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).

Tabs Content

Clinical Overview

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

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 Lab Tests

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

Recommended Use

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

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

Recommended Use

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)

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

Recommended Use

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

Immunobullous Disease Panel, Epithelial 3001409
Method: Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay

Recommended Use

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

Basement Membrane Zone Antibody Panel 3001410
Method: Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay

Recommended Use

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

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

Recommended Use

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

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

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

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

Recommended Use

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

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

Recommended Use

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

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

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

`Pemphigus Antibody IgA 0092106
Method: Indirect Fluorescent Antibody

Recommended Use

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

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

Recommended Use

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 ≥4 U/mL units, then EMA IgA by IFA testing will be added

See Immunobullous Skin Diseases Testing algorithm

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

Recommended Use

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

Clinical sensitivity/specificity – >99%

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

See Immunobullous Skin Diseases Testing algorithm

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

Recommended Use

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

Reflex pattern - positive screen reflexes to IgA antibody testing for tTG/TG2 and DGP; negative IgA testing for tTG/TG2 and DGP reflexes to IgG antibody testing for tTG/TG2 and DGP

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

Recommended Use

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

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

Recommended Use

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

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

Recommended Use

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

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

Recommended Use

Do not use to screen for CD

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

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

Recommended Use

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)

Clinical sensitivity – 100%

Clinical specificity – 3%

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

Medical Experts

Leiferman, Kristin M., MD, Consultant, Immunodermatology at ARUP Laboratories; Co-Director, Immunodermatology Laboratory, Professor of Dermatology, University of Utah

Tebo, Anne E., PhD, D(ABMLI), Medical Director, Immunology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

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

Resources 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

Testing Algorithms

Epithelial Antibody-Associated Immunobullous Diseases Testing

Read more about Epithelial Antibody-Associated Immunobullous Diseases Testing

Educational Videos

Content Review:

September 2017

Last Update: August 2019

Dermatitis Herpetiformis

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

Differential Diagnosis

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology and Immunopathophysiology

Immunohistology and Dermatopathology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Epithelial Antibody-Associated Immunobullous Diseases Testing

ARUP Laboratories

ARUP Websites

ARUP Consult


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Dermatitis Herpetiformis

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

Differential Diagnosis

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology and Immunopathophysiology

Immunohistology and Dermatopathology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Epithelial Antibody-Associated Immunobullous Diseases Testing

ARUP Laboratories

ARUP Websites

ARUP Consult