Fibromyalgia-like Joint/Muscle Pain and Synovitis in Non-celiac Wheat Sensitivity Patients

Recently it has been reported that a consistent percentage of the general population 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' (NCGS). In a previous paper the investigators suggested the term 'Non-Celiac Wheat Sensitivity' (NCWS), since it is not known what component of wheat causes the symptoms in NCGS patients, and the investigators also showed that these patients had a high frequency of coexistent multiple food hypersensitivity. The clinical picture of NCWS is characterized by combined gastrointestinal (bloating, abdominal pain, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and extra-intestinal and/or systemic manifestations (headache, depression, anxiety, 'foggy mind,' tiredness, dermatitis or skin rash, fibromyalgia-like joint/muscle pain, leg or arm numbness, and anemia). Nowadays no data are available on the characteristic of 'rheumatologic' symptoms of NCWS patients. Therefore, the aims of the present study are: 1) to investigate the prevalence of fibromyalgia-like joint/muscle pain in NCWS patient, 2) to search for possible ultrasonographic alterations (i.e. synovitis) of hands and feet joints of NCWS patients, and 3) to evaluate modification of fibromyalgia-like joint/muscle pain in NCWS patients after a gluten free diet period of almost 6 months.

Study Overview

• Status: Completed
• Conditions: Non-celiac Wheat Sensitivity
• Intervention / Treatment: Other: Gluten free diet

Detailed Description

Recently it has been reported that a consistent percentage of the general population 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' (NCGS). In a previous paper the investigators suggested the term 'Non-Celiac Wheat Sensitivity' (NCWS), since it is not known what component of wheat causes the symptoms in NCGS patients, and the investigators also showed that these patients had a high frequency of coexistent multiple food hypersensitivity. CD is an immunological disorder whose best-known manifestations are gastrointestinal symptoms. However, early joint manifestations are common and frequently overlooked features of the disease. Similarly, the clinical picture of NCWS is characterized by combined gastrointestinal (bloating, abdominal pain, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and extra-intestinal and/or systemic manifestations (headache, depression, anxiety, 'foggy mind,' tiredness, dermatitis or skin rash, fibromyalgia-like joint/muscle pain, leg or arm numbness, and anemia). Nowadays no data are available on the characteristic of 'rheumatological' symptoms of NCWS patients. Therefore, the aims of the present study are: 1) to investigate the prevalence of fibromyalgia-like joint/muscle pain in NCWS patient, 2) to search for possible ultrasonographical alterations (i.e. synovitis) of hands and feet joints of NCWS patients, and 3) to evaluate modification of fibromyalgia-like joint/muscle pain in NCWS patients after a gluten free diet period of almost 6 months.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Palermo, Italy, 90129
    • Department of Internal Medicine, University Hospital of Palermo
  • Agrigento
    • Sciacca, Agrigento, Italy, 92019
      • Department of Internal Medicine, Giovanni Paolo II Hospital of Sciacca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All the patients met the recently proposed criteria:

• negative serum anti-tissue transglutaminase and antiendomysium (EmA) immunoglobulin (Ig) A and IgG antibodies
• absence of intestinal villous atrophy
• IgE-mediated immunoallergic tests negative to wheat and cow's milk protein (skin prick tests and/or serum specific IgE detection).

Adjunctive criteria adopted in our patients were:

• resolution of the gastrointestinal and extra-intestinal symptoms on a standard elimination diet, without wheat, cow's milk, egg, tomato, chocolate, or other food(s) causing self-reported symptoms
• symptom reappearance on double-blind placebo-controlled (DBPC) wheat challenge, performed as described previously. DBPC cow's milk protein challenge will be also performed to diagnose cow's milk protein allergy.

Exclusion Criteria:

Exclusion criteria will be:

• age <18 years
• positive EmA in the culture medium of the duodenal biopsies, even if the villi to crypts ratio in the duodenal mucosa was normal
• self-exclusion of wheat from the diet and refusal to reintroduce it before entering the study
• other organic gastrointestinal diseases
• previously diagnosed rheumatic diseases
• nervous system disease and/or major psychiatric disorder
• physical impairment limiting physical activity
• menopause; steroid and sex steroid therapy, hormone replacement therapy or ovariectomy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: NCWS patients; Fifty consecutive adult patients with an irritable bowel syndrome (IBS)-like clinical presentation, according to Rome III criteria, and a definitive diagnosis of NCWS. The patients will be recruited between January 2017 and January 2018 at 2 centers: the Department of Internal Medicine at the University Hospital of Palermo, Italy, and the Department of Internal Medicine of the Hospital of Sciacca, Agrigento, Italy. All subjects will undergo clinical evaluation and hands and feet joints ultrasonography at the Rheumatology Unit of the University of Palermo, Italy.	Other: Gluten free diet; The investigators will evaluate the prevalence of fibromyalgia-like joint/muscle pain and the possible ultrasonographical alterations (i.e. synovitis) of hands and feet joints in NCWS patient at baseline (i.e. at the moment of diagnosis) and after a gluten free diet period of almost 6 months.
No Intervention: CD patients; Fifty sex- and age-matched subjects with CD, diagnosed according to standard criteria during the same study period and enrolled, at the same 2 centers, as first control group. All subjects will undergo clinical evaluation and hands and feet joints ultrasonography at the Rheumatology Unit of the University of Palermo, Italy.
No Intervention: IBS patients; Fifty sex- and age-matched subjects with IBS unrelated to NCWS or other food 'intolerance', diagnosed according to standard criteria during the same study period and enrolled, at the same 2 centers, as second control group. All subjects will undergo clinical evaluation and hands and feet joints ultrasonography at the Rheumatology Unit of the University of Palermo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of fibromyalgia-like joint/muscle pain in NCWS patients	Prevalence of fibromyalgia-like joint/muscle pain in NCWS patient using an ad hoc questionnaire and orientated clinical examination (tenders and triggers point evaluation)	up to 12 months
Hands and feet joints ultrasonography alterations	Hands and feet joints ultrasonography alterations in NCWS patients.	up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modification of fibromyalgia-like joint/muscle pain in NCWS patients after gluten free diet	Modification of fibromyalgia-like joint/muscle pain, by visual analogic scale, in NCWS patients after a gluten free diet period of almost 6 months.	up to 12 months
Modifications of hands and feet joints ultrasonography alterations in NCWS patients after gluten free diet	Modifications of hands and feet joints ultrasonography alterations in NCWS patients after a gluten free diet period of almost 6 months.	up to 12 months

Collaborators and Investigators

• Sponsor: University of Palermo

Publications and helpful links

General Publications

• Mansueto P, Seidita A, D'Alcamo A, Carroccio A. Non-celiac gluten sensitivity: literature review. J Am Coll Nutr. 2014;33(1):39-54. doi: 10.1080/07315724.2014.869996.
• 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. Am J Gastroenterol. 2012 Dec;107(12):1898-906; quiz 1907. doi: 10.1038/ajg.2012.236. Epub 2012 Jul 24.
• Mansueto P, Seidita A, D'Alcamo A, Carroccio A. Role of FODMAPs in Patients With Irritable Bowel Syndrome. Nutr Clin Pract. 2015 Oct;30(5):665-82. doi: 10.1177/0884533615569886. Epub 2015 Feb 18.
• Carroccio A, D'Alcamo A, Mansueto P. Nonceliac wheat sensitivity in the context of multiple food hypersensitivity: new data from confocal endomicroscopy. Gastroenterology. 2015 Mar;148(3):666-7. doi: 10.1053/j.gastro.2014.11.047. Epub 2015 Jan 24. No abstract available.
• Carroccio A, Soresi M, D'Alcamo A, Sciume 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. BMC Med. 2014 Nov 28;12:230. doi: 10.1186/s12916-014-0230-2.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Actual): June 1, 2018
• Study Completion (Actual): March 1, 2020

Study Registration Dates

• First Submitted: December 30, 2016
• First Submitted That Met QC Criteria: January 12, 2017
• First Posted (Estimate): January 16, 2017

Study Record Updates

• Last Update Posted (Actual): April 28, 2020
• Last Update Submitted That Met QC Criteria: April 26, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: fibromyalgia; synovitis; Non-celiac Wheat Sensitivity
• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Pain; Neurologic Manifestations; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Muscular Diseases; Neuromuscular Diseases; Musculoskeletal Pain; Hypersensitivity; Myalgia; Fibromyalgia; Myofascial Pain Syndromes; Synovitis
• Other Study ID Numbers: ACPM13

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