Dermatitis Herpetiformis

Clinical Background

Dermatitis herpetiformis is a chronic, pruritic skin disease that is usually associated with intestinal gluten sensitivity (celiac disease).

Epidemiology

Incidence – 10-39/100,000
Age – all ages; peak onset is 20s-30s
Sex – M>F (minimal)
Ethnicity – most common in those of northern European descent but occurs in all ethnic groups

Risk Factors

Gluten-sensitive enteropathy (celiac disease)
Lymphoma
Autoimmune disease (eg, lupus, thyroid, diabetes)
Oral aphthae

Pathophysiology and Immunopathophysiology

Granular and/or fibrillar deposition of IgA antibodies in dermal papillae and, less commonly, in blood vessels
Neutrophilic microabscesses in the dermal papillae
Dermal infiltration of neutrophils and eosinophils

Clinical Presentation

Intense pruritus with excoriations
Papulovesicular lesions and urticarial wheals in a symmetrical distribution – classically involves extensor surfaces of arms, knees and buttocks
Chronic eczematoid skin changes

Treatment

Dietary modification to eliminate gluten ingestion
Dapsone

Diagnosis

Indications for testing – chronic pruritic dermatitis/skin lesions in patient with or without known celiac disease after other, more common diseases ruled out
- Most dermatitis herpetiformis cases have associated celiac disease
Laboratory testing
- Initial testing – serology
  - Pemphigus and pemphigoid panels and endomysial antibodies or celiac screen; also epidermal transglutaminase
  - All tests are recommended unless a specific immunobullous skin disease type is suspected due to the potential for overlapping clinical features
  - Epidermal transglutaminase antibody testing may be helpful as a supplemental diagnostic test for dermatitis herpetiformis; test has relatively high specificity
  - IgA endomysial antibodies – order screen IgA tissue transglutaminase assay and epidermal transglutaminase antibody assay; in addition, assess for celiac disease
    - IgA deficient and/or in atypical cases, perform IgG endomysial and tissue transglutaminase antibody testing
    - IgA endomysial antibody titers >1:10 and increased IgA tissue transglutaminase antibody levels are found in dermatitis herpetiformis and/or celiac disease; follow positive titers with subsequent serum testing
    - If testing is positive and patient does not have definitive diagnosis of celiac disease, diagnostic measure should be instituted to evaluate for celiac disease (gastroenterology consultation with consideration for small intestinal biopsy)
Histology
- Perilesional skin biopsy for cutaneous direct immunofluorescence – sample should be 3-5 mm from the edge of an active lesion and should be submitted in Michel’s (or Zeus) medium
  - Granular or fibrillar IgA deposits at or beneath the basement membrane zone (BMZ) – deposits may be sparse and widely distributed
  - If initial biopsy is negative, additional perilesional biopsy may increase yield

Differential Diagnosis

Bullous impetigo
Bullous lupus erythematosus
Contact dermatitis
Eczema (other types including atopic and asteatotic)
Herpes simplex or herpes zoster
Pemphigoid
Pemphigus
Prurigo nodularis
Scabies
Urticaria

Additional Information

Indications for Laboratory Testing

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

Test Name and Number	Recommended Use	Limitations	Follow Up
Cutaneous Direct Immunofluorescence, Biopsy 0092572 Method: Direct Immunofluorescence	Determine presence and staining pattern of immunoglobulins (IgG, IgM, IgA), third component of complement (C3) and fibrinogen in perilesional skin biopsy specimen(s) from patients suspected of having dermatitis herpetiformis; granular and/or fibrillar IgA staining along BMZ, especially in dermal papillae, is characteristic If celiac disease is suspected but not yet identified, testing should be performed in conjunction with serology testing for pemphigus and pemphigoid or celiac disease	Immunopathologic findings may sometimes show similarities to lupus erythematosus Granular and fibrillar IgA immune deposits may be sparse in dermatitis herpetiformis Perilesional skin biopsy or biopsies (3-5 mm from edge of an active lesion) are best to detect characteristic findings, which may not be present in lesional skin Tissue must be submitted in Michel’s or Zeus medium; this test cannot be performed on formalin-fixed tissue	Test is best performed in conjunction with serum testing for IgA endomysial and tissue transglutaminase antibodies and followed with IgA endomysial antibodies to monitor disease activity and response to therapy Patients with indeterminate results should have antibody levels monitored for disease activity
Celiac Disease Reflexive Panel 0051065 Method: Nephelometry/Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay	Diagnose celiac disease in association with suspected or known dermatitis herpetiformis Panel includes immunoglobulin A; tissue transglutaminase antibodies IgA and IgG; and gliadin peptide antibodies IgA and IgG	Because of overlapping clinical features among immunobullous diseases, recommend initial testing concurrently with Pemphigoid Panel (0092001) and Pemphigus Panel (0090650)
Epidermal Transglutaminase (TGe) Antibody, IgA 2001599 Method: Enzyme-Linked Immunosorbent Assay	Use along with endomysial antibody, IgA/Celiac Disease Panel, and Pemphigus and Pemphigoid Panels to differentiate various immunobullous skin diseases in patients suspected to have any type Perilesional skin biopsy of lesions should accompany serology testing if immunobullous skin disease is suspected	May not be positive in all patients with dermatitis herpetiformis; when present, provides supplemental autoantibody information in the disease This antibody is likely specific for dermatitis herpetiformis but whether levels correlate with disease activity is not known
Pemphigoid Panel - Epithelial Basement Membrane Zone IgG & IgA, BP180 & BP230 IgG Antibodies 0092001 Method: Enzyme-Linked Immunosorbent Assay/Indirect Immunofluorescence	Use along with endomysial antibody, IgA/celiac disease dual antigen screen, and pemphigus panel to differentiate various immunobullous skin diseases in patients suspected to have any type of such disorders Panel includes epithelial basement membrane zone IgG & IgA antibodies on human split skin and monkey esophagus substrates by IIF, BP180 & BP230 IgG antibodies by ELISAs Perilesional skin biopsy of lesions should accompany serology testing if immunobullous skin disease is suspected	Clinical correlation necessary because the incidence of false-positives, although rare, increases with age Because of clinical overlap among immunobullous diseases and similar names, testing for pemphigoid may be confused with testing for pemphigus and misordered	Perilesional skin biopsy by direct immunofluorescence is helpful in diagnosis (85-100% of dermatitis herpetiformis, pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, and pemphigus cases are positive)
Pemphigus Panel - IgG Epithelial Cell Surface Antibodies and Levels of IgG Desmoglein 1 and Desmoglein 3 Antibodies, Serum 0090650 Method: Enzyme-Linked Immunosorbent Assay/Indirect Immunofluorescence	Use along with endomysial antibody, IgA, and Pemphigoid Panel tests to differentiate immunobullous skin diseases in patients suspected to have any type of such disorders Perilesional skin biopsy of lesions should accompany serology testing if immunobullous skin disease is suspected	Clinical correlation necessary because the incidence of false-positives, although rare, increases with age Because of clinical overlap among immunobullous diseases and similar names, testing for pemphigoid may be confused with testing for pemphigus and misordered	Perilesional skin biopsy by direct immunofluorescence is helpful in diagnosis (85-100% of dermatitis herpetiformis, pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, and pemphigus cases are positive)
Tissue Transglutaminase Antibody, IgA with Reflex to Endomysial Antibody, IgA Titer by IFA 0050734 Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody	Test or follow patient suspected of having dermatitis herpetiformis and/or celiac disease	May be negative if patient is following a gluten-free diet False-positive IgA antibody levels may occur in other inflammatory bowel diseases	Can be used to monitor disease activity and response to therapy Patients with borderline/indeterminate results should be monitored for disease activity
Celiac Disease Dual Antigen Screen with Reflex 2002026 Method: Nephelometry/Indirect Fluorescent Antibody/Enzyme-Linked Immunosorbent Assay	Diagnose celiac disease in association with suspected or known dermatitis herpetiformis Components include celiac disease dual antigen screen; tissue transglutaminase antibodies IgA and IgG; and gliadin peptide antibodies IgA and IgG Monitor celiac disease and dermatitis herpetiformis during treatment	Patients on a gluten-free diet may be negative Some patients with dermatitis herpetiformis will also be negative	Monitor increased IgA endomysial and tissue transglutaminase antibodies

Additional Tests Available

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Tissue Transglutaminase Antibody, IgA 0097709 Method: Enzyme-Linked Immunosorbent Assay	Do not use as single test in evaluation of immunobullous skin disease
Tissue Transglutaminase Antibody, IgG 0056009 Method: Enzyme-Linked Immunosorbent Assay	Do not use as single test in evaluation of immunobullous skin disease

Additional Information

Endomysial antibody testing (IgA and IgG) and tissue transglutaminase antibody testing (IgA and IgG) can also be ordered through the Immunodermatology Laboratory with serum sent along with biopsy; both IIF and ELISA are performed and correlated with direct immunofluorescence.