Dermatitis herpetiformis L13.0

Author: Prof. Dr. med. Peter Altmeyer

Co-Autor: Dr. Lucian Cajacob

Our authors

Last updated on: 29.10.2020

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Synonym(s)

Dermatite polymorphic douloureuse; Dermatitis herpetiformis Duhring; DH; DhD; Duhring Brocq disease; Duhring`s disease; Duhring's disease; hidroa bullosa; Hidroa herpetiformis; Hidroa mitis et gravis; Hidroa pruriginosa; Maladie de Duhring; NGS; Nonceliac gluten sensitivity

History
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Fox, 1880; Duhring, 1884

Definition
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Rare, non-celiac, gluten-sensitive, chronic autoimmune disease (autoantigen is the epidermal transglutaminase) with disseminated, occasionally herpetiform, excoriated, bright red, 0.1-0.2 cm large, urticarial papules, papulovesicles and pure vesicles. Severe forms are characterized by inflammatory plaques which can transform into flat painful ulcers. Burning or stinging itching is characteristic of vesicular efflorescences. This form of itching is the main symptom that leads the patient to the doctor. In the ulcerative form of DhD, pain is a prominent feature.

The disease is understood as a cutaneous manifestation of gluten sensitivity(celiac disease). However, manifest intestinal symptoms are observed in only about 25% of cases of dermatitis herpetiformis patients.

Occurrence/Epidemiology
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Incidence: 0.1-1.0 /100,000 inhabitants/year. The incidence is higher in Scandinavia (1.0/100,000 inhabitants/year) than in Central Europe (0.1/100,000). DhD is rare in Japan (Makino T et al. 2019)

Etiopathogenesis
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Different triggers are discussed:

  • Autoimmune disease with IgA - antibody formation against epidermal transglutaminase (tGA), a crucial antigen in the endomysium.
  • Frequently (95-100% of cases) there are associations with HLA class II molecules (DQ2). A smaller proportion (2-10%) expresses the DQ8 haplotype serologically. HLA-DQ2 and -DQ8-negative patients do not develop DhD.
  • Associations with thyroid antibodies and/or thyroid diseases(Hashimoto's thyroiditis).
  • Detection of IgA antibodies against the celiac disease autoantigen(tissue transglutaminase).
  • In addition, predisposing factors are frequently described, including:
    • Particular sensitivity to halogens, especially iodine
    • Focal events
    • Malignant tumours or systemic diseases, especially B-cell lymphomas (in contrast to celiac disease, in which T-cell lymphomas are increasingly observed (Collin P et al. 2017).
    • Changes in the jejunal villi (these are detectable in only about 1/4 of all DhD patients - (Collin P et al. 2017).

The pathogenesis of celiac disease and DhD is initially based on the same mechanisms. In case of genetic disposition (see above) and environmental factors, a systemic autoimmune disease with specific IgA antibodies directed against transglutaminases develops.

In the skin 6 isoenzymes of transglutaminases (Tg) can be found. Most of them play a role in cornification. Mutations in the gene of transglutaminase 1 (TGM1) lead to the clinical picture of lamellar ichthyosis. For unknown reasons, intestinal changes (in contrast to celiac disease) in DhD are clinically asymptomatic initially and also in the later course of the disease (see symptomatic celiac disease below).

In this respect, there is no gluten withdrawal in these patients either! After several years of gluten provocation, this non-dietary behaviour leads to the formation of high-affinity AK against transglutaminases (TG). These high-affinity AK against transglutaminases, which occur in serum, form immune complexes with the epidermal transglutaminase (TG isoenzymes), which is important for DhD.

The circulating IgA-TG immune complexes can be deposited in the renal glomeruli (possible development of IgA nephropathy) as well as in lesional and also healthy skin (papilla tips, basement membrane). There they can be detected immunohistologically (direct immunofluorescence).

It is remarkable that in patients with celiac disease IgA deposits can also be detected in non-inflammatory skin. These findings contradict the etiopathogenetic significance of papillary immune complex deposits for the dermal inflammation of DhD (Antiga E et al. (2019). In any case, DhD is the only dermatological autoimmune disease for which the trigger factor(gluten) is known. Together with other gluten-induced diseases, celiac disease and DhD are grouped together under the umbrella term of gluten-sensitive diseases (GSK).

Manifestation
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Occurrence is possible at any age. Affected are mainly adults between the ages of 25-55 years. Men are affected slightly more often than women (M:F = 6:4).

Children are rarely affected.

Localization
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Mostly symmetrical distribution pattern.

Affected are mainly upper shoulder girdle (sometimes in acne-like distribution), glutaeal region, capillitium, forearm extensor sides, elbows, thigh and lower leg extensor sides, knee regions.

Less frequently affected are the face and ear region (also in the external auditory canals).

Mucous membranes are usually free. However, apthous, painful lesions of the oral and genital mucous membranes are observed.

Occasionally "herpes simplex-like" lesions of the red of the lips are also found.

Clinical features
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Sudden, rarely also slow creeping onset with symmetrical, disseminated, strongly itching to burning or stinging, 0.1-0.2 cm large, urticarial erythema. Within this erythema, grouped papules and/or vesicles are formed.

Formation of a synchronous polymorphism with vesicles, wheals, papules, encrusted erosions, but also protracted and therapy-resistant ulcers and variously large scars.

More rarely, "aphthous" oral or genital mucous membrane involvement is observed.

An extremely chronic course is characteristic. Episodes last from one month to over 1 year. Intermissions can last from weeks to years.

In cases of marked gluten sensitivity, dietary errors lead to acute relapses with itching to painful, highly red urticarial exanthema, possibly combined with rhinopathic and bronchitic symptoms.

Chronic enteropathy is similar to idiopathic steatorrhea but not obligatory.

In (rare) dermatitis herpetiformis in childhood there is a close correlation to a gluten-sensitive enteropathy (sprue) .

Laboratory
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In some cases blood eosinophilia. Antibody detection: Anti-Gliadin-AK, Anti-Endomysium-AK, AK against tissue transglutaminase, AK against epidermal transglutaminase (most sensitive serological test to secure the diagnosis).

Histology
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Formation of subepidermal fissures up to vesicles; blister formation below the lamina densa. In the initial stage (urticarial stage) infiltrate from neutrophil granulocytes in the upper and middle dermis with focal epidermotropy. Sometimes also leukocytoclasia. In the stage of blister formation neutrophil and eosinophil granulocytes form intrapapillary microabscesses, which are almost pathognomonic, but not always detectable (serial cuts). Frequently necrosis of the basal epidermis cells. In the stage of the mature subepidermal bladder, an increasingly lymphocytic infiltrate with numerous neutrophil granulocytes at the base of the bladder as well as at the lateral bladder margin is observed. Eosinophilic granulocytes are in the minority.

Direct Immunofluorescence
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Fine granular deposition of IgA and complement, usually continuous along the dermo-epidermal junction, but also focal in the papilla tips; detection in both affected and unaffected skin. IgA transglutaminase immune complexes can also be detected in the wall of small vessels.

In Japanese patients DhD with fibrillar deposits of IgA immune complexes in the papillary dermis has been described ( Makino T et al. 2019).

Therapy
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Diet and substitution of vitamins and iron:

  • Consistent gluten-free diet: With a gluten-free diet, about 1/3 of all patients remain apparition-free even without therapy. Avoid all cereal products (barley, oats, rye, wheat). Even in the absence of steatorrhoea, villi atrophy can be histologically confirmed in most patients. The required dose of dapsone can often be reduced by diet.
  • Diet low in iodine: No iodized salt, no sea fish, few dairy products, selected sausages and meat products (since often treated with iodized salt), no iodine-containing medication.
  • Medicine of the 1st choice is Dapson 50-150 mg/day up to max. 300 mg/day (e.g. Dapson-Fatol), Cave! Met-Hb formation! Before starting therapy, determine the glucose-6-phosphate dehydrogenase! After the symptoms have subsided, minimum maintenance dose for years. Attempt to stop after 6 months at the earliest.
  • alternatively colchicine: In case of sulfonamide intolerance colchicine (e.g. colchicine dispersed) 3 times 0.5 mg/day.
  • alternatively: in refractory cases, trial with Ciclosporin A (e.g. Sandimmun Optoral) 5 mg/kg bw/day, if necessary increase the dose to 7 mg/kg bw/day.
  • In cases of severe itching antihistamines such as Desloratadine (e.g. Aerius) 1-2 tbl/day. For gluten-induced enteropathy treatment by internists, good effect can be achieved with sulfasalazine (e.g. azulfidine) in medium dosage (3-6 g/day).
  • Iron substitution: Hb deficit in g/l × 25 = total iron requirement in mg.
    • Perorally: (e.g. Ferro sanol duodenal) 2(-3)times 50 mg/day, later 2(-3)times 100 mg/day p.o. if possible on an empty stomach.
    • Intravenous: (e.g. Ferrlecit) rarely necessary, adults 3.2-5.0 ml/day slowly i.v.
    • Intramuscular: (e.g. Ferrum Hausmann) adults 4 ml/day i.m., infants: 5 mg/kg bw/day p.o., distributed over 3 ED over 3 months. Intramuscular administration in infants (e.g. Ferrum Hausmann): zigzag injection (skin pigmentation!). Hb deficit (age norm) × KG (in kg) × 3.5 = iron requirement in mg. 1-2 ml i.m. every 2nd day. Cave! No simultaneous administration with tetracyclines, antacids, colestyramine, penicillamine.
  • Vit. B12 substitution (e.g. Neurotrat B 12): induction with 1000-2000 μg/week i.m., i.v., or s.c. Reticulocytes increasing after 5-8 days. Maintenance dose: 100-300 μg every 2 months.
  • Folic acid substitution (e.g. Folic acid-Hevert): 5-15 mg/day p.o. Children: 5-10 mg/day p.o. over 4 weeks or 0.2 mg/day parenterally over 4 weeks.
  • Vit D Substitution: Vit D3 (Dekristol, Vigantoletten): 5000-10.000 IU/day p.o. over 6 weeks, later 2000-5000 IU/day over several months. Absolutely calcium supply (4 times/day 250 mg p.o.).
  • Experimental: In individual cases, the use of antibiotics can produce significant positive effects. The penicillinase-resistant betalactam antibiotic flucloxacillin, for example, is effective in medium or low doses.

External therapy
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Antipruriginous treatment e.g. with 3% Polidocanol cream (e.g. Thesit or as a formulation: Polidocanol cream 2-5%).

S.a.u. Antipruriginosa. In case of a highly inflammatory character short-term or intermittent weak or moderately strong glucocorticoid creams/emulsions like 0.05% betamethasone lotio (e.g. Betagalen, R030 ).

Tables
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Gluten- and iodine-free diet for dermatitis herpetiformis Duhring

Food

allowed

prohibited

Bread

Potato, corn, rice, soybean flour

all kinds of bread, pastry and cakes made from common cereals see above

fruit

all species

Vegetables

all species

Dairy products

(little about iodine)

natural dairy products such as fresh milk, natural yoghurt, kefir, soured milk, buttermilk, cream

Fruit yoghurt (often contains undeclared binders), grain yoghurt

Grease

animal fats, margarine, coconut fat, sunflower oil, safflower oil, corn oil, pure mayonnaise

Wheat germ oil, marinades and sauces made with flour

Binders

corn starch (e.g. Mondamin), potato starch

Noodles

Meat

pure meat

meat products prepared and stretched with pasta, products pretreated with iodine salt

Spices

all spices except

Iodine salt

Cheese

all cheeses except

Processed cheese, other forms of processed cheese which may contain added starch

Desserts, sweets

Pudding made from permitted flour types, starch, gelatine, sweets, jam/jelly, jam, honey, Nutella, chocolate without cereal additives

cakes, tarts, puddings, finished products made from cereal flour

Beverages

all fruit juices, mineral water, tea, coffee, wine, cocoa, corn beer

all types of beer (except corn beer)

Diet/life habits
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In a patient with long-standing "dyshidrotic vesicles", which were highly hemorrhagic, Mr. Rose was able to detect histologically and serologically a dermatitis herperiformios. After precise instructions on a gluten-free diet, the patient ordered a fish mash on the plane, after which a severe episode occurred. In the meantime he reacts so strongly to iodine that he can only tolerate irisaches, because only irisaches are fed without iodine salt.

Note(s)
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Diagnosis:

  • Clinic, Histology (intrapapillary microabscesses)
  • Jejunum biopsy
  • Immunohistology (detection of the granularly deposited IgA complexes at the dermo-epidermal junction).
  • Serological antibody detection (see above).

Literature
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  1. Antiga E et al (2019) Dermatitis Herpetiformis: Novel Perspectives.
    Front Immunol 10:1290.
  2. Bogenrieder T et al. (2003) From the New World. Louis A. Duhring and Dermatitis Herpetiformis. Dermatologist 54: 167-172
  3. Collin P, Reunala T (2003) Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists. At J Clin Dermatol 4: 13-20
  4. Collin P et al (2017) Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease.
  5. Ann Med 49:23-31.
  6. Duhring LA (1884) Dermatitis herpetiformis. Journal of the American Medical Association 3: 225-229
  7. Fox WT (1880) A clinical study of the hydroa. Archives of Dermatology 6: 16-52
  8. Hervonen K et al (2014) Dermatitis herpetiformis in children: a long-term follow-up study. Br J Dermatol 171:1242-124
  9. Kadunce DP et al (1993) The effect of an elmental diet with and without gluten on disease acitivity in dermatitis herpetiformis. J Invest Dermatol 97: 175-182
  10. Vomit LM (2013) Dermatitis herpetiformis, the celiac disease of the skin! Arq Gastroenterol 50:231-235
  11. Makino T et al (2019) Fibrillar-type dermatitis herpetiformis. Eur J Dermatol 29:115-120.
  12. Marietta EV et al (2008) Transglutaminase autoantibodies in dermatitis herpetiformis and celiac sprue. J Invest Dermatol 128:332-325.
  13. Misri R et al (2019) Atypical manifestations of disseminated cutaneous botryomycosis mimicking dermatitis herpetiformis in an immunocompetent adult woman.Indian J Dermatol Venereol Leprol 85:511-513.
  14. Murphy LA et al (2003) Dermatitis herpetiformis converting into bullous pemphigoid: a study of three cases. Br J Dermatol 149 (Suppl 64): 17
  15. Nicolas ME et al (2003) Dermatitis herpetiformis. Int J Dermatol 42: 588-600
  16. Rose C et al (2010) Clinic, histology and immunopathology in 32 patients with dermatitis herpetiformis Duhring. JDDG 8: 265-271
  17. Sardy M et al (2002) Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 195: 747-757
  18. Sardy M et al (2009) Dermatitis herpetiformis. Dermatologist 60: 627-632
  19. Smith AD et al (2002) Neutrophil CD11b, L-selectin and Fc IgA receptors in patients with dermatitis herpetiformis. Br J Dermatol 147: 1109-1117

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