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FeedbackDermatitis 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).
Quick Answers for Clinicians
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
- Celiac testing concurrently with immunopathology – see Celiac Disease
- 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
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Testing for Blistering Skin Diseases Test Number Test Name Skin Diseases Recommended Use Pemphigoid Antibody Panel - Epithelial Basement Membrane Zone Antibodies, IgG and IgA, BP180 and BP230 Antibodies, IgG
Diagnosis
Disease activity monitoring
Collagen Type VII Antibody IgG by ELISA
Epidermolysis bullosa acquisita
Some bullous lupus erythematosus
Diagnosis
Disease activity monitoring
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
Pemphigus Antibody IgA
IgA variant pemphigus including intraepidermal neutrophilic IgA dermatosis and subcorneal pustular dermatosis
Diagnosis
Disease activity monitoring
- In relevant clinical situations, consider
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Test Number Test Name Skin Diseases Recommended Use Paraneoplastic Pemphigus Antibody Screen
Diagnosis
Herpes Gestationis Factor (Complement-Fixing Basement Membrane Zone Antibody IgG)
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
- HLA-DQ2 (encoded by HLA-DQA1*05 and HLA-DQB1*02)
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 Laboratory Tests
Order concurrently with serum antibody testing and fixed tissue histopathology for assessment of patient with pruritic, urticarial, blistering, crusted, 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
Direct Immunofluorescence
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)
Quantitative Immunoturbidimetry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay//Semi-Quantitative Indirect Fluorescent Antibody
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay
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
Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Indirect Fluorescent Antibody (IFA)/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Indirect Fluorescent Antibody (IFA)/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Indirect Fluorescent Antibody (IFA)
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/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 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
Semi-Quantitative Indirect Fluorescent Antibody
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Acceptable single screening test for CD; CD reflexive cascade or tissue transglutaminase antibody, IgA is preferred test for screening patients with suspected CD
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Not recommended for use in the initial evaluation of celiac disease
May be useful to rule out celiac disease in selective clinical situations (eg, when a patient has started a gluten-free diet prior to testing or when small bowel histologic findings are equivocal) or to identify risk (eg, in individuals who have first-degree family members with celiac disease)
Polymerase Chain Reaction/Massively Parallel Sequencing, or Polymerase Chain Reaction/Sequence-Specific Oligonucleotide Probe Hybridization
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
Semi-Quantitative Indirect Fluorescent Antibody (IFA)
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Indirect Fluorescent Antibody (IFA)
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
Semi-Quantitative Indirect Fluorescent Antibody (IFA)
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
Semi-Quantitative Complement Fixation/Indirect Fluorescent Antibody (IFA)/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Determine whether to use IgA or IgG tissue transglutaminase (tTG/TG2) and deamidated gliadin peptide (DGP) assays
Quantitative Immunoturbidimetry
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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
Semi-Quantitative Indirect Fluorescent Antibody
Medical Experts
Leiferman
Tebo
References
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Dermatology - Dermatitis herpetiformis and linear IgA bullous dermatosis, ch 31
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Fitzpatrick’s Dermatology in General Medicine - Dermatitis herpetiformis, ch 61
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Additional detail about each test listed below can be found in the ARUP Laboratory Test Directory (LTD). In addition, each test name links directly to the LTD.