Dermatitis Herpetiformis

Diagnosis

Indications for Testing

  • Chronic pruritic dermatitis/skin lesions in patient with or without known celiac disease after other, more common diseases ruled out

Laboratory Testing

  • Initial serum testing
    • Perform concurrently with histology
    • Due to the potential for overlapping clinical features, all of the following tests are recommended unless a specific immunobullous skin disease type is suspected 
      • Pemphigoid and pemphigus panels
      • Celiac disease evaluation
        • Suggested initial tests
          • Tissue transglutaminase (tTG) also known as transglutaminase 2 (TG2) IgA antibodies with reflex to endomysial antibody (EMA)
            • If increased IgA tTG antibody levels are positive
          • Epithelial skin antibody and tTG IgA with reflex to EMA
          • IgA epidermal transglutaminase (eTG) also known as transglutaminase 3 (TG3) antibodies – highly specific for dermatitis herpetiformis (DH)
          • Celiac disease dual antigen screen – alternative to above testing; less sensitive
        • If patient has known IgA deficiency  – perform IgG testing along with IgA testing
          • IgA deficiency – more common than IgA absence or total lack
          • Many celiac patients with IgA deficiency will have increased IgA tTG and positive IgA EMA even with low total serum IgA; however, if IgA is absent, they will not have increased tTG or positive EMA
        • If patient has not received diagnosis of celiac disease – consider gastroenterology consultation for consideration of small-intestine biopsy
        • Increased IgA epidermal transglutaminase (transglutaminase type 3 or TG3) antibody level – distinctly characteristic of and supports diagnosis of DH
          • TG3 – dominant antigen to which IgA antibodies develop in DH
          • Most patients with DH have gluten sensitivity with celiac disease and characteristic IgA antibodies to tissue transglutaminase (transglutaminase type 2 or TG2)
          • Patients with DH – have antibody profile specific for TG3 with higher avidity than to TG2

Histology

  • Perilesional skin biopsy for cutaneous direct immunofluorescence is highly sensitive – specimen should be perilesional, 3-5 mm from the edge of an active lesion
    • Granular or fibrillar IgA deposits at or beneath the basement membrane zone (BMZ) in dermal papillary tips is pathognomonic
      • Granular IgA beneath the BMZ is also found in lupus erythematosus along with other granular immune deposits – the concentration of grains in dermal papillae characterizes DH
      • Deposits may be sparse and widely distributed – principal target antigen is epidermal transglutaminase
      • If initial biopsy is negative, additional perilesional biopsy may increase yield

Differential Diagnosis

Monitoring

  • Monitor therapy/adherence to gluten-free diet
    • IgA endomysial antibodies
    • IgA tissue transglutaminase antibodies
    • IgA epidermal transglutaminase (eTG), transglutaminase 3 (TG3) ELISA

Clinical Background

Dermatitis herpetiformis (DH) is a chronic, pruritic skin disease usually associated with gluten-sensitive enteropathy (GSE – celiac disease).

Epidemiology

  • Incidence – 10-39/100,000
  • Age – all ages; peak onset is 20s-40s
    • DH and chronic bullous disease of childhood are the most common autoimmune bullous diseases of childhood
      • Both have histologically identical pictures and can only be differentiated by direct immunofluorescence (DIF)
  • Sex – M>F
  • Ethnicity – most common in those of northern European descent but occurs in all ethnic groups

Risk Factors

Pathophysiology and Immunopathophysiology

  • Strong association with HLA genotype DQ A1*0501, B1*02 (which encodes HLA-DQ2 heterodimers)
  • Most patients with DH have mild celiac disease, but not all patients with celiac disease have DH
    • Both GSE and DH patients have antibodies to (common epitopes) tissue transglutaminase (tTG/TG2) and epidermal transglutaminase (eTG/TG3)
    • Patients with DH have markedly stronger avidity antibodies to TG3

Immunohistology and Dermatopathology

  • Granular and/or fibrillar deposition of IgA antibodies in dermal papillae and, less commonly, in blood vessels by DIF
    • Cryosections of perilesional skin biopsies required for DIF microscopy
  • Classically, a subepidermal blister with neutrophil (and occasionally eosinophil) microabscesses within dermal papillae by histological examination of fixed tissue

Clinical Presentation

  • Papulovesicular lesions and urticarial wheals in a symmetrical distribution
    • Classically involves extensor elbows and knees, buttocks, scalp, shoulders, sacral areas
  • Chronic eczematoid skin changes, excoriations
    • Often have intense pruritus
  • Oral lesions are rare

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence
(Direct Fluorescent Antibody Stain)

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

For skin involvement, biopsy perilesional skin

For mucous membrane involvement, biopsy nonlesional mucosa

Use in testing for celiac disease (celiac reflexive panel), which is associated with dermatitis herpetiformis in most cases, along with pemphigoid and pemphigus panel tests

See Immunobullous Skin Diseases Testing algorithm

May be inaccurate if tissue not taken from correct perilesional location; specimen must have epidermis/epithelium and basement membrane zone (BMZ)

Granular and fibrillar IgA immune deposits may be sparse; use of more than one specimen increases detection of diagnostic findings

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

Initial concurrent and repeat serum testing for IgA endomysial and tissue transglutaminase antibodies to make diagnosis and to follow disease activity

Patients with indeterminate results should have repeat DIF biopsy

Patients with changing clinical features should have repeat DIF biopsy because antibody profiles may change over time

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

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

Reflex pattern – if tTG IgA is ≥20 units, then EMA IgA by IFA testing will be added

See Immunobullous Skin Diseases Testing algorithm

May be negative if patient is following a gluten-free diet

False-positive IgA antibody levels may occur in other inflammatory bowel diseases

Do not use in IgA-deficient individuals; acceptable reflex screening test for celiac disease

Celiac Disease Reflexive Panel or Tissue Transglutaminase (tTG) Antibody, IgA, assay is the preferred screening test

Use tissue transglutaminase (tTG) antibody, IgA with reflex to endomysial antibody, IgA by IFA for initial diagnosis and to follow disease activity in dermatitis herpetiformis

Repeat test for indeterminate results and/or continuing clinical consideration of dermatitis herpetiformis

Epidermal Transglutaminase (etG/tTG3) Antibody, IgA by ELISA 2010902
Method: Enzyme-Linked Immunosorbent Assay

Aids in diagnosis of dermatitis herpetiformis and monitoring of disease activity in response to gluten-free diet therapy; highly specific

Use with tissue transglutaminase (tTG) antibody, IgA with reflex to endomysial antibody, IgA by IFA for initial diagnosis and to follow disease activity in dermatitis herpetiformis

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

See Immunobullous Skin Diseases Testing algorithm

Performed only by request of the Immunodermatology Laboratory

May not be positive in all patients with dermatitis herpetiformis, including those who are IgA-deficient and those following a gluten-free diet

Use with tissue transglutaminase (tTG) antibody, IgA with reflex to endomysial antibody, IgA by IFA for initial diagnosis and to follow disease activity in dermatitis herpetiformis

Repeat test for indeterminate results and/or continuing clinical consideration of dermatitis herpetiformis

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

Preferred antibody panel for initial diagnostic assessment and disease monitoring in pemphigoid, epidermolysis bullosa acquisita, and linear IgA bullous dermatosis

Panel components include IgG and IgA epithelial BMZ antibodies and IgG bullous pemphigoid BP180 & 230 antigens

To order individual component tests, refer to antibody testing for IgG BMZ, IgA BMZ, and/or IgG bullous pemphigoid BP180 & 230 antigens

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

Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity (85-100% of pemphigus, pemphigoid, linear IgA disease, epidermolysis bullosa acquisita, and dermatitis herpetiformis cases are positive)

See Immunobullous Skin Diseases Testing algorithm

Clinical correlation necessary because the incidence of false positives, although rare, increases with age

Dermatitis herpetiformis may not be detected when parts of monkey esophagus substrate without smooth muscle (proximal 2/3) are used

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

Use pemphigoid panel to monitor pemphigoid disease activity; use relevant tests to monitor other immunobullous disease activity

Repeat pemphigoid panel for indeterminate results and/or continuing clinical consideration of immunobullous disease

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

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 DIF

Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity (85-100% of pemphigus, pemphigoid, linear IgA disease, epidermolysis bullosa acquisita, and dermatitis herpetiformis cases are positive)

See Immunobullous Skin Diseases Testing algorithm

Useful for pemphigus immunobullous disease but likely will not detect dermatitis herpetiformis because test identifies IgG rather than the IgA antibodies that characterize dermatitis herpetiformis

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

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

Testing for IgG pemphigus antibody types (most common) also may be confused with IgA pemphigus testing (rare disorder)

Use pemphigus panel to monitor pemphigus disease activity; use relevant tests to monitor other immunobullous disease activity

Repeat pemphigus panel for indeterminate results and/or continuing clinical consideration of immunobullous disease

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

General screen for immunobullous diseases

Test includes IgG and IgA 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 & 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

Use along with tTG IgA with reflex to endomysial antibody for diagnosis of dermatitis herpetiformis

See Immunobullous Skin Diseases Testing algorithm

Does not include testing for antibodies to target pemphigoid antigens, BP180 and BP230, or to target pemphigus antigens desmoglein 1 and 3 which may be more sensitive diagnostic markers in some cases (levels correlate with disease activity)

Although helpful in screening for immunobullous disease, test is not as sensitive as combination of pemphigus and pemphigoid panels

Use epithelial skin antibody test or both pemphigoid and pemphigus panels to follow patients with changing clinical features because antibody profiles may change over time

Endomysial Antibody, IgA by IFA 0050736
Method: Semi-Quantitative Indirect Fluorescent Antibody

Use along with tissue transglutaminase antibody testing to diagnose celiac disease in association with dermatitis herpetiformis

Perilesional skin biopsy for DIF is helpful in diagnosis (>90% of dermatitis herpetiformis cases are positive)

Clinical sensitivity/specificity – >99%

See Immunobullous Skin Diseases Testing algorithm

EMA-positive sera may show the prozone phenomenon

Antibodies are either very weak or negative at the initial screening dilution; sera will be screened at higher dilutions

Sera containing anti-smooth muscle antibodies (ASMA) will interfere with the detection of EMA IgG; sera should be further tested at higher dilutions

Use endomysial antibody, IgA by IFA and/or tissue transglutaminase (tTG) antibody, IgA and/or epidermal transglutaminase (eTG) antibody, IgA tests to follow dermatitis herpetiformis disease activity unless IgA deficient or predominant IgG antibodies
Celiac Disease Dual Antigen Screen with Reflex 2002026
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Diagnose celiac disease in association with suspected or known dermatitis herpetiformis

Components include celiac disease dual antigen screen; tissue transglutaminase antibodies IgA and IgG; and gliadin peptide antibodies IgA and IgG

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

Reflex pattern – if celiac disease dual antigen screen is ≥20 units, then tTG IgA and gliadin peptide IgA will be added; if tTG IgA and gliadin peptide IgA are negative, tTG IgG and gliadin peptide IgG will be added

Clinical sensitivity/specificity – >99%

EMA-positive sera may show the prozone phenomenon

Antibodies are either very weak or negative at the initial screening dilution; sera will be screened at higher dilutions

Sera containing anti-smooth muscle antibodies (ASMA) will interfere with the detection of EMA IgG; sera should be further tested at higher dilutions

May be negative if patient is following a gluten-free diet

Some patients with DH will also be negative

Use to establish diagnosis of celiac disease which is present in virtually all patients with dermatitis herpetiformis

Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Tissue Transglutaminase (tTG) Antibody, IgA 0097709
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Not recommended as single test in evaluation of immunobullous skin disease

Do not use in IgA deficient individuals

Use to monitor disease activity

May be positive in inflammatory bowel disease and other disorders than celiac disease and associated dermatitis herpetiformis

Use tissue transglutaminase (tTG) antibody, IgA and/or endomysial antibody, IgA by IFA and/or epidermal transglutaminase (eTG) antibody, IgA tests to follow dermatitis herpetiformis disease activity unless IgA deficient or predominant IgG antibodies

See Immunobullous Skin Diseases Testing algorithm

EMA-positive sera may show the prozone phenomenon

Antibodies are either very weak or negative at the initial screening dilution; sera will be screened at higher dilutions

Sera containing anti-smooth muscle antibodies (ASMA) will interfere with the detection of EMA IgG; sera should be further tested at higher dilutions

Clinical sensitivity/specificity – >99%

Tissue Transglutaminase Antibody, IgG 0056009
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Not recommended as single test in evaluation of immunobullous skin disease

Order in patients with suspected celiac disease and documented IgA deficiency

May be used for monitoring

If IgA deficient and/or IgG celiac disease antibodies are present, use tissue transglutaminase IgG and/or endomysial antibody, IgG to follow dermatitis herpetiformis disease activity

See Immunobullous Skin Diseases Testing algorithm

EMA-positive sera may show the prozone phenomenon

Antibodies are either very weak or negative at the initial screening dilution; sera will be screened at higher dilutions

Sera containing anti-smooth muscle antibodies (ASMA) will interfere with the detection of EMA IgG; sera should be further tested at higher dilutions

Clinical sensitivity/specificity – >99%

Endomysial Antibody, IgG 2005501
Method: Semi-Quantitative Indirect Fluorescent Antibody

Use in IgA deficient individuals to evaluate for celiac disease associated with dermatitis herpetiformis

If IgA deficient and/or IgG celiac disease antibodies are present, use tissue transglutaminase IgG and/or endomysial antibody, IgG to follow dermatitis herpetiformis disease activity

See Immunobullous Skin Diseases Testing algorithm

EMA-positive sera may show the prozone phenomenon

Antibodies are either very weak or negative at the initial screening dilution; sera will be screened at higher dilutions

Sera containing anti-smooth muscle antibodies (ASMA) will interfere with the detection of EMA IgG; sera should be further tested at higher dilutions

Clinical sensitivity/specificity – >99%