Dermatitis Herpetiformis

  • Diagnosis
  • Algorithms
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

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

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

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

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.

Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence
(Direct Fluorescent Antibody Stain)

Limitations

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

Follow Up

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

Limitations

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

Follow Up

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

Limitations

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

Follow Up

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

Limitations

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

Follow Up

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

Limitations

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)

Follow Up

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)

Limitations

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

Follow Up

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

Limitations

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

Follow Up

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

Limitations

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

Follow Up

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

Related Tests

General References

Alonso-Llamazares J, Gibson LE, Rogers RS. Clinical, pathologic, and immunopathologic features of dermatitis herpetiformis: review of the Mayo Clinic experience. Int J Dermatol. 2007; 46(9): 910-9. PubMed

Baum S, Sakka N, Artsi O, Trau H, Barzilai A. Diagnosis and classification of autoimmune blistering diseases. Autoimmun Rev. 2014; 13(4-5): 482-9. PubMed

Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part I. Epidemiology, pathogenesis, and clinical presentation. J Am Acad Dermatol. 2011; 64(6): 1017-24; quiz 1025-6. PubMed

Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part II. Diagnosis, management, and prognosis. J Am Acad Dermatol. 2011; 64(6): 1027-33; quiz 1033-4. PubMed

Hull C, Zone J. Dermatitis herpetiformis and linear IgA bullous dermatosis, Ch 31. In Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology, 3rd ed. Waltham, MA: Elsevier Inc, 2012.

Kárpáti S. Dermatitis herpetiformis. Clin Dermatol. 2012; 30(1): 56-9. PubMed

Mihai S, Sitaru C. Immunopathology and molecular diagnosis of autoimmune bullous diseases. J Cell Mol Med. 2007; 11(3): 462-81. PubMed

Nakajima K. Recent advances in dermatitis herpetiformis. Clin Dev Immunol. 2012; 2012: 914162. PubMed

Ronaghy A, Katz S, Hall R. Dermatitis herpetiformis, ch 61. In Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick’s Dermatology in General Medicine, 8th ed. San Francisco: McGraw-Hill Medical, 2012.

Schmidt E, Zillikens D. The diagnosis and treatment of autoimmune blistering skin diseases. Dtsch Arztebl Int. 2011; 108(23): 399-405, I-III. PubMed

Zone JJ, Meyer LJ, Petersen MJ. Deposition of granular IgA relative to clinical lesions in dermatitis herpetiformis. Arch Dermatol. 1996; 132(8): 912-8. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Hull CM, Liddle M, Hansen N, Meyer LJ, Schmidt L, Taylor T, Jaskowski TD, Hill HR, Zone JJ. Elevation of IgA anti-epidermal transglutaminase antibodies in dermatitis herpetiformis. Br J Dermatol. 2008; 159(1): 120-4. PubMed

Jaskowski TD, Hamblin T, Wilson AR, Hill HR, Book LS, Meyer LJ, Zone JJ, Hull CM. IgA anti-epidermal transglutaminase antibodies in dermatitis herpetiformis and pediatric celiac disease. J Invest Dermatol. 2009; 129(11): 2728-30. PubMed

Medical Reviewers

Last Update: January 2016