral involvement
- Tolerating oral intake
- Reliable follow-up
Observation/Admission criteria
- Significant mucosal involvement (≥2 sites) with impaired oral intake [1][6]
- Inability to maintain hydration
- Severe pain requiring parenteral analgesia
- Ocular involvement requiring subspecialty care
- Diagnostic uncertainty (concern for SJS/TEN) — consider burn center transfer if SJS/TEN suspected [5]
- Immunocompromised patients with severe disease
Specialist consultation triggers
- Dermatology: Diagnostic uncertainty, severe/recurrent EM, need for biopsy
- Ophthalmology: Any ocular involvement (urgent)
- Infectious disease: Unclear infectious trigger, immunocompromised host
18. Follow Up / Return Precautions
Follow-up timing
- Mild EM minor: PCP or dermatology follow-up in 1–2 weeks
- EM major: close follow-up within 3–5 days of discharge; ophthalmology follow-up if ocular involvement
Return precautions — instruct patients to return immediately for:
- Worsening or spreading rash, new blistering, skin peeling
- Inability to eat or drink
- Eye pain, vision changes, or eye discharge
- High fever, feeling very unwell
- Difficulty breathing
Patient counseling
- EM is typically self-limited and resolves in 2–4 weeks [2]
- Lesions may leave temporary dark marks (post-inflammatory hyperpigmentation) but usually no permanent scarring
- If HSV-triggered, discuss antiviral prophylaxis to prevent recurrence [8]
- Identify and avoid any suspected drug trigger permanently
- Expected recovery: skin lesions fade over 2–4 weeks; mucosal lesions may take longer
References
1. Erythema Multiforme. — Kechichian E, Dupin N, Wetter DA, et al. EClinicalMedicine. 2024.
2. Erythema Multiforme: Recognition and Management. — Trayes KP, Love G, Studdiford JS. American Family Physician. 2019.
3. Correlations Between Clinical Patterns and Causes of Erythema Multiforme Majus, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis: Results of an International Prospective Study. — Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Archives of Dermatology. 2002.
4. Erythema Multiforme in Children. — Goldman RD. Canadian Family Physician Medecin De Famille Canadien. 2022.
5. Erythema Multiforme, Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis - Diagnosis and Treatment. — Grünwald P, Mockenhaupt M, Panzer R, Emmert S. Journal Der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 2020.
6. Clinical Features, Diagnosis, and Treatment of Erythema Multiforme: A Review for the Practicing Dermatologist. — Sokumbi O, Wetter DA. International Journal of Dermatology. 2012.
7. Current Perspectives on Erythema Multiforme. — Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Clinical Reviews in Allergy & Immunology. 2018.
8. Management of Acquired Bullous Skin Diseases. — Fine JD. The New England Journal of Medicine. 1995.
9. Intravenous Immunoglobulin as a Therapy for Severe or Steroid-Recalcitrant Erythema Multiforme Major: A Case Series. — Mo S, Nguyen J, Wang CY, et al. Clinical and Experimental Dermatology. 2026.
10. Recurrent Erythema Multiforme: A Therapeutic Proposal for a Chronic Disease. — Dias de Oliveira NF, Miyamoto D, Maruta CW, Aoki V, Santi CG. The Journal of Dermatology. 2021.
11. Triggers, Clinical Manifestations, and Management of Pediatric Erythema Multiforme: A Systematic Review. — Zoghaib S, Kechichian E, Souaid K, et al. Journal of the American Academy of Dermatology. 2019.
12. Erythema Multiforme. — Stampien TM, Schwartz RA. American Family Physician. 1992.
13. Oral Mucosal Diseases: Erythema Multiforme. — Scully C, Bagan J. The British Journal of Oral & Maxillofacial Surgery. 2008.
14. Interventions for Erythema Multiforme: A Systematic Review. — de Risi-Pugliese T, Sbidian E, Ingen-Housz-Oro S, Le Cleach L. Journal of the European Academy of Dermatology and Venereology : JEADV. 2019.
15. Evaluation of Thalidomide Treatment of Patients With Chronic Erythema Multiforme: A Multicenter Retrospective Cohort Study. — Roux C, Sbidian E, Bouaziz JD, et al. JAMA Dermatology. 2021.