Pemphigus vulgaris is a life-threatening autoimmune blistering disease characterized by flaccid intraepidermal bullae and erosions of skin and mucous membranes due to IgG autoantibodies against desmoglein (Dsg) 3 and, variably, Dsg1. Loss of keratinocyte cohesion (acantholysis) produces fragile blisters, painful erosions, and significant morbidity from infection, pain, and fluid loss. Diagnosis integrates clinical findings, histopathology, and direct/indirect immunofluorescence with ELISA for Dsg1/3. First-line therapy combines systemic corticosteroids with steroid-sparing immunosuppressants or rituximab; modern regimens using early rituximab achieve higher remission and steroid-sparing benefits.
Epidemiology
- Incidence ~0.5–3 per 100,000/year; higher in Mediterranean, Middle Eastern, Ashkenazi Jewish, and South Asian populations.
- Peak onset 40–60 years; mucosal-dominant disease more common in PV than in pemphigus foliaceus.
Pathophysiology
- IgG4-predominant autoantibodies against Dsg3 (mucosal) and Dsg1 (mucocutaneous) disrupt desmosomes, leading to acantholysis.
- HLA associations (e.g., DRB10402, DQB10503) and environmental triggers; certain drugs (thiols like penicillamine, ACE inhibitors, rifampin) implicated.
Clinical Features
- Painful oral erosions (buccal mucosa, palate) often first sign; dysphagia, odynophagia.
- Flaccid bullae that rupture easily to denuded erosions on normal-appearing or mildly erythematous skin; positive Nikolsky sign.
- Scalp, face, chest, axillae; mucocutaneous PV includes skin plus mucosa; vegetans variant with hypertrophic plaques in flexures.
Differential Diagnosis
- Bullous pemphigoid (tenser bullae, urticarial base, elderly, subepidermal on histology), mucous membrane pemphigoid, aphthous/erosive lichen planus, Behçet disease, Stevens–Johnson syndrome, paraneoplastic pemphigus (polymorphous eruption with severe stomatitis and associated neoplasia).
Diagnostic Workup
- Biopsy of fresh lesion edge for H&E: suprabasal acantholysis with “row of tombstones.”
- Perilesional biopsy for direct immunofluorescence (DIF): intercellular “fishnet” IgG and C3 in epidermis.
- Serum studies: indirect immunofluorescence (IIF) on monkey esophagus/other substrates; ELISA titers for Dsg1 and Dsg3 correlate with activity.
- Baseline labs for systemic therapy; screen for hepatitis B/C, HIV, TB prior to rituximab.
Management
- General measures
- Wound care, pain control, infection prevention; oral hygiene with topical anesthetics, steroid rinses; nutritional support if odynophagia.
- Avoid trauma and friction; manage fluid/electrolyte balance in extensive disease.
- Systemic therapy
- Corticosteroids: prednisone ~0.5–1.0 mg/kg/day for control, then taper.
- Early rituximab (anti-CD20): now guideline-preferred first-line with steroids; induction 1000 mg day 1 and 15 or 375 mg/m2 weekly ×4; maintenance dosing reduces relapse.
- Steroid-sparing immunosuppressants: mycophenolate mofetil, azathioprine (TPMT/NUDT15 testing advisable), methotrexate, cyclophosphamide (reserve for refractory).
- IVIG as adjunct in refractory or when rapid steroid-sparing needed.
- Emerging/adjunct: anti–neonatal Fc receptor (FcRn) inhibitors (e.g., efgartigimod) reduce pathogenic IgG; BTK inhibitors and CAAR-T cell therapies under investigation.
- Topical/local therapy
- High-potency topical steroids for localized skin lesions; intralesional steroids for small recalcitrant plaques; dexamethasone mouth rinses for oral disease; antifungal prophylaxis for candidiasis risk.
- Monitoring and prophylaxis
- Infection vigilance; PJP prophylaxis when on high-dose steroids with another immunosuppressant.
- Vaccinations prior to rituximab when possible; avoid live vaccines during/after B-cell depletion.
- Monitor Dsg ELISA titers as adjunct to clinical assessment.
Prognosis
- With modern therapy, most achieve remission or minimal disease activity; relapses common but manageable.
- Mortality now low but higher than general population due to infections and treatment adverse effects.
References (recent guidelines and key reviews)
- European S3 and international guidelines for pemphigus management, 2020–2024 updates.
- AAD/BSID consensus statements on rituximab-first strategies, 2022–2024.
- Trials of rituximab vs steroid-sparing agents; IVIG and FcRn inhibitors, 2021–2024.