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 fluorescent antibody (IFA) 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. 

Immunohistopathology

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 ELISAs and IFAs.

ELISAs both identify and semiquantify autoantibodies.  In IFA 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 particular surfaces in the substrates being tested. IFA 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). 

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, are 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 IFA, 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.  Because pemphigus types with IgG cell surface antibodies are more common than those with IgA antibodies (ie, IgA pemphigus), ruling out IgG pemphigus is recommended before testing for IgA pemphigus. 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, BP 180, BP 230, 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

IFA 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 levels rather than IgG.

ARUP Laboratory Tests

Additional detail about each test listed below can be found in the ARUP Laboratory Test Directory (LTD). In addition, each test name links directly to the LTD.

Immunohistopathology

Use with serum antibody testing and formalin-fixed tissue histopathology for assessment of pruritic, urticarial, blistering, crusted, and/or erosive disorders (including possible pemphigus variants); perilesional specimen recommended for blisters and/or erosions

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

Optimal specimen location varies according to disease type, blistering or nonblistering

Components: cutaneous DIF, biopsy; EER cutaneous DIF, biopsy; DIF includes IgG, IgG4, IgM, IgA, C3, and fibrinogen with diagnostic interpretation of staining patterns

Serum Testing

Use as initial testing panel to aid in diagnosing and distinguishing among skin and mucous membrane disorders, including pemphigus and pemphigoid variants, epidermolysis bullous acquisita (EBA), linear IgA bullous dermatosis, linear IgA disease variants, bullous lupus erythematosus and IgG pemphigus subtypes

Semiquantitative IFA and ELISA; positive limiting-dilution end-point antibody titer (IFA) and antibody level in units (ELISA)

Components:  IFA for IgG and IgA BMZ antibodies (pemphigoid, EBA, linear IgA disease), includes split-skin substrate; and IgG and IgA cell surface antibodies (IgG and IgA pemphigus subtypes), includes intact skin substrate; ELISAs for IgG antibodies to BP 180, BP 230, type VII collagen, desmoglein 1, and desmoglein 3

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

Semiquantitative IFA and ELISA; positive limiting-dilution end-point antibody titer (IFA) and antibody level in units (ELISA)

To assess for pemphigus along with other immunobullous diseases, order concurrently with Basement Membrane Zone Antibody Panel and Pemphigus Antibody IgA

Alternatively, order Immunobullous Disease Panel, Epithelial (note that this test is included as part of the Immunobullous Disease Panel

Components: IFA for IgG epithelial cell surface antibodies; ELISAs for IgG antibodies to desmoglein 1 and IgG desmoglein 3 (all components included in immunobullous disease panel)

Use to monitor disease in patients diagnosed with pemphigus and increased IgG desmoglein 1 and/or 3 antibodies

Semiquantitative ELISA; antibody level in units

Decreased diagnostic sensitivity and specificity compared with pemphigus antibody panel; consider ordering with IgG epithelial cell surface antibody

For initial diagnosis and assessment of disease progression/changes and intermittent monitoring, preferred test is pemphigus antibody panel testing or Immunobullous Disease Panel, Epithelial

Components: ELISAs for IgG antibodies to desmoglein 1 and desmoglein 3 (included in the immunobullous disease panel and in the pemphigus antibody panel, IgG)

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

Semiquantitative IFA; positive limiting-dilution end-point antibody titer(s)

Decreased diagnostic sensitivity and specificity compared with pemphigus antibody panel; consider ordering with IgG desmoglein 1 and IgG desmoglein 3 antibodies

For initial diagnosis and disease monitoring, preferred test is pemphigus antibody panel or Immunobullous Disease Panel, Epithelial

Components: IFA for IgG cell surface antibodies (included in the immunobullous disease panel, the pemphigus antibody panel, IgG, and the epithelial skin antibody panel)

Use to assess and monitor patients with possible IgA pemphigus, a rare disease with certain clinical and histopathologic subtypes

Semiquantitative IFA; positive limiting-dilution end-point antibody titer(s)

If other types of pemphigus are of diagnostic consideration, order Immunobullous Disease Panel, Epithelial, first or this test concurrently with panel test for IgG pemphigus antibodies

Components: IFA for IgA cell surface antibodies (included in the immunobullous disease panel and the epithelial skin antibody panel)

General initial test for immunobullous diseases and monitoring EBA and linear IgA disease expression (test does not include ELISAs for specific disease-related antigenic targets)

Semiquantitative IFA; positive limiting-dilution end-point antibody titer(s)

Consider ordering with ELISAs for IgG desmoglein 1 and IgG desmoglein 3 antibodies for suspected pemphigus and/or IgG bullous pemphigoid antigens, BP 180 and BP 230, antibodies for suspected pemphigoid, IgG collagen type VII antibody for suspected EBA

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

Components:  IFA for IgG and IgA BMZ antibodies (pemphigoid, EBA, linear IgA disease) and IgG and IgA cell surface antibodies (IgG and IgA pemphigus subtypes) (all components included in immunobullous disease panel, epithelial)

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

References

  1. 31498102

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

    PubMed
Additional Resources
  • 28492232

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

    PubMed