Erythema Multiforme

Overview

Erythema multiforme (EM) is an acute, self-limited, inflammatory skin condition that presents as a spectrum of mucocutaneous reactions. The hallmark feature is the development of characteristic target-like lesions, which appear as concentric rings with a dark center, pale middle ring, and erythematous outer border. This distinctive appearance, resembling a "bull's-eye" or target, gives the condition its name—"multiforme" referring to the varied appearance of the lesions.

The condition is classified into two main forms: erythema multiforme minor (EM minor) and erythema multiforme major (EM major). EM minor typically involves only the skin with minimal or no mucous membrane involvement, while EM major includes significant mucous membrane involvement, particularly affecting the oral cavity, eyes, and genital areas. The distinction between these forms is crucial for determining appropriate treatment approaches and predicting clinical outcomes.

Erythema multiforme represents a hypersensitivity reaction mediated by immune complexes and T-cell responses. The condition most commonly affects young adults between 20-40 years of age, though it can occur at any age. While the acute phase typically resolves within 2-4 weeks, recurrent episodes may occur, particularly in cases triggered by herpes simplex virus infections. Understanding the various triggers, clinical presentations, and management strategies is essential for optimal patient outcomes and prevention of complications.

The prognosis for erythema multiforme is generally favorable, especially for the minor form. However, severe cases with extensive mucous membrane involvement can lead to significant morbidity, including scarring, vision problems, and difficulty eating or swallowing. Early recognition and appropriate treatment can minimize complications and reduce the duration of symptoms, making prompt medical evaluation important for suspected cases.

Symptoms

Erythema multiforme presents with a characteristic pattern of symptoms that can range from mild skin involvement to severe systemic manifestations. The clinical presentation varies depending on the form and severity of the condition.

Primary Skin Manifestations

• Skin rash - Distinctive target-like lesions with concentric rings
• Target lesions - Classic "bull's-eye" appearance with three zones of color
• Raised papules and plaques - Often symmetrically distributed
• Vesicles and bullae - May develop within target lesions
• Erythematous macules - Flat, red spots that may progress to target lesions

Mucous Membrane Involvement

• Mouth ulcer - Painful erosions and ulcerations in oral cavity
• Difficulty in swallowing - Due to oral and throat involvement
• Lip swelling and crusting - Hemorrhagic crusts on lips
• Conjunctival irritation - Eye redness and discharge
• Genital ulcerations - Painful lesions on genital mucosa

Systemic Symptoms

• Fever - Often present in more severe cases
• Vomiting - May occur with systemic involvement
• Malaise and fatigue - General feeling of illness
• Arthralgia - Joint pain and stiffness
• Headache - Associated with systemic inflammation

Distribution Patterns

The lesions of erythema multiforme typically follow specific distribution patterns:

• Acral distribution: Predominantly affects hands, feet, wrists, and ankles
• Symmetrical pattern: Lesions appear symmetrically on both sides of the body
• Extensor surfaces: Preference for extensor aspects of extremities
• Face and neck: May be involved in more extensive cases
• Palms and soles: Can be affected, especially in severe forms

Lesion Evolution

The characteristic target lesions evolve through several stages:

• Initial stage: Red macules appear, often with central darkening
• Development: Lesions expand centrifugally, developing concentric rings
• Mature lesions: Classic three-zone appearance with dark center, pale middle, and red outer ring
• Resolution: Lesions fade over 7-14 days, may leave hyperpigmentation

Severity Classifications

Erythema Multiforme Minor

• Typical target lesions on acral sites
• Minimal or no mucous membrane involvement
• Usually asymptomatic or mild symptoms
• Self-limited course

Erythema Multiforme Major

• Extensive skin involvement with atypical targets
• Significant mucous membrane involvement (>2 sites)
• Systemic symptoms including fever
• Potential for complications

Causes

Erythema multiforme results from an immune-mediated hypersensitivity reaction triggered by various infectious agents, medications, and other factors. Understanding these triggers is crucial for both treatment and prevention strategies.

Infectious Triggers

Viral Infections

• Herpes simplex virus (HSV):
  • Most common trigger, accounting for up to 90% of recurrent cases
  • Both HSV-1 and HSV-2 can trigger EM
  • EM typically occurs 1-3 weeks after HSV outbreak
  • Recurrent HSV infections lead to recurrent EM episodes
• Epstein-Barr virus (EBV): Associated with infectious mononucleosis
• Cytomegalovirus (CMV): Less common viral trigger
• Hepatitis B virus: Can precipitate EM episodes
• Adenovirus: Respiratory infections may trigger EM
• Influenza virus: Seasonal flu can occasionally cause EM

Bacterial Infections

• Mycoplasma pneumoniae:
  • Common trigger in children and young adults
  • Often associated with respiratory symptoms
  • May cause more severe forms of EM
• Streptococcus species: Group A streptococcal infections
• Staphylococcus aureus: Skin and soft tissue infections
• Salmonella species: Gastrointestinal infections

Other Infectious Agents

• Histoplasmosis: Fungal infection
• Coccidioidomycosis: Valley fever
• Parapoxvirus: Orf virus from sheep and goats

Medication-Induced Erythema Multiforme

Drug-induced EM typically occurs 1-3 weeks after medication initiation:

• Antibiotics:
  • Sulfonamides (most common drug trigger)
  • Penicillins and derivatives
  • Tetracyclines
  • Macrolides
• Antiepileptic drugs:
  • Phenytoin
  • Carbamazepine
  • Phenobarbital
  • Lamotrigine
• NSAIDs: Non-steroidal anti-inflammatory drugs
• Allopurinol: Gout medication
• Vaccines: Rarely, various vaccines can trigger EM

Other Triggers

• Malignancy: Underlying cancers, particularly lymphomas
• Autoimmune diseases: Systemic lupus erythematosus, inflammatory bowel disease
• Physical factors: UV radiation, cold exposure
• Food allergens: Rarely implicated
• Pregnancy: Hormonal changes may trigger episodes

Pathophysiology

The development of erythema multiforme involves complex immunological mechanisms:

• Type III hypersensitivity: Immune complex-mediated reaction
• T-cell activation: CD8+ T-cells target keratinocytes
• Cytokine release: Inflammatory mediators cause tissue damage
• Molecular mimicry: Cross-reactivity between antigens and self-tissues
• Genetic predisposition: HLA associations suggest genetic factors

Idiopathic Cases

In approximately 50% of cases, no specific trigger can be identified. These idiopathic cases may represent:

• Subclinical infections not detected by routine testing
• Genetic predisposition to hypersensitivity reactions
• Environmental factors not yet fully understood
• Multiple minor triggers acting synergistically

Risk Factors

Several factors can increase an individual's likelihood of developing erythema multiforme or experiencing more severe forms of the condition.

Demographic Factors

• Age:
  • Most common in young adults (20-40 years)
  • Children can be affected, especially with Mycoplasma infections
  • Elderly patients may have more severe presentations
• Gender:
  • Slight male predominance overall
  • HSV-associated EM more common in males
  • Drug-induced EM shows equal gender distribution

Medical History

• Previous episodes: History of EM increases recurrence risk
• Recurrent HSV infections: Strong predictor of recurrent EM
• Immunocompromised status:
  • HIV/AIDS
  • Organ transplant recipients
  • Cancer patients undergoing chemotherapy
  • Chronic corticosteroid use
• Autoimmune disorders:
  • Systemic lupus erythematosus
  • Inflammatory bowel disease
  • Multiple sclerosis

Genetic Factors

• HLA associations:
  • HLA-DQB1*0301: Associated with HSV-induced EM
  • HLA-B*1502: Risk factor for drug-induced reactions
  • Family history of EM or similar reactions
• Pharmacogenetic factors: Variations in drug metabolism genes

Environmental and Lifestyle Factors

• Infection exposure:
  • Healthcare workers (increased infection risk)
  • Daycare workers and teachers
  • Travelers to endemic areas
• Medication use:
  • Multiple concurrent medications
  • History of drug allergies
  • Recent medication changes
• UV exposure: Excessive sun exposure may trigger episodes
• Stress: Physical or emotional stress may precipitate attacks

Concurrent Medical Conditions

• Atopic dermatitis: May increase susceptibility
• Allergic rhinitis: Suggests hyperreactive immune system
• Asthma: Associated with increased allergy risk
• Chronic kidney disease: Affects drug metabolism
• Liver disease: Impairs drug clearance

Seasonal and Geographic Factors

• Spring and fall: Higher incidence of respiratory infections
• Endemic regions: Areas with specific infectious diseases
• Climate changes: Temperature and humidity variations

Diagnosis

The diagnosis of erythema multiforme is primarily clinical, based on the characteristic appearance of target lesions and clinical history. However, differentiation from other vesiculobullous disorders requires careful evaluation and sometimes additional testing.

Clinical Evaluation

History Taking

• Symptom onset and progression: Rapid development over days
• Trigger identification:
  • Recent infections (particularly HSV, Mycoplasma)
  • New medications within 1-3 weeks
  • Recent vaccinations
  • Sun exposure or physical trauma
• Previous episodes: History of recurrent lesions
• Associated symptoms: Fever, malaise, joint pain
• Family history: Similar reactions in relatives

Physical Examination

• Skin assessment:
  • Distribution pattern (acral, symmetrical)
  • Lesion morphology (target-like appearance)
  • Presence of three-zone configuration
  • Percentage of body surface area involved
• Mucous membrane examination:
  • Oral cavity (lips, buccal mucosa, tongue)
  • Ocular involvement (conjunctiva, cornea)
  • Genital examination when indicated
  • Respiratory tract assessment
• Systemic evaluation: Vital signs, lymph nodes, organ involvement

Diagnostic Criteria

Major Criteria

• Typical target lesions with three zones
• Acral distribution
• Symmetrical pattern

Minor Criteria

• Atypical target lesions (two zones only)
• Mucous membrane involvement
• Histopathological features consistent with EM

Laboratory Tests

While EM is primarily a clinical diagnosis, certain tests may be helpful:

• Trigger identification:
  • HSV PCR from recent lesions
  • Mycoplasma serology and PCR
  • Complete blood count with differential
  • Liver function tests if drug-induced suspected
• Inflammatory markers: ESR, CRP for systemic involvement
• Autoimmune screening: ANA, if autoimmune disease suspected

Histopathological Features

Skin biopsy may be performed when diagnosis is uncertain:

• Interface dermatitis: Basal cell layer damage
• Keratinocyte necrosis: Individual cell death
• Lymphocytic infiltrate: Predominantly around dermal-epidermal junction
• Subepidermal clefting: May progress to bullae
• Direct immunofluorescence: Usually negative

Differential Diagnosis

Several conditions can mimic erythema multiforme:

• Stevens-Johnson syndrome/TEN:
  • More extensive mucosal involvement
  • Atypical targets or flat lesions
  • Positive Nikolsky sign
  • Usually drug-induced
• Bullous pemphigoid: Different age group, chronic course
• Urticaria: Transient lesions, different morphology
• Fixed drug eruption: Fixed location, hyperpigmentation
• Viral exanthem: Usually lacks target morphology
• Contact dermatitis: Distribution follows contact pattern

Severity Assessment

Determining disease severity guides treatment decisions:

• Mild (EM minor):
  • Typical targets on acral sites
  • No or minimal mucosal involvement
  • Good general condition
• Severe (EM major):
  • Extensive skin involvement
  • Significant mucosal involvement (≥2 sites)
  • Systemic symptoms present
  • Risk of complications

Treatment Options

Treatment of erythema multiforme focuses on supportive care, managing symptoms, identifying and eliminating triggers, and preventing complications. The approach varies based on disease severity and underlying causes.

General Management Principles

• Supportive care: Primary focus for most cases
• Trigger elimination: Discontinue causative medications
• Symptom relief: Pain and itch management
• Complication prevention: Particularly for mucosal involvement
• Monitoring: Watch for disease progression

Mild Cases (EM Minor)

Topical Treatments

• Topical corticosteroids:
  • Medium-potency steroids for skin lesions
  • Triamcinolone acetonide 0.1% cream
  • Apply twice daily for 1-2 weeks
  • Avoid on face and intertriginous areas
• Calamine lotion: For itch relief and drying
• Cool compresses: Provide symptomatic relief
• Emollients: Maintain skin barrier function

Oral Medications

• Antihistamines:
  • Cetirizine 10mg daily or loratadine 10mg daily
  • Diphenhydramine for nighttime sedation
  • Helps with itching and discomfort
• Analgesics:
  • Acetaminophen for pain relief
  • Avoid NSAIDs if they were potential triggers

Severe Cases (EM Major)

Systemic Corticosteroids

• Indications:
  • Extensive skin involvement
  • Significant mucosal involvement
  • Systemic symptoms
• Dosing:
  • Prednisone 1-2 mg/kg/day (max 80mg)
  • Continue for 1-2 weeks, then taper
  • Monitor for side effects

Hospitalization Criteria

• Inability to maintain oral intake
• Severe mucosal involvement
• Signs of dehydration or electrolyte imbalance
• Suspected secondary infection
• Difficulty distinguishing from SJS/TEN

Mucosal Care

Oral Care

• Topical anesthetics:
  • Lidocaine 2% gel or solution
  • Benzocaine lozenges
  • Apply before meals
• Oral hygiene:
  • Gentle brushing with soft toothbrush
  • Chlorhexidine mouthwash
  • Avoid alcohol-based products
• Nutritional support:
  • Soft, non-irritating diet
  • Avoid spicy, acidic, or hot foods
  • Nutritional supplements if needed

Ocular Care

• Ophthalmology consultation: For any eye involvement
• Artificial tears: Preservative-free formulations
• Topical antibiotics: If secondary infection suspected
• Cycloplegic agents: For painful ciliary spasm

Trigger-Specific Treatment

HSV-Associated EM

• Antiviral therapy:
  • Acyclovir 400mg twice daily
  • Valacyclovir 500mg twice daily
  • For prophylaxis in recurrent cases
• Duration: Long-term suppressive therapy may be needed

Mycoplasma-Associated EM

• Antibiotics:
  • Azithromycin 500mg daily for 5 days
  • Doxycycline 100mg twice daily for 10 days
  • Levofloxacin for severe cases

Recurrent EM Management

• Trigger avoidance: Identify and eliminate known triggers
• Prophylactic antiviral therapy: For HSV-associated recurrent EM
• Immunosuppressive therapy:
  • Azathioprine for frequent recurrences
  • Mycophenolate mofetil as alternative
  • Requires monitoring and specialist care

Experimental and Alternative Treatments

• Thalidomide: For refractory cases (requires special monitoring)
• Dapsone: Anti-inflammatory effects
• Levamisole: Immunomodulatory therapy
• Plasmapheresis: For severe, treatment-resistant cases

Prevention

Prevention of erythema multiforme focuses on identifying and avoiding known triggers, managing underlying conditions, and implementing strategies to reduce recurrence risk.

Trigger Identification and Avoidance

Medication-Related Prevention

• Drug allergy documentation:
  • Maintain detailed records of triggering medications
  • Wear medical alert bracelet or carry allergy card
  • Inform all healthcare providers about drug reactions
  • Check for cross-reactive medications
• Medication review:
  • Regular review with healthcare provider
  • Consider alternative medications when possible
  • Gradual introduction of new medications
  • Monitor closely when starting new drugs

Infection Prevention

• HSV prevention:
  • Prophylactic antiviral therapy for recurrent HSV
  • Stress management to reduce HSV reactivation
  • Adequate sleep and nutrition
  • UV protection to prevent HSV reactivation
• General infection prevention:
  • Good hand hygiene practices
  • Avoid close contact with ill individuals
  • Stay current with recommended vaccinations
  • Prompt treatment of respiratory infections

Lifestyle Modifications

• Sun protection:
  • Daily broad-spectrum SPF 30+ sunscreen
  • Protective clothing and hats
  • Avoid peak sun hours (10 AM - 4 PM)
  • Seek shade when outdoors
• Stress management:
  • Regular exercise and physical activity
  • Adequate sleep (7-9 hours nightly)
  • Stress reduction techniques (meditation, yoga)
  • Professional counseling if needed
• Immune system support:
  • Balanced, nutritious diet
  • Adequate hydration
  • Avoid smoking and excessive alcohol
  • Regular medical check-ups

Recurrence Prevention

• Long-term antiviral therapy:
  • For HSV-associated recurrent EM
  • Acyclovir 400mg twice daily
  • Valacyclovir 500mg daily
  • Duration based on recurrence frequency
• Immunomodulatory therapy:
  • For frequent recurrences not related to HSV
  • Azathioprine or mycophenolate mofetil
  • Requires specialist supervision
  • Regular monitoring for side effects

Patient Education

• Recognition of early symptoms:
  • Identify prodromal symptoms
  • Monitor for target lesion development
  • Know when to seek medical attention
• Emergency preparedness:
  • Have emergency action plan
  • Know warning signs of severe disease
  • Maintain list of emergency contacts

When to See a Doctor

While mild cases of erythema multiforme may be managed with supportive care, many situations require prompt medical evaluation to ensure proper diagnosis and treatment.

Immediate Medical Attention Required

• Difficulty breathing or swallowing
• Extensive skin involvement (>10% body surface area)
• High fever (>38.5°C/101.3°F)
• Signs of dehydration or inability to maintain oral intake
• Severe eye involvement with vision changes
• Signs of secondary bacterial infection
• Rapid progression of lesions
• Severe systemic symptoms

Seek Medical Care Within 24 Hours

• Development of characteristic target lesions
• Mouth ulcer that interferes with eating or drinking
• Difficulty in swallowing that persists
• Fever associated with skin rash
• Eye redness, pain, or discharge
• Genital lesions or pain
• New medication recently started with skin reaction

Schedule Routine Appointment

• Recurrent episodes of similar rashes
• Persistent skin lesions without clear cause
• Need for trigger identification
• Family history of similar reactions
• Questions about prevention strategies

Follow-up Care

• During acute episode:
  • Monitor for complications
  • Assess treatment response
  • Adjust therapy as needed
• After resolution:
  • Review triggers and prevention strategies
  • Discuss long-term management plans
  • Monitor for post-inflammatory changes
• For recurrent cases:
  • Regular dermatology follow-up
  • Consider prophylactic therapy
  • Monitor for underlying conditions

Emergency Warning Signs

Call emergency services immediately if experiencing:

• Severe difficulty breathing
• Signs of anaphylaxis (swelling of face, lips, tongue)
• Rapid progression to widespread blistering
• Signs of sepsis (high fever, rapid heart rate, confusion)
• Severe dehydration with altered mental status

Specialist Referrals

• Dermatologist:
  • Uncertain diagnosis
  • Severe or recurrent disease
  • Need for specialized treatments
• Ophthalmologist:
  • Any eye involvement
  • Vision changes
  • Persistent eye symptoms
• Immunologist/Allergist:
  • Suspected drug allergy
  • Multiple drug reactions
  • Need for allergy testing

Related Conditions

Several conditions share clinical features with erythema multiforme or may occur in association with it:

• Stevens-Johnson Syndrome - More severe mucocutaneous reaction
• Toxic Epidermal Necrolysis - Severe form of SJS with extensive skin involvement
• Herpes Simplex Virus Infection - Common trigger for recurrent EM
• Mycoplasma Pneumonia - Bacterial infection that can trigger EM
• Bullous Pemphigoid - Autoimmune blistering disease
• Pemphigus Vulgaris - Another autoimmune blistering condition
• Urticaria - May present with target-like lesions
• Fixed Drug Eruption - Localized drug reaction
• Viral Exanthem - Skin rashes caused by viral infections
• Contact Dermatitis - Allergic or irritant skin reaction