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Dermatitis herpetiformis (DH) 

Dermatitis herpetiformis (DH) is characterized by (a) pruritic, papulovesicular skin eruption, (b) granular junctional deposits of IgA, (c) dermal papillary collection of neutrophils and (d) a gluten-sensitive enteropathy (GSE) in most cases. Celiac disease (CD) and DH are the two forms of GSE that have the GSE specific autoantibodies to tTG. Serum tests reveal tTG antibodies by both the more specific indirect IF tests for IgA endomysial antibodies (AEmA) and the more sensitive ELISA tests. DH mostly occurs between the third and the fourth decade of life. Unlike CD, DH has a male preponderance. It has been also reported to occur in pediatric patients, but the exact incidence of DH during childhood is unknown.

Dermatitis herpetiformis (DH) mostly occurs in a patient's 30s and 40s and more males are afflicted than females

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

Selected References

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  1. Hall RP 3rd, Katz SI. Dermatitis herpetiformis. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ editors. Fitzpatrick’s Dermatology in General Medicine. New York: McGraw Hill; 2008. p. 500-504.

  2. Antiga, E., Maglie, R., Quintarelli, L., Verdelli, A., Bonciani, D., Bonciolini, V., & Caproni, M. (2019). Dermatitis herpetiformis: novel perspectives. Frontiers in immunology, 10, 1290.

  3. Kumar V, Lerner A, Valeski JE, Beutner EH, Chorzelski TP, Kowalewski C. Relative Sensitivity and Specificity of Serodiagnostic tests for gluten-sensitive enteropathy A. Comparative studies on IgA-class endomysial (IgA- EmA) and IgA-class anti-reticulin antibodies (IgA-ARA) in celiac disease. In: Chorzelski TP, Beutner EH, Kumar V, Zalewski TK editors. Serologic diagnosis of celiac disease. Boca Raton (FL): CRC Press ;1990. p. 127-136.

  4. Rose C, Armbruster FP, Ruppert J et al. Autoantibodies against epidermal transglutaminase are a sensitive diagnostic marker in patients with dermatitis herpetiformis on normal or gluten-free diet. J Am Acad Dermatol; 2009;61:39-43.

  5. Sardy M, Karpati S, Merkl B, Paulsson M, Smyth. N. Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 2002;195(6):747-757.

  6. Eckert, R. L., Sturniolo, M. T., Broome, A. M., Ruse, M., & Rorke, E. A. (2005). Transglutaminase function in epidermis. Journal of Investigative Dermatology, 124(3), 481-492.

  7. Frezza, V., Terrinoni, A., Pitolli, C., Mauriello, A., Melino, G., & Candi, E. (2017). Transglutaminase 3 Protects against Photodamage. The Journal of investigative dermatology, 137(7), 1590-1594.

  8. Donaldson MR, Zone JJ, L. Schmidt A et al. Epidermal transglutaminase deposits in perilesional and uninvolved skin in patients with dermatitis herpetiformis. J Invest Dermatol 2007; 127(5): 1268– 1271.

  9. Borroni G, Biagi F, Ciocca O, Vassallo C, Carugno A, Cananzi R, Campanella J, Bianchi PI, Brazzelli V, Corazza GR. IgA anti-epidermal transglutaminase autoantibodies: a sensible and sensitive marker for diagnosis of dermatitis herpetiformis in adult patients. J Eur Acad Dermatol Venereol. 2013 Jul;27(7):836-41.

  10. Beutner EH, Baughman RD, Austin BM, et al. A case of dermatitis herpetiformis with IgA endomysial antibodies but negative direct immunofluorescence findings. J Am Acad Dermatol 2000; 43: 329–3.

  11. Antiga, E., & Caproni, M. (2015). The diagnosis and treatment of dermatitis herpetiformis. Clinical, cosmetic and investigational dermatology, 8, 257.

  12. Betz J, Grover R, Ullman L. Evaluation of IgA eTG ELISA in suspected dermatitis herpetiformis patients.

  13. Jaskowski TD, Hamblin T, Wilson AR, et al. IgA anti- epidermal transglutaminase antibodies in dermatitis herpetiformis and pediatric celiac disease. J Invest Dermatol 2009; 129: 2728–2730.

  14. Beutner EH, Plunkett RW. Methods for diagnosing dermatitis herpetiformis. J Am Acad Dermatol 2006; 55: 1112–1113.

  15. Kelly CP, Bai JC, Liu E, Leffler DA. Advances in diagnosis and management of celiac disease. Gastroenterology. 2015 May;148(6):1175-86.

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