Erythema Multiforme

• Antigen presentation and T-cell activation: Following exposure to an inciting agent (classically HSV), processed antigens are presented to CD8+ T lymphocytes via major histocompatibility complex (MHC) class I molecules on dendritic cells. This generates a robust CD8+ cytotoxic T-cell response that cross-reacts between viral antigens and keratinocyte surface antigens, particularly those altered by viral infection or drug haptenization. The T-cell receptor recognizes peptide-MHC complexes, leading to activation, clonal expansion, and trafficking of these T cells to skin and mucous membranes via upregulation of adhesion molecules (particularly E-selectin and ICAM-1) in postcapillary venules.

• Immune complex formation and complement activation: In addition to direct T-cell cytotoxicity, circulating immune complexes form from the interaction of pathogenic antigens with corresponding immunoglobulins (primarily IgM and IgG). These complexes deposit in dermal blood vessels and at the dermal-epidermal junction, activating the classical complement pathway. Complement activation generates C3a and C5a anaphylatoxins, which recruit and activate neutrophils and mast cells, perpetuating inflammation and contributing to the characteristic histopathologic findings of vasculitis and dermal infiltration.

• Keratinocyte apoptosis and epithelial destruction: The accumulated CD8+ T cells recognize infected or drug-haptenized keratinocytes and deliver cytotoxic signals through Fas-FasL interaction and perforin/granzyme B pathways, leading to programmed cell death. This selective targeting of the epidermis (particularly the basal layer) results in the characteristic vacuolar interface dermatitis and keratinocyte apoptosis seen on histology. The extent of keratinocyte apoptosis determines disease severity: EM features scattered individual cell death, whereas SJS and TEN show confluent epidermal necrosis affecting >30% of the body surface area.

• Molecular mimicry and HSV persistence: In the majority of recurrent EM cases associated with HSV, viral DNA can be detected in lesional and perilesional skin by polymerase chain reaction (PCR), even when viral culture is negative. This suggests that latent or episodic viral replication drives chronic immune stimulation. The HSV envelope glycoproteins (gG, gC) share epitopes with certain skin-associated antigens, permitting molecular mimicry—a mechanism by which T-cell recognition of viral peptides cross-reacts with structurally similar self-antigens on keratinocytes, perpetuating disease activity even after viral clearance.

• Genetic predisposition and HLA associations: Certain HLA alleles, particularly HLA-B35 and HLA-DR53, are overrepresented in patients with recurrent EM, suggesting genetic control of immune responsiveness to inciting antigens. Additionally, polymorphisms in genes encoding tumor necrosis factor (TNF)-α and other cytokines influence the magnitude and character of the inflammatory response, explaining variable disease severity among individuals exposed to identical triggers.

• Dysregulation of regulatory T cells (Tregs): Some evidence suggests that impaired Treg function or insufficient recruitment of Tregs to affected skin permits unopposed effector T-cell responses. Tregs normally suppress autoreactive T cells through production of IL-10 and TGF-β; their deficiency or dysfunction would allow persistent CD8+ T-cell activation and perpetuation of disease.

• Herpes simplex virus (HSV) infection: Both HSV-1 and HSV-2 can trigger EM, though HSV-1 is more commonly implicated. Post-herpetic EM typically develops 7–14 days after primary or recurrent HSV infection (oral, genital, or asymptomatic viral shedding) and may be accompanied by minimal or atypical herpetic lesions that the patient may not recognize. Recurrent EM is virtually pathognomonic for HSV-associated disease. Viral DNA has been demonstrated in skin lesions in up to 80% of cases using PCR, even when standard cultures are negative. Notably, systemic acyclovir therapy can prevent recurrent EM episodes in HSV-seropositive patients.

• Medications: Sulfonamides (particularly trimethoprim-sulfamethoxazole) and penicillins are classic drug triggers, accounting for 10–15% of EM cases. Sulfonamides are thought to act as haptens, forming immunogenic complexes with carrier proteins and triggering drug-specific T-cell responses. Other implicated drugs include NSAIDs, anticonvulsants (phenytoin, phenobarbital, carbamazepine), allopurinol, barbiturates, oral contraceptives, and more recently anti-TNF agents. The temporal relationship between drug initiation and EM onset (typically 1–3 weeks) provides diagnostic clues. Importantly, drug-induced EM often lacks recurrence upon re-exposure (unlike HSV-associated EM), but re-exposure should be avoided given the unpredictability of immune responses.

• Mycoplasma pneumoniae infection: This pathogen accounts for 5–15% of non-HSV EM cases, particularly in children and young adults. EM associated with Mycoplasma typically occurs during or shortly after respiratory infection and is characterized by a higher frequency of mucosal involvement and systemic symptoms compared with HSV-associated EM. The mechanism is thought to involve both direct antigenic stimulation and molecular mimicry, as Mycoplasma antigens share epitopes with certain skin and mucous membrane proteins.

• Other infections: Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B and C viruses, HIV, tuberculosis, fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis), and streptococcal infections have been associated with EM, though less frequently than HSV or Mycoplasma. The temporal relationship between infection and EM onset and serologic evidence support causation in these cases.

• Malignancy-associated EM: Paraneoplastic EM, though rare, has been documented in association with lymphoproliferative disorders (particularly lymphoma), lung cancer, and other malignancies. The mechanism likely involves tumor-associated antigens triggering cross-reactive immune responses against skin.

• Idiopathic EM: In approximately 25–50% of EM cases, particularly recurrent EM, no identifiable trigger is found despite comprehensive evaluation. This likely represents cases in which the inciting antigen (often asymptomatic or subclinical HSV reactivation) is not detected by standard clinical assessment or laboratory testing.

• Targetoid (iris) lesions: The pathognomonic finding in EM is the "true target" or "iris" lesion, which consists of three concentric zones: a central area of necrosis or vesiculation (red to purple or even black), surrounded by a pale or edematous intermediate zone, and an erythematous outer ring. These lesions typically measure 2–3 cm in diameter but can vary. The three-zone architecture reflects the gradient of immune cell infiltration and keratinocyte apoptosis from the dermal-epidermal junction outward. Lesions are monomorphous (uniform in appearance), unlike the polymorphous lesions of urticaria or other eruptions. They typically emerge in crops on the extremities (dorsal hands and feet), with involvement following a centripetal distribution pattern.

• Pruritus and pain: Lesions are often accompanied by mild pruritus or burning sensation but are notably nonpruritic or minimally pruritic compared with many other dermatologic conditions—this clinical pearl helps differentiate EM from drug rashes and urticaria. Mucosal lesions are typically painful, particularly when eating or drinking, and may be preceded by soreness or discomfort several days before visible erosions appear.

• Systemic symptoms in EM minor: Patients typically present with mild constitutional symptoms including low-grade fever (temperature usually <38.5°C), malaise, and arthralgia (particularly affecting hands, wrists, knees, and ankles). These symptoms precede or accompany the cutaneous eruption by days and typically resolve within weeks.

• Oral mucosal involvement: In EM major, oral involvement is near-universal, beginning with erythema and edema of the lips and mucous membranes, followed by painful hemorrhagic crusting and erosions particularly affecting the buccal mucosa, gingiva, tongue, and palate. Patients may report severe mouth pain, difficulty eating, dysphagia, and sialorrhea. The extent of oral involvement correlates with disease severity and systemic toxicity.

• Genital mucosal involvement: Painful erosions and ulcerations of the genitalia occur in 25–50% of EM major cases, with involvement of the glans in males and vulva/vagina in females. This can lead to dysuria, genital pain with ambulation, and psychological distress.

• Ocular involvement: Conjunctival involvement develops in up to 25% of EM major cases, presenting with conjunctival erythema, edema, petechiae, and pseudomembrane formation. Patients report ocular irritation, photophobia, and foreign body sensation. Severe cases can progress to symblepharon formation (adhesions between eyelid and conjunctiva) and corneal ulceration with potential vision-threatening sequelae if untreated.

• Respiratory involvement: Upper respiratory tract involvement (pharyngeal and laryngeal) is uncommon but can cause dyspnea, stridor, and respiratory compromise, particularly if laryngeal edema develops. This represents a medical emergency requiring airway management.

• Gastrointestinal involvement: Esophageal and gastric involvement is rare in EM but more common in SJS/TEN. When present, patients may experience dysphagia, epigastric pain, nausea, and vomiting. Severe GI involvement can lead to bleeding and perforation requiring surgical intervention.

• Physical examination findings: Beyond the characteristic targetoid lesions on extremities, examination may reveal facial edema, particularly involving the lips and perioral region. Lymphadenopathy (regional or generalized) is common. In EM major, extensive oral erosions with hemorrhagic crusting of lips is typical. The Nikolsky sign (epidermal separation with gentle lateral pressure) is negative or weakly positive in EM, distinguishing it from SJS/TEN, where it is strongly positive.

• Clinical variants and atypical presentations: Some patients present with atypical lesions (fewer or larger than classic targetoid lesions) or bullous EM (vesiculation and blister formation more prominent than typical). Rarely, purpuric or vesicular lesions predominate. EM sine eritema (minimal or absent mucosal involvement despite significant systemic symptoms) is an uncommon variant.

• Clinical history and triggering factors: A thorough temporal history is critical—documenting recent HSV infection (oral or genital), new medications (particularly antibiotics or NSAIDs), systemic infections, or recurrent cutaneous eruptions provides strong diagnostic support. A classic history of recurrent EM episodes separated by asymptomatic intervals of weeks to months, each preceded by oral herpetic lesions or unrecognized viral reactivation, is virtually diagnostic of HSV-associated EM. The interval between HSV infection and EM onset (typically 7–14 days) should be documented.

• Physical examination pearls: The presence of "true" three-zone target lesions on extremities (especially dorsal hands and feet) with monomorphous distribution in successive crops is the gold standard for diagnosis. The predominance of involvement on extensor surfaces and acral (distal) areas distinguishes EM from drug rashes, which often spare these areas. Critically, assess the extent of mucosal involvement (<10% of body surface area with EM minor; >10% with EM major) and the character of mucosal lesions (painful erosions with EM vs. confluent epidermal necrosis with SJS/TEN). The negative or weakly positive Nikolsky sign argues against SJS/TEN.

• Histopathology: While not required for diagnosis, skin biopsy can support clinical diagnosis when presentation is atypical or uncertain. Classic findings include: (1) lymphocytic infiltration of the dermis, particularly around vessels (vasculitis) and at the dermal-epidermal junction; (2) vacuolar interface dermatitis with basal layer keratinocyte death; (3) scattered individual keratinocyte apoptosis (not confluent); (4) intact stratum corneum (distinguishing from SJS/TEN); and (5) dermal edema. Direct immunofluorescence (DIF) is typically negative or shows nonspecific IgM/C3 deposition in vessel walls, which is not diagnostic but can exclude bullous pemphigoid or other autoimmune conditions.

• Herpes simplex virus detection: HSV serology (IgM and IgG antibodies) can document HSV exposure history, though seroconversion may have occurred before EM onset in recurrent cases. HSV PCR from lesional skin or blood has high sensitivity (70–90%) for detecting viral DNA in EM and is increasingly available; positive PCR strongly supports HSV-associated EM. Viral culture of vesicular lesions is less sensitive than PCR but can identify HSV if performed on fresh lesions. Direct fluorescent antibody (DFA) staining of lesions is less sensitive than culture or PCR.

• Laboratory tests—routine studies: Complete blood count (CBC) typically shows mild leukocytosis (WBC usually 7,000–12,000/μL) with lymphocytic predominance, reflecting the inflammatory response. Atypical lymphocytes may be present, particularly if EBV infection is the trigger. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are typically mildly elevated (ESR 20–40 mm/h) but are nonspecific.

• Mycoplasma pneumoniae and other serologies: When clinical presentation or epidemiologic context (e.g., respiratory symptoms, school-aged children) suggests Mycoplasma trigger, Mycoplasma serology (complement fixation, PCR, or IgM ELISA) should be obtained. Similarly, EBV serology (VCA-IgM, VCA-IgG,

Initial stabilisation (EM major)

• Airway and hydration assessment first: stridor, drooling, or hoarseness signals laryngeal involvement and warrants urgent airway evaluation. Extensive oral erosions cause poor intake — assess for dehydration and admit for IV fluids if the patient cannot swallow.
• Stop the suspected culprit drug immediately and never rechallenge. This is the single intervention that alters course in drug-associated disease.
• Urgent ophthalmology consultation for any ocular symptom, to prevent symblepharon and corneal scarring.

First-line therapy

• Supportive/symptomatic care is the mainstay, since EM is self-limited over roughly 2–4 weeks. No US society guideline addresses EM specifically; standard dermatologic practice and expert consensus favor medium-potency topical corticosteroids (e.g., triamcinolone) for cutaneous lesions, oral antihistamines (e.g., hydroxyzine) for burning/pruritus, and topical anesthetic/antiseptic mouth rinses (e.g., viscous lidocaine, dexamethasone rinse) plus a soft diet for oral disease.
• Treat the trigger: for *Mycoplasma*-associated disease, a macrolide (azithromycin) provides appropriate coverage for M. pneumoniae — an extrapolation from IDSA/ATS community-acquired pneumonia recommendations for that pathogen, since those recommendations address pneumonia rather than mucocutaneous disease and antibiotics have not been shown to alter the course of the eruption itself.
• Note that starting acyclovir after the eruption has already appeared does not shorten an established episode — the immune cascade is downstream of viral replication.

Escalation and definitive management

• Suppressive antiviral therapy is the definitive treatment for recurrent EM: acyclovir 400 mg PO twice daily (or valacyclovir once daily) continued for at least 6 months, dosing consistent with CDC STI Treatment Guidelines for HSV suppression. Give a trial even when HSV is not serologically confirmed, since subclinical reactivation is common.
• Antiviral-refractory recurrent EM: immunomodulators such as dapsone, hydroxychloroquine, azathioprine, or mycophenolate mofetil, ideally dermatology-directed.
• Systemic corticosteroids (prednisone) are sometimes used briefly for severe mucosal EM major, but evidence is weak and they may prolong disease and promote recurrence.

Emergencies

• Laryngeal/upper airway involvement: mucosal edema and erosion narrow the airway. Signalled by stridor, hoarseness, drooling, or dyspnea — secure the airway before it closes.
• Sight-threatening ocular disease: conjunctival pseudomembranes and inflammation lead to symblepharon, trichiasis, corneal ulceration, and permanent visual loss. Signalled by photophobia, pain, or visible pseudomembrane; requires same-day ophthalmology.
• Secondary bacterial infection and sepsis: eroded skin and mucosa lose barrier function, permitting Staphylococcus aureus and streptococcal invasion. Signalled by purulent crusting, expanding erythema, high fever, or hypotension.
• Progression/misclassification as SJS–TEN: worsening confluent dusky erythema, sheet-like detachment, and a strongly positive Nikolsky sign indicate a different, higher-mortality disease requiring burn-unit-level care.

Non-emergent disease complications

• Dehydration and malnutrition: painful oral erosions limit intake; signalled by tachycardia, decreased urine output, and rising BUN/creatinine ratio.
• Genitourinary strictures and adhesions: healing mucosal erosions scar, producing vaginal synechiae, urethral stricture, or phimosis; signalled by dysuria or obstructed voiding weeks later.
• Esophageal stricture from healing mucosal erosion — late dysphagia.
• Post-inflammatory hyperpigmentation: melanin incontinence from interface damage; cosmetically distressing but resolves. True scarring is uncommon in EM.
• Recurrence: the most common outcome in HSV-driven disease, with multiple episodes per year.

Treatment-related complications

• Systemic corticosteroids: hyperglycemia, masked infection, and adrenal suppression; rebound flare on taper.
• Dapsone: dose-dependent hemolysis (severe in G6PD deficiency), methemoglobinemia (saturation gap, chocolate-brown blood), and agranulocytosis — check G6PD before starting.
• Hydroxychloroquine: retinopathy with cumulative dosing; the American Academy of Ophthalmology recommends baseline and periodic screening.
• Azathioprine: myelosuppression, exaggerated in TPMT/NUDT15-deficient patients.
• Oral acyclovir/valacyclovir: generally well tolerated, but clearance is renal — reduce the dose in chronic kidney disease and maintain adequate hydration, since inadequate hydration with high systemic exposure predisposes to crystalline nephropathy and a rising creatinine.

• **The true target (iris) lesion is the buzzword**: three concentric zones, acral and extensor predominant, monomorphous, appearing in crops. Two-zone "atypical targets" on the trunk point toward SJS instead.
• Recurrent EM = HSV until proven otherwise. This is the single association examiners test. Recurrence is rarely drug-related and should prompt evaluation for HSV, though repeated exposure to a culprit drug can reproduce the eruption — which is why rechallenge is avoided.
• Best next step in recurrent EM: start suppressive oral antiviral therapy (acyclovir 400 mg PO twice daily or valacyclovir daily, per CDC HSV suppression dosing) — even without positive HSV serology, since subclinical reactivation drives most cases.
• Acyclovir started after the rash appears does not abort the episode. The pathology is a CD8+ T-cell response downstream of viral replication; antivirals are prophylactic, not abortive. A stem offering "acyclovir now" for an established eruption is the trap.
• EM is not on the SJS/TEN spectrum. EM is HSV-driven, Nikolsky-negative, and low-mortality; SJS/TEN is drug-driven, Nikolsky-positive, with confluent full-thickness epidermal necrosis. Do not classify EM by percent body surface detachment.
• A child with cough, a mycoplasma-consistent illness, and severe mucositis with sparse skin lesions: think *Mycoplasma*-induced rash and mucositis. Get a chest radiograph and M. pneumoniae testing, and treat the infection with a macrolide.
• Urticaria multiforme is the classic distractor, especially in toddlers: annular urticarial plaques are intensely pruritic, migratory, and resolve individually within 24 hours, whereas EM lesions are fixed for days and only mildly pruritic. Dermatographism and acral edema favor urticaria.
• Systemic steroids are not the answer for prophylaxis. They neither reliably shorten EM nor prevent recurrence, and may prolong it — antiviral suppression is the definitive strategy.