Pemphigus

Blistering Skin Disease

  • Diagnosis
  • Algorithms
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

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

  • 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

Pemphigus is an autoimmune blistering disease that affects epithelium, including skin and mucous membranes.

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
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Desmoglein 1 and Desmoglein 3 Antibodies in Pemphigus, IgG 0090649
Method: Enzyme-Linked Immunosorbent Assay

Tissue Transglutaminase (tTG) Antibody, IgA with Reflex to Endomysial Antibody, IgA by IFA 0050734
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Epithelial Cell Surface Antibody IgG 0090266
Method: Indirect Fluorescent Antibody

`Pemphigus Antibody IgA 0092106
Method: Indirect Fluorescent Antibody

Epithelial Skin Antibody 0090299
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Pemphigus Antibody Panel - Epithelial Cell Surface Antibodies and Desmoglein 1 and Desmoglein 3 Antibodies, IgG 0090650
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Pemphigoid Antibody Panel - Epithelial Basement Membrane Zone Antibodies, IgG and IgA, BP180 and BP230 Antibodies, IgG 0092001
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence

Limitations 

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

General References

Asarch A, Gürcan HM, Ahmed R. A current review of juvenile pemphigus vulgaris: analysis of data on clinical outcomes. Am J Clin Dermatol. 2010; 11(1): 21-33. PubMed

Baroni A, Lanza A, Cirillo N, Brunetti G, Ruocco E, Ruocco V. Vesicular and bullous disorders: pemphigus. Dermatol Clin. 2007; 25(4): 597-603, ix. PubMed

Baum S, Sakka N, Artsi O, Trau H, Barzilai A. Diagnosis and classification of autoimmune blistering diseases. Autoimmun Rev. 2014; 13(4-5): 482-9. PubMed

Grando SA. Pemphigus in the XXI century: new life to an old story. Autoimmunity. 2006; 39(7): 521-30. PubMed

Kershenovich R, Hodak E, Mimouni D. Diagnosis and classification of pemphigus and bullous pemphigoid. Autoimmun Rev. 2014; 13(4-5): 477-81. PubMed

Mao X, Nagler AR, Farber SA, Choi EJ, Jackson LH, Leiferman KM, Ishii N, Hashimoto T, Amagai M, Zone JJ, Payne AS. Autoimmunity to desmocollin 3 in pemphigus vulgaris. Am J Pathol. 2010; 177(6): 2724-30. PubMed

Parker SR, MacKelfresh J. Autoimmune blistering diseases in the elderly. Clin Dermatol. 2011; 29(1): 69-79. PubMed

Patrício P, Ferreira C, Gomes MM, Filipe P. Autoimmune bullous dermatoses: a review. Ann N Y Acad Sci. 2009; 1173: 203-10. PubMed

Schmidt E, Zillikens D. Modern diagnosis of autoimmune blistering skin diseases. Autoimmun Rev. 2010; 10(2): 84-9. PubMed

Venugopal SS, Murrell DF. Diagnosis and clinical features of pemphigus vulgaris. Immunol Allergy Clin North Am. 2012; 32(2): 233-43, v-vi. PubMed

Medical Reviewers

Last Update: September 2017