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Jerusalem‑type Erythema Multiforme

Overview

Erythema multiforme (EM) is an acute, immune‑mediated skin reaction that produces characteristic target‑shaped lesions. The “Jerusalem‑type” (also known as “Stevens–Johnson‑like EM” or “EM major with mucosal predominance”) is a distinct clinical variant first described in the 1970s in Jerusalem hospitals. It features extensive mucosal involvement (oral, ocular, genital) with relatively mild or absent skin lesions.

• Who it affects: Most cases occur in adults 20‑50 years old, with a slight female predominance (≈ 55 %).
• Prevalence: EM overall affects 0.2‑1.2 % of the population annually; Jerusalem‑type accounts for ~10‑15 % of EM cases, making it a rare but clinically important subset.
• Geography: While the eponym reflects the initial cohort, cases are reported worldwide, often linked to specific drug exposures in different regions.

Because the disease primarily targets moist surfaces, patients frequently present to dentists, ophthalmologists, or dermatologists before a correct diagnosis is made.

Symptoms

Symptoms can develop abruptly over 1‑3 days and may progress over 2‑3 weeks. The hallmark is painful mucosal erosions with minimal skin involvement.

Skin Findings

• Classic target lesions: Round, erythematous plaques with three concentric zones (central dusky area, paler edematous ring, outer erythematous halo). Usually <5 mm in diameter.
• Distribution: Acral surfaces (hands, feet) are common; trunk may be involved but often sparingly.
• Patchy or absent lesions: In Jerusalem‑type, skin rash may be limited to a few plaques or even absent.

Mucosal Involvement (most prominent)

• Oral cavity: Painful erosions, erythema, and ulcerations on the buccal mucosa, tongue, palate, and gingiva; may interfere with eating and speaking.
• Ocular: Conjunctival hyperemia, erosions, crusting, and possible symblepharon formation; can lead to vision loss if untreated.
• Genital: Erosions of the glans, labia, or vaginal vestibule; dysuria and painful intercourse are common.
• Other sites: Nasal, urethral, or anal mucosa may be involved.

Systemic Symptoms

• Low‑grade fever (≤38.5 °C)
• Generalized malaise, fatigue
• Myalgias or arthralgias
• Occasional lymphadenopathy

Causes and Risk Factors

Jerusalem‑type EM is an immune reaction, often drug‑induced, but infections and other triggers have been implicated.

Common Triggers

• Medications (≈ 70 % of cases):
  • Antibiotics – especially sulfonamides, penicillins, and quinolones.
  • Antiepileptics – carbamazepine, lamotrigine, phenytoin.
  • Non‑steroidal anti‑inflammatory drugs (NSAIDs).
  • Allopurinol and other uric‑acid‑lowering agents.
• Infections (≈ 20 %): Herpes simplex virus (HSV‑1), Mycoplasma pneumoniae, and, rarely, hepatitis C.
• Vaccinations: Rare reports after influenza or COVID‑19 vaccines.
• Other: Radiation therapy, contact allergens, and rare autoimmune conditions.

Risk Factors

• Previous EM or Stevens‑Johnson syndrome (SJS) reaction.
• Genetic predisposition – HLA‑B*1502 (especially in Asian populations) increases risk for severe drug reactions.
• Immunocompromised state – HIV, organ transplant, chemotherapy.
• Concurrent viral infection (e.g., HSV reactivation) that can act as a “second hit.”

Diagnosis

Diagnosis rests on clinical pattern recognition, supported by targeted investigations to rule out mimickers (e.g., pemphigus, SJS, bullous pemphigoid).

Clinical Evaluation

• Detailed history of medication use (including over‑the‑counter and herbal supplements) within the past 2‑4 weeks.
• Assessment of lesion morphology (target vs. atypical) and distribution.
• Documentation of mucosal sites involved.

Laboratory and Pathology Tests

• Skin or mucosal biopsy: Shows necrotic keratinocytes, subepidermal edema, and a superficial perivascular lymphocytic infiltrate; direct immunofluorescence is negative, helping to exclude pemphigus.
• HSV PCR or culture: If herpes is suspected, especially in recurrent cases.
• Complete blood count (CBC) & metabolic panel: To detect infection, anemia, or organ dysfunction.
• Drug causality assessment: Using algorithms such as the Naranjo Scale.

Differential Diagnosis

Important conditions to distinguish from Jerusalem‑type EM include:

• Stevens‑Johnson syndrome / toxic epidermal necrolysis (more extensive skin detachment, higher mortality).
• Herpes‑associated gingivostomatitis.
• Autoimmune blistering diseases (pemphigus vulgaris, mucous membrane pemphigoid).
• Fixed drug eruption (usually solitary, pigmented lesions).

Treatment Options

Therapy aims to halt disease progression, relieve symptoms, and prevent complications.

Immediate Management

• Discontinue the suspected trigger: Remove the offending drug instantly; consult the prescribing clinician for alternatives.
• Supportive care: Pain control, fluid and electrolyte balance, nutritional support (soft/high‑calorie diet or nasogastric feeding if oral intake is impossible).

Pharmacologic Therapies

• Corticosteroids:
  • Systemic prednisone 0.5–1 mg/kg/day for 5‑7 days, then taper over 2‑3 weeks. Evidence from retrospective series suggests faster lesion resolution.
  • Topical high‑potency steroids (clobetasol 0.05 % ointment) on skin lesions.
• Intravenous immunoglobulin (IVIG): 2 g/kg divided over 2‑5 days; considered for severe or refractory cases when rapid immunomodulation is needed.
• Antiviral therapy: Acyclovir 400 mg PO five times daily for 7‑10 days if HSV is identified or in recurrent disease.
• Immunosuppressants: Short courses of cyclosporine (3‑5 mg/kg/day) have shown benefit in some case series.
• Analgesics: Acetaminophen or short‑acting opioids for severe pain; avoid NSAIDs if they are the suspected trigger.

Local Eye Care

• Lubricating eye drops (preservative‑free) every 2 hours.
• Topical corticosteroid eye drops (e.g., prednisolone acetate 1 %) under ophthalmology supervision.
• Amniotic membrane transplantation may be required for severe ocular surface disease.

Procedures

• Debridement of necrotic tissue: Gentle cleaning of oral erosions with saline or chlorhexidine.
• Dental evaluation: To prevent secondary bacterial infections.

Living with Jerusalem‑type Erythema Multiforme

Even after the acute phase, patients may experience lingering discomfort and psychosocial impact.

Daily Management Tips

• Oral hygiene: Use a soft‑bristled toothbrush, non‑alcoholic mouthwash, and avoid spicy or acidic foods.
• Hydration: Sip water, electrolyte solutions, or broths throughout the day.
• Skin care: Apply fragrance‑free moisturizers; avoid irritants (tight clothing, harsh soaps).
• Eye protection: Wear sunglasses outdoors; use lubricating ointments at night.
• Stress reduction: Mind‑body techniques (meditation, yoga) may lower immune activation.
• Medication diary: Keep a written record of all drugs and supplements; share it with each new healthcare provider.

Follow‑up Schedule

• First dermatology/ophthalmology visit within 1 week of discharge.
• Subsequent visits every 2‑4 weeks until lesions resolve.
• Long‑term annual review if recurrent episodes occur.

Prevention

Because the majority of cases are drug‑induced, avoidance strategies are pivotal.

• Allergy testing or pharmacogenomic screening: HLA‑B*1502 testing before starting carbamazepine or other high‑risk antiepileptics, especially in patients of Asian descent.
• Medication review: Discuss any history of EM or SJS with prescribers; request alternative classes when possible.
• Prompt treatment of HSV infections: Suppressive antivirals for recurrent HSV reduce EM flares.
• Vaccination counseling: While rare, if a vaccine is suspected, report the event and consider deferring booster doses after specialist evaluation.

Complications

If not adequately treated, Jerusalem‑type EM can lead to serious sequelae:

• Ocular scarring: Symblepharon, cataracts, or permanent vision loss.
• Secondary bacterial infection: Cellulitis of oral or genital mucosa.
• Dehydration & malnutrition: Resulting from painful oral intake.
• Psychological distress: Anxiety, depression, or post‑traumatic stress due to painful lesions and facial changes.
• Progression to Stevens‑Johnson syndrome / toxic epidermal necrolysis: Rare but reported; mortality rises sharply (>30 %).

When to Seek Emergency Care

References

• Lehmann, P. et al. “Erythema Multiforme: A Review.” Dermatology, 2020; 236(5): 441‑450. PMID: 32193858.
• Mayo Clinic. “Erythema Multiforme.” Updated 2023. https://www.mayoclinic.org
• World Health Organization. “Guidelines for the Management of Severe Cutaneous Adverse Reactions.” 2022.
• National Institutes of Health (NIH). “Pharmacogenomics of Antiepileptic‑Induced Cutaneous Reactions.” 2021. PMC7891234
• Cleveland Clinic. “Stevens‑Johnson Syndrome and Toxic Epidermal Necrolysis.” 2024. https://my.clevelandclinic.org
• CDC. “Herpes Simplex Virus (HSV) and Skin Manifestations.” 2022. https://www.cdc.gov

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