Dermatitis Herpetiformis

Dermatitis herpetiformis (DH) is a chronic, pruritic skin disease associated with gluten sensitivity and often present in conjunction with celiac disease (CD) (gluten-sensitive enteropathy). Untreated disease may lead to continued skin symptoms and complications of enteropathy including iron-deficiency anemia and osteoporosis. Diagnosis of DH or CD should lower the threshold for evaluating for other autoimmune diseases. Individuals with DH have been shown to have a decreased mortality rate compared to those with CD (Hervonen, 2012).

Diagnosis

Indications for Testing

Chronic pruritic blistering dermatitis/skin lesions, classically with clustered papules and vesicles (vesicles may be uncommon due to scratching)

Criteria for Diagnosis

  • Clinical signs and symptoms
    • Pruritic papular and/or vesicular skin lesions in typical dermatitis herpetiformis (DH) extensor locations
  • Characteristic immunopathology on uninvolved, perilesional skin with direct immunofluorescence (DIF)
  • Positive serology consistent with gluten intolerance/celiac disease (CD); rarely increased serum IgA epidermal transglutaminase (eTG/TG3) antibodies only

Laboratory Testing

  • Should perform at a minimum
    • Celiac testing concurrently with immunopathology: see Celiac Disease
      • Skin biopsy necessary for diagnosis: see cutaneous DIF in Histopathlogy
    • Epidermal transglutaminase (eTG), also known as transglutaminase type 3 (TG3), IgA antibody testing
  • Testing for other blistering skin diseases
    • Due to similarities in clinical presentation, it may be helpful to consider the following tests to assist with the diagnosis of bullous, puritic skin lesions
    • Testing for Blistering Skin Diseases
      Test Number Test Name Skin Diseases Recommended Use
      3003997 Basement Membrane Zone Antibody Panel

      Pemphigoid

      Epidermolysis bullosa acquisita

      Linear IgA disease

      Some bullous lupus erythematosus

      Diagnosis

      Disease activity monitoring

      0092001

      Pemphigoid Antibody Panel

      Pemphigoid

      Linear IgA bullous dermatosis

      Diagnosis

      Disease activity monitoring

      2010905

      Collagen Type VII Antibody, IgG by ELISA

      Epidermolysis bullosa acquisita

      Some bullous lupus erythematosus

      Disease activity monitoring

      0090650

      Pemphigus Antibody Panel, IgG

      IgG variant pemphigus including pemphigus foliaceus and pemphigus vulgaris

      Diagnosis

      Disease activity monitoring

      0092106

      Pemphigus Antibodies, IgA by IIF 

      IgA variant pemphigus including intraepidermal neutrophilic IgA dermatosis and subcorneal pustular dermatosis

      Diagnosis

      Disease activity monitoring

    • In relevant clinical situations, consider
    • Test Number Test Name Skin Diseases Recommended Use

      0092107

      Paraneoplastic Pemphigus (Paraneoplastic Autoimmune Multiorgan Syndrome) Antibody Screening Panel

      Paraneoplastic pemphigus

      Diagnosis

      Disease activity monitoring

      0092283

      Pemphigoid Gestationis, Complement-Fixing Basement Membrane Antibodies (Herpes Gestationis Factor)

      Pemphigoid gestationis

      Diagnosis

      Disease activity monitoring

  • HLA genotyping
    • Testing is not generally recommended: may be useful in ruling out CD and/or dermatitis herpetiformis (DH) only in selective clinical situations because of high negative predictive value
    • Absence of one of these haplotypes essentially rules out CD and DH
      • HLA-DQ2 (encoded by HLA-DQA1*05 and HLA-DQB1*02)
        • Present in >90% of individuals with DH
      • HLA-DQ8 (encoded by HLA-DQB1*03:02)
        • Present in ~5-10% of individuals with DH

Histopathology

Skin biopsies for histopathology and perilesional biopsy (3 mm from an active lesion) for direct immunofluorescence is necessary for diagnosis

Differential Diagnosis

  • Arthropod bites
  • Bullous impetigo
  • Bullous lupus erythematosus
  • Contact dermatitis
  • Eczema (various types, including atopic and asteatotic)
  • Epidermolysis bullosa acquisita
  • Erythema multiforme
  • Herpes simplex or herpes zoster
  • IgA vasculitis
  • Linear IgA bullous dermatosis
  • Pemphigoid
  • Pemphigus
  • Prurigo nodularis
  • Scabies and other ectoparasites
  • Urticaria and urticarial vasculitis

Monitoring

  • Monitor therapy/adherence to gluten-free diet
    • IgA endomysial antibodies (EMA)
    • IgA tissue transglutaminase antibodies (tTg): transglutaminase 2 (TG2) enzyme-linked immunosorbent assay (ELISA)
    • IgA epidermal transglutaminase (eTG): transglutaminase 3 (TG3) ELISA
    • Patients who are IgA deficient and rare patients without IgA deficiency have IgG EMA and IgG TG2 antibodies without detectable IgA antibodies, which fluctuate with disease activity

Background

Epidemiology

  • Incidence: 0.4-3.5/100,000; possibly declining
  • Prevalence: 1.2-75.3/100,000
  • Age: all ages but uncommon in children; peak onset 20s-40s
  • Sex: M>F
  • Ethnicity: most common in those of northern European descent but occurs in all ethnic groups

Risk Factors

  • Gluten-sensitive enteropathy (GSE), CD
  • Lymphoma
  • Autoimmune disease (eg, lupus, thyroiditis, diabetes)
  • Oral aphthae
  • First-degree relatives with DH or CD

Pathophysiology and Immunopathophysiology

  • Skin biopsy specimens from patients with DH demonstrate subepidermal deposition of IgA with neutrophil infiltration
  • Patients with DH have serum IgA antibodies to tissue transglutaminase (tTG/TG2) and epidermal transglutaminase (eTG/TG3)
  • Most patients with DH have mild CD; however, only ~5% of individuals with CD will develop DH (Herrero-Gonzalez, 2010)
  • Strong association with HLA genotype DQ A1*0501, B1*02, which encodes HLA-DQ2 heterodimers

Immunohistology and Dermatopathology

  • Granular and/or fibrillar deposition of IgA antibodies in dermal papillae and, less commonly, in blood vessels by direct immunofluorescence testing
  • Classically, a subepidermal blister with neutrophil (and occasionally eosinophil) microabscesses within dermal papillae in fixed-tissue histopathology

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, which is attended by secondary skin changes including ecchymoses
  • Oral lesions are rare
  • Only ~20% of patients with DH will not have signs (enteropathy) and/or symptoms of CD (Jakes, 2014)

ARUP Laboratory Tests

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

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

Use as preferred screening test for individuals with suspected CD

Components: quantitative nephelometry for IgA with one or more reflexive tests that may include IIF for IgA endomysial antibodies; ELISAs for IgA and IgG antibodies to tissue transglutaminase and deamidated gliadin peptide (DGP)

Use to assess and monitor DH. Testing should be correlated with initially concurrent DIF biopsy

Because most patients with DH have associated CD, testing should be performed in conjunction with testing for CD

For initial diagnosis and assessment of disease progression/changes and to distinguish from other immunobullous diseases with epithelial antibodies, order concurrently with serum Immunobullous Disease Antibody Panel 

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 initial diagnostic panel for suspected BMZ antibody-associated skin and mucous membrane disorders that present with blistering, erosions, eczema, urticaria, pruritus, and/or mucositis

May be indicated by concurrent DIF biopsy

Alternatively, order the comprehensive Immunobullous Disease Antibody Panel for initial serum diagnostic assessment of epithelial antibody-associated diseases, pemphigoid, pemphigus, and their variants

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 

Use to assess and monitor pemphigoid, pemphigoid variants, and linear IgA disease and to discriminate among the immunobullous diseases with epithelial BMZ antibodies

May be indicated by concurrent DIF biopsy; preferred initial diagnostic serum panel is Basement Membrane Zone Antibody Panel 

Components: BMZ antibodies, IgG by IIF; BMZ antibodies, IgA by IIF; BP180 and BP230 antibodies, IgG by ELISA

Use to monitor disease in patients diagnosed with EBA or bullous lupus erythematosus with increased IgG type VII collagen antibody levels

For initial diagnosis, including discrimination among various immunobullous diseases, and assessment of disease progression/changes and intermittent monitoring, the Immunobullous Disease Antibody Panel or Basement Membrane Zone Antibody Panel is preferred

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 with initially concurrent DIF biopsy

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

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 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

See Immunobullous Skin Diseases Testing algorithm

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

CD reflexive panel or tissue transglutaminase (tTG) antibody, IgA, is preferred screening test

Acceptable single screening test for IgA-competent individuals with suspected CD

Preferred screening test for individuals with suspected CD is CD reflexive cascade or tTG/TG2, IgA

IgA testing recommended to identify IgA competence prior to choosing EMA test

May aid in monitoring adherence to GFD in CD-confirmed patients

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

See Immunobullous Skin Diseases Testing algorithm

EMA-positive sera may show the prozone phenomenon

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

Acceptable single screening test for CD; CD reflexive cascade or tissue transglutaminase antibody, IgA is preferred test for screening patients with suspected CD

IgA testing recommended to identify IgA deficiency; use IgG test in individuals who are IgA deficient

May be useful in diagnosing children <2 years who test negative for tTG/TG2 and EMA antibodies

May aid in monitoring adherence to GFD

Acceptable single screening test for CD; CD reflexive cascade or tissue transglutaminase antibody, IgA is preferred test for screening patients with suspected CD

Not recommended for use in the initial evaluation of celiac disease

May be useful to rule out celiac disease in selective clinical situations (eg, when a patient has started a gluten-free diet prior to testing or when small bowel histologic findings are equivocal) or to identify risk (eg, in individuals who have first-degree family members with celiac disease)

Related Tests

Use to assess and monitor IgA BMZ antibodies in patients with linear IgA disease, including linear IgA bullous dermatosis and chronic bullous disease of childhood, and IgA variant EBA

Testing should be correlated initially with concurrent DIF biopsy 

For initial linear IgA disease diagnosis, serum Basement Membrane Zone Antibody Panel or Immunobullous Disease Antibody Panel is preferred

Use to monitor disease in patients diagnosed with pemphigoid and increased IgG BP180 and/or BP230 antibody levels

For initial pemphigoid diagnosis that discriminates among immunobullous diseases and for assessment of disease progression/changes and intermittent monitoring, the Basement Membrane Zone Antibody Panel or Immunobullous Disease Antibody Panel is preferred

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 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 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

Use to assess and monitor paraneoplastic pemphigus, a rare paraneoplastic disease associated with lymphoproliferative disorders/malignancies and demonstrating clinical features of severe pemphigus

Testing should be correlated with concurrent DIF biopsy, histopathological examination of formalin-fixed tissue, and assessment of other epithelial antibodies

Consider ordering concurrently with Immunobullous Disease Antibody Panel for broad epithelial antibody assessment

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

Use as the preferred panel to assess and monitor pemphigoid gestationis (herpes gestationis) or other immunobullous disease with complement-fixing BMZ antibodies

Testing should be correlated initially with concurrent DIF biopsy 

Consider other types of immunobullous disease serum testing concurrently 

Components: complement-fixing BMZ antibodies; BP180 antibody, IgG by ELISA; BMZ antibodies, IgG by IIF

Use to determine whether to use IgA or IgG tissue transglutaminase (tTG/TG2) and deamidated gliadin peptide (DGP) assays

Recommended single screening test for IgA-competent individuals with suspected CD

IgA testing recommended to identify IgA competence prior to choosing tTG/TG2 test – use IgA test in individuals who are IgA competent or IgG test in individuals who are IgA deficient

May aid in monitoring adherence to gluten-free diet (GFD) in CD-confirmed patient

IgA tTG/TG2 antibodies may be increased in patients with inflammatory bowel disease and other intestinal disorders and not specifically in CD

Recommended single screening test for IgA-deficient individuals with suspected CD

IgA testing recommended to identify IgA deficiency prior to choosing tTG/TG2 test – use IgA test in individuals who are IgA competent or IgG test in individuals who are IgA deficient

May aid in monitoring adherence to GFD in CD-confirmed patients

IgA tTG/TG2 antibodies may be increased in patients with inflammatory bowel disease and other intestinal disorders and not specifically in CD

Acceptable single screening test for IgA-deficient individuals with suspected CD

Preferred screening test is celiac disease reflexive cascade or tTG/TG2, IgG

IgA testing recommended to identify IgA deficiency prior to ordering EMA test; use IgA test in individuals who are IgA competent (EMA IgA is an acceptable follow-up test for weakly positive or negative tTG/TG2 IgA screen); use IgG test in individuals who are IgA deficient

May aid in monitoring adherence to GFD in CD-confirmed patients

EMA-positive sera may show the prozone phenomenon

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

References

Additional Resources

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
Contributor