Erythema Multiforme: Symptoms, Types, Causes and Treatment

Erythema multiforme (EM) is a fascinating and sometimes perplexing condition that sits at the crossroads of dermatology, immunology, and infectious disease. Characterized by its sudden, often dramatic skin eruptions—and, in some cases, mucosal involvement—EM can range from a mild, self-limiting annoyance to a life-threatening syndrome. Understanding its symptoms, types, causes, and treatment is essential for patients, caregivers, and clinicians alike. In this comprehensive guide, we break down the key aspects of EM, drawing on the latest evidence and expert perspectives.

Symptoms of Erythema Multiforme

Recognizing the symptoms of erythema multiforme is the first step toward effective diagnosis and management. While EM is best known for its distinctive skin lesions, its manifestations can be surprisingly diverse, affecting both the skin and mucous membranes.

Symptom	Description	Frequency/Severity	Source(s)
Target Lesions	Concentric rings, “bull’s-eye”	Classic, highly characteristic	4 8 11 15
Skin Eruption	Erythematous, raised plaques	Common, often symmetrical	1 4 7 8 15
Mucosal Lesions	Sores, erosions in mouth, genitals	Variable, more in severe EM	1 3 7 8 11
Pruritus/Burning	Itching, discomfort	Mild to moderate	3 11 15
Systemic Symptoms	Fever, malaise, joint pain	Occasional, severe types only	2 7 8 15

Table 1: Key Symptoms

The Classic "Target" Lesion

At the heart of EM’s clinical picture is the “target” or “iris” lesion—a round patch with concentric rings of color change. These lesions are typically symmetrically distributed, especially on the backs of hands, feet, and extensor surfaces of the arms and legs. They may start as red spots, then evolve into plaques with central clearing and darker edges, giving the classic "bull’s-eye" appearance 4 8 11 15.

Skin and Mucous Membrane Involvement

• Skin Involvement: In most cases, EM presents as multiple, fixed (lasting at least 7 days) lesions. These are often raised, erythematous, and may blister in severe cases, but are usually not as extensive as those seen in Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) 1 7 15.
• Mucosal Involvement: About one-third of patients develop erosions or blisters on mucous membranes, such as the mouth, eyes, or genitals. This is more common in EM major and can cause pain, difficulty eating, or swelling 1 3 7 11.

Systemic and Other Symptoms

• Systemic Symptoms: Fever, malaise, and joint aches sometimes accompany more severe forms, especially those with extensive mucosal involvement or the "febrile type" described in older literature 2 7 8 15.
• Itching and Burning: These sensations are common but typically less intense than in other skin conditions like urticaria 3 11 15.

Symptom Progression and Duration

• Onset: EM usually develops abruptly over 1–3 days.
• Persistence: Individual lesions remain fixed for at least 7 days, in contrast to urticaria, where lesions usually resolve within 24 hours 15.
• Resolution: Most cases are self-limited, resolving within 2–4 weeks, but recurrences can occur, especially in HSV-associated EM 12 15.

Types of Erythema Multiforme

Not all EM cases are created equal. The condition spans a spectrum—from mild to life-threatening. Understanding the distinctions is crucial for tailoring management and anticipating complications.

Type	Defining Features	Mucosal Involvement	Source(s)
EM Minor	Target lesions, little/no mucosa	Absent or single site	1 4 7 8
EM Major	Extensive skin, ≥2 mucosal sites	Marked	1 4 7 8 11
SJS/TEN	Widespread necrosis, severe mucositis	Severe, systemic	1 7 8 15
Febrile EM	High fever, articular pain, GI symptoms	Variable	2
Recurrent EM	Multiple flares/year, often HSV-related	Often oral/genital	5 12 14

Table 2: Types of Erythema Multiforme

EM Minor: The Classic and Most Common Form

• Definition: Symmetrical target lesions on the extremities, with little to no mucosal involvement. Usually mild and self-limiting 1 4 7 8.
• Distribution: Typically on hands, feet, arms, legs; trunk less frequently involved.
• Course: Resolves in a few weeks; recurrences possible, especially if HSV-triggered 12 15.

EM Major: More Severe and Involving Mucosa

• Definition: Target lesions with marked mucosal involvement (two or more sites—mouth, eyes, genitals) 1 4 7 8 11.
• Symptoms: Painful mucosal erosions, severe oral involvement can impair nutrition and hydration.
• Complications: Rarely, systemic symptoms and organ involvement.

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

• Overlap with EM: SJS and TEN are considered by some as severe variants of EM, while others classify them as distinct 1 7 8 15.
• Features: Widespread skin necrosis, severe mucosal involvement, significant morbidity/mortality (up to 15%) 1 7.
• Triggers: More often drug-induced than classic EM.

Febrile Type of EM

• Description: Rare type featuring high fever, joint pains, and sometimes GI symptoms 2.
• Prognosis: Usually favorable, resolves with supportive care.

Recurrent and Atypical Forms

• Recurrent EM: Defined by multiple episodes per year, commonly triggered by HSV. Oral mucosa often involved 5 12 14.
• Atypical EM: Includes lichenoid, granulomatous, or infiltrative variants—rare, sometimes challenging to diagnose 14.

Causes of Erythema Multiforme

Understanding what triggers EM is key to effective prevention and treatment. While infections—especially herpes simplex virus—are the most common culprits, a wide range of other factors can also be responsible.

Cause Type	Example Triggers	Frequency/Importance	Source(s)
Infection	HSV, Mycoplasma pneumoniae	Most common	1 4 5 8 9 14 15
Medication	Sulfonamides, anticonvulsants, others	Frequent in severe EM/SJS	5 6 14 15
Vaccines	Various (rare)	Uncommon	14
Autoimmune	Systemic diseases, immunotherapy	Rare	14 15
Unknown	Idiopathic cases	Variable, especially in EM	4 12 14

Table 3: Common Causes of EM

Infectious Triggers

• Herpes Simplex Virus (HSV): The leading cause, especially in recurrent and EM minor cases. A classic pattern is EM flaring 7–10 days after an HSV outbreak 1 4 5 8 9 12 14.
  • Mechanism: Immune response to viral DNA or antigens in skin or mucosa 9 11 14.
• Mycoplasma pneumoniae: Especially in children and adolescents; more likely to cause EM major or severe mucosal disease 3 4 8 14.
• Other Infections: Coxsackie virus, hepatitis C, Epstein-Barr virus, and others have been implicated, though less commonly 14.

Medication-Induced EM

• Common Offenders: Sulfonamides, penicillins, anticonvulsants (phenytoin, phenobarbital, valproic acid), allopurinol, and more. These are more often associated with severe EM, SJS, or TEN 5 6 14 15.
• Mechanism: Drug-induced immune reactions, sometimes involving Fas-FasL mediated apoptosis 1 7.

Vaccines and Other Causes

• Vaccination: Rare reports link EM to various vaccines, though cases are unusual 14.
• Immunotherapy and Autoimmune Disease: Newer cancer treatments (e.g., checkpoint inhibitors) and autoimmune conditions can occasionally trigger EM 14 15.
• Idiopathic: In some cases, no clear cause is found 4 12 14.

Pathogenesis: The Immune Connection

• Immune Complexes: Deposition in skin vessels, activation of complement, and T cell-mediated cytotoxicity are central to tissue damage 10 11 14.
• Genetic and Environmental Factors: May influence susceptibility and recurrence, but are not fully understood 14.

Treatment of Erythema Multiforme

The management of EM varies widely depending on severity, underlying cause, and patient factors. While most cases resolve spontaneously, targeted treatments can hasten recovery and prevent complications.

Treatment Type	Purpose/Indication	Example Agents/Actions	Source(s)
Symptomatic	Relief of itching, pain, inflammation	Topical steroids, antihistamines	11 15
Antiviral	HSV-associated or recurrent EM	Acyclovir, valacyclovir	12 14 15
Systemic Therapy	Severe or unresponsive EM	Dapsone, azathioprine, JAK inhibitors	12 14
Hospitalization	Severe mucosal involvement, dehydration	IV fluids, supportive care	11 13 15
Drug Withdrawal	Suspected drug-induced EM/SJS/TEN	Stop offending agent	5 6 14 15

Table 4: Main Treatment Approaches

Supportive and Symptomatic Care

• Mild Cases: Most patients benefit from topical corticosteroids and oral antihistamines to reduce itching and inflammation 11 15.
• Oral/Mucosal Involvement: Pain control and maintenance of hydration are critical if the mouth or other mucosae are involved 11 15.

Treating Underlying Causes

• Antiviral Therapy: For HSV-associated EM, continuous or "on demand" acyclovir (or related drugs) can significantly reduce recurrences 12 14 15.
  • Resistance/Non-response: Switching to a different antiviral, or in rare cases, adding dapsone or immunosuppressants may help 12 14.
• Antibiotics: Only indicated if there is an active bacterial infection (e.g., Mycoplasma pneumoniae).

Systemic and Advanced Therapies

• Systemic Steroids: Historically used for severe cases (especially SJS), but recent evidence suggests they may not always speed recovery and could increase complications 13. Their use is now limited and controversial.
• Immunomodulators: Dapsone, azathioprine, and newer agents like JAK inhibitors or apremilast are considered for resistant or chronic EM 12 14.
• Hospitalization: Necessary for severe mucosal disease, poor oral intake, or systemic illness—focus is on IV fluids, wound care, and monitoring 11 13 15.

When to Seek Specialist Care

• Severe EM, SJS, or TEN: These are medical emergencies requiring multidisciplinary management, often in burn units or intensive care 1 7 8 15.
• Recurrent EM: Dermatology or infectious disease referral is advised for frequent or unresponsive cases 12 14 15.

Conclusion

Erythema multiforme is a complex, immune-mediated disorder notable for its distinct skin and, sometimes, mucosal lesions. While often self-limited, its potential for recurrence or progression to severe forms (like SJS/TEN) makes timely recognition and management critical.

Key Takeaways:

• Symptoms: Classic target lesions, sometimes accompanied by mucosal sores and systemic symptoms in severe cases.
• Types: EM minor and major are main forms; severe variants include SJS and TEN, with distinct clinical profiles.
• Causes: Most commonly triggered by infections (especially HSV), though medications and other factors can also play a role.
• Treatment: Ranges from supportive care and antivirals to immunomodulators and hospitalization in severe cases; drug withdrawal is essential in suspected medication-induced EM.

A patient-centered approach, careful assessment of cause and severity, and individualized treatment are essential to optimize outcomes in erythema multiforme.