Clinical trial NCT02248545: Autoimmune Diseases And Serum Anti-Nuclear Antibodies Positivity In Non-Celiac Wheat Sensitivity Patients
Official title: Autoimmune Diseases And Serum Anti-Nuclear Antibodies Positivity In Non-Celiac Wheat Sensitivity Patients
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Non-Celiac Wheat Sensitivity
Keywords: Non-Celiac Wheat Sensitivity
Autoimmune diseases
Anti-nuclear antibodies
Celiac disease
Irritable bowel syndrome
Lead sponsor: University of Palermo
Sponsor class: OTHER
First posted: 2014-09-25
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study included consecutive adult patients with irritable bowel syndrome (IBS)-like clinical presentation, according to Rome II criteria, and a definitive diagnosis of NCWS, referred at the Internal Medicine Department of the University Hospital of Palermo, Italy, and at the Internal Medicine Department of the Hospital of Sciacca, Agrigento, Italy, between July 2011 and July 2013.

Brief summary: Celiac disease (CD) is an immune-based reaction to dietary gluten (storage protein for wheat, barley, and rye) that primarily affects the small intestine in genetically predisposed patients and resolves with exclusion of gluten from the diet. Patients with CD show circulating autoantibodies (anti-transglutaminase, anti-tTG) and suffer from the destruction of a specific tissue cell type (the enterocytes) by CD8+ T cells. Furthermore, other autoimmune diseases have been reported in association to CD in 20-30% of the cases. In the last few year, a new clinical entity emerged, which seems include patients who consider themselves to be suffering from problems caused by wheat and/or gluten ingestion, even though they do not have CD or wheat allergy. This clinical condition has been named "Non-Celiac Gluten Sensitivity" (6), but, in a recent paper, the investigators suggested the term "Non-Celiac Wheat Sensitivity" (NCWS), since, to date, it is not known what component of wheat really causes the symptoms. The doubt areas about the NCWS regard also its pathogenesis as, despite some papers evidenced an intestinal immunologic activation, others excluded it. To explore the presence of autoimmunity in NCWS, the investigators evaluated: a) the frequency of autoimmune diseases and b) the frequency of serum anti-nuclear antibodies (ANA) positivity in newly diagnosed NCWS, compared to CD patients.

Detailed description: Celiac disease (CD) is an immune-based reaction to dietary gluten (storage protein for wheat, barley, and rye) that primarily affects the small intestine in genetically predisposed patients and resolves with exclusion of gluten from the diet. Although CD is not surely placed among the autoimmune diseases, patients with CD show circulating autoantibodies (anti-transglutaminase, anti-tTG) and suffer from the destruction of a specific tissue cell type (the enterocytes) by CD8+ T cells. Furthermore, other autoimmune diseases have been reported in association to CD in 20-30% of the cases. In the last few year, a new clinical entity emerged, which seems include patients who consider themselves to be suffering from problems caused by wheat and/or gluten ingestion, even though they do not have CD or wheat allergy. This clinical condition has been named "Non-Celiac Gluten Sensitivity" (6), but, in a recent paper, the investigators suggested the term "Non-Celiac Wheat Sensitivity" (NCWS), since, to date, it is not known what component of wheat really causes the symptoms. The doubt areas about the NCWS regard also its pathogenesis as, despite some papers evidenced an intestinal immunologic activation, others linked NCWS to the dietary FODMAPs (Fermentable Oligo-di and Mono-saccharides, And Polyols) load, thus excluding an immunologic involvement in the NCWS. To explore the presence of autoimmunity in NCWS, in the present study the investigators evaluated: a) the frequency of autoimmune diseases and b) the frequency of serum anti-nuclear antibodies (ANA) positivity in newly diagnosed NCWS and CD patients.

Eligibility criteria: Inclusion Criteria:

* To diagnose NCWS the recently proposed criteria were adopted. All the patients met the following criteria
* negative serum anti-transglutaminase (anti-tTG) and anti-endomysium (EmA) IgA and IgG antibodies
* absence of intestinal villous atrophy
* negative IgE-mediated immune-allergy tests to wheat (skin prick tests and/or serum specific IgE detection)
* resolution of the IBS symptoms on standard elimination diet, excluding wheat, cow's milk, egg, tomato, chocolate, and other self-reported food(s) causing symptoms
* symptom reappearance on double-blind placebo-controlled (DBPC) wheat challenge. As we previously described in other studies, DBPC cow's milk protein challenge and other "open" food challenges were performed too.
* Additional inclusion criteria were:
* age \>18 years
* follow-up duration longer than six months after the initial diagnosis
* at least two outpatient visits during the follow-up period.

Exclusion Criteria:

* positive EmA in the culture medium of the duodenal biopsies, also in the case of normal villi/crypts ratio in the duodenal mucosa
* self-exclusion of wheat from the diet and refusal to reintroduce it, before entering the study
* other "organic" gastrointestinal disorders
* nervous system disease and/or major psychiatric disorder
* physical impairment limiting physical activity
* menopause
* steroid and sex steroid therapy, hormone replacement therapy or ovariectomy.

Primary outcomes:
measure: Organ- and non-organ specific autoantibodies
timeFrame: At first visit
Secondary outcomes:
measure: Questionnaire for autoimmunity.
timeFrame: At first visit
Other outcomes:
Locations:
city: Sciacca
country: Italy
facility: Internal Medicine Department of the Hospital of Sciacca (Agrigento)
state: Agrigento
city: Palermo
country: Italy
facility: Gastroenterology Unit of the "Civico" Hospital of Palermo
city: Palermo
country: Italy
facility: Internal Medicine Department of the University Hospital of Palermo
Study officials:
affiliation: Internal Medicine Department of the Hospital of Sciacca (Agrigento)
name: Antonio Carroccio, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA; American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013 May;108(5):656-76; quiz 677. doi: 10.1038/ajg.2013.79. Epub 2013 Apr 23.
citation: Sollid LM, Jabri B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol. 2013 Apr;13(4):294-302. doi: 10.1038/nri3407. Epub 2013 Mar 15.
citation: Sategna Guidetti C, Solerio E, Scaglione N, Aimo G, Mengozzi G. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders. Gut. 2001 Oct;49(4):502-5. doi: 10.1136/gut.49.4.502.
citation: Biagi F, Pezzimenti D, Campanella J, Corazza GR. Gluten exposure and risk of autoimmune disorders. Gut. 2002 Jul;51(1):140-1. doi: 10.1136/gut.51.1.140-a. No abstract available.
citation: Verdu EF, Armstrong D, Murray JA. Between celiac disease and irritable bowel syndrome: the "no man's land" of gluten sensitivity. Am J Gastroenterol. 2009 Jun;104(6):1587-94. doi: 10.1038/ajg.2009.188.
citation: Catassi C, Bai JC, Bonaz B, Bouma G, Calabro A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, Francavilla R, Elli L, Green P, Holtmeier W, Koehler P, Koletzko S, Meinhold C, Sanders D, Schumann M, Schuppan D, Ullrich R, Vecsei A, Volta U, Zevallos V, Sapone A, Fasano A. Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013 Sep 26;5(10):3839-53. doi: 10.3390/nu5103839.
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. No abstract available.
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 Sensitivity. Am J Gastroenterol. 2021 May 1;116(5):1015-1023. doi: 10.14309/ajg.0000000000000919.