RARE DISEASE
Dermatitis herpetiformis
Dermatitis herpetiformis
Dermatitis herpetiformis
Synonyms: Duhring-Brocq disease
Synonyms: Duhring-Brocq disease
Synonyms: Duhring-Brocq disease
Drug discovery
1
drug
With orphan designation
Overview
Dermatitis herpetiformis (DH) is a chronic autoimmune blistering skin condition linked to gluten sensitivity and celiac disease. It presents with intensely pruritic, symmetrical papulovesicular eruptions on extensor surfaces (elbows, knees, buttocks). Diagnosis is confirmed via skin biopsy with granular IgA deposits in dermal papillae. A lifelong gluten-free diet is the cornerstone of treatment, supplemented by dapsone or sulfonamides for symptom control. DH carries increased risks of thyroid disorders, lymphoma, and other autoimmune conditions [1][6][16].
Categories: rare skin diseases
Research Papers
270 drug discovery papers about Dermatitis herpetiformis, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
270 drug discovery papers about Dermatitis herpetiformis, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-05-22 | Letter: Supporting the Role of Enzyme Therapy in Management of Coeliac Disease
I appreciate the opportunity to comment on the review article by Bonner et al. [1]. The article rightly highlights the duodenum as the site where enzymatic interaction with gluten will be most beneficial. The caricain-based supplement was the first technology proposing the small intestine as the site of enzyme activity through extensive in vitro studies and clinical trials. The product formulation involves the combination of an acid-resistant coating and superdisintegrant excipients to ensure rapid release of the enzyme in the duodenum, post gastric emptying. There it neutralises partially digested gluten immunogenic peptides (GIPs) in conjunction with brush border peptidases before symptoms and immune activation occur. Caricain (EC 3.4.22.30) is a well-characterised cysteine endopeptidase derived from Carica papaya which cleaves proline-rich motifs in gluten [2]. It offers a high degree of protection against the toxic action of gliadin on rat liver lysosomes [3], mimicking pathological alterations to lysosomes seen in the mucosa of the small intestine [4]. Caricain rapidly digests GIPs in pepsin trypsin-treated gliadin [5] and also extensively hydrolyses Wheat ⍺-Amylase Trypsin Inhibitors (ATIs) [6]. Unlike exopeptidases (DPPIV), which inefficiently degrade gluten [5, 7] caricain rapidly degrades GIPs into non-immunogenic fragments, including the 33-mer, under physiologically relevant conditions (pH 3–7) and is stable to the action of gastric proteases, trypsin, and pepsin [5]. Missing from the review of Bonner et al. are two important peer-reviewed reports of randomised, double-blind, placebo-controlled clinical studies published in an international searchable journal. The first study evaluated caricain's efficacy in dermatitis herpetiformis. Despite a substantial gluten challenge (6 g/day for 14 days), supplementation with caricain demonstrated significant protective effects with an 81% reduction in skin lesion area (19.5 to 3.7 cm2; p = 0.02), 71% decrease in new lesions, and 38% decline in pruritus compared to placebo [8]. The second study investigated the effects of caricain supplementation in patients with coeliac disease in remission undergoing a controlled gluten challenge for 42 days. Overall symptom scores and five individual symptoms (well-being, fatigue, nausea/vomiting, stomach pain and cramps, at day 14) favoured caricain over placebo (p < 0.01 for each). Dropouts occurred almost exclusively in the group randomised to placebo, due to the clinical effects of the gluten challenge; those randomised to caricain tolerated the challenge well [9]. Indeed, the large, statistically significant effects were secured even with a small sample size. The observed protective effects support caricain's intended role to mitigate the effects of inadvertent gluten exposure. Enzyme therapies like caricain offer protection against gluten before it triggers immune responses. The mechanism is localised to the gastrointestinal lumen, with no direct effects on the immune system or intestinal healing. This distinction is critical to avoid misclassification as disease-modifying treatments. The authors are to be commended for bringing attention to the benefits of enzyme therapy in the management of coeliac disease, which these studies support. Finlay Macrae: conceptualization, writing – original draft, writing – review and editing, methodology, project administration. This article is linked to Bonner et al. paper. To view this article, visit https://onlinelibrary.wiley.com/doi/10.1111/apt.70014 and https://onlinelibrary.wiley.com/doi/10.1111/apt.70205. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2020-07-16 | Sourdough Fermentation Degrades Wheat Alpha-Amylase/Trypsin Inhibitor (ATI) and Reduces Pro-Inflammatory Activity
The ingestion of gluten-containing foods can cause wheat-related disorders in up to 15% of wheat consuming populations. Besides the role of gluten, α-amylase/trypsin inhibitors (ATI) have recently been identified as inducers of an innate immune response via toll-like receptor 4 in celiac disease and non-celiac wheat sensitivity. ATI are involved in plant self-defense against insects and possibly in grain development. Notably, they are largely resistant to gastrointestinal proteases and heat, and their inflammatory activity affects not only the intestine, but also peripheral organs. The aim of this study was to understand the changes of ATI throughout the sourdough and yeast-fermented bread-making processes. ATI tetramers were isolated, fluorescein-labelled, and added to a mini-dough bread-making system. When the pH decreased below 4.0 in sourdough fermentation, the ATI tetramers were degraded due to the activation of aspartic proteases, whilst in yeast fermentation, ATI tetramers remained intact. The amylase inhibitory activity after sourdough fermentation decreased significantly, while the concentration of free thiol groups increased. The glutathione reductase activity of Fructilactobacillus sanfranciscensis did not contribute to the reduction of ATI tetramers. Compared to the unfermented wheat, sourdough fermentation was able to decrease the release of pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor alpha (TNF-α) in quantitative ATI extracts added to the human monocytic cell line THP-1. The current data suggest that sourdough fermentation can degrade ATI structure and bioactivity, and point to strategies to improve product development for wheat sensitivity patients.
2018-03-06 | A randomised, double-blind, cross-over trial to evaluate bread, in which gluten has been pre-digested by prolyl endoprotease treatment, in subjects self-reporting benefits of adopting a gluten-free or low-gluten diet
Abstract The aim of the present study was to determine if the enzyme Aspergillus niger prolyl endoprotease (ANPEP), which degrades the immunogenic proline-rich residues in gluten peptides, can be used in the development of new wheat products, suitable for gluten-sensitive (GS) individuals. We have carried out a double-blind, randomised, cross-over trial with two groups of adults; subjects, self-reporting benefits of adopting a gluten-free or low-gluten diet (GS, n 16) and a control non-GS group ( n 12). For the trial, volunteers consumed four wheat breads: normal bread, bread treated with 0·8 or 1 % ANPEP and low-protein bread made from biscuit flour. Compared with controls, GS subjects had a favourable cardiovascular lipid profile – lower LDL (4·0 ( sem 0·3) v . 2·8 ( sem 0·2) mmol/l; P =0·008) and LDL:HDL ratio (3·2 ( sem 0·4) v . 1·8 ( sem 0·2); P =0·005) and modified haematological profile. The majority of the GS subjects followed a low-gluten lifestyle, which helps to reduce the gastrointestinal (GI) symptoms severity. The low-gluten lifestyle does not have any effect on the quality of life, fatigue or mental state of this population. Consumption of normal wheat bread increased GI symptoms in GS subjects compared with their habitual diet. ANPEP lowered the immunogenic gluten in the treated bread by approximately 40 %. However, when compared with the control bread for inducing GI symptoms, no treatment effects were apparent. ANPEP can be applied in the production of bread with taste, texture and appearance comparable with standard bread.
2016-05-05 | The Effect of Enzyme Therapy on Skin Symptoms and Immune Responses in Patients with Dermatitis Herpetiformis
Background: The aetiology of coeliac disease (CD) has many similarities to that of dermatitis herpetiformis (DH), except that DH lesions are mainly manifested in the skin. Mucosal enzyme deficiency plays an important part in CD pathology. Clinical studies indicated that the gluten exposure in CD could be partly corrected by the use of enzyme supplementation. Objective: Enzyme therapy, using enterically coated tablets containing caricain, was investigated as a means of protecting patients with DH against wheat gluten. Methods: A randomized, placebo-controlled clinical trial was carried out on 20 DH patients in clinical remission. The patients were divided into two groups of 10, one group given a placebo daily and the other the enzyme â containing tablets. Both groups were challenged with 6g of gluten daily in a double-blind trial. Symptoms and signs of skin involvement were recorded and graded at the start of the trial, after 7 days and after 14 days. Blood was also taken at the start and after 14 days and assayed for IgA EMA and anti-gliadin antibodies. Results: After 7 days the major features associated with DH were more severe and more common with the placebo compared with enzyme therapy. Before 14 days, seven patients in total, six on placebo, had to withdraw from the trial because of the effects of the gluten challenge whilst 2 patients on therapy developed blisters, erythema and itching. Serological tests indicated that IgA EmA antibodies and anti-gliadin antibodies after 14 days were not affected significantly, but indicated that abnormally high antibodies titers of both types were present in 8 patients at the start of the trial, suggesting the need for enzyme therapy in addition to the normal gluten-free diet for patient well-being. Conclusions: This study supports the use of enzyme supplementation as a safeguard for patients with DH on a nominal gluten-free diet.
2015-09-04 | Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease
Objective
The short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn9s disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals.
Design
TSLP isoforms—long and short—and receptors—TSLPR and interleukin (IL)-7Rα—were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed.
Results
Mucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies.
Conclusions
Reduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD.
small molecules
2026-09-22 | DIAGNOSTIC METHODS AND ADVANCES IN THE TREATMENT OF HERPETIFORM DERMATITIS
Dermatitis herpetiformis (DH) is a chronic autoimmune skin disease associated with gluten-sensitive enteropathy, characterized by intensely pruritic papulovesicular lesions with a predominantly symmetrical distribution on the extensor surfaces. The aim of this study was to examine the main diagnostic methods and therapeutic advances used in the management of DH. A narrative literature review was conducted in PubMed using the search terms “Dermatitis Herpetiformis” and “Therapy,” and publications from the past 5 years were selected. It was found that direct immunofluorescence of the perilesional skin is the gold standard for diagnosis, while serological markers—especially antibodies against tissue and epidermal transglutaminase—serve a complementary role and are useful for monitoring. HLA-DQ2/DQ8 genotyping has a high negative predictive value. Treatment is based on a gluten-free diet, combined with dapsone for rapid control of skin manifestations, although its use requires close monitoring due to hematologic toxicity. New strategies, including modulation of the gut microbiota, show potential as adjuvant therapy but still require more robust clinical evidence.
2026-08-20 | Dapsone: A Comprehensive Review of Its Pharmacological Foundations, Clinical Indications, and Management
Dapsone (4,4'-diaminodiphenyl sulfone) is a sulfone antibiotic with a storied history in pharmacotherapy, initially synthesized in the early 20th century and repurposed over decades for a diverse range of infectious and inflammatory conditions. While its FDA-approved indications are primarily restricted to leprosy, dermatitis herpetiformis, and acne vulgaris, its off-label utilization spans a remarkable spectrum of neutrophilic and autoimmune dermatoses, as well as infectious disease prophylaxis. This review provides a comprehensive, evidence-based analysis of dapsone's pharmacodynamic properties, focusing on its dual mechanism of action: competitive inhibition of the folic acid synthesis pathway in Mycobacterium leprae and modulation of neutrophilic inflammation through interference with the myeloperoxidase-halide system and leukotriene B4-mediated chemotaxis. Furthermore, the review elucidates its complex pharmacokinetic profile, characterized by near-complete oral absorption, extensive hepatic metabolism via the cytochrome P450 system, and a prolonged and variable elimination half-life, which necessitates careful dose individualization. The clinical applications of dapsone are scrutinized, detailing standardized multidrug regimens for leprosy and dose-titration strategies for dermatitis herpetiformis, while also outlining its therapeutic potential in various off-label contexts. A critical component of this review is the analysis of dapsone's significant adverse effect profile, which includes dose-dependent hemolytic anemia, methemoglobinemia, and the potentially life-threatening dapsone hypersensitivity syndrome, thereby underscoring the imperative for rigorous baseline and ongoing patient monitoring. The review synthesizes this information to provide a pragmatic framework for interprofessional healthcare teams, emphasizing the collaborative roles of physicians, pharmacists, and nurses in optimizing therapeutic outcomes while minimizing patient risk.
2026-07-31 | Gluten-Responsive Probable Pediatric Dermatitis Herpetiformis Mimicking Varicella in a Five-Year-Old Child: A Case Report
Background: Dermatitis herpetiformis (DH) is a gluten-associated autoimmune vesiculobullous dermatosis that is rare in children and may resemble infectious eruptions, particularly varicella. Case presentation: A 5-year-old boy presented with persistent, painful, and intensely pruritic grouped vesicles and tense bullae, predominantly affecting the posterior trunk and upper back. Although he had a history of varicella at 3 years of age, the current episode was not preceded by known varicella exposure, fever, or prodromal symptoms. The eruption was initially diagnosed as varicella due to its vesiculobullous morphology, and a 5-day course of acyclovir was administered. Over approximately 1 month of close monitoring, some lesions transiently dried and faded, but new grouped vesicles and bullae repeatedly appeared, became more widespread, and remained painful and pruritic. Recurrent flares were subsequently observed after ingestion of gluten-containing foods. Laboratory findings were unremarkable except for eosinophilia of 14% and a serum IgE of 91.88 IU/mL. IgA-based celiac serology, histopathology, and direct immunofluorescence were not performed because the parents declined. The clinical pattern, gluten-associated recurrence, lack of sustained response to acyclovir, and improvement with gluten avoidance supported a working diagnosis of gluten-responsive probable pediatric DH. Clinical improvement was achieved with lesion-directed topical therapy, symptomatic treatment, and a strict gluten-free diet. Conclusion: This case underscores a varicella-mimicking, gluten-responsive probable pediatric DH presentation and highlights the importance of transparent reporting of diagnostic uncertainty when confirmatory testing is unavailable.
2026-07-14 | Exuberant Dermatitis Herpetiformis With Oral Involvement Mimicking Behçet Disease and Disseminated Herpetic Infection: The Crucial Role of Direct Immunofluorescence.
Dermatitis herpetiformis (DH) is a chronic autoimmune blistering dermatosis associated with gluten-sensitive enteropathy and characterized by intensely pruritic papulovesicular eruptions, typically distributed symmetrically on extensor surfaces. Although DH classically presents with grouped vesicles and excoriated papules, atypical and exuberant manifestations may represent a substantial diagnostic challenge, frequently mimicking infectious, inflammatory, and autoimmune blistering disorders. We report the case of a 30-year-old woman presenting with a one-year history of progressive, intensely pruritic vesiculobullous and erosive lesions involving the trunk and extremities, accompanied by painful oral ulcerations, hemorrhagic crusts, extensive excoriations, secondary bacterial infection, and diffuse post-inflammatory hyperpigmentation. The patient was initially diagnosed with Behçet disease and subsequently hospitalized for suspected disseminated herpetic infection, receiving systemic corticosteroids and intravenous acyclovir without significant clinical improvement. Dermatological examination revealed widespread erosive and vesiculobullous lesions associated with severe inflammatory activity and oral aphthoid ulcerations. Histopathological examination of active lesions demonstrated intraepidermal blister formation associated with eosinophilic infiltrate and scattered acantholytic cells, findings that initially suggested alternative autoimmune blistering disorders. Direct immunofluorescence (DIF) demonstrated characteristic granular IgA deposition predominantly localized at the tips of dermal papillae, confirming the diagnosis of DH despite atypical histopathological findings. Serological evaluation further revealed positive anti-tissue transglutaminase and anti-endomysial antibodies, corroborating the diagnosis. Treatment with dapsone combined with a strict gluten-free diet resulted in marked clinical improvement. This case highlights the importance of clinicopathological and immunopathological correlation in atypical presentations of autoimmune blistering diseases and underscores the essential role of DIF in establishing the diagnosis of DH.
2026-01-08 | Health Risks Associated with a Long-Term Gluten-Free Diet and the Potential Protective Role of Anthocyanins.
Gluten-free diets (GFDs) are gaining popularity worldwide. Originally, GFDs were designed for individuals with gluten intolerance, including conditions such as celiac disease, non-celiac gluten sensitivity, gluten ataxia, or dermatitis herpetiformis. However, many individuals without gluten sensitivity have subsequently adopted this diet, leading to a growing demand for gluten-free food products. Meanwhile, the health risks associated with a long-term gluten-free diet (LTGFD) and the inherent related issues, such as nutrient imbalances, remain uncertain. Scientific studies have indicated that obesity, non-alcoholic fatty liver disease (NAFLD), dysbiosis, and poor mental health represent the most probable health risks associated with a LTGFD. Moreover, high fat and simple carbohydrate content, increased calorie content, and vitamin deficiencies, including vitamin B derivatives (B1, B2, B3, B5, B6, B7, B9, and B12), vitamin D, and minerals (Fe, Mg, Se, and Zn), are key components in a GFD that are at the helm of health issues due to a LTGFD. Anthocyanins, a class of flavonoids found predominantly in red, purple, and blue fruits and vegetables, may provide a promising solution to alleviate health risks associated with a LTGFD due to their inherent antioxidant, anti-inflammatory, neuroprotective, anti-diabetic, and anti-obesity properties. Therefore, this review critically examines in vivo, in vitro, clinical, and mechanistic studies to explore the potential of anthocyanin-enriched GFDs in alleviating the health risks associated with a LTGFD, highlighting their significant advantages over regular GFDs.
antibodies
2025-12-15 | A systematic review of therapeutic and paradoxical roles of tumor necrosis factor α inhibitors in autoimmune blistering diseases.
Autoimmune blistering diseases (AIBDs), including pemphigus diseases, pemphigoid diseases, linear immunoglobulin A (IgA) bullous dermatosis (LABD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH), are a group of diseases clinically characterized by erosions and blisters that involve the skin and mucosa. Tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine, plays a critical role in their pathogenesis. TNF-α inhibitors are used for their immunomodulatory effects but may also induce paradoxical autoimmune blistering. This systematic review aimed to synthesize current evidence on therapeutic and paradoxical effects of TNF-α inhibitors in these diseases. A systematic search of PubMed, Scopus, and Embase was conducted up to March 7th, 2025, following PRISMA guidelines. Studies eligible for inclusion were original human research articles in English reporting therapeutic or paradoxical effects of TNF-α inhibitors, including infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab, on autoimmune bullous diseases. Risk of bias was evaluated using the NIH and Murad et al. assessment tools. A total of 35 studies with 68 patients were included in the treatment application group and 29 studies with 31 subjects were included in the paradoxical reaction group. Infliximab was most frequently associated with favorable outcomes in pemphigus vulgaris (PV), bullous pemphigoid (BP), and EBA, with multiple reports of sustained remission. Etanercept showed partial to complete responses in some cases of PV and BP; however, it was associated with paradoxical induction of BP in several patients. Adalimumab demonstrated therapeutic efficacy in PV and MMP, yet was the most common agent implicated in paradoxical BP and LABD. Paradoxical effects were most often observed in patients treated for non-dermatologic conditions such as rheumatoid arthritis or Crohn's disease. TNF-α inhibitors, particularly infliximab, show therapeutic promise in refractory AIBDs. However, their potential to paradoxically induce blistering diseases, especially with adalimumab and etanercept, necessitates careful patient selection, close monitoring, and individualized risk-benefit assessment.
2025-06-27 | HX02 From arsenic to rituximab: a history of dermatitis herpetiformis
Abstract Dr Edward Tilbury Fox was the first to describe dermatitis herpetiformis (DH) in 1872, calling it ‘hydroa herpetiformis’. In 1884, Louis Duhring first used the term ‘dermatitis herpetiformis’, due to the grouped herpetiform vesicles. Early therapies were limited: for the wealthy, a visit to Harrogate spa, oral arsenic and sulfur ointment were preferred; a 3-week stay in hospital was the alternative for others. Additional treatments included quinine, belladonna, strychnine and ergot. Norman Walker declared that the prognosis was: ‘good…if the patient does not commit suicide on account of the mental disturbance brought about by the itching, but with regard to a speedy cure it is undeniably bad’ (Walker N, Percival GH. An Introduction to Dermatology, 10th edn. Edinburgh: W. Green, 1939). Various early 20th century doctors noted anecdotal benefits of dietary restriction. In 1912, a patient with intractable DH cleared entirely after a fortnight taking nothing but water. Dermatologists struggled to persuade subsequent patients ‘to undergo more than two or three days of starvation’. The first major breakthrough came in 1950, when it was recognized that dapsone immediately abolished the itch and rash, and it became the mainstay of treatment. In 1966, Janet Marks showed the association between DH and coeliac disease (CD), noting the high proportion of patients with DH with abnormalities of the small intestinal mucosa. This was corroborated in 1968, when Lionel Fry observed improvements in the skin, intestinal mucosa and nutrition of a small number of patients with DH following a gluten-free diet (GFD). From 1977, once Timo Reunala proved in a larger study that both the disease burden and reliance on dapsone reduced drastically in patients maintaining a GFD, it became standard therapy. Jejunal biopsy is no longer routine in patients with DH; all are assumed to have gluten sensitivity. The 1969 observation of IgA deposits at the dermal papillae of uninvolved skin suggested the role of antibodies in its aetiology. In 1972, demonstration of the association of the specific human leucocyte antigen (HLA) haplotypes such as HLA-A8 with both DH and CD implied a genetic predisposition. Serum antiepidermal transglutaminase antibodies have since been shown to be a specific diagnostic marker for DH and CD. A GFD and dapsone remain the cornerstones of treatment, with IgA deposits on skin immunofluorescence the gold-standard diagnostic test. Rituximab has been reported to cause complete remission. Ongoing research into the immunopathogenesis of DH may lead to more targeted treatments.
2025-03-11 | Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity.
Autoantibodies against the enzyme transglutaminase 3 (TG3) are characteristic to the gluten-sensitive skin disorder dermatitis herpetiformis (DH), which is an extraintestinal manifestation of celiac disease. We here demonstrate that TG3-specific B cells can activate gluten-specific CD4+ T cells through B-cell receptor (BCR)-mediated internalization of TG3-gluten enzyme-substrate complexes. Stereotypic anti-TG3 antibodies using IGHV2-5/IGKV4-1 gene segments enhance the catalytic activity of TG3, and this effect translates into increased gluten presentation to T cells when such antibodies are expressed as BCRs. The crystal structure of TG3 bound to an IGHV2-5/IGKV4-1 Fab shows that antibody binding to a β-sheet in the catalytic core domain causes the enzyme to adopt the active conformation. This mechanism explains the production of stereotypic anti-TG3 autoantibodies in DH and highlights a role for TG3-specific B cells as antigen-presenting cells for gluten-specific T cells. Similar boosting effects of autoreactive BCRs could be relevant for other autoimmune diseases, including rheumatoid arthritis.
2023-06-01 | P12 A flare of dermatitis herpetiformis precipitated by etanercept
Abstract We report the case of a 79-year-old man who presented with an acute, intensely pruritic, widespread rash, which, on examination, consisted of symmetrical, haemorrhagic nodules and vesicles with some desquamation affecting the extensor surfaces of the arms, flexor surfaces of the legs and the natal cleft. He had a history of coeliac disease (for which he had adhered to a strict gluten-free diet since 1997) and rheumatoid arthritis. He had his first dose of the anti-tumour necrosis factor (TNF) agent etanercept prior to this episode to manage his arthritis. A punch biopsy for histopathology showed subepidermal blisters with a predominance of neutrophils. Eosinophils were also present to the level of the eccrine coils within the dermis, with eosinophilic flame figures but no eosinophil spongiosis at the edges of the blister. Direct immunofluorescence showed granular IgM and IgA in the dermal papillae, and a similar reaction was seen with fibrinogen. These histological findings were strongly suggestive of dermatitis herpetiformis (DH). Owing to diagnostic uncertainty on presentation, initial treatment was with high-dose topical steroids and emollient. and a yellow card was completed. Since this presentation, he has had no further flares and has not required dapsone. Multidisciplinary team discussion decided that the patient should avoid other anti-TNF treatments, but he has found relief for multiple months with rituximab and has had no cutaneous adverse events on this agent. The aetiology of DH following anti-TNF treatment is not immediately clear. Increased immunogenicity and cytokine release have been hypothesized to be part of the pathology of many adverse reactions to anti-TNF agents. It is conceivable that the cytokine release ordinarily seen in DH is replicated by the administration of anti-TNF agents. There have been many cases of anti-TNF agents leading to worsening eczema and psoriasis. Interestingly, these conditions have been found to upregulate TNF-α, a feature that is also seen in DH. This appears to be the first case described in the literature of etanercept-induced DH. A reaction with infliximab was reported in 2008, with a similar rash and histology consistent with DH, but it differed as the patient had no prior diagnosis of coeliac disease and presented after their second dose (Marakli SS, Uzun S, Ozbek S, Tuncer I. Dermatitis herpetiformis in a patient receiving infliximab for ankylosing spondylitis. Eur J Dermatol 2008; 18:88–9).
2022-03-25 | Assessment of Clinical and Laboratory Use of the Cutaneous Direct Immunofluorescence Assay.
Dermatologists submit direct immunofluorescence (DIF) biopsies on a daily basis, using an assay detecting immunoreactant deposition with a panel that has traditionally comprised immunoglobulin (Ig) G, IgA, IgM, C3, and fibrin, with or without albumin antibodies. To evaluate and compare the frequency of immunoreactants in DIF biopsies submitted over an 8-year period and assess use by dermatologists based on clinical impression. A quality improvement study was conducted in a community outreach reference laboratory associated with a large academic medical center. Results of 2050 consecutive DIF skin biopsies submitted to the laboratory between April 1, 2012, and June 12, 2020, were analyzed by final pathologic diagnosis and antibody subtype positivity, in comparison with clinical impression. Biopsies in which the submitting physician had not performed the biopsy were excluded. Histopathologic findings and the results of DIF biopsies using the standard 6-antibody panel were evaluated in correlation with the submitted clinical diagnosis to assess immunoreactivity of the assay. Of 2050 DIF biopsies submitted, 367 (17.9%) were positive; IgG, IgA, and C3 alone identified all primary immunobullous disease cases (pemphigoid, pemphigus, linear IgA, and dermatitis herpetiformis), and IgA, C3, and fibrin antibodies alone identified all vasculitis cases. A panel of IgG, IgA, IgM, and fibrin identified all cases of lupus erythematosus. DIF results were positive in less than half of cases of hematoxylin and eosin biopsy-confirmed lupus erythematosus (23 of 47 [49%]). A total of 247 biopsies were submitted for clinical diagnoses not optimally supported on DIF: lichen planus, porphyria, and connective tissue disease. The findings of this study suggest that there is a knowledge gap among dermatologists relating to the opportunity for high-value, cost-conscious use of DIF. The practice of reflexive antibody testing using a 6-antibody panel for all DIF biopsies is likely unnecessary. DIF protocols tailored to the clinical diagnosis may enhance cost-effectiveness without loss of test sensitivity or specificity.
proteins
2025-05-22 | Letter: Supporting the Role of Enzyme Therapy in Management of Coeliac Disease
I appreciate the opportunity to comment on the review article by Bonner et al. [1]. The article rightly highlights the duodenum as the site where enzymatic interaction with gluten will be most beneficial. The caricain-based supplement was the first technology proposing the small intestine as the site of enzyme activity through extensive in vitro studies and clinical trials. The product formulation involves the combination of an acid-resistant coating and superdisintegrant excipients to ensure rapid release of the enzyme in the duodenum, post gastric emptying. There it neutralises partially digested gluten immunogenic peptides (GIPs) in conjunction with brush border peptidases before symptoms and immune activation occur. Caricain (EC 3.4.22.30) is a well-characterised cysteine endopeptidase derived from Carica papaya which cleaves proline-rich motifs in gluten [2]. It offers a high degree of protection against the toxic action of gliadin on rat liver lysosomes [3], mimicking pathological alterations to lysosomes seen in the mucosa of the small intestine [4]. Caricain rapidly digests GIPs in pepsin trypsin-treated gliadin [5] and also extensively hydrolyses Wheat ⍺-Amylase Trypsin Inhibitors (ATIs) [6]. Unlike exopeptidases (DPPIV), which inefficiently degrade gluten [5, 7] caricain rapidly degrades GIPs into non-immunogenic fragments, including the 33-mer, under physiologically relevant conditions (pH 3–7) and is stable to the action of gastric proteases, trypsin, and pepsin [5]. Missing from the review of Bonner et al. are two important peer-reviewed reports of randomised, double-blind, placebo-controlled clinical studies published in an international searchable journal. The first study evaluated caricain's efficacy in dermatitis herpetiformis. Despite a substantial gluten challenge (6 g/day for 14 days), supplementation with caricain demonstrated significant protective effects with an 81% reduction in skin lesion area (19.5 to 3.7 cm2; p = 0.02), 71% decrease in new lesions, and 38% decline in pruritus compared to placebo [8]. The second study investigated the effects of caricain supplementation in patients with coeliac disease in remission undergoing a controlled gluten challenge for 42 days. Overall symptom scores and five individual symptoms (well-being, fatigue, nausea/vomiting, stomach pain and cramps, at day 14) favoured caricain over placebo (p < 0.01 for each). Dropouts occurred almost exclusively in the group randomised to placebo, due to the clinical effects of the gluten challenge; those randomised to caricain tolerated the challenge well [9]. Indeed, the large, statistically significant effects were secured even with a small sample size. The observed protective effects support caricain's intended role to mitigate the effects of inadvertent gluten exposure. Enzyme therapies like caricain offer protection against gluten before it triggers immune responses. The mechanism is localised to the gastrointestinal lumen, with no direct effects on the immune system or intestinal healing. This distinction is critical to avoid misclassification as disease-modifying treatments. The authors are to be commended for bringing attention to the benefits of enzyme therapy in the management of coeliac disease, which these studies support. Finlay Macrae: conceptualization, writing – original draft, writing – review and editing, methodology, project administration. This article is linked to Bonner et al. paper. To view this article, visit https://onlinelibrary.wiley.com/doi/10.1111/apt.70014 and https://onlinelibrary.wiley.com/doi/10.1111/apt.70205. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
2020-07-16 | Sourdough Fermentation Degrades Wheat Alpha-Amylase/Trypsin Inhibitor (ATI) and Reduces Pro-Inflammatory Activity
The ingestion of gluten-containing foods can cause wheat-related disorders in up to 15% of wheat consuming populations. Besides the role of gluten, α-amylase/trypsin inhibitors (ATI) have recently been identified as inducers of an innate immune response via toll-like receptor 4 in celiac disease and non-celiac wheat sensitivity. ATI are involved in plant self-defense against insects and possibly in grain development. Notably, they are largely resistant to gastrointestinal proteases and heat, and their inflammatory activity affects not only the intestine, but also peripheral organs. The aim of this study was to understand the changes of ATI throughout the sourdough and yeast-fermented bread-making processes. ATI tetramers were isolated, fluorescein-labelled, and added to a mini-dough bread-making system. When the pH decreased below 4.0 in sourdough fermentation, the ATI tetramers were degraded due to the activation of aspartic proteases, whilst in yeast fermentation, ATI tetramers remained intact. The amylase inhibitory activity after sourdough fermentation decreased significantly, while the concentration of free thiol groups increased. The glutathione reductase activity of Fructilactobacillus sanfranciscensis did not contribute to the reduction of ATI tetramers. Compared to the unfermented wheat, sourdough fermentation was able to decrease the release of pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor alpha (TNF-α) in quantitative ATI extracts added to the human monocytic cell line THP-1. The current data suggest that sourdough fermentation can degrade ATI structure and bioactivity, and point to strategies to improve product development for wheat sensitivity patients.
2018-03-06 | A randomised, double-blind, cross-over trial to evaluate bread, in which gluten has been pre-digested by prolyl endoprotease treatment, in subjects self-reporting benefits of adopting a gluten-free or low-gluten diet
Abstract The aim of the present study was to determine if the enzyme Aspergillus niger prolyl endoprotease (ANPEP), which degrades the immunogenic proline-rich residues in gluten peptides, can be used in the development of new wheat products, suitable for gluten-sensitive (GS) individuals. We have carried out a double-blind, randomised, cross-over trial with two groups of adults; subjects, self-reporting benefits of adopting a gluten-free or low-gluten diet (GS, n 16) and a control non-GS group ( n 12). For the trial, volunteers consumed four wheat breads: normal bread, bread treated with 0·8 or 1 % ANPEP and low-protein bread made from biscuit flour. Compared with controls, GS subjects had a favourable cardiovascular lipid profile – lower LDL (4·0 ( sem 0·3) v . 2·8 ( sem 0·2) mmol/l; P =0·008) and LDL:HDL ratio (3·2 ( sem 0·4) v . 1·8 ( sem 0·2); P =0·005) and modified haematological profile. The majority of the GS subjects followed a low-gluten lifestyle, which helps to reduce the gastrointestinal (GI) symptoms severity. The low-gluten lifestyle does not have any effect on the quality of life, fatigue or mental state of this population. Consumption of normal wheat bread increased GI symptoms in GS subjects compared with their habitual diet. ANPEP lowered the immunogenic gluten in the treated bread by approximately 40 %. However, when compared with the control bread for inducing GI symptoms, no treatment effects were apparent. ANPEP can be applied in the production of bread with taste, texture and appearance comparable with standard bread.
2016-05-05 | The Effect of Enzyme Therapy on Skin Symptoms and Immune Responses in Patients with Dermatitis Herpetiformis
Background: The aetiology of coeliac disease (CD) has many similarities to that of dermatitis herpetiformis (DH), except that DH lesions are mainly manifested in the skin. Mucosal enzyme deficiency plays an important part in CD pathology. Clinical studies indicated that the gluten exposure in CD could be partly corrected by the use of enzyme supplementation. Objective: Enzyme therapy, using enterically coated tablets containing caricain, was investigated as a means of protecting patients with DH against wheat gluten. Methods: A randomized, placebo-controlled clinical trial was carried out on 20 DH patients in clinical remission. The patients were divided into two groups of 10, one group given a placebo daily and the other the enzyme â containing tablets. Both groups were challenged with 6g of gluten daily in a double-blind trial. Symptoms and signs of skin involvement were recorded and graded at the start of the trial, after 7 days and after 14 days. Blood was also taken at the start and after 14 days and assayed for IgA EMA and anti-gliadin antibodies. Results: After 7 days the major features associated with DH were more severe and more common with the placebo compared with enzyme therapy. Before 14 days, seven patients in total, six on placebo, had to withdraw from the trial because of the effects of the gluten challenge whilst 2 patients on therapy developed blisters, erythema and itching. Serological tests indicated that IgA EmA antibodies and anti-gliadin antibodies after 14 days were not affected significantly, but indicated that abnormally high antibodies titers of both types were present in 8 patients at the start of the trial, suggesting the need for enzyme therapy in addition to the normal gluten-free diet for patient well-being. Conclusions: This study supports the use of enzyme supplementation as a safeguard for patients with DH on a nominal gluten-free diet.
2015-09-04 | Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease
Objective
The short isoform of thymic stromal lymphopoietin (TSLP), a cytokine constitutively expressed by epithelial cells, is crucial in preserving immune tolerance in the gut. TSLP deficiency has been implicated in sustaining intestinal damage in Crohn9s disease. We explored mucosal TSLP expression and function in refractory and uncomplicated coeliac disease (CD), a T-cell-mediated enteropathy induced by gluten in genetically susceptible individuals.
Design
TSLP isoforms—long and short—and receptors—TSLPR and interleukin (IL)-7Rα—were assessed by immunofluorescence, immunoblotting and qRT-PCR in the duodenum of untreated, treated, potential and refractory patients with CD. The ability of the serine protease furin or CD biopsy supernatants to cleave TSLP was evaluated by immunoblotting. The production of interferon (IFN)-γ and IL-8 by untreated CD biopsies cultured ex vivo with TSLP isoforms was also assessed.
Results
Mucosal TSLP, but not TSLPR and IL-7Rα, was reduced in untreated CD and refractory CD in comparison to treated CD, potential CD and controls. Transcripts of both TSLP isoforms were decreased in active CD mucosa. Furin, which was overexpressed in active CD biopsies, was able to cleave TSLP in vitro. Accordingly, refractory and untreated CD supernatants showed higher TSLP-degrading capacity in comparison to treated CD and control supernatants. In our ex vivo model, both TSLP isoforms significantly downregulated IFN-γ and IL-8 production by untreated CD biopsies.
Conclusions
Reduced mucosal TSLP expression may contribute to intestinal damage in refractory and untreated CD. Further studies are needed to verify whether restoring TSLP might be therapeutically useful especially in refractory patients with CD.
small molecules
2026-09-22 | DIAGNOSTIC METHODS AND ADVANCES IN THE TREATMENT OF HERPETIFORM DERMATITIS
Dermatitis herpetiformis (DH) is a chronic autoimmune skin disease associated with gluten-sensitive enteropathy, characterized by intensely pruritic papulovesicular lesions with a predominantly symmetrical distribution on the extensor surfaces. The aim of this study was to examine the main diagnostic methods and therapeutic advances used in the management of DH. A narrative literature review was conducted in PubMed using the search terms “Dermatitis Herpetiformis” and “Therapy,” and publications from the past 5 years were selected. It was found that direct immunofluorescence of the perilesional skin is the gold standard for diagnosis, while serological markers—especially antibodies against tissue and epidermal transglutaminase—serve a complementary role and are useful for monitoring. HLA-DQ2/DQ8 genotyping has a high negative predictive value. Treatment is based on a gluten-free diet, combined with dapsone for rapid control of skin manifestations, although its use requires close monitoring due to hematologic toxicity. New strategies, including modulation of the gut microbiota, show potential as adjuvant therapy but still require more robust clinical evidence.
2026-08-20 | Dapsone: A Comprehensive Review of Its Pharmacological Foundations, Clinical Indications, and Management
Dapsone (4,4'-diaminodiphenyl sulfone) is a sulfone antibiotic with a storied history in pharmacotherapy, initially synthesized in the early 20th century and repurposed over decades for a diverse range of infectious and inflammatory conditions. While its FDA-approved indications are primarily restricted to leprosy, dermatitis herpetiformis, and acne vulgaris, its off-label utilization spans a remarkable spectrum of neutrophilic and autoimmune dermatoses, as well as infectious disease prophylaxis. This review provides a comprehensive, evidence-based analysis of dapsone's pharmacodynamic properties, focusing on its dual mechanism of action: competitive inhibition of the folic acid synthesis pathway in Mycobacterium leprae and modulation of neutrophilic inflammation through interference with the myeloperoxidase-halide system and leukotriene B4-mediated chemotaxis. Furthermore, the review elucidates its complex pharmacokinetic profile, characterized by near-complete oral absorption, extensive hepatic metabolism via the cytochrome P450 system, and a prolonged and variable elimination half-life, which necessitates careful dose individualization. The clinical applications of dapsone are scrutinized, detailing standardized multidrug regimens for leprosy and dose-titration strategies for dermatitis herpetiformis, while also outlining its therapeutic potential in various off-label contexts. A critical component of this review is the analysis of dapsone's significant adverse effect profile, which includes dose-dependent hemolytic anemia, methemoglobinemia, and the potentially life-threatening dapsone hypersensitivity syndrome, thereby underscoring the imperative for rigorous baseline and ongoing patient monitoring. The review synthesizes this information to provide a pragmatic framework for interprofessional healthcare teams, emphasizing the collaborative roles of physicians, pharmacists, and nurses in optimizing therapeutic outcomes while minimizing patient risk.
2026-07-31 | Gluten-Responsive Probable Pediatric Dermatitis Herpetiformis Mimicking Varicella in a Five-Year-Old Child: A Case Report
Background: Dermatitis herpetiformis (DH) is a gluten-associated autoimmune vesiculobullous dermatosis that is rare in children and may resemble infectious eruptions, particularly varicella. Case presentation: A 5-year-old boy presented with persistent, painful, and intensely pruritic grouped vesicles and tense bullae, predominantly affecting the posterior trunk and upper back. Although he had a history of varicella at 3 years of age, the current episode was not preceded by known varicella exposure, fever, or prodromal symptoms. The eruption was initially diagnosed as varicella due to its vesiculobullous morphology, and a 5-day course of acyclovir was administered. Over approximately 1 month of close monitoring, some lesions transiently dried and faded, but new grouped vesicles and bullae repeatedly appeared, became more widespread, and remained painful and pruritic. Recurrent flares were subsequently observed after ingestion of gluten-containing foods. Laboratory findings were unremarkable except for eosinophilia of 14% and a serum IgE of 91.88 IU/mL. IgA-based celiac serology, histopathology, and direct immunofluorescence were not performed because the parents declined. The clinical pattern, gluten-associated recurrence, lack of sustained response to acyclovir, and improvement with gluten avoidance supported a working diagnosis of gluten-responsive probable pediatric DH. Clinical improvement was achieved with lesion-directed topical therapy, symptomatic treatment, and a strict gluten-free diet. Conclusion: This case underscores a varicella-mimicking, gluten-responsive probable pediatric DH presentation and highlights the importance of transparent reporting of diagnostic uncertainty when confirmatory testing is unavailable.
2026-07-14 | Exuberant Dermatitis Herpetiformis With Oral Involvement Mimicking Behçet Disease and Disseminated Herpetic Infection: The Crucial Role of Direct Immunofluorescence.
Dermatitis herpetiformis (DH) is a chronic autoimmune blistering dermatosis associated with gluten-sensitive enteropathy and characterized by intensely pruritic papulovesicular eruptions, typically distributed symmetrically on extensor surfaces. Although DH classically presents with grouped vesicles and excoriated papules, atypical and exuberant manifestations may represent a substantial diagnostic challenge, frequently mimicking infectious, inflammatory, and autoimmune blistering disorders. We report the case of a 30-year-old woman presenting with a one-year history of progressive, intensely pruritic vesiculobullous and erosive lesions involving the trunk and extremities, accompanied by painful oral ulcerations, hemorrhagic crusts, extensive excoriations, secondary bacterial infection, and diffuse post-inflammatory hyperpigmentation. The patient was initially diagnosed with Behçet disease and subsequently hospitalized for suspected disseminated herpetic infection, receiving systemic corticosteroids and intravenous acyclovir without significant clinical improvement. Dermatological examination revealed widespread erosive and vesiculobullous lesions associated with severe inflammatory activity and oral aphthoid ulcerations. Histopathological examination of active lesions demonstrated intraepidermal blister formation associated with eosinophilic infiltrate and scattered acantholytic cells, findings that initially suggested alternative autoimmune blistering disorders. Direct immunofluorescence (DIF) demonstrated characteristic granular IgA deposition predominantly localized at the tips of dermal papillae, confirming the diagnosis of DH despite atypical histopathological findings. Serological evaluation further revealed positive anti-tissue transglutaminase and anti-endomysial antibodies, corroborating the diagnosis. Treatment with dapsone combined with a strict gluten-free diet resulted in marked clinical improvement. This case highlights the importance of clinicopathological and immunopathological correlation in atypical presentations of autoimmune blistering diseases and underscores the essential role of DIF in establishing the diagnosis of DH.
2026-01-08 | Health Risks Associated with a Long-Term Gluten-Free Diet and the Potential Protective Role of Anthocyanins.
Gluten-free diets (GFDs) are gaining popularity worldwide. Originally, GFDs were designed for individuals with gluten intolerance, including conditions such as celiac disease, non-celiac gluten sensitivity, gluten ataxia, or dermatitis herpetiformis. However, many individuals without gluten sensitivity have subsequently adopted this diet, leading to a growing demand for gluten-free food products. Meanwhile, the health risks associated with a long-term gluten-free diet (LTGFD) and the inherent related issues, such as nutrient imbalances, remain uncertain. Scientific studies have indicated that obesity, non-alcoholic fatty liver disease (NAFLD), dysbiosis, and poor mental health represent the most probable health risks associated with a LTGFD. Moreover, high fat and simple carbohydrate content, increased calorie content, and vitamin deficiencies, including vitamin B derivatives (B1, B2, B3, B5, B6, B7, B9, and B12), vitamin D, and minerals (Fe, Mg, Se, and Zn), are key components in a GFD that are at the helm of health issues due to a LTGFD. Anthocyanins, a class of flavonoids found predominantly in red, purple, and blue fruits and vegetables, may provide a promising solution to alleviate health risks associated with a LTGFD due to their inherent antioxidant, anti-inflammatory, neuroprotective, anti-diabetic, and anti-obesity properties. Therefore, this review critically examines in vivo, in vitro, clinical, and mechanistic studies to explore the potential of anthocyanin-enriched GFDs in alleviating the health risks associated with a LTGFD, highlighting their significant advantages over regular GFDs.
antibodies
2025-12-15 | A systematic review of therapeutic and paradoxical roles of tumor necrosis factor α inhibitors in autoimmune blistering diseases.
Autoimmune blistering diseases (AIBDs), including pemphigus diseases, pemphigoid diseases, linear immunoglobulin A (IgA) bullous dermatosis (LABD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH), are a group of diseases clinically characterized by erosions and blisters that involve the skin and mucosa. Tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine, plays a critical role in their pathogenesis. TNF-α inhibitors are used for their immunomodulatory effects but may also induce paradoxical autoimmune blistering. This systematic review aimed to synthesize current evidence on therapeutic and paradoxical effects of TNF-α inhibitors in these diseases. A systematic search of PubMed, Scopus, and Embase was conducted up to March 7th, 2025, following PRISMA guidelines. Studies eligible for inclusion were original human research articles in English reporting therapeutic or paradoxical effects of TNF-α inhibitors, including infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab, on autoimmune bullous diseases. Risk of bias was evaluated using the NIH and Murad et al. assessment tools. A total of 35 studies with 68 patients were included in the treatment application group and 29 studies with 31 subjects were included in the paradoxical reaction group. Infliximab was most frequently associated with favorable outcomes in pemphigus vulgaris (PV), bullous pemphigoid (BP), and EBA, with multiple reports of sustained remission. Etanercept showed partial to complete responses in some cases of PV and BP; however, it was associated with paradoxical induction of BP in several patients. Adalimumab demonstrated therapeutic efficacy in PV and MMP, yet was the most common agent implicated in paradoxical BP and LABD. Paradoxical effects were most often observed in patients treated for non-dermatologic conditions such as rheumatoid arthritis or Crohn's disease. TNF-α inhibitors, particularly infliximab, show therapeutic promise in refractory AIBDs. However, their potential to paradoxically induce blistering diseases, especially with adalimumab and etanercept, necessitates careful patient selection, close monitoring, and individualized risk-benefit assessment.
2025-06-27 | HX02 From arsenic to rituximab: a history of dermatitis herpetiformis
Abstract Dr Edward Tilbury Fox was the first to describe dermatitis herpetiformis (DH) in 1872, calling it ‘hydroa herpetiformis’. In 1884, Louis Duhring first used the term ‘dermatitis herpetiformis’, due to the grouped herpetiform vesicles. Early therapies were limited: for the wealthy, a visit to Harrogate spa, oral arsenic and sulfur ointment were preferred; a 3-week stay in hospital was the alternative for others. Additional treatments included quinine, belladonna, strychnine and ergot. Norman Walker declared that the prognosis was: ‘good…if the patient does not commit suicide on account of the mental disturbance brought about by the itching, but with regard to a speedy cure it is undeniably bad’ (Walker N, Percival GH. An Introduction to Dermatology, 10th edn. Edinburgh: W. Green, 1939). Various early 20th century doctors noted anecdotal benefits of dietary restriction. In 1912, a patient with intractable DH cleared entirely after a fortnight taking nothing but water. Dermatologists struggled to persuade subsequent patients ‘to undergo more than two or three days of starvation’. The first major breakthrough came in 1950, when it was recognized that dapsone immediately abolished the itch and rash, and it became the mainstay of treatment. In 1966, Janet Marks showed the association between DH and coeliac disease (CD), noting the high proportion of patients with DH with abnormalities of the small intestinal mucosa. This was corroborated in 1968, when Lionel Fry observed improvements in the skin, intestinal mucosa and nutrition of a small number of patients with DH following a gluten-free diet (GFD). From 1977, once Timo Reunala proved in a larger study that both the disease burden and reliance on dapsone reduced drastically in patients maintaining a GFD, it became standard therapy. Jejunal biopsy is no longer routine in patients with DH; all are assumed to have gluten sensitivity. The 1969 observation of IgA deposits at the dermal papillae of uninvolved skin suggested the role of antibodies in its aetiology. In 1972, demonstration of the association of the specific human leucocyte antigen (HLA) haplotypes such as HLA-A8 with both DH and CD implied a genetic predisposition. Serum antiepidermal transglutaminase antibodies have since been shown to be a specific diagnostic marker for DH and CD. A GFD and dapsone remain the cornerstones of treatment, with IgA deposits on skin immunofluorescence the gold-standard diagnostic test. Rituximab has been reported to cause complete remission. Ongoing research into the immunopathogenesis of DH may lead to more targeted treatments.
2025-03-11 | Enzyme-activating B-cell receptors boost antigen presentation to pathogenic T cells in gluten-sensitive autoimmunity.
Autoantibodies against the enzyme transglutaminase 3 (TG3) are characteristic to the gluten-sensitive skin disorder dermatitis herpetiformis (DH), which is an extraintestinal manifestation of celiac disease. We here demonstrate that TG3-specific B cells can activate gluten-specific CD4+ T cells through B-cell receptor (BCR)-mediated internalization of TG3-gluten enzyme-substrate complexes. Stereotypic anti-TG3 antibodies using IGHV2-5/IGKV4-1 gene segments enhance the catalytic activity of TG3, and this effect translates into increased gluten presentation to T cells when such antibodies are expressed as BCRs. The crystal structure of TG3 bound to an IGHV2-5/IGKV4-1 Fab shows that antibody binding to a β-sheet in the catalytic core domain causes the enzyme to adopt the active conformation. This mechanism explains the production of stereotypic anti-TG3 autoantibodies in DH and highlights a role for TG3-specific B cells as antigen-presenting cells for gluten-specific T cells. Similar boosting effects of autoreactive BCRs could be relevant for other autoimmune diseases, including rheumatoid arthritis.
2023-06-01 | P12 A flare of dermatitis herpetiformis precipitated by etanercept
Abstract We report the case of a 79-year-old man who presented with an acute, intensely pruritic, widespread rash, which, on examination, consisted of symmetrical, haemorrhagic nodules and vesicles with some desquamation affecting the extensor surfaces of the arms, flexor surfaces of the legs and the natal cleft. He had a history of coeliac disease (for which he had adhered to a strict gluten-free diet since 1997) and rheumatoid arthritis. He had his first dose of the anti-tumour necrosis factor (TNF) agent etanercept prior to this episode to manage his arthritis. A punch biopsy for histopathology showed subepidermal blisters with a predominance of neutrophils. Eosinophils were also present to the level of the eccrine coils within the dermis, with eosinophilic flame figures but no eosinophil spongiosis at the edges of the blister. Direct immunofluorescence showed granular IgM and IgA in the dermal papillae, and a similar reaction was seen with fibrinogen. These histological findings were strongly suggestive of dermatitis herpetiformis (DH). Owing to diagnostic uncertainty on presentation, initial treatment was with high-dose topical steroids and emollient. and a yellow card was completed. Since this presentation, he has had no further flares and has not required dapsone. Multidisciplinary team discussion decided that the patient should avoid other anti-TNF treatments, but he has found relief for multiple months with rituximab and has had no cutaneous adverse events on this agent. The aetiology of DH following anti-TNF treatment is not immediately clear. Increased immunogenicity and cytokine release have been hypothesized to be part of the pathology of many adverse reactions to anti-TNF agents. It is conceivable that the cytokine release ordinarily seen in DH is replicated by the administration of anti-TNF agents. There have been many cases of anti-TNF agents leading to worsening eczema and psoriasis. Interestingly, these conditions have been found to upregulate TNF-α, a feature that is also seen in DH. This appears to be the first case described in the literature of etanercept-induced DH. A reaction with infliximab was reported in 2008, with a similar rash and histology consistent with DH, but it differed as the patient had no prior diagnosis of coeliac disease and presented after their second dose (Marakli SS, Uzun S, Ozbek S, Tuncer I. Dermatitis herpetiformis in a patient receiving infliximab for ankylosing spondylitis. Eur J Dermatol 2008; 18:88–9).
2022-03-25 | Assessment of Clinical and Laboratory Use of the Cutaneous Direct Immunofluorescence Assay.
Dermatologists submit direct immunofluorescence (DIF) biopsies on a daily basis, using an assay detecting immunoreactant deposition with a panel that has traditionally comprised immunoglobulin (Ig) G, IgA, IgM, C3, and fibrin, with or without albumin antibodies. To evaluate and compare the frequency of immunoreactants in DIF biopsies submitted over an 8-year period and assess use by dermatologists based on clinical impression. A quality improvement study was conducted in a community outreach reference laboratory associated with a large academic medical center. Results of 2050 consecutive DIF skin biopsies submitted to the laboratory between April 1, 2012, and June 12, 2020, were analyzed by final pathologic diagnosis and antibody subtype positivity, in comparison with clinical impression. Biopsies in which the submitting physician had not performed the biopsy were excluded. Histopathologic findings and the results of DIF biopsies using the standard 6-antibody panel were evaluated in correlation with the submitted clinical diagnosis to assess immunoreactivity of the assay. Of 2050 DIF biopsies submitted, 367 (17.9%) were positive; IgG, IgA, and C3 alone identified all primary immunobullous disease cases (pemphigoid, pemphigus, linear IgA, and dermatitis herpetiformis), and IgA, C3, and fibrin antibodies alone identified all vasculitis cases. A panel of IgG, IgA, IgM, and fibrin identified all cases of lupus erythematosus. DIF results were positive in less than half of cases of hematoxylin and eosin biopsy-confirmed lupus erythematosus (23 of 47 [49%]). A total of 247 biopsies were submitted for clinical diagnoses not optimally supported on DIF: lichen planus, porphyria, and connective tissue disease. The findings of this study suggest that there is a knowledge gap among dermatologists relating to the opportunity for high-value, cost-conscious use of DIF. The practice of reflexive antibody testing using a 6-antibody panel for all DIF biopsies is likely unnecessary. DIF protocols tailored to the clinical diagnosis may enhance cost-effectiveness without loss of test sensitivity or specificity.
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Drug Discovery Landscape
1 orphan drug designation for Dermatitis herpetiformis.
1 orphan drug designation for Dermatitis herpetiformis.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Sulfapyridine | small molecules | FDA | — | Jacobus Pharmaceutical Company |
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