What are the differential diagnoses for a 24‑year‑old woman with target‑type plaques, oral and genital erosions, fever, arthralgia, photosensitivity, eosinophilia, elevated ESR, proteinuria with cellular casts, positive ANA (speckled), anti‑ds‑DNA, rheumatoid factor, and a skin biopsy showing necrotic epidermis, subepidermal blister and apoptotic keratinocytes?

Differential Diagnoses for This Clinical Presentation

The primary differential diagnosis is systemic lupus erythematosus (SLE) with cutaneous manifestations, not erythema multiforme major, based on the constellation of fever, arthralgia, photosensitivity, proteinuria with cellular casts, positive ANA (speckled pattern), anti-dsDNA positivity, and mucocutaneous erosions in a young woman. 1, 2

Primary Diagnosis: Systemic Lupus Erythematosus

The clinical and laboratory profile strongly indicates SLE rather than erythema multiforme:

Key Diagnostic Features Supporting SLE

Renal involvement is the most statistically significant marker distinguishing cutaneous lupus from systemic disease. The presence of proteinuria (3+, 150 mg/dl) and cellular casts (1-3/LPF) has the highest statistical relevance for systemic lupus involvement. 1

Serologic markers further confirm SLE:

• Positive ANA with speckled pattern combined with positive anti-dsDNA antibodies strongly supports SLE diagnosis 3, 2
• Anti-dsDNA antibodies are independently enriched in patients with proteinuria and cellular casts 2, 4
• The combination of high ANA titers (+++), anti-dsDNA positivity, and renal manifestations indicates systemic disease rather than isolated cutaneous lupus 1

Systemic manifestations align with SLE:

• Arthralgias involving bilateral knees, elbows, and ankles are significantly associated with SLE, particularly in patients with positive anti-dsDNA 1, 2
• Photosensitivity is a recognized SLE criterion, though interestingly, anti-dsDNA positive patients may have lower rates of photosensitivity 2
• Constitutional symptoms (fever, elevated ESR of 95 mm/hr) indicate active systemic inflammation 1

Mucocutaneous involvement in SLE context:

• Oral and genital erosions can occur as presenting features of SLE, though vulval ulceration as initial presentation is rare 5
• The hemorrhagic crusting of lips and nasal mucosa is consistent with mucosal lupus involvement 5

Secondary Differential Diagnoses to Exclude

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)

This diagnosis is unlikely despite the initial clinical impression of erythema multiforme major:

• No drug exposure history: SJS/TEN is predominantly drug-triggered, and this patient has no history of drug intake before lesion onset 6, 7
• Wrong lesion morphology: SJS/TEN features flat atypical targets or purpuric macules with epidermal detachment, not the described plaques with central dark red crust and peripheral erythematous rings 6, 7
• Systemic features don't fit: The presence of proteinuria, cellular casts, positive ANA, and anti-dsDNA are not features of SJS/TEN 6
• Histopathology pattern: While both conditions show necrotic keratinocytes, the systemic autoimmune markers point away from SJS/TEN 6

DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)

This can be excluded based on:

• No drug exposure: DRESS typically occurs 2-6 weeks after drug initiation, and this patient has no drug history 8, 9
• Wrong laboratory profile: The patient has leukocytosis (12,870 cells/µL) but the differential doesn't show the characteristic eosinophilia (>700/µL or >10% of WBCs) required for DRESS 8, 9
• Mucosal involvement pattern: DRESS has notably mild or absent mucosal involvement, whereas this patient has prominent oral and genital erosions 8
• Autoantibody profile: Positive ANA and anti-dsDNA are not features of DRESS syndrome 9

Pemphigus Vulgaris

Less likely because:

• Age and presentation: While pemphigus can present with oral erosions, the systemic features (fever, arthralgia, photosensitivity, renal involvement) are not characteristic 6
• Histopathology: The biopsy showed subepidermal blistering, whereas pemphigus vulgaris shows suprabasal acantholysis 6
• Autoantibody profile: The positive ANA and anti-dsDNA point toward SLE rather than pemphigus 6

Bullous Pemphigoid

Can be excluded based on:

• Age: Bullous pemphigoid typically affects elderly patients (>70 years), not a 24-year-old woman 6
• Systemic features: The fever, arthralgia, photosensitivity, and renal involvement are not features of bullous pemphigoid 6
• Clinical context: The autoimmune serologies (ANA, anti-dsDNA) indicate systemic autoimmune disease rather than isolated bullous disease 6

Behçet Disease

Should be considered but is less likely:

• Mucocutaneous involvement: Behçet disease presents with oral and genital aphthae, which could explain the erosions 6
• However, missing features: The patient lacks the characteristic pseudofolliculitis, and the positive anti-dsDNA strongly favors SLE over Behçet disease 6
• Renal involvement pattern: Proteinuria with cellular casts is more characteristic of lupus nephritis than Behçet disease 1, 4

Critical Clinical Pitfalls

Do not dismiss renal findings: The combination of proteinuria and cellular casts is the most powerful predictor of systemic lupus involvement and should never be overlooked in a patient with cutaneous manifestations and positive autoantibodies. 1

Do not anchor on initial morphologic impression: The "target-like" lesions may superficially resemble erythema multiforme, but the complete clinical picture—particularly the systemic features and autoantibody profile—must guide diagnosis. 7

Do not wait for complete ACR criteria: This patient already demonstrates multiple SLE features (malar-like erythematous plaque on nose, photosensitivity, oral/genital ulcers, arthralgia, renal involvement, positive ANA, positive anti-dsDNA, hematologic abnormalities). Early recognition and treatment are essential. 1, 2