What is the pathogenesis of dermatitis herpetiformis (DH)?

From the Guidelines

Dermatitis herpetiformis is an autoimmune blistering skin condition that develops as a manifestation of gluten sensitivity, triggered by a complex immune-mediated process involving IgA antibodies against tissue transglutaminase (tTG) and epidermal transglutaminase (eTG) in genetically predisposed individuals. The disease begins when patients with celiac disease or gluten sensitivity consume gluten, which stimulates the production of IgA antibodies against tTG 1. These antibodies cross-react with eTG, a closely related enzyme found in the skin. The resulting IgA-eTG immune complexes deposit in the dermal papillae at the dermal-epidermal junction.

Key Factors in Pathogenesis

• Genetic factors play a significant role, with over 90% of patients carrying the HLA-DQ2 or HLA-DQ8 haplotypes, the same genetic markers associated with celiac disease
• The immune-mediated process triggers an inflammatory cascade, activating neutrophils and other inflammatory cells that release proteolytic enzymes, causing separation at the basement membrane and formation of the characteristic subepidermal blisters
• The pathogenesis directly informs treatment, which centers on strict gluten elimination to reduce antibody production, as recommended for patients with celiac disease and dermatitis herpetiformis 1

Treatment Implications

• Treatment of dermatitis herpetiformis requires a strict, lifelong adherence to a gluten-free diet (GFD), similar to the management of celiac disease 1
• Consultation with an experienced dietician, referral to a support group, and clinical follow-ups for compliance are recommended to ensure adequate education, motivation, and support for patients to achieve this diet
• Additional treatment may include dapsone to inhibit neutrophil activity until dietary changes take effect, although this is not explicitly mentioned in the provided evidence 1

From the Research

Pathogenesis of Dermatitis Herpetiformis

The pathogenesis of dermatitis herpetiformis (DH) is closely linked to celiac disease, with both conditions sharing the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8) and improving with a gluten-free diet 2. Key aspects of DH pathogenesis include:

• The presence of granular immunoglobulin A (IgA) deposits in the papillary dermis, which is a hallmark of the disease 3, 2
• The role of transglutaminase 3 as the autoantigen in DH, with immune complexes forming at the site of IgA deposition 3
• The involvement of the small bowel, with most patients having villous atrophy or celiac-type inflammatory changes, despite the absence of overt gastrointestinal symptoms 3, 2
• The generation of circulating autoantibodies against tissue transglutaminase (tTG) and epidermal transglutaminase (eTG) in DH patients 2

Clinical and Histopathologic Features

DH is characterized by:

• Intense pruritus and a blistering, symmetrical rash typically affecting the elbows, knees, and buttocks 3, 2
• Polymorphic lesions, including papules, vesicles, and small blisters, distributed in typical anatomical sites 2
• Histopathologic findings of granular IgA deposits at the dermal-epidermal junction, detectable by direct immunofluorescence (DIF) 2

Diagnostic Challenges

The diagnosis of DH can be complicated by:

• Atypical presentations of the disease, which may not exhibit the typical clinical or serological features of celiac disease 2
• The presence of granular IgA deposits in non-DH inflammatory skin diseases, which may lead to diagnostic confusion 2
• The need for revised diagnostic criteria, emphasizing clinical aspects of the disease along with DIF and serum autoantibody testing 2