Extraintestinal Non Celiac Wheat Sensitivity

Non-celiac Gluten Sensitivity Clinical Trial

Official title:

Extraintestinal Manifestations in Non Celiac Wheat Sensitivity

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04769180
• Other study ID #: ACPM27
• Status: Completed
• Start date: January 1, 2000
• Est. completion date: January 1, 2021

Study information

• Verified date: February 2021
• Source: University of Palermo
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: January 1, 2021
• Est. primary completion date: January 1, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

NCWS 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.

Related Conditions & MeSH terms

• Hypersensitivity
• Non-celiac Gluten Sensitivity

Intervention

Other:
• Evaluation of extraintestinal manifestations
The researchers evaluated the prevalence and kind of extraintestinal symptoms in NCWS patients and the possible relationship between the clinical, serological, genetic and histological characteristics of the NCWS patients and the number and kind of extraintestinal manifestations, using, as control groups, CD and IBS patients.

Locations

Country	Name	City	State
Italy	Department of Internal Medicine, University Hospital of Palermo	Palermo
Italy	Internal Medicine Division of the "Cervello-Villa Sofia" Hospital	Palermo	PA

Sponsors (1)

Lead Sponsor	Collaborator
University of Palermo

Country where clinical trial is conducted

Italy, 

References & Publications (7)

Carroccio A, Giambalvo O, Blasca F, Iacobucci R, D'Alcamo A, Mansueto P. Self-Reported Non-Celiac Wheat Sensitivity in High School Students: Demographic and Clinical Characteristics. Nutrients. 2017 Jul 19;9(7). pii: E771. doi: 10.3390/nu9070771. — View Citation

Carroccio A, Mansueto P, Iacono G, Soresi M, D'Alcamo A, Cavataio F, Brusca I, Florena AM, Ambrosiano G, Seidita A, Pirrone G, Rini GB. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. A — View Citation

Carroccio A, Rini G, Mansueto P. Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gastroenterology. 2014 Jan;146(1):320-1. doi: 10.1053/j.gastro.2013.08.061. Epub 2013 Nov 22. — View Citation

Carroccio A, Soresi M, D'Alcamo A, Sciumè C, Iacono G, Geraci G, Brusca I, Seidita A, Adragna F, Carta M, Mansueto P. Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: a prospective observation study. — View Citation

Mansueto P, Soresi M, Candore G, Garlisi C, Fayer F, Gambino CM, La Blasca F, Seidita A, D'Alcamo A, Lo Sasso B, Florena AM, Geraci G, Caio G, Volta U, De Giorgio R, Ciaccio M, Carroccio A. Autoimmunity Features in Patients With Non-Celiac Wheat Sensitivi — View Citation

Mansueto P, Soresi M, La Blasca F, Fayer F, D'Alcamo A, Carroccio A. Body Mass Index and Associated Clinical Variables in Patients with Non-Celiac Wheat Sensitivity. Nutrients. 2019 May 29;11(6). pii: E1220. doi: 10.3390/nu11061220. — View Citation

Soresi M, Incandela S, Mansueto P, Incandela G, La Blasca F, Fayer F, D'Alcamo A, Florena AM, Carroccio A. Gynecological Disorders in Patients with Non-celiac Wheat Sensitivity. Dig Dis Sci. 2021 Jan;66(1):167-174. doi: 10.1007/s10620-020-06184-8. Epub 20 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluation of extraintestinal symptoms in NCWS patients	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.	Up to 15 years
Primary	Evaluation of extraintestinal symptoms in CD patients	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.	Up to 15 years
Primary	Evaluation of extraintestinal symptoms in IBS patients unrelated to NCWS or other food allergies/intolerances.	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.	Up to 15 years