Erythema Multiforme

Erythema multiforme minor — erythema multiforme von Hebra.

• Self-limited but potentially recurrent disease.
• Abrupt onset of papular "target" lesions; vast majority appear within 24 hours.
• Two target lesion types: (1) typical — ≥3 zones; (2) atypical papular — only 2 zones and/or poorly defined border.
• Target lesions favor acrofacial sites.
• EM minor: typical/occasionally atypical papular targets, little/no mucosal involvement, no systemic symptoms.
• EM major: typical/occasionally atypical papular targets, SEVERE mucosal involvement + systemic features.
• HSV = most common precipitating factor.
• Diagnosis requires CLINICOPATHOLOGIC correlation, NOT histology alone.
• EM does NOT carry risk of progressing to TEN.

• 1860: Ferdinand von Hebra first described EM — mild, sudden onset of hundreds of red papules evolving into "target" lesions (some resembling "herpes iris"); NO prodrome or mucosal lesions; recognized recurrence pattern ("typus annuus" — recurring each spring).
• 1950: Bernard Thomas subdivided into EM minor (= von Hebra's disease) and EM major (severe mucosal necrosis + EM-like skin lesions).
• Confusion arose because some US authors considered EM major to include SJS — recent evidence clarifies SJS and EM major are DISTINCT disorders, though biologic overlap can make individual cases challenging.

• Predominantly young adults; very uncommon in childhood. Slight male preponderance, no racial predilection. Exact incidence unknown.

• Mucocutaneous immune reaction in the setting of infection in predisposed individuals.
• HSV = most common associated agent (types 1 and 2); also M. pneumoniae (also associated with SJS), Histoplasma capsulatum (may occur more with concomitant erythema nodosum), parapoxvirus (orf) — less frequent. EBV evidence inconclusive.
• Rarely drugs/systemic disease — consider SJS, generalized bullous fixed drug eruption, polymorphous exanthematous drug eruption, or urticaria multiforme instead if "drug-induced EM" is suspected.
• Physical triggers (trauma, cold, UV, orthovoltage irradiation) can trigger outbreaks related to underlying infectious/drug/systemic causes.
• No clearly defined genetic predisposition; small studies suggest HLA-DQw3 (DQB1*301 split), DRw53, Aw33 — DIFFERENT from SJS/TEN HLA associations.

HSV/M. pneumoniae mechanism:

• Preceding herpes labialis noted in ~50% of EM patients; usually precedes target lesions by 3-14 days (most commonly HSV-1 in children/young adults, documented HSV-2 in adolescents/young adults).
• HSV DNA detected within early red papules/outer target zone in 80% of EM patients (most often DNA polymerase-encoding sequences); HSV cannot usually be cultured (low-level replication).
• HSV-specific host response: normal HSV immunity but difficulty clearing virus from infected cells; HSV DNA may persist in skin for 3 months after lesion healing.
• Mechanism: HSV DNA sequence expression in skin → recruitment of virus-specific Th1 cells producing IFN-γ → "autoimmune" response from T cells responding to autoantigens released by lysed/apoptotic virus-antigen-containing cells. HSV DNA fragments transported to future EM lesion sites by peripheral blood CD34+ Langerhans cell precursors PRIOR to each eruption.
• M. pneumoniae: severe acro-mucosal presentation (mucositis, conjunctivitis, targetoid/bullous eruptions), most common in young boys/adolescents, associated with community-acquired pneumonia; M. pneumoniae cultured from EM-like bullae (etiologic role suggested, though autoimmune molecular mimicry — as in M. pneumoniae-related Guillain-Barré — is an alternative explanation).

• Four clinical criteria distinguish EM from SJS/TEN: (1) elementary lesion type; (2) distribution/topography; (3) presence/absence of overt mucosal lesions; (4) presence/absence of systemic symptoms.

Table 20.1 comparison:

Elementary lesions: Typical target = <3cm, regular round shape, well-defined border, ≥3 distinct zones (e.g., 2 concentric color rings around central circular zone with epidermal damage — bulla/crust); central zone often dusky → "bull's eye." Early lesions may be "iris" lesions (central dusky + red outer zone) evolving to 3 zones. Only a limited number of lesions may be fully typical at any time — full skin exam essential.

• Atypical PAPULAR target (EM): round, edematous, PALPABLE, only 2 zones/poorly defined border — distinguish from MACULAR atypical targets of SJS/TEN (non-palpable except possible central vesicle/bulla).

Distribution: preferentially extremities and face; target lesions favor UPPER extremities (dorsal hands/forearms most frequent); palms, neck, face, trunk also common; legs less frequent. Can appear in sunburned areas. Lesions tend to group (elbows/knees). Koebner phenomenon possible (target lesions at sites of prior injury — must PRECEDE EM onset, doesn't occur once EM lesions present).

Mucosal lesions: severe in EM major, absent/mild (few, mildly symptomatic) in EM minor. Vesiculobullous → painful erosions of buccal mucosa/lips (less commonly ocular/genital). Lip erosions develop painful crusts; anogenital erosions often large/polycyclic with moist base.

Systemic symptoms: almost always in EM major, absent/limited in EM minor. Fever + asthenia typically precede/accompany. Occasional arthralgias/joint swelling, atypical-pneumonia-like pulmonary involvement (unclear if EM manifestation vs concurrent Mycoplasma infection). Renal/hepatic/hematologic abnormalities RARE in EM major.

Natural history: nearly all lesions appear within 24h, full development by 72h. Pruritic/burning sensations possible. Individual lesions FIXED at same site ≥7 days. Episode typically lasts 2 weeks, heals without sequelae (rare exception: ocular damage in EM major without prompt eye care). Occasional postinflammatory hyper/hypopigmentation. Recurrences common (HSV-associated) — von Hebra's "one recurrence each spring"; most have 1-2 episodes/year; immunosuppressive drugs (e.g., oral corticosteroids) → MORE frequent/longer episodes (5-6/year or near-continuous overlapping disease), increased secondary bacterial infection risk. Rarely, months-long protracted course.

• Clinicopathologic diagnosis, NOT purely histologic — findings characteristic but NOT specific; most useful for EXCLUDING LE/vasculitis.
• Keratinocyte = target of inflammation; apoptosis of individual/clustered keratinocytes = earliest finding. Evolution: mild spongiosis, focal vacuolar basal degeneration, superficial dermal edema, perivascular lymphocytic infiltrate with epidermal exocytosis.
• IF nonspecific: granular IgM/C3 around superficial vessels and focally at DEJ. HSV antigens detectable in keratinocytes by IF; HSV genomic DNA by PCR.
• Compared to SJS: MORE prominent dermal inflammation, MORE discrete epidermal "necrolysis" — NO large areas of full-thickness necrosis in EM.

• Overdiagnosis trap: non-dermatologists often mislabel giant annular urticaria ("urticaria multiforme") as EM.
• Urticaria vs EM: Urticaria = central zone normal/transiently dusky, lesions transient (<24h, document via ink-circling), new lesions appear DAILY, may have angioedema (face/hands/feet). EM = central zone DAMAGED (dusky/bullous/crusted), lesions FIXED ≥7 days, ALL lesions appear within first 72h, NO edema. Subcutaneous epinephrine clears urticaria in 20 min but does NOT change EM lesions.
• Other target-like mimics: fixed drug eruptions, Kawasaki disease, EAC, Sweet syndrome, various vasculitides — biopsy helpful. Significant overlap with generalized bullous fixed drug eruption (total lesion count — especially at FIRST episode — helps: fewer lesions favor FDE).
• Recurrent childhood EM may mimic polymorphous light eruption/juvenile spring eruption (sun-induced, spring onset).
• Systemic LE lesions can mimic target lesions (other SLE features usually present); Rowell syndrome = LE patients with ONLY EM-like lesions. Kawasaki disease in children can also show EM-like lesions. Early urticarial vasculitis may mimic EM targets — histology, ESR, autoantibodies, low complement help distinguish.
• MIRM (Mycoplasma-induced rash and mucositis)/RIME (reactive infectious mucocutaneous eruption): debated whether distinct entity or within EM major/SJS spectrum — see below.

• Topical: antiseptics for eroded skin, antiseptic/antihistamine rinses + local anesthetics for oral lesions; ophthalmology co-management for eye involvement.
• No controlled trials for acute EM systemic therapy. Identify/treat precipitating factor if possible (HSV suppression, see below) — antiviral therapy has MINIMAL impact if started AFTER acute EM appears.
• Most EM (especially minor) needs only symptomatic treatment: oral antihistamines ×3-4 days for stinging/burning.
• Severe EM with functional impairment: consider early systemic corticosteroids (prednisone 0.5-1mg/kg/day ×3-5 days, or pulse methylprednisolone 20mg/kg/day ×3 days) — despite lack of controlled studies and ongoing infection-risk controversy.
• HSV-associated recurrent EM prophylaxis (≥6 months): oral valacyclovir 500-1000mg/day, famciclovir 250mg BID, or acyclovir 10mg/kg/day divided — double-blind placebo-controlled study demonstrated acyclovir efficacy in young adults; benefit can persist even after discontinuation. Non-responders: double dose or switch antiviral. Antivirals ineffective if EM triggered by non-HSV factors.
• Refractory recurrent EM (unvalidated, inconsistent efficacy): azathioprine 100mg/day (months), prednisone 0.5mg/kg/day (months), thalidomide, dapsone, cyclosporine, MMF, PUVA. JAK inhibitors may be considered for persistent EM.

---

• Children and adolescents >> adults. Prodrome (cough, malaise, fever) precedes eruption by ~1 week.
• Predominant MUCOSAL involvement: severe mucositis, typically ≥2 mucosal sites (oral, ocular, anogenital, nasal).
• Absent/sparse polymorphic cutaneous involvement (<10% BSA) — typically vesiculobullous or atypical target lesions, occasionally subcorneal pustules.
• MIRM: clinical/lab evidence of M. pneumoniae (pharyngeal PCR; IgM/IgG serologies — serial measurements may be needed; ELISpot assay for Mycoplasma-specific IgM antibody-secreting cells improves sensitivity/specificity).
• RIME: evidence of other triggering infection (often respiratory — e.g., Chlamydophila pneumoniae, adenovirus, enteroviruses, human metapneumovirus, influenza B, parainfluenza type 2, rhinovirus, SARS-CoV-2).
• Often benign course, excellent prognosis (<5% need intensive care, up to 10% may develop ocular sequelae).
• Treatment: supportive care/pain management similar to SJS + systemic antimicrobials if infectious trigger identified; systemic corticosteroids (prednisone 1mg/kg/day ×5-7 days) optional if severe; case reports of etanercept, IVIg, cyclosporine.
• Prior to this terminology, patients were diagnosed as incomplete/atypical/acro-mucosal SJS, Mycoplasma-associated EM major/SJS, Fuchs syndrome, or Mycoplasma-associated mucositis.

---

• Erythema multiforme (EM) is an immune-mediated disease characterised by target lesions that can occur anywhere on the skin and mucous membranes, most commonly on the extremities (hands and feet). Causality (infections, autoimmune disease, drugs) might be found but not always.
• EM, Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN or Lyell syndrome) were considered to form a spectrum from mild to severe. There has been a re-evaluation of this concept, with a tendency to consider EM minor and EM major as part of one spectrum, commonly following infections (especially herpesvirus), often recurrent in nature. Sometimes EM is due to drug reactions; in many cases no underlying cause is found.
• SJS and TEN are discussed in detail in Chapter 118, more closely linked to drug sensitivities, though TEN in children secondary to mycoplasma and herpesvirus infections has been reported. SJS and TEN may be regarded as severe variants of a single disease.
• EM is best regarded as a self-limiting cytotoxic dermatitis resulting from cell-mediated hypersensitivity, most commonly to drugs or infection. Presents clinically with a spectrum of macular, papular, or urticarial lesions, as well as the classic acral iris or "target lesions". Lesions may involve the palms or trunk, as well as oral and genital mucosal membranes, associated with erosions.
• SJS (first described in 1922) comprises extensive EM of the trunk and mucous membranes, accompanied by fever, malaise, myalgia, and arthralgia.
• Lyell first reported TEN in 1956, characterised by extensive, sheet-like skin erosions with widespread purpuric macules or flat, atypical target lesions, accompanied by severe involvement of the conjunctival, corneal, irideal, buccal, labial, and genital mucous membranes.
• EM major occurs in younger males, frequently recurs, has less fever and milder mucosal lesions, and lacks association with collagen vascular diseases, HIV infection, or cancer. Herpes simplex is associated with SJS in up to 10% of cases and may be recurrent.
• SJS (occasional skin blisters/erosions covering less than 10% of body surface area) is differentiated from TEN (typically sheet-like erosions involving more than 30% of body surface). However, 10–20% of adult cases (higher percentage in children) even experienced clinicians and histopathologists are unable to classify, having features of both groups. Each case requires careful ongoing evaluation for disease progression, especially if more than 10% BSA affected and/or signs of systemic disease, especially in the first few days, and escalation in disease management if indicated (Chapter 118).

Immunology

• Clinical reaction pattern of EM associated with many different triggering factors in genetically predisposed individuals. Immune profile of lesional skin from both infection-associated and drug-triggered EM gives pathogenesis clues.
• HLA studies show association with HLA-B62 (B15), HLA-B35, and HLA-DR53 in recurrent EM cases. Immune complexes (in skin and circulation), autoantibodies against epithelial cells, and autoantibodies against desmosomal plaque proteins desmoplakin I and II (with suprabasal acantholysis) also demonstrated. CD4+ T cells found in the dermis, CD8+ T cells in the epidermis of lesional skin.
• Herpesvirus-infected peripheral blood mononuclear cells (PBMCs) induce upregulation of CD54+ and MHC class I molecules in adjacent, non-infected human dermal microvascular endothelial cells in vitro, with consequent increased endothelial binding of PBMCs. HSV DNA identified in lesions of herpes-induced EM.
• Proposed that PBMC antigen-presenting cells (macrophages, dermal dendritic cells, or Langerhans cells) phagocytose HSV DNA and transport fragments to distant skin sites — leads to recruitment of HSV-specific CD4+ Th1 cells, enhancing IFN-α production. An inflammatory cascade follows: expression of IFN-α-induced genes, increased sequestration of circulating leukocytes, monocytes and NK cells, and recruitment of autoreactive T cells.
• By extrapolation, drug hapten-specific T cells could be involved in the pathogenesis of drug-induced EM. PBMCs from a patient with carbamazepine-induced EM at time of disease showed increased binding to ICAM-1-positive heterologous keratinocytes and to autologous keratinocytes in vitro, completely inhibited by antibodies to LFA-1 (the ligand for ICAM-1).
• Perforin-positive cells may mediate apoptotic cell death in EM and SJS. Monocyte chemotactic protein 1 (MCP-1), RANTES, macrophage IFN-α-inducible gene (Mig), and IFN-α-inducible protein 10 (IP-10) were expressed by basal keratinocytes above, and mononuclear cells within, inflammatory foci — contributing to cell-specific and spatially restricted recruitment of mononuclear cells in acute EM inflammation.
• EM major has been reported after sequential use of two immune checkpoint inhibitors, nivolumab and ipilimumab, for advanced melanoma treatment — these drugs reverse the imbalance of antitumour self-tolerance and enhance T-cell response, blocking both the PD-1 and CTLA-4 pathways.

• Potential triggering factors listed in Box 47.1. Most common association: preceding herpes simplex infection (facial or genital) or a Mycoplasma infection, especially when conjunctival/corneal involvement occurs. Other viral/bacterial infections and vaccination have also been incriminated.
• SARS-CoV-2 has more recently been associated with EM-type lesions in adults and children, often in association with peripheral chilblain-like lesions. Other cases caused by drugs; in up to 50% no associated trigger identified.

Some triggers of erythema multiforme

• Viral infections: Herpes simplex virus; Mycoplasma infections; acquired immune deficiency syndrome; adenovirus; cytomegalovirus; hepatitis B; infectious mononucleosis; lymphogranuloma inguinale; milker nodules; mumps; orf; poliomyelitis; psittacosis; SARS-CoV-2; vaccinia; varicella; variola.
• Bacterial infections: A wide range recorded, including rickettsiae.
• Fungal infections: Histoplasmosis.
• Drug reactions: Including vaccinations.
• Contact reactions.
• Miscellaneous: Carcinoma, lymphoma, leukaemia; granulomatosis with polyangiitis; lupus erythematosus (Rowell syndrome); polyarteritis nodosa; polymorphic light eruption; pregnancy, premenstrual, "autoimmune progesterone dermatitis"; sarcoidosis; X-ray therapy.

• EM regarded as a well-recognised pattern of adverse cutaneous drug reaction. As new drugs develop, EM-type lesions reported in association with them. However, in a prospective study of EM cases, only 10% were drug related. In another study, antecedent medication use (especially cephalosporins) recorded in 59% of EM patients and 68% of SJS patients.
• Drugs all too frequently, and controversially, implicated on inadequate evidence; description of some reactions as "EM like" doesn't help. Confirmation of drug sensitivity really necessitates re-exposure to the drug, which may carry unacceptable risk and is not usually performed, making diagnosis uncertain.
• Some drugs with notoriety for triggering EM shown in Box 47.2 — ranging from historical/infrequently used therapies to newer agents, including antibiotics, anticonvulsants, NSAIDs, statins, immunotherapy, and vaccinations.

Drugs reported as causing erythema multiforme

• Antibiotics: Cephalosporins (ceftazidime); erythromycin; penicillins and ampicillin; quinolones; rifampicin; sulphonamides (co-trimoxazole, sulfadoxine–pyrimethamine); sulphones; tetracyclines; thiacetazone; vancomycin.
• Antifungal preparations: Griseofulvin; nystatin; terbinafine.
• Antiretroviral drugs: Abacavir; nevirapine.
• NSAIDs: Fenbufen; ibuprofen; paracetamol (acetaminophen); pyrazolone derivatives (antipyrine, phenylbutazone, phenazone); salicylates; sulindac.
• Immunotherapy: Ipilimumab; nivolumab; pembrolizumab.
• Metals and other elements: Arsenic; bromides; gold; iodides; mercury.
• Anticonvulsants: Barbiturates; carbamazepine; hydantoin derivatives; lamotrigine; trimethadione.
• Antihypertensives: Furosemide; hydralazine; minoxidil; thiazide diuretics.
• Statins: Pravastatin; simvastatin.
• Drugs acting on the central nervous system: Lithium; mianserin; phenothiazines; trazodone.
• Miscellaneous: Allopurinol; chlorpropamide; codeine; cyclophosphamide; danazol; methaqualone; nitrogen mustard; pentazocine; phenolphthalein; progesterone; topical agents (see text); vaccination.

• Allergic contact dermatitis may present with EM-like reactions. Substances involved usually potent sensitisers such as Primula obconica, poison ivy, a variety of weeds, laurel oil, Alpinia galanga (spicy edible Thai ginger), diphenylcyclopropenone, and bromofluorene.
• A large number of topical medications can induce EM-like eruptions, including balsam of Peru, chloramphenicol, econazole, ethylenediamine, furazolidone, mafenide acetate cream (used for burns), the muscle relaxant mephenesin, neomycin, nifuroxime, promethazine, scopolamine, sulphonamides, ophthalmic anticholinergic preparations (scopolamine hydrobromide and tropicamide drops), vitamin E, the antimycotic agent pyrrolnitrin, proflavine, topical steroids, topical nitrogen mustard, sesquiterpene lactones in herbal medicine, bufexamac, phenylbutazone, nitroglycerin patch, tea tree oil, and para-phenylenediamine (including in a henna tattoo).
• A topical ketoprofen-containing tape provoked a photocontact dermatitis and subsequent EM. EM reported with use of rubber gloves and with blister beetle dermatitis.
• Contact with several environmental substances may induce EM-like reactions, including nickel, formaldehyde, trichloroethylene, phenyl sulphone derivative, the insecticide methyl parathion, a glyphosate pesticide, epoxy compounds, trinitrotoluene, cutting oil, and bisphenol A.

• Some authors refer to "epidermal" and "dermal" subtypes of EM, but this is just a function of biopsy timing relative to lesion development. Most important changes: necrotic keratinocytes in the epidermis (which can be zonal) and in the upper dermis — a spectrum belonging to the lichenoid, band-like, or cytotoxic CD8+ T-cell reaction patterns.
• Pathology of EM variable, may overlap with fixed drug eruption and SJS, most florid in TEN, requiring good clinicopathological correlation to guide diagnosis. Timing of biopsy in the evolution of the reactive erythema is important.
• Initially in EM, a dermal, angiocentric, mixed infiltrate with progressive alignment and tagging of cytotoxic lymphocytes along the dermal–epidermal junction. Results in degenerative alterations in basal keratinocytes and, with chronicity, progressive squamatisation and dyskeratosis.
• Some cases have prominent dermal inflammatory changes, with an interstitial and perivascular lymphohistiocytic infiltrate (sometimes with eosinophils if drug related), papillary oedema, and vasodilatation. Rarely, red blood cell extravasation can occur without vasculitis.
• Vacuolar liquefaction degeneration of the basal layer, epidermotropism of CD8+ lymphocytes, subepidermal blister formation, and often (if chronic) individually necrotic apoptotic cells and pigmentary incontinence with papillary melanophages. Such changes occur especially in classic EM with target lesions.
• In more severe bullous cases, subepidermal bullae and necrosis of the whole epidermis, as in TEN. Histology of oral lesions similar to skin, with a spectrum of similar pathological changes and very marked degenerative changes in the epithelium.

• Can occur at any age, including in neonates or young children. In general, course is an eruption developing over a few days, resolving in 2–3 weeks usually without scarring. Repeated attacks associated with recurrent herpes simplex are frequent, optimally managed with adjunctive antiviral medication to suppress future outbreaks.
• Lesions classically evolve as macular, papular, or urticarial lesions, developing into classic iris or target lesions, with preferential distribution on the distal extremities. Lesions may involve the palms or trunk, as well as oral and genital mucous membranes.
• Lesions dull red, flat, or slightly raised maculopapules, which may remain small or increase in size to reach a diameter of 1–3cm in 48h. Target lesions usually less than 3cm in diameter, rounded, with three zones: a central area of dusky redness or purpura, a middle paler zone of oedema, and an outer ring of redness with a well-defined edge. Atypical target lesions have only two zones.
• Lesions appear in successive crops for a few days, fade in 1–2 weeks, sometimes leaving dusky discoloration. May be few or profuse.
• Characteristically, dorsa of the hands, palms, wrists, feet, and extensor aspects of elbows/knees affected; less commonly the face. Sometimes outbreak localised to just the lips or hands. May be occasional red/pink lesions, erosions, or bullae limited to mucous membranes while patient otherwise well. Photoaggravation of EM well recognised in association with HSV and statins.
• Because diagnosis depends on clinical and pathological appearance, criteria for diagnosing atypical cases are difficult to apply. However, cases exist where clinical picture is atypical but histology nevertheless shows characteristic changes. EM-like lesions reported in the setting of acute generalised exanthematous pustulosis.
• Lesions many centimetres in diameter may remain stationary or enlarge slowly over several weeks or months (persistent EM). Rarely, cases with otherwise typical morphology/histology may develop lesions almost continuously rather than episodically. EM along the Blaschko lines reported, as has disseminated granuloma annulare following EM minor.
• Rowell syndrome comprises lupus erythematosus associated with EM-like skin lesions, and immunological findings of speckled antinuclear antibodies, anti-La or anti-Ro antibodies, and positive rheumatoid factor. Wide acceptance of this syndrome as a distinct entity is not universal.

• Differential diagnosis is wide and is that for most bullous disorders, particularly when there is predominantly mucosal involvement and obvious blistering clinically. Drug eruptions such as vancomycin-induced linear IgA disease, and lupus erythematosus, must be excluded, along with pemphigoid and other autoimmune bullous conditions, and toxic erythemas of unknown cause.
• Stem cell transplantation reactions may be difficult to differentiate from EM. Distinction between atypical EM and urticarial vasculitis can be difficult but histology should help. Kawasaki disease (Chapter 26) may resemble EM, but characteristic red lips, strawberry tongue, red and swollen palms/soles, and lymphadenopathy should permit a clinical diagnosis. Differential diagnosis of mouth lesions considered elsewhere (Chapter 108).

• Management dependent on disease extent. Localised bullous forms may be self-limiting or require topical corticosteroids for limited disease and/or oral corticosteroids if more widespread with symptomatic relief required. Ocular involvement requires early ophthalmologist referral.
• In more severe cases, good nursing is paramount, and such cases may require the sort of attention used for TEN, in a dermatological high-dependency unit or intensive therapy/burns unit. Value of systemic corticosteroids still debated, but relief of systemic symptoms such as fever is achieved.
• For more severe cases, prednisolone at an initial dosage of 30–60mg/day, decreasing over 1–4 weeks, may be used.
• Antiviral therapy with agents such as aciclovir for EM triggered by overt herpes simplex infections tends to be disappointing once the eruption has appeared — also true for recurrent cases, even when prescribed at the first sign of recurrent herpes. However, long-term prophylactic use may be quite helpful; a dosage of 200mg three times daily may be appropriate, but smaller or larger doses may be needed. Relapses tend to occur when the drug is omitted.
• Some patients with recurrent EM without overt herpes infection can be helped by prophylactic aciclovir, implying recurrent herpes infection may nevertheless be responsible. Aciclovir has also been reported to prevent recurrent polyarthritis associated with EM. Burnett et al. found HSV DNA polymerase and VP5 protein expressed in 75% of those with HSV-associated EM.
• Thalidomide has been used in a few cases to prevent relapses of recurrent EM. Other drugs used mainly in idiopathic or postherpetic EM: dapsone, azathioprine, mycophenolate mofetil, and ciclosporin.

• Rare cutaneous and/or mucocutaneous eruption characterized by target lesions
• Benign course but frequent recurrences
• Most cases related to herpes simplex virus (HSV) infection; medications are NOT frequent causes
• Frequent recurrences can be prevented by long-term anti-HSV medications
• Thalidomide is usually effective in recalcitrant recurrent cases

---

• Erythema multiforme (EM): acute, self-limited, usually mild, often relapsing mucocutaneous syndrome
• Usually related to an acute infection, most often recurrent HSV infection
• Defined only by clinical characteristics: target-shaped plaques with or without central blisters, predominant on face and extremities
• No specific pathology, unique cause, or biologic marker → confusing nosology
• Medical literature still contains many figurate erythemas reported as EM
• ICD-9 still classifies SJS and TEN under the heading of EM
• Chapter definition based on classification of Bastuji-Garin et al.:
• SJS and TEN = severity variants of the same process (epidermal necrolysis, EN), separated from EM (see Chapter 40)
• Validity challenged by some reports, especially children and Mycoplasma pneumoniae-related cases
• Confirmed by several studies, especially the prospective international Severe Cutaneous Adverse Reactions (SCAR) study: compared with SJS/TEN, EM had different demographics, clinical presentation, severity, and causes
• Original name (von Hebra): erythema exudativum multiforme; "erythema multiforme" now universally accepted
• EM minor: mucous membranes spared or minimally affected (e.g., lips)
• EM majus (major, EMM): at least two mucosal sites involved

Erythema Multiforme Subtypes

• EM minor: skin lesions without mucous membrane involvement
• EM major: skin lesions with mucous membrane involvement
• Herpes-associated EM (HAEM)
• Mucosal EM (Fuchs syndrome, ectodermosis pluriorificialis): mucous membrane lesions without cutaneous involvement

---

• Considered relatively common; true incidence unknown (mainly hospitalized cases reported)
• Severe cases requiring hospitalization: 1 to 6 per million per year
• EM minor is more frequent than EM major
• Many other eruptions (annular urticaria, serum sickness-like eruption) are erroneously called EM
• All ages, but mostly adolescents and young adults
• Slight male preponderance (M:F ≈ 3:2)
• Recurrent in at least 30% of patients
• No established underlying disease increases risk
• HIV and collagen vascular disorders do NOT increase risk of EM (in contrast to epidermal necrolysis)
• Cases may occur in clusters → suggests infectious agents
• No variation with ethnicity or geography
• Genetics: HLA-DQB1\*0301 in 66% of EM patients vs 31% of controls
• Association stronger in herpes-associated EM
• Overall association relatively weak; familial cases rare

---

• Most cases related to infections

Herpes Simplex Virus

• HSV = most common cause, principally in recurrent cases
• Proof of causality: clinical experience, epidemiology, HSV DNA detected in lesions, and prevention of EM by suppression of HSV recurrences
• Clinical link with herpes established in about one-half of cases
• 10% to 40% of cases without clinical suspicion of herpes are herpes related (HSV DNA by PCR in lesions)
• EM begins on average 7 days after a herpes recurrence (delay can be substantially shorter)
• Not all symptomatic herpes recurrences are followed by EM; asymptomatic recurrences can induce EM → link often overlooked
• HSV-1 usually, but HSV-2 can also induce EM (proportion reflects population prevalence of subtypes)

Mycoplasma pneumoniae

• Second major cause of EM; may be the first in pediatric cases
• Presentation often less typical and more severe than HSV-associated
• Relationship often difficult to establish: pneumonia signs can be mild; organism usually not directly detected
• PCR of throat swabs = most sensitive technique
• Serology diagnostic: IgM antibodies or more than twofold increase in IgG in samples obtained after 2 or 3 weeks
• M. pneumoniae-related EM can recur

Other Infections

• Circumstantial evidence only (case reports/small series): orf virus, varicella zoster virus, parvovirus B19, hepatitis B and C, infectious mononucleosis, various other bacterial/viral infections
• Immunization implicated in children

Drugs

• Rare cause of EM with mucous membrane lesions
• Most reports of "drug-associated EM" are imitators (e.g., annular urticaria, maculopapular eruption with some target-like lesions)
• "EM-like" dermatitis may result from contact sensitization → also an imitator despite clinical/histopathologic similarities

Idiopathic EM

• No HSV or other cause identified; fairly common in routine practice
• HSV found in situ by PCR in up to 40% of "idiopathic" recurrent cases
• Some respond to prophylactic antivirals (likely asymptomatic HSV triggers); others resistant

---

• Extensively investigated for herpes-associated EM; unknown if same for other causes
• Complete infective HSV never isolated from HAEM lesions
• PCR: keratinocytes contain only DNA fragments, always including the viral polymerase (Pol) gene
• HSV Pol DNA in basal keratinocytes and lower spinous layers; viral Pol protein is synthesized
• HSV-specific T cells (including cytotoxic cells) recruited → followed by nonspecific inflammatory amplification by autoreactive T cells
• Cytokines produce the delayed hypersensitivity-like histopathology
• HSV is in blood for a few days during overt recurrence; if keratinocytes were infected from circulating virus, disseminated herpes (not EM) would result
• Transport of HSV DNA to epidermis by immune cells that engulf virus and fragment its DNA:
• Monocytes, macrophages, and especially CD34+ Langerhans cell precursors bearing skin-homing cutaneous lymphocyte-associated antigen (CLA)
• Upregulated adhesion molecules increase binding of HSV-containing mononuclear cells to endothelium → dermal inflammation
• These cells transmit the Pol gene to keratinocytes
• Viral genes may persist a few months, but Pol protein expression lasts only a few days → explains transient lesions (specific immune response to Pol, amplified by autoreactive cells)
• Mechanisms/regulation different from drug reactivity leading to SJS/TEN
• Why only a small proportion of recurrent herpes patients develop EM: incomplete fragmentation of viral DNA, increased circulating CD34+ cells, and/or increased immune response to Pol protein

---

Approach to the Patient

• Step 1: suspect EM clinically; biopsy/labs mainly if diagnosis not definite
• Step 2: decide on hospitalization — when EMM oral lesions impair feeding, SJS suspected, or severe constitutional symptoms
• Step 3: establish cause — history of recurrent herpes, chest radiography, documenting M. pneumoniae
• Is it EM?
• Pro: typical papules with target features; acral distribution; mucous membrane erosions; previous episodes
• Con: transient lesions; widespread erythema; macules and blisters, flat targets; subacute evolution
• Maybe/No → biopsy, direct IF, serum antibodies → consider urticaria, ADR with some EM-like features, autoimmune blisters, SJS
• What is the cause?
• History of recurrent herpes → HAEM → acyclovir prophylaxis
• Cough/URT infection → MP-related EM
• Other infection (e.g., orf) → post-infection EM
• No clue → herpes serology: positive → possible HAEM (frequent recurrences → acyclovir prophylaxis); negative → idiopathic EM (frequent recurrences → azathioprine, thalidomide)

History

• Prodromal symptoms absent in most cases; if present, mild URI-like (cough, rhinitis, low-grade fever)
• In EMM, fever >38.5°C (101.3°F) in one-third of cases
• History of prior attack(s) in at least one-third of patients → aids diagnosis
• Review preceding 3 weeks for precipitating agents, especially recurrent herpes

Cutaneous Lesions

• Abrupt onset; in most, all lesions appear within 3 days (some have several crops in one episode)
• Often a limited number of lesions, but up to hundreds
• Symmetric, acral distribution on extensor surfaces of extremities (hands and feet, elbows, knees), face, neck; less often thighs, buttocks, trunk
• Often appear acrally first, then spread centripetally
• Koebner phenomenon (mechanical) and actinic factors (sun-exposed sites) influence distribution
• Usually asymptomatic (occasional burning/itching)
• "Multiforme" diversity is mainly within each single lesion; lesions usually similar in a given patient at a given time
• Typical lesion: highly regular, circular, wheal-like erythematous papule/plaque persisting 1 week or longer
• Size a few mm to ~3 cm; may expand slightly over 24 to 48 hours
• Periphery erythematous/edematous; center becomes violaceous and dark; central regression/relapse → concentric rings
• Center often turns purpuric and/or necrotic or becomes a tense vesicle/bulla → classic target or iris lesion
• Typical target = at least three concentric components:

1. Dusky central disk, or blister
2. Infiltrated pale ring
3. Erythematous halo

• Raised atypical targets: only two rings
• All EM lesions are papular — in contrast with macules, typical of epidermal necrolysis (SJS–TEN)
• Some patients: mostly livid vesicles over slightly darker center, encircled by erythematous margin
• Larger lesions with central bulla and marginal ring of vesicles = herpes iris of Bateman; may be more frequent in M. pneumoniae-related EMM
• Unusual: same patient may have targets in one episode and plaques in another; mucosae severely involved in some episodes, spared in others
• Extent: usually well under 10% BSA
• In 88 hospital EMM cases (SCAR study): median 1% BSA
• Very rare extensive cases with "giant" targets and several mucosal sites may be hard to distinguish from SJS
• Individual lesion lasts <2 weeks; residual discoloration may persist months; no scarring

Mucous Membrane Lesions

• Present in up to 70% of patients, most often limited to the oral cavity
• Predilection sites: lips (cutaneous and mucosal sides), nonattached gingivae, ventral tongue
• Hard palate and attached gingivae usually spared
• Cutaneous lip: identifiable targets may be seen
• Mucosa proper: erosions with fibrinous deposits; occasionally intact vesicles/bullae
• Rarely extends to throat, larynx, trachea, bronchi
• Eyes: pain and bilateral conjunctivitis with vesicles and erosions
• Nasal, urethral, anal mucosae may be inflamed/eroded
• Ectodermosis pluriorificialis (Fuchs syndrome): rare; severe involvement of two or three mucosal sites without skin lesions
• Often relapsing → suggests HSV related
• Typical skin targets may arise with new attacks

Relationship to Recurrent Herpes

• In >70% of recurrent EM, an HSV recurrence precedes the rash
• Herpes labialis predominates over genital or other sites
• Usually follows recurrent herpes but may follow primary HSV infection
• Average interval 7 days (range 2 to 17 days); lag period specific for individual patients
• Small number: HSV recrudescence and EM simultaneous
• Not all EM episodes preceded by evident HSV; not all HSV episodes followed by EM
• HSV recurrences may precede HSV-related EM by many years

Related Physical Findings

• EM minor: fever/constitutional symptoms usually absent; examination normal
• EMM: fever >38.5°C (101.3°F) in 32%
• Mouth erosions very painful → impaired alimentation; may be unable to close mouth, drooling bloodstained saliva
• Cervical lymphadenopathy usually present in these patients
• Painful genital erosions → reflex urinary retention
• Cough, polypnea, hypoxia in M. pneumoniae-related cases

---

Histopathologic Analysis

• Early lesions:
• Lymphocyte accumulation at dermal–epidermal interface with exocytosis
• Lymphocytes attached to scattered necrotic keratinocytes (satellite cell necrosis)
• Spongiosis, vacuolar degeneration of basal layer
• Focal junctional and subepidermal cleft formation
• Papillary dermis may be edematous; dense mononuclear infiltrate, more abundant in older lesions
• Ectatic vessels with swollen endothelium; possible extravasated RBCs and eosinophils
• Immunofluorescence negative or nonspecific
• Advanced: subepidermal blister may form, but necrosis rarely involves the entire epidermis
• Late: melanophages may be prominent
• vs SJS–TEN: SJS–TEN has moderate to absent dermal inflammation and much more pronounced epidermal necrosis; appearances overlap and do not always allow distinction
• Main reason for biopsy = rule out other diagnoses (autoimmune blistering disease, Sweet syndrome, vasculitis)

Other Laboratory Tests

• No specific laboratory tests for EM
• Severe cases: elevated ESR, moderate leukocytosis, increased acute-phase proteins, mildly elevated liver aminotransferases
• Respiratory symptoms → chest radiograph, plus PCR of throat swab and paired serology (2- or 3-week interval) for M. pneumoniae
• Causality work-up important when frequent recurrences and long-term antiviral prevention considered, and when no clinical evidence of herpes
• HSV can rarely still be isolated from initial labial herpes lesion
• HSV Pol gene amplification from biopsy not done routinely
• Negative HSV serology helps exclude herpes-associated EM
• HLA-DQB1\*0301: positive predictive value too low for clinical value

---

• Retrospective analysis of 66 pediatric cases discharged with EM: 24 (36%) clearly not EM
• Most frequent misdiagnoses: urticaria and maculopapular drug eruption (figurate erythema to amoxicillin, erroneously reported as drug-induced EM)
• Rowell syndrome: cutaneous LE with often erosive circinate EM-like lesions; subacute evolution, positive DIF, and ANA exclude EM
• Sweet syndrome can mimic EM minor; biopsy easily distinguishes
• Paraneoplastic pemphigus (and rarely other autoimmune blistering diseases, e.g., linear IgA) may show target-like lesions
• Antidesmoplakin "EM major": originally reported as EMM with anti-desmoplakin antibodies; acute recurrent course like EMM, but acantholysis, IgG deposits around basal cells, and serum anti-desmoplakin antibodies distinguish it
• SJS — better considered a separate disease; recognize promptly for three reasons:

1. Possibility of life-threatening complications
2. Risk of progression to TEN
3. Need for urgent withdrawal of suspected drug(s)

• Alerting features: pain, constitutional symptoms, severe mucosal erosions, rapid progression, dusky or violaceous skin lesions
• Mucosa-only EM: diagnosis especially difficult, often made when later bouts include a few skin lesions; consider pemphigus, cicatricial pemphigoid, allergic or toxic contact stomatitis, toxic erosive stomatitis, aphthous lesions, lichen planus

Differential Diagnosis of Erythema Multiforme

• DIF = direct immunofluorescence testing

---

• Mild course in most cases; each attack subsides within 1 to 4 weeks
• Recovery complete, usually no sequelae except transient discoloration
• Rare: ocular erosions of EMM → severe residual eye scarring
• M. pneumoniae-related EMM may cause severe erosive bronchitis, rarely with sequelae
• Recurrences common; may characterize the majority of cases
• Large series of recurrent EM: mean 6 attacks/year (range 2 to 36); mean total disease duration 6 to 9 years
• 33% persisted >10 years
• Up to 50 recurrences described in a single patient
• Severity of episodes highly variable and unpredictable
• Frequency and cumulative duration not correlated with severity
• Frequency and severity decrease spontaneously over time (after 2 years or longer), paralleling improvement of recurrent HSV when causal
• In a substantial proportion of recurrent cases, no cause determined
• Continuous EM / persistent EM: small fraction with prolonged series of overlapping attacks

---

• Aims: reduce duration of fever, eruption, and hospitalization

Systemic Corticosteroids

• Retrospective series/small trials: seem to shorten fever and eruption but may lengthen hospitalization due to complications
• Poor methodology (small series mixing idiopathic, virus-associated EM, and drug-induced SJS)
• Systemic corticosteroids cannot be recommended

Antivirals for Established Episodes

• Anti-HSV drugs for established postherpetic EM episodes are useless

Mycoplasma pneumoniae

• Symptomatic infection → antibiotics: macrolides in children; macrolides or quinolone in adults
• No evidence it improves associated EM → when asymptomatic infection suggested only by serology, treatment not mandatory

Symptomatic

• Painful mouth erosions: liquid antacids, topical glucocorticoids, local anesthetics

---

• Continuous oral anti-HSV therapy (see Chapter 231) effective in preventing recurrences of herpes-associated EM, with or without clinical evidence that herpes is the trigger
• Topical acyclovir prophylaxis does NOT prevent recurrent herpetic EM
• Azathioprine: in a series of 65 recurrent EM patients, 11 treated when all else failed → beneficial in all 11
• Mycophenolate mofetil can also be useful
• Thalidomide: retrospective uncontrolled analyses show moderate efficacy; probably most effective treatment of recurrent/persistent cases resistant to anti-HSV drugs
• Levamisole: appeared useful in one RCT; but agranulocytosis is a severe and not exceptional adverse effect → permitted in only a few countries; benefit–risk ratio probably too low to support use in EM

• 1860, von Hebra first described erythema exudativum multiforme.
• Original disease = EM minor (minus) or HSV-associated EM (HAEM) — strongly associated with herpetic infection.
• EM major (majus): multiple mucous membranes, more intense, fever/arthralgias — most often Mycoplasma-caused; better termed infection-induced rash and mucositis (IIRM), mycoplasma-induced rash and mucositis (MIRM), or reactive infectious mucocutaneous eruption (RIME).
• SJS/TEN usually represent adverse DRUG reactions (see Chapter 6).

• HAEM; EM major (most often Mycoplasma; MIRM/IIRM/RIME); chronic oral EM; contact dermatitis–induced EM; radiation-induced EM; idiopathic.

• Recurrent self-limited, usually young adults, seasonal (spring/fall), each episode 1-4 weeks.
• Lesions: sharply marginated erythematous macules → raised edematous papules over 24-48 hours, up to several cm.
• Classic "target"/"iris" lesion — THREE ZONES: central dusky purpura; elevated edematous pale ring; surrounding macular erythema. Central area may be bullous.
• Typical targets best observed on palms and soles. Symmetric, acral, initially dorsal hands. Dorsal feet, extensor limbs, elbows, knees, palms, soles typically involved.
• ~10% have more widespread truncal lesions. Koebner/photoaccentuation possible.
• Mucosal involvement in 25%, usually limited to oral mucosa — indurated plaques, target lesions, or erosions.

• Unilateral/segmental papules and plaques, few or solitary, up to 20 cm. Erythematous → dusky center → desquamates.
• Subcutaneous nodules resembling erythema nodosum may be simultaneously present. HSV DNA identifiable by PCR in lesions. Acyclovir suppression prevents lesions.

• Febrile prodrome, sometimes arthralgias. All ages; face/extremities centered, more often includes truncal lesions (papular, erythematous to dusky).
• Mucous membrane disease prominent, often severe oral/lip hemorrhagic sloughing; less commonly genital/ocular mucosa.
• SJS distinguished by purpura or bullae in MACULAR lesions of the trunk.
• "Urticaria multiforme" (children): polycyclic urticarial lesions with dusky centers, frequently misdiagnosed as EM — represents urticaria; EM histologic changes NEVER present.

• HAEM: HSV-1 more common trigger than HSV-2; lesions appear 1-3 weeks (average 10 days) after herpes outbreak. Not every herpes episode precedes EM; some EM outbreaks lack recognizable herpetic lesion.
• PCR/in situ hybridization: HSV DNA/antigens found in EM minor lesions. Majority of "idiopathic" EM minor cases associated with recurrent HSV — treatable with suppressive antivirals.
• Autoantibodies to desmosomal molecules reported (pathogenic vs. incidental unclear).
• EM major associated with Mycoplasma and other pulmonary infections (MIRM/RIME/IIRM); minority from HSV or medication reaction. COVID-19/SARS-CoV-2 and rarely vaccines can trigger EM (esp. infants).

• Similar in HAEM and EM major, not predictive of etiology. Extent depends on lesion duration/biopsy site.
• Normal basket-weave stratum corneum, vacuolar interface reaction, cellular necrosis out of proportion to lymphocyte number.
• Dermal infiltrate largely mononuclear, around upper dermal vessels/DEJ. Activated T lymphocytes: cytotoxic/suppressor more in epidermis, helper T in dermis. NO leukocytoclastic vasculitis. Eosinophils may be present but rarely prominent, not predictive of etiology.

• Fixed drug eruption: deeper infiltrate, eosinophils/neutrophils, papillary dermal fibrosis, melanophages.
• GVHD: more compact stratum corneum, follicular involvement.
• Pityriasis lichenoides: lymphocyte in every vacuole, erythrocyte extravasation, neutrophil margination in dermal vessels.
• Lupus erythematosus: compact hyperkeratosis, deeper periadnexal infiltrate, dermal mucin, BMZ thickening.

• With bullae, distinguish from bullous arthropod reactions and autoimmune bullous diseases (pemphigus if mucosal prominent; bullous pemphigoid if small lesions with peripheral erythema). Paraneoplastic pemphigus may mimic Mycoplasma-induced EM major — DIF may be necessary.

• EM minor: prevention of herpetic outbreaks central. Daily sunscreen (face/lips) to prevent UVB-induced HSV outbreaks.
• If ineffective or genital HSV cause: chronic suppressive oral antiviral (valacyclovir 500 mg-1 g/day, or famciclovir), may increase dose. Prevents recurrences in up to 90% of HSV-related cases.
• Intermittent antiviral treatment/topical antivirals: minimal benefit for preventing HAEM.
• Most HAEM self-limited; symptomatic treatment often sufficient. Oral lesions: "swish and spit" with lidocaine, diphenhydramine, kaolin.
• Extensive: intermittent oral steroids or long-term dapsone, cyclosporine, azathioprine, mycophenolate, or thalidomide. Apremilast and rituximab for recalcitrant cases. Concurrent antivirals if HSV present.
• Widespread unresponsive EM: manage as severe drug-induced SJS.

• Limited/most prominent in oral cavity; otherwise well. 60% female, mean age 43. ~25% have recurrent, self-limited, cyclic disease.
• Oral cavity ONLY site in 45%; oral+lip in 30%; skin also involved in 25%. Tongue, gingiva, buccal mucosa most severely affected. Almost universally eroded (± pseudomembrane).
• Important to exclude fixed drug eruption. No well-designed treatment trials; topical corticosteroids helpful (fluocinonide gel 0.05%); "swish and spit" for symptomatic relief (warn about dampened gag reflex).

---