Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous condition characterized by the abrupt onset of distinctive target-shaped lesions distributed symmetrically over the extremities 1, 2, 3. First described by Ferdinand von Hebra in 1860, the disorder represents a delayed-type hypersensitivity reaction directed predominantly against epidermal keratinocytes 5, 6. While historically classified alongside more severe cutaneous adverse reactions, erythema multiforme is now firmly recognized as a distinct clinicopathological entity separate from Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 4, 5. The disease manifests in two primary clinical subsets: erythema multiforme minor, characterized by typical target lesions with minimal or absent mucosal involvement, and erythema multiforme majus, which features prominent mucosal erosions accompanied by cutaneous lesions 2, 5. Understanding the specific triggering agents, pathophysiological mechanisms, and clinical parameters is essential for accurate diagnosis and effective management 2.
1. Etiology & Risk Factors
- Infectious Triggers: Herpes simplex virus (HSV types 1 and 2) is the most frequent identifiable precipitant, accounting for over 70% of recurrent erythema multiforme cases; viral DNA can frequently be detected within the lesional skin via polymerase chain reaction 2, 5. Mycoplasma pneumoniae is another major infectious trigger, particularly common in children and adolescents, frequently presenting with pronounced mucositis and prominent constitutional symptoms 2, 4. Other infectious triggers include Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, histoplasmosis, and streptococcal species 1, 3.
- Pharmacological Agents: Drug-induced erythema multiforme is less common than infectious etiology but is well-documented 3, 5. Associated medications include sulfonamides, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants (e.g., phenytoin, carbamazepine), and penicillins 1, 7.
- Immunizations & Miscellaneous Factors: Vaccination against various pathogens (including influenza, tetanus, and hepatitis B) has been temporally linked to the development of erythema multiforme 3, 6. Autoimmune disorders, malignancies, and physical stimuli such as ultraviolet radiation and deep X-ray therapy serve as rare predisposing or precipitating factors 3, 5.
- Idiopathic Cases: In approximately 25% to 50% of patients, no definitive infectious or pharmacologic trigger can be determined despite exhaustive clinical evaluation, leading to a classification of idiopathic erythema multiforme 2, 5.
2. Pathophysiology
The pathogenesis of erythema multiforme is fundamentally a cell-mediated (type IV) immune response triggered by circulating antigenic fragments that deposit in cutaneous and mucosal microvasculature 3, 6. When precipitated by herpes simplex virus, viral DNA fragments are transported to the skin by circulating peripheral blood mononuclear cells 2, 5. Keratinocytes subsequently express viral proteins, initiating an antigen-specific immune cascade 1, 5.
This process recruits clonally expanded CD8+ cytotoxic T lymphocytes into the epidermis, where they release perforin, granzyme B, and interferon-gamma 2, 5. These cytotoxic mediators induce widespread apoptotic cell death of basal and suprabasal keratinocytes 1, 2. Concurrently, localized immune complex deposition and complement activation in the superficial dermal blood vessels produce localized microvascular damage, dermal edema, and erythrocyte extravasation 3, 7. This structural alteration creates the concentric ring morphology characteristic of target lesions, wherein central epidermal necrosis is surrounded by edematous pallor and a peripheral erythematous inflammatory halo 3, 5, 7.
3. Clinical Presentation & Classic Clinical Signs
- History & Cardinal Symptoms: Patients typically report an abrupt eruption of skin lesions that develop over 24 to 72 hours, frequently preceded by a prodrome of mild malaise, fever, arthralgia, or a history of recurrent herpes labialis 1 to 3 weeks prior to the rash 2, 3. Cutaneous lesions are often mildly pruritic, burning, or painful 3. When mucosal involvement is present, patients experience severe oral pain, odynophagia, conjunctival irritation, or dysuria, which can significantly impair oral intake and hydration 2, 4.
- Physical Examination & Named Clinical Signs: The cutaneous eruption is characterized by a symmetrical distribution with a marked predilection for the acral extremities (extensor surfaces of the hands, forefeet, palms, soles, knees, and elbows), spreading centripetally toward the trunk 2, 3. The hallmark lesion is the typical target lesion (also termed iris lesion), which consists of at least three distinct concentric zones: a dark, dusky, or blistered center, a surrounding pale edematous ring, and an outermost erythematous halo 3, 5, 7. Atypical target lesions possess only two zones or have poorly defined borders but retain a raised, palpable consistency 2. Individual lesions remain fixed in place for a minimum of seven days, distinguishing erythema multiforme from migratory urticarial plaques 3. Mucosal lesions, when present in erythema multiforme majus, typically affect the oral cavity (labial mucosa, buccal mucosa, and tongue) with painful erythema, vesicles, and superficial ulceration covered by whitish pseudomembranes 2, 4. Ocular involvement ranges from mild conjunctivitis to painful keratitis and corneal ulceration 4.
4. Diagnostic Workup & Interpretation (Laboratory, Imaging & ECG/Pathology)
| Diagnostic Modality / Test | Expected Clinical & Radiological / Laboratory Finding |
|---|---|
| Gold-Standard Investigation | Skin punch biopsy of an early target lesion demonstrating interface dermatitis, keratinocyte apoptosis within the epidermis, basal cell vacuolization, and variable subepidermal blister formation with sparse lymphocytic infiltration. |
| Laboratory Panel | Complete blood count (CBC) typically revealing normal or mildly elevated white blood cell count; elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) reflecting acute systemic inflammation. |
| Imaging / Radiology (X-ray, US, CT, MRI) | Chest radiography indicated in patients with prominent respiratory symptoms or suspected Mycoplasma pneumoniae infection to evaluate for atypical pneumonia, patchy interstitial infiltrates, or pulmonary consolidation. |
| ECG / Histopathology / Procedural | Serological testing and polymerase chain reaction (PCR) assays for Herpes simplex virus and Mycoplasma pneumoniae titers to identify the underlying precipitating trigger. |
5. Staging, Classification & Clinical Scoring Systems
| Criterion / Stage / Score Component | Clinical Threshold, Points & Management Implication |
|---|---|
| Erythema Multiforme Minor | Typical or atypical target lesions distributed symmetrically on acral extremities; mucosal involvement is completely absent or restricted to a single mucosal site (mild oral erosions). Managed largely with outpatient symptomatic care 2, 5. |
| Erythema Multiforme Majus | Typical or atypical target lesions with involvement of two or more mucosal sites (e.g., oral, ocular, and/or genital) with skin detachment involving less than 10% of the total body surface area. Often requires inpatient admission for pain control and supportive care 2, 4. |
6. Differential Diagnosis
| Differential Condition | Distinguishing Clinical, Biochemical & Imaging Features |
|---|---|
| Stevens-Johnson Syndrome (SJS) | Features widespread purpuric macules, atypical flat targets, and extensive full-thickness epidermal necrosis with skin detachment exceeding 10% body surface area; prominent mucosal involvement is universal, drug-induced etiology predominates. |
| Urticaria | Presents with intensely pruritic, erythematous wheals and edematous plaques that are transient, migratory, and individually resolve entirely within 24 hours (unlike fixed erythema multiforme lesions lasting >7 days) 3. |
| Bullous Pemphigoid | Characterized by tense subepidermal bullae arising on normal or urticarial skin in elderly patients; lacks true target lesions; direct immunofluorescence demonstrates linear IgG and C3 deposition along the basement membrane zone. |
| Fixed Drug Eruption | Presents as sharply demarcated, round or oval erythematous to violaceous plaques that recur in the exact same anatomical location upon re-exposure to the offending medication; lacks acral targetoid distribution. |
7. Management & Treatment Protocol
- Initial Stabilization & Resuscitation: Assess airway patency, hydration status, and nutritional intake, particularly in patients with severe oral mucositis who cannot tolerate oral fluids 2, 4. Provide intravenous fluid resuscitation and specialized oral care rinses (e.g., viscous lidocaine, diphenhydramine, and antacid mixtures) as needed 2.
- First-Line Medical / Pharmacological Therapy (with exact adult dosing):
- Identification and Treatment of Triggers: Discontinue any suspected causative medications immediately 3, 5. If herpes simplex virus is suspected or confirmed, initiate episodic antiviral therapy (e.g., acyclovir 400 mg orally five times daily or valacyclovir 1000 mg orally twice daily for 7 to 10 days) 7. For Mycoplasma pneumoniae infection, administer a macrolide or respiratory fluoroquinolone (e.g., azithromycin 500 mg orally on day 1, followed by 250 mg orally once daily on days 2 through 5) 2, 4.
- Symptomatic Cutaneous Therapy: Mild cutaneous lesions are managed with topical emollients and mid-to-high potency topical corticosteroids (e.g., triamcinolone acetonide 0.1% cream applied topically to affected areas twice daily) 5. Oral antihistamines (e.g., cetirizine 10 mg orally once daily) can be utilized for symptomatic relief of pruritus 5.
- Recurrent Erythema Multiforme Prophylaxis: For patients with frequent HSV-associated recurrences (≥5 episodes per year), initiate continuous suppressive antiviral therapy with acyclovir 400 mg orally twice daily or valacyclovir 500 mg to 1000 mg orally once daily for a trial period of 6 months 7. Refractory cases may require referral to a dermatologist for immunomodulatory agents such as dapsone, azathioprine, or mycophenolate mofetil 2, 7.
- Surgical / Interventional Indications: Dermatological or ophthalmological surgical intervention is rarely required unless severe ocular symblepharon formation mandates lysis of adhesions by an ophthalmologist 4. Hospitalization is indicated for patients with severe mucosal involvement, intractable pain, or inability to maintain oral hydration 2.
8. Complications & Prognosis
- Acute Complications: Severe oral and pharyngeal mucositis leading to dehydration, secondary bacterial superinfection of cutaneous and mucosal lesions, temporary post-inflammatory hypopigmentation or hyperpigmentation, and acute ocular involvement including conjunctival scarring, keratitis, and visual impairment 2, 4.
- Chronic & Recurrent Sequelae: Frequent recurrences can occur over several years, particularly in patients with latent herpes simplex virus infection who do not receive suppressive antiviral prophylaxis 3, 7.
- Prognosis: Erythema multiforme minor is a self-limiting condition that typically resolves spontaneously within 2 to 4 weeks without permanent scarring 6, 7. Erythema multiforme majus carries a higher morbidity related to mucosal pain and scarring, but the overall prognosis remains highly favorable with appropriate supportive care and recurrence prophylaxis 2, 4.
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