What is the pathophysiology and treatment of pemphigus?

Pathophysiology of Pemphigus

Pemphigus is an autoimmune disease characterized by IgG antibodies targeting desmosomal proteins, primarily desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), resulting in loss of keratinocyte adhesion (acantholysis) and intraepidermal blister formation. 1

Immunopathogenesis

Autoantibody Profile and Target Antigens

• Primary autoantibodies:
  • Desmoglein 3 (Dsg3): Main antigen in pemphigus vulgaris (PV)
  • Desmoglein 1 (Dsg1): Main antigen in pemphigus foliaceus (PF)
  • 50-60% of PV patients have antibodies to both Dsg3 and Dsg1 1

Mechanism of Blister Formation

1. Autoantibody binding: IgG antibodies bind to desmosomal proteins
2. Acantholysis: Loss of keratinocyte cell-cell adhesion occurs
3. Intraepithelial separation: Results in characteristic suprabasal clefting in PV
4. Clinical manifestation: Appears as flaccid blisters and erosions 2

Desmoglein Distribution and Clinical Phenotype

• The distribution pattern of Dsg1 and Dsg3 in different epithelia explains the clinical presentation:
  • Mucosal PV: Predominantly anti-Dsg3 antibodies
  • Mucocutaneous PV: Both anti-Dsg3 and anti-Dsg1 antibodies
  • Skin-predominant disease: Higher levels of anti-Dsg1 antibodies 3

Additional Pathogenic Mechanisms

• Recent studies have identified antibodies against other targets:
  • 9-alpha nicotinic acetylcholine receptor (AChR) may contribute to acantholysis 4
  • Cholinergic agonists can protect against antibody-induced acantholysis in experimental models 4

Clinical Presentation and Diagnosis

Clinical Features

• Oral mucosa: First site of involvement in majority of cases
• Skin lesions: Typically appear as flaccid blisters that rupture easily, leaving painful erosions
• Disease course: Usually chronic-relapsing with significant impact on quality of life 1, 2

Diagnostic Approach

1. Histopathology: Suprabasal acantholysis and blister formation
2. Direct immunofluorescence (DIF): Linear deposits of IgG and/or C3 in intercellular spaces of epidermis
3. Indirect immunofluorescence (IIF): Circulating IgG antibodies binding to epithelial cell surfaces
4. ELISA: Direct measurement of anti-Dsg1 and anti-Dsg3 antibodies in serum 1

Treatment Approach

First-Line Therapy

• Systemic corticosteroids: The mainstay of initial treatment
  • Effectively induces disease remission
  • Prednisolone is FDA-approved for pemphigus 5
  • Significantly reduced mortality from 75% to current levels 1

Adjuvant Therapies

• Rituximab: Anti-CD20 monoclonal antibody

  • Now considered first-line therapy in many centers
  • Results in higher remission rates and faster prednisone tapering 2
  • Targets B cells responsible for autoantibody production

• Steroid-sparing immunosuppressants:

  • Azathioprine, mycophenolate mofetil, cyclophosphamide
  • Used to reduce corticosteroid doses and associated side effects 1

Treatment Goals

1. Initial phase: Induce disease remission
2. Maintenance phase: Minimize drug doses while maintaining disease control
3. Ultimate goal: Complete treatment withdrawal 1

Complications and Prognosis

Mortality and Morbidity

• Pre-corticosteroid era: 75% mortality
• Current mortality: Significantly lower but still elevated due to treatment complications
• Mucosal-predominant PV: 1-17% mortality
• Mucocutaneous PV: 34-42% mortality 1

Treatment Complications

• Infections are a major cause of morbidity and mortality
• Long-term corticosteroid use leads to significant adverse effects
• Immunosuppressive agents carry their own risks 2

Monitoring

• Regular clinical assessment of disease activity
• Antibody titers may correlate with disease activity
• Vigilance for signs of infection and other treatment complications 1

Special Considerations

Pregnancy

• Careful selection of immunosuppression is required
• Prednisolone is preferred (90% inactivated by placenta)
• Azathioprine may be used as a steroid-sparing agent
• Avoid mycophenolate mofetil, methotrexate, and cyclophosphamide 1

Emerging Therapies

• B-cell targeted therapies beyond rituximab
• Chimeric Autoantibody Receptor T-cells targeting autoreactive B-cells
• Therapies aimed at restoring immune tolerance to desmogleins 2

Pemphigus remains a challenging autoimmune disease, but advances in understanding its pathophysiology have led to improved treatment strategies and outcomes. Early diagnosis and appropriate treatment are essential to reduce morbidity and mortality.