INTRODUCTION
Celiac disease (CD) is a chronic, immune-mediated disorder with an estimated global prevalence of approximately 1% [1]. CD can occur at any age and presents with a broad spectrum of clinical manifestations.
Based on the clinical presentation at diagnosis, CD is commonly classified into classical, non-classical, and subclinical forms. The classical form, most typically observed in children under 5 years of age, is characterized by symptoms of malabsorption such as chronic diarrhoea, poor appetite, weight loss, abdominal distension, muscle wasting, and mood disturbances. In rare cases, delayed diagnosis may lead to a life-threatening celiac crisis, presenting with severe diarrhoea, abdominal distension, dehydration, electrolyte imbalances, hypoalbuminemia, hypotension, and lethargy.
Non-classical CD represents the most common presentation and is associated with non-specific gastrointestinal symptoms including recurrent abdominal pain, bloating, diarrhoea, or constipation. Additionally, patients may present with extraintestinal manifestations such as persistent iron deficiency, chronic fatigue, or hypertransaminasemia, as well as nutritional deficiencies (vitamin D, vitamin B12, folate, iron, or zinc deficiency), arthralgia or arthritis, alopecia, recurrent stomatitis, and chronic urticaria.
Subclinical CD is often asymptomatic and is usually identified through screening in high-risk populations, such as first-degree relatives of individuals with CD, or through population-based screening programs. In adults, CD is more frequently associated with extraintestinal manifestations and long-term complications, including an increased risk of certain malignancies [2].
The diagnosis of CD is typically confirmed by an intestinal biopsy. Serological testing provides important supportive evidence, particularly the detection of anti-endomysial antibodies (EMA) and anti-tissue transglutaminase antibodies (anti-tTG), which demonstrate high sensitivity and specificity. Anti-gliadin antibodies (AGA), although previously used, are currently considered less reliable diagnostic markers [2].
AIM
The aim of this review was to summarize current knowledge on the cutaneous manifestations of CD, including their pathogenesis and clinical presentation. Particular emphasis is placed on the importance of recognizing dermatological signs that may precede or accompany gastrointestinal symptoms.
Improved awareness of these manifestations is essential for dermatologists, gastroenterologists, and other clinicians involved in the diagnosis and management of CD. Early recognition may facilitate timely diagnosis, prompt initiation of a gluten-free diet (GFD), and reduction of complications associated with untreated disease.
MATERIAL AND METHODS
A literature search was conducted using the PubMed, Google Scholar, and ResearchGate databases. Only articles published in English were considered. The search strategy included the following keywords: “celiac disease”, “dermatitis herpetiformis”, “skin manifestations of celiac disease”, “cutaneous involvement in celiac disease”, “psoriasis”, “alopecia”, “atopic dermatitis”, and “gluten-free diet”.
Studies were included if they addressed dermatological manifestations associated with CD, including their pathogenesis, clinical presentation, diagnostic approaches, and therapeutic strategies. Only peer-reviewed articles with accessible full-text versions were considered. Studies unrelated to the topic, incomplete reports, or publications lacking sufficient methodological information or containing outdated or unreliable data were excluded.
To ensure the relevance and quality of the selected articles, preference was given to recent publications (within the last 10 years) providing evidence-based information regarding the dermatological management of CD. Studies involving both adult and paediatric populations were included. Systematic reviews, clinical trials, and observational studies were prioritized.
STATE OF KNOWLEDGE
Pathogenesis of celiac disease
CD results from a complex interaction between genetic predisposition and environmental factors. In genetically susceptible individuals carrying HLA-DQ2 and/or HLA-DQ8 haplotypes, ingestion of gluten – a protein fraction found in wheat, rye, barley and related cereal such as triticale – triggers an abnormal immune response in the small intestine. This process leads to the production of specific antibodies, including AGA, anti-tTG type 2, EMA, and anti-deamidated gliadin peptides (anti-DGP) antibodies. The resulting autoimmune inflammatory reaction causes damage to the intestinal mucosa and progressive atrophy of the small intestinal villi.
Dermatitis herpetiformis
Dermatitis herpetiformis (DH) is the most common cutaneous manifestation of CD with a higher prevalence in males. Clinically, it is characterized by a symmetrical polymorphic eruption consisting of small vesicles, papules, and erythematous lesions, typically distributed on extensor surfaces such as the elbows, knees, and buttocks [3]. Lesions may also occur on the scalp, upper back, abdomen, and groin. Intense pruritus is a hallmark feature and often leads to scratching, which obscures the primary lesions and results in erosions, crusts, and excoriations dominating the clinical picture [4]. Pruritus and skin lesions may be exacerbated by factors such as the use of indomethacin or increased dietary iodine intake [5].
Gastrointestinal symptoms are rare. Duodenal biopsy reveals varying degrees of villous atrophy in approximately 75% of patients, whereas the remaining 25% demonstrate inflammatory changes or lymphocytic enteritis without villous atrophy. Skin biopsy with direct immunofluorescence is essential for diagnosis, with granular deposition of immunoglobulin A (IgA) in the dermal papillae considered pathognomonic [3].
A strict GFD remains the cornerstone of therapy and is associated with an excellent long-term prognosis. Pharmacological treatment with dapsone provides rapid relief of pruritus and cutaneous lesions but does not replace dietary management [4].
Psoriasis
Psoriasis is considered one of the most common cutaneous manifestations of CD and has been reported more frequently in female patients with CD [6]. Clinically, psoriasis is characterized by well-demarcated erythematous plaques covered with silvery scales. Similar to CD, psoriasis is a T-cell-mediated inflammatory disorder resulting from complex interactions between genetic susceptibility, environmental triggers, and the immune dysregulation.
Epidemiological studies suggested a bidirectional association between psoriasis and CD. Patients with psoriasis have approximately a 2.16-fold increased likelihood of being diagnosed with CD, while individuals with CD have an estimated 1.8-fold higher risk of developing psoriasis. Furthermore, the risk of newly diagnosed psoriasis in individuals with CD is approximately 1.7 times higher than the general population.
Several mechanisms may explain this association. Genomic studies have identified overlapping susceptibility loci between psoriasis and CD. Increased intestinal permeability in CD may facilitate exposure to immunogenic antigens such as gliadin, which activates CD4+ T lymphocytes and promotes the production of interferon-gamma (IFN-γ), a cytokine associated with psoriasis severity. In psoriasis, increased keratinocyte proliferation results in excessive production of IL-1 and IL-18, which subsequently activates the Th1 immune response – a key mechanism in the pathogenesis of CD. Additionally, vitamin D deficiency resulting from malabsorption in CD may contribute to increased susceptibility to psoriasis.
Adherence to a GFD has been associated with the improvement of psoriatic symptoms in some patients and may reduce the prevalence or severity of psoriasis in individuals with CD [7].
Atopic dermatitis
Atopic dermatitis (AD) is the most common skin disease in children, affecting approximately 15–20% of children and 1–3% of adults. In most cases, the onset of the disease occurs before the age of 5.
AD is a chronic, recurrent inflammatory skin disease characterized by three distinct clinical phases. In the acute phase, skin lesions present as vesicular eruptions that exude and form crusts. In the subacute phase, dry, scaling papules and erythematous plaques develop. In the chronic phase, lichenification and thickening resulting from persistent scratching predominate.
Typical locations of lesions include the flexural surfaces of the elbows and knees, the anterior and lateral aspects of the neck, eyelids, forehead, face, wrists, dorsum of the hands, and feet [8].
The association between AD and CD may be explained by common pathophysiological mechanisms observed in both allergic and autoimmune diseases. Although the dominant immune responses differ (Th2 in allergic conditions such as AD and Th1 in autoimmune gastrointestinal diseases such as CD), several similarities between these conditions have been identified.
A primary common element is epithelial barrier dysfunction. In CD, genetic alterations have been identified in proteins involved in apical junction and tight junction complexes. Similarly, in AD, loss-of-function mutations in the filaggrin gene impair the integrity of the epidermal barrier. Disruption of epithelial integrity, often referred to as a “leaky epithelium”, may facilitate inappropriate immune responses to luminal antigens in the gastrointestinal tract in CD, or promote allergen sensitization through the skin, as observed in food allergies associated with AD.
Moreover, similar genetic mechanisms, including polymorphisms in genes encoding cytokines (e.g. interleukins) and other immune mediators, may contribute to the development of both conditions. For instance, alterations in genes encoding thymic stromal lymphopoietin (TSLP) may contribute to epithelial barrier dysfunction in AD and increased gluten sensitivity in CD.
Epidemiologically, both AD and CD show increasing prevalence in developed and developing countries, which may partly be explained by epigenetic factors [9].
Urticaria
Urticaria is a heterogeneous skin condition that may manifest in various forms, including acute or chronic, intermittent or persistent [10]. The acute form (duration ≤ 6 weeks) affects approximately 20% of the general population, whereas chronic urticaria affects up to 5% [11].
Urticaria results from the activation and degranulation of cutaneous mast cells, leading to the release of histamine and other inflammatory mediators. Clinically, it is characterized by the presence of wheals, angioedema, or both [12].
A strong association between chronic urticaria and autoimmune diseases has been demonstrated. Furthermore, the prevalence of urticarial eruptions exceeds 1.5% among patients with CD [13]. Genetic studies have also identified an association between chronic urticaria and human leukocyte antigen (HLA)-DQ8 alleles [14], which are notably linked to CD [15].
Aphthous stomatitis
CD may present with a variety of manifestations in the oral cavity; however, the most frequently described is recurrent aphthous stomatitis (RAS).
RAS is a common disorder that typically begins in childhood or adolescence. It is characterized by recurrent and painful small, round or ovoid ulcers with well-demarcated margins, erythematous halos, and yellow or grey fibrinous bases [16].
A systematic review published in 2017 demonstrated a significantly higher prevalence of aphthous stomatitis among patients with CD compared with healthy controls. Celiac patients were found to have a higher frequency of aphthous stomatitis. Approximately 25% of individuals with CD were affected by aphthous lesions, whereas the prevalence in healthy controls was about 11% [17].
Several factors are known to predispose individuals to the development of RAS, including local trauma, psychological stress, smoking cessation, and nutritional deficiencies such as iron, zinc, and vitamins B1, B2, B6, and B12 [18]. In addition, anemia – one of the most common clinical manifestations of CD – which may further contribute to the occurrence of RAS and potentially increase its severity in affected individuals [15].
Rosacea
Rosacea is a chronic inflammatory skin condition, more frequently affecting women than men. It primarily involves the central part of the face and manifests as flushing, persistent erythema, papules and pustules, telangiectasia with or without burning or stinging sensation. Additional features may include dry and rough skin, facial plaques or oedema, and phymatous changes [19, 20].
Studies have shown that patients with rosacea have approximately a twofold higher risk of CD compared with age-, sex-, and time-matched controls.
Rosacea and CD may share common genetic and immunological mechanisms. Genome-wide association studies (GWAS) have identified several genetic risk loci associated with rosacea, including HLA-DRB103:01, HLA-DQB102:01, and HLA-DQA1*05:01. Notably, the latter two loci are also strongly associated with CD.
Furthermore, a high prevalence of small intestinal bacterial overgrowth (SIBO) has been reported in patients with CD, particularly in those who continue to experience gastrointestinal symptoms despite adherence to a GFD. This suggests that SIBO may represent a shared pathogenic factor linking rosacea and CD [20–22].
Alopecia areata
Alopecia areata (AA) is an autoimmune disorder characterized by nonscarring hair loss, affecting up to 2% of the general population. AA typically presents as the sudden appearance of well-demarcated, round or oval patches of hair loss on the scalp, usually without visible signs of inflammation or scarring [23]. Trichoscopic features of AA include exclamation mark hairs, dystrophic hairs, and yellow dots [24].
Epidemiological studies have demonstrated a bidirectional association between AA and CD. Patients with AA show a significantly higher prevalence of CD compared with individuals without AA, while patients with CD also appear to have an increased prevalence of AA.
Both AA and CD involve dysregulation of immune tolerance. In CD, the presence of HLA DQ2 or HLA-DQ8 molecules promotes an immune response to gluten-derived peptides. Although the mechanisms underlying the loss of immune tolerance in AA are not fully understood, the epidemiological association between AA and CD suggests the presence of shared pathogenic pathways. This hypothesis is supported by case reports describing hair regrowth in patients with AA following the introduction of a GFD. It has been proposed that T-cell-mediated immune responses originating in the gastrointestinal tract may influence hair follicle immune privilege; however, further research is required to clarify this relationship [25]. Moreover, GWAS have identified shared genetic susceptibility loci between AA and CD [23].
Other skin conditions found in patients with celiac disease
The scientific literature also describes less common associations between CD and various dermatological conditions. These include leukocytoclastic vasculitis [26], and non-specific dermatological manifestations such as dry skin, easy bruising, brittle nails, and hair thinning [27].
Additionally, several other conditions have been reported in patients with CD, including juvenile dermatomyositis and dermatomyositis, vitiligo, systemic lupus erythematosus, lichen planus, lichen sclerosus, linear IgA bullous dermatosis, prurigo nodularis, pityriasis rubra pilaris, erythroderma, erythema nodosum, porphyria, cutaneous amyloidosis, generalized acquired cutis laxa, acquired hypertrichosis lanuginosa, ichthyosis, partial lipodystrophy, transverse leukonychia, dysplastic nevus syndrome, and congenital giant nevus [24].
CONCLUSIONS
CD is an autoimmune disease triggered by gluten intolerance that manifests not only with gastrointestinal symptoms but also with numerous extraintestinal symptoms. Cutaneous involvement represents an important clinical aspect of CD and may occasionally constitute the first or even the only symptom of the disease. The most characteristic skin manifestation is DH.
The coexistence of CD with various dermatological conditions suggests complex immunological and genetic mechanisms underlying the disease. Recognition of cutaneous manifestations of CD requires an interdisciplinary approach involving dermatological evaluation, histopathological assessment and appropriate serological testing.
Management of these manifestations primarily relies on a strict GFD, which can lead to remission of both intestinal and cutaneous symptoms.
