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.     

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.     

Vesiculobullous systemic lupus erythematosus: Report of two cases and a review of the literature

Vesicles and bullae complicating systemic lupus erythematosus (SLE) are relatively uncommon. Two young women with SLE presented with vesiculobullous eruptions on sun-exposed areas that resembled dermatitis herpetiformis (DH) histologically. There were active visceral manifestations of SLE in both patients, including mesangioproliferative glomerulonephritis. Granular deposits of IgG and/or IgM, along with IgA, were demonstrated along the basement membrane of skin by direct immunofluorescence microscopy. Review of fifteen additional cases of vesiculobullous SLE reported in the literature suggests that this cutaneous manifestation of SLE is associated with a high incidence of IgA deposits in skin and glomerulonephritis. The following criteria for the diagnosis of a distinct subset of vesiculobullous skin lesions occurring in patients with SLE are proposed: (1) a diagnosis of SLE based upon American Rheumatism Association (ARA) criteria; (2) vesicles and bullae arising upon but not limited to sun-exposed skin; (3) histopathology compatible with DH; (4) negative indirect immunofluorescence for circulating basement membrane zone (BMZ) antibodies; (5) direct immunofluorescence reveals IgG and/or IgM and often IgA at the BMZ.     

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.     

Pathophysiology of dermatitis herpetiformis: a model for cutaneous manifestations of gastrointestinal inflammation

Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease in which antigen presentation in the gastrointestinal mucosa results in cutaneous IgA deposition and distinct, neutrophil-driven cutaneous lesions. Our findings suggest that the qualitatively different immune response to gluten in the intestinal mucosa of patients with DH results in minimal clinical symptoms, allowing the continued ingestion of gluten and the eventual development of DH. Our model may provide a new way to understand the pathogenesis of other skin diseases associated with gastrointestinal inflammation such as pyoderma gangrenosum or erythema nodosum, or explain association of seronegative inflammatory arthritis with inflammatory bowel disease.     

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)     

Neutrophil CD11b,L-selectin and Fc IgA receptors in patients with dermatitis herpetiformis

BACKGROUND: The skin lesions found in patients with dermatitis herpetiformis (DH) are characterized by the presence of neutrophils at the dermal papillary tips in areas where the diagnostic cutaneous IgA deposits are found. Although the presence of the skin lesions of DH is known to be associated with gluten-sensitive enteropathy, the mechanisms that control the development of skin lesions are not known. OBJECTIVES: To determine if circulating neutrophils from patients with DH have evidence of priming as shown by increased expression of CD11b, decreased expression of L-selectin and increased function of neutrophil Fc IgA receptor. METHODS: Neutrophils from 12 normal subjects and 10 DH patients with active, ongoing disease and 14 DH patients with quiescent disease activity were examined by fluorescence-activated cell sorter for expression of cell surface CD11b, L-selectin expression, Fc IgA expression (CD89) and for the function of the Fc IgA receptor by determining the binding capacity of neutrophils for monoclonal human IgA. RESULTS: Neutrophils from patients with active, ongoing DH had increased expression of CD11b when compared with patients with inactive DH or normal subjects [mean net geometric mean channel fluorescence (GMCF): active DH, 403.3; inactive DH, 237.8; normal subjects, 290.5; P < 0.05]. L-selectin expression in both groups of DH patients was significantly lower than that seen in normal subjects (mean net GMCF: active DH, 363.2; inactive DH, 375.2; normal subjects, 432.7; P < 0.05). No difference in CD89 expression was seen in any of the groups; however, the function of Fc IgA receptor was increased in patients with active DH when compared with patients with inactive DH and normal subjects. CONCLUSIONS: Neutrophils from patients with active, ongoing DH show an increased expression of CD11b, decreased expression of L-selectin and increased ability to bind IgA, consistent with a pattern of priming of the neutrophils. This priming may occur in the gut as a result of the ongoing mucosal immune response that is present in patients with DH on a gluten-containing diet and may predispose neutrophils to localize in the skin of patients with 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.     

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.     

Cutaneous features of intravascular lymphoma

Intravascular lymphoma (IVL) is a subset of extranodal non-Hodgkin lymphoma, with an estimated incidence of <1 case per million people. It is characterised by extensive proliferation of lymphoma cells within small to medium-sized blood vessels. Most IVLs are B-cell tumours. IVL can present primarily in any organ system, including the skin. The disease is often disseminated at diagnosis. The overall mortality rate is thought to be >80%, and >50% of patients are diagnosed at postmortem examination. There is wide variability in the clinical appearance of cutaneous lesions, which may simulate inflammatory skin disease. Therefore, awareness by dermatologists is important to enable early diagnosis when cutaneous signs are present. We report two patients with unexplained systemic disease and a skin eruption, leading to the diagnosis of IVL, and outline the range of cutaneous features reported.     

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.     

Cutaneous plasmacytosis limited to the extremities in a white patient: an unusual clinical picture

Cutaneous plasmacytosis is an uncommon disease characterized by a cutaneous polyclonal plasma cell infiltrate usually associated with polyclonal hypergammaglobulinemia. It has predominantly been found in Japanese patients and it is rare in white patients. Clinically, this condition manifests as multiple red to dark brown skin lesions that mainly are located on the trunk. We report the case of a 66-year-old white woman who presented with reddish brown to violaceous macules and plaques restricted to the extremities. The histopathologic findings, laboratory data, and systemic studies led us to the diagnosis of cutaneous plasmacytosis.     

Cutaneous Metastases from Prostatic Cancer

The skin is involved in metastases from 2–9% of malignant tumors. These usually tend to spread to the skin relatively late in the course of the disease. Skin metastases of prostatic origin are quite uncommon and preferentially localized to the lower abdomen and genital area. We present a case of cutaneous metastasis from prostatic adenocarcinoma that preceded diagnosis of the primary tumor and was located on the neck.     

Cutaneous lymphocytomas: clinical and histological aspects

25 cases of cutaneous lymphocytoma were reviewed, of which 13 were benign lymphocytoma of the skin and 15 lymphocytic infiltration of the skin (Jessner). The clinical diagnosis benign lymphocytoma of the skin was in agreement with the histology, except in 2 patients where lymphocytic infiltration of the skin (Jessner) was the most likely clinical diagnosis. Of the 15 patients treated, 8 went into complete remission and 5 into partial remission. Eight patients suffered a relapse after partial and complete remission. The duration of the follow-up period varied between 2 months and 22 years. The histological diagnosis lymphocytic infiltration of the skin (Jessner) tallied in 9 patients with the clinical diagnosis, whereas in 6 patients the clinical diagnosis was benign lymphocytoma or pseudolymphoma. None of the patients developed systemic malignancy within the lymphoreticular system. A suspicious-looking skin lesion should always require further examination in order to exclude cutaneous manifestations of a systemic malignant lymphoreticular disease. The present histologic review demonstrates some uncertainty in diagnosing cutaneous lymhocytomas.l     

Cutaneous metastases from non-small cell lung cancer

BACKGROUND: Cutaneous metastases are an uncommon phenomenon that occurs in a few patients with metastatic disease. Early recognition of a cutaneous metastasis is important as it may be the presenting sign of an underlying malignancy. These metastases usually indicate advanced disease and carry a poor prognosis. OBJECTIVES: We present two cases with cutaneous metastasis from primary non-small cell lung cancer. We seek to familiarize dermatologists with the unusual presentations of cutaneous metastases. CONCLUSION: In our two cases, the diagnosis of the metastatic cutaneous lesion ultimately led to the correct diagnosis of an underlying malignancy.     

Clinical, pathologic, and immunopathologic features of dermatitis herpetiformis: review of the Mayo Clinic experience

BACKGROUND: Dermatitis herpetiformis (DH) is a cutaneous manifestation of gluten sensitivity, occasionally associated with other autoimmune disorders, and reportedly associated with an increased risk of lymphoproliferative disorders. We describe a series of patients with DH, focusing on associated disorders (particularly celiac disease), incidence of lymphoma, histopathology, and sensitivity of direct immunofluorescence (DIF) testing and serologic testing with antiendomysium antibodies for the diagnosis of DH. METHODS: The medical records of 264 patients with DH diagnosed between 1970 and 1996 were reviewed retrospectively. In addition, the records of six patients evaluated before the advent of DIF testing between 1932 and 1969 were reviewed. RESULTS: Established celiac disease was present in 12.6% of patients with DH, autoimmune systemic disorders in 22.2%, malignant neoplasms in 10.4%, sarcoidosis in four patients, and ulcerative colitis in six patients. Lymphoproliferative disorders were found in seven patients. The histopathologic examinations showed a marked predominance of neutrophils in the inflammatory infiltrate. DIF testing was positive in 92.4% of the patients tested. Indirect immunofluorescence assay indicated circulating antiendomysial antibodies in the sera of 40 of the 63 patients tested (63.5%). CONCLUSIONS: In this large series of patients with DH from a single institution, patients had a low incidence of symptomatic gluten-sensitive enteropathy, low risk of lymphoproliferative disorders, and associations with other systemic autoimmune disorders. The value of DIF testing in the diagnosis of DH was confirmed. The detection of antiendomysial antibodies by indirect immunofluorescence was less sensitive than indicated by other reports.     

Polymorphic cutaneous rhinosporidiosis

Rhinosporidiosis is a chronic granulomatous condition caused by Rhinosporidium seeberi primarily affecting the mucosa of the nose, eyes and sinuses. The patients usually present with nasal symptoms and skin involvement is uncommon [1-3]. Here, a patient with nasal rhinosporidiosis having two different morphological types of cutaneous lesions of rhinosporidiosis, coexisting at the same time and at the same site, is reported. The diagnosis was confirmed by FNAC (Fine Needle Aspiration Cytology) and skin biopsy from the skin lesions. To the best of my knowledge, such an unusual occurrence has not been reported earlier in literature.     

Unusual cutaneous features of syphilis in patients positive for human immunodeficiency virus

Dermatologists commonly find it difficult to diagnose syphilis, because of its protean clinical features. In cases of co‐infection with human immunodeficiency virus (HIV) syphilis may present particularly unusual clinical features, further confounding the diagnosis. We report two cases of syphilis/HIV co‐infection in Japanese patients showing uncommon skin features that made the diagnosis of syphilis difficult. These cases underline the need for dermatologists to be more aware of atypical cutaneous features of syphilis in patients positive for HIV.     

Hereditary benign telangiectasia

Hereditary benign telangiectasia is a very uncommon disorder characterized by generalized telangiectasias and angiomatous lesions of the skin. The diagnosis should be suspected in patients with such cutaneous signs, positive family history, no associated bleeding problems, and no mucosal involvement. We present a 74-year-old woman with typical clinical features of hereditary benign telangiectasia.     

Pseudotumoral cutaneous aspergillosis in chronic granulomatous disease, report of a pediatric case

ABSTRACT:: Invasive aspergillosis is a life-threatening condition in patients with chronic granulomatous disease (CGD). Skin invasion by Aspergillus occurs most commonly by contiguity to a neighboring cavity. We describe an unusual case of invasive cutaneous aspergillosis presented as a large burgeoning tumor in a 4-year-old girl with CGD who underwent surgical treatment for bifocal osteomyelitis of the left leg. The skin invasion occurred 4 months after a "successful" treatment of invasive pulmonary aspergillosis. Atypical presentation and diagnostic difficulties are discussed. Invasive cutaneous aspergillosis may be polymorphic. The diagnosis should be considered early in the etiological investigation of any suspicious skin lesions in CGD even in uncommon aspects such as burgeoning tumors.