Dermatitis Herpetiformis

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 dermatitis herpetiformis (DH) extensor locations
• Characteristic immunopathology on uninvolved, perilesional skin with direct immunofluorescence (DIF)
• Positive serology consistent with gluten intolerance/celiac disease (CD); rarely increased serum IgA epidermal transglutaminase (eTG/TG3) antibodies only

Laboratory Testing

• Should perform at a minimum
  • Celiac testing concurrently with immunopathology: see Celiac Disease
    • Skin biopsy necessary for diagnosis: see cutaneous DIF in Histopathlogy
  • 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

    (Refer to ARUP Immunobullous Disease Testing Comparison table for more information)
    Antibodies Tested	Skin Diseases	Recommended Use
    Basement membrane zone antibodies	Pemphigoid Epidermolysis bullosa acquisita Linear IgA disease Some bullous lupus erythematosus	Diagnosis Disease activity monitoring
    Pemphigoid antibody panel	Pemphigoid Linear IgA bullous dermatosis	Diagnosis Disease activity monitoring
    Collagen type VII antibody, IgG by ELISA	Epidermolysis bullosa acquisita Some bullous lupus erythematosus	Disease activity monitoring
    Pemphigus antibodies, IgG	IgG variant pemphigus including pemphigus foliaceus and pemphigus vulgaris	Diagnosis Disease activity monitoring
    Pemphigus antibodies, IgA by IIF	IgA variant pemphigus including intraepidermal neutrophilic IgA dermatosis and subcorneal pustular dermatosis	Diagnosis Disease activity monitoring

• 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

Histopathology

Skin biopsies 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)