Pemphigus

Pemphigus is an autoimmune blistering skin disease that affects the epithelium, including skin and mucous membranes. Broad serologic screening is recommended unless a specific immunobullous skin disease type is suspected.

Quick Answers for Clinicians

Which testing algorithms are related to this topic?

Diagnosis

Indications for Testing

Chronic, recurring bullae (blisters), erosive or crusting/scaling skin, and/or mucous membrane disease, not attributable to more common skin disorder

Laboratory Testing

  • Direct immunofluorescence (DIF) performed on perilesional skin biopsy
    • Immunohistology
      • Perilesional skin biopsy – cutaneous DIF submitted in Michel’s transport medium or Zeus fixative
        • Pemphigus vulgaris, vegetans, and foliaceus
          • IgG and C3 (third component of complement) are detected on cell surfaces (formerly referred to as intercellular substance) of epidermal and stratified squamous epithelial cells in and around affected skin areas
          • Location of IgG and C3 cell surface staining within epithelium may indicate subtype of pemphigus
            • Cell surface staining is typically around basal cells in pemphigus vulgaris and vegetans, whereas staining is higher in epithelium in pemphigus foliaceus
            • Enzyme-linked immunosorbent assay (ELISA) testing for desmoglein 1 and 3 antibodies may better distinguish pemphigus subtypes
        • Pemphigus erythematosus
          • Features of pemphigus and lupus erythematosus are present on histologic examination of formalin-fixed tissue and show cell surface antibodies with granular immune deposits at the basement membrane zone (BMZ) by DIF, with or without positive lupus serologies
        • IgA pemphigus (rare)
          • IgA (with or without C3) – detected on cell surfaces of epidermal and stratified squamous epithelial cells in and around affected areas
  • Initial serum testing – pemphigus panel, pemphigoid panel, and endomysial antibodies (all 3 tests for initial testing), or epithelial skin antibodies testing
    • Broad epithelial antibody screening recommended unless a specific immunobullous skin disease type is suspected due to overlap in clinical presentations of immunobullous disease
    • Pemphigus types with IgG cell surface antibodies are more common than IgA pemphigus – ruling out IgG pemphigus prior to testing for IgA pemphigus is recommended
  • Serum IgG cell surface antibody testing
    • IgG cell surface antibodies detected in serum by indirect fluorescent antibody (IFA) testing on intact human skin and monkey esophagus substrates
    • Testing for IgG cell surface and desmoglein antibodies is highly sensitive and specific for IgG pemphigus types – see Paraneoplastic Pemphigus topic
      • Up to 80% of pemphigus patients have IgG antibodies present in serum
        • Presence of IgG cell surface antibodies and desmoglein antibodies in serum correlates with disease activity in the most common types of pemphigus (pemphigus vulgaris and pemphigus foliaceus)
      • Useful for establishing the diagnosis of most pemphigus types
      • Can distinguish pemphigus from other immune-mediated skin disease, including other immunobullous diseases
      • Cell surface antibodies are pathogenic (not epiphenomena of the disease)
      • IFA is often positive in paraneoplastic pemphigus, showing cell surface antibody staining (desmoglein antibodies may or may not be positive)
  • Serum desmoglein 1 and 3 IgG antibodies
    • Desmoglein 1 autoantibodies predominate in pemphigus foliaceus (likely pemphigus erythematosus)
    • Desmoglein 3 autoantibodies are present in pemphigus vulgaris (likely pemphigus vegetans)
    • Although predominant antibodies differentiate the subtypes of pemphigus, overlap may occur
      • Patients with both skin and mucosal lesions may have IgG antibodies to desmogleins 1 and  3
      • Predominant antibody may change over course of disease
    • Nondesmoglein antibody pemphigus has been described – IFA testing and desmoglein 1 and 3 IgG antibodies testing are advised for diagnosis
  • Serum IgA cell surface antibody testing
    • Cell surface antibodies detected by IFA on intact human skin and monkey esophagus substrates
    • Testing for IgA cell surface antibodies is important in diagnosis of IgA pemphigus – highly sensitive and specific
    • Can distinguish IgA pemphigus from other pemphigus variants and other immune-mediated skin diseases

Differential Diagnosis

  • Infectious
  • Aphthous stomatitis
  • Other autoimmune skin diseases
  • Lichen planus
  • Erythema multiforme
  • Drug reaction
  • Vasculitis
  • Systemic lupus erythematosus
  • Stevens-Johnson syndrome
  • Transient acantholytic dermatosis (Grover disease)

Monitoring

  • IgG cell surface antibodies by indirect fluorescent antibody (IFA) testing and IgG desmoglein (desmoglein 1 and desmoglein 3) antibodies by enzyme-linked immunosorbent assay (ELISA)
    • Useful in monitoring disease activity and response to therapy in IgG pemphigus types
    • Levels of IgG antibodies to desmoglein 1 and/or desmoglein 3 fluctuate with disease activity – relative levels may change over time with associated clinical changes
  • IgA cell surface antibody by IFA – useful for monitoring disease activity and response to therapy in IgA pemphigus

Background

Epidemiology

  • Incidence – 1-5/million (Baum, 2014)
  • Age – all ages, including childhood; peak during 50s-60s
  • Sex – M:F, equal
  • Ethnicity
    • Pemphigus vulgaris – more common in patients of Ashkenazi Jewish or Mediterranean descent; HLA associated
    • Fogo selvagem (endemic pemphigus foliaceus) – rural areas of Brazil, Columbia, and Tunisia

Types of Pemphigus

  • IgG pemphigus – most common
    • Pemphigus vulgaris (70%)
      • Spontaneous
      • Drug induced
    • Pemphigus vegetans
    • Pemphigus foliaceus (20%)
      • Spontaneous
      • Drug induced
      • Fogo selvagem
    • Pemphigus erythematosus (Senear-Usher syndrome)
    • Pemphigus herpetiformis
  • Paraneoplastic pemphigus
    • Typically IgG antibodies
    • IgA antibodies – rarely described
  • IgA pemphigus – rare, with 2 main subsets
    • Subcorneal pustular dermatoses
    • Intraepidermal neutrophilic IgA dermatosis

Pathophysiology

  • Association with HLA genotypes DRB1*0402, DRB1*1401, and DQB1*0302 in Caucasians and DRB1*14 and DQB1*0503 in Japanese, indicating that antibody production is T-cell dependent
  • Autoantibodies to cell adhesion proteins in epithelium cause separation or suprabasilar keratinocyte acantholysis
  • Eosinophil infiltration, including eosinophil-associated spongiosis and abscesses
  • IgG pemphigus – most common
    • Presence of serum IgG cell surface antibodies with demonstrated pathogenic activity (not simply as epiphenomena of the disease)
      • IgG epithelial cell surface antibodies (formerly known as intercellular substance antibodies) detected by direct immunofluorescence (DIF) in perilesional skin and/or mucous membrane
      • Limiting dilution serum titers correlates with disease activity
    • Major (but not exclusive) antigenic targets for pathogenic antibodies in certain types of pemphigus are desmogleins, which are cell adhesion components of desmosomes in keratinocytes
      • Desmoglein 1 IgG antibodies predominate in pemphigus foliaceus and pemphigus erythematosus
        • Associated with nonmucosal lesions
        • Detected by enzyme-linked immunosorbent assay (ELISA)
        • Levels correlate with disease activity
      • Desmoglein 3 IgG antibodies predominate in pemphigus vulgaris and pemphigus vegetans
        • Associated with mucosal lesions
        • Detected by ELISA
        • Levels correlate with disease activity
      • Overlap occurs with antibodies to both desmoglein 1 and desmoglein 3; relative predominance of antibodies may change over time
        • Testing for desmoglein 1 and 3 antibodies by ELISA is performed to monitor relative levels in association with disease activity and response to therapy
        • Correlation with indirect fluorescent antibody (IFA) test findings reveals changing antibody profiles
  • IgA pemphigus
    • Rare form of pemphigus (most pemphigus cases have IgG antibodies)
      • IgA epithelial cell surface antibodies detected by DIF of perilesional skin
    • Serum IgA cell surface antibodies detected by IFA testing
      • Subcorneal pustular dermatosis (SPD) type – vesicles and pustules in a subcorneal or upper epidermal location
      • Intraepidermal neutrophilic (IEN) IgA dermatosis type – pustules throughout epidermis
  • Drug-induced pemphigus
    • Multiple drugs implicated
      • Some drugs may induce acantholysis without production of antibodies
      • Penicillamine and captopril have sulfhydryl groups that may interact with sulfhydryl groups in desmogleins to modify their antigenicity or interfere with adhesion activities
    • Disease typically remits once drug use is discontinued

Clinical Presentation

  • General signs and symptoms
    • Flaccid blisters on face, scalp, upper body, and intertriginous areas
      • Nikolsky sign – applying pressure on blister periphery extends lesion laterally
    • Mucosal lesions and erosions
  • Types of pemphigus
    • Pemphigus vulgaris
      • Initial presentation is usually oral ulcers with mucosal involvement
      • Subsequent development of superficial flaccid blisters and erosions on trunk, face, scalp, and proximal limbs, positive Nikolsky sign
    • Pemphigus vegetans – intertriginous and oral with involvement of tongue (cerebriform tongue)
      • Flaccid bullae and erosions (Neumann type)
      • Pustules (Hallopeau type)
    • Pemphigus foliaceus, including fogo selvagem – small superficial blisters typically on neck and upper trunk; "cornflake" scale, as in seborrheic distribution
      • No mucosal involvement
      • Positive Nikolsky sign
    • Pemphigus erythematosus (Senear-Usher syndrome) – rare form of pemphigus with features of lupus
      • Variant of pemphigus foliaceus
      • Predisposition for the face
    • Drug induced (may be either pemphigus vulgaris or foliaceus) – multiple drugs implicated
    • IgA pemphigus types (rare)
      • Pruritic vesicles and pustules with SPD (clinically similar to Sneddon-Wilkinson disease, but immunologically distinguishable)
      • Variable skin lesions with numerous pustules in IEN
    • Paraneoplastic pemphigus

ARUP Lab Tests

Order concurrently with serum antibody testing and fixed tissue histopathology for assessment of patient with pruritic, urticarial, blistering, and/or erosive disorders, including possible pemphigoid and pemphigoid variants, pemphigus and pemphigus subtypes, dermatitis herpetiformis, epidermolysis bullous acquisita, porphyria, and pseudoporphyria

Order concurrently with fixed tissue histopathology for assessment of patient with inflammatory, immune-mediated cutaneous disease, including possible lupus and lupus variants, vasculitis, drug reactions, lichen planus and lichenoid reactions

Refer to Immunobullous Skin Diseases Testing algorithm

Tissue must be submitted in Michel’s transport medium or Zeus tissue fixative; this test cannot be performed on formalin-fixed tissue

Initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria, including pemphigoid, pemphigoid variants, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, linear IgA disease variants, and IgG-pemphigus subtypes

Order concurrently with perilesional skin biopsy for direct immunofluorescence for initial diagnosis

Use for disease monitoring with semiquantitative antibody level assessments and tracking and for persistent unexplained disease and/or worsening disease activity

Recommended Use 

Preferred panel for initial assessment and disease monitoring in IgG-variant pemphigus

Panel components include antibody testing for IgG epithelial cell surface and IgG desmoglein 1 and 3; to order individual component tests, refer to epithelial skin antibody and/or desmoglein 1 and 3 antibodies in pemphigus, IgG

To screen for pemphigus along with other possible immunobullous diseases, order concurrently with antibody panel test for pemphigoid, IgG collagen type VII antibody, AND perilesional skin biopsy for direct immunofluorescence (DIF)

Refer to Immunobullous Skin Diseases Testing algorithm

Monitor disease in patient previously diagnosed with pemphigus and increased IgG desmoglein 1 and/or 3 antibodies; antibody levels correlate with disease activity; consider ordering with IgG epithelial cell surface antibody

If used to screen for pemphigus, this test has decreased sensitivity and specificity when compared to pemphigus antibody panel

For initial diagnosis and monitoring disease, antibody panel testing for pemphigus is preferred; panel components include IgG antibody testing for epithelial cell surface and IgG desmoglein 1 and 3

For diagnosing rare types of pemphigus, refer to IgA pemphigus antibody and paraneoplastic pemphigus

Refer to Immunobullous Skin Diseases Testing algorithm

Monitor patient with pemphigus who has positive IgG cell surface antibodies but normal IgG desmoglein 1 and/or 3 antibody levels

For initial diagnosis and disease monitoring, preferred test is pemphigus antibody panel; panel components include IgG epithelial cell surface antibodies and IgG desmoglein 1 and 3

May use to screen for pemphigus or pemphigoid; however, this test has decreased sensitivity and specificity when compared to panel tests for pemphigus antibodies or pemphigoid antibodies

Refer to Immunobullous Skin Diseases Testing algorithm

Assess and monitor patient with possible IgA pemphigus, a RARE disease with certain clinical and histopathological subtypes

If other types of pemphigus are of diagnostic consideration, order panel test for pemphigus antibodies first or concurrently with this test

Refer to Immunobullous Skin Diseases Testing algorithm

Initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria from suspected basement membrane zone antibody-associated disease (eg, bullous pemphigoid, pemphigoid variants, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, and linear IgA disease variants)

Order concurrently with perilesional skin biopsy for direct immunofluorescence for initial diagnosis

Use for disease monitoring with semiquantitative antibody assessments and tracking

Use along with pemphigoid and pemphigus panel tests and epidermal transglutaminase antibody, IgA, or use with epithelial skin antibody and epidermal transglutaminase antibody, IgA testing to initially diagnose and discriminate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

Refer to Immunobullous Skin Diseases Testing algorithm

Reflex pattern: if tTG IgA is ≥4 U/mL units, then EMA IgA by IFA testing will be added

General screen for immunobullous diseases

Test includes IgG and IgA basement membrane zone (BMZ) antibodies (pemphigoid, epidermolysis bullosa acquisita, linear IgA disease) and IgG and IgA cell surface antibodies (IgG and IgA pemphigus subtypes)

Consider ordering concurrently with IgG bullous pemphigoid (BP180 and 230) antigens for suspected pemphigoid and/or IgG desmoglein 1 and 3 antibodies for suspected pemphigus

For more sensitive and specific testing for pemphigoid or pemphigus, refer to antibody panels for pemphigus or pemphigoid

Refer to Immunobullous Skin Diseases Testing algorithm

Medical Experts

Contributor

Leiferman

 

Co-Director, Immunodermatology Laboratory, Professor of Dermatology, University of Utah

Consultant, Immunodermatology at ARUP Laboratories

Contributor

References

Additional Resources