Erythema multiforme

Overview and Definition

EM is recognised by a pattern, not by a trigger alone. Typical lesions are palpable targets on the distal limbs, although raised atypical targets and mucosal disease can occur. Most episodes settle spontaneously, but oral or ocular disease can cause substantial morbidity. EM and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are not severity grades of one disease.[1]

A typical target has three zones: a central dusky, purpuric or blistered area; a paler oedematous ring; and an outer erythematous ring. The complete lesion is raised. By contrast, SJS/TEN usually begins with painful purpuric macules or flat atypical targets that blister and detach. Trigger patterns help, but morphology and evidence of epidermal necrolysis determine the urgent clinical pathway.[1]

Classification and Current Nomenclature

The traditional examination language is EM minor and EM major. EM minor has the characteristic skin eruption with no mucosal disease or mild disease limited to one surface. EM major retains the same raised-target morphology but has more severe mucosal involvement, historically often involving at least two surfaces. These boundaries overlap, so a 2024 review proposes the more useful labels non-severe and severe EM, based on pain, oral intake and organ-threatening mucosal disease rather than counting sites alone.[1]

Reactive infectious mucocutaneous eruption (RIME) describes prominent infection-triggered mucositis with variable, often sparse skin disease. Mycoplasma pneumoniae-induced rash and mucositis (MIRM) is the M. pneumoniae-associated form of RIME. A systematic review proposed MIRM as distinct from both EM and SJS/TEN; later literature accepts the RIME umbrella but still debates whether RIME/MIRM overlaps a broad EM spectrum. Keep the labels separate in an answer and state the uncertainty.[2][10][1]

Epidemiology and Triggers

Reliable population data are sparse. Published estimates place prevalence between 0.01% and 1%, and young adults are most often affected; sex estimates vary between series. Avoid quoting a single precise incidence or a fixed male predominance.[1]

HSV-1 or HSV-2 is the best-established and most common recognised trigger. The preceding herpes lesion may be obvious, remote or subclinical, and HSV and EM episodes do not always run in parallel. M. pneumoniae is another important association, particularly when respiratory symptoms and severe mucositis coexist. Other infections and vaccines are reported, but a temporal association does not prove causation.[1]

Many recurrent cases remain idiopathic. In one referral series of 48 patients, HSV was the attributed cause in a minority and no cause was identified in more than half; therefore “recurrent EM is always HSV” is unsafe. Paediatric reports are also heterogeneous and vulnerable to historical misclassification, so investigate the clinical syndrome rather than assuming M. pneumoniae is the dominant childhood trigger.[6][7]

Drug causality is possible but uncommon and difficult to establish because SJS/TEN and other drug eruptions have often been labelled EM. A recent drug, flat purpuric lesions, skin pain or detachment should activate an SJS/TEN assessment rather than a reassuring “drug-induced EM” label.[9][1]

Who gets it, and what lights the fuse

The best-studied model is herpes-associated EM, but it remains a model rather than a completed mechanism. Fragmented HSV DNA may be carried from the infection site by macrophages or CD34-positive progenitor cells to distant keratinocytes. Viral antigen expression then recruits a type 1 helper T-cell response with interferon-gamma signalling and autoreactive T-cell-mediated epidermal injury. The epidermis is responding to transported viral material; EM skin is not simply an active HSV infection.[1]

RIME/MIRM pathogenesis is also uncertain. Proposed mechanisms include direct epithelial injury and immune-complex-mediated vascular injury; neither should be presented as proven. Persistent EM may involve different inflammatory pathways from acute herpes-associated disease.[1]

Skin disease is symmetric, acral, and arrives in crops. Erythematous macules evolve into papules and targets over 24 to 72 hours on the extensor forearms and legs, dorsal hands and feet, palms, soles, elbows, knees and face; the trunk stays relatively quiet. Atypical cases show targetoid lesions without the full three-zone architecture, or vesicular and bullous variants — these are the ones that send you to biopsy.[1][7]

Skin

Lesions usually appear symmetrically on dorsal hands and feet and spread centripetally to extensor limbs and sometimes the face. Palms and soles may be involved. Individual lesions persist rather than migrating over hours. Crops can produce macules, papules, vesicles and bullae alongside mature targets; atypical targets can occur but remain raised in EM.[1]

Mucosa and systemic illness

Oral disease ranges from a few erosions to abrupt, extremely painful post-bullous erosions with haemorrhagic lip crusting and impaired intake. Ocular and genital surfaces may also be affected. The functional consequences — pain, hydration, nutrition, urinary symptoms and ocular surface injury — determine urgency.[1]

Systemic symptoms are usually mild in classic EM. Respiratory symptoms followed by prominent oral, ocular or urogenital mucositis with sparse or variable skin lesions should prompt assessment for RIME/MIRM. Do not force that presentation into EM major, and do not call it SJS/TEN solely because several mucosal sites are involved.[2][10]

• SJS/TEN: skin pain, purpuric macules or flat atypical targets with blistering, widespread or confluent blistering, and/or detachment; often trunk-predominant and drug-associated. A central blister within an otherwise raised three-zone EM target is compatible with EM.
• RIME/MIRM: respiratory prodrome and prominent mucositis with sparse or variable skin lesions; infection-triggered and nomenclaturally separate.
• Hand-foot-and-mouth disease: oral lesions plus acral vesicles, usually in a child or exposed adult; enterovirus context.
• Rowell syndrome or lupus-associated epidermal necrolysis: lupus phenotype or serology with targetoid/necrolytic lesions.
• Generalised fixed drug eruption, DRESS and AGEP: exposure chronology and their characteristic recurrent, systemic or pustular pattern distinguish them.
• Behçet disease and complex aphthosis: recurrent oral/genital ulcers without the characteristic acute raised-target eruption.[1]

Histopathology and Biopsy

Biopsy is not a definitive EM-versus-SJS/TEN test. It is useful when morphology is atypical, an autoimmune blistering disorder or lupus is possible, or clinicopathological correlation may change the emergency pathway. Sample a fresh representative lesion for routine histology; take a separate perilesional specimen for direct immunofluorescence when an immunobullous differential is being assessed.[1]

Typical EM shows an interface dermatitis with mild-to-moderate lymphocytes, basal vacuolar change and scattered apoptotic keratinocytes. Papillary dermal oedema and spongiosis vary. Confluent keratinocyte apoptosis, necrolysis and even detachment can occur, particularly in M. pneumoniae-associated disease, so “full-thickness necrosis means SJS/TEN” is false. Direct immunofluorescence is generally nonspecific rather than diagnostically positive or uniformly negative.[1][8]

Clinical Assessment and Trigger Work-up

At the bedside, first decide whether epidermal necrolysis or another emergency is possible. Record pain, lesion morphology, distribution, blistering, detachment and all mucosal sites. A positive Nikolsky sign or sloughing strongly supports an epidermal-necrolysis pathway, but its absence does not replace the full assessment. Check hydration, oral intake, urine symptoms, respiratory status and the ocular surface.[1]

• HSV: if a suspicious fresh oral, genital or skin lesion is present, sample it for PCR. Routine HSV antibody titres do not establish recurrent herpes-associated EM.
• Respiratory-associated severe disease: perform a full lung examination; obtain chest imaging and respiratory M. pneumoniae PCR where available, with serology interpreted in clinical context.
• Biopsy: use for atypical disease or a meaningful differential, not as an automatic test in classic mild EM.
• Drug assessment: document onset, stop a plausible culprit when a severe drug reaction is possible, and obtain urgent specialist advice rather than using an unvalidated EM drug list.[1]

Acute and Supportive Management

Most non-severe EM needs explanation, skin care and safety-netting rather than resuscitation. Admit when pain prevents oral intake, hydration or nutrition cannot be maintained, ocular/genital complications need specialist care, respiratory compromise is present, or SJS/TEN remains possible.[1]

• Skin: bland emollient or petrolatum; a topical corticosteroid may be considered for inflamed lesions.
• Pain and fever: use age-, comorbidity- and region-appropriate simple analgesia; severe mucosal pain may require inpatient opioid analgesia.
• Mouth: frequent gentle oral care, an antiseptic or local-anaesthetic rinse/gel where appropriate, and food/fluid modified to tolerance. Escalate to enteral hydration or feeding if oral intake fails.
• Eyes: same-day ophthalmology for symptoms or signs of ocular involvement. Preservative-free lubrication may be started; topical corticosteroid, antibiotic treatment or procedures belong under ophthalmology direction.
• Genital/urinary disease: barrier care, analgesia, monitoring for retention and gynaecology/urology input when severe.
• Antibiotics: treat confirmed or strongly suspected M. pneumoniae respiratory infection according to local antimicrobial guidance. The effect of antibiotics on the mucocutaneous course of RIME/MIRM is not established, so do not promise that a macrolide treats the eruption itself.[1][2]

Systemic corticosteroids are not routine therapy. In retrospective hospital practice, prednisone-equivalent doses of 0.5–1 mg/kg/day, reduced rapidly over 10–15 days, were used in some severe cases, but benefit on pain, intake or length of stay was not demonstrated. If considered at all, the phenotype must be secure and dermatology should lead the decision.[1][5]

Aciclovir started after the EM eruption is established has not been shown to shorten that acute episode. Treat a concurrent HSV infection for its own indication, but distinguish that from preventing future EM.[1][3]

Recurrent and Persistent EM

Continuous oral antiviral prophylaxis is first line for frequent or burdensome recurrent EM, including idiopathic recurrent EM because subclinical HSV can be contributory. Do not require an arbitrary “more than six attacks per year” threshold. Supported adult regimens are aciclovir 400 mg orally twice daily, valaciclovir 500 mg orally twice daily, or famciclovir 250 mg orally twice daily, initially for at least 6 months. Adjust for age, renal function, interactions, pregnancy and local formulary advice.[1][3][4]

The placebo-controlled trial directly supports continuous aciclovir, while evidence for the broader strategy is limited. Responders may continue prophylaxis for 1–2 years before a supervised withdrawal attempt; relapse can be managed by restarting the lowest effective regimen. Breakthrough disease should first prompt adherence review, dose/formulary review and reconsideration of the diagnosis.[4][1][5]

Dapsone, azathioprine, mycophenolate mofetil, thalidomide/lenalidomide and newer targeted agents have been reported for antiviral-refractory recurrent or persistent EM. Evidence consists mainly of small retrospective series and case reports, adverse-effect burdens are substantial, and no universal sequence is established. These are specialist options after the diagnosis and trigger assessment are revisited, not an MBBS prescribing list.[3][5][1]

Complications, Prognosis and Follow-up

Most acute EM resolves over days to a few weeks, but “benign” should not erase mucosal morbidity. Pain, dehydration, weight loss, ocular or genital scarring, pigmentary change and recurrence can occur. Severe RIME/MIRM also has reported mucosal damage, scarring and recurrence; published estimates are affected by referral and publication bias.[1][2]

Community discharge requires preserved oral intake, no concerning eye/genital/respiratory finding, no detachment phenotype and a clear return plan. Photograph lesions where consented, document drugs and likely infections, and arrange review for diagnostic uncertainty or recurrence. Recurrent or persistent targetoid disease despite adequate antiviral prophylaxis warrants dermatology review and reconsideration of autoimmune blistering disease, lupus, fixed drug eruption and paraneoplastic pemphigus.[1][6]

Special Populations

• Children: do not equate every respiratory prodrome with MIRM. Examine all mucosae, assess intake early and use local paediatric antimicrobial and medicine dosing when RIME/MIRM or pneumonia is diagnosed.[7][2]
• Pregnancy and lactation: preserve the same diagnostic distinctions; medicine choice and antiviral dose require obstetric/pharmacy review rather than a blanket safety statement.
• Older or immunocompromised patients: broaden the infection, drug-reaction and immunobullous differential; check renal function before oral antivirals and admit earlier when intake or diagnosis is unsafe.[1]

Evidence and Regional Practice

There is no single internationally harmonised EM guideline and treatment evidence is sparse. Local differences mainly reflect antiviral formularies, antimicrobial resistance guidance, access to dermatology/ophthalmology and thresholds for admission. The most defensible evidence statement is that supportive care is the acute cornerstone, continuous aciclovir has placebo-controlled evidence for recurrent EM, and systemic corticosteroid or specialist immunomodulator evidence remains low certainty.[4][5][1]