Erythema multiforme

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Erythema multiforme is an acute immune-mediated eruption with characteristic fixed target lesions, usually triggered by herpes simplex infection. Lesions typically begin acrally and extend along limbs over several days. They may itch, burn or feel tender but widespread skin pain and large areas of detachment are warning signs for another severe cutaneous reaction. Episodes commonly settle within two to four weeks, while HSV-associated disease can recur several times a year and cause substantial interruption to eating, work and sleep.

The diagnostic discipline is to describe what is present before applying the label. Record whether each target is raised or palpable and has three zones, whether distribution is acral or truncal, how long an individual lesion persists, and exactly which mucosal sites are involved. Photograph representative lesions in neutral light with consent. In deeply pigmented skin, examine side lighting, texture and the grey, violaceous or brown central zone; blanching and palpation can reveal an inflammatory rim that colour alone understates.

Older teaching treated erythema multiforme, SJS and TEN as one severity spectrum, but their dominant triggers, morphology and prognosis differ. Classic acral targets after HSV favour erythema multiforme. A new high-risk medicine followed by fever, marked skin pain, flat atypical targets or purpuric macules on the trunk, severe multi-site mucositis and detachment favours SJS or TEN and mandates emergency care. When uncertainty remains, manage to the more dangerous possibility while dermatology reviews the patient.

Key points

A classic erythema-multiforme target is a fixed round lesion with three concentric zones: a dusky or blistered centre, a paler oedematous ring and a sharply defined outer erythematous rim.
Lesions arise symmetrically on backs of hands, feet and extensor limbs and spread centripetally; they remain in the same place for days, unlike individual urticarial wheals.
On brown or black skin, the outer ring may be purple-brown and central duskiness grey or deep brown; palpability, oedema, blistering and the concentric outline may be clearer than red colour.
Herpes simplex virus is the common recurrent trigger and the target eruption often begins about ten days after a cold sore, although the herpes lesion may already have resolved.
Erythema multiforme major includes significant mucosal disease but remains clinically distinct from Stevens–Johnson syndrome and toxic epidermal necrolysis.
Prominent respiratory-associated mucositis with few skin lesions suggests reactive infectious mucocutaneous eruption rather than forcing every case into erythema multiforme.
Diagnosis is usually clinical; biopsy is useful for atypical, persistent or high-stakes presentations but histology must be interpreted with distribution, medicines, mucosa and skin pain.
First-line limited disease care is trigger review, emollient and symptom relief; severe mouth disease needs analgesia, hydration and assessment of nutrition, eyes and other mucosae.
Frequent HSV-associated recurrences merit continuous antiviral suppression, commonly aciclovir 400 mg twice daily for at least six months with specialist review.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Herpes simplex trigger

HSV-1 and HSV-2 account for many recurrent episodes through a delayed immune response rather than direct viral infection of each target.

Other infectious triggers

Respiratory and other infections occasionally precede target lesions, while severe infection-associated mucositis with sparse skin disease may fit RIME better.

Medicine association is uncommon

Medicines can precede erythema-multiforme-like eruptions, but a painful drug-related truncal eruption demands active assessment for SJS or TEN.

Some episodes remain unexplained

When no trigger is evident, morphology and clinical course should be reviewed before labelling disease idiopathic or prescribing long-term treatment.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Viral antigen reaches skin
HSV genetic material and antigen-associated immune signalling in keratinocytes recruit a cell-mediated response after the original mucocutaneous infection.
2
Interface injury forms zones
Cytotoxic injury at the epidermal junction produces central keratinocyte death, surrounding oedema and an outer inflammatory ring that evolves into a target.
3
Mucosa can share injury
The same epithelial immune reaction can erode lips, mouth, eyes or genital surfaces even when total skin detachment remains limited.
4
Immune memory permits recurrence
Repeated HSV reactivation can reproduce the delayed eruption, which explains why continuous viral suppression prevents episodes more effectively than late episodic treatment.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Classic target lesion

A fixed palpable round plaque has three sharply visible zones, often with a dusky vesicular centre and oedematous middle ring.

Acral symmetry

Targets cluster symmetrically on dorsal hands, feet and extensor limbs before spreading towards trunk and sometimes face.

Colour across pigmentation

Outer inflammation may look red, violaceous or brown while the centre appears grey, purple-black or blistered; texture and outline remain informative.

Mucosal erythema multiformeRed flag

Painful oral erosions and haemorrhagic lip crust can accompany classic skin targets; ocular, genital or airway symptoms increase severity and referral need.

HSV timing

A cold sore or genital herpes episode often precedes targets by several days, and recurrent eruptions may follow the same sequence.

SJS or TEN patternRed flag

Fever, skin pain, flat atypical truncal targets, purpura, extensive mucositis and detachment after medication indicate a different emergency phenotype.

Reactive infectious mucositis

Severe oral, ocular or genital inflammation after respiratory infection with sparse vesicles or targets suggests RIME, particularly in younger people.

Red flags requiring action

Skin pain, systemic toxicity, rapidly expanding central duskiness, epidermal detachment, inability to drink, reduced urine, breathing difficulty, visual symptoms, genital erosions, pregnancy, immunosuppression or diagnostic uncertainty requires same-day specialist assessment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Whole-skin and mucosal examinationFirst step
Why
Confirm target morphology, map severity and identify an SJS or TEN pattern.
Interpretation and limitations
Inspect scalp, eyes, mouth, genital and perianal mucosa and record pain, lesion height, three-zone structure and any detachment; ordinary-looking colour does not exclude mucosal severity.
02
Trigger chronology
Why
Link infection or medicine exposure to the correct clinical syndrome.
Interpretation and limitations
Record recent HSV lesions, respiratory symptoms, immunisation and every prescribed, over-the-counter and recreational substance with start and stop dates; temporal association alone does not prove causality.
03
HSV sampling when active
Why
Document a treatable recurrent trigger when vesicles or erosions are present.
Interpretation and limitations
PCR swab from a fresh herpes lesion is more useful than HSV serology, which mainly shows past exposure; a negative late swab does not exclude HSV-associated erythema multiforme.
04
Skin biopsy for uncertainty
Why
Support epidermal injury and exclude autoimmune blistering, vasculitis and other mimics.
Interpretation and limitations
Interface change, necrotic keratinocytes and variable epidermal necrosis are compatible but not uniquely diagnostic; clinicopathological correlation is essential because SJS can overlap histologically.
05
Severity-directed blood and fluid assessment
Why
Detect dehydration, renal injury, infection or systemic compromise in extensive disease.
Interpretation and limitations
Check observations, intake, urine, FBC, electrolytes, renal and liver tests when mucositis or systemic illness is significant; normal tests do not override evolving skin pain or ocular disease.
06
Respiratory-infection testing
Why
Investigate cough, fever or mucositis-dominant disease rather than testing every mild episode.
Interpretation and limitations
Use locally available pathogen PCR and chest assessment when the respiratory phenotype supports it; Mycoplasma serology can be difficult to interpret and should not define the eruption alone.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Stevens–Johnson syndrome

A medicine-related febrile illness with skin pain, flat atypical truncal targets, extensive mucositis and detachment requires emergency SJS or TEN management.

Urticaria

Itchy oedematous wheals migrate or disappear within a day and lack the persistent dusky three-zone centre of a true target.

Fixed drug eruption

One or several sharply demarcated dusky plaques recur at identical sites after the same medicine and leave conspicuous post-inflammatory pigment.

Autoimmune blistering disease

Tense or fragile blisters with characteristic mucosal patterns, histology and direct immunofluorescence lack the classic self-limited acral target sequence.

Urticarial vasculitis or lupus

Lesions lasting over a day with purpura, residual pigment, systemic inflammation or photosensitive interface features warrant biopsy and systemic assessment.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First diagnostic sequenceVerify targets before naming the eruptionFirst stepA sudden symmetrical annular or targetoid eruption is reported.

1Establish whether individual lesions are fixed for days and have three palpable zones, then map acral versus truncal distribution and photograph representative sites with consent.
2Examine all mucosae, measure skin pain and detachment and record systemic observations before asking about HSV, respiratory infection and a complete medicine timeline.
3Manage as possible SJS or TEN and seek same-day dermatology advice if targets are flat or atypical, pain or toxicity is prominent, multiple mucosae are severe or the diagnosis remains uncertain.

02First-line limited careRelieve symptoms and remove the active triggerFirst lineClassic targets are limited, the patient is systemically well and oral intake is secure.

1Explain the usual self-limited two-to-four-week course, use cool emollients and a short site-appropriate topical corticosteroid course for inflamed itchy plaques.
2Use a non-sedating oral antihistamine when itch is troublesome and simple analgesia when safe, while avoiding unneeded new medicines during diagnostic evolution.
3Treat active herpes according to its own indication and give return precautions for new mucosal pain, inability to drink, eye or genital symptoms, skin pain, blistering or spreading duskiness.

03Mucosal escalationProtect hydration, vision and epithelial surfacesEscalationPainful oral, ocular or genital disease limits function or creates diagnostic concern.

1Assess fluid intake, urine, weight, pain and airway and arrange same-day specialist review; admit for intravenous fluid, nutrition or analgesia when oral support is inadequate.
2Use meticulous mouth care, bland rinses and prescribed topical analgesic or corticosteroid preparations, checking total lidocaine exposure and swallowing safety rather than recommending improvised mixtures.
3Obtain urgent ophthalmology assessment for eye pain, photophobia or visual change and gynaecology, urology, ENT or respiratory input for other threatened mucosal sites.

04Recurrent HSV preventionSuppress the trigger continuouslyTypical erythema multiforme recurs repeatedly in temporal association with herpes simplex.

1Confirm the morphology and recurrence pattern, sample a fresh HSV lesion when feasible and exclude a fixed drug eruption or another repeated exposure.
2Offer continuous oral antiviral prophylaxis, commonly aciclovir 400 mg twice daily for at least six months, with renal, interaction, pregnancy and adherence review.
3Track both herpes episodes and target eruptions and reassess after the suppression period; seek dermatology advice for breakthrough disease, diagnostic doubt or need for longer therapy.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

Reduces itch and local inflammation in limited uncomplicated erythema multiforme alongside emollient and trigger care.

Site-appropriate topical corticosteroid

Apply a thin layer once daily to inflamed intact target plaques for up to seven to fourteen days, selecting potency by site and reviewing if blistering or spread continues.

Avoid potent products on eyelids, face or folds without supervision and do not apply into infected or deeply eroded skin; local improvement must not delay reassessment for SJS or mucosal compromise.

Suppresses HSV reactivation and is the preferred preventive strategy for frequent herpes-associated recurrences rather than episodic treatment after targets appear.

Aciclovir recurrent-disease suppression

Take 400 mg by mouth twice daily continuously for at least six months when recurrent HSV-associated erythema multiforme is confirmed, then review the need for continuation.

Adjust for renal impairment, maintain hydration and review neurotoxicity, nephrotoxicity, pregnancy and interacting nephrotoxic medicines; breakthrough lesions should trigger adherence and diagnostic review, not automatic dose escalation.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Dehydration and malnutrition

Painful oral erosions can prevent drinking and eating, causing renal injury, weight loss and need for inpatient analgesia and fluid support.

Ocular surface injury

Conjunctival inflammation can progress to epithelial defects, adhesions, dry eye and visual loss without prompt specialist examination and follow-up.

Genital or urinary scarring

Erosive genital disease causes pain, urinary difficulty and later adhesions or stenosis, requiring respectful examination and early specialist care.

Recurrent functional burden

Repeated HSV-associated episodes disrupt sleep, nutrition, employment, relationships and mental wellbeing even when each eruption eventually resolves.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

For an acute episode, review lesion spread, pain, blistering, oral intake, urine, temperature and every involved mucosal site until the trajectory is clearly improving.
Give photographed or written safety-net features and a contact route because an initially targetoid eruption may evolve or have been misclassified.
Record episode dates beside HSV or respiratory symptoms and all medicine exposures to expose a reproducible trigger and avoid falsely permanent drug labels.
During antiviral suppression, check renal function and interacting medicines according to risk and count both herpes reactivations and target eruptions as separate outcomes.
After severe eye, genital or oral disease, review for dryness, adhesions, scarring, dental harm, sexual or urinary difficulty and psychological impact.
Refer recurrent unexplained, persistent, atypical or treatment-resistant targetoid disease for dermatology review and reconsider lupus, autoimmune blistering, vasculitis and fixed drug eruption.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Three zones matter

The word target is often applied to any annular lesion, but a classic raised three-zone target is much more discriminating for erythema multiforme.

Wheals move quickly

Individual urticarial lesions usually fade within twenty-four hours, whereas erythema-multiforme targets stay fixed and evolve centrally over several days.

Herpes may have vanished

The triggering cold sore can heal before the immune eruption appears, so a careful preceding two-week history is more informative than current inspection alone.

Major does not mean SJS

Significant mucosal erythema multiforme is called EM major, but morphology, distribution and trigger still separate it from medicine-associated epidermal necrolysis.

Colour is one layer

In richly pigmented skin, concentric elevation, central vesiculation and fixed acral symmetry prevent dependence on a bright red outer ring.

Early episodic antiviral is late

Once targets emerge, treating a preceding HSV episode may not shorten that immune eruption; continuous suppression is used for frequent recurrences.

11Common pitfallsFrequent interpretation and management errors.

01
Calling every ringed lesion a target without confirming three zones, palpability and persistence.
02
Using erythema multiforme as a reassuring label for a painful medicine-related truncal eruption with detachment and multi-site mucositis.
03
Missing subtle grey, violaceous or brown central duskiness because the examination expects bright erythema on every skin tone.
04
Ordering HSV IgG to prove the cause of an individual episode when it mainly records common past exposure.
05
Prescribing repeated short antiviral courses after each target eruption instead of considering continuous suppression for frequent HSV-associated disease.
06
Treating severe oral pain at home without measuring hydration, urine output, ocular symptoms and the ability to swallow safely.