Dermatitis herpetiformis L13.0

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 burning or stinging"itch" is characteristic of vesicular efflorescences. This form of "itching pain" is the leading symptom that leads the pat. to the physician. In the ulcerative form of DhD, the stabbing-burning pain is also a prominent feature.

The disease is understood as a cutaneous manifestation of a(non-IgE-mediated), immunological gluten sensitivity(celiac disease). While DhD almost always also presents with (often asymptomatic) celiac disease, only a small proportion of celiac patients present with dermatitis herpetiformis.

Manifest intestinal symptoms are observed in only about 25% of cases of dermatitis herpetiformis patients.

The incidence of DhD ranges from 0.4 to 3.5 per 100,000 people per year, and the prevalence ranges from 11.2 to 75.3 per 100,000. The higher rates are often found in countries such as Finland, as this disease is preferentially found in individuals of Northern European descent. Conversely, DhD is rare in Asian populations (Makino T et al. 2019) and even less common in African Americans. DhD can occur at any age but is most commonly diagnosed between the ages of 30 and 40 years, with a mean of 43 years. Males predominate, with a ratio of 1.5:1-2:1 (Nguyen CN et al. 2021).

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

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
  • a focal disease
  • 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 jejunum villi (these are detectable in only about 1/4 of all DhD patients, which fits with the usually absent intestinal sympathetics - 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 keratinization. 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) in DhD initially and also in the later course of the disease often remain clinically asymptomatic(see symptomatic celiac disease). 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). These immune complexes circulate, 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) as granular fluorescence.

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).

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.

Mostly symmetrical distribution pattern.

Mostly affected are the upper shoulder girdle (sometimes in acneiform distribution), gluteal region, capillitium, extensor sides of the forearm, elbow regions, extensor sides of the thigh and lower leg, knee regions.

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

Mucous membranes are usually free. However, aphthous, painful erosions of the oral and genital mucosa are (rarely) observed.

Occasionally, although rarely, "herpes simplex-like" lesions of the labial redness are found.

Sudden, rarely also slowly insidious, onset with disseminated, symmetrical, intensely pruritic/burning or stabbing-painful, 0.1-0.2 cm large, urticarial erythema. Within these erythemas, grouped papules and/or vesicles form. The vesicles erode relatively quickly, leaving a small crusty papule.

There is the development of a "synchronous polymorphism" with vesicles, wheals, papules, crusted small erosions due to the relapsing nature of DhD, as well as prolonged and therapy-resistant ulcers and scars of varying sizes. This variegated pattern of efflorescences is mainly found on the elbows and buttocks. Aphthous oral or genital mucosal lesions may be observed, although rarely.

An extremely chronic course is characteristic. Relapses last from one month to more than 1 year. Intermissions may last weeks to years. Extension and intensity vary within wide limits. A minimal morphologic variant may be a skin completely free of symptoms with attack-like itching, a finding that poses differential diagnostic problems.

In cases of pronounced gluten sensitivity, dietary errors can lead, after hours or days, to acute relapsing activity with pruritic to painful, highly red urticarial exanthema, possibly combined with rhinopathic and bronchitic symptoms. Chronic enteropathy is possible but not obligatory (signs of celic disease).

On the other hand, the (rare) dermatitis herpetiformis in childhood has a close clinical correlation to a gluten-sensitive enteropathy (sprue) .

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.

Formation of subepidermal clefts to vesicles; blistering occurs below the lamina densa.

In the initial stage (urticarial stage), an infiltrate of neutrophilic granulocytes forms in the upper and middle dermis with focal epidermotropy. There is also leukocytoclasia in places.

In the blistering stage, neutrophilic and eosinophilic granulocytes form intrapapillary microabscesses that are nearly 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. When it is nevertheless 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).

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

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

Indirect immunofluorescence (after ruling out an IgA -deficiency): Detection of IgA-AK against transglutaminase 3, endomysium IgA-AK, AK against gliadin and possibly thyroid AK, and AK against parietal cells.

Direct immunofluorescence (DIF) is the diagnostic gold standard of DhD with a sensitivity of 90-95% and a specificity of 95-100%. Biopsies should be taken from uninvolved perilesional skin, as these regions contain significantly more IgA deposits and lesional biopsies generally have a higher false-negative rate. The pathognomonic finding in DIFs is granular IgA deposits in the dermal papillae and/or at the dermoepidermal interface.

However, DhD with IgA deposits exclusively along the dermoepidermal interface may be confused with linear bullous IgA dermatosis, in which case further serologic testing is required.

Less frequently, a fibrillar pattern of IgA deposits has been described in the skin tips of DhD patients. This pattern differs from the granular pattern in that the IgA deposits appear as linear streaks rather than fine granules. The fibrillar pattern is more common in Japan, where it can be found in up to 50% of patients.

In addition to IgA, IgM and C3 have also been detected at the dermal papillae and dermoepidermal interface.

If a patient with high clinical suspicion of DhD has a negative DIF result, consideration should be given to repeating the biopsy from a new, "normal" appearing, perilesional skin site. False-negative results occur in approximately 5% of biopsies. Note: A strict gluten-free diet may decrease IgA levels in the skin, which also affects DIF results, in contrast to pharmacological treatments that do not alter IgA deposition.

In this respect, the patient's diet must also be evaluated in IF diagnostics. If the patient is following a strict gluten-free diet, biopsy should be performed again after one month on a "normal" gluten-containing diet. In rare cases, even a rebiopsy in DhD patients may not lead to the desired result. In this case, the combination of clinical, histopathological and serological data must be used to establish the diagnosis.

Enteropathy: Most patients with DhD have evidence of some degree of celiac-like damage in their small intestine; however, this is usually milder than in celiac disease (CD). Consequently, patients with a history of DH may present with GI symptoms such as bloating, diarrhea, or constipation, but these are usually minor when they do occur. Because of the association with gluten-sensitive enteropathy, patients with DhD may experience complications of malabsorption such as nutrient deficiency, osteoporosis, short stature, anemia, and weight loss. However, these are rare in DhD, unlike celiac disease. They may also develop celiac-related complications such as sprue, ulcerative ileitis or non-Hodgkin's lymphoma, and malignancies of the gastrointestinal tract. As with celiac disease, the diagnosis of DhD is associated with a significantly increased risk of non-Hodgkin's lymphoma. However, this risk is increased only in the first five years after diagnosis. Both T-cell and B-cell lymphomas have been reported, with B-cell lymphomas being more common.

Neurologic dysfunction: In rare cases, gluten sensitivity has been associated with neurologic dysfunction such as cerebellar ataxia, polyneuropathies, epilepsy, myelopathy, and encephalopathy. Case reports have described DH to be associated with various neurological pathologies. The incidence rates of these disorders have not been studied in DhD but are probably low. Nevertheless, dermatologists should be aware of this association and refer to a neurologist when needed.

Autoimmune diseases and associated conditions: There are associations between a diagnosis of DhD and a variety of other autoimmune diseases, the most common being autoimmune thyroid disease and type I diabetes mellitus. Other less common conditions include pernicious anemia, multiple sclerosis, Sjögren's syndrome, SLE, rheumatoid arthritis, vitiligo, alopecia areata, dermatomyositis, sarcoidosis, Addison's disease, psoriasis, and atopic dermatitis. Most clinicians can easily screen patients with DhD for thyroid disease (TSH, T3, T4, and anti-thyroid peroxidase) and type 1 diabetes (serum glucose) and should test for other autoimmune diseases based on associated signs and symptoms. DhD is also associated with an increased risk of bullous pemphigoid . The diagnosis of DhD and subsequent diagnosis of BP have been reported at varying intervals. Therefore, dermatologists should be alert to the possibility of a new diagnosis of bullous pemphigoid if the clinical picture changes with the formation of large blisters and/or a gluten-free diet is no longer effective (Nguyen CN et al. 2021).

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; dosage: 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 an 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.

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 ).

Gluten- and iodine-free diet for dermatitis herpetiformis Duhring

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.

Diagnosis:

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

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