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.     

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.     

Dermatitis herpetiformis: problems,progress and prospects

Dermatitis herpetiformis (DH) is an IgA mediated blistering skin disease characterized by the presence of granular deposits of IgA in papillary dermis. The major significant advances in our understanding of DH have been the demonstration that DH patients also have coeliac diseases (CD) and that the rash is also gluten dependent. As a result, it is now possible to cure patients by gluten withdrawal from the diet. The other major significant finding has been the presence of IgA in the uninvolved, now used as the diagnostic criterion for the disease. Despite the fact that it has been known for over fifty years that gluten causes the enteropathy of CD, and for over thirty years the rash of DH, it is still not known how gluten produces these effects. Future immunological studies may look at ways of inducing tolerance to gluten peptides once the toxic ones have been identified. Vaccination against gluten peptides may also be possible in those affected with gluten sensitive disorders.     

Immunoglobulin, complement and epidermal transglutaminase deposition in the cutaneous vessels in dermatitis herpetiformis

BACKGROUND: Recently, epidermal transglutaminase (TG) has been identified within the papillary IgA granules in dermatitis herpetiformis (DH). Although IgA type autoantibodies to tissue and epidermal TGs are characteristic serological markers for DH, these antibodies do not bind to normal papillary skin structures. AIMS: To test the possibility of IgA immune complex precipitation within the vessel walls as a first step in the pathogenesis of skin symptoms, we analysed immunoglobulin, complement, and epidermal TG deposition along the vascular system of DH skin. METHODS: Punch biopsy specimen were taken from 116 DH patients' skin, and evaluated for the presence of vascular immune precipitates by direct immunofluorescence. Skin samples from 16 DH patients were also studied for tissue and epidermal TGs. RESULTS: In 74 (64%) of the 116 DH skin studied, significant vascular staining accompanied the DH-specific granular IgA fluorescence (IgA and C3 in 39 patients; IgA alone in 18; IgA, C3 and IgM together in five; IgM alone in 12). In most cases (92%), the precipitates were detected in the small vessels of the papillary dermis; however, a subpapillary vascular fluorescence was also observed in a few patients (8%). Skin IgA colocalized with epidermal TG in the vessel walls and within the scattered papillary peri- and intervascular DH bodies. Tissue TG did not colocalize either with the immunoglobulins or with the complement precipitates of the dermis. Furthermore, we could not detect keratinocyte TG in the DH bodies nor in the vessel walls. CONCLUSIONS: These findings support possible immune complex precipitation in the vessel walls of DH skin and further confirm the significance of epidermal but not tissue TG in the pathomechanism of skin symptoms.     

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.     

Transglutaminase autoantibodies in dermatitis herpetiformis and celiac sprue

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disorder that is associated with intestinal gluten sensitivity. Epidermal transglutaminase (TGe) and closely related tissue transglutaminase (tTG) are considered to be autoantigens in DH, because a majority of DH patients have IgA specific for TGe and for tTG. It is unknown where and how these autoantigen-specific IgAs are generated in DH. Results reported in this paper on nine DH patients on a gluten containing diet demonstrate that the levels of circulating anti-tTG IgA and anti-TGe IgA in DH are correlated with each other and that both appear to be correlated with the degree (extent) of enteropathy. An analysis of 15 untreated celiac sprue (CS) patients demonstrated that approximately 33% of CS patients had elevated levels of anti-TGe IgA. These results would indicate that intestinal damage is associated with the production of anti-tTG IgA and anti-TGe IgA in DH patients.     

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.     

疱疹样皮炎的研究进展

【摘要】 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要治疗手段。本文从流行病学、发病机制、临床表现、实验室检查、诊断及治疗等方面对疱疹样皮炎进行总结。     

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.     

Dermatitis herpetiformis

Dermatitis herpetiformis (DH) is a cutaneous manifestation of coeliac disease (CD), which causes an itching and blistering rash, typically on the elbows, knees and buttocks. DH and CD share a similar genetic background, small bowel mucosal alterations, and an autoimmune response against tissue transglutaminase in the serum and small bowel. DH is typically diagnosed during adulthood, and it is slightly more common among males than females. The incidence of DH seems to be decreasing, in contrast to the detected four‐fold increase in the incidence of CD. In addition to typical clinical picture, diagnosis of DH relies on the demonstration by direct immunofluorescence of pathognomonic granular IgA deposits in the papillary dermis. Circulating tissue transglutaminase antibodies support the diagnosis, but their absence does not exclude DH. Obtainment of small bowel mucosal biopsies is not necessary when DH is diagnosed, but if performed, the majority of patients are found to have villous atrophy, and even those with normal villous architecture evince CD‐type inflammation. The treatment of choice in DH is a strict, life‐long adherence to a gluten‐free diet (GFD). In addition to alleviating the symptoms of DH and healing the small bowel mucosal damage, a GFD increases the quality of life for patients, and decreases the risk for lymphoma in DH. Further, the mortality rate of patients with DH treated with a GFD seems to be lower than that of the general population. However, as changing to a GFD has a rather slow effect on the DH rash, patients with severe skin symptoms should additionally be treated with dapsone medication. This review article is based on a presentation given at the British Society for Medical Dermatology blistering skin diseases meeting 2019.     

Gluten intolerance and skin diseases

Gluten sensitivity with or without coeliac disease (CD) symptoms and intestinal pathology has been suggested as a potentially treatable cause of various diseases. CD is a chronic disease which improves on withdrawal of wheat gliadins and barley, rye and oat prolamins from the diet. There have been numerous reports linking CD with several skin conditions. A body of evidence shows that dermatitis herpetiformis is actually a cutaneous manifestation of CD. Autoimmune diseases, allergic diseases, psoriasis and miscellaneous diseases have also been described with gluten intolerance. Dermatologists should be familiar with the appraisal of gluten sensitive enteropathy and should be able to search for an underlying gluten intolerance (GI). Serological screening by means of antigliadin, antiendomysial and transglutaminase antibodies should be performed. HLA typing is often useful in association with serologic tests. Intestinal biopsy is usually needed to establish the diagnosis of CD or GI. Thus, gluten intolerance gives rise to a variety of dermatological manifestations which may benefit from a gluten-free diet.     

Two Japanese cases of dermatitis herpetiformis associated each with lung cancer and autoimmune pancreatitis but showing no intestinal symptom or circulating immunoglobulin A antibodies to any known antigens

Dermatitis herpetiformis (DH) is common in some Caucasian populations but extremely rare in Japanese, probably because of different immunogenetic backgrounds. We report two Japanese DH cases with typical clinical, histological and direct immunofluorescence features. However, no symptom of gluten‐sensitive enteropathy was shown. The diagnosis was confirmed by eliminating other autoimmune blistering diseases by indirect immunofluorescence, enzyme‐linked immunosorbent assays and immunoblotting. However, circulating immunoglobulin (Ig)A anti‐endomysium, reticulin and gliadin antibodies were not detected. IgA antibodies to tissue and epidermal transglutaminases were also negative. One case was associated with lung cancer and the other one with autoimmune pancreatitis. On review of 17 cases of DH reported in Japan over the previous 10 years, including our cases, one case was associated with gluten‐sensitive enteropathy, four with malignant neoplasms, two with autoimmune systemic disorders and one with psoriasis. Although our cases were typical of DH in clinical, histopathological and IgA deposit features, they showed different human leukocyte antigen haplotypes, no gluten‐sensitive enteropathy and no DH‐specific IgA antibodies, including those to epidermal and tissue transglutaminases. These results suggest that studies of unique characteristics in Japanese DH patients should facilitate further understanding of pathogenesis in DH.     

Circulating antibodies to gliadin subfractions in dermatitis herpetiformis and linear IgA dermatoses

Dermatitis herpetiformis (DH) and coeliac disease are associated and the rash of DH is gluten-dependent. The gliadin fraction responsible for the rash is unknown. In linear IgA dermatoses the role of gluten in the skin eruption remains controversial.
Anti-gliadin antibodies (AGA) were measured by an enzyme-linked immunosorbent assay in 10 normal controls; 35 patients with dermatitis herpetiformis (DH); 14 adults with linear IgA disease; and 13 patients with chronic bullous dermatosis of childhood. The presence of enteropathy was assessed by jejunal biopsy and intra-epithelial lymphocyte (IEL) counts.
DH with normal IEL counts on normal diet: IgG and IgA-AGA identical to controls. DH with raised IEL counts on gluten-free diet: slightly elevated IgG and IgA-AGA. DH with raised IEL counts on a normal diet: IgG and IgA were higher, with median IgG 1:2048 (control 1:512) median IgA 1:512 (control 1:128). DH patients with high IgG AGA had elevated titres to α, β, γ, and ω subfractions. The highest levels were for α and the lowest for ω.
For linear IgA disease IgG is normal but adults had raised IgA-AGA compared to controls ( P = 0.005).
In dermatitis herpetiformis the presence of anti-gliadin antibody was dependent on the degree of enteropathy, and, if present, was directed against all gliadin subfractions. The significance of the elevated IgA—AGA in the linear IgA disease is unknown.     

Antibodies to tissue transglutaminase as serologic markers in patients with dermatitis herpetiformis.

Dermatitis herpetiformis is a gluten-sensitive disease with a symmetrically distributed blistering over extensor surfaces. The association with celiac disease is further supported by the high rate of immunoglobulin A autoantibodies to endomysium in patients with dermatitis herpetiformis, which are highly specific and sensitive indicators of celiac disease. Therefore, we determined immunoglobulin A antibodies to tissue transglutaminase, the recently discovered endomysial autoantigen in celiac disease, in patients with dermatitis herpetiformis and controls. Sera of 61 patients with dermatitis herpetiformis, as characterized by granular immunoglobulin A deposits in the subepidermal basement membrane and known endomysial antibody titers (determined by indirect immunofluorescence) as well as 84 control sera of patients with dermal or intestinal diseases unrelated to dermatitis herpetiformis, were analyzed for circulating immunoglobulin A antibodies to tissue transglutaminase by enzyme-linked immunosorbent assay. Immunoglobulin A anti-tissue transglutaminase titers in patients with dermatitis herpetiformis were significantly elevated above the controls. Furthermore, the immunoglobulin A anti-tTG titers showed a positive correlation with semiquantitative endomysial antibody data. Compared with endomysial antibodies, determination of immunoglobulin A anti-tissue transglutaminase reached a specificity and sensitivity of 97.6% and 89.1%. Patients with dermatitis herpetiformis have elevated immunoglobulin A autoantibodies to tissue transglutaminase, confirming its pathogenic relation with celiac disease and further supporting the usefulness of this novel assay for screening and therapy control.     

Experience with a gluten free diet in the treatment of linear IgA disease

A study was undertaken to determine whether the skin eruption of linear IgA disease (LAD) was gluten dependent. Six patients with LAD were treated with a gluten free diet (GFD) for an average period of 33 months (range 19-48). Although one patient with LAD had an enteropathy which was clearly gluten sensitive, there was no convincing evidence that the rash of any of the patients responded to a GFD. Four of the six patients showed no significant alteration in their drug requirements. The remaining 2 patients showed a fall in minimum drug requirement but there was no increase after gluten challenge indicating that they were entering spontaneous remission. This contrasts to the situation in dermatitis herpetiformis, where both the rash and the enteropathy are gluten dependent. These data add further to the evidence that LAD and dermatitis herpetiformis are separate entities.     

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: preparation of papillary dermis and the effect of proteolytic enzymes on the IgA deposits

A technique has been devised to isolate the thin papillary part of the dermis from punch biopsies. Papillary dermis has been treated with various proteolytic enzymes in order to release or solubilize the granular IgA deposits from the papillary dermis of patients with dermatitis herpetiformis. Incubation of the thin skin preparations with pepsin caused a disappearance of the specific fluorescence with antibodies to human IgA. After peptic digestion small amounts of IgA could be detected in the supernatants. There was some evidence that this amount was larger for preparations from patients with dermatitis herpetiformis than from controls. Corresponding procedures with trypsin, collagenase, or elastase had no detectable effect on the IgA deposits. The experiments with elastase seemed to give support for previous reports on association between the granular IgA deposits and the microfibrils of elastic fibers.     

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.     

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.     

Erythema elevatum diutinum arising in the setting of dermatitis herpetiformis

Dermatitis herpetiformis is an autoimmune blistering disease characterized by granular deposits of immunoglobulin A (IgA) in dermal papillae. Erythema elevatum diutinum is a chronic form of vasculitis associated with IgA paraproteinemia. We report a patient with dermatitis herpetiformis who developed characteristic erythema elevatum diutinum lesions on the elbows and knees despite sulfone therapy. We speculate that the different patterns of IgA deposition in the skin account for the clinical manifestation of these 2 uncommon disorders.