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Dermatitis herpetiformis in Japan: an update.

BACKGROUND: Although dermatitis herpetiformis (DH) is a relatively common disease in Caucasian populations, it is rare in Asian populations including the Japanese. We encountered a Japanese case of DH which showed granular IgA and C3 deposits in the papillary dermis and which was associated with gluten-sensitive enteropathy but no HLA-B8/DR3/DQ2. OBJECTIVE: The purpose of this study is to describe the characteristics of Japanese DH cases, since most of them have been reported in Japanese language and dermatologists outside Japan are not familiar with the characteristics of Japanese DH. METHODS: We have reviewed all 34 Japanese DH cases reported previously. RESULTS: We found several features of Japanese DH compared with Caucasian DH, such as a high frequency of the fibrillar pattern, rarity of gluten-sensitive enteropathy and an absence of the HLA-B8/DR3/DQ2 haplotype. CONCLUSION: There might be significant differences in pathophysiology between Caucasian and Japanese DH cases.

Biopsy, Needle↗

Nutritional status in patients with dermatitis herpetiformis.

Nutritional status of 86 patients with dermatitis herpetiformis (DH) was defined by anthropometric measurements and hematological and biochemical laboratory tests to establish prevalence of malabsorption and malnutrition. Anthropometric measurements in DH patients were comparable to normal control patients. Four individuals were of short stature; two had had diarrhea and failed to thrive in childhood. Abnormalities attributable to nutritional deficiency were detected in only 6 of the 86, whereas drug-associated hematological or biochemical changes were present in 36 of 55 subjects treated with dapsone or sulfapyridine. Twenty patients had hemolytic anemia or macrocytosis related to drug therapy. Only two had anemias attributable to malabsorption; one was iron deficient, the other folate deficient. Two other patients were mildly Fe deficient and two had slight folate deficiency; they lacked other stigmata of malabsorption. Drug-induced hematological and biochemical abnormalities were more common than changes that suggest nutritional disease, even though most DH patients had an enteropathy at presentation.

Adolescent↗

[Agranulocytosis induced by dapsone prescribed for dermatitis herpetiformis].

INTRODUCTION: Dapsone is a drug widely prescribed in dermatology. It can lead to undesirable side effects including hematologic disorders. CASE REPORT: A patient with dermatitis herpetiformis was treated with dapsone. Agranulocytosis developed 6 weeks later and was revealed by fever and pneumonia which resolved under antibiotics. The agranulocytosis regressed without specific treatment after drug withdrawal. Blood counts returned to normal 2 weeks later. DISCUSSION: Dapsone-induced agranulocytosis is in common (1/10,000 to 1/20,000). The drug is widely prescribed, particularly for leprosy. Nevertheless, when dapsone is prescribed for dermatitis herpetiformis, the risk of agranulocytosis increases 25-fold reaching 1/400. The indication for dapsone must always made carefully, with surveillance of the blood counts every 15 days during the first 3 months of treatment for dermatitis herpetiformis.

Agranulocytosis↗

Male sex hormone status in dermatitis herpetiformis.

In twenty-eight men with dermatitis herpetiformis (DH) the mean serum testosterone levels were within normal limits, but high levels were found in three patients with partial villous atrophy and two who had normal jejunal biopsies. The introduction of a gluten-free diet in patients with villous atrophy produced a statistically significant fall in the testosterone level in those able to discontinue their drug treatment but not in those noticing no change or only a reduction in drug requirements. The serum levels of luteinizing hormone or follicle-stimulating hormone were increased in nine patients; only one of these had a raised testosterone level and six were over 60 years of age. Four out of twenty married males with DH had no children, a figure higher than expected. Three of these men had elevated gonadotrophin levels although none had an increased serum testosterone. Thus, raised levels of testosterone and gonadotrophin were found in only a minority of men with DH, in contrast to the more marked changes previously reported in males with coeliac disease.

Adult↗

Factors influencing small bowel changes in dermatitis herpetiformis.

Factors influencing small bowel morphology in dermatitis herpetiformis (DH) were investigated by comparing patients with DH and normal small bowel biopsies to patients with DH and abnormal small bowel biopsies. The mean age of 18 patients with morphological changes in small bowel (38 years) was significantly lower (P less than 0-001) than the mean age of nine patients with normal bowel mucosa (60 years). HLA typing confirmed the high frequency of HLA-B8 in DH (64%) but HLA-B8 was unrelated to the presence or severity of small bowel lesions. Four patients had diarrhoea with progressive weight loss or abdominal cramps subsequently responsive to gluten withdrawal. In this subgroup serum levels of IgG and IgM were significantly lower than in patients with normal small bowel mucosa. Small bowel involvement appeared to be independent of the duration and severity of skin disease, and the deposition of immunoglobulin and complement (C3) in the dermal papillae of skin adjacent to skin lesions.

Adult↗

[Immunopathology of dermatitis herpetiformis and bullous pemphigoid (author's transl)].

Dermatitis herpetiformis and bullous pemphigoid are similar enough clinically to have been considered for some time as two forms of the same disease. Their histologic and ultrastructural characteristics are a more accurate mean of differenciation: employed essentially with respect to early lesions and the mode of bullous formation. But immunologic analysis is especially helpful in distinguishing the two. This study involves the analysis of acquired data concerning these two entities: 1) The nature, form, and topography of immunoglobulin and complement deposits examined under the light microscope and by immuno-electron microscopy methods. 2) Other modifications of he immunologic status of affected subjects. 3) The supposed nature of causative antigens. 4) The suggested pathogenic mechanisms. There exist discrepancies in the information at hand concerning these domains: the most important number of latest data relate to DH and notably: - The relationship between DH and gluten sensitive enteropathy for which are considered the clinical, histologic, immunologic characteristics and the relationship of this enteropathy with celiac sprue disease, the role of a gluten free diet on skin lesions and immune deposits. - The relationship between DH and specific histocompatible antigens. The data has revealed some important perspectives on the pathogenesis of these bullous skin lesions.

Antibodies↗

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.

Cell Line↗

Ultrastructural localization of immunoglobulins in skin of patients with dermatitis herpetiformis.

A multistep immunocytochemical method utilizing horseradish peroxidase as an immunologically bound marker was used to detect and localize IgA deposits in skin of patients with dermatitis herpetiformis at the ultrastructural level. IgA was found in the upper papillary dermis forming irregular aggregates in seemingly haphazard distribution. These aggregates were associated with microfibrillar bundles and with the microfibrillar component of the elastic tissue. IgA was also detected on anchoring fibrils, but showed no topical relationship to the basal lamina which was always spared. This finding indicates that basal lamina components do not serve as target sites for the immunologic reaction occurring in dermatitis herpetiformis. The selective affinity of IgA deposits to microbfibrillar bundles may be relevant to the hypothesis that the skin pathology in dermatitis herpetiformis is caused by circulating gluten-antigluten complexes, trapped in the skin by reticulin-bound antireticulin antibodies which cross-react with gluten.

Dermatitis Herpetiformis↗

The ultrastructural changes in the skin in dermatitis herpetiformis after withdrawal of dapsone.

The development of skin lesions in patients with dermatitis herpetiformis after the withdrawal of their dapsone therapy was studied with the electron microscope. In control biopsies from patients prior to cessation of treatment, membrane-bound vacuoles were found beneath the basal lamina of the epidermis as previously described. After dapsone withdrawal, there was an apparent increase in the number of vacuoles and occasionally several vacuoles appeared to have coalesced forming an early blister. At this stage, the basal lamina and associated hemidesmosomes were normal although in places there were small discontinuities in the basal lamina. Where the reaction was more intense, vacuoles and cells, mainly eosinophils, were embedded in fibrin de posits. Above this, the basal lamina was usually disrupted with involvement of the basal epidermal cells. These results suggest that the vacuoles do play a part in the formation of the pathological lesion in dermatitis herpetiformis. In addition, the basal lamina is shown to be only secondarily involved. The nature of the vacuoles has still to be elucidated.

Biopsy↗

Dermatitis herpetiformis and vitiligo.

A 36-year-old woman developed vitiligo in areas with active dermatitis herpetiformis. Both diseases have been associated with autoimmune disorders. However, in the present case the vitiligo is believed to be an isomorphic reaction to the dermatitis herpetiformis lesions.

Adult↗

Detection of gluten in human sera by an enzyme immunoassay: comparison of dermatitis herpetiformis and celiac disease patients with normal controls.

We have developed a triple sandwich enzyme immunoassay to detect circulating gluten in human sera. With human sera containing known amounts of added gluten as controls, the assay was sensitive in the range of 0.75 to 75 micrograms of gluten per ml of serum. Forty-one control subjects were compared to 21 patients with dermatitis herpetiformis and 11 patients with celiac disease. The dermatitis herpetiformis and celiac disease patients had significant elevation of serum gluten values over the control subjects. Circulating gluten antigenemia is a previously unrecognized feature which may be important in understanding the pathogenesis of dermatitis herpetiformis and celiac disease.

Adult↗

Dermatitis herpetiformis and celiac disease associated with Addison's disease.

We treated two patients with dermatitis herpetiformis and Addison's disease, and one patient with celiac disease without the rash, but with Addison's disease and juvenile diabetes. In two of the patients, the concomitant diseases also included a thyroid disease. The predisposing factors to the multiple endocrine disorders in these patients with gluten-sensitive skin and/or small intestinal disease remained unknown. Two of the three patients had HLA-B8, none was known to have affected relatives, and the Addison's disease appeared before, at the same time, or after the patients contracted dermatitis herpetiformis or celiac disease.

Addison Disease↗

Cutaneous IgA subclasses in dermatitis herpetiformis and linear IgA disease.

The subclasses of the cutaneous IgA were studied in 8 patients with dermatitis herpetiformis and 4 with linear IgA disease. The cutaneous IgA in dermatitis herpetiformis consisted of both IgA1 and IgA2, although IgA1 predominated. This demonstrated that the IgA is polyclonal and may be both mucosal and blood derived. The IgA in linear IgA disease was exclusively IgA1, confirming previous work, and suggesting that mucosal IgA may not make a major contribution to the skin deposits.

Antibodies, Monoclonal↗

Intestinal permeability in dermatitis herpetiformis.

Differential absorption of D-xylose and 3-0-methyl-D-glucose, and unmediated intestinal permeation (simple diffusion) of lactulose and L-rhamnose, have been investigated in 20 patients with dermatitis herpetiformis. Both iso-osmolar and hyperosmolar test solutions were employed and the results were compared with those obtained from a group of healthy adult volunteers. The findings in each patient have been correlated with small intestinal histology. The majority of patients with villous atrophy had abnormally raised intestinal lactulose permeation and lactulose/rhamnose permeability ratios, whereas patients with normal small intestinal morphological grading did not differ significantly from the healthy control group in this respect. There was a high incidence of delayed plasma D-xylose absorption peaks in dermatitis herpetiformis irrespective of small intestinal histological findings. These results imply that abnormal intestinal permeability in dermatitis herpetiformis is the result of gluten-induced damage to the mucosa rather than an inherent primary defect. It is therefore improbable that the rash in this condition is purely a manifestation of increased intestinal permeation of antigen.

3-O-Methylglucose↗

Dermatitis herpetiformis and bullous pemphigoid: a developing association confirmed by immunoelectronmicroscopy.

We report a case of dermatitis herpetiformis associated with bullous pemphigoid in which the clinical, histopathological and immunopathological findings were corroborated by direct immunoelectronmicroscopy performed on normal and peri-lesional skin biopsies. Western immunoblotting detected the 180 kDa BPAG2 consistent with bullous pemphigoid. HLA-typing confirmed the DR3 DQ2 haplotype associated with dermatitis herpetiformis.

Aged↗

Characterization of T lymphocyte and monocyte populations in HLA B8/DRw3 normal individuals and in patients with dermatitis herpetiformis.

Normal individuals who possess the HLA B8/DRw3 haplotype as well as patients with dermatitis herpetiformis have been found to have a number of immunologic abnormalities including decreased numbers of E rosette-positive, Fc IgG receptor-bearing lymphocytes (referred to as TG cells), and increased numbers of cells which spontaneously secrete immunoglobulin. HLA B8/DRw3-positive normal individuals also have an increased risk for the development of a number of immunologically mediated diseases. Since many of these findings are suggestive of B-cell hyperreactivity and since TG cells were initially thought to represent a portion of the T suppressor cell network, we have examined the peripheral blood mononuclear (PBM) cell populations of 14 normal HLA B8/DRw3-positive individuals, 14 patients with dermatitis herpetiformis (all of whom were HLA B8/DRw3-positive), and 9 non-HLA B8/DRw3 individuals using flow cytometry and monoclonal antibodies of the OK and Leu series directed against cell surface antigens. Normal HLA B8/DRw3 individuals were found to have a significantly lower percentage of PBM cells that expressed both OKT8 and Leu-2a when compared to normal non-HLA B8/DRw3 individuals (p less than .05 Student's t-test). When the ratio of T helper cells (OKT4 and Leu-3a) to T suppressor cells (OKT8 and Leu-2a) was calculated for each individual studied, normal HLA B8/DRw3 individuals were found to have a significantly elevated ratio (Leu-3a/Leu-2a = 2.41 +/- .16, mean +/- SEM) when compared to non-HLA selected individuals (Leu-3a/Leu-2a = 1.73 +/- .05) (p less than 0.025). In addition, normal HLA B8/DRw3 individuals had decreased numbers of TG cells when compared to normal non-HLA B8/DRw3 individuals (B8/DRw3 = 6.4 +/- .74%, non-B8/DRw3 = 13.2 +/- 1.0%, mean +/- SEM, p less than .01). In order to determine the cell surface marker characteristics of TG cells, purified TG cells from both normal HLA B8/DRw3 individuals and non-HLA B8/DRw3 individuals were studied using the Leu series monoclonal antibodies and OKM1. Good agreement was found in the percentages of cells expressing each cell surface marker between the two groups. In addition, the TG cells were found to be predominately T cells (78% Leu-1-positive), with both T helper cells (40% Leu-3a-positive) and T suppressor cells (30% Leu-2a-positive) present. These results suggest that the suppressor cell activity associated with the TG subset is not due to a depletion of the T helper cell subset, and that the decreased numbers of TG cells in HLA B8/DRw3 individuals is not due to a preferential loss of cells bearing Leu-1, Leu-2a, Leu-3a, or OKM1.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Binding of wheat gliadin in vitro to reticulum in normal and dermatitis herpetiformis skin.

We have demonstrated by indirect immunofluorescence that wheat gliadin binds in vitro to reticulin-like fibrils present in cryostat sections of human skin, and rat liver, kidney and stomach. Gliadin was seen to bind to fibrils throughout the dermis of both normal and dermatitis herpetiformis skin, and this was particularly striking in the dermal papillae. Serum from 2 dermatitis herpetiformis patients who did not have antireticulin antibody gave reticulin staining when retested by immunofluorescence on cryostat sections of rat tissue pretreated with gliadin. Gliadin treated sections may prove useful in screening patients with gluten sensitive enteropathy for anti-gliadin antibody. Binding of gliadin to skin sites in dermatitis herpetiformis patients and subsequent deposition of antigliadin antibody at these sites may be involved in the development of skin lesions.

Animals↗