Pemphigus

Pemphigus refers to a group of uncommon and severe autoimmune blistering skin diseases that affect the epithelium, including skin and mucous membranes. The pemphigus diseases are caused by pathogenic autoantibodies against desmoglein 1 and desmoglein 3, two adhesion proteins found in keratinocytes.  When the autoantibodies bind to the desmoglein 1 and 3 proteins, keratinocyte separation (acantholysis) occurs, which leads to blistering in the skin and mucous membranes.   Because pemphigus is rare and has features that mimic other more common disorders, diagnosis can be challenging and often delayed.  Diagnosis is based on clinical characteristics, histopathologic features, and the detection of disease-specific autoantibodies in tissue and/or serum using direct immunofluorescence (DIF) microscopy, indirect immunofluorescence (IIF) testing (also referred to as indirect immunofluorescence, or IIF), and enzyme-linked immunosorbent assays (ELISAs).    Given the overlapping clinical presentations among the various epithelial antibody-associated immunobullous cutaneous diseases, broad serologic screening is recommended unless a specific disease type is suspected and/or supported by characteristic findings.

Quick Answers for Clinicians

What are the various subtypes of pemphigus, and how are they distinguished?

Pemphigus vulgaris and pemphigus foliaceus are the two primary subtypes of pemphigus.   Of these, pemphigus vulgaris is the more common.   Other forms include pemphigus vegetans (a subset of pemphigus vulgaris), pemphigus erythematosus, pemphigus herpetiformis, paraneoplastic pemphigus, and IgA pemphigus. (Unlike most pemphigus variants, which are mediated by IgG cell surface antibodies, IgA pemphigus involves IgA antibodies.) Endemic pemphigus, also known as fogo selvage, is a variant of pemphigus foliaceus that occurs in some rural regions of the world (eg, South America and Tunisia).  In most patients, the subtype of pemphigus is identified by the desmoglein molecule that is targeted, in conjunction with clinical findings.  Refer to the Clinical Indications and Features of Pemphigus Subtypes table and the Pemphigus Types and Primary Associated Autoantigens table.

What are risk factors for pemphigus?

A predisposing factor for pemphigus diseases is the presence of HLA gene variants such as HLA-DRB1*04:02 and HLA-DQB1*05:03, alleles that are reportedly detected in most patients with pemphigus vulgaris.  Other HLA alleles associated with pemphigus include DRB1*04, DRB1*08, DRB1*14, DQB1*05:03, and DQB1*03:02, among others.  Four non-HLA genes have also been linked to pemphigus: DSG3, TAP2, ST18, and IL6. In addition, exposure to certain medications, including penicillamine and captopril; environmental exposure to pesticides, ionizing radiation, and ultraviolet light; and burns, surgical procedures, viral infections, and stressful events have been reported as risk factors for pemphigus development. 

Are other diseases associated with pemphigus?

An increased prevalence of other autoimmune diseases (eg, rheumatoid arthritis, autoimmune thyroid disease, and myasthenia gravis), psoriasis, and neurologic disease (eg, dementia, epilepsy, Parkinson disease) is found in patients with pemphigus.  An increased prevalence of hematologic and other malignancies also is found,  but malignancies are rare except in paraneoplastic pemphigus, which is defined by a malignancy association.

What is the Nikolsky sign, and what significance does it have in pemphigus?

In patients with the Nikolsky sign, light rubbing of the outermost skin layer, such as with a finger or pencil eraser, leads to separation of the epidermis/epithelium. This is sometimes referred to as the direct Nikolsky sign  and is a common presenting manifestation in patients with pemphigus, particularly pemphigus vulgaris and pemphigus foliaceus.  In patients with the indirect Nikolsky sign, finger pressure applied to an intact blister can cause the blister to spread laterally or expand; this manifestation is associated with the active phase of pemphigus vulgaris.  The Nikolsky sign is considered to have moderate sensitivity but high specificity for pemphigus  and can help to distinguish pemphigus from pemphigoid diseases.  Refer to the Clinical Indications and Features of Pemphigus Subtypes table.

Where can I find information on testing for other epithelial-antibody associated immunobullous diseases?

ARUP Consult has an overview of Epithelial-Antibody Associated Immunobullous Diseases, as well as specific information on pemphigoidpemphigoid gestationisepidermolysis bullosa acquisita (EBA)linear IgA disease, and dermatitis herpetiformis. Visit our algorithm for testing steps for the various diseases.

Indications for Testing

Testing for pemphigus is appropriate in patients with chronic, recurring bullae (blisters), erosive or crusting/scaling skin, or mucous membrane disease that is not attributable to a more common cutaneous disorder.

Clinical Indications and Features of Pemphigus Subtypes
Subtype Indications and Features

Pemphigus vulgarisa

Fragile, flaccid bullae that evolve into erosions, crusting, Nikolsky sign; oral ulcers are commonly an initial presenting symptom

Three forms: mucosal dominant, with limited skin involvement; mucocutaneous, which affects both skin and mucosa; and cutaneous

Pemphigus vegetans (variant of pemphigus vulgaris)

Erythematous, vegetating intertriginous plaques

Pemphigus foliaceusab

Superficial, flaccid bullae and erosions, often in seborrheic regions, hyperkeratotic scales with crusting, Nikolsky sign, skin erythema; no mucosal involvement

Pemphigus erythematosus (variant of pemphigus foliaceus with features of SLE; also known as Senear-Usher syndrome)

Superficial erosions, erythema, crusting, often of malar and seborrheic areas

Endemic pemphigus (variant of pemphigus foliaceus with genetic and environmental cofactors, primarily in Brazil; also known as fogo selvagem)

Superficial erosions, erythema, crusting, localized to seborrheic areas, head, and upper chest; generalized, erythrodermic presentation also observed

Pemphigus herpetiformis

Erythematous, bullous, vesicular, pustular, or papular lesions, typically with severe pruritus and in a herpetiform pattern; mucosal involvement is uncommon

Neonatal pemphigus

Transient blistering in a neonate from transplacental transfer of pathogenic antibodies; resolves within a month; most commonly from mother with pemphigus vulgaris but also possible from mother with pemphigus foliaceus

IgA pemphigus (2 major subtypes: subcorneal pustular dermatosis and intraepidermal neutrophilic IgA dermatosis)

Fragile blisters filled with fluid that evolve into pustules, pruritus; mucosal involvement is uncommon

Paraneoplastic pemphigus

Various possible lesion types: flaccid and/or tense bullae, erosions, urticarial lesions, erythema multiforme-like lesions, lichen planus-like lesions, flat scaly papules; mucosal involvement (often oral and ocular); pulmonary involvement; associated with presence of neoplasms

aPemphigus vulgaris and pemphigus foliaceus can also be drug induced; implicated drugs include thiol-containing medications (eg, penicillamine and captopril), masked thiols (eg, penicillins and cephalosporins), and enalapril.

bFogo selvagem is a variant of pemphigus foliaceus that is endemic in certain areas of Brazil and North America and has the same clinical, histopathologic, and immunopathologic profile as pemphigus foliaceus.

SLE, systemic lupus erythematosus

Sources: Schmidt, 2019 ; Witte, 2018 ; Baum, 2014 ; Karray, 2020 ; Otten, 2014 

Laboratory Testing

Diagnosis

In addition to clinical and histopathologic features, diagnosis of pemphigus depends on detection of immunoglobulin G (IgG) and/or complement component 3 (C3) on the membranes of keratinocytes with DIF microscopy of perilesional tissue, along with detection of antibodies against desmoglein 1 and/or desmoglein 3 in serum.  In IgA pemphigus, IgA (rather than IgG) is detected, although IgG pemphigus is more common. Rare, nonclassical IgG/IgA pemphigus variants have been described. 

Immunopathology

DIF microscopy of perilesional skin biopsy tissue is important in an evaluation for pemphigus. Pemphigus is characterized by the binding of IgG antibodies and deposition of C3 on the surfaces of cells within the epidermis and/or the epithelium.  The location of the IgG and C3 cell surface staining within the epithelium may help to differentiate among the pemphigus subtypes (although further testing is needed for definitive subtype determination). For example, in pemphigus vulgaris and pemphigus vegetans, cell surface staining is typically more pronounced in the suprabasal epidermis/epithelium, whereas in pemphigus foliaceus, staining is observed in subcorneal regions.  In pemphigus erythematosus, characteristics of both pemphigus and SLE are present on histopathologic examination of formalin-fixed tissue. DIF examination in pemphigus erythematosus also reveals features of both disorders, consisting of cell surface antibodies with granular immune deposits at the basement membrane zone (BMZ),  with or without positive SLE serologies. In IgA pemphigus, IgA (with or without C3) is detected on cell surfaces of epidermal and stratified squamous epithelial cells in and around affected areas.

Serum Tests

In addition to DIF microscopy, evaluation for pemphigus involves detection and identification of circulating autoantibodies, including IgG cell surface antibodies against desmoglein 1 and 3, which are highly characteristic of pemphigus. Available serum tests include IIFs and ELISAs.

With IIF serum testing, the patient serum is overlaid on epithelial tissue substrates (specifically, human or monkey esophagus substrates ) to determine if there are antibodies in the circulation that target cell surfaces in the substrates being tested. IIF testing enables visualization of deposition patterns. Different substrates may be more sensitive for specific diseases (eg, monkey esophagus has been reported to have greater sensitivity for pemphigus vulgaris, whereas human tissues, including esophagus and skin, may be more sensitive for pemphigus foliaceus).  Limiting-dilution, end-point titers of antibody reactivity are semi-quantitative assessments of antibody amounts. ELISAs both identify specific cell surface components that are antibody targets permitting identification of disease subtypes and semiquantify autoantibodies. 

Cell surface antibodies are generally pathogenic,  and antibody levels often correlate with disease activity in the most common forms of pemphigus, pemphigus vulgaris, and pemphigus foliaceus.   Certain IgG subclasses, specifically IgG4 and IgG1, may be associated with active as opposed to remittent disease.   Of note, a significant number of patients with pemphigus, up to 30%, have positive IgG cell surface antibodies by IIF, but normal IgG desmoglein 1 and IgG desmoglein 3 antibodies by ELISA, indicating that they have antibodies to different desmoglein epitopes than those expressed in the ELISAs and/or antibodies to other epithelial adhesion molecules.  Pemphigus types with IgG cell surface antibodies are more common than those with IgA antibodies (ie, IgA pemphigus), though IgA cell surface antibodies may be observed in some pemphigus variants along with positive IgG cell surface antibodies. The presence of IgA cell surface antibodies in patients with negative/normal IgG antibodies is sensitive and specific for IgA pemphigus and can help to distinguish this type from other forms of pemphigus and from other immunobullous skin diseases.

Broad epithelial antibody screening is generally recommended due to the overlapping clinical presentations among immunobullous skin diseases. Panel tests can be used to test for a variety of autoantibodies implicated in the various diseases. Refer to ARUP Lab Tests below.

Pemphigus subtypes demonstrate differences in associated autoantigens, as outlined in the following table.

Pemphigus Types and Primary Associated Autoantigens
Pemphigus vulgarisa Desmoglein 3 with or without desmoglein 1b
Pemphigus foliaceusa Desmoglein 1
Pemphigus erythematosusa Desmoglein 1 and/or desmoglein 3 (antinuclear antibodies also are detected)
Pemphigus herpetiformisa Desmoglein 1, less commonly desmoglein 3, desmocollin 1, and/or desmocollin 3
IgA pemphigusc Desmocollin 1, desmoglein 1 and/or desmoglein 3
Paraneoplastic pemphigusd Envoplakin, periplakin, desmoglein 1, desmoglein 3, desmoplakin I, desmoplakin II, piplakin, BP180, BP230, α2-macroglobulinlike-1, laminin-332, plectin, and desmocollin 1, desmocollin 2, and desmocollin 3

aAssociated with IgG autoantibodies.

bMucosal-dominant pemphigus vulgaris demonstrates IgG antibodies to desmoglein 3, whereas the mucocutaneous form may demonstrate IgG antibodies to both desmogleins 1 and 3, and the cutaneous form demonstrates primarily IgG antibodies to desmoglein 1. 

cAssociated with IgA autoantibodies.

dMainly associated with IgG autoantibodies; patients with IgA paraneoplastic pemphigus antibodies have also been described.

Sources: Witte, 2018 ; Karray, 2020 ; Otten, 2014 ; On, 2015 

Monitoring

IIF tests and ELISAs have utility in monitoring disease activity and response to therapy, given that antibody levels reflect disease activity in the most common forms of pemphigus.   Moreover, one predominant pemphigus type can transition to another over time. Monitoring of IgA pemphigus involves assessment of IgA antibody levels rather than IgG.

ARUP Laboratory Tests

Additional detail about the tests below can be found in the ARUP Immunobullous Disease Testing Comparison table.

Immunopathology

Use with serum immunobullous disease/epithelial antibody testing and formalin-fixed tissue histopathology for assessment of pruritic, urticarial, blistering, and/or erosive disorders

Use with formalin-fixed tissue histopathology for assessment of inflammatory, immune-mediated cutaneous disease

Optimal specimen location and complementary serum testing and/or histopathology examination vary according to disease type; note that specimen location and transport medium/fixative are different for direct immunofluorescence testing and fixed-tissue histopathology

Serum Testing

Use as initial comprehensive testing panel to aid in the diagnosis of and distinguishing among skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria

Use for assessment of suspected epithelial antibody-associated immunobullous diseases, pemphigoid and pemphigus and their variants, that are not clinically distinguishable, have nonspecific features, potentially express overlapping epithelial antibodies, and/or are indicated by concurrent DIF biopsy

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA; collagen type VII antibodies, IgG by ELISA; cell surface antibodies, IgG by IIF; desmoglein 1 and 3 antibodies, IgG by ELISA; cell surface antibodies, IgA by IIF

Use as the preferred serum antibody panel to assess and monitor IgG-variant pemphigus (includes pemphigus foliaceus and pemphigus vulgaris), which present with blistering and erosive disease affecting skin and mucous membranes

Testing should be correlated initially with concurrent DIF biopsy

Components: cell surface antibodies, IgG by IIF; desmoglein 1 and desmoglein 3 antibodies, IgG by ELISA

Use to monitor disease in patients diagnosed with various pemphigus variants and increased IgG desmoglein 1 and/or IgG desmoglein 3 antibodies; antibody levels correlate with disease activity 

For initial diagnosis, Pemphigus Antibody Panel, IgG has greater diagnostic sensitivity and specificity and is preferred in the assessment of disease progression/changes and for intermittent monitoring of IgG pemphigus variants

For more comprehensive evaluation, consider Immunobullous Disease Antibody Panel

Use to assess and monitor cell surface antibodies in patients with IgG pemphigus variants with normal IgG desmoglein 1 and IgG desmoglein 3 antibody levels

Testing should be correlated initially with concurrent DIF biopsy

For comprehensive testing, consider ordering the Immunobullous Disease Antibody Panel

Use to assess and monitor IgA pemphigus or other nonclassical pemphigus subtypes with both IgA and IgG cell surface antibodies

Testing should be correlated initially with concurrent DIF biopsy

Consider ordering concurrently with serum Pemphigus Antibody Panel, IgG if other types of pemphigus are diagnostic considerations

Use to monitor linear IgG and IgA BMZ antibody-associated diseases and IgG and IgA cell surface antibody-associated diseases in which antibody levels by ELISAs may not be increased and/or to assess for changing patterns of epithelial antibody expression

May be used as general initial serum test for immunobullous diseases; however, for more sensitive and specific serum testing that includes ELISAs for pemphigoid and EBA or for IgG variant pemphigus, refer to Basement Membrane Zone Antibody Panel or Pemphigus Antibody Panel, IgG

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; cell surface antibodies, IgG by IIF; cell surface antibodies, IgA by IIF

References

  1. 31498102

    Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet. 2019;394(10201):882-894.

Additional Resources
  • 28492232

    Kasperkiewicz M, Ellebrecht CT, Takahashi H, et al. PemphigusNat Rev Dis Primers. 2017;3:17026.

  • Medical Experts

    Contributor

    Leiferman

    Picture of Kristin M. Leiferman, MD

     

    Co-Director, Immunodermatology Laboratory, Professor of Dermatology, and Adjunct Professor of Pathology, University of Utah
    Medical Director, Immunodermatology, ARUP Laboratories