Extraintestinal Non Celiac Wheat Sensitivity

Completed

• Conditions: Non-celiac Gluten Sensitivity
• Interventions: Other: Evaluation of extraintestinal manifestations

• Registration Number: NCT04769180
• Lead Sponsor: University of Palermo

Brief Summary

Non Celiac Gluten Sensitivity (NCGS), or, better, Non Celiac Wheat Sensitivity (NCWS), since it is not known the real pathogenetic component(s) of grain, is a syndrome characterized by a cohort of symptoms, both gastrointestinal and extraintestinal, related to the ingestion of gluten/wheat-containing food in subjects who are not affected by celiac disease (CD) or wheat allergy. In particular, the possibility of extraintestinal manifestations in this condition has been suggested by some reports. In most cases, they are characterized by vague symptoms, such as headache, 'foggy mind', fatigue, joint and muscle pain, leg or arm numbness (i.e., fibromyalgia-like symptoms), even if more specific complaints have been described. A possible neurological involvement has been underlined by NCWS association with gluten encephalopathy, gluten ataxia, and gluten peripheric neuropathy. NCWS patients may show even psychiatric diseases, such as anxiety, depression, and psychosis. Other described extraintestinal manifestations are dermatitis, (eczema or skin rash), gynecological disorders, and anemia. In addition, the association of NCWS with autoimmune diseases, such as autoimmune thyroiditis, and presence of anti-nuclear or other autoantibodies has been demonstrated, suggesting that, similarly to CD, NCWS might be considered as an immune system-related disease, and this aspect should be of relevance. In conclusion, the novelty of this matter has generated an expansion of literature data about the clinical features of the disease, with the unavoidable consequence that some reports are often based on low levels of evidence. The aims of the present study were to: a) retrospectively evaluate the prevalence and kind of extraintestinal symptoms in a large cohort of NCWS patients; b) to research for a possible relationship between the clinical, serological, genetic and histological characteristics of the NCWS patients and the number and kind of extraintestinal manifestations. As control groups, the researchers used CD and Irritable Bowel Syndrome (IBS) patients unrelated to NCWS or other food allergies/intolerances.

Detailed Description

Non Celiac Gluten Sensitivity (NCGS), or, better, Non Celiac Wheat Sensitivity (NCWS), since it is not known the real pathogenetic component(s) of grain, is a syndrome characterized by a cohort of symptoms, both gastrointestinal and extraintestinal, related to the ingestion of gluten/wheat-containing food in subjects who are not affected by celiac disease (CD) or wheat allergy. In detail, NCWS is distinguished by symptoms that typically take place soon after gluten/wheat ingestion, withdraw with gluten/wheat exclusion, and relapse following gluten/wheat challenge (i.e., double-blinded placebo-controlled, DBPC, gluten/wheat challenge, used for diagnostic purpose) within hours or days. The gastrointestinal clinical picture of NCWS is a combination of irritable bowel syndrome (IBS)-like manifestations, such as abdominal pain, bloating, diarrhea, or constipation, or alternation of diarrhea and constipation, and dyspepsia like-symptoms, such as postprandial heaviness, early satiety, and epigastric pain or burning. However, the possibility of extraintestinal manifestations in this condition has been suggested by some reports. In most cases, they are characterized by vague symptoms, such as headache, 'foggy mind', fatigue, joint and muscle pain, leg or arm numbness (i.e., fibromyalgia-like symptoms), even if more specific complaints have been described. A possible neurological involvement has been underlined by NCWS association with gluten encephalopathy, gluten ataxia, and gluten peripheric neuropathy. NCWS patients may show even psychiatric diseases, such as anxiety, depression, and psychosis. Other described extraintestinal manifestations are dermatitis, (eczema or skin rash), gynecological disorders, and anemia. In addition, the association of NCWS with autoimmune diseases, such as autoimmune thyroiditis, and presence of anti-nuclear or other autoantibodies has been demonstrated, suggesting that, similarly to CD, NCWS might be considered as an immune system-related disease, and this aspect should be of relevance. In conclusion, the novelty of this matter has generated an expansion of literature data about the clinical features of the disease, with the unavoidable consequence that some reports are often based on low levels of evidence. Therefore, only studies performed on large samples, with the inclusion of control groups, may be able to clearly establish whether the large information from the literature regarding extraintestinal NCWS manifestations could be supported by evidence-based agreements. Therefore, the aims of the present study were to: a) retrospectively evaluate the prevalence and kind of extraintestinal symptoms in a large cohort of NCWS patients, diagnosed by DBPC gluten/wheat challenge; b) to research for a possible relationship between the clinical, serological, genetic and histological characteristics of the NCWS patients and the number and kind of extraintestinal manifestations. As control groups, the researchers used CD and IBS patients unrelated to NCWS or other food allergies/intolerances.

Study Timeline

• Study Start: 2000-01-01
• Primary Completion: 2020-01-01
• Study Completion: 2021-01-01
• Status Verified: 2021-02
• Study First Submitted: 2021-02-20
• Study First Submitted QC: 2021-02-20
• Last Update Submitted: 2021-02-20
• Study First Posted: 2021-02-24
• Last Update Posted: 2021-02-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

NCWS was diagnosed after CD or WA had been ruled out in all the studied patients according to the following criteria:

• (1) negative serum assays for serum CD-anti-tissue transglutaminase (anti-tTG) immunoglobulin (Ig) A and anti-deamidated gliadin peptide (anti-DGP) IgG antibodies; (2) absence of intestinal villous atrophy, documented in all the patients carrying the DQ2 and/or the DQ8 HLA haplotypes (thus irrespective of CD-specific serum antibody negativity), evaluated when patients had a minimum intake of 100 g of wheat daily since at least 2 weeks; (3) negative IgE-mediated immune-allergy tests to wheat (skin prick tests and/or specific serum IgE detection); (4) resolution of symptoms on a standard elimination diet, without wheat, cow's milk, yeast, and other food(s) causing self-reported symptoms, followed by symptom reappearance on a DBPC wheat challenge. Additional inclusion criteria were: age older than 18 years, follow-up duration longer than 12 months after the initial diagnosis, and at least 2 outpatient visits during the follow-up period.

NCWS

Exclusion Criteria

• (1) positive anti-endomysial antibodies (EmA) in the culture medium of the duodenal biopsies, also in the case of normal villi/crypts ratio in the duodenal mucosa; (2) self-exclusion of wheat from the diet and refusal to reintroduce it before entering the study; (3) other previously diagnosed gastrointestinal disorders; (4) nervous system disease and/or major psychiatric disorder; (5) physical impairment limiting physical activity.

CD Inclusion Criteria:

• (1) positive serum anti-tTG and EmA IgA and IgG antibodies; (2) presence of intestinal villous atrophy.

CD Exclusion Criteria:

• (1) self-exclusion of wheat from the diet and refusal to reintroduce it before entering the study; (2) other previously diagnosed gastrointestinal disorders; (3) nervous system disease and/or major psychiatric disorder; (4) physical impairment limiting physical activity.

IBS Inclusion Criteria:

• IBS diagnosis was made in accordance with the Rome IV criteria. None of these patients improved on the same standard elimination diet followed by the patients with NCWS for 4 weeks, thus confirming that the IBS diagnosis was unrelated to NCWS or other food allergies/intolerances. The patients kept a food diary during the elimination diet period to monitor their adherence to the diet; patients who did not strictly adhere to the elimination diet were not included in this study group. In patients with a diarrhea-predominant IBS presentation, the exclusion of other diagnoses was based on the assays recently suggested by the American Gastroenterology Association

IBS Exclusion Criteria:

• (1) self-exclusion of wheat from the diet and refusal to reintroduce it before entering the study; (2) other previously diagnosed gastrointestinal disorders; (3) nervous system disease and/or major psychiatric disorder; (4) physical impairment limiting physical activity.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Patients affected with NCWS	Evaluation of extraintestinal manifestations	100 patients with a definitive diagnosis of NCWS, based on DBPC gluten/wheat challenge.
Patients affected with IBS not related to NCWS or other food allergies/intolerances	Evaluation of extraintestinal manifestations	50 patients affected with IBS, according to the Rome IV criteria, not related to NCWS or other food allergies/intolerances, sex- (± 5%) and age-matched (± 2 years) with the NCWS patients, selected at random during the study period.
Patients affected with CD	Evaluation of extraintestinal manifestations	50 patients affected with CD, sex- (± 5%) and age-matched (± 2 years) with the NCWS patients, selected at random during the study period.

Primary Outcome Measures

Name	Time	Method
Evaluation of extraintestinal symptoms in CD patients	Up to 15 years	Evaluation of systemic (malaise, fatigue), dermatological (eczema or skin rash), neurological (headache, 'foggy mind', gluten encephalopathy, gluten ataxia, gluten peripheric neuropathy, leg or arm numbness), psychiatric (anxiety, depression, psychosis), musculoskeletal (joint and muscle pain), gynaecological, and hematological (anemia) symptoms in CD patients.
Evaluation of extraintestinal symptoms in IBS patients unrelated to NCWS or other food allergies/intolerances.	Up to 15 years	Evaluation of systemic (malaise, fatigue), dermatological (eczema or skin rash), neurological (headache, 'foggy mind', gluten encephalopathy, gluten ataxia, gluten peripheric neuropathy, leg or arm numbness), psychiatric (anxiety, depression, psychosis), musculoskeletal (joint and muscle pain), gynaecological, and hematological (anemia) symptoms in IBS patients unrelated to NCWS or other food allergies/intolerances.
Evaluation of extraintestinal symptoms in NCWS patients	Up to 15 years	Evaluation of systemic (malaise, fatigue), dermatological (eczema or skin rash), neurological (headache, 'foggy mind', gluten encephalopathy, gluten ataxia, gluten peripheric neuropathy, leg or arm numbness), psychiatric (anxiety, depression, psychosis), musculoskeletal (joint and muscle pain), gynaecological, and hematological (anemia) symptoms in NCWS patients.

Trial Locations

Locations (2)

Department of Internal Medicine, University Hospital of Palermo; 🇮🇹 Palermo, Italy

Internal Medicine Division of the "Cervello-Villa Sofia" Hospital; 🇮🇹 Palermo, PA, Italy