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Verdelli A, Corrà A, Mariotti EB, Aimo C, Quintarelli L, Ruffo di Calabria V, Donati ME, Bonciolini V, Antiga E, Caproni M. Skin gluten-related disorders: new and old cutaneous manifestations to be considered. Front Med (Lausanne) 2023; 10:1155288. [PMID: 37265490 PMCID: PMC10229844 DOI: 10.3389/fmed.2023.1155288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 04/28/2023] [Indexed: 06/03/2023] Open
Abstract
The term gluten-related disorders (GRD) refer to a spectrum of different clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals, including coeliac disease (CD), wheat allergy and non-celiac gluten sensitivity (NCGS). GRD are characterized by a large variety of clinical presentations with both intestinal and extra-intestinal manifestations. The latter may affect almost every organ of the body, including the skin. Besides the well-known association between CD and dermatitis herpetiformis, considered as the cutaneous specific manifestation of CD, many other muco-cutaneous disorders have been associated to GRD. In this review, we analyzed the main features of dermatological diseases with a proven association with GRD and those that improve after a gluten-free diet, focusing on the newly described cutaneous manifestations associated with NCGS. Our main hypothesis is that a "cutaneous-gluten sensitivity," as specific cutaneous manifestation of NCGS, may exist and could represent a diagnostic marker of NCGS.
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Affiliation(s)
- Alice Verdelli
- Department of Health Sciences, Rare Dermatological Diseases Unit, Azienda USL Toscana Centro, European Reference Network-Skin Member, Florence, Italy
| | - Alberto Corrà
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | | | - Cristina Aimo
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Lavinia Quintarelli
- Department of Health Sciences, Rare Dermatological Diseases Unit, Azienda USL Toscana Centro, European Reference Network-Skin Member, Florence, Italy
| | | | - Marta Elettra Donati
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | | | - Emiliano Antiga
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Marzia Caproni
- Department of Health Sciences, Rare Dermatological Diseases Unit, Azienda USL Toscana Centro, European Reference Network-Skin Member, Florence, Italy
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Antiga E, Maglie R, Quintarelli L, Verdelli A, Bonciani D, Bonciolini V, Caproni M. Dermatitis Herpetiformis: Novel Perspectives. Front Immunol 2019; 10:1290. [PMID: 31244841 PMCID: PMC6579917 DOI: 10.3389/fimmu.2019.01290] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 05/21/2019] [Indexed: 02/06/2023] Open
Abstract
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.
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Affiliation(s)
- Emiliano Antiga
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Roberto Maglie
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Lavinia Quintarelli
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Alice Verdelli
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Diletta Bonciani
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Veronica Bonciolini
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Marzia Caproni
- Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
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Cutaneous and Mucosal Manifestations Associated with Celiac Disease. Nutrients 2018; 10:nu10070800. [PMID: 29933630 PMCID: PMC6073559 DOI: 10.3390/nu10070800] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 06/15/2018] [Accepted: 06/18/2018] [Indexed: 12/12/2022] Open
Abstract
Celiac disease (CD) is an immune-mediated, gluten-induced enteropathy that affects predisposed individuals of all ages. Many patients with CD do not report gastrointestinal symptoms making it difficult to reach an early diagnosis. On the other hand, CD is related to a wide spectrum of extra-intestinal manifestations, with dermatitis herpetiformis (DH) being the best characterized. These associated conditions may be the clue to reaching the diagnosis of CD. Over the last few years, there have been multiple reports of the association between CD and several cutaneous manifestations that may improve with a gluten-free diet (GFD). The presence of some of these skin diseases, even in the absence of gastrointestinal symptoms, should give rise to an appropriate screening method for CD. The aim of this paper is to describe the different cutaneous manifestations that have been associated with CD and the possible mechanisms involved.
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Bresler SC, Granter SR. Utility of direct immunofluorescence testing for IgA in patients with high and low clinical suspicion for dermatitis herpetiformis. Am J Clin Pathol 2015; 144:880-4. [PMID: 26572994 DOI: 10.1309/ajcpxivsr6ozk1hu] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
OBJECTIVES The purpose of this study was to examine the utility of direct immunofluorescence (DIF) testing for the characteristic immunoglobulin A deposits of dermatitis herpetiformis (DH) in patients stratified into high and low clinical suspicion subgroups. METHODS We retrospectively analyzed the results of H&E and DIF testing in 77 cases of suspected DH and separated them into high and low clinical suspicion subgroups based on clinical impression at the time of biopsy. RESULTS The overall sensitivity and specificity of routine (H&E) histologic evaluation were 0.75 and 0.951, respectively. Although there were 13 cases of DH (of 36 total cases) in the high clinical suspicion subgroup, there were only three (of 41 total cases) in the low clinical suspicion subgroup. In the high clinical suspicion subgroup, the positive predictive value (PPV) was 0.9, and the negative predictive value (NPV) was 0.846. Alternatively, the PPV was 0.6 and the NPV was 1.0 for the low clinical suspicion subgroup. Histologic false negatives did occur, but all were in patients within the high clinical suspicion subgroup. CONCLUSIONS It is anticipated that the NPV and PPV will vary due to differing clinical practice characteristics; however, in patients with a low clinical suspicion for DH, these data argue that it may be reasonable to first perform a biopsy for routine histologic evaluation before requesting DIF analysis.
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Abstract
Case finding for celiac disease (CD) is becoming increasingly common practice and is conducted in a wide range of clinical situations ranging from the presence of gastrointestinal symptoms to failure to thrive in children, prolonged fatigue, unexpected weight loss and anemia. Case finding is also performed in associated conditions, such as autoimmune thyroid disease, dermatitis herpetiformis and type 1 diabetes, as well as in patients with irritable bowel syndrome, unexplained neuropsychiatric disorders and first-degree relatives of patients with diagnosed CD. This aggressive active case finding has dramatically changed the clinical characteristics of newly diagnosed patients. For instance, higher numbers of patients who present with extraintestinal symptoms are now being diagnosed with CD. Current recommendations state that due to a high risk for complications if the disease remains undiagnosed, patients with extraintestinal symptoms due to CD require appropriate diagnosis and treatment. Despite criticism regarding the cost-effectiveness of case finding in CD, such an aggressive approach has been considered cost-effective for high-risk patients. The diagnosis of CD among patients with extraintestinal symptoms requires a high degree of awareness of the clinical conditions that carry a high risk for underlying CD. Also, understanding the correct use of specific serology and duodenal histology is key for an appropriate diagnostic approach. Both procedures combined are able to confirm diagnosis in the vast majority of cases. However, in certain circumstances, serology and even duodenal histology cannot confirm or rule out CD. A common cause of negative IgA serology is IgA deficiency. For such eventuality, IgG-based serological tests can help confirm the diagnosis. Importantly, some histologically diagnosed cases still remain seronegative despite exclusion of IgA deficiency. On the other hand, duodenal histology may be normal despite the presence of CD-specific antibodies and active CD. This has been clearly demonstrated in some cases of untreated dermatitis herpetiformis, but may also be due to the patchy condition of CD or lesions that are not adequately recognized by nonexpert endoscopists and/or pathologists. The effectiveness of agluten-free diet depends on the clinical end point addressed. A good example is the outcome of bone loss. While risk for fracture normalizes after the first year of dietary treatment, bone parameters measured by densitometry may not be normalized in the long-term follow-up. Moreover, it is still unclear how far an early gluten-free diet will positively affect associated autoimmune diseases like type 1 diabetes and autoimmune thyroiditis.
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Tovoli F, Masi C, Guidetti E, Negrini G, Paterini P, Bolondi L. Clinical and diagnostic aspects of gluten related disorders. World J Clin Cases 2015; 3:275-284. [PMID: 25789300 PMCID: PMC4360499 DOI: 10.12998/wjcc.v3.i3.275] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 10/28/2014] [Accepted: 12/17/2014] [Indexed: 02/05/2023] Open
Abstract
Gluten is one of the most abundant and widely distributed components of food in many areas. It can be included in wheat, barley, rye, and grains such as oats, barley, spelt, kamut, and triticale. Gluten-containing grains are widely consumed; in particular, wheat is one of the world’s primary sources of food, providing up to 50% of the caloric intake in both industrialized and developing countries. Until two decades ago, celiac disease (CD) and other gluten-related disorders were believed to be exceedingly rare outside of Europe and were relatively ignored by health professionals and the global media. In recent years, however, the discovery of important diagnostic and pathogenic milestones led CD from obscurity to global prominence. In addition, interestingly, people feeding themselves with gluten-free products greatly outnumber patients affected by CD, fuelling a global consumption of gluten-free foods with approximately $2.5 billion in United States sales each year. The acknowledgment of other medical conditions related to gluten that has arisen as health problems, providing a wide spectrum of gluten-related disorders. In February 2011, a new nomenclature for gluten-related disorders was created at a consensus conference in London. In this review, we analyse innovations in the field of research that emerged after the creation of the new classification, with particular attention to the new European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for CD and the most recent research about non-celiac gluten sensitivity.
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Huber C, French LE, Hafner J. Response to letter to the editor on skin manifestations of celiac disease: not always dermatitis herpetiformis. Int J Dermatol 2014; 53:e383-4. [PMID: 24899090 DOI: 10.1111/ijd.12347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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