Clinical Presentation, Diagnostics, and Classification of Erythema Multiforme
Objective
Apply diagnostic and classification criteria to assess a patient with erythema multiforme (EM) and guide risk stratification and escalation of care.
1. Clinical Manifestations
Early recognition of concentric target lesions, mucosal involvement, and systemic signs is essential for timely classification and management. The clinical picture helps differentiate Erythema Multiforme (EM) from more severe mucocutaneous reactions.
Target Lesions
- Classic Appearance: Lesions feature three distinct concentric zones: a central dusky or necrotic area, a surrounding pale and edematous ring, and an outer erythematous halo.
- Distribution: Typically shows a symmetric acral distribution, appearing on the dorsal hands and feet, with potential to extend proximally to the arms, legs, and trunk.
- Evolution: Individual lesions evolve over 24–48 hours, but new crops of lesions can continue to appear for up to two weeks.
Mucosal Involvement
- EM minor: Mucosal involvement is absent or limited to mild oral erosions.
- EM major: One or more mucosal sites are affected, which can include:
- Oral: Painful erosions and hemorrhagic crusting on the buccal mucosa, lips, and tongue.
- Ocular: Conjunctival hyperemia, which can progress to pseudomembrane formation or corneal ulceration if severe.
- Genital: Erosions can cause significant pain, dysuria, and create a risk for secondary infection or long-term strictures.
Systemic Symptoms
- A prodrome of low-grade fever (≤38.5 °C), malaise, and arthralgias may precede the rash by 1–3 days, especially in infection-triggered cases.
- Severe systemic toxicity, such as hypotension or significant organ dysfunction, is uncommon in classic EM and should raise suspicion for an alternative diagnosis like Stevens–Johnson syndrome (SJS).
Case Vignette: A 25-year-old presents with pruritic, well-defined targetoid lesions on the hands and feet, accompanied by a mild fever. There are no oral or ocular erosions. These findings are highly consistent with EM minor and make a diagnosis of Stevens–Johnson syndrome unlikely.
2. Diagnostic Workup
The diagnostic process aims to confirm EM, identify potential triggers, and confidently exclude critical mimickers like SJS/TEN.
A. Laboratory Tests
- Complete Blood Count (CBC): To evaluate for leukocytosis or lymphopenia, which can be associated with underlying infections.
- Basic Metabolic Panel: To assess baseline renal and hepatic function, which is crucial for drug dosing and monitoring for systemic effects.
- Inflammatory Markers (CRP, ESR): Can be elevated and may be useful for monitoring the disease course, though they are non-specific.
- Infectious Workup:
- HSV PCR: A swab from a fresh lesion for Herpes Simplex Virus (HSV-1/HSV-2) PCR has a high yield (>70%) in recurrent EM and can confirm the most common trigger.
- Mycoplasma pneumoniae Serology/PCR: Should be considered in febrile patients, especially children, presenting with respiratory symptoms alongside the rash.
B. Skin Biopsy and Direct Immunofluorescence (DIF)
- Histopathology: Reveals a characteristic vacuolar interface dermatitis with apoptotic keratinocytes and basal vacuolization. A mild, superficial perivascular lymphocytic infiltrate is typical. Importantly, full-thickness epidermal necrosis is minimal or absent.
- Direct Immunofluorescence (DIF): Often shows granular deposits of IgM, IgG, and C3 along the dermoepidermal junction. This test is also crucial for ruling out autoimmune blistering diseases like bullous pemphigoid, which would show linear IgG deposits.
Clinical Pearl: Biopsy Technique
For optimal diagnostic yield, perform a 4 mm punch biopsy from the erythematous, edematous margin of an active, early target lesion. Avoid the necrotic center, as inflammatory changes may be obscured by necrosis, leading to a non-specific result.
C. Differential Diagnosis
- Fixed Drug Eruption: Presents as one or more solitary, well-demarcated dusky plaques that recur in the same location upon re-exposure to a drug. Leaves behind post-inflammatory hyperpigmentation.
- SJS/TEN: Characterized by widespread, poorly defined, coalescing macules that progress to flaccid bullae and extensive epidermal detachment. Systemic toxicity and involvement of at least two mucosal sites are hallmarks. Histology shows full-thickness epidermal necrosis, distinguishing it from the interface pattern of EM.
3. Classification and Severity Stratification
Proper classification based on mucosal involvement and body surface area (BSA) of detachment is critical. It distinguishes EM from the SJS/TEN spectrum, which has vastly different implications for management and prognosis.
| Classification | Mucosal Involvement | Epidermal Detachment (% BSA) |
|---|---|---|
| Erythema Multiforme Minor | None or one site (mild) | <10% |
| Erythema Multiforme Major | One or more sites | <10% |
| Stevens-Johnson Syndrome (SJS) | Two or more sites | <10% |
| SJS/TEN Overlap | Widespread | 10–30% |
| Toxic Epidermal Necrolysis (TEN) | Widespread | >30% |
SCORTEN Severity Score (for SJS/TEN)
SCORTEN is a validated tool to predict mortality in SJS/TEN. One point is assigned for each of the following seven criteria at admission:
- Age >40 years
- Presence of an associated malignancy
- Heart rate >120 bpm
- Initial epidermal detachment >10% of BSA
- Serum urea >10 mmol/L (>28 mg/dL)
- Serum glucose >14 mmol/L (>252 mg/dL)
- Serum bicarbonate <20 mmol/L
Controversy: Applying SCORTEN to EM Major
There is no universally accepted, EM-specific severity score. While SCORTEN was validated specifically for SJS/TEN, its components (e.g., tachycardia, metabolic derangements) can serve as useful “red flags” to identify patients with severe EM major who may be at higher risk for complications or require a higher level of care. However, its use in EM major for prognostication remains unvalidated and should be approached with caution.
4. Clinical Decision Points and Management
Classification directly informs the required level of care, necessary consultations, and therapeutic interventions.
A. ICU Admission Triggers
- Hemodynamic Instability: Persistent hypotension or tachycardia unresponsive to initial fluid resuscitation.
- Extensive Mucosal Involvement: Severe oral erosions compromising nutritional intake or laryngeal/tracheal involvement threatening the airway.
- Organ Dysfunction: Evidence of acute kidney injury, liver dysfunction, or respiratory compromise.
- High-Risk Score: While not validated for EM, a SCORTEN score of ≥2 in a patient on the SJS/TEN spectrum indicates a need for ICU-level care. A similar threshold may be considered for patients with EM major who have significant comorbidities.
B. Early Consultation
- Dermatology: Essential for confirming the diagnosis, guiding biopsy timing and technique, and directing overall management.
- Ophthalmology: Crucial for any patient with ocular involvement to perform a thorough exam and prevent long-term sequelae like symblepharon (adhesions), dry eye syndrome, or vision loss.
- Gynecology/Urology: Recommended for managing significant genital lesions to provide local care, manage pain, and prevent adhesions or strictures.
C. Therapeutic Details
Antiviral Therapy (for HSV-associated EM)
Mechanism: Acyclovir is a guanosine analog that, once phosphorylated, inhibits viral DNA polymerase, halting HSV replication.
| Parameter | Details |
|---|---|
| Indication | Confirmed or highly suspected HSV-triggered recurrent EM. |
| Acute Dosing | Oral acyclovir 400 mg five times daily for 5–7 days. For severe cases or inability to tolerate PO, IV acyclovir 5 mg/kg every 8 hours. |
| Monitoring | Monitor renal function (BUN, creatinine), especially with IV therapy. Dose must be adjusted for CrCl ≤50 mL/min. |
| Pearls | Initiate at the very first sign of a recurrent rash to maximize efficacy. Continuous daily prophylaxis is effective for preventing frequent recurrences. |
| Pitfalls | Ineffective for EM triggered by other causes (e.g., Mycoplasma, drugs). Delaying treatment diminishes its benefit. |
Systemic Corticosteroids
Mechanism: Exert broad anti-inflammatory and immunosuppressive effects by inhibiting cytokine production and immune cell function.
| Parameter | Details |
|---|---|
| Indication | EM major with significant, debilitating mucosal involvement or severe systemic symptoms. Use in EM minor is not recommended. |
| Dosing | Prednisone 0.5–1 mg/kg/day PO. For severe cases, consider IV methylprednisolone 1 mg/kg/day. Taper slowly over 2–4 weeks. |
| Monitoring | Blood glucose, blood pressure, signs of infection. Consider GI prophylaxis in high-risk patients. |
| Pearls | May shorten the duration of fever and eruption if started early. A slow taper is crucial to prevent rebound flares. |
| Pitfalls | Use is controversial due to limited high-quality evidence. May increase the risk of secondary infection or mask sepsis. |
Other Immunomodulators
For severe, refractory cases of EM major, other therapies like intravenous immunoglobulin (IVIG), cyclosporine, or other immunosuppressants may be considered. However, their use is off-label and based on case series or extrapolation from SJS/TEN data. Management of such cases should be directed by a dermatology specialist.
References
- Bastuji-Garin S, Rzany B, Stern RS, et al. Classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129(1):92-96.
- Grünwald P, Mockenhaupt M, Fux R, et al. Erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis – diagnosis and treatment. J Dtsch Dermatol Ges. 2020;18(5):547-553.
- Assier H, Bastuji-Garin S, Revuz J, Roujeau JC. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders. Arch Dermatol. 1995;131(5):539-543.
- Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994;331(19):1272-1285.
- Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002;138(8):1019-1024.
- Harr T, French LE. S3 Guideline: Diagnosis and treatment of epidermal necrolysis (Stevens-Johnson syndrome/SJS, toxic epidermal necrolysis/TEN). J Dtsch Dermatol Ges. 2011;9 Suppl 1:S1-S7.
