Wheat-free Diet in the Treatment of Sjogren's Syndrome
- Conditions
- Sjogren's SyndromeNon-celiac Gluten Sensitivity
- Interventions
- Dietary Supplement: Rice/turkey free diet (R/TFD) groupDietary Supplement: Wheat/milk free diet (W/MFD) group
- Registration Number
- NCT05644795
- Lead Sponsor
- University of Palermo
- Brief Summary
Recent data show that some foods can increase intestinal mucosa permeability and immune activation of subjects with gastrointestinal (GI) symptoms. Wheat seems the most frequent food which activates this inflammatory response and can cause both GI and extra-intestinal symptoms. Patients suffering from wheat-related troubles, in absence of celiac disease diagnosis, can suffer from non-celiac wheat sensitivity (NCWS) and our previous studies showed that about 25% of them are also affected by autoimmune diseases (AD). A gluten-free diet (GFD) can influence inflammatory pattern of AD, including Sjogren's syndrome (SS). Thus, the investigators would enquire if SS patients may also suffer from NCWS and how a wheat-free diet (WFD) modifies their clinical features, and inflammatory and cytokine pattern. The investigators will also assess how wheat reintroduction, by an open challenge, modifies their clinical parameters, intestinal permeability, and both local and systemic inflammatory response.
- Detailed Description
In recent years, the existence of a wheat-related disorder, in patients who do not suffer from celiac disease (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%. Conflicting data have been reported about the underlying physiopathology. 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 signalling mechanisms. 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.
An increasing number of data have shown that patients with NCWS could have an association with autoimmune diseases, including thyroiditis, undifferentiated connective tissue disease, psoriatic arthritis, spondylarthritis, and Sjogren's syndrome (SS).
SS is an autoimmune disease characterized by an infiltrate of mononuclear cells, mainly lymphocytes, in the exocrine glands, especially the salivary and lacrimal glands. Some preliminary data suggested that a GFD can reduce sialadenitis and increase salivary flow in SS and CD patients. Furthermore, some SS patients have an inflammatory response (release of nitric oxide) to a rectal gluten challenge.
Based on these evidences, as well as on the ability of gluten/wheat to increase intestinal permeability, altering zonulin mechanisms of regulation and signalling, 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 SS and that its intake may be able to worsen symptoms in affected patients. In our 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 to cause the loss of normal occludins function, ultimately leading to an increased 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 cells. Such local inflammatory response would have systemic repercussions with alteration of normal cytokine pattern and infiltration of monocytes/macrophages and T cells in the salivary and lacrimal glands, thus being able to contribute, as an environmental factor, to the onset and exacerbation of the clinical manifestations of SS.
Therefore, the investigators hypothesize that a wheat-free diet (WFD) can reduce the inflammatory state and ameliorate the clinical symptoms in SS patients. This hypothesis will be evaluated in both SS patients with associate GI symptoms and in those without GI symptoms. 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 mechanisms. The project results will provide data about a possible therapeutic role of a WFD in SS and will improve the knowledges about the axis between the intestinal permeability and the systemic inflammation in SS.
More specifically, the investigators aim to:
* identify the prevalence of self-reported NCWS in SS patients;
* assess the overall effect that a WFD plus cow's milk products free diet (CMPFD) determines in symptoms control of the patients affected with SS; 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;
* evaluate, by an open wheat challenge, the real frequency of a coexistent NCWS condition;
* assess the possible role played by wheat ingestion in the pathogenesis and molecular mechanisms of SS and NCWS by analysing the variation of intestinal permeability and gut microbiota, in association with cytokines and lymphocytes pattern typical of SS.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 30
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Comparator: rice/turkey free diet (R/TFD) group Rice/turkey free diet (R/TFD) group Patients randomized to control group will go to a 2 months elimination diet (rice and turkey's meat). After 2 months of elimination diet they will crossover to a 2 months elimination diet (wheat and cow's milk products). After 2 months of elimination diet they will go to an open challenge, with reintroduction of wheat. After 2 weeks of open diet or whenever rheumatologic, intestinal and/or extraintestinal symptoms should return or intensify, patients will end the study. Active Comparator: wheat/milk free diet (W/MFD) group Wheat/milk free diet (W/MFD) group Patients randomized to intervention group will go to a 2 months elimination diet (wheat and cow's milk products). After 2 months of elimination diet they will go to an open challenge, with reintroduction of wheat. After 2 weeks of open diet or whenever rheumatologic, intestinal and/or extraintestinal symptoms should return or intensify, patients will end the study.
- Primary Outcome Measures
Name Time Method Effect of WFD plus CMPFD in symptoms of SS patients as assessed by ESSDAI From the start of the study (T0) to 2 months of wheat elimination diet (T1). To define effects induced by a WFD plus CMPFD in SS patient's symptoms. The following score will be used: EULAR SS Disease Activity Index (ESSDAI, a systemic disease activity index, consisting of 12 domains, 11 related to organ involvement and 1 biological domain, cut-off values of \>5 and \<14 defining moderate, and \>14 severe systemic disease activity).
Self-perceived non-celiac wheat sensitivity (NCWS) questionnaire in SS patients Before enter the study To identify SS patients reporting a self-perceived NCWS; all patients will be asked to answer, consecutively, to a validated questionnaire for the self-assessment of wheat and other foods' intolerance. This is a questionnaire self-compiled by patients consisting of three sections: 1) general information (eg. age, sex, highest completed education level, etc.) 2) wheat-related symptoms (sore 0 = no symptoms, score = 1, symptoms after wheat intake; if score = 1 other question qualitatively inquire the symptoms evoked by wheat intake, eg. what kind of symptoms, how long patient perceive this problem, etc.); 3) other foods-related symptoms (score 0 = no symptoms, score 1 = symptoms after intake of other foods; if score = 1 other question qualitatively inquire the symptoms evoked by the intake of the specific food reported by the patients, eg. what kind of symptoms, how long patient perceive this problem, etc.)
Effect of WFD plus CMPFD in symptoms of SS patients as assessed by ESSPRI From the start of the study (T0) to 2 months of wheat elimination diet (T1). To define effects induced by a WFD plus CMPFD in SS patient's symptoms. The following score will be used: European League Against Rheumatism (EULAR) SS Patient Reported Index \[ESSPRI, a self-evaluation index measuring symptoms, including pain, fatigue, and dryness, each symptom measured with a single 0, no symptoms, to 10, severe symptoms, scores \<5 indicating low and \>5 high disease activity).
Effect of WFD plus CMPFD in symptoms of SS patients as assessed by GSRS From the start of the study (T0) to 2 months of wheat elimination diet (T1). To define effects induced by a WFD plus CMPFD in SS patient's symptoms. The following score will be used: Gastrointestinal Symptom Rating Scale (GSRS), assessment scale for irritable bowel syndrome-like and functional dyspepsia-like symptoms, providing for a score ranging from 15 (no gastrointestinal symptoms) to 60 (uncontrolled gastrointestinal symptoms).
Effect of WFD plus CMPFD in symptoms of SS patients as assessed by Extraintestinal symptoms rating scale. From the start of the study (T0) to 2 months of wheat elimination diet (T1). To define effects induced by a WFD plus CMPFD in SS patient's symptoms. The following score will be used: Extraintestinal symptoms rating scale, a scoring system based on the symptoms most frequently observed in NCWS patients, providing for a score ranging from 9 (no extra intestinal symptoms) to 34 (uncontrolled extra intestinal symptoms).
- Secondary Outcome Measures
Name Time Method Salivary flux From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Salivary flux (ml/min) will be studied by standard sialometry.
Effect of open wheat challenge in symptoms of SS patients as assessed by GSRS. From T1 to 2 weeks of open wheat challenge (T2int and T3con). To evaluate, by an open wheat challenge, the frequency of a coexistent NCWS condition in SS patients, both of the intervention group (T2int) and the control group (T3con). Gastrointestinal Symptom Rating Scale (GSRS), assessment scale for irritable bowel syndrome-like and functional dyspepsia-like symptoms, providing for a score ranging from 15 (no gastrointestinal symptoms) to 60 (uncontrolled gastrointestinal symptoms).
Effect of open wheat challenge in symptoms of SS patients as assessed by ESSPRI. From T1 to 2 weeks of open wheat challenge (T2int and T3con). To evaluate, by an open wheat challenge, the frequency of a coexistent NCWS condition in SS patients, both of the intervention group (T2int) and the control group (T3con). The following score will be used: European League Against Rheumatism (EULAR) SS Patient Reported Index \[ESSPRI, a self-evaluation index measuring symptoms, including pain, fatigue, and dryness, each symptom measured with a single 0, no symptoms, to 10, severe symptoms, scores \<5 indicating low and \>5 high disease activity).
Effect of open wheat challenge in symptoms of SS patients as assessed by ESSDAI. From T1 to 2 weeks of open wheat challenge (T2int and T3con). To evaluate, by an open wheat challenge, the frequency of a coexistent NCWS condition in SS patients, both of the intervention group (T2int) and the control group (T3con). The following score will be used: EULAR SS Disease Activity Index (ESSDAI, a systemic disease activity index, consisting of 12 domains, 11 related to organ involvement and 1 biological domain, cut-off values of \>5 and \<14 defining moderate, and \>14 severe systemic disease activity).
Salivary dosage of immunoglobulin G From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory salivary analysis will be performed to assess immunoglobulin G
Salivary dosage of IL-6 From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory salivary analysis will be performed to assess interleukin (IL)-6.
Effect of open wheat challenge in symptoms of SS patients as assessed by Extraintestinal symptoms rating scale. From T1 to 2 weeks of open wheat challenge (T2int and T3con). To evaluate, by an open wheat challenge, the frequency of a coexistent NCWS condition in SS patients, both of the intervention group (T2int) and the control group (T3con). Extraintestinal symptoms rating scale, a scoring system based on the symptoms most frequently observed in NCWS patients, providing for a score ranging from 9 (no extra intestinal symptoms) to 34 (uncontrolled extra intestinal symptoms).
Salivary dosage of immunoglobulin A From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory salivary analysis will be performed to assess immunoglobulin A.
Salivary dosage of lactoferrin From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory salivary analysis will be performed to assess lactoferrin.
Salivary dosage of beta 2-microglobulin From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory salivary analysis will be performed to assess beta 2-microglobulin.
Salivary dosage of IL-2 From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory salivary analysis will be performed to assess interleukin (IL)-2
Laboratory blood analysis in SS and NCWS patients to assess ESR From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory blood analysis will be performed to assess erythrocyte sedimentation rate (ESR).
Laboratory blood analysis in SS and NCWS patients to assess CRP From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory blood analysis will be performed to assess C-reactive protein (CRP).
Laboratory blood analysis in SS and NCWS patients to assess RF. From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory blood analysis will be performed to assess rheumatoid factor (RF).
Laboratory blood analysis in SS and NCWS patients to assess C3 From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory blood analysis will be performed to assess C3
Laboratory blood analysis in SS and NCWS patients to assess C4. From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory blood analysis will be performed to assess C4.
Laboratory blood analysis in SS and NCWS patients to assess complete blood count. From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory blood analysis will be performed to assess complete blood count.
Peripheral blood cytofluorimetric analysis to evaluate expression of lymphocytes typical of SS. From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Peripheral blood cytofluorimetric analysis will be performed to assess expression of lymphocytes typical of SS pathogenetic pattern:interferon type I signature in cluster of differentiation (CD)14+ monocytes
Gut microbiota assessment in SS and NCWS patients. From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Gut microbiota assessment will be performed by quantification of gut microbiota on stools samples.
Laboratory blood analysis in SS and NCWS patients to assess beta 2-microglobulin. From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Laboratory blood analysis will be performed to assess beta 2-microglobulin.
Peripheral blood ELISA analysis of inflammatory cytokines in SS and NCWS patients. From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Peripheral blood ELISA analysis of inflammatory cytokines pattern will be performed to assess: C-X-C Motif Chemokine Ligand 13 (CXCL13)
Peripheral blood ELISA analysis of intestinal permeability markers in SS and NCWS patients. From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Peripheral blood ELISA analysis of intestinal permeability markers will be performed to assess: F-Actin
LA/MA test in SS and NCWS patients. From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Lactulose/Mannitol (LA/MA) test will be performed to assess in vivo intestinal permeability.
Fecal ELISA analysis of inflammatory gut marker in SS and NCWS patients. From the start of the study (T0) to 2 months of wheat elimination diet (T1), to 2 weeks of open wheat challenge (T2int and T3con). Fecal ELISA analysis of inflammatory gut marker will be performed to assess fecal calprotectin.
Trial Locations
- Locations (3)
Rheumatology Department of the University Hospital of Palermo
🇮🇹Palermo, PA, Italy
Internal Medicine Division of the "Cervello-Villa Sofia" Hospital
🇮🇹Palermo, PA, Italy
Internal Medicine Department of the University Hospital of Palermo
🇮🇹Palermo, Italy