Dermatitis Herpetiformis

Indications for Testing

Chronic pruritic dermatitis/skin lesions in patient with or without known celiac disease after other, more common diseases ruled out
- Most DH cases have associated celiac disease

Laboratory Testing

Initial testing – serology
- Due to the potential for overlapping clinical features, all of the following tests are recommended unless a specific immunobullous skin disease type is suspected
  - Pemphigus and pemphigoid panels
  - Endomysial antibodies (for celiac screen)
    - IgA endomysial antibodies – order IgA tTG assay preferentially unless patient is IgA deficient or presentation is atypical; in those cases, perform IgG endomysial and tTG antibody testing
      - If IgA endomysial antibody titers are >1:10 and increased IgA tTG antibody levels are found along with clinical features of DH 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 measures should be instituted to evaluate for celiac disease (gastroenterology consultation with consideration for small-intestine biopsy)

Histology

Perilesional skin biopsy for cutaneous direct immunofluorescence is highly sensitive – specimen should be 3-5 mm from the edge of an active lesion
- Granular or fibrillar IgA deposits at or beneath the basement membrane zone (BMZ) is pathogenomic – deposits may be sparse and widely distributed; principal target antigen is epidermal transglutaminase
- If initial biopsy is negative, additional perilesional biopsy may increase yield

Differential Diagnosis

Arthropod bites
Bullous impetigo
Bullous lupus erythematosus
Churg-Strauss syndrome
Contact dermatitis
Eczema (other types, including atopic and asteatotic)
Erythema multiforme
Herpes simplex or herpes zoster
Henoch Schönlein purpura (IgA vasculitis)
Linear IgA bullous dermatosis
Pemphigoid
Pemphigus
Prurigo nodularis
Scabies and other ectoparasites
Urticaria and urticarial vasculitis
Wegener granulomatosis

Monitor therapy/adherence to gluten-free diet
- IgA endomysial antibodies
- IgA tissue transglutaminase antibodies

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
- Most common autoimmune bullous disease of childhood
Sex – M:F, equal
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 and not all patients with celiac disease get DH
- Both GSE and DH patients have antibodies to (common epitopes) tissue transglutaminase (TG2) and epidermal transglutaminase (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
Classically, a subepidermal blister with neutrophilic (and occasionally eosinophilic) microabscesses within normal dermal papillae
Cryosections of perilesional skin biopsies are required for direct immunofluorescence microscopy

Clinical Presentation

Intense pruritus with excoriations
Papulovesicular lesions and urticarial wheals in a symmetrical distribution – classically involves extensor elbows and knees, buttocks, scalp, shoulders and sacral areas
Chronic eczematoid skin changes, excoriations

Treatment

Dietary modification to eliminate gluten ingestion
Dapsone or sulfapyridine

Tests generally appear in the order most useful for common clinical situations

Test name: Cutaneous Direct Immunofluorescence, Biopsy

ARUP #: 0092572

Methodology: Direct Immunofluorescence
(Direct Fluorescent Antibody Stain)

Use:

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; characteristic staining in 95% of affected patients

If celiac disease is suspected but not yet identified, testing should be performed in conjunction with serology testing for celiac disease, pemphigus and pemphigoid

Limitations:

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 in dermatitis herpetiformis

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

Follow-up:

Concurrent serum testing with pemphigoid panel is the most sensitive for diagnosis and for determining subtype of subepidermal blistering disease

Patients with indeterminate results should have repeat biopsy for direct immunofluorescence and antibody levels monitored for disease activity

Test name: Celiac Disease Reflexive Panel

ARUP #: 0051065

Methodology: Quantitative Nephelometry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use:

Diagnose celiac disease in association with suspected or known dermatitis herpetiformis

Panel includes total serum immunoglobulin A, tissue transglutaminase antibodies IgA and IgG, and gliadin peptide antibodies IgA and IgG

Limitations:

Because of overlapping clinical features among immunobullous diseases, recommend initial testing concurrently with Pemphigoid Panel and Pemphigus Panel

Test name: Pemphigoid Panel - Epithelial Basement Membrane Zone IgG & IgA, BP180 & BP230 IgG Antibodies

ARUP #: 0092001

Methodology: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Use:

Diagnose most types of pemphigoid, epidermolysis bullosa acquisita, linear IgA disease (including linear IgA bullous dermatosis and childhood immunobullous disease)

Panel includes epithelial BMZ IgG & IgA antibodies by IFA on split human skin and monkey esophagus substrates, BP180 & BP230 IgG antibodies by ELISA

Use in conjunction with pemphigus panel and endomysial antibody IgA testing to differentiate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

IgG BP180 and BP230 antibody levels may be useful in monitoring disease

Limitations:

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

Follow-up:

Perilesional skin biopsy by direct immunofluorescence (DIF) is helpful in diagnosis

Test name: Pemphigus Panel - IgG Epithelial Cell Surface Antibodies and Levels of IgG Desmoglein 1 and Desmoglein 3 Antibodies, Serum

ARUP #: 0090650

Methodology: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Use:

Diagnose most types of pemphigus and monitor disease activity and response to therapy

Panel tests for IgG epithelial cell surface antibodies by indirect immunofluorescence (IFA) on intact human skin and monkey esophagus substrates and IgG desmoglein 1 and IgG desmoglein 3 antibodies by ELISA

Use along with pemphigoid panel and endomysial IgA antibody testing, or epithelial skin antibody testing to distinguish the various disorders in patients suspected or known to have any type of immunobullous disease

Limitations:

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

Because of clinical overlap among immunobullous diseases and similar names, testing for pemphigus may be confused with testing for pemphigoid and misordered; testing for IgG pemphigus antibody types (most common) also may be confused with IgA pemphigus testing (rare disorder)

Follow-up:

Concurrent perilesional skin biopsy evaluated by direct immunofluorescence (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)

Use pemphigus panel to monitor disease activity and response to therapy

Test name: Tissue Transglutaminase (tTG) Antibody, IgA with Reflex to Endomysial Antibody, IgA by IFA

ARUP #: 0050734

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Use:

Use along with pemphigoid and pemphigus panel tests, or epithelial skin antibody testing to differentiate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

Limitations:

May be negative if patient is following a gluten-free diet

False-positive IgA antibody levels may occur in other inflammatory bowel diseases

Follow-up:

Perilesional skin biopsy by DIF is helpful in diagnosis (>90% of dermatitis herpetiformis cases are positive)

Patients with borderline/indeterminate results should be monitored for disease activity

Test name: Celiac Disease Dual Antigen Screen with Reflex

ARUP #: 2002026

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use:

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