Extraintestinal Non Celiac Wheat Sensitivity

February 20, 2021 updated by: Pasquale Mansueto, University of Palermo

Extraintestinal Manifestations in Non Celiac Wheat Sensitivity

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Palermo, Italy, 90127
        • Department of Internal Medicine, University Hospital of Palermo
    • PA
      • Palermo, PA, Italy, 90146
        • Internal Medicine Division of the "Cervello-Villa Sofia" Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 65 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

The researchers evaluated the extraintestinal manifestations in 3 groups of patients: (1) 100 patients with a definitive diagnosis of NCWS, based on DBPC gluten/wheat challenge; (2) 50 patients affected with CD, sex- (± 5%) and age-matched (± 2 years) with the NCWS patients, selected at random during the study period; (3) 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.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Patients affected with NCWS
100 patients with a definitive diagnosis of NCWS, based on DBPC gluten/wheat challenge.
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.
Other Names:
  • Extraintestinal manifestations
Patients affected with CD
50 patients affected with CD, sex- (± 5%) and age-matched (± 2 years) with the NCWS patients, selected at random during the study period.
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.
Other Names:
  • Extraintestinal manifestations
Patients affected with IBS not related to NCWS or other food allergies/intolerances
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.
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.
Other Names:
  • Extraintestinal manifestations

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Evaluation of extraintestinal symptoms in NCWS patients
Time Frame: 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.
Up to 15 years
Evaluation of extraintestinal symptoms in CD patients
Time Frame: 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.
Up to 15 years
Evaluation of extraintestinal symptoms in IBS patients unrelated to NCWS or other food allergies/intolerances.
Time Frame: 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.
Up to 15 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Palermo

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2000

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 1, 2020

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 1, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 20, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 20, 2021

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 24, 2021

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 24, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 20, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • ACPM27

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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