Dermatitis Herpetiformis
- Diagnosis
- Algorithms
- Monitoring
- Background
- Lab Tests
- References
- Related Topics
- Videos
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
- Most patients with DH have gluten sensitivity with celiac disease and characteristic IgA antibodies to tissue transglutaminase
- 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)
- Increased IgA epidermal transglutaminase antibody level – distinctly characteristic of and supports diagnosis of DH
- TG3 – dominant antigen to which IgA antibodies develop in DH
- Patients with DH – have antibody profile specific for TG3 with higher avidity than to TG2
- Increased IgA epidermal transglutaminase antibody level – distinctly characteristic of and supports diagnosis of DH
- Celiac disease dual antigen screen – alternative to above testing; less sensitive
- Tissue transglutaminase (tTG) also known as transglutaminase 2 (TG2) IgA antibodies with reflex to endomysial antibody (EMA)
- 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
- Suggested initial tests
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
- Granular or fibrillar IgA deposits at or beneath the basement membrane zone (BMZ) in dermal papillary tips is pathognomonic
Differential Diagnosis
- Arthropod bites
- Bullous impetigo
- Bullous lupus erythematosus
- Contact dermatitis
- Eczema (other types, including atopic and asteatotic)
- 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
- 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)
- DH and chronic bullous disease of childhood are the most common autoimmune bullous diseases of childhood
- Sex – M>F
- Ethnicity – most common in those of northern European descent but occurs in all ethnic groups
Risk Factors
- GSE
- Lymphoma
- Autoimmune disease (eg, lupus, thyroiditis, diabetes)
- Oral aphthae
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
- ~20% have signs and/or symptoms of celiac disease (Jakes, 2014)
Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence
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
For skin involvement, biopsy perilesional skin
For mucous membrane involvement, biopsy nonlesional mucosa
Use in testing for celiac disease (celiac reflexive panel), which is associated with dermatitis herpetiformis in most cases, along with pemphigoid and pemphigus panel tests
See Immunobullous Skin Diseases Testing algorithm
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
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
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
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
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
Order with celiac disease serology testing for patient with possible DH
IgA epidermal transglutaminase (transglutaminase 3 or TG3) antibodies are pathogenic in dermatitis herpetiformis, 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
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
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
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 BMZ antibodies and IgG bullous pemphigoid BP180 & 230 antigens
To order individual component tests, refer to antibody testing for IgG BMZ, IgA BMZ, and/or IgG bullous pemphigoid BP180 & 230 antigens
To screen for pemphigoid along with other possible immunobullous diseases, order concurrently with the pemphigus antibody panel IgG collagen type VII antibody, AND perilesional skin biopsy for direct immunofluorescence (DIF)
Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity (85-100% of pemphigus, pemphigoid, linear IgA disease, epidermolysis bullosa acquisita, and dermatitis herpetiformis cases are positive)
See Immunobullous Skin Diseases Testing algorithm
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
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
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 skin antibody 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, AND perilesional skin biopsy for DIF
Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity (85-100% of pemphigus, pemphigoid, linear IgA disease, epidermolysis bullosa acquisita, and dermatitis herpetiformis cases are positive)
See Immunobullous Skin Diseases Testing algorithm
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)
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)
General screen for immunobullous diseases
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)
Consider ordering concurrently with IgG bullous pemphigoid (BP180 & 230) 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
Use along with tTG IgA with reflex to endomysial antibody for diagnosis of dermatitis herpetiformis
See Immunobullous Skin Diseases Testing algorithm
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
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
Acceptable single screening test for IgA-competent individuals with suspected CD
Preferred screening test for individuals with suspected CD is celiac disease reflexive cascade or tTG, IgA
IgA testing recommended to identify IgA competence prior to choosing EMA test
May aid in monitoring adherence to GFD in celiac disease-confirmed patients
Clinical sensitivity/specificity – >99%
Perilesional skin biopsy for DIF is helpful in diagnosis (>90% of dermatitis herpetiformis cases are positive)
See Immunobullous Skin Diseases Testing algorithm
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
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
Acceptable reflexive screening test for CD
Screen includes tTG antibodies IgA and IgG, and DGP antibodies IgA and IgG
CD reflexive cascade or tTG IgA tests preferred for screening patients with suspected CD
Reflex pattern - positive screen reflexes to IgA antibody testing for tTG and DGP; negative IgA testing for tTG and DGP reflexes to IgG antibody testing for tTG and DGP
Clinical sensitivity/specificity - >99%
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
Use to establish diagnosis of celiac disease which is present in virtually all patients with dermatitis herpetiformis
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.
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.
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: August 2016
