Gluten-free diet for dermatitis herpetiformis: the long-term effect on cutaneous, immunological and jejunal manifestations

In 32 patients with dermatitis herpetiformis (DH) we studied the effect of gluten-free (22 patients) and gluten-reduced (10 patients) diet for periods ranging between 15 and 43 months. Variables such as cutaneous manifestations, dependence on dapsone, IgA deposits in the skin, small-bowel function, and jejunal mucosal morphology were studied. 59% of the patients on gluten-free diet could stop dapsone medication and remain symptom-free, compared with 10% on gluten-reduced diet. The time needed to achieve this therapeutic response varied from 5 to 31 months. IgA decreased in the skin to a degree which roughly paralleled the morphological normalization of the jejunal mucosa. In no patient, however, did the IgA completely disappear. It is suggested that IgA is not the main factor inducing DH symptoms, but rather a secondary phenomenon. Repeated jejunal biopsies revealed normalization of the mucosal histology in 52% of the patients on gluten-free diet, compared with none in the gluten-reduced diet group.     

Dermatitis herpetiformis

The state of our understanding of the pathogenesis of DH relies on the integration of several key characteristics: (1) a high frequency of the HLA antigens HLA-B8, HLA-DR3, and HLA-DQw2, (2) an associated GSE, (3) the resolution of both the skin lesions and gut abnormalities in response to a gluten-free diet, and (4) the presence of granular deposits of IgA in normal and perilesional skin. The role of the HLA class II antigens expressed in patients with DH most likely relates to the afferent or initiating arm of the immune system. The association of the HLA-A1, -B8, -DR3, -DQw2 haplotype with Sjogren's syndrome, chronic hepatitis, Graves' disease, and other presumably immunologically mediated diseases, as well as the evidence that some normal HLA-B8, -DR3 individuals have an abnormal in vitro lymphocyte response to wheat protein and mitogens and have abnormal Fc-IgG receptor-mediated functions, suggests that this HLA haplotype or genes linked closely to it may confer a generalized state of immune susceptibility on its carrier, the exact phenotypic expression of which depends on other genetic or environmental determinants. It also is clear, from the association of DH with GSE and the ability to control the cutaneous manifestations of DH with a gluten-free diet, that the gut disease is a critical factor in the pathogenesis of DH. Several pathogenetic theories about the origin of the cutaneous IgA deposits in DH have been proposed, one of which states that the IgA is produced in the gut mucosa as a response to a dietary antigen or gut epithelial antigen and then cross-reacts with the skin of patients with DH. A second hypothesis is that the IgA produced in the gut binds to an antigen and is deposited in skin as an antigen-antibody complex. Finally, it could be that the gut mucosal abnormality simply allows an unknown antigen access to the central immune system where an IgA antibody is produced that binds to skin. The failure to detect circulating IgA anti-basement membrane zone antibodies in patients with DH suggests that either the structures to which the IgA binds are not present in normal skin without DH, that IgA cannot bind to these structures in vitro, or that the circulating IgA is too scant for detection with conventional methods. Finally, it must be considered that the IgA deposited in DH skin may bind as a result of non-antigen-antibody interactions that cannot be duplicated in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical guidelines for the diagnosis and treatment of dermatitis herpetiformis

Dermatitis herpetiformis is an autoimmune blistering disease that appears as a cutaneous manifestation of gluten intolerance. It is one of a group of disorders that have gluten sensitivity in common, including celiac disease and gluten ataxia. Patients with dermatitis herpetiformis present with a pruritic papulovesicular rash on extensor surfaces and on the buttocks. Immunological studies demonstrate the presence of specific immunoglobulin (Ig) A anti-endomysial and anti-transglutaminase antibodies. The finding of granular deposits of IgA along the dermal-epidermal junction is pathognomonic of dermatitis herpetiformis. Treatment of dermatitis herpetiformis is based on a life-long, strict gluten-free diet, which improves all clinical aspects of gluten sensitivity, and dapsone, a drug that is only effective for the skin manifestations.     

TCR Vbeta expression in the small bowel of patients with dermatitis herpetiformis and gluten sensitive enteropathy. Limited expression in dermatitis herpetiformis and treated asymptomatic gluten sensitive enteropathy

Dermatitis herpetiformis (DH) is a blistering skin disease characterized by cutaneous deposits of IgA and an associated, most often asymptomatic, gluten sensitive enteropathy (GSE). Gluten sensitive enteropathy is also seen in patients that do not have skin disease or cutaneous IgA deposits, but do have significant gastrointestinal (GI) complaints. Patients with DH and with GSE without skin disease have similar small bowel morphologic changes and HLA associations and both the skin disease and the GI symptoms can be controlled by a gluten free diet. It is not known what factors allow almost all patients with DH to continue to eat gluten and not develop symptomatic gastrointestinal disease. We have examined the expression of the Vbeta T-cell receptor (TCR) in the small bowel of patients with DH (n=11) and of patients with both symptomatic (n=10) and asymptomatic (n=7) GSE without skin disease to determine if differences in the pattern of TCR Vbeta expression are associated with differences in the clinical manifestations of these diseases. TCR Vbeta expression was analyzed using RT-PCR from small bowel biopsies. Patients with DH and those with GSE without skin disease that were on a gluten free diet and asymptomatic were found to express 6.6 and 5.6 out of 20 Vbeta families respectively, with no single family preference. Examination of peripheral blood lymphocytes from these patients did not reveal any restriction of TCR Vbeta family expression. In contrast, patients with symptomatic GSE expressed 12.6 Vbeta families (P< 0.05), with no consistent preferential expression of any single Vbeta family between patients. Patients with DH, who are continuing to ingest wheat, show a more restricted pattern of TCR Vbeta utilization, similar to that of treated patients with GSE without skin disease, and significantly different from GSE without skin disease patients eating gluten. These findings suggest that the restricted nature of the TCR Vbeta expression may play a role in the different clinical manifestations of dermatitis herpetiformis and isolated gluten sensitive enteropathy.     

Co-localization of IgA and TG3 on healthy skin of coeliac patients

BACKGROUND: Dermatitis herpetiformis (DH), the skin's expression of coeliac disease (CD), is induced by the presence of IgA antibodies and epidermal transglutaminase (TG3) as the main autoantigen, stored in the papillary dermis and on the vessel walls. AIMS: To evaluate the presence of IgA and TG3 deposits, considered to be the first step in inducing DH, in healthy skin of coeliac patients without cutaneous manifestations. METHODS: Punch biopsies were taken from 11 consecutive coeliac patients, two with DH and nine without cutaneous manifestations, three of whom were adhering to a gluten-free diet (GFD), and evaluated for the presence of deposits in the upper dermis and vessel walls by immunofluorescence and confocal microscopy. RESULTS: In coeliac patients affected by DH we found the presence of IgA and TG3 deposits mainly on the upper dermis, but also in vessel walls. In all coeliac patients without DH and also in those patients who were following a strict GFD, we found widely variable deposits of IgA and TG3 in both the papillary dermis and the vessel walls, although a lower intensity of the fluorescence signal was detected than with coeliac patients affected by DH. Double immunostaining with anti-IgA and anti-TG3 antibodies showed a strong co-localization in the upper dermis in patients with DH and a weaker co-localization in those without DH. CONCLUSIONS: We have demonstrated the presence of IgA and TG3 deposits in the healthy skin of coeliac patients, which are considered to play a central role in the pathogenesis of DH.     

The pathogenesis of dermatitis herpetiformis: recent advances

Over the last two decades a rapid expansion of our knowledge regarding dermatitis herpetiformis has occurred, including the discovery of IgA in the skin, the discovery of an associated gluten-sensitive enteropathy, the noting of an increased prevalence of the human lymphocyte antigens (HLA)-B8 and -DRw3, and the documentation that the skin disease of many dermatitis herpetiformis patients can be controlled by a gluten-free diet. It has also been noted that two distinct forms of dermatitis herpetiformis occur, those with granular deposits of IgA at the dermoepidermal junction (85%-95% of dermatitis herpetiformis patients) and those with linear IgA deposits (10%-15% of dermatitis herpetiformis patients). These findings are reviewed with particular emphasis on the form of dermatitis herpetiformis associated with granular IgA deposits. The current findings regarding the nature and origin of the cutaneous IgA deposits, the role of the gluten-sensitive enteropathy, and the spectrum of both the immunologic and the nonimmunologic abnormalities associated with dermatitis herpetiformis are presented, and from these data pathophysiologic mechanisms are proposed that may be involved in dermatitis herpetiformis.     

Dermatitis herpetiformis

Dermatitis herpetiformis (DH) is a chronic, polymorphic, pruritic skin disease that develops mostly in patients with latent gluten-sensitive enteropathy. DH patients usually present with skin manifestations only and are not aware of the underlying small-bowel problems. Owing to the granular immunoglobulin (Ig) A deposition at the tips of the papillary dermis and to the subepidermal blister formation associated with neutrophilic accumulations underlying the basement membrane, DH is considered to be an autoimmune blistering disease. Contrary to the other bullous disorders, DH patients have no circulating autoantibodies binding to the cutaneous basement membrane components or to other adherent structures of the skin, but they have gluten-induced IgA autoantibodies against transglutaminase (TG) 2 and TG3. The serum IgA against tissue TG2 is a most specific and sensitive serologic marker of gluten-sensitive enteropathy and is equivalent to the perviously described IgA endomysium antibodies. DH could be a cutaneous IgA-epidermal TG3 immunocomplex disease, developing only in a few patients with gluten-sensitive enteropathy as a second gluten-dependent disease. The main treatment of DH today is a strict, life-long gluten-free diet. Untreated DH patients should be regularly monitored for malabsorption and lymphomas. Associated autoimmune diseases are more common among DH patients. Family screening for gluten sensitivity is also strongly suggested.     

Characterization of the mucosal immune response to dietary antigens in patients with dermatitis herpetiformis

The association of dermatitis herpetiformis (DH) with granular IgA deposits at the dermal-epidermal junction and a gluten sensitive enteropathy (GSE) suggests that a mucosal immune response may play an important role in the pathogenesis of DH. The degree of antigenic restriction, the immunoglobulin class and subclass response to dietary antigens, and the relationship of antibodies against dietary antigens to IgA-containing circulating immune complexes (CIC) in patients with DH, however, are not known. We have examined the serum of 33 patients with DH for IgG and IgA antibodies against gliadin, and against 3 dietary proteins not thought to be related to GSE, beta-lactoglobulin (beta-lacto), bovine gamma globulin (BGG), and casein. Eleven of 33 (33%) patients with DH had IgA anti-gliadin antibodies, whereas IgA antibodies against beta-lacto were found in 11 of 33 patients (33%), against BGG in 15 of 32 (47%), and against casein in 6 of 33 (18%); 17 of 32 (53%) patients had IgA antibodies against one or more of these dietary antigens. Significantly higher levels of IgA antibodies were detected against beta-lacto (2,500 +/- 2,320 ng/ml, mean +/- SEM) and BGG (2,340 +/- 1,890 ng/ml) than gliadin (1,250 +/- 851 ng/ml) in this group of antibody positive patients (p less than 0.05, Wilcoxon signed ranks test). Eleven of 17 patients with IgA antibodies against dietary antigens were found to have IgA-containing CIC, whereas only one of the 15 antibody negative patients had IgA-containing CIC (p = 0.0008, Fisher's exact test). IgA anti-gliadin antibodies were found to contain both IgA1 and IgA2 with a significantly increased proportion of IgA2 when compared with the IgA2 composition of the total serum IgA (IgA2: anti-gliadin antibodies = 34 +/- 4.2%; total serum IgA = 19 +/- 4.8%, p = 0.02, Students paired t test). IgG antibodies against these antigens were found to occur slightly more frequently in amounts not significantly greater than IgA antibodies. This data demonstrates that a serum IgA and IgG antibody response to dietary antigens occurs in approximately 50% of DH patients with a higher proportion of IgA2 than total serum IgA and does not appear to be restricted to gliadin. This is significantly different from the pattern of cutaneous immunoreactants in patients with DH, and suggests that the deposition of IgA in DH skin may be the result of an atypical mucosal immune response, a non-immunologic interaction of IgA1 and DH skin, or arise from a non-mucosal source.     

Juvenile dermatitis herpetiformis: an immunoelectron microscopic study

Three children with persistent maculopapular and urticarial lesions and vesicles at the predilection sites of dermatitis herpetiformis (DH) were shown to exhibit typical granular, papillary IgA and C3 deposits in the tips of the dermal papillae, as demonstrated by direct immunofluorescence. By immunoelectron microscopy, the IgA deposits were associated with the microfibrils of the elastic fibres as has been described in DH of the adult. C3 deposits were scattered throughout the papillary dermis. Despite the similarity of the clinical appearance, history with regard to gluten sensitive enteropathy (GSE) varied in these three cases. In one child, the skin lesions appeared following faults in the gluten free diet on which he was kept for coeliac disease. Another child developed the skin lesions during a gluten free diet which was not strictly followed; no recurrences of gastrointestinal symptoms accompanied the eruption of DH. In the third case, no evidence for GSE in patient's history or in jejunal biopsies was present at the time of onset of DH.     

IgA-binding structures in dermatitis herpetiformis skin are independent of elastic-microfibrillar bundles

Dermatitis herpetiformis (DH) is characterized in part by the presence of granular deposits of IgA in the papillary dermis just beneath the dermal-epidermal junction. The nature of the structures to which IgA binds in DH skin, however, has not been clearly demonstrated. Previous immunoelectron-microscopy studies using the peroxidase-antiperoxidase technique have concluded that the IgA may bind to abnormal elastic microfibrillar bundles. Recently, antibodies have been developed against a major component of the elastic microfibril bundles, fibrillin. In addition, another dermal matrix protein, hexabrachion, has been characterized and found in normal human skin in a distribution similar to the IgA deposits of DH. Utilizing antibodies against fibrillin, hexabrachion, and human IgA and immunoelectronmicroscopy with immunogold staining techniques, we have examined the skin from patients with DH in order to localize the IgA deposits. Normal-appearing skin from five patients with DH exhibited electron-dense patches within the dermis, which were not seen in skin from normal subjects. These structures were sometimes adjacent to the basement membrane zone, but appeared amorphous and without a well-defined fibrillar structure. The electron-dense patches were labeled with anti-human IgA, but not with antibodies to fibrillin or hexabrachion. The anti-IgA antibody did not label the normal basement membrane. These studies confirm the presence of abnormal electron-dense, amorphous structures in the skin of patients with DH. Due to this lack of association with the elastic microfibril bundles and the lack of labeling with antibodies against fibrillin, we suggest that these deposits are distinct from the microfibrillar bundles of elastic tissue and may represent IgA bound to degraded basement membrane or isolated dermal deposits of IgA.     

Dermatitis herpetiformis. Cutaneous deposition of polyclonal IgA1

Dermatitis herpetiformis (DH) is a pruritic papulovesicular skin disorder of unknown cause, characterized by granular IgA deposits in the dermis along the dermoepidermal junction. It is associated with gluten-sensitive enteropathy and increased IgA production by gut lymphoid tissue. We report four cases of immunologically documented DH studied by immunofluorescence technique. Monoclonal antibodies against the IgA subclasses IgA1 and IgA2 were used. IgA1 without IgA2 was found in the cutaneous deposits in each case. The IgA1 had both kappa and lambda light chains in approximately equal quantities. Because normal gut-associated lymphoid tissue produces 70% IgA1 and 30% IgA2, while circulating IgA is primarily IgA1, it could be concluded that the IgA in the skin of DH patients is not produced in the gut. However, the subclass restriction of the IgA produced by pathologic gut-associated lymphoid tissue is unknown. Alternatively, both IgA1 and IgA2 may be produced by the gut, but only IgA1 is involved in the production of cutaneous lesions.     

Treatment of dermatitis herpetiformis and linear IgA bullous dermatosis

Dermatitis herpetiformis (DH) and linear IgA bullous dermatosis (LABD) are IgA-mediated autoimmune bullous diseases. They share an identical histopathology, but are differentiated on the basis of the pattern of IgA deposition on direct immunofluorescence. While DH responds to a gluten-free diet, LABD rarely responds to gluten restriction. In the management of DH, adhering to a gluten-free diet promotes healing of small intestine villus atrophy, resolution of cutaneous disease, and lowers the risk of lymphoma. Dapsone is palliative but not curative in the treatment of DH and LABD. Patients taking systemic dapsone or sulfa-based medication for the treatment of DH or LABD should have a reasonable knowledge of the inherent side effects.     

Long-term follow-up of dermatitis herpetiformis in children

Dermatitis herpetiformis was diagnosed in seventy-six children by its clinical features and by detection of granular IgA deposits in the papillary dermis of perilesional skin. Enteric alterations demonstrated by measurement of D-xylose absorption and by small intestinal biopsies were detected in over 90% of all patients. A complete follow-up was obtained for all children who were followed for 3 to 10 years. Treatment with a gluten-free diet alone led to a reversal of the intestinal abnormality in 100% of our children and to the disappearance of cutaneous lesions in 82% of reported cases. This suggests that a complete remission of symptoms can be obtained with a gluten-free diet alone. Dapsone alone is effective therapy for the rash but does not affect the intestinal alterations. Furthermore, the lack of side effects to dietetic therapy for a long period of time makes the diet the treatment of choice in this disease.     

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.     

Immunoglobulin A deposition in jejunal mucosa of children with dermatitis herpetiformis

Previously we have shown by indirect immunofluorescence (IF) technique that a special IgA antibody in the sera of patients with dermatitis herpetiformis (DH) binds to the structures of the normal jejunum. Now we show by direct IF that specific IgA deposits are present in the proximal jejunum of 11/12 DH and 2/2 celiac patients before a gluten-free diet (GFD). The IgA deposition was in a tubular pattern underlying the villous and crypt epithelial basement membranes and in the lamina propria. This IgA deposition diminished or was not detectable in DH patients under a GFD for a year, and became detectable under gluten challenge in three DH patients. One patient with celiac disease and IgA deficiency, four with other intestinal diseases, and four without jejunal damage had neither jejunal IgA deposition nor circulating IgA anti-jejunal antibody. The deposition of IgA in the jejunum seemed to be correlated with the presence of IgA anti-jejunal antibody in the serum and with the presence of jejunal damage, but the degree of jejunal atrophy, the titer of the anti-jejunal antibody, and the intensity of jejunal IgA deposition in DH patient were not clearly related. Deposition of IgA in the jejunum in DH did not clearly correlate with the activity of the skin symptoms and thus may not be directly related to the pathogenesis of the skin disease of DH.     

IgA anti‐epidermal transglutaminase autoantibodies: a sensible and sensitive marker for diagnosis of dermatitis herpetiformis in adult patients

Background Dermatitis herpetiformis (DH) is a rare gluten‐sensitive blistering itchy skin disease, strictly related to coeliac disease (CD). Direct immunofluorescence, demonstrating IgA granular deposits localized either in the dermal papillae or along the dermo‐epidermal junction, is currently the gold standard for diagnosis of DH. It has been shown that DH immunocomplexes contain epidermal transglutaminase (eTG) and that sera from patients with DH contain antibodies specifically directed against eTG. Objectives We studied the usefulness of serum eTG antibodies in discriminating between DH, CD and other gastrointestinal and dermatologic diseases. Methods eTG antibodies were tested in 308 adult patients’ sera: 44 patients with untreated dermatitis herpetiformis (UDH), 99 patients with untreated coeliac disease (UCD), 70 dermatological controls and 95 gastrointestinal controls. Results In UDH eTG antibody levels were significantly higher than in DH patients on gluten‐free diet, UCD, gastrointestinal controls and dermatological controls. In UCD eTG antibodies strongly correlated with tissue transglutaminase (tTG) antibodies, whereas in UDH no significant correlation was observed. Conclusion Serum IgA eTG antibody determination can efficiently distinguish UDH from other dermatological itchy diseases and is highly sensitive to gluten‐free diet.     

Cutaneous Immunofluorescence in Dermatomyositis

ABSTRACT: Seven patients with dermatomyositis who displayed severe skin and muscle disease, and in whom coexistent systemic lupus erythematosus (LE) was excluded, were evaluated by direct immunofluorescent biopsies of skin lesions. Specimens from six showed deposits of immunoglobulins and complement in small to moderate amounts at the dermal-epidermal junction zone. These deposits were usually in the form of focal granular accumulations which lacked continuity and were not well developed as are those seen in LE, or fluorescent subepidermal hyaline bodies. One patient, however, had a more well developed hand of immunoglobulins at the dermal-epidermal junction. All normal skin specimens in these patients were negative by immunofluorescence.
These findings were helpful in clarifying differences in cutaneous immunofluorescence between dermatomyositis and LE, indicating that dermatomyositis specimens can usually be differentiated from those of LE patients. but demonstrating the possibility that confusion might rarely occur in interpreting a lesional immunofluorescent biopsy in dermatomyositis.     

IgA linear dermatosis (author's transl)]

Besides the typical forms of dermatitis herpetiformis (DH) and bullous pemphigoid (BP) of adults and children, there are cases combining clinical, histological and electronmicroscopic features of both. Linear continuous IgA deposits along basement membrane zone (BMZ) are a most characteristic finding. They differ from the granular IgA deposits in DH, even if these are also distributed along the BMZ (however, preserving as a rule their granular pattern). IgG circulating anti-BMZ antibodies are absent, whereas in some cases IgA anti-BMZ antibodies may be found. In contrast to DH, there is no gluten-sensitive enteropathy, and the gluten-free diet is ineffective. The recognition of this bullous disease as a distinct entity is of practical significance because these cases respond well to combined treatment with sulfones and corticosteroids, all in small doses. Because of diagnostic importance of linear IgA deposits at BMZ we have proposed the name IgA linear dermatosis. In children a counterpart of IgA linear dermatosis of adults is chronic bullous disease of childhood (CBDC), which we propose to call IgA linear dermatosis of childhood.     

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。     

Palmar Purpura: An Atypical Presentation of Childhood Dermatitis Herpetiformis

Abstract: Dermatitis herpetiformis (DH) is seen most commonly as a pruritic, papulovesicular eruption in young children or adolescents. Differentiation from other bullous diseases of childhood may be difficult. We report the first case of an adolescent in whom pruritic, palmar, purpuric macules and papules were the only manifestations of DH. The patient later developed typical vesiculobullous extensor lesions and symptomatic gluten-sensitive enteropathy (GSE). All lesions and GSE symptoms resolved with dapsone and a gluten-free diet. Our purpose is to illustrate an unusual presentation of pediatric DH.