Dermatitis herpetiformis L13.0

Author: Prof. Dr. med. Peter Altmeyer

Co-Autor: Dr. med. Lucian Cajacob

All authors of this article

Last updated on: 07.07.2022

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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, gluten-sensitive, chronic autoimmune disease (autoantigen is epidermal transglutaminase) with disseminated, occasionally herpetiform, excoriated, bright red, 0.1-0.2 cm urticarial papules, papulovesicles and pure vesicles. Severe courses are characterized by inflammatory plaques that may transform into shallow painful ulcers. A characteristic feature of vesiculous efflorescences is a burning or pricking itch. This form of itching is the leading symptom that leads the pat. to the physician.

In the ulcerative form of DhD, the stabbing-burning pain is a prominent feature.

The disease is understood to be a cutaneous manifestation of non-IgE-mediated immunological 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 population/year. In Scandinavia, the incidence is higher (1.0/100,000 population/year) than in Central Europe (0.1/100,000).

In Japan, DhD is rare (Makino T et al. 2019).

Overall, the incidence of DhD appears to be declining, this in contrast to the observed fourfold increase in the incidence of celiac disease (Salmi TT 2019).

Etiopathogenesis
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Various 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%) serologically express the DQ8 haplotype. HLA-DQ2 and -DQ8 negative patients do not develop DhD.
  • Associations with thyroid antibodies and/or thyroid disease(Hashimoto's thyroiditis).
  • Detection of IgA antibodies to the autoantigen of celiac disease(tissue transglutaminase). Circulating tissue transglutaminase antibodies support the diagnosis, but their absence does not rule out DhD (Salmi TT 2019). They are undetectable especially after prolonged gluten abstinence!
  • In addition, predisposing factors are described in clusters, including:
    • Particular sensitivity to halogens, especially iodine.
    • Focal events
    • Malignant tumors or systemic diseases, especially B-cell lymphomas (in contrast to celiac disease in which increased T-cell lymphomas are 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 are initially based on the same mechanisms. With genetic predisposition (see above) and environmental factors present, a systemic autoimmune disease develops with specific (IgA) antibodies directed against transglutaminases.

Remarks: In the skin, 6 isoenzymes of transglutaminases (Tg) can be found. Most of them play a role in cornification. Thus, 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) remain clinically asymptomatic in DhD initially and also in the later course of the disease (see symptomatic celiac disease below). In this respect, gluten abstinence does not take place in these patients either! This non-dietetic behavior leads after several years of "unwanted and permanent gluten provocation" to the formation of high-affinity AK against transglutaminases (TG). The antibodies appearing in the serum form immune complexes with the epidermal transglutaminase(IgA-TG isoenzymes). The immune complexes circulate and can be deposited in renal glomeruli (possible development of IgA nephropathy) as well as in lesional and healthy skin (papillary tips, basement membrane). There they can be detected immunohistologically (direct immunofluorescence).

Remarkably, in patients with celiac disease IgA deposits are also detectable in non-inflammatory skin. These findings contradict the etiopathognetic significance of papillary immune complex deposits for the dermal inflammation of DhD (Antiga E et al. 2019). Anyway, DhD is the only dermatological autoimmune disease whose trigger factor(gluten) is known. Together with other gluten-induced diseases, celiac disease and DhD are grouped under the umbrella term of gluten-sensitive diseases (GSD).

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 slowly insidious onset with symmetrical, disseminated, strongly pruritic to burning or stinging, urticarial erythema 0.1-0.2 cm in size. Within these erythemas, grouped papules and/or vesicles form.

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

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

An extremely chronic course is characteristic. Relapses last from one month to more than 1 year. Intermittent episodes may last from weeks to years.

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

Chronic enteropathy, similar to idiopathic steatorrhea, is possible but not obligatory.

In the (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 for confirming diagnosis). Note: After months of gluten abstinence, the antibody levelsdecrease and can also become completely negative.

However, experience shows that there are also serologically negative cases of DhD.

Histology
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Formation of subepidermal clefts up to vesicles; blister formation below the lamina densa. In the initial stage (urticarial stage) infiltrate of neutrophilic granulocytes in the upper and middle dermis with focal epidermotropy. In places also leukocytoclasia. In the blistering stage, neutrophilic and eosinophilic granulocytes form intrapapillary microabscesses that are almost pathognomonic but not always detectable (serial sections). Frequent necrosis of basal epidermal cells. In the mature subepidermal blister stage, there is an increasingly lymphocytic infiltrate with numerous neutrophilic granulocytes at the base of the blister as well as at the lateral edge of the blister. Eosinophilic granulocytes are in the minority.

Small bow el biopsy: Collection of small bowel mucosal biopsies is not required in the diagnosis of DH, but when performed, villous atrophy is seen in the majority of patients, and celiac-type inflammation is present even in patients with normal villous architecture (Salmi TT 2019).

Direct Immunofluorescence
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Fine granular deposition of IgA and complement, mostly continuous along the dermo-epidermal junction, but also focally in the papillae tips; detection both in 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).

Indirect immunofluorescence (after exclusion of IgA deficiency): detection of IgA-AK against transglutaminase 3, endomysium IgA-AK, AK against gliadin and possibly thyroid AK as well as AK against parietal cells.

Therapy
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Diet and substitution of vitamins and iron:

  • Consistent gluten-free diet: The treatment of choice for DH is strict, lifelong adherence to a gluten-free diet. In addition to relieving the symptoms of DH and healing the small intestinal mucosal damage, a gluten-free diet increases patients' quality of life and reduces the risk of lymphoma in DH (Salmi TT 2019).
  • With a gluten-free diet, about 1/3 of all patients remain symptom-free without therapy. Avoidance of all grain products (barley, oats, rye, wheat). Even in the absence of signs of celiac disease (steatorrhea), villous atrophy can be histologically confirmed in most patients.
  • Low iodine diet: No iodized salt, no sea fish, few dairy products, selected sausage and meat products (as often treated with iodized salt), no iodine-containing drugs.
  • Drug of 1st choice is still dapsone 50-150 mg/day to max. 300 mg/day (e.g. dapsone-fatol), Cave! Met-Hb formation! Determine glucose-6-phosphate dehydrogenase before starting therapy! After symptoms have subsided, minimum maintenance dose for years. Attempt to discontinue after 6 months at the earliest.
  • alternatively colchicine: in case of sulfonamide intolerance colchicine (e.g. colchicine dispert) 3 times 0.5 mg/day.
  • alternative: in refractory cases try ciclosporin A (e.g. Sandimmun Optoral) 5 mg/kg bw/day, if necessary increase dose to 7 mg/kg bw/day.
  • In severe pruritus, antihistamines such as desloratadine (e.g. Aerius) 1-2 tbl/day. In gluten-induced enteropathy, treatment by internist, 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. preferably on empty stomach.
    • Intravenously: (e.g. Ferrlecit) rarely necessary, adults 3.2-5.0 ml/day i.v. slowly.
    • Intramuscular: (e.g. Ferrum Hausmann) adults 4 ml/day i.m., infants: 5 mg/kg bw/day p.o., spread over 3 ED over 3 months. Intramuscular administration in infants (e.g., Ferrum Hausmann): Zigzag injection (skin pigmentation!). Hb deficit (age norm) × bw (in kg) × 3.5 = iron requirement in mg. 1-2 ml i.m. every 2nd day. Caveat. No concomitant 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. for 4 weeks or 0.2 mg/day parenterally for 4 weeks.
  • Vit. D substitution: Vit D3 (Dekristol, Vigantoletten): 5000-10,000 IU/day p.o. for 6 weeks, later 2000-5000 IU/day for several months. Calcium supplementation (4 times/day 250 mg p.o.) is essential.
  • Experimental: In individual cases, the use of antibiotics can produce significant positive effects. For example, the penicillinase-resistant beta-lactam antibiotic flucloxacillin is also 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 very strongly hemorrhagic, Mr. Rose was able to prove histologically and serologically a dermatitis herperiformios. After precise instruction on a gluten-free diet, the patient ordered a fish dish on the plane, after which a severe flare-up occurred. In the meantime he reacts so strongly to iodine that he can only tolerate Irish meat, because only this is 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.
  2. Front Immunol 10:1290.
  3. Bogenrieder T et al (2003) From the New World. Louis A. Duhring and dermatitis herpetiformis. Dermatologist 54: 167-172
  4. Collin P, Reunala T (2003) Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists. Am J Clin Dermatol 4: 13-20.
  5. Collin P et al (2017) Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease.
  6. Ann Med 49:23-31.
  7. Duhring LA (1884) Dermatitis herpetiformis. Journal of the American Medical Association 3: 225-229.
  8. Fox WT (1880) A clinical study of the hydroa. Archives of Dermatology 6: 16-52
  9. Hervonen K et al (2014) Dermatitis herpetiformis in children: a long-term follow-up study. Br J Dermatol 171:1242-124
  10. 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
  11. Kotze LM (2013) Dermatitis herpetiformis, the celiac disease of the skin! Arq Gastroenterol 50:231-235
  12. Makino T et al (2019) Fibrillar-type dermatitis herpetiformis. Eur J Dermatol 29:115-120.
  13. Marietta EV et al (2008) Transglutaminase autoantibodies in dermatitis herpetiformis and celiac sprue. J Invest Dermatol 128:332-325.
  14. 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.
  15. Murphy LA et al (2003) Dermatitis herpetiformis converting into bullous pemphigoid: a study of three cases. Br J Dermatol 149 (Suppl 64): 17
  16. Nicolas ME et al (2003) Dermatitis herpetiformis. Int J Dermatol 42: 588-600
  17. Rose C et al (2010) Clinic, histology and immunopathology in 32 patients with dermatitis herpetiformis Duhring. JDDG 8: 265-271
  18. Salmi TT (2019) Dermatitis herpetiformis. Clin Exp Dermatol 44:728-731
  19. Sardy M et al (2002) Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 195: 747-757
  20. Sardy M et al (2009) Dermatitis herpetiformis. Dermatologist 60: 627-632
  21. 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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