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

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 section
    • 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 are 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
  • 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

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)
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

Limitations 

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

Celiac Disease Reflexive Cascade 2008114
Method: Quantitative Nephelometry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay//Semi-Quantitative Indirect Fluorescent Antibody

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

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

Collagen Type VII Antibody IgG by ELISA 2010905
Method: Enzyme-Linked Immunosorbent Assay

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

`Pemphigus Antibody IgA 0092106
Method: Indirect Fluorescent Antibody

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 

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

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

Limitations 

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

Celiac Disease Dual Antigen Screen with Reflex 2002026
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Deamidated Gliadin Peptide (DGP) Antibody, IgA 0051357
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Deamidated Gliadin Peptide (DGP) Antibody, IgG 0051359
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Celiac Disease Dual Antigen Screen 0051689
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

F-Actin (Smooth Muscle) Antibody, IgA 0051724
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Celiac Disease (HLA-DQ2, and HLA-DQ8) Genotyping 2005018
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Limitations 

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

Guidelines

Caproni M, Antiga E, Melani L, Fabbri P, Italian Group for Cutaneous Immunopathology. Guidelines for the diagnosis and treatment of dermatitis herpetiformis. J Eur Acad Dermatol Venereol. 2009; 23(6): 633-8. PubMed

Herrero-González JE. Clinical guidelines for the diagnosis and treatment of dermatitis herpetiformis. Actas Dermosifiliogr. 2010; 101(10): 820-6. PubMed

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

Antiga E, Caproni M. The diagnosis and treatment of dermatitis herpetiformis. Clin Cosmet Investig Dermatol. 2015; 8: 257-65. 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

Bonciani D, Verdelli A, Bonciolini V, D'Errico A, Antiga E, Fabbri P, Caproni M. Dermatitis herpetiformis: from the genetics to the development of skin lesions. Clin Dev Immunol. 2012; 2012: 239691. PubMed

Borroni G, Biagi F, Ciocca O, Vassallo C, Carugno A, Cananzi R, Campanella J, Bianchi PI, Brazzelli V, Corazza GR. IgA anti-epidermal transglutaminase autoantibodies: a sensible and sensitive marker for diagnosis of dermatitis herpetiformis in adult patients. J Eur Acad Dermatol Venereol. 2013; 27(7): 836-41. PubMed

Hervonen K, Alakoski A, Salmi TT, Helakorpi S, Kautiainen H, Kaukinen K, Pukkala E, Collin P, Reunala T. Reduced mortality in dermatitis herpetiformis: a population-based study of 476 patients. Br J Dermatol. 2012; 167(6): 1331-7. PubMed

Hervonen K, Salmi TT, Kurppa K, Kaukinen K, Collin P, Reunala T. Dermatitis herpetiformis in children: a long-term follow-up study. Br J Dermatol. 2014; 171(5): 1242-3. 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.

Jakes AD, Bradley S, Donlevy L. Dermatitis herpetiformis Duhring. Praxis (Bern 1994). 2014; 103(18): 1085-8. PubMed

Jakes AD, Bradley S, Donlevy L. Dermatitis herpetiformis. BMJ. 2014; 348: g2557. PubMed

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.

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

Content Reviewed: 
September 2017

Last Update: October 2017