Dermatitis herpetiformis: Novel advances and hypotheses

Dermatitis herpetiformis (DH) is a gluten-sensitive autoimmune blistering disorder with a chronic-relapsing course. Very recently, several Authors reported atypical cases of patients with DH, suggesting that different clinical subsets may exist at least among different ethnicities and that the classical picture of DH probably need a significant revision. Moreover, different pathogenetic aspects of the disease are currently under investigation, including the role of epidermal transglutaminase, apoptosis and inflammatory cells in the occurrence of skin lesions, in order to explain why only a subgroup of celiac patients will develop DH. Finally, although gluten-free diet is still regarded as the only curative approach to the disease, it is very hard to comply with and even small amounts of gluten can re-activate the disease. Therefore, different therapeutical approaches for the spectrum DH/celiac disease are still under investigation. In the present paper, the most recent advances in DH will be discussed, and a novel interpretation of the disease based on the data emerging from the Literature will be proposed.     

疱疹样皮炎的研究进展

疱疹样皮炎是一种与乳糜泻相关的自身免疫性大疱病,多发于携带HLA-DQ2或HLA-DQ8等位基因的高加索人.研究表明,疱疹性皮炎患者血清中存在多种针对转谷氨酰胺酶等抗原的抗体,表皮型转谷氨酰胺酶是其自身抗原.疱疹样皮炎的发病除与遗传和麦胶敏感有关外,还可能与肠道菌群微生态失衡有关.无麦胶饮食和氨苯砜仍然是疱疹样皮炎的主...     

Management of dermatitis herpetiformis

The major treatment strategies for DH are gluten restriction or medical treatment with sulfones. Control of the cutaneous manifestations, but not the gastrointestinal changes, is rapid with dapsone. In addition to control of the cutaneous signs and symptoms of DH, dietary gluten restriction also induces improvement of gastrointestinal morphology and is possibly protective against the development of lymphoma.     

疱疹样皮炎的血清学研究进展

疱疹样皮炎是一种与肠病有关的谷胶敏感性皮肤病,皮损表现为瘙痒性的红斑、丘疹、水疱,直接免疫荧光所见的IgA在真皮乳头层颗粒状沉积对疱疹样皮炎诊断有重要价值。尽管病理学检查和直接免疫荧光一直被认为是疱疹样皮炎诊断的金标准,但对于一些症状不典型或取材位置不当无法确诊的病例,血清学检查有着不可替代的作用,血清学检查对于疱疹样皮炎患者的疗效评估和随访均具有重要价值。随着对疱疹样皮炎发病机制的不断认识,新的血清学检测技术也在不断进步,同时通过血清学检查对DH患者血清中多种抗体水平的分析,为疱疹样皮炎发病机制的研究提供了更多线索。     

Pathophysiology of dermatitis herpetiformis: a model for cutaneous manifestations of gastrointestinal inflammation

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease in which antigen presentation in the gastrointestinal mucosa results in cutaneous IgA deposition and distinct, neutrophil-driven cutaneous lesions. Our findings suggest that the qualitatively different immune response to gluten in the intestinal mucosa of patients with DH results in minimal clinical symptoms, allowing the continued ingestion of gluten and the eventual development of DH. Our model may provide a new way to understand the pathogenesis of other skin diseases associated with gastrointestinal inflammation such as pyoderma gangrenosum or erythema nodosum, or explain association of seronegative inflammatory arthritis with inflammatory bowel disease.     

Dermoscopy examination of petechial lesions in a patient with Dermatitis Herpetiformis

An uncommon skin manifestation of Dermatitis Herpetiformis is palmar and plantarpurpura. Dermoscopic examination is useful for any skin condition since it allowsrecognition of structures that are not discernible to the naked eye. A 22 year-oldCaucasian man was admitted with excoriated lesions and pruritus. Petechial lesionscould be seen on volar aspect of the digits on the hands and feet. Dermoscopyexamination revealed erythematous and violaceous dots and erythematous and browndots.     

Antiendomysial antibody — useful serological indicator of dermatitis herpetiformis

Summary Antiendomysial antibodies (EmA) of the IgA class are directed against reticulin components of the primate smooth muscle and are markers of gluten-sensitive enteropathy. These antibodies occur in essentially all active cases of celiac disease and in about 70% of dermatitis herpetiformis (DH) patients. IgA deposits in the dermal papillae of the skin are the hallmark of DH and are employed routinely in establishing its diagnosis. The incidence of IgA deposits in skin varies depending upon the site and type of biopsy specimen taken.We studied sera and skin biopsy specimens for EmA and for IgA deposits in the skin from 11 DH patients. EmA were detected in the sera of 10 of the 11 cases. Of these 11 patients, 9 were positive for IgA deposits in their skin, as revealed by direct immunofluorescence (IF). The immune deposits were detected in the normal, and not in the lesional skin. DH cases that were initially negative on biopsy and serum positive for EmA were found to be positive when a repeat biopsy of the normal skin was performed. Thus, serological studies in conjunction with direct IF studies of the normal skin are useful in making a diagnosis of DH.Presented at the Society for Investigative Dermatology Meeting, Washington, DC, May 2, 1986     

Dermatitis herpetiformis: pathophysiology,clinical presentation, diagnosis and treatment

Researches on DH have shown that it is not just a bullous skin disease, but a cutaneous-intestinal disorder caused by hypersensitivity to gluten. Exposure to gluten is the starting point of an inflammatory cascade capable of forming autoantibodies that are brought to the skin, where they are deposited, culminating in the formation of skin lesions. These lesions are vesico-bullous, pruritic, and localized especially on elbows, knees and buttocks, although atypical presentations can occur. Immunofluorescence of perilesional area is considered the gold standard for diagnosis, but serological tests help in cases where it is negative. Patients who follow glutenfree diets have better control of symptoms on the skin and intestine, as well as lower risks of progression to lymphoma. Dapsone remains the main drug for treatment, but it requires monitoring of possible side effects, some potentially lethal.     

Should all patients with dermatitis herpetiformis follow a gluten-free diet?

Aim To assess the effect of a gluten-free diet in Irish patients with dermatitis herpetiformis, and whether treatment with a gluten-free diet is as important for patients with a normal small bowel biopsy us for those with villous atrophy. Background Though a gluten-free diet is recommended in the management of dermatitis herpetiformis, many patients find it intolerably restrictive. To date we have recommended it only to patients with abnormal small bowel histology. Methods Forty patients with dermatitis herpetiformis who attended our clinic between 1979 and 1994 were studied retrospectively. Villous atrophy was present in 20 (64%) of 31 initial small bowel biopsies in patients not on a gluten-free diet. Results The median time to a 50% reduction in dapsone requirements was 6 months in patients who followed a gluten-free diet. (n = 14). 10.5 months in those who had a gluten-reduced diet (n = 4) and 10.5 months in those who took a normal diet (n = 22). Four of 14 patients (29%) on a gluten-free diet were able to discontinue medication in 1–5 years compared with 2 of 22 (9%) on a normal diet. The mean time to a 50% reduction in dapsone requirements was similar in patients with and without villous atrophy. 9.3 versus 9.0 months in patients on a gluten-free diet and 12.0 versus 15.3 months in patients on a normal diet. Conclusion We conclude that a gluten-free diet should be strongly encouraged in all dermatitis herpetiformis patients, since those with normal small bowel biopsy findings benefit equally from the diet as do those with villous atrophy.     

Circulating IgA- and IgG-class antigliadin antibodies in dermatitis herpetiformis detected by enzyme-linked immunosorbent assay

Summary A sensitive and technically simple enzymelinked immunosorbent assay (ELISA) was developed to demonstrate circulating IgA- and IgG-class antibodies to gliadin, a component of wheat gluten. Serum samples from 24 patients with dermatitis herpetiformis (DH), 5 with coeliac disease (CD) and 75 normal controls were analysed. Antigliadin antibodies (AGA) of the IgA class were detected in 71% of DH patients, all of the CD patients and 19% of the controls. IgG-AGA was found in over 90% of DH patients and controls and in all of the CD patients. The mean ELISA values of both IgA- and IgG-class AGA were significantly higher in DH patients than in the controls. The occurrence of circulating IgA-class AGA is compatible with the hypothesis that these antibodies can be deposited in the skin, e.g. as immune complexes, or due to cross-reactivity of gliadin and dermal reticulin.Supported by grants from the Foundation for Finnish Chemical Research     

Sequential studies of gliadin antibodies in patients with dermatitis herpetiformis

Summary Sequential studies of circulating gliadin antibodies (IgG, IgA, IgM, IgD) were performed in 24 patients with dermatitis herpetiformis (DH) by an ELISA. Three groups of patients were studied: (a) 14 patients who responded to a gluten-free diet and were able to stop their drug therapy, (b) 5 patients who did not respond to a gluten-free diet, (c) 5 patients with normal jejunal biopsies, who did not receive a gluten-free diet. Most of the serum gliadin antibodies detected were of IgG class, but in several patients IgA gliadin antibodies were found in addition. When the patients were on a normal diet, 63% had elevated IgG gliadin antibody titres (titres which exceeded the maximum titre of the controls by one dilution) and there were no significant differences between the three groups. When the patients were followed up, there was a significant fall in the gliadin antibody titres in those who responded to a gluten-free diet compared to the two other groups of patients. Thus assays of IgG gliadin antibodies might be helpful in some patients in judging the complicance of patients on a gluten-free diet.     

IgA anti-endomysial antibody detection in the serum of patients with dermatitis herpetiformis following gluten challenge

Summary This study reports the appearance of IgA-class anti-endomysial antibodies in the serum of 8 out of 12 patients with dermatitis herpetiformis who were challenged with gluten after a number of years of control of the rash with a strict gluten-free diet. Although there was no evidence for the antibodies having any pathogenic role in the rash of dermatitis herpetiformis, their presence may be related to the deterioration in the gluten-sensitive enteropathy.     

Distribution of monkey esophagus antigens reactive with IgA-class antibodies in the sera of dermatitis herpetiformis patients

Summary Antibodies of IgA class reactive to the lining of the smooth muscle bundles, i.e., endomysium (EmA), are present in the sera of patients with dermatitis herpetiformis and coeliac disease. These antibodies can be detected on monkey esophagus, a substrate of choice for pemphigus and pemphigoid antibodies. The amount of antigen reactive with IgA-EmA is greatest in the lower portion of the esophagus and decreases towards the uppermost part.This work was supported in part by the Summerhill Foundation and by the Polish Academy of Medicine     

An exception within the group of autoimmune blistering diseases: dermatitis herpetiformis, the gluten-sensitive dermopathy

Dermatitis herpetiformis (DH) is characterized by chronic, itching papules, seropapules, small vesicles and, exceptionally, large blisters. The distribution of these polymorphic symptoms around the elbow, knee, buttock, and back is suggestive of the diagnosis. DH is further confirmed by the accumulation of granulocytes at the papillary dermis, resulting in a subepidermal split formation and by the presence of a unique, granular IgA precipitate in the uppermost dermis. Prognosis is predominantly determined by other autoimmune pathologies, malabsorption, or very rarely by lymphomas. Some of these diseases can be prevented by an early-onset, strict gluten-free diet, which is therefore the suggested treatment option.     

A simple method for elution of IgA deposits from the skin of patients with dermatitis herpetiformis

Summary To better understand the role of autoimmunity in the pathogenesis of dermatitis herpetiformis, linear IgA bullous dermatosis or other skin disorders, the antigenic specificity of the immune reactants bound in vivo in the skin must be identified. In order to do so, one must first be able to elute these immune reactants from the skin. We describe here a simple method of eluting not only specifically bound IgG, but also IgA and other immunoglobulins and complement components from skin biopsy material. The method involves cutaneous washing of the entrapped serum proteins in PBS pH 7 and pH 5 buffers followed by specific immunoglobulin elutions at pH 3 and 2. The IgA deposits which could not be removed by this treatment were eluted by a combination of low pH (0.5 M citrate pH 2) and a chaotropic agent (2 M NaCl). The relative concentration of IgA in eluates when quantitated by fluoroimmunoassay were three-to five-fold higher in dermatitis herpetiformis skin biopsy specimens, than in eluates of bullous pemphigoid or normal skin biopsy specimens.     

疱疹样皮炎研究进展

疱疹样皮炎(dermatitis herpetiformis,DH)是一种与乳糜泻密切相关的自身免疫性大疱性皮肤病,多见于高加索人群,亚洲人群少见.遗传学研究发现高加索人DH的遗传风险因子为HLA-DQ2和HLA-DQ8,已纳入诊断标准,国人DH风险因子为HLA-B?0801和HLA-DRB1?0301,尚未纳入诊断标...     

Serum antibodies to wheat germ agglutinin and gluten in patients with dermatitis herpetiformis

Summary It has been speculated that gluten may play a role in the pathogenesis of dermatitis herpetiformis (DH) because it can act as a lectin. The lectin activity of gluten preparations was recently identified as wheat germ agglutinin (WGA). IgG and IgA serum antibodies to WGA and gluten were therefore measured in patients with DH and coeliac disease (CD) by an enzylac-linked immunosorbent assay (ELISA). Compared with healthy controls, both patients categories had increased IgG and IgA activities to WGA and gluten, the CD group showing the highest antibody levels. DH patients with subtotal villous atrophy tended to have higher activities than those with no villous changes or only minor changes. No significant difference in the gluten-to-WGA ratio of IgA or IgG antibodies was found when DH patients were compared with CD patients. If WGA plays a pathogenetic role in DH, then DH patients must have dermal characteristics, as yet undefined, that explain the initiation of their skin disease.