S2k guidelines (consensus statement) for diagnosis and therapy of dermatitis herpetiformis initiated by the European Academy of Dermatology and Venereology (EADV).

INTRODUCTION: Dermatitis herpetiformis (DH) is a chronic, pruritic, gluten-induced skin disorder characterized by subepidermal granular IgA deposition and a variable degree of enteropathy identical to that seen in coeliac disease. So far, there has been no European consensus about the management of DH. METHODS: The guidelines were created by small subgroups of a guideline committee consisting of 26 specialists from various medical fields and one patients' representative. The members of the committee then discussed the guidelines and voted for the final version at two consensus meetings. The guidelines were developed under the support of the European Academy of Dermatology and Venereology (EADV) and in collaboration with the European Dermatology Forum (EDF). RESULTS: The guidelines summarize evidence-based and expert-based recommendations (S2 level) for the management of DH (see Appendix). CONCLUSION: These guidelines will improve the quality of management of DH and support dermatologists in their diagnostic and therapeutic decisions.

Current Concepts of Dermatitis Herpetiformis.

Dermatitis herpetiformis (DH) is an autoimmune skin disease that causes itchy, blistering rash, typically on the elbows, knees and buttocks. DH and coeliac disease share the same genetic background, gluten-dependent enteropathy and antibody response against tissue transglutaminase. DH is currently considered a cutaneous manifestation of coeliac disease, and the prevailing hypothesis is that DH develops as a late manifestation of subclinical coeliac disease. The incidence of DH is decreasing contemporarily with the increasing incidence of coeliac disease. The IgA immune response in DH skin is directed against epidermal transglutaminase, while the autoantigen in the gut is tissue transglutaminase. Granular IgA deposition in the papillary dermis is pathognomonic for DH, and is a finding used to confirm the diagnosis. The treatment of choice for DH is a life-long gluten-free diet, which resolves the rash and enteropathy, increases quality of life, and offers a good long-term prognosis.

Ex vivo Culture of Duodenal Biopsies from Patients with Dermatitis Herpetiformis Indicates that Transglutaminase 3 Antibody Production Occurs in the Gut.

Coeliac disease and dermatitis herpetiformis (DH) are characterized by autoantibodies targeting transglutaminase (TG)2 and TG3, respectively. Previous studies show that TG2 antibodies are produced in the gut and can be assessed in organ culture of small-intestinal biopsies from patients with coeliac disease. Thus far, no studies have investigated TG3 antibodies in organ culture of biopsies from patients with DH, or exploited the method in DH. The aim of this study was to investigate TG3 and TG2 antibody responses in serum and small-intestinal biopsies from patients with DH with active disease, and from those in remission. The majority of patients with DH were negative for both serum and organ culture medium TG2-targeting antibodies. Surprisingly, patients with active DH secreted TG3 antibodies into the culture medium despite seronegativity. In patients secreting high levels of TG3 antibodies into the culture medium, we also detected TG3-antibody-positive cells in the small-intestinal mucosa. These findings suggest that TG3 antibodies can be investigated in the organ culture system and that their secretion occurs in the small intestine, especially in active DH.

Dermatitis Herpetiformis Refractory to Gluten-free Dietary Treatment.

Dermatitis herpetiformis (DH) is a blistering skin disease, which is regarded as an extra-intestinal manifestation of coeliac disease. Refractory cases of coeliac disease, that do not respond to a gluten-free diet and which carry an increased risk of lymphoma, are well-known in coeliac disease. To determine whether refractory cases of DH with active rash and persistent small bowel atrophy occur we analysed our series of 403 patients with DH. Seven (1.7%) patients, who had been on a gluten-free diet for a mean of 16 years, but who still required dapsone to treat the symptoms of DH, were identified. Of these, one patient died from mucinous adenocarcinoma before re-examination. At re-examination skin immunoglobulin A (IgA) deposits were found in 5/6 refractory and 3/16 control DH patients with good dietary response. Small bowel mucosa was studied at re-examination from 5 refractory and 8 control DH patients and was normal in all 5 refractory and 7/8 control DH patients. One refractory DH patient died from adenocarcinoma, but no lymphoma developed in any of the patients. This study documents for the first time refractory DH, in which the rash is non-responsive to a gluten-free diet, but the small bowel mucosa heals. This differs from refractory coeliac disease, in which the small bowel mucosa does not heal on a gluten-free diet.

Concomitant bullous pemphigoid and dermatitis herpetiformis.

Dermatitis herpetiformis and bullous pemphigoid are bullous autoimmune diseases of the skin microscopically characterized by subepidermal blisters. We present a 77-year-old patient with an 18-month history of disseminated pruritic papular lesions. Direct immunofluorescence microscopy revealed linear deposition of IgG at the basement membrane zone as well as granular deposits of IgA in the papillary dermis. Circulating IgG antibodies against BP180, BP230 and gliadin as well as IgA reactivity against endomysium, tissue transglutaminase, and gliadin were detected compatible with both bullous pemphigoid and dermatitis herpetiformis. Here, we review the English literature on all previously reported patients with co-occurrence of both entities. Interestingly, in previous cases, tissue-bound and serum autoantibodies against the respective target antigens had not yet been completely characterized.

Dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is an autoimmune, pleiomorphic, papulovesicular disorder associated with celiac disease and gluten sensitivity. DH is characterized by subepidermal bullae on hematoxylin and eosin staining and granular immunoglobulin A deposits in the dermal papillae using the direct immunofluorescence method. Antibodies to tissue transglutaminase and epidermal transgulatminase can be measured serologically, although biopsy is still required for definitive diagnosis of DH. Gluten free diet (GFD) is the first-line therapeutic approach that can alleviate both cutaneous and intestinal manifestations of this condition, while dapsone and sulfones target the skin eruption only. Combined therapy with GFD and dapsone is an initial treatment of choice to control the cutaneous manifestations of DH. This article will provide a comprehensive review of DH, including its epidemiology, clinical and pathological findings, diagnostic evaluation, and management.

Novel therapeutic/integrative approaches for celiac disease and dermatitis herpetiformis.

Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Gluten is a protein component in wheat and other cereals like rye and barley. At present, the only available treatment is a strict gluten-free diet. Recent advances have increased our understanding of the molecular basis for this disorder. Last decade has seen new scientific developments in this disease and led to the formulation of new concepts of pathophysiology that offer possible targets for new treatments or interventions integrative to the gluten-free diet.

Guidelines of the Italian societies of gastroenterology on the diagnosis and management of coeliac disease and dermatitis herpetiformis.

INTRODUCTION: Coeliac disease and dermatitis herpetiformis are immune-mediated diseases triggered by the consumption of gluten in genetically predisposed individuals. These guidelines were developed to provide general practitioners, paediatricians, gastroenterologists, and other clinicians with an overview on the diagnosis, management and follow-up of coeliac patients and those with dermatitis herpetiformis. METHODS: Guidelines were developed by the Italian Societies of Gastroenterology. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists and a paediatrician with expertise in this field. RESULTS: These guidelines provide a practical guidance for the diagnosis, management and follow-up of coeliac patients and dermatitis herpetiformis in children and adults, both in primary care and in specialist settings. We developed four sections on diagnosis, gluten-free diet, follow-up and risk of complications in adults, one section focused on diagnosis and follow-up in children and one on the diagnosis and management of dermatitis herpetiformis. CONCLUSIONS: These guidelines may support clinicians to improve the diagnosis and management of patients with coeliac disease.

Dermatitis herpetiformis. Part II. Diagnosis, management, and prognosis.

The prompt recognition of the clinical features of dermatitis herpetiformis (DH) is important, but securing a definitive diagnosis requires further work-up. Recent advances in understanding of the immunologic basis for DH have led to the development and wider availability of serologic testing, which is rapidly becoming an essential part of the diagnosis and management of DH. Part II of this series will detail the diagnosis, treatment, and follow-up for patients with DH, and will particularly focus on recent advances in the field.

Impetigo herpetiformis with gestational hypertension: a case report and literature review.

BACKGROUND: Impetigo herpetiformis (IH) is a rare skin disorder that occurs during pregnancy. It was previously associated with high maternal and fetal mortality and morbidity, but now has a better prognosis. CASE REPORT: We report a case of a pregnant woman with IH who presented with generalized erythematous pustular eruptions in the 32nd week of gestation. The IH progressed rapidly, and gestational hypertension was observed in the 36th week. The lesions did not subside, despite treatment with corticosteroids and phototherapy. She delivered a healthy male baby via cesarean section in the 37th week. One month after her delivery, her skin returned to normal, except for residual pigmentation, with complete recovery 3 months postpartum. CONCLUSION: An experienced medical team comprising obstetricians, dermatologists, perinatologists and neonatologists is critical to aggressively treat this life-threatening specific dermatosis of pregnancy and to prevent ensuing complications, such as fluid and electrolyte imbalance, secondary infection and placental insufficiency.

Celiac disease of the joint.

A 42-year-old woman presented with a 3-week history of left knee pain and swelling. She had suffered dermatitis herpetiformis for 12 years, proved by skin biopsy. She had never been on gluten-free diet. Knee pain increased with motion and her gait was antalgic. On admission, she was mainly dependent on wheelchair due to pain and limitation. Treatment plan consisted of gluten-free diet, stretching and strengthening exercises, analgesic or nonsteroidal anti-inflammatory drugs when needed. She responded well to gluten-free diet. Association of joint involvement and dermatitis herpetiformis is more than just coincidental. Possible immunopathogenesis and role of gluten-free diet on arthritis treatment are discussed.

Dermatitis Herpetiformis: An Update on Diagnosis and Management.

Dermatitis herpetiformis (DH), presenting with an intense itch and blistering symmetrical rash, typically on the elbows, knees, and buttocks, is a cutaneous manifestation of celiac disease. Though overt gastrointestinal symptoms are rare, three-fourths of patients with DH have villous atrophy in the small bowel, and the rest have celiac-type inflammatory changes. DH affects mostly adults and slightly more males than females. The mean age at onset is about 50 years. DH diagnosis is confirmed by showing granular immunoglobulin A deposits in the papillary dermis. The DH autoantigen, transglutaminase 3, is deposited at the same site in tightly bound immune complexes. At present, the DH-to-celiac disease prevalence is 1:8. The incidence of DH is decreasing, whereas that of celiac disease is increasing, probably because of improved diagnostics. In DH, the treatment of choice for all patients is a gluten-free diet (GFD) in which uncontaminated oats are allowed. At onset, most patients need additional dapsone to rapidly control the rash and itching. Dapsone can be stopped after a mean of 2 years, and a strict lifelong GFD alone is required. Dietary adherence offers an excellent long-term prognosis for patients with DH, with a normal quality of life and all-cause mortality.

Guidelines for the diagnosis and treatment of dermatitis herpetiformis.

Dermatitis herpetiformis is a rare disease that should be considered the cutaneous expression of a gluten-sensitive enteropathy indistinguishable from celiac disease. Dermatitis herpetiformis is often misdiagnosed and to date no guidelines for the management of dermatitis herpetiformis have been published in Literature. The present guidelines have been prepared for dermatologists by the Group for Cutaneous Immunopathology of the Italian Society of Dermatology and Venereology. They reflect the best data available at the time of preparation and the clinical experience of the authors and the members of the Italian Group for Cutaneous Immunopathology. The diagnosis of dermatitis herpetiformis is established clinically, histologically, immunopathologically and serologically. A gluten-free diet (GFD) is the treatment of choice for patients with dermatitis herpetiformis. Dapsone and/or other drugs should be used during the period until the GFD is effective. In conclusion, the present guidelines provide evidence-based guidance for the diagnosis and treatment of dermatitis herpetiformis.

Consensus on the treatment of autoimmune bullous dermatoses: dermatitis herpetiformis and linear IgA bullous dermatosis - Brazilian Society of Dermatology.

Dermatitis herpetiformis and linear IgA bullous dermatosis are autoimmune diseases that present with pruritic urticarial papules and plaques, with formation of vesicles and blisters of subepidermal location, mediated by IgA antibodies. Mucosal lesions are present only in linear IgA bullous dermatosis. The elaboration of this consensus consisted of a brief presentation of the different aspects of these dermatoses and, above all, of an updated literature review on the various therapeutic options that were discussed and compared with the authors' experience, aiming at the treatment orientation of these diseases in Brazil. Dermatitis herpetiformis is a cutaneous manifestation of celiac disease, and can be controlled with a gluten-free diet and dapsone. On the other hand, linear IgA bullous dermatosis arises spontaneously or is triggered by drugs, and can be controlled with dapsone, but often requires the association of systemic corticosteroids and eventually immunosuppressants.

European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders.

This guideline presents recommendations for the management of coeliac disease (CD) and other gluten-related disorders both in adults and children. There has been a substantial increase in the prevalence of CD over the last 50 years and many patients remain undiagnosed. Diagnostic testing, including serology and biopsy, should be performed on a gluten-containing diet. The diagnosis of CD is based on a combination of clinical, serological and histopathological data. In a group of children the diagnosis may be made without biopsy if strict criteria are available. The treatment for CD is primarily a gluten-free diet (GFD), which requires significant patient education, motivation and follow-up. Slow-responsiveness occurs frequently, particularly in those diagnosed in adulthood. Persistent or recurring symptoms necessitate a review of the original diagnosis, exclude alternative diagnoses, confirm dietary adherence (dietary review and serology) and follow-up biopsy. In addition, evaluation to exclude complications of CD, such as refractory CD or lymphoma, should be performed. The guideline also deals with other gluten-related disorders, such as dermatitis herpetiformis, which is a cutaneous manifestation of CD characterized by granular IgA deposits in the dermal papillae. The skin lesions clear with gluten withdrawal. Also, less well-defined conditions such as non-coeliac gluten sensitivity (NCGS) and gluten-sensitive neurological manifestations, such as ataxia, have been addressed. Newer therapeutic modalities for CD are being studied in clinical trials but are not yet approved for use in practice.

Dermatitis Herpetiformis: Novel Perspectives.

Dermatitis herpetiformis (DH) is an inflammatory disease of the skin, considered the specific cutaneous manifestation of celiac disease (CD). Both DH and CD occur in gluten-sensitive individuals, share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8), and improve following the administration of a gluten-free diet. Moreover, almost all DH patients show typical CD alterations at the small bowel biopsy, ranging from villous atrophy to augmented presence of intraepithelial lymphocytes, as well as the generation of circulating autoantibodies against tissue transglutaminase (tTG). Clinically, DH presents with polymorphic lesions, including papules, vesicles, and small blisters, symmetrically distributed in typical anatomical sites including the extensor aspects of the limbs, the elbows, the sacral regions, and the buttocks. Intense pruritus is almost the rule. However, many atypical presentations of DH have also been reported. Moreover, recent evidence suggested that DH is changing. Firstly, some studies reported a reduced incidence of DH, probably due to early recognition of CD, so that there is not enough time for DH to develop. Moreover, data from Japanese literature highlighted the absence of intestinal involvement as well as of the typical serological markers of CD (i.e., anti-tTG antibodies) in Japanese patients with DH. Similar cases may also occur in Caucasian patients, complicating DH diagnosis. The latter relies on the combination of clinical, histopathologic, and immunopathologic findings. Detecting granular IgA deposits at the dermal-epidermal junction by direct immunofluorescence (DIF) from perilesional skin represents the most specific diagnostic tool. Further, assessing serum titers of autoantibodies against epidermal transglutaminase (eTG), the supposed autoantigen of DH, may also serve as a clue for the diagnosis. However, a study from our group has recently demonstrated that granular IgA deposits may also occur in celiac patients with non-DH inflammatory skin diseases, raising questions about the effective role of eTG IgA autoantibodies in DH and suggesting the need of revising diagnostic criteria, conceivably emphasizing clinical aspects of the disease along with DIF. DH usually responds to the gluten-free diet. Topical clobetasol ointment or dapsone may be also applied to favor rapid disease control. Our review will focus on novel pathogenic insights, controversies, and management aspects of DH.

Treatment Update of Autoimmune Blistering Diseases.

The treatment of refractory autoimmune blistering diseases (AIBDs) has always been a challenge. Because randomized controlled trials are lacking, treatment has been based on analysis of anecdotal data. The last 2 decades has seen the use of rituximab become a conventional treatment in the therapeutic armamentarium of AIBDs, leading to its Food and Drug Administration indication for pemphigus vulgaris in 2018. We review the current updated data on the use of rituximab including dosing, protocols, and its role in the algorithm of AIBDs. In addition, we discuss several promising novel emerging therapeutic agents for AIBDs.