Psoriasis is a systemic chronic inflammatory immune-mediated disease whose etiopathogenetic mechanisms involve genetic predisposition, and immunological and environmental factors. Its prevalence is about 3% in adults, and it is characterized by well-demarcated, erythematous plaques, covered by silvery-white scales, in elbows, knees, trunk, and scalp. However, psoriasis is far from being considered just a dermatologic condition because the cytokine's cascade, which lays behind its inflammatory and immune-mediated pathogenesis, can determine multiple systemic manifestations. In addition, several patients with psoriasis often complains of gastrointestinal (GI) symptoms. Therefore, authors focused their attention over the gut-skin axis and its possible pathogenetic and immunoregulatory role in psoriasis (i.e., altered gut barrier, increased blood concentration of gut microbiota-derived metabolites, systemic inflammation). In this context, several dietetic approaches (e.g., Mediterranean, low calories, protein-restricted, vegetarian diets, and gluten-free diet, GFD) have shown a certain efficacy in improve psoriasis cutaneous and systemic manifestations. In recent years, the existence of a wheat-related disorder in patients who do not suffer from CD or wheat allergy (WA) has been definitively ascertained and defined as Non-Celiac Wheat Sensitivity (NCWS). Its prevalence in the general population is unknown, but self-reported NCWS is around 10%. This condition is characterized by both GI and extraintestinal symptoms, which are triggered by wheat ingestion. In these patients, wheat ingestion might lead to alteration in intestinal permeability and gut microbiota and to systemic immune activation and inflammation. Based on the evidence of gut involvement in the pathogenesis and clinical manifestation of psoriasis, as well as on the ability of gluten/wheat to increase intestinal permeability, it could be hypothesized that gluten/wheat may represents one of the pathogenetic environmental factors of psoriasis and that its intake may be able to worsen symptoms in affected patients. The investigators hypothesize that a wheat-free diet (WFD) can reduce the inflammatory state and ameliorate the clinical symptoms in psoriasis patients. The successive clinical and immunologic reaction to the re-exposure to wheat ingestion, performed by an open challenge, will be also evaluated to confirm a wheat-dependent mechanism and to understand the underlining physiopathology.

Psoriasis is a systemic chronic inflammatory immune-mediated disease whose etiopathogenetic mechanisms involve genetic predisposition, as well as immunological and environmental factors. Its prevalence is about 3% in adults, and it is characterized by well-demarcated, erythematous plaques, covered by silvery-white scales, in elbows, knees, trunk, and scalp, with a typical pair distribution. However, psoriasis is far from being considered just a dermatologic condition because the cytokine's cascade [including interleukin (IL)-1β, IL-17, IL-22, IL-23, Interferon (IFN)-γ, and Tumor Necrosis Factor (TNF)-α], which lays behind its inflammatory and immune-mediated pathogenesis, can determine multiple systemic manifestations. Several reports assess that, especially in moderate-to-severe psoriasis, the same inflammatory cytokines, found in cutaneous plaques, can be found in blood, and should be considered the enhancers of a chronic inflammatory condition, which, in long-term, will flow in systemic comorbidities, such as psoriatic arthritis, cardiovascular diseases, diabetes mellitus, obesity, nonalcoholic fatty liver disease, and inflammatory bowel disease.

In addition, a variable percentage of psoriatic patients (0.2-4.3%) may present with concomitant celiac disease (CD), a well-known immune-mediated bowel disease, as well as patients suffering from CD have an increased risk of psoriasis development, and, finally, several patients with psoriasis often complains of gastrointestinal (GI) symptoms.

These evidences have recently induced authors to focus their attention over the gut-skin axis and its possible pathogenetic and immunoregulatory role in psoriasis. In this context, some studies analyzed the role of intestinal permeability and, more specifically, of the gut barrier integrity, proving that an altered gut barrier is associated with GI symptoms, systemic inflammation, and increased blood concentration of gut microbiota-derived metabolites (e.g., trimethylamine N-oxide). Confirming a strict relationship between psoriasis and gut, from a clinical point of view, several dietetic approaches (e.g., Mediterranean, low calories, protein-restricted, and vegetarian diets) have shown a certain efficacy in improve psoriasis cutaneous and systemic manifestations. Moreover, some authors showed a positive effect of a gluten-free diet (GFD) over Psoriasis Area and Severity Index (PASI) score, even if contrasting data are reported, and, to date, no large randomized controlled trials have been performed.

In recent years, the existence of a wheat-related disorder in patients who do not suffer from CD or wheat allergy (WA) has been definitively ascertained and defined as Non-Celiac Wheat Sensitivity (NCWS). Its prevalence in the general population is unknown, but self-reported NCWS is around 10%. This condition, initially named as Non-Celiac Gluten Sensitivity, assuming that, as in CD, gluten was the main culprit, is characterized by both GI [irritable bowel syndrome (IBS)-like and functional dyspepsia-like] and extraintestinal (e.g., fatigue, neuropsychiatric disorders, dermatitis, gynecological alterations, etc.) symptoms, which are triggered by wheat ingestion. Moreover, an increasing number of data have shown that patients with NCWS could have an association with autoimmune diseases, including thyroiditis, Sjogren's syndrome, undifferentiated connective tissue disease, and psoriatic arthritis. Conflicting data have been reported about the underlying physiopathology and possible symptom's triggers. Some authors identified a prevalent role for fermentable oligosaccharides-disaccharides-monosaccharides and polyols (FODMAPs), other the activation of both innate and acquired immunity. More recently, it has been shown that wheat has high concentrations of wheat amylase-trypsin inhibitors (ATIs), proteins able to activate innate immunity via toll-like receptor-4 (TLR-4) on myeloid cells. Orally ingested ATIs increase intestinal inflammation by activating gut and mesenteric lymphnode myeloid cells. A possible role in this fragmented and articulated context has been attributed to alteration of intestinal permeability. It has been known for years how exposure to gliadin, both in CD and in healthy patients (albeit with reduced levels in the latter), is able to alter intestinal permeability acting on zonulin release and signaling mechanisms. When the integrity of the intestinal barrier is compromised, penetration of toxic wheat peptides into the intestinal lamina propria could be favored, determining the onset of an inflammatory response activated by local immune system through the intervention of antigen presenting cells (APC), particularly dendritic ones. Finally, both psoriatic and NCWS patients seems to have quantitative and qualitative disbalances of gut microbiota, which could influence severity and course of these diseases. However, data on this point are conflicting and this correlation is far from being unanimously accepted.

Based on the evidence of gut involvement (i.e., influence of GFD on symptoms, increased intestinal permeability, altered microbiota) in pathogenesis and clinical manifestation of psoriasis, as well as on the ability of gluten/wheat to increase intestinal permeability, altering zonulin mechanisms of regulation and signaling, and the ability of some of its components (ATIs, but not only) to activate a local inflammatory response, it could be hypothesized that gluten/wheat may represents one of the pathogenetic environmental factors of psoriasis and that its intake may be able to worsen symptoms in affected patients.

In the investigators' hypothesis, exposure to gluten/wheat would cause a release of zonulin, which, binding to the surface of the intestinal epithelial cells, is able to modify cell cytoskeleton and cause the loss of normal occludins function, ultimately leading to an increased intestinal monolayer permeability. This increase in permeability would result in greater exposure of the immune system cells to gluten/wheat molecules via activation of TLR-4, with an increase in the infiltration and activation of myeloid cells in the intestinal mucosa and an augmented activity of lymphnode dendritic and myeloid cells. Such local inflammatory response, associated with an increase of circulating antigens coming from the gut's modified permeability, would have systemic repercussions, with alteration of normal cytokine pattern (e.g., increase of IL-1β, IL-22, IL-23, and TNF-α) and activation of plasmacytoid dendritic cells, as well as of other innate immune cells, in the skin. This background, in predisposed patients, represents the trigger for activation of myeloid dendritic cells and macrophages, IL-12, IL-23, and TNF-α-mediated recruitment of T helper type 17 (Th17) and T cytotoxic type 17 (Tc17) lymphocytes, and production of a new cytokines pattern (mainly IL-17A, and IFN-γ), which can stimulate keratinocytes to proliferate and produce antimicrobial peptides and other proinflammatory cytokines. Such complex cytokine's pattern produced by immune cells and keratinocytes, creates a positive feedback loop, perpetuating the inflammatory response which leads to clinical manifestation of psoriasis.

Therefore, the investigators hypothesize that a wheat-free diet (WFD) can reduce the inflammatory state and ameliorate the clinical symptoms in psoriatic patients. The successive clinical and immunologic reaction to the re-exposure to wheat ingestion, performed by an open challenge, will be also evaluated to confirm a wheat-dependent mechanism and to understand the underlining physiopathology.

Overall, the project results might provide data about a possible therapeutic role of a WFD in psoriasis, improve the knowledges about the relationship between intestinal permeability and systemic inflammation in psoriasis, and reveal, at least in part, the pathogenic mechanisms underlying NCWS.

Starting from the hypothesis of an altered gut-skin axis, based on altered intestinal permeability and systemic response, the investigators aim to:

1. identify the prevalence of self-reported NCWS in psoriatic patients;
2. assess the overall effect that a WFD plus cow's milk products free diet (CMPFD) determines in symptoms control and quality of life (QoL) of the patients affected with psoriasis; the investigators decided to include a CMPFD in association with a WFD because, according to several authors, including our previous studies, NCWS, and more generally gluten-related disorders, are often associated with multiple foods intolerance, first of all cow's milk products intolerance;
3. evaluate, by an open wheat challenge, the real frequency of a coexistent NCWS condition;
4. assess the possible role played by wheat ingestion in the pathogenesis and molecular mechanisms of psoriasis and NCWS by analyzing the variation of intestinal permeability and gut microbiota, in association with cytokine pattern typical of psoriasis.

Inclusion criteria of psoriasis patients

• age >18 and <65 years;
• no systemic therapy for psoriasis for at least 3 months before inclusion in the study;
• negativity of anti-deamidated gliadin protein (anti-DGP) immunoglobulins (Ig) class A (IgA) and immunoglobulins (Ig)G, anti-tissue transglutaminase (anti-tTG) class IgA and IgG, and Endomysium antibodies (EmA);
• absence of WA (negative prick-test and/or specific serum immunoglobulins (Ig)E assay for wheat, gluten, and gliadin).

Exclusion criteria of psoriasis patients age <18 and >65 years;

• severe chronic plaque-type psoriasis (based on BSA);
• self-exclusion of gluten/wheat from the diet and refusal to reintroduce it, for diagnostic purposes, before entering the study;
• pregnancy;
• alcohol and/or drug abuse;
• Helicobacter pylori and other bacterial and/or parasitic infections;
• diagnosis of chronic inflammatory bowel disease and other organic pathology affecting the digestive system (e.g., severe liver disease), nervous system diseases, major psychiatric disorders, immunological deficits, and impairments that limit physical activity;
• diagnosis of cancer
• treatment with steroids and/or immunological therapies;
• patients undergoing chemotherapy and/or radiotherapy.