What is pemphigus?

What is Pemphigus?

Pemphigus is a group of potentially life-threatening autoimmune diseases characterized by IgG antibodies targeting desmosomal proteins (primarily desmoglein 3 and desmoglein 1), resulting in intraepithelial blistering and erosions of the skin and mucous membranes due to loss of cell-to-cell adhesion (acantholysis). 1, 2

Disease Classification

Pemphigus encompasses three major subtypes with distinct clinical presentations:

• Pemphigus Vulgaris (PV): The most common variant, characterized by IgG antibodies against desmoglein 3 (Dsg3), with approximately 50-60% of patients also developing Dsg1 autoantibodies 1, 2
• Pemphigus Foliaceus: Characterized by antibodies primarily against desmoglein 1 3
• Paraneoplastic Pemphigus: A rare variant associated with underlying malignancy 4

Pathophysiology

The autoimmune attack disrupts keratinocyte adhesion through the following mechanism:

• IgG autoantibodies bind to desmoglein proteins in desmosomes, which are critical cell-cell adhesion structures 3
• This antibody binding causes acantholysis (separation of keratinocytes from each other) 1, 5
• The specific desmoglein targeted and its tissue distribution determine where blisters form 3
• Suprabasal acantholysis produces the characteristic intraepithelial split seen on histology 1, 2

Clinical Presentation

Pemphigus Vulgaris Specific Features

The oral mucosa is the first site of involvement in the majority of PV cases, and diagnostic delay is very common when disease remains confined to oral surfaces. 1, 2

• Oral lesions present as flaccid blisters that rapidly rupture, leaving painful erosions primarily on the palatal mucosa 2, 5
• Skin involvement typically follows oral lesions by an average lag period of 4 months 1
• A minority of patients present with cutaneous erosions first, but oral erosions eventually occur in most cases 1
• Peak frequency occurs in the third to sixth decades of life 2
• Certain ethnic groups show increased susceptibility, including Ashkenazi Jews and those of Mediterranean and Indian origin 6, 7

Diagnostic Criteria

Diagnosis requires three independent parameters:

Histological Examination

• Perilesional skin or mucosal biopsy showing suprabasal acantholysis with blister formation 1, 2

Direct Immunofluorescence (DIF)

• DIF remains the gold-standard diagnostic investigation, showing characteristic deposition of IgG and/or complement on the cell surfaces of epithelial keratinocytes (intercellular spaces). 1, 2
• Sensitivity of 89% in oral biopsies 2

Serological Testing

• Indirect immunofluorescence (IIF) demonstrates circulating IgG antibodies but is less sensitive than DIF 1, 2
• ELISA testing offers direct measurement of Dsg1 and Dsg3 antibodies in serum with increased sensitivity 1, 2
• IIF and ELISA should be considered complementary tests 1

Disease Severity and Prognosis

Historical Mortality

Before the introduction of corticosteroids in the early 1950s, pemphigus vulgaris had an average mortality of 75%, primarily from dehydration or secondary systemic infections. 1, 2

Contemporary Outcomes

• Mortality varies significantly by clinical phenotype 1, 2
• Predominantly mucosal PV: 1-17% mortality 1, 2
• Mucocutaneous PV: 34-42% mortality 1, 2
• Mucocutaneous PV tends to be more severe, responding slower to treatment and less likely to achieve remission off-treatment than purely mucosal disease 1

Treatment Principles

The main aim of treatment is to reduce inflammatory response and autoantibody production to achieve disease remission:

• Systemic corticosteroids remain the mainstay of therapy 5, 7
• Adjuvant immunosuppressive agents (such as azathioprine) are commonly used for steroid-sparing effects 5, 7
• Rituximab (anti-CD20 monoclonal antibody) has emerged as a promising therapeutic option that may become first-line therapy 8, 3
• In the FDA-approved rituximab study for pemphigus vulgaris, patients receiving rituximab with short-term prednisone achieved superior complete remission rates compared to prednisone monotherapy 8

Key Clinical Pitfalls

Diagnostic delay is very common when PV is confined to the oral mucosa, as oral lesions may precede cutaneous involvement by months and can be misdiagnosed as other oral conditions. 2

• Always maintain high clinical suspicion for pemphigus in patients with persistent oral erosions 1, 2
• Obtain both histology and DIF from perilesional tissue; in isolated oral disease, take DIF from uninvolved buccal mucosa 1
• Without treatment, patients can develop severe complications including esophageal and laryngeal stenosis, strictures, and in the case of ocular involvement (mucous membrane pemphigoid), blindness 1