Review: dermatitis herpetiformis

Dermatitis herpetiformis (DH) or Duhring-Brocq disease is a chronic bullous disease characterized by intense itching and burning sensation in the erythematous papules and urticarial plaques, grouped vesicles with centrifuge growth, and tense blisters. There is an association with the genotypes HLA DR3, HLA DQw2, found in 80-90% of cases. It is an IgA-mediated cutaneous disease, with immunoglobulin A deposits appearing in a granular pattern at the top of the dermal papilla in the sublamina densa area of the basement membrane, which is present both in affected skin and healthy skin. The same protein IgA1 with J chain is found in the small intestinal mucosa in patients with adult celiac disease, suggesting a strong association with DH. Specific antibodies such as antiendomysium, antireticulina, antigliadin and, recently identified, the epidermal and tissue transglutaminase subtypes, as well as increased zonulin production, are common to both conditions, along with gluten-sensitive enteropathy and DH. Autoimmune diseases present higher levels of prevalence, such as thyroid (5-11%), pernicious anemia (1-3%), type 1 diabetes (1-2%) and collagen tissue disease. The chosen treatment is dapsone and a gluten-free diet.     

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。     

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     

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.     

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     

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.     

中国疱疹样皮炎特征分析：1958—2018年文献回顾

【摘要】 目的 总结我国疱疹样皮炎患者的疾病特征。方法 检索中国知网、万方和Pubmed数据库中公开发表的中国人疱疹样皮炎相关文献,根据纳入及排除标准对临床表现、普通病理、免疫病理特点进行筛选,分析符合诊断标准患者的疾病特征。结果 纳入55例疱疹样皮炎患者,发病年龄（44.9 ± 18.5）岁,男女比例约2.5∶1,平均诊断延迟4.1年。皮损主要表现为红斑基础上的紧张性水疱,分布在臀区、肘部、背部、膝部等部位。39例描述组织病理表现,37例可见表皮下疱,17例存在中性粒细胞浸润。33例描述皮损周围组织直接免疫荧光表现,31例可见IgA颗粒状沉积,23例沉积部位为真皮乳头。39例描述了治疗情况,其中25例使用氨苯砜或氨苯砜联合无谷胶饮食治疗,治疗效果明显,皮损多在1个月内消退。结论 中国疱疹样皮炎主要表现为红斑基础上的紧张性水疱,直接免疫荧光主要表现为IgA颗粒状沉积,病因可能具有遗传学特点,氨苯砜治疗效果良好。     

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.     

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.     

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...     

Fibrillar IgA deposition may be associated with atypical dermatitis herpetiformis – a report of two cases

We report two cases of known dermatitis herpetiformis (DM) who presented with atypical clinical dermatological features. The first case, a 31-year-old woman, presented with an itchy urticated eruption on the abdomen and trunk, while the second case, a 50-year-old woman developed a scaly psoriasiform eruption on the extensor aspects of her knees and elbows. In each case, direct immunofluorescence of a perilesional skin biopsy showed a fibrillar pattern of IgA deposition at the basement membrane zone. Pre-embedding immunoelectron microscopy of these 2 specimens, using a 1 nm gold probe and silver enhancement, showed colloid gold panicle deposition around microfibril bundles in the dermal papillae. Recent studies have shown that fibrillin, a 350 kDa glycoprotein, is also associated with these microfibril bundles.
Serological tissue typing in our first case confirmed the presence of HLA-B8. B18. DR3 and DQw2 antigens consistent with dermatitis herpetiformis. In the second case, there was a notable absence of the antigens B17 and B27 typically found in psoriasis but HLA-AI, BX and DQ1 antigens were present, as commonly seen in dermatitis herpetiformis. Our findings would suggest that cases of dermatitis herpetiformis with fibrillar IgA deposition at the BMZ on direct IMF may show an atypical clinical presentation. In addition, our imunoelectron microscopy findings may provide a further clue to an ultrastructural abnormality in this disease.     

Guidelines for the diagnosis and treatment of dermatitis herpetiformis

Dermatitis herpetiformis is a rare disease that should be considered the cutaneous expression of a gluten-sensitive enteropathy indistinguishable from celiac disease. Dermatitis herpetiformis is often misdiagnosed and to date no guidelines for the management of dermatitis herpetiformis have been published in Literature. The present guidelines have been prepared for dermatologists by the Group for Cutaneous Immunopathology of the Italian Society of Dermatology and Venereology. They reflect the best data available at the time of preparation and the clinical experience of the authors and the members of the Italian Group for Cutaneous Immunopathology. The diagnosis of dermatitis herpetiformis is established clinically, histologically, immunopathologically and serologically. A gluten-free diet (GFD) is the treatment of choice for patients with dermatitis herpetiformis. Dapsone and/or other drugs should be used during the period until the GFD is effective. In conclusion, the present guidelines provide evidence-based guidance for the diagnosis and treatment of dermatitis herpetiformis.

Conflicts of interest

None declared.     

Long-term remission in patients with dermatitis herpetiformis on a normal diet

BACKGROUND: A life-long gluten-free diet is the treatment of choice for dermatitis herpetiformis, which is considered to be coeliac disease of the skin. OBJECTIVES: To investigate the effects on long-term remission of dermatitis herpetiformis in patients who underwent a gluten challenge and subsequently reintroduced dietary gluten. PATIENTS AND METHODS: We studied 38 patients (14 male and 24 female) with biopsy-confirmed dermatitis herpetiformis. They had followed a gluten-free diet for a mean of 8 years, achieving clinical remission and intestinal normalization. The patients were asked to reintroduce gluten in their diet and agreed to undergo skin and intestinal biopsies during the follow-up. RESULTS: Of the 38 patients abandoning a gluten-free diet, 31 reported the onset of rash within an average of 2 months. Seven subjects (three males, mean age 15 years at challenge) experienced no clinical or histological relapses (median follow-up 12 years), and lost IgA immunoglobulin from the skin. The two series of patients differed in terms of age at diagnosis (mean age: 26.6 vs. 6 years), the use of dapsone (one of 31 vs. four of seven) and adherence to the gluten-free diet (strict compliance in 26 of 31 vs. none of seven). CONCLUSIONS: Our data suggest that the ingestion of small doses of gluten in childhood and/or the use of an anti-inflammatory drug may modify the immunological response inducing immune tolerance. We report long-term clinical and histological remissions in seven patients with dermatitis herpetiformis after the reintroduction of dietary gluten.     

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.