Dermatitis herpetiformis presenting as chronic urticaria

Childhood dermatitis herpetiformis (DH) is an immunobullous disease associated with gluten-sensitive enteropathy. This disease is rare in children and is typically characterized by intensely pruritic vesicles on the extensor surfaces. Definitive diagnosis of DH depends on the direct immunofluorescence finding of granular or fibrillar IgA deposits along the basement membrane zone of biopsied perilesional skin. We report an 11-year-old boy with an unusual presentation of DH characterized by a 7-month history of chronic urticaria-like skin lesions. He had evanescent, largely asymptomatic, urticarial wheals on his trunk, face, and extremities that were unresponsive to conventional therapy for urticaria. Skin biopsy specimen findings were consistent with DH and direct immunofluorescence of perilesional skin was diagnostic. The patient had no symptoms of gluten-sensitive enteropathy at the time of diagnosis, and his skin lesions rapidly cleared with dapsone therapy. This patient serves to highlight an unusual presentation of childhood DH and the need to consider this diagnosis when evaluating chronic urticarial lesions in children.     

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.     

Dietary management of dermatitis herpetiformis

Dermatitis herpetiformis (DH) is an extremely itchy, papulovesicular skin disease characterized in part by the presence of IgA at the dermal-epidermal junction. Eighty-five percent to 90% of DH patients have granular deposits of IgA at the dermal-epidermal junction, and essentially all of these patients have an associated, for the most part asymptomatic, gluten-sensitive enteropathy (GSE). The association of GSE and DH suggested that the cutaneous manifestations of DH could be controlled by the use of a gluten-free diet. Institution of a gluten-free diet in patients with DH and granular IgA deposits has been shown to be effective in controlling the cutaneous eruption of DH. Seventy percent to 100% of patients who begin a strict gluten-free diet have been shown to be able to decrease the dosage of medication needed to control their DH after a mean of eight to 18 months on the diet. Furthermore, 40% to 70% of patients with DH can control their skin disease completely, without any medication, after longer periods of time on the gluten-free diet (two years and longer). Although the gluten-free diet has been shown to be of great benefit in the control of the skin manifestations of DH, at the present time there is no evidence to suggest that the gluten-free diet is in any way protective against the risk of intestinal lymphoma that has been documented in GSE. Evaluation of the cutaneous IgA deposits in DH skin after long periods of time on a gluten-free diet suggests that there may be a slight decrease in the intensity of the IgA deposits, but the true pathogenetic relationship between the cutaneous IgA deposits, the cutaneous manifestations of DH, and the associated GSE remains unknown.     

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。     

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.     

An HLA class II region restriction fragment length polymorphism (RFLP) in patients with dermatitis herpetiformis: association with HLA-DP phenotype

Dermatitis herpetiformis (DH) is characterized in part by an associated gluten-sensitive enteropathy (GSE), and a strong association with the HLA antigens HLA-A1, -B8, -DR3, and -DQw2, essentially identical to that seen in patients with isolated GSE (celiac disease). A 4.0-kb RsaI RFLP has been identified using a DQ beta-chain cDNA and localized to the HLA-DP beta-chain region. This RFLP has been found more frequently in patients with isolated GSE than in normal HLA matched controls. We have analyzed genomic DNA from 24 patients with DH and 15 HLA-matched controls to determine if this 4.0-kb RsaI RFLP was present in patients with DH. Twenty-one of 24 (87%) of patients with DH were found to have this RFLP as compared to 7 of 10 (70%) HLA-DR3, -DQw2 matched control subjects (p = 0.23). Thus, the 4.0-kb RsaI RFLP detected in patients with isolated GSE is also present in patients with DH; however, its frequency in DH patients does not differ significantly from that of HLA matched controls. Family studies of patients with DH revealed that although the 4.0-kb RsaI RFLP segregated with the HLA-A1, -B8, -DR3, -DQw2 haplotype in one family, it did not segregate with this disease-associated haplotype in two other families. In both patient and control populations, this RFLP was associated with HLA-DPw1 or -DPw3 phenotypes; 25 of 26 (96%) HLA-DPw1 or -DPw3 subjects were found to have this RFLP compared to only 1 of 6 (17%) who did not express HLA-DPw1 or -DPw3 (pc = 0.0009). These population and family data suggest that this 4.0-kb RsaI RFLP is primarily associated with the HLA-DPw1, -DPw3 phenotype, rather than the clinical manifestations of DH. These data further document that the strongest association of DH with HLA antigens remains with HLA-DQw2 and HLA-DR3 antigens.     

Dietary gluten challenge does not influence the levels of circulating immune complexes in patients with dermatitis herpetiformis

To examine the relationship between the gluten-sensitive enteropathy (GSE) and IgA circulating immune complexes (CIC) in dermatitis herpetiformis (DH) a series of dietary gluten-challenge studies were performed in patients with DH and patients with ordinary GSE. Serial serum samples were monitored for IgA-, IgG-, and IgM-containing CIC levels. In the first study, 9 DH patients and 5 controls were fed 20 g of gluten flour as a breakfast meal on 1 of 2 consecutive study days. DH patients did not develop or increase their levels of CIC after gluten-challenge or gluten-free meals. There was no significant difference between the DH patients and the control group in regard to development of CIC. To evaluate the effect of dietary gluten in another form, 8 DH patients were given meals containing 100 g of boiled Canadian cracked wheat. Two patients with ordinary GSE were also challenged with cracked wheat. Again there was no elevation or induction of CIC above baseline determinations by gluten-challenge meals. These studies suggest that dietary gluten does not induce the formation of CIC in patients with DH.     

Palmar petechiae in dermatitis herpetiformis: a case report and clinical review

Palmar petechiae or purpura is an unusual finding in dermatitis herpetiformis (DH) that occurs in children but is only rarely reported in adults. We describe a 46-year-old man with DH who presented with the classic pruritic papulovesicular eruption and associated volar finger and palmar petechiae. We discuss recent advances in the pathogenesis and treatment of DH.     

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)     

Childhood dermatitis herpetiformis: a case report and review of the literature

Dermatitis herpetiformis (DH) is a chronic pruritic cutaneous eruption associated with gluten-sensitive enteropathy (celiac disease [CD]) and immunoglobulin A (IgA) deposition in the skin. While the disease is not uncommon among adolescents, DH is rarely seen in prepubertal patients. Children with DH present similarly to adults; however, uncommon skin findings have been reported. Because of an increased risk for autoimmune diseases and lymphoma, accurate diagnosis and treatment are imperative. We present a case of DH in a 6-year-old Latino boy previously diagnosed with atopic dermatitis and recurrent urticaria. Our aim is to highlight the various cutaneous presentations of DH and encourage clinicians to consider this diagnosis in young patients with recalcitrant atypical skin disease.     

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.     

Leuprolide acetate-induced dermatitis herpetiformis

Dermatitis herpetiformis (DH) is a chronic, pruritic, papulovesicular dermatosis on extensor surfaces that is characterized by a neutrophilic infiltrate and granular immunoglobulin A deposition at the dermal papillae. Although the presence of immunoglobulin A in the skin and the severity of DH are known to be associated with gluten intake, few drugs have been implicated in the induction of DH. We report a case of DH triggered by intramuscular injections of leuprolide acetate, a gonadotropin-releasing hormone analog, in a patient with a history of prostate cancer.     

Failure of intradermal skin testing with gluten to produce delayed hypersensitivity reactions in patients with dermatitis herpetiformis

Dermatitis herpetiformis (DH) is characterized by a rash and a gluten-sensitive enteropathy (GSE) indistinguishable from that of coeliac disease. T-cell-mediated mechanisms have been implicated in the pathogenesis of GSE. It seems feasible that intradermal injection of gluten, in patients known to have GSE, could lead to an influx of T cells sensitized to gluten, with subsequent development of a delayed hypersensitivity-type reaction. Six patients with DH and three normal subjects had intradermal injections of‘Frazer's fraction III’ (FFIII; the partial peptic tryptic digest of gluten which is known to be antigenic) and phosphate-buffered saline (PBS) as a control. Skin biopsies were taken at PBS and FFIII injection sites at 48 h. In addition, two of the patients with DH had biopsies taken of FFIII injection sites at 6 h. Monoclonal antibodies and the avidin-biotin-peroxidase technique were used to stain for T cells in the skin biopsies. A monoclonal antibody to a neoepitope exposed in the terminal complement complex and an immunofluorescent method were used to detect the presence of terminal complement component in biopsies taken from two of the control subjects and two of the patients. Both patients and control subjects developed a weal and flare within a few minutes of injecting the FFIII, and this persisted for up to 6 h. No skin reaction was present in either the patients or the control subjects at 48 h. No skin reaction was visible at any time following injection of PBS. There was no increase in T cells in biopsies taken at 6 or 48 h from the FFIII injection sites compared with the PBS injection sites. Terminal complement component was present in the biopsies taken from DH patients at both the PBS and FFIII injection sites (6 and 48 h), but was absent from the biopsies taken from the control subjects. Normal delayed hypersensitivity responses to a battery of common recall antigens showed that the lack of response to FFIII was antigen specific. Thus, this study suggests that the T cells sensitized to gluten in patients with GSE are unable to migrate to the skin.     

Pruritic rash on the buttocks after a beach vacation: a case report

A 56-year-old man sought treatment after a vacation for an intensely pruritic skin eruption involving the buttocks. On physical examination, annular plaques were noted. Workup revealed dermatitis herpetiformis (DH) and subclinical celiac disease.     

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.     

IgA multiple myeloma presenting as an acquired bullous disorder

A 63-year-old man presented with an intensely pruritic vesiculo-bullous eruption on the limbs and was subsequently found to have an IgA kappa multiple myeloma. The eruption clinically and histologically was suggestive of linear IgA disease (LAD), dermatitis herpetiformis (DH), epidermolysis bullosa acquisita (EBA), or bullous lupus erythematosus (LE), with the skin biopsy revealing subepidermal bullae and dermal papillary micro-abscesses. However, direct immunofluorescence showed a unique pattern of diffuse dermal IgA staining. Although chemotherapy produced a dramatic resolution of the lesions, which paralleled the fall in serum IgA paraprotein level, the myeloma later became progressive and the resulting paraprotein increase was accompanied by recurrence of the eruption. We propose that this patient's rash was the presenting manifestation of his multiple myeloma, and was a consequence of transudation of IgA paraprotein into the dermis.     

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.     

Dermatitis herpetiformis in monozygous twins—concordance for dermatitis herpetiformis and gluten-sensitive enteropathy

A pair of monozygous male twins concordant for dermatitis herpetiformis (DH) and gluten-sensitive enteropathy (GSE) are reported. Presentation of DH in the twins was asynchronous, with one affected at the age of 20, the other at the age of 27. Neither twin had symptoms of malabsorption but duodenojejunal villous atrophy was confirmed histologically.     

A comparison of histocompatibility antigens in dermatitis herpetiformis and adult coeliac disease

The incidence of histocompatibility antigens HL-A, 4a and 4b was studied in thirty-eight patients with dermatitis herpetiformis (DH) and thirty-six patients with adult coeliac disease (ACD). The 4b antigen was found in all the DH and ACD patients. HL-A 8 was found in 89% of patients with ACD--similar to the incidence reported in previous studies--and in 79% of patients with DH, a higher incidence than in previous studies which may be due to stricter criteria being used here to diagnose DH. There was no significant difference in the incidence of HL-A 8 between those patients with DH whose small intestinal biopsies appeared macroscopically abnormal and those with a normal macroscopic appearance. These findings suggest that patients with DH form a single disease group and do not support the concept previously postulated that there are two groups of patients with DH, one with an increased incidence of HL-A 8 antigen similar to that in ACD who have a gluten sensitive enteropathy (GSE), and another with a normal incidence of HL-A 8 antigen and without enteropathy.     

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.