Gluten-Related Dermatological Disorders K90.0

The term gluten-related disorders (GRD) refers to a spectrum of different clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals. GRDs are characterized by both intestinal and extra-intestinal manifestations, including neurological, cutaneous, oral and musculoskeletal manifestations (Tovoli F et al. 2015).

The term gluten-related dermatological disorders (GRDDs) is characterized by a wide variety of dermatological manifestations, which may have extracutaneous manifestations in addition to their cutaneous manifestations. Although the dermatological manifestations of GRDs are clinically well described, their prevalence is often poorly understood (Laurikka P et al. 2018). In addition to the known association between CD and dermatitis herpetiformis, which is considered a cutaneous specific manifestation of CD, numerous other muco-cutaneous diseases have been associated with GRDD in recent decades (Verdelli A et al. 2023).

In addition, there is the clinical picture of "non-celiac gluten sensitivity" with clinical symptoms analogous to those of CD.

Autoimmunological

• Dermatitis herpetiformis
• Linear IgA dermatosis
• Type 1 diabetes mellitus (the prevalence of celiac disease in pediatric and adult type 1 diabetics is given as 4.4% to 11%.
• Addison's syndrome (so-called immune Addison's adrenalitis / autoimmune adrenalitis)
• Hashimoto's thyroiditis
• Autoimmune hepatitis
• Primary biliary cirrhosis
• Dermatomyositis
• Systemic lupus erythematosus
• Chilblain's lupus
• Sjögren's syndrome
• Systemic scleroderma
• Vitiligo (Abenavoli L et al. (2019)
• Lichen sclerosus
• Pemphigus

Autoinflammatory

• Psoriasis
• Pityriasis rubra pilaris (Randle HW et al.(1980)
• Erythroderma
• Erythema elevatum diutinum
• Erythema necrolyticum migrans (Thorisdottir K et al. 1994)
• Pityriasis lichenoides
• Erythema nodosum

Allergic

• Atopic dermatitis (AD)
• Urticaria (acute and chronic urticaria)

Other suspected links between skin diseases and CD

• RAS (recurrent apthous stomatitis)
• Rosacea
• Behçet's disease
• Cutaneous vasculitis
• Erythema nodosum (Fretzayas A et al. 2011)
• Pityriasis lichenoides
• Lichen planus (also oral lichen planus) (Cigic L et al. 2015)
• Porphyria variegata with beta-thalassaemia (Dal Sacco D et al. 2004)
• Prurigo nodularis (Francesco Stefanini G et al. (1999)
• Nodular cutaneous amyloidosis in combination with Sjögren's syndrome and CD (Katsikas GA et al. 2008)
• Lamellar ichthyosis (Nenna R et al. (2011)
• Acquired hypertrichosis lanuginosa
• Partial lipodystrophy
• Generalized acquired cutis laxa (García-Patos V et al. 1996)
• IgA deficiency: IgA deficiency is significantly more common in people with coeliac disease than in the normal population (approx. 2-3%).
• Lactose intolerance

The prevalence of gluten-sensitive enteropathy (coeliac disease) has increased significantly over the last 50 years. Incidences have also increased, partly due to better diagnostic tools and thorough screening of individuals who are considered high-risk patients. The majority of CD patients worldwide still remain undiagnosed (see celiac disease below). The prevalence of most skin conditions associated with CD is unknown as they are mostly casuistic individual contributions.

In zoeliac disease,gluten leads to a complex pathological reaction of the intestinal mucosa and the immune system. Enterocytes of the small intestine produce an increased number of different HLA classes (especially HLA DQ2, HLADQ8). 98% of coeliac disease patients have these HLA antibodies (but also 30% of the normal population). Certain sections of the gluten protein (gliadin peptides) bind to the increased HLA DQ2 antigens. A prerequisite for this is that gluten components only trigger the immune reaction once they have been modified by transglutaminase 2 (TG2).

Despite the improved understanding of the pathogenic aspects of GRD, the mechanisms leading to the occurrence of associated dermatologic (including extracutaneous) diseases remain unclear (Caproni, Met al. 2012). The most likely hypotheses relate to the loss of immune tolerance in genetically predisposed individuals and to the increased intestinal permeability that allows the release of gluten-related peptides, leading to autoimmune reactions, vascular changes and subsequent vitamin and amino acid malabsorption (Verdelli A et al. 2023).

The immune reactions in CD are very wide-ranging. A likely explanation lies in the presence of increased intestinal permeability in both patient groups, which is related to the direct toxic effect of gliadin on the surface of the intestinal epithelium. This allows gluten peptides and other related peptides to enter the bloodstream and trigger various inflammatory or autoimmune processes that can affect any organ or tissue, which may be the result of an aberrant immune response. In the submucosa of the small intestine, starting from the action of tissue transglutaminase type 2, which unfolds gluten, a cascade of events occurs, triggering a Th1 response that stimulates B lymphocytes, which release IgE and other immunoglobulins, which play an important role in the occurrence of urticaria and AD, and a Th2 response mediated by T lymphocytes that causes the release of proinflammatory cytokines such as TNF-α and interferon gamma (IFNγ), which play an important role in various types of immune-mediated dermatitis such as psoriasis. In addition, these immunological responses can also cause the production of circulating immune complexes due to antigen-antibody interactions that are prevalent in vasculitic lesions.

Dermatitis herpetiformis Duhring: Dermatitis herpetiformis Duhring (DhD) is an epiphenomenon of gluten-sensitive enteropathy - see below. Dermatitis herpetiformis.

Dermatomyositis: The association of dermatomyositis and celiac disease (CD) has been reported several times, a genetic predisposition seems to play an important role (Soo Song M et al. 2006; Marie I et al. 2001; Iannone F et al. 2001). In patients with concomitant CD and dermatomyositis, a gluten-free diet can improve DM (Muddasani S 2021).

Systemic lupus erythematosus: CD individuals have a threefold increased risk of systemic lupus erythematosus compared to the general population (Ludvigsson JF et al. 2021). A recent study found a prevalence of 3% for biopsy-proven CD in SLE patients (Soltani Z et al. 2021). In an adolescent SLE population, CD was even detected in 6% of patients (Hamseya AM et al. 2020).

Chilblain lupus: Another autoimmunological skin disease associated with CD is chilblain lupus. The links are still unclear (Mašić M et al. 2022; Lemieux A et al. 2020).

Sjögren's syndrome: The association between Sjögren's syndrome (SS) and CD has been described in several case reports (Balaban DV et al. 2020). The prevalence of CD in patients with SS is between 1.2 % and 6.5 % (Ayar K et al. 2020)

Systemic scleroderma: The coexistence of CD and systemic sclerosis (SSc) has been reported in some publications. Prevalences ranged from 4% to 8% (Nisihara R et al. 2011), although the link between these two conditions remains controversial.

Alopecia areata: Overlapping symptoms include alopecia areata (AA). The risk of developing alopecia areata is three times higher in patients with CD than in the general population (Bondavalli P et al. 1998; Xing L et al. 2014). Improvements in AA after starting a gluten-free diet (GFD) in CD patients have been observed (Corazza GR et al. 1995).

Vitiligo: The relationship between CD and vitiligo is still controversial. Some authors found a higher incidence of vitiligo in CD patients, others could not confirm this correlation (Verdelli et al. 2023)

Psoriasis: The risk of developing psoriasis is increased by a factor of 1.7 (1.54-1.92) in people with coeliac disease. A recent meta-analysis found the overlap of 10 psoriasis susceptibility loci with those of CD, including a single nucleotide polymorphism (rs6822844) that is strongly associated with CD and with both psoriasis and psoriatic arthritis (Collaborative Association Study of Psoriasis (CASP) 2012). Considering the altered intestinal barrier in CD, it can be assumed that increased permeability to immunogenic triggers may lead to a higher prevalence of immune-mediated diseases (Verdelli A et al. 2023). In addition, a meta-analysis (Bhatia BK et al. 2014) showed a higher rate of positive anti-gliadin IgA antibodies in patients with psoriasis compared to control subjects, suggesting a possible role of gluten in the aetiogenesis of these patients. Other studies indicate a correlation between the level of CD antibodies and the severity of psoriasis or psoriatic arthritis (Woo, WK et al. 2004)

Atopic dermatitis: In a large study by Shalom et al. (Shalom G et al. 2020) of 116,816 patients (including 45,157 adults), atopic dermatitis was associated with a significantly higher prevalence of CD. The prevalence of AD was significantly higher in a pediatric celiac population compared to ulcerative colitis or Crohn's disease. Children with atopic dermatitis were found to be four times more likely to develop CD. Of note is a case-control study of 4,114 adult patients in which the incidence of Alzheimer's disease is threefold higher in CD patients and twofold higher in their relatives than in their spouses.

RAS (recurrent apthous stomatitis): In a meta-analysis (Nieri M et al. 2017), the authors demonstrated a higher incidence of recurrent aphthous stomatitis (RAS) in CD patients (OR: 3.79, 95%CI: 2.67-5.3). This association was mainly studied in pediatric populations. It is not known whether RAS lesions are directly influenced by gluten sensitivity disorder or whether they are related to low serum levels of iron, folic acid and vitamin B12 or deficiency of trace elements due to malabsorption in patients with untreated CD. Local and systemic conditions, immunologic and microbial factors, and oral dysbiosis may also play a pathogenic role in these mucosal ulcers.

Chronic spontaneous urticaria: In one study, the odds ratio for the presence of CD in patients with CU was 26.9 (95% CI, 6.6-110.17; p < 0.0005) compared to controls. Therefore, CD screening should be suggested in CU (Kolkhir P et al. 2017)

Rosacea: A link between CD and rosacea has also been demonstrated. One study showed a higher risk of CD in women with rosacea. In a cohort study, the prevalence of CD was higher in patients with rosacea compared to controls (Egeberg A et al. 2017).

Cutaneous vasculitis: Several studies have found an association between CD and cutaneous vasculitis (CV). The literature suggests that CV is more likely to occur in patients with poorly controlled CD and that a GFD may improve CV lesions in such cases (Meyers S et al. 1981).

Acrodermatitis enteropatica as a consequence of CD: A typical feature of CD is malabsorption and subsequent deficiency of trace elements. Among these, zinc deficiency is the most common and causes diffuse alopecia and seborrhoidal scaling in the perioral regions and around the genitals and bends of the arms. In these patients, the skin symptoms improve with a GFD and oral zinc supplementation.

Neurological-psychiatric diseases (affecting a dermatologic consultation):

• Migraine: a prevalence study describes a 3.8-fold increased risk of migraine for people with coeliac disease.
• Depression and anxiety disorders
• Epilepsy: A large epidemiological study (n= 29,000 celiac disease patients and 143,000 controls) describes an up to 1.7-fold increased risk for the manifestation of epilepsy.

Other

• IgA deficiency: IgA deficiency is significantly more common in people with coeliac disease than in the normal population (approx. 2-3%).
• Irritable bowel syndrome (IBS): For those affected, the overall risk of coeliac disease is about 4 times higher. Screening IBS patients for coeliac disease makes sense. In people with microscopic colitis, concomitant coeliac disease is detected in approx. 5% of cases
• Skin symptoms as a consequence of intestinal malabsorption: Secondary intestinal malabsorption can also cause muco-cutaneous manifestations due to nutrient deficiency. Zinc deficiency in CD patients has been associated with crusty-erythematous-scaly dermatitis localized in perioral regions, genitalia and skin folds. In addition, diffuse alopecia, stomatitis, balanitis, vulvitis and proctitis have also been found in these patients (Rodrigo L et al. 2018). Iron deficiency is associated with atrophy, xerosis, pruritus, hair loss, atrophic glossitis, angular stomatitis and koilonychia, while vitamin A deficiency can cause pytiriasis rubra pilaris-like lesions. Low serum levels of vitamin B12 and folic acid have been associated with angular stomatitis, glossitis, oral aphthosis and hyperpigmentation (Rodrigo L et al. (2018). Finally, pellagroid phenomena may also occur.
• Oral involvement: CD patients are affected by both dental and oral mucosal abnormalities, including enamel defects, RAS, delayed tooth eruption, multiple caries, angular cheilitis, atrophic glossitis, dry mouth and tongue burning. Furthermore, higher prevalences of enamel defects are observed.

There are no specific guidelines for the diagnosis and treatment of skin conditions associated with CD, with the exception of DH. Suspicion of a possible association is mainly based on a careful history and on the persistence or worsening of skin lesions despite standard treatment and diet and requires specific dermatologic skills. Histologic, immunopathologic and serologic examinations as well as other tests (e.g. patch test) may contribute to the correct diagnosis. A GFD is mandatory in all patients and may be helpful in resolving skin lesions in conjunction with current treatment guidelines.

If there are corresponding symptoms, the indication for a diagnosis should be made generously. Various antibodies are formed. In addition to antibodies against the gluten protein itself (gliadin antibodies), antibodies against tissue transglutaminase also occur. Tissue transglutaminase TG2 is the autoantigen of the anti-endomysial antibody (EMA). The inflammatory process leads to apoptosis of the enterocytes and atrophy of the villi. This results in a reduction of the resorption surface and resorption disorders.

Most of the casuistically described associations can be considered coincidental, such as the association between CD and alopecia areata (AA), the prevalence of which is similar in CD patients as in the general population. Alopecia areata improves or sometimes disappears with a GFD, but the effectiveness of a diet could be explained by a non-specific regulation of the immune response.

A non-celiac gl uten sensitivity should be considered in the differential diagnosis.

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