Skin & Subcutaneous Tissue

Erythema multiforme: diagnosis and management

Clinical Overview and When to Suspect Erythema Multiforme

— Peak age 20–40 years, slight male predominance

— Recurrence rate ~30%, almost always HSV-driven

— Abrupt symmetric eruption on acral surfaces (dorsal hands, extensor forearms, palms, soles, elbows, knees, face)

— Lesions evolve over 72 hours into the classic three-zone target: dusky/blistered center, pale edematous ring, erythematous halo

— Recent HSV outbreak (1–3 weeks prior) or Mycoplasma pneumoniae infection (especially in children/adolescents)

— New drug exposure (NSAIDs, sulfonamides, anticonvulsants, allopurinol) — though drugs more often cause SJS/TEN than EM

— EM minor: typical targets, minimal or no mucosal involvement, no systemic symptoms

— EM major: typical targets PLUS involvement of ≥1 mucosal surface (oral most common), often with fever/arthralgia; <10% BSA epidermal detachment distinguishes it from SJS

Board pearl: The single most important historical question in suspected EM is "Have you had a cold sore or genital herpes outbreak in the last 1–3 weeks?" — HSV accounts for >90% of recurrent EM, and identifying this drives long-term suppressive therapy decisions.

Key distinction: EM is NOT on the SJS/TEN spectrum in current classification — it is a distinct entity with different triggers (infection > drug), better prognosis, and different management. Mislabeling has therapeutic consequences.

Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous reaction characterized by target (iris) lesions, typically self-limited, lasting 2–4 weeks.

Pathophysiology: CD8+ T-cell–mediated cytotoxic response to viral antigens (most often HSV-1/2 DNA fragments deposited in keratinocytes), or drug-related antigenic triggers.

Epidemiology

Suspect EM when an ambulatory patient presents with:

Two clinical subtypes

Family medicine relevance: most cases are diagnosed and managed entirely outpatient with reassurance, symptomatic care, and trigger identification.

Presentation Patterns and Key History

— Day 0–2: erythematous round macules/papules, 2 cm or smaller, symmetric distribution

— Day 2–4: lesions expand and develop concentric color zones (true target with three rings is pathognomonic)

— Day 4–7: full eruption; lesions remain fixed in location for ≥7 days (unlike urticaria, which migrates within 24 h)

— Week 2–4: gradual fading with post-inflammatory hyperpigmentation, no scarring

— Oral cavity (90% of mucosal cases): painful erosions on lips, buccal mucosa, tongue; hemorrhagic crusting of vermilion border

— Ocular, genital, anal less common; if prominent, reconsider SJS

— HSV history: orolabial or genital herpes outbreaks; ask about recurrent EM episodes following them

— Recent infections: Mycoplasma (especially in <20 y/o with cough), EBV, histoplasmosis, parapoxvirus (orf), COVID-19

— Medication review (start dates within 1–8 weeks): sulfa antibiotics, NSAIDs, phenytoin, carbamazepine, lamotrigine, allopurinol, penicillins

— Vaccinations in prior month (rare trigger)

— Systemic symptoms: severe pain, dysphagia, dysuria, eye pain, skin pain out of proportion → red flags for SJS/TEN

— Recurrent EM = ≥3 episodes/year; nearly always HSV-driven even when no visible herpetic lesion precedes attack

— Average 6 episodes/year if untreated

Step 3 management: In the outpatient setting, when a patient describes "the same rash on my hands after every cold sore," document HSV-associated recurrent EM and initiate chronic antiviral suppression (covered in chunk 15) — do not just treat each flare reactively.

Prodrome (EM major or Mycoplasma-associated): low-grade fever, malaise, myalgias, mild URI symptoms for 1–14 days before rash; often absent in EM minor.

Rash evolution timeline

Distribution clue: acral and centripetal spread (extremities → trunk), opposite of viral exanthems

Mucosal involvement (EM major)

Key history checklist to anchor diagnosis

Recurrence pattern

Physical Exam Findings and Severity Assessment

— Three concentric zones: dusky/violaceous or blistered center, pale edematous middle ring, erythematous outer halo

— Diameter usually <3 cm, round, well-demarcated, fixed location

— Palpable (raised), unlike the atypical macular targets of SJS

— Lips: hemorrhagic crusting is classic for EM major

— Buccal/palate: shallow erosions, NOT confluent sheets

— Eyes: check for conjunctival injection, discharge, photophobia — if present, urgent ophthalmology

— Genitals/perianal: erosions raise concern for SJS

— Negative in EM — lateral pressure does not extend the blister

— Positive in SJS/TEN, pemphigus — critical bedside discriminator

— EM: epidermal detachment essentially 0% (occasional small central blisters only)

— SJS: <10%; SJS/TEN overlap: 10–30%; TEN: >30%

— Usually normal in EM minor

— Low-grade fever, mild tachycardia acceptable in EM major

— Hypotension, high fever, tachypnea, altered mental status → not EM; evaluate for SJS/TEN, DRESS, staph scalded skin, sepsis

CCS pearl: On a Step 3 CCS case, ordering "skin exam including mucous membranes and Nikolsky sign" plus vital signs is the foundation. A negative Nikolsky with three-zone targets on dorsal hands essentially clinches EM and steers you away from the SJS/TEN workup pathway.

Hallmark lesion: the typical target

Atypical papular targets also acceptable in EM: only two zones, raised, palpable — still considered EM if morphology and distribution fit

Distribution: symmetric on extensor extremities, dorsal hands/feet, palms/soles, face, elbows, knees; trunk involvement is minor and late

Mucosal exam (do not skip)

Nikolsky sign

BSA assessment

Vital signs and systemic exam

Diagnostic Workup — Initial Evaluation

— CBC with differential: mild leukocytosis acceptable; eosinophilia >1.5 K → think DRESS

— CMP: baseline LFTs and creatinine (drug reactions can cause hepatitis/AKI)

— CRP/ESR: nonspecific, mildly elevated

— Pregnancy test before any systemic therapy in reproductive-age women

— HSV PCR from any active vesicle or oral ulcer; serology (HSV IgG) less useful — most adults are seropositive

— Mycoplasma pneumoniae evaluation if respiratory prodrome or pediatric/adolescent patient:

· Mycoplasma IgM and/or PCR from nasopharyngeal/throat swab

· Chest X-ray if cough, hypoxia, or auscultatory findings

— Consider EBV, CMV, hepatitis B/C, HIV in atypical or recurrent cases without HSV/Mycoplasma evidence

— Build a medication chart with start dates relative to rash onset (drug-induced EM: typically 1–3 weeks after exposure)

— Discontinue all non-essential suspected drugs immediately — do not wait for confirmation

— Generally not indicated in straightforward EM

— Chest X-ray if Mycoplasma suspected

— ECG only if syncope, palpitations, or QT-prolonging therapy planned

— BSA >5%, severe mucosal disease, fever >39 °C, lymphadenopathy, facial edema, transaminitis → evaluate for SJS/TEN or DRESS

Board pearl: Mycoplasma pneumoniae–associated mucocutaneous disease in a child with prominent oral, ocular, and genital erosions but minimal skin findings is now classified as MIRM (Mycoplasma-induced rash and mucositis) — a distinct entity, not EM, with better prognosis than SJS.

EM is a clinical diagnosis. No laboratory test confirms it; testing is targeted to (a) exclude SJS/TEN/DRESS, (b) identify a treatable trigger, (c) assess severity in EM major.

Initial outpatient labs (EM major or atypical presentation)

Trigger-directed testing

Drug timeline reconstruction

When to image / ECG

Red flag findings prompting expanded workup

Diagnostic Workup — Confirmatory Studies and Biopsy

— Diagnosis uncertain

— Atypical morphology or distribution

— Concern for SJS/TEN, fixed drug eruption, autoimmune blistering disease, urticarial vasculitis

— Recurrent or refractory cases before committing to long-term therapy

— 4 mm punch biopsy from the edge of a fresh target lesion (includes erythematous border and central change)

— Send for H&E; add direct immunofluorescence (DIF) from perilesional skin if pemphigoid or vasculitis on differential

— Apoptotic (necrotic) keratinocytes at all epidermal levels

— Vacuolar interface dermatitis with basal cell damage

— Dermal lymphocytic infiltrate, often perivascular

— No full-thickness epidermal necrosis (that finding suggests SJS/TEN)

— DIF typically negative or nonspecific

— SJS/TEN: confluent full-thickness epidermal necrosis with subepidermal detachment, sparse dermal infiltrate

— Fixed drug eruption: similar interface change PLUS deep dermal pigment incontinence

— Urticarial vasculitis: leukocytoclastic vasculitis with fibrin in vessel walls

— If no HSV history and ≥3 episodes/year: consider HSV PCR from lesional skin (not just serum), evaluate for inflammatory bowel disease, hepatitis C, occult malignancy

— Patch testing rarely useful

— HLA testing (e.g., HLA-B*15:02 for carbamazepine in Asian patients) — relevant if SJS is on the differential, less so for pure EM

— Lymphocyte transformation test: research use only

Key distinction: Biopsy cannot reliably separate EM from early SJS in every case — clinical features (BSA, mucosal severity, Nikolsky, systemic toxicity) drive triage, while histology supports and excludes mimics. Do not delay management awaiting pathology.

Skin biopsy: not routinely required but indicated when:

Biopsy technique

Histopathology of EM

Distinguishing histology

Recurrent EM workup

Ancillary in drug-suspected cases

Risk Stratification and Management Logic

— Use SCORTEN only if SJS/TEN suspected; not applicable to true EM

— Features mandating dermatology/ED referral: BSA >10%, Nikolsky+, severe mucositis, hemodynamic instability, transaminitis, eosinophilia, facial edema

— EM minor: no/minimal mucosal involvement, no systemic symptoms → outpatient symptomatic care

— EM major: significant mucositis, fever, malaise → outpatient if tolerating PO and pain controlled; admit if dehydrated, severe oral disease preventing intake, or ocular involvement

— HSV: most common; treat if active lesions, suppress if recurrent

— Mycoplasma: treat with azithromycin or doxycycline (≥8 y/o)

— Drug: discontinue suspected agent; document in chart and allergy list with reaction type

— Outpatient (most cases): stable vitals, tolerating PO, mild–moderate pain, no eye involvement, reliable follow-up in 3–7 days

— Admit: inability to maintain hydration, severe mucositis, suspicion of SJS, immunocompromised host, social barriers to follow-up

— EM minor: resolves 2–3 weeks, no scarring, mortality essentially zero

— EM major: resolves 3–6 weeks, possible mucosal scarring, mortality <1%

Step 3 management: The decision tree on exam often hinges on disposition — a stable adult with classic targets on hands, mild lip erosions, normal vitals, and tolerating fluids is a home management patient with dermatology follow-up in 1 week, not an admission. Over-triaging is a wrong answer.

Step 1: Confirm it is EM, not SJS/TEN/DRESS/AGEP — this is the single highest-stakes decision.

Step 2: Classify EM minor vs EM major

Step 3: Identify and remove/treat the trigger

Step 4: Tailor symptomatic therapy (chunk 7)

Step 5: Plan follow-up and prevention (chunks 15–16)

Disposition criteria

Severity grading for prognosis discussion

Pharmacotherapy — First-Line Treatment

— Topical mid-potency corticosteroid (triamcinolone 0.1% ointment) BID to non-facial, non-intertriginous lesions × 1–2 weeks

— Low-potency (hydrocortisone 2.5%) for face/folds

— Cool compresses, bland emollients, oatmeal baths

— Oral antihistamines (cetirizine, hydroxyzine) for pruritus

— "Magic mouthwash": viscous lidocaine 2% + diphenhydramine + antacid, swish-and-spit before meals

— Topical corticosteroids: dexamethasone elixir 0.5 mg/5 mL swish-and-spit QID; or clobetasol gel applied to discrete erosions

— Soft, cool diet; avoid acidic/spicy foods

— Maintain hydration; consider IV fluids if intake <1 L/day

— HSV-associated EM, acute episode: antivirals do NOT shorten the current EM eruption once it has started, but treat active herpetic lesion with acyclovir 400 mg TID × 5 days or valacyclovir 1 g BID × 5 days

— Mycoplasma: azithromycin 500 mg day 1, then 250 mg days 2–5, or doxycycline 100 mg BID × 7–10 days

— Drug-induced: stop the drug, document allergy, no rechallenge

— Consider prednisone 0.5–1 mg/kg/day tapered over 2–3 weeks for severe EM major with disabling mucositis

— Avoid in HSV-driven recurrent EM (may prolong viral shedding and increase recurrence)

— Not first-line in uncomplicated EM

Board pearl: A common distractor: starting acyclovir during an acute EM flare does not abort the current rash — its role is chronic suppression to prevent future episodes in HSV-associated recurrent EM (≥6 episodes/year or severe episodes).

General principle: EM is self-limited; therapy is supportive and trigger-directed. No proven disease-modifying therapy shortens an acute episode.

Symptomatic skin care

Oral mucositis management

Trigger-specific therapy

Systemic corticosteroids — controversial

Pain control: acetaminophen first-line; short-course opioids only for severe mucositis

Expanded Pharmacology and Refractory Disease

— Acyclovir 400 mg PO BID × 6 months minimum, then reassess

— Valacyclovir 500 mg PO daily (better adherence, similar efficacy)

— Famciclovir 250 mg PO BID as alternative

— Trial duration: at least 6 months continuous; many patients require indefinite suppression

— If breakthrough on standard dose, increase to valacyclovir 1 g daily before declaring failure

— Confirm adherence and adequate dosing first

— Consider HSV resistance testing

— Second-line agents (dermatology-directed):

· Dapsone 100–200 mg/day (check G6PD first)

· Hydroxychloroquine 200–400 mg/day (baseline ophthalmologic exam, screen Q12 months after 5 years)

· Azathioprine 100–150 mg/day (check TPMT/NUDT15 genotype)

· Mycophenolate mofetil 1–2 g/day

· Thalidomide (last resort; teratogenic, REMS program)

— Short-course systemic corticosteroids as above

— IVIG and cyclosporine are reserved for SJS/TEN, not standard for EM

— Update EHR allergy list with specific reaction ("erythema multiforme" rather than "rash")

— Avoid entire class if cross-reactivity likely (e.g., sulfonamide antibiotics)

— Provide patient with written list and MedicAlert recommendation

— Live vaccines contraindicated during immunosuppressive therapy

— Pneumococcal and influenza vaccines recommended before initiating long-term immunosuppression

Step 3 management: For a patient with ≥3 EM episodes/year following cold sores, the correct answer is almost always valacyclovir 500 mg daily for ≥6 months, with reassessment at 6–12 months rather than reactive treatment of each flare. This is the highest-yield outpatient management point on this topic.

Chronic HSV suppression for recurrent EM (cornerstone of long-term management)

Antiviral-refractory recurrent EM (continued recurrences despite ≥6 months of adequate suppression)

Severe acute EM major adjuncts (limited evidence)

Drug allergy documentation

Vaccination considerations

Special Populations — Elderly and Renal/Hepatic Impairment

— EM less common >65; new-onset rash in this group should heighten suspicion for drug-induced SJS/TEN, bullous pemphigoid, or paraneoplastic etiologies

— Polypharmacy increases drug-trigger probability — perform systematic medication reconciliation including OTC, supplements, recently discontinued drugs

— Lower threshold for biopsy and dermatology referral

— Increased risk of dehydration from mucositis; check orthostatic vitals, BUN/Cr

— Acyclovir: dose-adjust for CrCl

· CrCl 25–50: 400 mg q12h (suppression)

· CrCl 10–25: 400 mg q24h

· CrCl <10: 200 mg q24h

· Monitor for acyclovir-induced crystalline nephropathy and neurotoxicity (confusion, myoclonus, tremor) — ensure hydration

— Valacyclovir: similar adjustments; preferred for adherence but higher cost

— NSAIDs: avoid in CKD; use acetaminophen for analgesia

— Antivirals generally safe; no major hepatic dose adjustment needed

— Avoid hepatotoxic drugs (azathioprine, methotrexate) for chronic suppression without close LFT monitoring

— Acetaminophen ≤2 g/day in cirrhosis

— HSV reactivation may be more severe and prolonged

— Consider higher-dose antivirals during acute herpetic episodes (valacyclovir 1 g TID × 7–10 days)

— Lower threshold to admit for IV acyclovir if disseminated HSV suspected

— Acyclovir 200–400 mg post-HD on dialysis days

— Avoid loading doses; risk of accumulation and neurotoxicity is high

Board pearl: Acyclovir neurotoxicity in an elderly CKD patient on standard-dose oral acyclovir presents with confusion, hallucinations, and myoclonus — discontinue, hydrate, and consider hemodialysis for severe cases. This is a common Step 3 safety/pharmacology vignette.

Elderly patients

Renal impairment dosing

Hepatic impairment

Frail/immunocompromised

Dialysis patients

Special Populations — Pregnancy and Pediatrics

— EM is uncommon but reported, often HSV-triggered or pregnancy-associated (rare)

— Acyclovir and valacyclovir are Category B (legacy); considered safe across all trimesters and routinely used for genital HSV suppression at 36 weeks to prevent neonatal HSV

— Avoid systemic corticosteroids in first trimester if possible (cleft palate risk — small but discussed); if essential, prednisone <20 mg/day preferred

— Avoid tetracyclines (doxycycline) — if Mycoplasma trigger, use azithromycin

— Avoid sulfonamides near term (kernicterus risk)

— Coordinate with OB: severe mucositis affecting nutrition warrants nutritional consult and possible admission

— In children, Mycoplasma pneumoniae is the most common trigger; HSV second

— MIRM (Mycoplasma-induced rash and mucositis): severe mucositis with sparse or absent skin lesions — distinct entity, treat Mycoplasma + supportive care; better prognosis than SJS

— Pediatric drug triggers: antibiotics (amoxicillin, sulfonamides), anticonvulsants

— Doxycycline acceptable ≥8 years; azithromycin preferred <8 years

— Acyclovir pediatric dose: 20 mg/kg PO 4×/day (max 800 mg/dose) for acute HSV; suppression: 20 mg/kg BID

— Hydration and pain control are paramount; admit for inability to maintain oral intake

— Avoid aspirin (Reye syndrome) for fever

— Address stigma, transmission risk, and confidentiality (state-specific minor consent laws apply for STI care)

— Discuss condom use and disclosure to partners

— Acyclovir and valacyclovir are compatible with breastfeeding (minimal milk transfer)

Key distinction: A child with prominent oral, ocular, and urethral erosions but only a few skin targets, a recent cough, and positive Mycoplasma serology has MIRM, not classic EM or SJS — treat with macrolide + supportive care; corticosteroids/IVIG controversial but commonly used in severe cases.

Pregnancy

Pediatrics

Adolescents and HSV counseling

Breastfeeding

Complications and Adverse Outcomes

— Post-inflammatory hyperpigmentation (especially in darker skin types) — fades over months; counsel on sun protection (SPF 30+) to minimize

— Hypopigmentation less common

— Scarring is rare in EM (helps distinguish from SJS/TEN, which often scars)

— Oral: secondary bacterial/candidal superinfection, dehydration, weight loss, dental caries from prolonged poor hygiene

— Ocular (less common in pure EM, more in SJS): conjunctival scarring, symblepharon, dry eye, corneal opacification, vision loss — any eye involvement warrants ophthalmology evaluation

— Genital/urethral: dysuria, urinary retention; rarely strictures

— Esophageal: odynophagia, rarely strictures

— 30% of EM patients have recurrences; HSV-driven cases may recur 6–10 times/year

— Significant impact on quality of life — depression, work/school absence

— Systemic corticosteroids: hyperglycemia, hypertension, mood changes, osteoporosis (long-term), infection risk

— Acyclovir/valacyclovir: nephrotoxicity (crystal nephropathy), rare TTP/HUS at high IV doses, neurotoxicity in renal impairment

— Dapsone: hemolytic anemia (G6PD), methemoglobinemia, agranulocytosis, dapsone hypersensitivity syndrome

— Hydroxychloroquine: retinal toxicity (cumulative dose >1000 g or >5 years), GI upset

— Calling SJS/TEN "EM" delays appropriate care (burn-unit-level support, ICU)

— Calling EM "urticaria" leads to unnecessary epinephrine, missed HSV suppression opportunity

— Drug-induced EM relabeled as "viral rash" → rechallenge risk and severe second reaction

CCS pearl: If a CCS case shows a patient with what looked like EM evolving to >10% BSA detachment, positive Nikolsky, and worsening mucositis over 48–72 hours, immediately re-triage to SJS/TEN protocol: transfer to burn unit or ICU, fluid resuscitation, ophthalmology, urology, and stop all suspect drugs.

Cutaneous complications

Mucosal complications (EM major)

Recurrence and chronicity

Treatment-related adverse events

Misdiagnosis hazards

When to Escalate Care

— Stable vitals, no systemic toxicity

— Tolerating oral intake and hydration

— Mild–moderate skin involvement <10% BSA

— No or mild mucositis

— No ocular involvement

— Reliable follow-up within 3–7 days

— Inability to maintain oral intake due to severe oral mucositis

— Dehydration requiring IV fluids

— Pain uncontrolled on outpatient regimen

— Immunocompromised host with active HSV

— Social barriers (homelessness, poor follow-up access)

— Pediatric patient with significant mucositis

— Diagnosis uncertain

— Atypical features or rapid progression

— Recurrent disease requiring long-term immunosuppression decisions

— Concern for SJS/TEN, DRESS, autoimmune blistering disease

— Any ocular symptom (pain, photophobia, discharge, vision change)

— Conjunctival erythema or erosions on exam

— Prevention of symblepharon is time-sensitive

— Evolution to SJS/TEN (>10% BSA, Nikolsky+, full-thickness epidermal loss)

— Hemodynamic instability or sepsis

— Respiratory compromise (airway mucositis)

— ENT/oral medicine: severe oral disease, difficulty with hygiene

— Urology: urinary retention from genital erosions

— GI: odynophagia/dysphagia with suspected esophageal involvement

— Infectious disease: refractory HSV, atypical viral triggers, HIV-positive patient

— Worsening skin pain, new blisters, eye pain, inability to drink, fever >39 °C, confusion → return immediately

Step 3 management: A stable patient with classic EM and mild oral erosions should be discharged with topical steroids, magic mouthwash, oral antiviral if HSV trigger, and dermatology follow-up in 1 week. Routine hospital admission for EM is a wrong answer.

Outpatient management is appropriate when:

Admit to general medical floor when:

Urgent dermatology consultation when:

Urgent ophthalmology consultation when:

Transfer to ICU/burn unit when:

Other specialty consults

Patient education for return precautions

Key Differentials — Other Reactive/Inflammatory Skin Conditions

— Macular atypical targets, trunk-predominant, Nikolsky positive, >1 mucosal surface severely involved, BSA detachment 1–30% (SJS) or >30% (TEN)

— Trigger: drugs >> infections (opposite of EM)

— Severe systemic toxicity, high mortality

— Key distinction: EM has acral typical targets, Nikolsky negative, BSA ≈0%, infection > drug trigger

— Urticaria: wheals migrate within 24 hours, intensely pruritic, no dusky center, respond to antihistamines

— Urticarial vasculitis: lesions fixed >24 hours, painful, leave bruising — biopsy shows leukocytoclastic vasculitis

— EM lesions are fixed for ≥7 days with true three-zone target

— Recurs at same site with drug rechallenge

— Solitary or few round dusky/violaceous plaques, often genital or lip

— Heals with marked hyperpigmentation

— Common triggers: NSAIDs, sulfa, tetracyclines, laxatives

— Drug Reaction with Eosinophilia and Systemic Symptoms

— Onset 2–8 weeks after drug initiation (longer than EM/SJS)

— Facial edema, lymphadenopathy, fever, eosinophilia, hepatitis, atypical lymphocytes

— Morbilliform rash > targetoid; mortality 10%

— Sudden pustular eruption on erythematous base, flexural predominance, high fever, neutrophilia

— Onset within 48 hours of drug (often beta-lactam)

— Tender erythematous plaques/pseudovesicles, fever, neutrophilia; associated with malignancy, IBD, pregnancy

Board pearl: The three-question discriminator between EM and SJS/TEN: (1) Where did it start? (acral = EM; trunk/face = SJS); (2) Is Nikolsky positive? (no = EM); (3) How much BSA is detached? (~0% = EM; ≥1% = SJS spectrum).

Stevens-Johnson syndrome (SJS) / TEN

Urticaria / urticarial vasculitis

Fixed drug eruption

DRESS syndrome

AGEP (acute generalized exanthematous pustulosis)

Sweet syndrome

Key Differentials — Other-Category Mimics

— Hand-foot-mouth disease (coxsackievirus A16, enterovirus 71): vesicles on palms, soles, oral mucosa in young children — overlaps with EM but lesions are vesicular gray-white macules, not true targets

— Atypical measles, parvovirus B19 ("slapped cheek" + lacy reticular rash): distribution and morphology differ

— COVID-19: pernio-like, urticarial, or rarely EM-like eruptions reported

— Bullous pemphigoid: tense bullae on urticarial base, elderly, pruritic, DIF shows linear IgG/C3 at BMZ

— Pemphigus vulgaris: flaccid bullae, Nikolsky+, severe mucosal disease, DIF shows intercellular IgG

— Linear IgA bullous dermatosis: drug-induced (vancomycin), annular "string of pearls" vesicles

— Subacute cutaneous lupus erythematosus: annular erythematous plaques on sun-exposed areas, ANA/anti-Ro positive, no true target

— Rowell syndrome: lupus + EM-like lesions, rare

— Henoch-Schönlein purpura (IgA vasculitis): palpable purpura on lower extremities/buttocks, abdominal pain, arthralgias, hematuria

— Cutaneous small-vessel vasculitis: palpable purpura, not target lesions

— Single expanding annular erythema with central clearing — "bullseye" can be confused with target

— No three-zone morphology, slowly expands over days–weeks, often single lesion, tick exposure history

— Slowly migrating annular plaques with trailing scale; chronic, not acute

— Smooth annular papules, dorsal hands/feet, chronic, no central dusky change

— Urticarial rash, arthralgias, fever 1–3 weeks after drug (cefaclor in children classically) or biologic

Key distinction: Erythema migrans of Lyme disease is a single, slowly expanding, painless annular lesion with central clearing — not a fixed multi-lesion symmetric acral target eruption. A patient with one bullseye after a hike needs doxycycline, not an EM workup.

Viral exanthems

Autoimmune blistering diseases

Connective tissue disease

Vasculitis

Erythema migrans (Lyme disease)

Erythema annulare centrifugum

Granuloma annulare

Serum sickness / serum sickness-like reaction

Secondary Prevention and Long-Term Plan

— Document specific causative drug with reaction type ("erythema multiforme") in EHR allergy list

— Provide written drug avoidance list including cross-reactive agents

— Update problem list with "recurrent EM" diagnosis if applicable

— Indications: ≥6 episodes/year, severe episodes, or significant quality-of-life impact

— Valacyclovir 500 mg PO daily (preferred for adherence)

— Acyclovir 400 mg PO BID (lower cost)

— Continue minimum 6 months, then attempt taper/discontinuation; many patients require indefinite therapy

— If breakthrough: increase to valacyclovir 1 g daily or split BID dosing

— Counsel: suppression prevents new episodes but does not abort an attack already in progress

— Single episodes are typical; no long-term prophylaxis indicated

— Educate on recognizing recurrent respiratory infection

— Lifetime avoidance of culprit and class

— Medical alert bracelet for severe reactions

— Pharmacist medication reconciliation at every encounter

— Routine immunizations per CDC schedule — EM is not a contraindication

— Document vaccine if temporally associated; report to VAERS

— Sun protection (SPF 30+, hats) for 3–6 months over lesion sites to limit hyperpigmentation

— HSV trigger reduction: stress management, lip balm with SPF, avoid sun exposure if UV-triggered HSV

— Recurrent disease can cause depression/anxiety — screen with PHQ-2/GAD-2 at follow-up

— Support groups and patient education resources (American Academy of Dermatology)

Step 3 management: For the recurrent HSV-EM patient, the single most important long-term intervention is chronic antiviral suppression — this is the highest-yield outpatient management decision and frequently the right answer on exam stems.

Trigger avoidance and documentation

HSV-associated recurrent EM — suppressive therapy

Mycoplasma-related EM

Drug-induced EM

Vaccinations

Lifestyle and sun protection

Behavioral health

Follow-Up, Monitoring, and Counseling

— Telephone or visit at 3–5 days to confirm improvement, address pain control, reinforce trigger avoidance

— Office visit at 1–2 weeks to verify resolution, document trigger, initiate suppression if recurrent

— Dermatology referral for recurrent, atypical, or refractory cases

— Baseline: BUN/creatinine, CBC

— Annual: renal function, especially in patients >60 or with CKD

— Counsel on hydration, especially during illness

— Document number of breakthrough episodes per year to assess efficacy

— Dapsone: G6PD before initiation; CBC weekly × 4 weeks, then monthly × 6 months, then quarterly; LFTs and methemoglobin level if symptoms

— Hydroxychloroquine: baseline ophthalmologic exam, repeat at 5 years then annually; CBC, LFTs annually

— Azathioprine: TPMT/NUDT15 genotype before start; CBC and LFTs weekly × 4 weeks, then monthly

— Mycophenolate: CBC monthly, contraception (teratogenic)

— Recognize early symptoms of recurrence (tingling, prodromal cold sore, early target lesions)

— When to seek care urgently: eye pain, inability to drink, fever, new mucosal involvement, skin pain out of proportion, blistering >5% BSA

— Sun protection over healing lesions

— Adherence to antiviral suppression — daily, not PRN

— Continue routine cancer screening, BP, lipids, vaccines per USPSTF

— Address any deferred preventive care during acute illness at follow-up

— Specific lesion morphology, BSA, mucosal involvement, Nikolsky status

— Suspected trigger and basis

— Treatment plan and patient education provided

— Return precautions

Board pearl: When counseling a patient starting hydroxychloroquine for refractory recurrent EM, the mandatory teaching point is baseline and annual (after year 5) ophthalmologic screening for retinal toxicity — a frequent Step 3 patient-safety question.

Acute episode follow-up cadence

Monitoring on chronic antiviral suppression

Monitoring on second-line immunosuppressants

Patient counseling priorities

Health maintenance integration

Documentation in chart

Ethical, Legal, and Patient Safety Considerations

— Failure to document a drug-induced EM reaction precisely in the EHR is a major patient-safety hazard — vague entries like "rash" can lead to rechallenge with potentially fatal SJS/TEN

— Use specific terms: "erythema multiforme due to trimethoprim-sulfamethoxazole, 2024"

— Communicate to patient: provide written allergy list, recommend MedicAlert bracelet for severe reactions

— Update pharmacy records and notify all treating clinicians

— Discuss off-label nature of antiviral suppression for EM (it is on-label for HSV suppression itself)

— Review risks: nephrotoxicity, drug interactions, cost, adherence

— Document shared decision-making

— On hospital discharge after EM major: ensure dermatology follow-up within 1–2 weeks, provide medication reconciliation explicitly listing the avoided culprit drug, send discharge summary to PCP within 48 hours

— Common safety lapse: patient discharged without antiviral suppression prescription despite documented recurrent HSV-EM

— Adolescents seeking HSV care: most states allow minor consent for STI/HSV testing and treatment without parental notification — know your state's law

— Document confidentiality discussion

— Severe drug reactions should be reported to FDA MedWatch

— Vaccine-associated reactions: report to VAERS

— These reports support post-marketing surveillance and patient safety

— Cost of chronic valacyclovir can be a barrier — generic acyclovir is inexpensive and equally effective with appropriate dosing

— Patient education materials in preferred language and at appropriate health literacy level

— Don't dismiss new mucocutaneous eruption in a patient with "known EM" — each episode requires re-evaluation for SJS/TEN evolution

— Document reassessment at each visit

Step 3 management: A patient discharged after sulfonamide-induced EM who later presents to an urgent care with sinusitis must have the allergy clearly reviewed and TMP-SMX avoided — the chart, patient education, and pharmacy systems must all reflect this. Rechallenge risks fatal SJS/TEN.

Drug allergy documentation and patient safety

Informed consent for chronic antiviral suppression

Transitions of care

Pediatric and adolescent consent

Mandatory reporting and adverse event surveillance

Health equity considerations

Avoiding diagnostic anchoring

High-Yield Associations and Rapid-Fire Facts

— HSV (>50% of cases, >90% of recurrent)

— Mycoplasma pneumoniae (especially children/adolescents)

— Drugs: sulfonamides, NSAIDs, anticonvulsants (phenytoin, carbamazepine, lamotrigine), allopurinol, penicillins

— Other infections: EBV, CMV, histoplasmosis, parapoxvirus (orf), HIV

— "Target lesion" with three concentric zones = EM

— "Iris lesion" = synonym

— Acral, symmetric, fixed ≥7 days, palpable = EM

— Hemorrhagic crusting of lips = EM major or SJS — check Nikolsky and BSA

— "Cold sore 1–3 weeks ago" = HSV-associated EM

— Urticaria: lesions move within 24 h; EM is fixed

— SJS: trunk-predominant, atypical macular targets, Nikolsky+, >1% BSA detachment

— Erythema migrans: single, expanding, after tick bite

— Fixed drug eruption: same site recurs with drug; marked hyperpigmentation

— EM: apoptotic keratinocytes + vacuolar interface dermatitis, no full-thickness necrosis

— Topical steroids + symptomatic care = mainstay

— Acyclovir/valacyclovir suppression = recurrent HSV-EM

— Azithromycin or doxycycline = Mycoplasma trigger

— Stop the drug = drug-induced EM

— Antivirals do NOT abort an acute EM eruption

— Mycoplasma > HSV in kids

— MIRM = severe mucositis + sparse skin lesions + Mycoplasma → distinct from EM/SJS

— Acyclovir: renal dose adjustment, neurotoxicity in CKD

— Dapsone: G6PD testing

— Hydroxychloroquine: retinal screening

— Azathioprine: TPMT/NUDT15 testing

— EM minor: resolves 2–3 weeks, no scarring

— Recurrence: 30%, mostly HSV-driven

— Mortality: essentially zero (EM minor); <1% (EM major)

Board pearl: If the stem mentions palms and soles + cold sore 2 weeks ago + symmetric round lesions with dusky center and pale ring, the answer is erythema multiforme — and the long-term plan is valacyclovir suppression, not lifelong steroids.

Top triggers (memorize order)

Classic exam buzzwords

Discriminators from look-alikes

Histology pearl

Treatment pearls

Pediatric pearls

Pharmacology safety pearls

Prognosis

Board Question Stem Patterns

— "A 28-year-old man presents with symmetric round lesions on the dorsa of both hands and forearms, each with a dusky center, pale ring, and red halo. Two weeks ago he had a cold sore. Lesions are non-pruritic and have been present for 5 days unchanged. Vitals normal. Lips show mild crusting."

— Answer: erythema multiforme — manage with topical triamcinolone, symptomatic care, plan suppressive valacyclovir if recurrent

— "A 45-year-old woman started TMP-SMX 10 days ago. Now has confluent dusky macules on trunk, denuded sheets on shoulder with positive Nikolsky, oral and conjunctival erosions, fever 39.5 °C."

— Answer: SJS/TEN — stop drug, transfer to burn unit/ICU, NOT erythema multiforme

— "A 32-year-old has had 8 episodes of target lesions on his hands over the past year, each preceded by an oral cold sore."

— Answer: chronic valacyclovir 500 mg daily × 6+ months

— "An 11-year-old with 1-week cough now has severe oral erosions, mild conjunctival redness, and a few target lesions on hands. CXR shows patchy infiltrate. Mycoplasma IgM positive."

— Answer: azithromycin + supportive care (MIRM/Mycoplasma-associated mucocutaneous disease)

— "A patient reports lesions that come and go within hours, intensely itchy, leaving no mark."

— Answer: urticaria, treat with antihistamines — not EM

— "Patient with prior sulfonamide-induced EM is prescribed TMP-SMX for UTI in urgent care."

— Answer: medication error — appropriate response is to discontinue, update allergy list, choose alternative (nitrofurantoin)

— "Elderly CKD patient on suppressive acyclovir develops confusion, myoclonus."

— Answer: acyclovir toxicity — discontinue, hydrate, adjust dose, consider HD

— "Single expanding bullseye on thigh after hiking in Connecticut."

— Answer: Lyme disease, treat with doxycycline

CCS pearl: On CCS, common correct orders for EM include: complete skin and mucous membrane exam, HSV PCR from lesion, Mycoplasma serology if indicated, topical triamcinolone, magic mouthwash, valacyclovir, dermatology consult if atypical, and follow-up in 1 week. Avoid ordering systemic steroids reflexively.

Stem 1 — Classic HSV-EM presentation

Stem 2 — EM vs SJS discrimination

Stem 3 — Recurrent EM management

Stem 4 — Pediatric Mycoplasma trigger

Stem 5 — Differential with urticaria

Stem 6 — Drug allergy documentation safety

Stem 7 — Acyclovir neurotoxicity

Stem 8 — Erythema migrans vs EM

One-Line Recap

Erythema multiforme is an acute, self-limited, immune-mediated mucocutaneous eruption defined by symmetric fixed acral target lesions, most often triggered by HSV (or Mycoplasma in children), diagnosed clinically, treated supportively with topical steroids and symptomatic care, and prevented from recurring through chronic antiviral suppression in HSV-associated disease.

Board pearl: When the stem gives you acral targets + recent HSV outbreak + Nikolsky negative + minimal mucosal disease, choose erythema multiforme and pair it with valacyclovir suppression as the definitive long-term answer — this is the single most testable concept on this topic.

Diagnosis is clinical: three-zone target lesions on dorsal hands/forearms, Nikolsky negative, <1% BSA detached, fixed for ≥7 days — distinguishes EM from SJS/TEN, urticaria, and erythema migrans.

Triggers drive management: HSV in adults (most common, especially recurrent EM), Mycoplasma in children/adolescents, drugs less common than in SJS/TEN — always perform medication reconciliation and ask about recent cold sores or respiratory infection.

Acute therapy is supportive: topical mid-potency corticosteroids, oral antihistamines, magic mouthwash for oral lesions, hydration, and treatment of the underlying trigger (acyclovir/valacyclovir for active HSV, azithromycin/doxycycline for Mycoplasma, stop the offending drug). Antivirals do not abort an established EM flare.

Long-term prevention is the highest-yield management point: for recurrent HSV-associated EM (≥6 episodes/year or severe episodes), prescribe chronic valacyclovir 500 mg daily (or acyclovir 400 mg BID) for at least 6 months, document the trigger and any drug allergy meticulously in the EHR with reaction type, ensure dermatology follow-up for refractory cases, and screen ophthalmology if eye involvement.