Dermatitis herpetiformis (DH) 

IgA Epidermal transglutaminase 3 (eTG) antibodies

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• ​Epidermal transglutaminase 3 (eTG) is a recently reported autoantigen in DH and GSE. In DH, autoantibodies also appear to bind to eTG, whereas in isolated GSE, autoantibodies bind to tissue transglutaminase (tTG). eTG is an enzyme expressed in the epidermis that is homologous with, but not identical to tTG. Epidermal transglutaminase 3 (eTG) is a calcium dependent enzyme expressed in the spinous layer of the epidermis and plays a role in epidermal terminal differentiation, formation of the cornified cell envelop, and protection of keratinocytes against UVB-induced apoptosis. Patients with DH produce two IgA antibody populations against eTG. The first population binds exclusively with eTG, whereas the second one cross-reacts with both eTG and tTG. The cross-reactive eTG-specific antibodies are found in GSE without DH as well but demonstrate a lower avidity for eTG than in patients with DH. Furthermore, eTG but not tTG co-localizes with granular IgA deposits in the skin of patients with DH and levels of antibodies against eTG correlate with the extent of enteropathy in DH but not in GSE without DH. Taken together, these data suggest that eTG rather than tTG is the autoantigenic target in patients with DH. Sardy M et al. also demonstrated that in CD patients, the median antibody concentration against IgA tissue transglutaminase antibodies (tTG) was higher than against IgA epidermal transglutaminase antibodies (eTG), and this was reversed for DH patients. Rose et al. suggested that eTG is the most sensitive serologic marker both in gluten-free diet DH patients and in untreated DH. Borroni et al suggested that eTG antibodies can distinguish DH from other clinically similar skin diseases.

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Diagnosis

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• Clinical and histological studies can be evocative but do not provide a definitive diagnosis. Clinical presentation of DH in children can mimic skin conditions such as atopic dermatitis, scabies, papular urticaria, and impetigo, whereas eczema, other autoimmune blistering diseases, nodular prurigo, urticaria, and polymorphic erythema should be considered in adults. Routine histology studies reveal subepidermal vesicles and accumulation of neutrophils in the papillary dermis. The histopathology of a DH can resemble other bullous conditions.

• Three features of DH aid in its diagnosis:

1. typical pruritic, vesicular skin lesions

2. granular junctional IgA deposits as seen by direct IF

3. positive tests for tTG and eTG antibodies.

• Most DH cases are direct IF positive but negative direct IF has been reported in DH. Therefore, to rule out DH, both direct IF of biopsy and serum studies for AEmA, tTG (ELISA) and the recently available test for eTG (ELISA) antibodies are needed.

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Direct immunofluorescence studies

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• DIF has a sensitivity of 95-100% for the diagnosis of DH and hence considered as the diagnostic gold standard. DIF studies of uninvolved perilesional skin from patients with DH shows granular deposits of IgA at the dermal papillae/basement membrane with accentuation at the papillary tips. Occasionally, granular IgM, IgG or C3 deposits at the dermal–epidermal junction and/or at the dermal papillae can also be seen. DIF should be performed on uninvolved perilesional skin, since in skin lesions IgA can be removed by inflammatory cells. Moreover, patients must be on normal diet, because IgA deposits can disappear from the skin in period of times variable from weeks to months in patients on a gluten-free diet.

Serology

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• IgA anti-endomysium antibodies (EmA), IgA and IgG anti-deamidated gliadin peptides (DGP), and IgA anti-tissue transglutaminase (tTG) antibodies are considered specific and sensitive serologic markers for gluten sensitive enteropathies such as celiac disease and dermatitis herpetiformis (DH). Although the IgA isotype of these antibodies usually predominates in celiac disease and dermatitis herpetiformis, individuals may also produce IgG isotypes, particularly if the individual is IgA deficient. Additionally, IgA epidermal transglutaminase antibodies (eTG) have recently been reported to be a useful marker for diagnosing DH in untreated patients as well as for monitoring disease activity.

• IgA EmA antibodies are directed against primate smooth muscle reticular connective tissue and are an important marker for gluten induced enteropathies, celiac disease and dermatitis herpetiformis. The finding of IgA-endomysial antibodies (EMA) is highly specific for dermatitis herpetiformis or celiac disease. This test has shown to have a specificity close to 100% and a sensitivity ranging from 52% to 100% for the initial diagnosis of celiac disease and DH. The titer of IgA EmA correlates with the severity of the disease.

• The sensitivity and specificity of commercially available IgA tTG ELISA tests for the diagnosis of DH have been reported to range from 42% to 99% and 92% to 100%, respectively. Compliance with gluten free diet leads to the disappearance or significant decrease of both IgA tTG antibodies and EmA.

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Dermatitis herpetiformis (DH) Tests