Gluten‐related skin disorders: clinical presentation, diagnostic and treatments

Summary

Gluten‐related disorders (GRDs) encompass a spectrum of clinical manifestations triggered by gluten ingestion in genetically susceptible individuals. These disorders include celiac disease (CD) and non‐celiac gluten sensitivity (NCGS) and present with both intestinal and extraintestinal symptoms, including skin manifestations. Besides the well‐known association between CD and dermatitis herpetiformis, considered as the cutaneous manifestation of CD, other dermatoses have been associated to GRDs. In this paper, we provide a concise overview of the clinical appearance, diagnosis and therapeutic management of GRDs, a tool which we hope will facilitate clinicians when faced with this challenging group of diseases.

INTRODUCTION

Gluten related disorders (GRDs) are a broad spectrum of immune‐mediated clinical manifestations triggered by gluten ingestion. ¹ Coeliac disease (CD) is the best‐characterized disease within this wide clinical spectrum. Gluten sensitivity refers to all GRDs, including those ones with serological positivity for gluten sensitivity related antibodies but without gastrointestinal symptoms. ¹ The association between CD and dermatitis herpetiformis (DH), which is considered the skin manifestation of CD, is the best known. However, several other skin disorders have also been reported in association with CD, including psoriasis, atopic dermatitis (AD), and chronic urticaria (CU). ² In addition, skin manifestations have been reported also in patients with non‐coeliac gluten sensitivity (NCGS), which is characterized by symptoms triggered by gluten ingestion that improve on gluten‐free diet (GFD). ³ In this work we discuss all skin manifestations related to gluten intake.

DERMATITIS HERPETIFORMIS

DH was described in 1884 by the American dermatologist Louis Adolphus Duhring. ⁴ DH is characterized by extremely itching papules and small blisters, characteristically arranged in a herpetiform pattern. ⁵ Our current understanding of DH is based on milestone works from the sixties that revealed the link of DH to CD and to intestinal inflammation and that identified immunoglobulin (Ig) type A as the pathologic trigger of disease. ⁶ , ⁷ , ⁸ Serological analysis of pathological IgA ultimately enabled the detection of epidermal anti‐transglutaminase (TG) 3 antibodies as the main autoantigen of DH. ⁹ TG are a group of nine enzymes with multiple functions and differential expression among tissues. ¹⁰ Only TG2 and TG7 are ubiquitously expressed, while TG1, TG2, TG3 and TG5 are expressed in the skin, mainly in the epidermis. ¹⁰ This family of proteins share similar structure and function and has both regulatory and functional capacities. Except band 4.2 protein, which lost enzymatic activity during evolution, the other members of the family (TG 1–7 and factor XIIIa) are involved in transamidation/deamidation activity. ¹⁰

Serological analysis of pathological IgA ultimately enabled the detection of epidermal anti‐TG 3 antibodies as the main autoantigen of DH.

EPIDEMIOLOGY

DH is a rare disease that primarily affects Caucasian patients, mainly due to its strong association with the distribution of predisposing human leukocyte antigens (HLA) in the population and the high consumption of wheat. ⁵ Indeed, DH has been considered extremely rare among Asian and African populations due to the low prevalence of DH‐predisposing HLA‐DQ2 and HLA‐DQ8, which are always present in Caucasian DH patients, as well as the lower wheat consumption in these regions. ¹¹ However, DH prevalence in Asian and African countries could also be underestimated, because of DH misdiagnosis due to its rarity among these populations. ¹¹ The prevalence in Europe and USA ranges between 11.2 and 39.2 patients per 100.000 inhabitants, while the incidence in the adult population in Europe and USA ranges between 0.4 and 2.6 new patients per 100.000 inhabitants per year. ¹² The highest prevalence and incidence have been reported in Finland, with 75.3 cases per 100,000 inhabitants and an incidence of 3.5 new cases per 100,000 inhabitants per year, respectively. ¹³ Although the incidence of CD has increased in recent decades, the incidence of DH has significantly declined, likely due to the earlier detection of CD. ¹⁴ DH can occur at any age, but it is mostly observed between the third and the fourth decade of life. ¹⁵ The male/female ratio in the adult population varies according to the studies, ranging from 2 : 1 to 1 : 1. ¹³ , ¹⁵ Epidemiological data on pediatric patients are limited, and published results have been inconsistent. A Finnish prospective study reported DH in only 4% of cases, whereas an Italian study of 159 DH patients found that 36% of the study population were pediatric patients. ¹⁶ One possible explanation for these differences might be that the clinical features of DH can be similar to those of AD, and therefore DH might be underestimated in the pediatric population. ¹⁷

DH is a rare disease that primarily affects Caucasian patients, mainly due to its strong association with the distribution of predisposing HLA in the population and the high consumption of wheat.

PATHOGENESIS

DH has a complex pathogenesis based on three pillars: genetic susceptibility, gluten‐sensitive enteropathy (GSE), and the production of antibodies against TG2 in the intestinal tissue and TG3 in the skin. Between 5% and 10% of DH patients have a first‐degree relative affected by DH or CD. ¹⁸ , ¹⁹ HLA‐DQ2 (DQA1*0501 and DQB1*02 alleles) and DQ8 (DQA1*03 and DQB1*0302 alleles), which are crucially involved in processing the gluten antigen gliadin, have been reported respectively in about 85% and 15% of DH patients. ²⁰ , ²¹ , ²² GSE is caused by gliadin intake, a derivate from gluten that is found in wheat, rye, barley, kamut, spelt and triticale. After ingestion, gluten is dissembled into different molecules. Gliadin is a product of gluten digestion and is eventually deamidated by TG2, which increases the antigenic potential of gliadins. Deamidated gliadins can be captured by dendritic cells of susceptible patients and be presented to T helper cells. ²³ Antibody production occurs when autoreactive T cells stimulate B cell maturation and promote antibody production against gliadin and TG2. ²³ Autoantibodies against TG2 arise in the gut due to the presence of gliadin‐TG2 complexes and TG2‐TG2‐gluten multimers. ²³ Some DH patients also produce autoantibodies against TG6. ²⁴ Although both CD and DH patients develop autoantibodies targeting both TG2 and TG3, only in DH patients show IgA autoantibodies against epidermal TG, which are detected as granular deposits at the skin papillary tips by direct immunofluorescence (DIF). ⁹ , ²³ It has not been demonstrated, how the pathological step leading to anti‐TG3 antibodies and DH occurs, but it is suggested that chronic exposure to gliadin leads to epitope spreading phenomena with production of antibody against TG3. ²⁵ This immunological explanation is in line with the clinical observation that CD does not develop concomitantly with DH but rather prior to its manifestation. The pathogenesis of pruritus is still largely unclear. Different pathways have been shown to play a role, including neurogenic inflammation, mechanical dysesthesias, and inflammatory cytokines. Substance P a non‐opioid neuropeptide leads to mast cells degranulation, which releases not only histamine, but also several cytokines, like interleukin (IL)‐1, IL‐6 and IL‐8. ²⁶ This process causes widening of vessels, increase of cell adhesion molecule expression in the endothelium cells, migration of immune cells to the skin and angiogenesis intensification, which lead to inflammation and pruritus. ²⁶ In addition, it was suggested that expression of thymic stromal lymphopoietin, an epithelial cell‐derived cytokine, correlates with intensity of pruritus. ²⁶ Furthermore, it has been reported that IL‐31 is largely involved in pruritic dermatoses related to a prevalent Th2 type inflammation. ²⁷ Indeed, overexpression of IL‐31 induces pruritus and accumulation of mast cells in murine skin. ²⁸ Furthermore, a recent study showed an elevation of IL‐31 both in serum and skin of DH patients. ²⁹ In addition, an overexpression of different neuropeptides was detected in the skin of DH patients. ²⁶

DH has a complex pathogenesis based on three pillars: genetic susceptibility, GSE, and the production of antibodies against TG2 in the intestinal tissue and TG3 in the skin.

Clinical differential diagnosis

DH skin features should be distinguished from several skin diseases, including several autoimmune blistering diseases and non‐autoimmune skin diseases, including scabies and disseminated folliculitis (Table 1).

TABLE 1.

Differential diagnoses of dermatitis herpetiformis and gluten‐related disorders.

Autoimmune blistering diseases		Non‐autoimmune diseases
Disease	Main clues	Disease	Main clues
Anti‐laminin γ1 pemphigoid	-Detection of anti‐laminin‐γ1 antibodies by immunoblot	Allergic contact dermatitis	-Detection of allergen by patch test
Bullous pemphigoid	-Detection of IgG and/or C3 deposits along the BMZ in a linear pattern by DIF -Detection of IgG against BP180 and BP230 by ELISA	Arthropod bite reactions	-Compatible medical history -Presence of itchy erythematous papules arranged in a linear pattern on the extremities
Bullous systemic lupus erythematosus	-Presence of blisters mainly on the trunk, upper extremities, supraclavicular region, face, vermillion border, and oral mucosa -Detection of serum IgG autoantibodies against dsDNA -Detection of large deposits of mucin the reticular dermis by histopathological examination	Atopic dermatitis	-Compatible medical history -Association with allergic asthma and/or allergic rhinoconjunctivitis -According to age, involvement of different areas (e.g., cheeks and folds in pediatric patients)
Epidermolysis bullosa acquisita	-Detection of IgG against collagen VII by ELISA	Disseminated folliculitis	-Presence of follicular pustules -Positive bacterial swab
IgA pemphigus	-Detection of IgA autoantibodies against desmocollin 1 by immunoblot -Detection of IgA staining in the intercellular spaces by DIF	Prurigo nodularis	-Elderly individuals -Itchy erythematous, excoriated nodules, involving mainly the extremities
Linear IgA dermatosis	-Detection of IgA deposits along the BMZ in a linear pattern by DIF	Prurigo pigmentosa	-Compatible medical history -Association with diabetes -Main involvement of the chest and/or neck
Pemphigus herpetiformis	-Detection of IgG against desmoglein 1 and 3 by ELISA -Detection of IgG autoantibodies against desmocollin 1 and 3 by immunoblot -Detection of intercellular staining with IgG and C3 by DIF	Scabies	-Involvement of more individuals of the same family or group -Detection of burrows (fine, wavy and slightly scaly lines), especially in the main body folds

Abbr.: BMZ, basal membrane zone; BP, bullous pemphigoid; DIF, direct immunofluorescence; ELISA, enzyme‐linked immunosorbent assay; IB, immunoblot.

CLINICAL PRESENTATION

DH clinical features are very characteristic. Primary lesions are represented by grouped erythematous papules with vesicles on top, arranged in a herpetiform pattern (Figure 1a). ⁵ , ³⁰ However, because of the severe pruritus, scratch‐induced erosions and excoriations can modify the clinical presentation (Figure 1b). Pruritus is the pivotal symptom of DH, and its absence makes the diagnosis of DH unlikely. Papules are symmetrically distributed on the extensor surfaces of the extremities (especially elbows and knees), neck (Figure 1c), and buttocks. ⁵ , ³⁰ The involvement of face, front head (Figure 1d), and groin can be also observed. ⁵ , ³⁰ Usually, lesions heal without scarring, and post‐inflammatory hyper‐ or hypopigmentation is frequent. ⁵ , ³⁰ Mucosal involvement is rare, but erythematous macules and erosions of the oral mucosa with soreness or a burning sensation have been described. ³¹ , ³² In addition, dental abnormalities have been reported in patients with DH, mostly horizontal grooves, defects in enamel color, and enamel pits. ³³ , ³⁴ Atypical skin manifestations have been also reported. Pediatric patients, and rarely adults, can show asymptomatic palmoplantar petechiae, mostly at the dominant hand or foot. ³⁵ , ³⁶ Furthermore. DH with palmoplantar keratosis and prurigo pigmentosa‐like lesions have been also reported anecdotally. ³⁷ , ³⁸ , ³⁹

Primary lesions are represented by grouped erythematous papules with vesicles on top, arranged in a herpetiform pattern.

FIGURE 1.

Clinical features of dermatitis herpetiformis. (a) Grouped erythematous papules arranged in an herpetiform pattern. (b) Skin excoriation due to intense pruritus, typical for dermatitis herpetiformis. (c) Small blisters on erythematous skin in a patient with phototype V according to Fitzpatrick's phototype classification. (d) Excoriations on the forehead.

DIAGNOSIS

Diagnosis of DH relies on a group of different investigations and should be performed in patients with clinical lesions compatible with DH. While DIF is the pivotal diagnostic tool for correct diagnosis, histological examination and serological analysis can help to complete the diagnostic panel. ⁴⁰ The diagnostic workout can be divided between major criteria for DH diagnosis (positive medical history for CD, clinical presentation and positive DIF) (Table 2) and secondary criteria, including histology, serological diagnostic and duodenal biopsy (Table 3). DIF should be performed on intact skin, 1–3 mm beside affected skin. ⁴⁰ It is mandatory to perform DIF before starting dapsone or GFD, because both can rapidly lead to false negative results. ⁴⁰ DIF typically detects granular IgA deposits along the dermo‐epidermal junction (DEJ) and in the vessels of papillary tips (Figure 2a). ⁵ , ³⁰ Less frequently, IgA deposition can be observed in elastic fibers, arrector pili muscles, fibers around hair follicles, and in the basement membrane of sweat glands and ducts. ⁴¹ Occasionally, IgA deposits can be detected along the basement membrane of the hair follicles and in the vessels of reticular dermis. ⁴¹ Furthermore, fibrinogen deposition at the same sites of IgA deposits can be observed. ⁴¹ Minor criteria can be helpful in establishing the correct diagnosis in doubtful cases (Table 3). Histology should always be performed together with DIF. Histological findings are characteristic, but definitively not specific for DH. A rich neutrophilic infiltrate is typically found in the dermal papillae and leads to the formation of the so‐called neutrophilic microabscesses (Figure 2b–d). A subepidermal detachment of the basement membrane can be detected in blistering lesions (Figure 2b,c). In the dermis, a mixed inflammatory infiltrate mostly consisting of neutrophils, eosinophils and T cells is common. Serological tests can be divided into indirect immunofluorescence (IIF) and enzyme‐linked immunosorbent assay (ELISA), the latter being standardized and easier to perform. Serological analysis of circulating IgA against TG2 by ELISA is useful for detecting autoantibodies and can be also considered as a tool for monitoring the compliance of patients on GFD. ⁴² Moreover, the use of ELISA to detect IgA against TG3 can be considered in addition to the TG2 ELISA, since TG3 antibodies can be detected also in subgroup of DH patients that do not present TG2 antibodies. ⁴⁰ , ⁴³ Antibody testing against anti‐gliadin or anti‐deamidated gliadin are not recommended due to the lack of standardized kits and specificity. ⁴⁰ IIF on monkey or rabbit esophagus can be used to detect IgA endomysial antibodies (EMA), showing a honeycomb‐like endomysial staining pattern around smooth muscle fibers. ⁴⁴ While the sensibility of this technique ranges from 60% to 90% in untreated DH patients, the specificity is nearly 100%. ⁴⁴ Recently, a study showed that monkey liver as a substrate shows similar specificity combined to high sensitivity (90%). ⁴⁵ HLA‐DQ2/DQ8 typing is not recommended routinely in the diagnosis of DH but may be considered as an extension of the basic diagnostic in selected cases. ⁴⁰ An assessment of small bowel inflammation status might be useful to evaluate the level of enteropathy in DH patients and to sensitize them on the pivotal importance of GFD. Finally, ancillary tests such as the iodine patch test could be performed in very rare and selected cases. ⁴⁰ , ⁴⁶

DIF should be performed on intact skin, 1–3 mm beside affected skin. It is mandatory to perform DIF before starting dapsone or GFD, because both can rapidly lead to false negative results.

TABLE 2.

Major criteria for the diagnosis of dermatitis herpetiformis.

Major criteria
Positive medical history for CD
Itchy erythematous papules and vesicles arranged in a herpetiform pattern involving mainly lower back, gluteal region, knees, and elbows
Detection of IgA in a granular pattern on the top of the dermal papillae by DIF

Abbr.: CD, celiac disease; DIF, direct immunofluorescence; DH, dermatitis herpetiformis.

TABLE 3.

Minor criteria to support the diagnosis of dermatitis herpetiformis in case of repeatedly negative direct immunofluorescence.

Minor criteria	Comments
Skin biopsy compatible with DH	Neutrophilic microabscesses in the dermal papillae; edema of the dermal papillae; subepidermal splitting
Duodenal biopsy compatible with CD	Severely atrophic mucosa with complete loss of villi; enhanced epithelial apoptosis; crypt hyperplasia
HLA haplotypes genotyping	Detection of HLA‐DQ2/DQ8
Positivity by at least one serological test *	Detection of IgA antibodies against TG2 or TG3 by ELISA; detection of EMA by IIF
Quick response to dapsone	Partial clinical response within 1 week on dapsone 1–2 mg/kg BW/day
Response to a long‐term GFD	Improvement of the clinical picture
Positive iodine patch test or oral iodine challenge (to be considered only in selected cases)	Development of DH lesions after iodine patch test or iodine ingestion

Abbr.: BW, bodyweight; CD, celiac disease; DIF, direct immunofluorescence; DH, dermatitis herpetiformis; EMA, endomysial antibodies; GFD, gluten‐free diet; HLA, human leukocyte antigen; IIF, indirect immunofluorescence; TG, transglutaminase.

^*See text for more details.

FIGURE 2.

Histological and immunopathological features of dermatitis herpetiformis. (a) Detection of granular IgA deposits along the dermo‐epidermal junction by direct immunofluorescence. (b, c) Subepidermal detachment with neutrophilic microabscess (hematoxylin‐eosin stain [HE], original magnification x 4). (d) Detail of a neutrophilic microabscess (HE, x 20).

DH‐associated disorders

Overall, DH patients seem to have a decreased mortality and lower risk for cerebrovascular insults. This has been attributed to the consequences of a rigorous lifestyle (GFD, less smoking, body activity). ⁴⁷ Still, the disease seems to be associated with some autoimmune and hematological disorders. Indeed, autoimmune thyroiditis has been reported in up to 11% of DH patients. ⁴⁸ The association between DH and autoimmune connective tissue disorders, such as systemic lupus erythematosus (SLE), is weaker than that with autoimmune thyroid disorders. ⁴⁹ More in detail, an incidence of SLE in 1.3% of patients with DH was reported in a retrospective study, while in another retrospective study on 264 DH patients only six patients with SLE were identified. ⁴⁹ , ⁵⁰ Furthermore, an association between DH and dermatomyositis or Sjögren's disease has been only anecdotally reported. ⁵⁰ , ⁵¹ Some patients also show concomitant pernicious anemia (ranging from 1.3% to 3%) and type I diabetes mellitus (between 1% and 2%). ⁵² , ⁵³ Intriguingly, an association between DH and bullous pemphigoid (BP) has been recently identified. ⁵⁴ According to a recent retrospective case‐control study with 3,397 BP patients, DH increased the risk of BP 22‐fold, with a mean time of 3 years from the diagnosis of DH to the diagnosis of BP. ⁵⁴ Importantly, the risk seems to be present only in patients affected by DH, whereas CD alone does not represent a risk factor for BP. Considering that all DH patients are affected by (subclinical) CD, they show an increased risk of non‐Hodgkin lymphomas and gastrointestinal malignancies. ⁵⁵ The risk in DH is increased between six to ten‐fold in the first 5 years. ⁵⁶ , ⁵⁷ In contrast to CD, the mortality rate in DH patients due to lymphoma is significantly lower. ⁵⁷ Especially in affected children, there seems to be an association between AD and DH. ⁵⁸ Based on these reports, it is recommended to exclude thyroid disorders by testing for thyroid stimulating hormone, triiodothyronine and thyroxine. Lymphoproliferative and autoimmune connective tissue disorders should be excluded only when clinical suspicion is present. In children with AD‐like clinical features that worsen after meals DH should be suspected.

THERAPY

DH patients should be educated to avoid permanently wheat, barley, rye, and all foods containing these cereals, because a strict lifelong GFD is the mainstay of treatment for DH. ⁵⁹ Because oats may be contaminated by gluten traces from other cereals, only non‐contaminated pure oats should be allowed in GFD. Indeed, safety of oats in DH has been largely demonstrated in two short‐term challenges and one long‐term follow‐up study. ⁶⁰ , ⁶¹ , ⁶² Adherence to a strict GFD leads to improvement of the clinical picture and itching. A complete remission of DH symptoms can be achieved after a mean of two years on a GFD, but the symptoms start to improve within a variable time between several weeks and a few months. ⁶³ , ⁶⁴ However, as reported in the most recent European guidelines, it is of pivotal importance to stress that patients with a clinical suspicion of DH should not start with a GFD until the diagnosis is confirmed. ⁴⁰ In DH patients on GFD, serum IgA antibodies against TG2 are no longer detectable within 3 years. ⁶⁵ On the contrary, alternating antibody levels on GFD indicates an inadequate compliance. By contrast, skin IgA and TG3 deposits in the papillary dermis can persist even longer than 3 years, and dermal immune deposits can be detected even in asymptomatic patients after several years on GFD. ⁶⁶ In addition, gluten challenge studies in adults with DH demonstrated relapse of skin lesions and villous atrophy following gluten intake, demonstrating definitively that a lifelong GFD is of central relevance in all patients with DH. Indeed, Mansikka et al. reported a relapse in 18 gluten‐challenged patients (95%) in a prospective study on 19 DH patients after a meantime of 5.8 months. ⁶⁶ Similar results were published by Leonard et al., who reported a relapse of DH rash in eleven out of twelve patients (92%) after reintroducing gluten. ⁶⁷ Seven of these patients (64%) also developed villous atrophy. ⁶⁷ Finally, Bardella et al. reported that 31 out of 38 DH patients (81%) complained of recurrence of skin lesions within a mean time of 2 months after starting a normal diet. ⁶⁸ Because cutaneous manifestations may last up to 24 months after the introduction of a GFD and strongly limit quality of life, most DH patients need a systemic therapy. ¹² , ⁴⁰ Despite the lack of randomized controlled trials, dapsone is considered the first line treatment for DH. ¹² , ⁴⁰ DH usually shows a very positive response to dapsone with skin clearance within a few weeks. Its effect can be probably linked to the effect of dapsone on neutrophil oxidase. The initial dapsone dose in adults ranges between 25 and 50 mg/day, which can be gradually increased up to 200 mg/day with an usual maximum dose of 2 mg/kg bodyweight (BW)/day. ⁴⁰ In remittent patients, a reduction to 0.5–1 mg/kg BW/day can generally control pruritus and prevent the development of new cutaneous lesions. ¹² , ³⁰ In the pediatric population, the starting dose of dapsone ranges from 1 to 2 mg/kg BW/day and the maintenance dose usually lies between 10%–25% of the initially effective dose. ⁴⁰ The activity of serum glucose‐6‐phosphate dehydrogenase should be determined before dapsone administration. ⁶⁹ Renal impairment does not affect the dose of dapsone, while in case of hepatic impairment, more frequent laboratory controls should be performed. The most common side effects of dapsone include abdominal pain, drug sensitivity reactions, hemolysis, methemoglobinemia, nausea, and vomiting. ⁶⁹ Therefore, complete and differential blood count, methemoglobin, reticulocyte count, liver and renal parameters should be controlled weekly for the first 4 weeks, then every two weeks from week 5 to 8, and then every 3 months. ⁶⁹ In case of contraindications or inefficacy of dapsone, alternative therapies may be considered, including sulfonamides (sulfasalazine, sulfapyridine, and sulfamethoxypyridazine) and tetracyclines in association with nicotinamide, respectively 500 mg q.i.d and 500 mg t.i.d. ⁴⁰ According to the most recent European guidelines, cyclosporine and systemic corticosteroids must be avoided, whereas the use of colchicine remains doubtful. ⁴⁰

DH patients should be educated to avoid permanently wheat, barley, rye, and all foods containing these cereals, because a strict lifelong GFD is the mainstay of treatment for DH.

Despite the lack of randomized controlled trials, dapsone is considered the first line treatment for DH.

Other skin disorders associated with celiac disease

While the link between DH and CD is epidemiologically and immunologically explained, some other skin diseases have been demonstrated to be more frequent in patients with CD, although immunological explanations between these diseases and CD could not be elucidated so far. Alopecia areata (AA), AD, psoriasis, and CU have been associated with CD. ⁷⁰ , ⁷¹ AD has been more frequently detected in children and adults with CD than in the general population. ⁷² , ⁷³ In a large population‐based cohort study with 1115 adult CD patients, it has been reported that AD is about three times more frequent in patients with CD and two times more frequent in their relatives than in the general population. ⁷⁴ Similarly, a recent Finnish retrospective register‐based study detected a significant association between AD and CD/DH in children. ⁵⁸ Over the past years, several case reports described an association between urticaria and CD. ⁷⁵ , ⁷⁶ , ⁷⁷ However, case‐control studies showed inconsistent results. ⁷⁸ , ⁷⁹ , ⁸⁰ In a large population‐based cohort study with 28,900 CD patients, the development of CU in 453 patients with CD and no previous diagnosis of CU has been reported, showing a 1.5‐fold increased risk of urticaria, with a slightly higher risk for CU. ⁸¹ Furthermore, in a large study from Israel enrolling 12,778 patients with CU, a 27‐fold increased risk of developing CD has been found. In some children with concomitant CU and CD a GFD induced complete remission of CU. ⁷⁹ , ⁸⁰ Overall, these findings suggest that there might be a subgroup of CU patients that develop CU because of CD. The association between psoriasis and CD has been extensively studied. In a recent meta‐analysis, a significantly increased detection of IgA antigliadin antibodies in patients with psoriasis has been reported. ⁸² Intriguingly, this group of patients experienced beneficial effects on psoriasis following GFD. ⁸² In line with these findings, other independent studies assessed a higher frequency of psoriasis in patients with established CD. ⁸³ , ⁸⁴ A possible explanation could be that CD and psoriasis share genetic susceptibility loci in eight genes that regulate innate and adaptive immune responses. ⁸⁵ , ⁸⁶ The association of CD with AA is still unclear. Corazza et al. first described the association between AA and CD and another population‐based cohort study identified an increased risk of developing CD in AA. ⁸⁷ , ⁸⁸ Similarly to psoriasis and CU, AA showed improvement on GFD. ⁸⁹

Gluten sensitivity and neurologic disorders

GS has been associated with several neurologic diseases, including cerebellar ataxia (also known as gluten ataxia), peripheral neuropathy and encephalopathy. ²⁴ , ⁹⁰ However, no accurate estimates of the prevalence of neurological manifestations of GS in the general population have been reported so far. The prevalence of neurological manifestations among patients with established CS has been reported between 10% and 22.5%. ²⁴ , ⁹¹ The diagnosis is based on the serological detection of antibodies against TG6, which can be also found in patients with DH. ⁹² Dermatologists should be aware of this association and refer to a neurologist when necessary.

Non‐coeliac gluten sensitivity and skin disorders

Describing the main features of NCGS and focusing on their skin manifestations can be extremely helpful for managing these patients. NCGS is characterized by symptoms triggered by gluten ingestion which improve on GFD in subjects not affected by CD. ³ Cooper et al. reported the first cases of NCGS in 1980, describing eight adult female patients with abdominal pain and chronic diarrhea who reported dramatic relief on GFD and return of symptoms after gluten challenge. ⁹³ In contrast to CD, HLA‐DQ2 or HLA‐DQ8 have been reported in only 50% of NCGS patients, and autoimmunity does not appear to play a pathogenetic role, whereas the innate immune system has been proposed as a pivotal player in NCGS. ⁹⁴ , ⁹⁵ Furthermore, an impaired intestinal epithelial barrier has been identified in in vivo and ex vivo studies. ⁹⁶ The prevalence of NCGS ranges between 0.5% and 13% in the general population, with a higher prevalence in women in their 3rd and 4th decade of life. ⁹⁷ NCGS diagnosis relies on exclusion of CD and improvement of the symptoms after gluten withdrawal. ⁹⁸ The clinical presentation of NCGS includes gastrointestinal symptoms, such as abdominal pain, bloating and alteration of bowel habits, variably associated with not specific systemic symptoms such as fatigue, headache, joint pain and different skin lesions. ⁹⁸ Only few data on skin manifestations in NCGS have been published so far. It has been reported that about 30% of NCGS patients were affected also by AD. ⁹⁹ Furthermore, it has been found out that NCGS patients with nickel allergy showed a higher frequency of erythema, diffuse itching and urticaria after wheat ingestion than NCGS patients without nickel allergy. ¹⁰⁰ Bonciolini et al. described variable and unspecific skin manifestations in 17 NCGS patients. ¹⁰¹ Indeed, some patients developed DH‐like skin manifestations in some cases, while other patients showed eczematous or psoriasiform papules and plaques. Faina et al. described skin manifestations in 65% of cases in a cohort of 163 NCGS patients. ¹⁰² The authors reported eczematous lesions in 45% of patients, urticaria‐like lesions in 36% and psoriasiform lesions in 9% of cases. All the patients complained of intense itch, which was the only symptom in about 10% of cases. Some authors have postulated that granular deposition of C3 along the DEJ at DIF could be a clue to NCGS. ¹⁰³ Indeed, in a cohort of 45 NCGS patients about 23% showed DH‐like lesions without gastrointestinal symptoms, but a granular C3 deposit at DEJ were detected by DIF. ¹⁰⁴ Clinically, these patients complained of severe refractory itch, which promptly improved on GFD. ¹⁰⁴

NCGS is characterized by symptoms triggered by gluten ingestion which improve on GFD in subjects not affected by CD.

Concluding remarks

In addition to the well‐known association between DH and CD, other skin diseases can represent an extra‐intestinal manifestation of GDR. Dermatologists should recognize these manifestations, especially when resistant to corticosteroid therapy, since they may improve on GFD without any additional therapies. Clinical and immunological studies on larger populations of NCGS patients could lead to the definition of a specific skin pattern, which could be helpful to make an early diagnosis of intestinal bowel disease.

CONFLICT OF INTEREST STATEMENT

None.

CME QUESTIONS/ LERNERFOLGSKONTROLLE

1. Welche gastrointestinale Erkrankung ist bei Patienten mit Dermatitis herpetiformis obligat vorhanden?

   1. Zöliakie
   2. Morbus Crohn
   3. Rektokolitis ulcerosa
   4. Peptisches Ulkus
   5. Gastroösophagealer Reflux
2. Was findet man normalerweise bei einer direkten Immunfluoreszenz bei Dermatitis herpetiformis?

   1. Wabenförmiges epidermales Muster
   2. Lineares IgG
   3. Lineares IgM
   4. IgA‐Ablagerungen innerhalb der Papillarspitzen
   5. Interzelluläre epidermale IgA‐Ablagerungen
3. Welches Antigen eignet sich am besten für einen ELISA‐Test (Enzyme‐linked Immunosorbent Assay) zur Diagnose von Dermatitis herpetiformis?

   1. Bullöses Pemphigoid‐Antigen 180
   2. Transglutaminase 2
   3. Transglutaminase 3
   4. Deamidiertes Gliadin
   5. Desmoglein 1
4. Welcher der folgenden diagnostischen Tests gehört nicht zur Routineuntersuchung bei der Diagnose der Dermatitis herpetiformis?

   1. Direkte Immunfluoreszenz
   2. Typisierung menschlicher Leukozytenantigene (HLA)
   3. Indirekte Immunfluoreszenz
   4. Enzyme‐linked Immunosorbent Assay (ELISA)
   5. Interferon‐Gamma‐Release Assay
5. Welches ist das Medikament der Wahl zur Behandlung der Dermatitis herpetiformis?

   1. Mycophenolatmofetil
   2. Azathioprin
   3. Rituximab
   4. Dapson
   5. Methotrexat
6. Welche der folgenden Aussagen zu einer glutenfreien Ernährung trifft nicht zu?

   1. Sie muss streng und lebenslang durchgeführt werden.
   2. Führt zu einem schnellen Abklingen der Zöliakiesymptome, wirkt aber nur langsam auf Hautläsionen.
   3. Schützt vor Lymphomen.
   4. Verbessert die Mineralisierung der Knochen und die allgemeine Lebensqualität.
   5. Kann Nicht‐Weizen‐Getreide enthalten.
7. Welche der folgenden Hautmerkmale sind charakteristisch für Dermatitis herpetiformis?

   1. Verstreute kleine Papeln und Bläschen, die in einem herpetiformen Muster angeordnet sind.
   2. Ausgedehnte Erosionen mit erhabenen Rändern, die von schnell wachsenden kleinen Papeln ausgehen.
   3. Scharfe Plaques mit wachsartigem Aussehen an den Unterschenkeln.
   4. Akrale (Hände und Füße) Blasenbildung auf erythematösem Grund.
   5. Asymmetrische Schwellung und Verhärtung der Unterlippe.
8. Welche der folgenden Erkrankungen kann bei Patienten mit Dermatitis herpetiformis und Zöliakie vorliegen?

   1. Vorhofflimmern und Diabetes Typ II
   2. Typ‐I‐Allergien und allergische Rhinokonjunktivitis
   3. Autoimmunthyreoiditis und Lymphom
   4. Wiederkehrendes Fieber und rheumatoide Arthritis
   5. Pyoderma gangraenosum und Akne
9. Welche der folgenden Differentialdiagnosen sollte bei Dermatitis herpetiformis in Betracht gezogen werden?

   1. Atopische Dermatitis
   2. Plaque‐Psoriasis
   3. Pemphigus vulgaris
   4. Pityriasis rubra pilaris
   5. Mycosis fungoides
10. Welche der folgenden Möglichkeiten ist eine Nebenwirkung von Dapson?

    1. Unterleibsschmerzen
    2. Hämolyse
    3. Methämoglobinämie
    4. Erbrechen
    5. Alle vorherigen Antworten sind richtig.

Liebe Leserinnen und Leser, der Einsendeschluss an die DDA für diese Ausgabe ist der 30. September 2025.

Die richtige Lösung zum Thema „Okkludierende kutane Vaskulopathien: Seltene Differenzialdiagnosen“ in Heft 04/2025 ist: 1b, 2d, 3c, 4b, 5b, 6a, 7d, 8b, 9d, 10d

Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg.akademie-dda.de ein.

Didona D, Maglie R, Solimani F. Gluten‐related skin disorders: clinical presentation, diagnostic and treatments. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2025;23:857–867. 10.1111/ddg.15704