Dermatitis Herpetiformis

Dermatitis herpetiformis (DH) is a chronic, pruriticskin 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).

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Epithelial Antibody-Associated Immunobullous Diseases Testing

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 locations
  • Characteristic immunopathology on uninvolved, perilesional skin with direct immunofluorescence
  • Positive serology consistent with gluten intolerance/celiac disease (CD); rarely increased serum IgA epidermal transglutaminase antibodies only

Laboratory Testing

  • Should perform at a minimum
    • Celiac testing concurrently with immunopathology – see Celiac Disease
      • Biopsy necessary for diagnosis – see cutaneous direct immunofluorescence in Histology
    • 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

      0092001

      Pemphigoid Antibody Panel - Epithelial Basement Membrane Zone Antibodies, IgG and IgA, BP180 and BP230 Antibodies, IgG

      Pemphigoid

      Epidermolysis bullosa acquisita

      Linear IgA bullous dermatosis

      Diagnosis

      Disease activity monitoring

      2010905

      Collagen Type VII Antibody IgG by ELISA

      Epidermolysis bullosa acquisita

      Some bullous lupus erythematosus

      Diagnosis

      Disease activity monitoring

      0090650

      Pemphigus Antibody Panel - Epithelial Cell Surface Antibodies and Desmoglein 1 and Desmoglein 3 Antibodies, IgG

      IgG variant pemphigus including pemphigus foliaceus and pemphigus vulgaris

      Diagnosis

      Disease activity monitoring

      0092106

      Pemphigus Antibody IgA

      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 Antibody Screen

      Paraneoplastic pemphigus

      Diagnosis

      0092283

      Herpes Gestationis Factor (Complement-Fixing Basement Membrane Zone Antibody IgG)

      Pemphigoid gestationis

      Diagnosis
  • 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

Histology

Skin biopsy 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

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 Lab Tests

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

See Immunobullous Skin Diseases Testing algorithm

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

Preferred reflex screening test for celiac disease (CD)

Depending on initial results from IgA screening, one or more tests may be added for clinical interpretation

  • Tissue transglutaminase (tTG/TG2) antibody, IgA
  • Tissue transglutaminase (tTG/TG2) antibody, IgG
  • Endomysial antibody, IgA
  • Deamidated gliadin peptide antibody, IgA
  • Deamidated gliadin peptide antibody, IgG
  • Celiac disease dual antigen screen

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

Order with celiac disease serology testing for patient with possible dermatitis herpetiformis (DH)

IgA epidermal transglutaminase (transglutaminase 3 or TG3) antibodies are pathogenic in DH, and an increased level is distinctly characteristic of the disorder

For initial diagnosis and to discriminate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease; order concurrently with testing for epithelial cell surface antibody or refer to antibody panel tests for pemphigoid and pemphigus

See Immunobullous Skin Diseases Testing algorithm

Initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria, including pemphigoid, pemphigoid variants, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, linear IgA disease variants, and IgG-pemphigus subtypes

Order concurrently with perilesional skin biopsy for direct immunofluorescence for initial diagnosis

Use for disease monitoring with semiquantitative antibody level assessments and tracking and for persistent unexplained disease and/or worsening disease activity

Initial diagnostic panel for skin and mucous membrane disorders that present with blistering, erosions, eczema, pruritus, and/or urticaria from suspected basement membrane zone antibody-associated disease (eg, bullous pemphigoid, pemphigoid variants, epidermolysis bullosa acquisita, linear IgA bullous dermatosis, and linear IgA disease variants)

Order concurrently with perilesional skin biopsy for direct immunofluorescence for initial diagnosis

Use for disease monitoring with semiquantitative antibody assessments and tracking

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

Bullous pemphigoid and other pemphigoid variants, epidermolysis bullosa acquisita, and linear IgA bullous dermatosis present with blistering, erosions, pruritus, and urticaria, which affect skin and mucous membranes

To order individual component tests, refer to antibody testing for IgG BMZ, IgA BMZ, and/or IgG bullous pemphigoid BP180 and BP230 antigens

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

See Immunobullous Skin Diseases Testing algorithm

Panel components include IgG and IgA epithelial basement membrane zone (BMZ) antibodies and IgG bullous pemphigoid BP180 and BP230 antigen antibodies

Initial diagnosis and disease monitoring of epidermolysis bullosa acquisita

To further evaluate IgG BMZ antibodies, consider ordering with pemphigoid antibody panel

Consider other types of BMZ antibody-associated disease testing (ie, epithelial BMZ antibody IgA and herpes gestationis factor)

To discriminate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease, refer to pemphigoid antibody panel – epithelial BMZ antibodies, IgG and IgA, BP180 and BP230 antibodies, IgG and pemphigus antibody panel – epithelial cell surface antibodies and desmoglein 1 and desmoglein 3 antibodies, IgG

See Immunobullous Skin Diseases Testing algorithm

Preferred panel for initial assessment and disease monitoring in IgG-variant pemphigus; pemphigus vulgaris and pemphigus foliaceus are the most common types of pemphigus with blistering and erosive disease affecting skin and mucous membranes

To screen for pemphigus along with other possible immunobullous diseases, order concurrently with antibody panel test for pemphigoid, IgG collagen type VII antibody, pemphigus antibody IgA, paraneoplastic pemphigus antibody screen, AND perilesional skin biopsy for DIF

See Immunobullous Skin Diseases Testing algorithm

Panel components include antibody testing for IgG epithelial cell surface and IgG desmoglein 1 and 3; to order individual component tests, refer to epithelial cell surface antibody IgG and/or desmoglein 1 and 3 antibodies in pemphigus IgG

Assess and monitor patient with possible IgA pemphigus, a RARE disease with certain clinical and histopathological subtypes

If other types of pemphigus are of diagnostic consideration, order pemphigus antibody panel – epithelial cell surface antibodies and desmoglein 1 and desmoglein 3 antibodies, IgG first or concurrently with this test

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 reflexive screening test for CD

Screen includes tTG/TG2 antibodies IgA and IgG, and deamidated gliadin peptide (DGP) antibodies IgA and IgG

CD reflexive cascade or tTG/TG2 IgA tests preferred for screening patients with suspected CD

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 IgA test in individuals who are IgA competent

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

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

Screen includes tTG/TG2 antibodies IgA and IgG, and DGP antibodies IgA and IgG​

Do not use to screen for CD

May be used to estimate severity of intestinal villous atrophy in confirmed CD

Not for initial evaluation of CD

Useful in ruling out CD (high negative predictive value) in selective clinical situations such as

  • Equivocal small bowel histopathologic finding (Marsh I-II) in seronegative individuals
  • Evaluation of individuals on a GFD in whom no testing for CD was done before GFD
  • Individuals with discrepant celiac-specific serology and histopathology
  • Strong serologic evidence and clinical suspicion and desire to avoid small bowel biopsy (eg, children)

Rare diagnostic errors can occur due to primer-site mutations

Copy number of each detected allele will not be determined

Other HLA types will not be detected

Other genetic and nongenetic factors that influence CD are not evaluated

Related Tests

Assess and monitor patient with linear IgA disease, including linear IgA bullous dermatosis and positive IgA basement membrane zone (BMZ) antibodies, either epidermal (roof) pattern or dermal (floor) pattern

Consider ordering concurrently with epithelial BMZ antibody IgG, bullous pemphigoid antigens (BP180 and BP230), IgG antigens, and/or collagen type VII antibody IgG

Monitor disease in patient previously diagnosed with pemphigoid and increased IgG BP180 and/or BP230 antibodies; IgG BP180 antibody levels correlate with disease activity in some patients with pemphigoid; consider ordering with epithelial BMZ antibody IgG

If used to screen for pemphigoid, this test has decreased sensitivity and specificity when compared to pemphigoid antibody panel (epithelial BMZ antibodies and BP180 and BP230 antibodies, IgG)

For initial diagnosis and monitoring disease, pemphigoid antibody panel (epithelial BMZ antibodies and BP180 and BP230 antibodies IgG) is preferred

For diagnosing epidermolysis bullosa acquisita, refer to collagen type VII antibody IgG

Monitor disease in patient previously diagnosed with pemphigus and increased IgG desmoglein 1 and/or 3 antibodies; antibody levels correlate with disease activity; consider ordering with epithelial cell surface antibody IgG

If used to screen for pemphigus, this test has decreased sensitivity and specificity when compared to pemphigus antibody panel – epithelial cell surface antibodies and desmoglein 1 and desmoglein 3 antibodies, IgG

For initial diagnosis and monitoring disease, pemphigus antibody panel – epithelial cell surface antibodies and desmoglein 1 and desmoglein 3 antibodies, IgG is preferred

For diagnosing rare types of pemphigus, refer to pemphigus antibody IgA and paraneoplastic pemphigus antibody screen

General screen for immunobullous diseases

Consider ordering concurrently with IgG bullous pemphigoid (BP180 and BP230) 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

See Immunobullous Skin Diseases Testing algorithm

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)

Assess patient with possible paraneoplastic pemphigus (PNP), a RARE paraneoplastic disease associated with lymphoproliferative disorders/malignancies and severe pemphigus clinical features with characteristic IgG antibodies to rodent substrates

If other, more common, types of pemphigus are of diagnostic consideration, order pemphigus antibody panel first or concurrently with this test

If IgA paraneoplastic antibody testing is required, request through ARUP Client Services 800-242-2787 option 2

Assess and monitor patient with possible pemphigoid gestationis (herpes gestationis)

Pemphigoid gestationis is a rare disease of pregnancy; consider other types of immunobullous disease testing (ie, epithelial BMZ antibody IgA, collagen type VII antibody IgG by ELISA, and/or pemphigus antibody panel – epithelial cell surface antibodies and desmoglein 1 and desmoglein 3 antibodies, IgG

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

Panel not recommended for screening celiac disease (CD)

Preferred screening test is celiac disease reflexive cascade or tissue transglutaminase antibody, IgA testing for individuals with normal levels of serum IgA

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

See Immunobullous Skin Diseases Testing algorithm

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

See Immunobullous Skin Diseases Testing algorithm

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

See Immunobullous Skin Diseases Testing algorithm

Medical Experts

Contributor

Leiferman

 

Kristin M. Leiferman, MD

Co-Director, Immunodermatology Laboratory, Professor of Dermatology, University of Utah

Consultant, Immunodermatology at ARUP Laboratories

Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®

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