What is pemphigus, including its disease type and pathology?

Pemphigus: Disease Overview and Pathology

Pemphigus is a group of potentially life-threatening autoimmune blistering diseases characterized by IgG autoantibodies targeting desmosomal proteins (primarily desmoglein 1 and 3), resulting in intraepidermal acantholysis that manifests clinically as flaccid blisters and erosions of the skin and mucous membranes. 1, 2

Disease Classification and Subtypes

Pemphigus encompasses several distinct clinical variants, each with unique characteristics:

Major Subtypes

• Pemphigus Vulgaris (PV): The most common variant, characterized by IgG antibodies directed against desmoglein 3 (Dsg3), with approximately 50-60% of patients also having Dsg1 autoantibodies 1, 3, 2

  • Oral mucosa is the first site of involvement in the majority of cases, with disease potentially remaining confined to mucosal surfaces or extending to involve skin (average lag period 4 months) 1
  • Presents with suprabasal acantholysis and blister formation histologically 1
  • Peak frequency occurs in the third to sixth decades of life 1

• Pemphigus Foliaceus (PF): Characterized by autoantibodies against desmoglein 1 (Dsg1) 2

  • More superficial blistering pattern compared to PV 4

• Paraneoplastic Pemphigus: Associated with underlying malignancies 4, 5, 2

• Pemphigus Herpetiformis: An atypical variant with distinct clinical presentation 4, 5

• IgA Pemphigus: Characterized by IgA rather than IgG autoantibodies 4, 5

Pathophysiology

Autoimmune Mechanism

• The disease results from an autoimmune process where IgG antibodies target keratinocyte desmosomal cadherins, interfering with the adhesive function of these molecules 6
• This antibody-antigen interaction leads to separation of keratinocytes (acantholysis) and clinical manifestation of blistering 6
• The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms 2

Histological Features

• Intraepidermal cleavage is the hallmark histological finding, distinguishing pemphigus from subepidermal blistering diseases like bullous pemphigoid 4
• Suprabasal acantholysis and blister formation are highly suggestive of PV 1
• Direct immunofluorescence (DIF) shows characteristic deposition of IgG in the intercellular spaces of the epidermis 1

Genetic Factors

• There is a fairly strong genetic background with linkage to HLA class II alleles 3
• Certain ethnic groups are especially susceptible, including Ashkenazi Jews and those of Mediterranean and Indian origin 3

Clinical Presentation

Pemphigus Vulgaris Specific Features

• Oral erosions occur in almost all cases, with the oral mucosa being the first site of involvement in the majority 1
• Cutaneous lesions present as flaccid blisters that readily rupture, with new bullae developing as older ones rupture and ulcerate 3, 6
• Oral lesions consist of small blisters or erosions found mainly on the palatal mucosa 1

Disease Severity Stratification

• Studies differentiating by clinical phenotype show lower mortality in patients with predominantly mucosal PV (1-17%) compared to those with mucocutaneous PV (34-42%) 1

Diagnostic Criteria

Diagnosis requires three independent groups of criteria 6:

1. Clinical features: Flaccid blisters and erosions on skin and oral mucosa
2. Histologic findings: Epidermal acantholysis
3. Immunological tests: Circulating and skin-fixed antibodies against keratinocyte surface antigens

Laboratory Confirmation

• Direct Immunofluorescence (DIF): Perilesional, intact skin or clinically uninvolved tissue shows IgG deposition in intercellular spaces 1

  • Sensitivity of DIF is 89% in oral biopsies compared with 85% for indirect immunofluorescence (IIF) 1

• Indirect Immunofluorescence (IIF): Demonstrates circulating IgG binding in a linear pattern at the basement membrane 1

• ELISA Testing: Direct measurement of Dsg1 and Dsg3 antibodies in serum, offering advantages over IIF and potentially superseding this technique 1

Epidemiology and Prognosis

Historical Context and Mortality

• Before the introduction of corticosteroids in the early 1950s, the mortality of PV was approximately 75% on average, mainly from dehydration or secondary systemic infections 1, 3
• The prognosis, mortality, and clinical outcomes in pemphigus have undergone dramatic change throughout the years with modern immunosuppressive therapy 4

Disease Burden

• Pemphigus is a rare disease with considerable variation in epidemiological features across different regions of the world 4
• The disease has a chronic course leading to high morbidity and mortality 4
• Observational studies examining comorbidities and associations among patients with pemphigus are scarce and sometimes inconclusive 4

Pathophysiological Roles of Immune Cells

• The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity 2
• This understanding has led to the development of targeted therapies, particularly rituximab (anti-CD20+ B cell therapy), which is a promising therapeutic option that may soon become first-line therapy 2

Key Clinical Pitfalls

• Delayed diagnosis: Oral lesions may precede cutaneous involvement by months, and pemphigus may be misdiagnosed as other oral conditions 1
• Incomplete diagnostic workup: All three diagnostic criteria (clinical, histological, and immunological) should be confirmed; relying on clinical features alone can lead to misdiagnosis 6
• Distinguishing from bullous pemphigoid: The level of cleavage (intraepidermal in pemphigus vs. subepidermal in bullous pemphigoid) is critical for correct diagnosis and treatment planning 4