Dermatitis herpetiformis

Authors: Professors Paolo Fabbri 1 and Marzia Caproni

Creation date: November 2003 Update: February 2005

Scientific editor: Professor Benvenuto Giannotti

1II Clinica Dermatologica, Dipartimento di Scienze Dermatologiche, Università degli Studi di Firenze, Via degli Alfani 37, 50121, Firenze, Italy. [email protected]

Summary Keywords Disease name and synonyms Definition Clinical manifestations Differential diagnosis Etiopathogenesis Management – treatment Diagnostic criteria – methods References

Summary herpetiformis (DH) is a subepidermal bullous disease characterized by chronic recurrence of itchy, erythematous , urticarial wheals and grouped vesicles that appear symmetrically on the extensor surfaces, buttocks and back. Children and young adults are mostly affected. Prevalence is estimated to be about 10 to 39 cases/100,000/year, with incidence ranging from 0,9 (Italy) to 2,6 (Northern Ireland) new cases/100,000/year. The disease is the cutaneous expression of a -sensitive enteropathy identifiable with celiac disease. The clinical and histological pictures of both entities are quite similar. Granular IgA deposits at the dermo-epidermal junction, and together with activated CD4+ Th2 are supposed to represent the main immune mechanisms that co- operate in the pathogenesis of the disease. A strict gluten withdrawal from diet represents the basis for treatment.

Keywords autoimmune bullous diseases, celiac disease, tissue , anti-endomysium , anti- tissue transglutaminase antibodies, gluten sensitivity, .

deposits at the dermal papillae represent the immunological marker of the disease, that is strictly associated with a gluten-sensitive Disease name and synonyms enteropathy (GSE), indistinguishable from celiac - (DH), disease (CD). 1 - Duhring-Brocq disease, - Duhring’s dermatitis.

Definition DH is an autoimmune subepidermal blistering disease characterized by chronic and recurrent eruptions of erythematous, urticarial, papular, vesicular and bullous lesions. Granular IgA

Fabbri P and Caproni M. Dermatitis herpetiformis. Orphanet Encyclopedia. February 2005. http://www.orpha.net/data/patho/GB/uk-DermatitisHerpetiformis.pdf 1

Prevalence , prurigo, . When vesico- DH is relatively more frequent than the bullae are present, multiforme must be autoimmune bullous dermatoses belonging to excluded, as well as some other autoimmune the bullous group. Its prevalence is bullous diseases with particular regards to estimated to be about 10 to 39 cases/100,000, , linear IgA dermatosis and with incidence ranging from 0,9 (Italy) to 2,6 non-autoimmune bullous conditions, such as (Northern Ireland) new cases/100,000/year. transient acantholytic dermatosis (Grover’s Males are affected slightly more frequently than disease). Clinical doubts can be sometimes females 2 The disease is less frequent in Blacks. 3 eliminated only by direct Dermatitis herpetiformis occurs mainly between (DIF) performed on perilesional healthy . the age of 20 and 55, but is occasionally seen in children, usually after the age of 5. 4 Etiopathogenesis DH and CD are both gluten-sensitive diseases with a common immunogenetic background. Clinical manifestations They share a strong association with class II The onset of DH may be acute or gradual, and histocompatibility locus antigens DR3 and pruritus is usually the first and predominant DQW2 and with the alleles DQA1*0501 and symptom. Early lesions are pleomorphic, B1*0201 of chromosome 6. 10 Currently, consisting of itchy, erythematous papules and immunopathological mechanisms leading to urticarial wheals that appear symmetrically on formation and bowel damage in DH are the extensor surfaces, buttocks, back, rarely on partially known. The discovery in 1967 by the face. Small grouped vesicles progressively Cormane 11 of granular deposits of IgA at the develop on plaques of erythema but they rapidly dermo-epidermal junction (DEJ) in the skin of erode/are excoriated, evolving into crusts and affected patients represents a cornerstone in our erosions. Rarely bullae 1-2 cm in diameter can understanding of the pathogenesis of DH. be seen. 5 Oral lesions, detectable in about 50% However the way IgA are deposited and the of patients, mainly consist of mucosal redness, structures to which they bind are still debated. It ulcerations, in tongue or oral . has been demonstrated that IgA detected in DH Pain or a burning sensation may accompany skin contain both γ and k chains, indicating that these lesions. 7 they are polyclonal. Besides the IgA1 are the Moreover, enamel defects are found in about predominant subclass and only in few cases J 80% of childhood DH cases and approximately chains and secretory component can be 50% of adult DH cases, 8 with slight structural detected suggesting these immunoglobulins may alterations and typical horizontal grooves. not have a mucosal origin. 12 A specific enteropathy occurs in 100% of Furthermore, circulating IgA1 to patients with DH. 3 Bowel disease (celiac endomysium (EMA) can be detected in both DH disease) is gluten-sensitive and responds to a (95% of patients in our series) and celiac withdrawal of and other gluten-containing disease; these antibodies are closely linked to grains from the diet. In most affected adults, the degree of intestinal abnormalities and are enteropathy may be present histologically but direct indicators of the patients’ adherence to a not patent clinically, whereas if presenting in gluten-free regimen (GFD), since their frequency childhood it commonly goes into spontaneous decreases to 18% after a six-month diet. remission during adolescence. 6 In 1997, Dieterich et al. 13 identified tissue The clinical symptoms vary greatly, depending transglutaminase (tTG) as the unknown on the length of small intestine involved. endomysial autoantigen in CD. This enzyme Malabsorption can cause diarrhea, steatorrhea, belongs to the transglutaminase (TG) family, foul-smelling flatus, , weight loss which in man consists of nine distinct proteins and weakness. Not uncommonly, no or minimal present in a wide variety of cell lines and intestinal symptoms are observed, and the showing conservation of certain enzimatically disease manifests itself instead as an isolated relevant domains. tTG is synthesized by a broad deficiency state of various vitamins or minerals spectrum of cell types but is usually retained in (anemia due to iron or folate deficiency, bone intracellular compartments. An abundant pain or pathological fractures secondary to extracellular release of cytosolic tTG, mainly by impaired absorption of vitamin D and calcium). 6 mononuclear or mesenchymal cells, follows the damage of the intestinal Differential diagnosis epithelium after gluten ingestion. It has also In view of the persistent pruritus that resists been demonstrated that tTG accepts dietary topical treatment, early DH has to be as a preferred substrate catalyzing the distinguished from other itching dermatoses like formation of gliadin-gliadin cross-links as well as

Fabbri P and Caproni M. Dermatitis herpetiformis. Orphanet Encyclopedia. February 2005. http://www.orpha.net/data/patho/GB/uk-DermatitisHerpetiformis.pdf 2

the incorporation of gliadin into complexes with must be educated and motivated by the other proteins and tTG itself. The antigenic neo- physician. thus created may initiate an immune Dapsone (diaminodiphenylsulphone) is the most response in genetically susceptible individuals, widely used drug for DH before diet-related finally directed both to gliadin and tTG. 13 improvement. Starting dose is 100 mg daily, but Recently, a positive correlation of IgA anti-tTG every effort should be made to reduce it to a levels with semiquantitative EMA titers was maintenance of 25-50 mg daily, because dose- demonstrated in both CD and in DH. 14,15 Celiac dependent methemoglobinaemia and hemolytic patients with early mucosal changes, anemia are serious adverse effects of this represented by increased intraepithelial drug. 20 lymphocytes, had low EMA titers and slightly In patients intolerant of dapsone, sulphapyridine raised IgA anti-tTG antibodies. On the contrary or sulphamethoxypyridazine can be substituted. IgA anti-tTG showed high values in those Although systemic corticosteroids are generally patients with biopsy-proven CD and strong EMA ineffective, topical steroids may be helpful in reactivity. 14,16 lessening pruritus. Moreover, recent findings by Sardy et al. 17 demonstrated that epidermal transglutaminase Diagnostic criteria – methods (eTG or TG3) is the major autoantigen In typical cases the diagnosis of DH can be recognised by IgA antibodies deposited in made relying on 3 main elements: lesional skin of DH. Cross-reacting antibodies to - Clinical features (pleomorphic and itchy tTG and eTG may be expected as a result of erythematous papules, urticarial wheals and high degree of sequence conservation among vesico-bullae predominantly located on the members of the TG family. Hence, it is extensor surfaces, buttocks and back). postulated that IgA autoantibodies against tTG - Histological picture (subepidermal bullae, cross-react with eTG in the skin. With continued and micro-abscessual gliadin exposure, specific cross-reacting accumulation within dermal papillae). antibodies with high affinity to eTG and low - Circulating anti-endomysium (EMA) and anti- affinity to tTG may develop among patients who tTG IgA antibodies. (these last yielding a 21 will go on to acquire DH. It is still unknown, sensitivity of 89.1% and a specificity of 97.6%). however, whether these antibodies develop - DIF of perilesional skin demonstrating granular against eTG as the primary antigen or occur as a deposition of IgA in the basement membrane consequence of “molecular mimicry”. zone, at top of dermal papillae. (sensitivity: 90%; 21 Nowadays, in addition to the proven role of specificity: 96% ). autoantibodies (that can fix complement, Provocation or exacerbation by inducing recruitment and activation of either by mouth or by patch test is not specific neutrophils) an increasing body of experimental for DH and is now considered outmoded. evidence supports the participation of cell- The diagnosis is confirmed ex juvantibus by the mediated immunity and of perivascular infiltrate early and excellent response to therapy with (mainly composed by CD4+ T lymphocytes dapsone. together with a varying number of neutrophils Gluten-sensitive enteropathy can be diagnosed and eosinophils) in the initiation and by jejunal biopsy (villous atrophy, hyperplasia of perpetuation of autoimmune response of DH. In criptae and mononuclear infiltration of the lamina fact, the presence of IgA deposits in uninvolved propria). skin supports the hypothesis that in the generation of DH lesions not only the IgA References antibodies and triggering of the complement 1. Hall, R.P. Dermatitis Herpetiformis. J Invest cascade could be implicated, but also the Dermatol 1992; 99, 873-881. cellular infiltrate which, through a Th2-cell- 2. Gawkrodger DJ, Blackwell JN, Gilmour HM et mediated immune response, is presumably al. Dermatitis herpetiformis: diagnosis, diet involved in recruiting polymorphonuclear and demography. Gut 1984; 25: 151-57. leukocytes. 18,19 3. Fabbri P. Dermatite erpetiforme. In: Immunodermatologia, 2 nd ed, ISED, Brescia, Management – treatment 2002. The therapy for DH is based on strict gluten 4. Pye RJ. Bullous eruptions. In: Champion RH, withdrawal from diet, which may not be simple to Burton JL, Burns DA, Breathnach SM, eds. achieve, since gluten-containing cereals are Rook/ Wilkinson/ Ebling, Textbook of th ubiquitous in processed foods and it is difficult to , 5 ed, Blackwell Science Ltd, avoid gluten in restaurant foods. The patient Oxford, 1992.

Fabbri P and Caproni M. Dermatitis herpetiformis. Orphanet Encyclopedia. February 2005. http://www.orpha.net/data/patho/GB/uk-DermatitisHerpetiformis.pdf 3

5. Braun-Falco O, Plewig G, Wolff HH, Burgdorf 15. Dieterich W, Laag E, Bruckner-Tuderman L WHC. In: Dermatology, Springer-Verlag eds. et al. Antibodies to tissue transglutaminase Berlin Heidelberg, 2000. as serologic markers in patients with 6. Ahnen DJ. Disorders of nutrient assimilation. dermatitis herpetiformis. J Invest Dermatol In: Kelley WN ed. Textbook of Internal 1999: 113: 133-136. Medicine, JB Lippincott Company, 16. Cardinali C, Degl'innocenti D, Caproni M, Philadelphia, 1989. Fabbri P. Is the search for serum antibodies 7. Lahteenoja H, Irjala K, Viander M et al. Oral to gliadin, endomysium and tissue mucosa is frequently affected in patients with transglutaminase meaningful in psoriatic dermatitis herpetiformis. Arch Dermatol 1998; patients? Relationship between the 134: 756-58. pathogenesis of and coeliac 8. Aine L. Coeliac-type permanent-tooth enamel disease. Br J Dermatol. 2002; 147(1): 187-8. defects. Ann Med 1996; 28: 9-12. 17. Sardy M, Karpati S, Merkl B et al. Epidermal 9. Elson CO. Gastronitestinal diseases with an transglutaminase is the autoantigen of autoimmune basis. In: Kelley WN ed. dermatitis herpetifiormis. J Exp Med 2002; Textbook of Internal Medicine, JB Lippincott 195: 747-57. Company, Philadelphia, 1989. 18. Caproni M, Feliciani C, Fuligni A et al. Th2- 10. Reunala T. Incidence of familial dermatitis like cytokine activity in dermatitis herpetiformis. Br J Dermatol 1996; 134: 394- herpetiformis. Br J Dermatol 1998; 138: 242- 98. 247. 11. Cormane RH. Immunofluorescent studies of 19. Giomi B, Cardinali C, Caproni M et al. the skin in erythematosus and other Immunological markers in dermatitis diseases. Pathologica Eur 1967; 2: 170-180. herpetiformis: anti-endomisium and anti- 12. Unsworth DJ, Payne AW, Leonard JN. IgA in transglutaminase antibodies in association dermatitis herpetiformis is dimeric. Lancet with increased myeloperoxidase and 1982: 2: 478-480. eosinophil cationic protein serum levels. Int J 13. Dieterich W, Ehnis T, Bauer M et al. Med Biol Environ 2001; 29(2): 149-153. Identification of tissue transglutaminase as 20. Collin P, Reunala T. Recognition and the autoantigen of celiac disease. Nat Med management of the cutaneous manifestations 1997; 3: 797-801. of celiac disease: a guide for dermatologists. 14. Dieterich W, Laag E, Schopper H et al. Am J Clin Dermatol 2003; 4(1): 13-20. Autoantibodies to tissue transglutaminase as 21. Nicolas MEO, Krause PK, Gibson LE et al. predictors of celiac disease. Dermatitis herpetiformis. Int J Dermatol 2003; Gastroenterology 1998; 115: 1317-21. 42: 588-60.

Fabbri P and Caproni M. Dermatitis herpetiformis. Orphanet Encyclopedia. February 2005. http://www.orpha.net/data/patho/GB/uk-DermatitisHerpetiformis.pdf 4