Pemphigus

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Immunobullous Skin Diseases Testing Algorithm

Clinical Background

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

Epidemiology

Incidence - 0.75-5 per million
Age of onset - any age including childhood, most commonly diagnosed in 40-60 year olds
Sex - M:F, equal distribution
Ethnicity
- Pemphigus vulgaris is more common in patients of Jewish or Mediterranean descent, HLA association
- Fogo Selvagem occurs endemically in rural areas of Brazil, Tunisia and Columbia

Types of Pemphigus

IgG pemphigus
- Pemphigus vulgaris
  - Spontaneous
  - Drug-induced
- Pemphigus vegetans
- Pemphigus foliaceus
  - Spontaneous
  - Drug-induced
  - Fogo Selvagem (Brazilian or endemic pemphigus)
- Pemphigus erythematosus
Paraneoplastic pemphigus
- Typically IgG antibodies
- IgA antibodies rare
IgA pemphigus
- Subcorneal pustular dermatoses (SPD)
- Intraepidermal neutrophilic IgA dermatosis (IEN)

Pathophysiology

Autoantibodies develop to cell adhesion proteins in epithelium causing separation or suprabasilar keratinocyte acantholysis
Eosinophil infiltration, including eosinophilic spongiosis and abscesses
IgG pemphigus types
- Serum IgG cell surface antibodies are present with demonstrated pathogenic activity (and not simply epiphenomena of the disease)
  - IgG epithelial cell surface antibodies (formerly known as intercellular substance antibodies) detected by direct immunofluorescence in perilesional skin and/or mucous membrane
  - Serum IgG cell surface antibodies detected by indirect immunofluorescence and correlate with disease activity
- The major antigenic targets for the pathogenic antibodies are desmogleins, cell adhesion components of desmosomes in keratinocytes
  - IgG desmoglein-1 antibodies predominate in pemphigus foliaceus and pemphigus erythematosus
    - Associated with nonmucosal lesions
    - Detected by enzyme linked immunosorbent assay (ELISA)
    - Levels correlate with disease activity
  - IgG desmoglein-3 antibodies predominate in pemphigus vulgaris and pemphigus vegetans and are associated with mucosal lesions
    - Detected by ELISA
    - Levels correlate with disease activity
  - Overlap occurs with antibodies to both desmoglein-1 and desmoglein-3 and the relative predominance of antibodies may change over time
    - Testing for both desmoglein-1 and desmoglein-3 antibodies by ELISA performed to monitor relative levels in association with disease activity and response to therapy
IgA pemphigus types
- Rare form of pemphigus, most pemphigus cases have IgG antibodies (see above)
- IgA epithelial cell surface antibodies detected by direct immunofluorescence of perilesional skin
- Serum IgA cell surface antibodies detected by indirect immunofluorescence
- Subcorneal pustular dermatosis (SPD) type
  - Vesicles and pustules in a subcorneal or upper epidermal location
- Intraepidermal neutrophilic IgA dermatosis (IEN) type
  - Pustules throughout the epidermis

Clinical Presentation

Flaccid blisters on face, scalp, upper body and intertriginous areas
- Nikolsky sign - applying pressure on blister periphery extends the lesion laterally
Mucosal blisters and erosions
Types
- Pemphigus vulgaris - initial presentation is usually oral with mucosal involvement
- Pemphigus vegetans - intertriginous and oral with involvement of tongue (cerebriform tongue)
  - Flaccid bullae and erosions (Neumann type)
  - Pustules (Hallopeau type)
- Pemphigus foliaceus, including Fogo Salvagem (Brazilian or endemic pemphigus)- blisters typically on neck and upper trunk, cornflake scale in seborrheic distribution
- Drug induced may be either pemphigus vulgaris or foliaceus
  - Multiple implicated drugs
- IgA pemphigus types, rare form of pemphigus
  - Pruritic vesicles and pustules in subcorneal pustular dermatosis (SPD)
  - Variable skin lesions with numerous pustules in intraepidermal neutrophilic IgA dermatosis (IEN)
- Skin lesions
  - Flaccid bullae
  - Lichenoid lesions
  - Erythematous maculopapular lesions with dusky centers mimicking erythema multiforme
  - Erythroderma
- Oral mucosal - characteristically involves vermilion border of lips
- Other organ system involvement
  - Gastrointestinal - esophagus mainly
  - Respiratory - bronchiolitis obliterans
  - Renal - nephrotic syndrome and glomerular nephritis

Treatment

Treatment, disease course and prognosis may vary with disease type identified

See Also

Dermatitis Herpetiformis

Epidermolysis Bullosa Acquisita

Immunobullous Skin Diseases Screening

Linear IgA Disease

Paraneoplastic Pemphigus

Pemphigoid

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Immunobullous Skin Diseases Testing Algorithm

Diagnosis

Indications for testing - presence of chronic bullous (blistering), erosive, or crusting/scaling skin and/or mucous membrane disease; other more common diseases ruled out
Laboratory testing
- Perilesional skin biopsy for direct immunofluorescence
- Immunohistology
  - Perilesional skin biopsy - cutaneous direct immunofluorescence submitted in Michel’s (or Zeus) medium
    - Pemphigus vulgaris, vegetans and foliaceus
      - IgG and C3 (3rd 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 it is higher in epithelium in pemphigus foliaceus
    - Pemphigus erythematosus
      - Features of pemphigus and lupus are present on histologic examination of formalin-fixed tissue and show cell surface antibodies with granular immune deposits at the basement membrane zone by direct immunofluorescence with or without positive lupus serologies
    - IgA pemphigus, rare form of pemphigus
      - IgA (with or without C3) is detected on cell surfaces of epidermal and stratified squamous epithelial cells in and around affected areas
- Initial serum screening - Pemphigus Panel, Pemphigoid Panel and endomysial antibodies (all 3 tests for initial testing) or Epithelial Skin Antibodies testing (see table of tests below)
  - Broad screening recommended unless a specific immunobullous skin disease type is suspected because of overlap in clinical immunobullous disease presentations
  - Pemphigus types with IgG cell surface antibodies are more common than IgA pemphigus, recommendation is to rule out IgG pemphigus first before testing for IgA pemphigus
- Serum IgG cell surface antibody testing
  - IgG cell surface antibodies detected in serum by indirect immunofluorescence (IFA)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
    - Up to 80% of pemphigus patients have IgG antibodies present in sera
    - The presence of IgG cell surface antibodies and desmoglein antibodies in serum correlates with disease activity
    - Important to establish 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)
    - In paraneoplastic pemphigus, indirect immunofluorescence is often positive showing cell surface antibody staining; however, desmoglein antibodies may or may not be positive in paraneoplastic pemphigus
- Serum IgG desmoglein 1 and desmoglein 3 antibody testing by ELISAs
  - Desmoglein 1 autoantibodies predominate in pemphigus foliaceus (and likely pemphigus erythematosus)
  - Desmoglein 3 autoantibodies are present in pemphigus vulgaris (and likely pemphigus vegetans)
  - Although the predominate antibodies differentiate the subtypes of pemphigus, overlap may occur
    - Patients with both skin and mucosal lesions may have IgG antibodies to both desmogleins 1 and 3
    - Relative levels of IgG desmoglein 1 and desmoglein 3 antibodies may change over time, with likely associated clinical changes
- Serum IgA cell surface antibody testing
  - Testing for IgA cell surface antibodies is important in establishing the diagnosis of IgA pemphigus, a rare variant of pemphigus; this testing is highly sensitive and specific
  - Can distinguish IgA pemphigus from other pemphigus variants and from other immune-mediated skin disease
  - Cell surface antibodies detected by indirect immunofluorescence (IFA) on intact human skin and monkey esophagus substrates

Disease Monitoring

Both IgG cell surface antibodies by IFA and IgG desmoglein (desmoglein 1 and desmoglein 3) antibodies by ELISA are useful in monitoring patient’s 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 of IgG desmoglein 1 and desmoglein 3 antibodies may change over time with associated clinical changes
IgA cell surface antibody monitoring by IFA is useful for monitoring disease activity and response to therapy in IgA pemphigus

Differential Diagnosis

Aphthous stomatitis
Behçet disease
Candidiasis
Drug reaction
Epidermolysis bullosa acquisita
Erythema multiforme
Lichen planus
Lupus erythematosus
Paraneoplastic pemphigus
Pemphigoid
Stevens Johnson syndrome
Viral infection, herpes (simplex) and coxsackie A16 (hand-foot-and-mouth disease)

Algorithm(s)

PDF algorithm(s) available at www.arupconsult.com.

Immunobullous Skin Diseases Testing Algorithm

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Cutaneous Direct Immunofluorescence, Biopsy

ARUP #: 0092572

Methodology: Direct Immunofluorescence

Use:

Determine presence and staining pattern of immunoglobulins (IgG, IgM, IgA), third component of complement (C3) and fibrinogen in perilesional skin or mucosal biopsy specimens from patients suspected of having pemphigus

Limitations:

Test may be inaccurate if tissue not taken from correct location, type and age of lesion may also be important (attached/intact epithelium or epidermis is needed)

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

Follow-up:

Concurrent serum testing for pemphigus is the most sensitive for diagnosis and to subtype disease

Test name: Pemphigus Panel - IgG Epithelial Cell Surface Antibodies and Levels of IgG Desmoglein 1 and Desmoglein 3 Antibodies, Serum

ARUP #: 0090650

Methodology: Enzyme-Linked Immunosorbent Assay/Indirect Immunofluorescence

Use:

For diagnosis of most types of pemphigus and for monitoring disease activity and response to therapy

Panel tests for IgG epithelial cell surface antibodies by IFA on intact human skin and monkey esophagus substrates and IgG desmoglein 1 and desmoglein 3 antibodies by ELISAs

Use along with Pemphigoid Panel and endomysial IgA antibody test testing, or Epithelial Skin Antibody testing to distinguish the various disorders in patients suspected or known to have any type of immunobullous disease

Limitations:

Clinical correlation is necessary since cell surface antibodies by IFA, usually in low titers, may be found in normal individuals because of blood group reactivity or in patients with fungal infections, burns, drug reactions and other dermatoses

Because of clinical overlap among immunobullous diseases and similar names, testing for pemphigus may be confused with testing for pemphigoid and misordered; testing for IgG pemphigus antibody types (most common) also may be confused with IgA pemphigus testing (rare)

Follow-up:

A concurrent perilesional skin biopsy for direct immunofluorescence is helpful for diagnosis because of increased sensitivity (>90% of pemphigus cases are positive); although it is not possible to reliably distinguish pemphigus subtypes based on direct immunofluorescence

Monitor disease activity and response to therapy with Pemphigus Panel

Test name: Pemphigoid Panel - Epithelial Basement Membrane Zone IgG & IgA, BP180 & BP230 IgG Antibodies

ARUP #: 0092001

Methodology: Enzyme-Linked Immunosorbent Assay/Indirect Immunofluorescence

Use:

For diagnosis of most types of pemphigoid, epidermolysis bullosa acquisita, linear IgA disease (including linear IgA bullous dermatosis and childhood immunobullous disease)

Panel includes epithelial basement membrane zone IgG & IgA antibodies by IFA on split human skin and monkey esophagus substrates, BP180 & BP230 IgG antibodies by ELISAs

IgG BP180 and BP230 antibody levels may be useful in monitoring disease activity and response to therapy

Limitations:

Clinical correlation necessary since incidence of false-positives, although rare, increases with age

Because of clinical overlap among immunobullous diseases and similar names, testing for pemphigoid may be confused with testing for pemphigus and misordered

Follow-up:

Perilesional skin biopsy by direct immunofluorescence is helpful in diagnosis (>90% of pemphigoid and epidermolysis bullosa acquisita cases are positive)

Test name: Tissue Transglutaminase Antibody, IgA with Reflex to Endomysial Antibody, IgA Titer by IFA

ARUP #: 0050734

Methodology: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Use:

Use along with Pemphigoid and Pemphigus Panel tests, or Epithelial Skin Antibody testing to differentiate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

Follow-up:

Perilesional skin biopsy by direct immunofluorescence is helpful in diagnosis (>90% of dermatitis herpetiformis cases are positive)

Test name: Epithelial Skin Antibody

ARUP #: 0090299

Methodology: Indirect Immunofluorescence

Use:

Use along with endomysial antibody, IgA, IgG Desmoglein 1 and Desmoglein 3 Antibodies and IgG BP 180 and BP 230 Antibodies tests to differentiate among the immunobullous skin diseases in patients suspected or known to have these disorders

Panel includes epithelial basement membrane zone IgG & IgA antibodies by IFA and IgG & IgA cell surface antibodies by IFA on split human skin, intact human skin and monkey esophagus substrates

Limitations:

Although helpful in screening for immunobullous disease, not as sensitive as combination of Pemphigus and Pemphigoid Panels

Follow-up:

Perilesional skin biopsy by direct immunofluorescence is helpful in diagnosis (>90% of pemphigus, pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, dermatitis herpetiformis cases are positive)

IgG Desmoglein 1 and Desmoglein 3 Antibodies and/or IgG BP 180 and BP 230 Antibodies tests are helpful to determine immunobullous disease subtype and to monitor response to therapy

Test name: IgG Desmoglein 1 & Desmoglein 3

ARUP #: 0090649

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Test for IgG desmoglein 1 and desmoglein 3 antibodies in patient suspected of having or known to have any type of pemphigus

Aid in establishing the diagnosis of pemphigus; may be more sensitive than IFA in some patients

Distinguish pemphigus foliaceus from pemphigus vulgaris and other immune-mediated skin disease

Order along with Epithelial Cell Surface Antibodies

Limitations:

These tests are components of the Pemphigus Panel

Pemphigus patients may have other cell surface antibodies than to desmoglein 1 and 3; therefore, recommend performing this test as Pemphigus Panel, which includes the ELISAs for IgG desmoglein 1 and 3 antibodies, or with IgG Epithelial Cell Surface Antibodies test or Epithelial Skin Antibody test

May not be positive in paraneoplastic pemphigus

Follow-up:

Patients with results in the borderline/indeterminate range should be monitored for disease activity

This test is variably positive in paraneoplastic pemphigus

Because patients with pemphigus may show antibody reactivity to cell surface antigens that change over time, testing by both indirect immunofluorescence for cell surface antibodies along with desmoglein 1 and desmoglein 3 ELISAs (Pemphigus Panel) is strongly recommended while monitoring patient’s response to therapy

Test name: Pemphigus IgA Antibodies

ARUP #: 0092106

Methodology: Indirect Immunofluorescence

Use:

Test for IgA cell surface antibodies in patients suspected of having IgA pemphigus and have tested negative for IgG pemphigus (cell surface) antibodies

Useful to distinguish IgA pemphigus from other immune-mediated diseases

Monitor response to therapy and disease activity in IgA pemphigus since titers likely correlate with disease activity

Limitations:

IgA pemphigus is a rare form of pemphigus; recommend testing for IgG autoantibody types with Pemphigus Panel concurrently or before ordering this test

Clinical correlation is necessary since cell surface antibodies, usually in low titers, may be found in normal individuals because of blood group reactivity

Follow-up:

A perilesional skin biopsy for direct immunofluorescence concurrently obtained with serum is helpful for diagnosis because of increased sensitivity in diagnosing IgA pemphigus