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Gluten-related Disorders in Familial Mediterranean Fever Patients

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ClinicalTrials.gov Identifier: NCT03563300
Recruitment Status : Completed
First Posted : June 20, 2018
Last Update Posted : April 17, 2019
Sponsor:
Information provided by (Responsible Party):
Pasquale Mansueto, University of Palermo

Brief Summary:
It is known that the gluten-containing grains can be responsible for human diseases related to gluten exposure. These forms of gluten intolerance represent a heterogeneous set of conditions, including celiac disease (CD), wheat allergy (WA) and not celiac gluten sensitivity (NCGS), that combined seems to affect about 5-10% of the general population. NCGS is the most recent gluten-related disease, characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects in whom either celiac disease or wheat allergy previously has been excluded. However, as it is not known what component of the cereals causes the symptoms in NCGS patients, the investigators prefer the label of "Not-celiac wheat sensitivity" (NCWS). Typically, the NCWS diagnosis is made by exclusion. Furthermore, similarly to CD, the investigators had demonstrated that NCWS may be associated with other autoimmune disease (i.e. Hashimoto's thyroiditis). Among these autoimmune conditions, in our daily out clinic work, the investigators have observed an association between self-reported NCWS and Familial Mediterranean Fever (FMF). Our preliminary observational data indicate that some FMF patients relate their symptoms (especially gastrointestinal) to gluten assumption, then excluding it from diet and using gluten-free products, with partial remission of gastrointestinal symptoms. Therefore, FMF and NCGS share some clinical features, such as abdominal pain, diarrhea, arthralgia and arthritis, and tend to be commonly associated with other inflammatory and autoimmune diseases. This study has 2 major aims: 1.To evaluate the real relationship between the wheat ingestion and the gastrointestinal manifestations presented by FMF patients, self-reporting a NCWS. 2. To identify possible immunologic markers that may explain the mechanism underling FMF abdominal attack and wheat ingestion.

Condition or disease Intervention/treatment Phase
Not-celiac Wheat Sensitivity (NCWS) Familial Mediterranean Fever (FMF) Other: Wheat flour Other: Placebo Comparator Not Applicable

Detailed Description:
It is known that the gluten-containing grains can be responsible for human diseases related to gluten exposure. These forms of gluten intolerance represent a heterogeneous set of conditions, including celiac disease (CD), wheat allergy (WA) and not celiac gluten sensitivity (NCGS), that combined seems to affect about 5-10% of the general population. NCGS is the most recent gluten-related disease. It is characterized by intestinal (i.e. irritable bowel syndrome, bloating, dyspepsia) and extra-intestinal symptoms (i.e. fatigue, headache, numbness, mental confusion) related to the ingestion of gluten-containing food, in subjects in whom either celiac disease or wheat allergy previously has been excluded. However, as it is not known what component of the cereals causes the symptoms in NCGS patients, the investigators prefer the label of "Not-celiac wheat sensitivity" (NCWS). Typically, the NCWS diagnosis is made by exclusion. In fact, in previous studies the investigators showed that patients self-reporting gastrointestinal symptoms related to wheat ingestion, could suffer not only from CD or WA, but from small intestinal bacterial overgrowth or inflammatory bowel diseases also. Furthermore, similarly to CD, the investigators had demonstrated that NCWS may be associated with other autoimmune disease (i.e. Hashimoto's thyroiditis). Among these autoimmune conditions, in our daily out clinic work, the investigators have observed an association between self-reported NCWS and Familial Mediterranean Fever (FMF). Familial Mediterranean fever (FMF) is the most frequent hereditary autoinflammatory disease, characterized by self-limited recurrent attacks of fever and serositis, resulting in pain in the abdomen, chest, joints and muscles. FMF is caused by mutations in MEFV gene, which encodes pyrin. Pyrin is implicated in a complex interplay with proteins involved in Toll-like receptor (TLR) signalling, PYD superfamily and procaspase-1 activation, suggesting a controlling role in inflammatory response. Abdominal pain is the most frequent symptom encountered in FMF; 95% of patients report this as the main symptom during at least some of their fever episodes, while 50% cite such an 'abdominal attack' as the first symptom of their disease. Presentation of a typical abdominal attack will resemble that of 'acute abdomen'. Onset is sudden and acute, leading to rapid development of symptoms within 1-2 hours. The abdominal pain is usually diffuse throughout the entire abdomen, although in some cases it may be localized; it may be very severe in intensity. This may be accompanied by any bowel activity, ranging from constipation (most often) to diarrhoea. The intensity of symptoms and signs of an inflammatory attack in FMF will decrease spontaneously after 12-24 hours, and usually, the attack resolves over the following 48 hours. Thus, after about 3 days the patient will be symptom-free again. Furthermore, so-called "incomplete" abdominal attacks may occur in FMF patients. These differ from 'typical' abdominal attacks in 1 or 2 features, which may include absence of fever, absence of 'true' peritonitis and/or localisation of the abdominal pain to a single specific abdominal area, minimal change in acute phase parameters. It may be difficult to differentiate an 'incomplete' abdominal attack from other causes of abdominal pain, mainly because of its atypical presentation. Our preliminary observational data indicate that some FMF patients relate their symptoms (especially gastrointestinal) to gluten assumption, then excluding it from diet and using gluten-free products, with partial remission of gastrointestinal symptoms. Therefore, FMF and NCGS share some clinical features, such as abdominal pain, diarrhea, arthralgia and arthritis, and tend to be commonly associated with other inflammatory and autoimmune diseases. However, to our knowledge, a relationship between FMF and NCGS has not been previously investigated. This study has 2 major aims: 1.To evaluate the real relationship between the wheat ingestion and the gastrointestinal manifestations presented by FMF patients, self-reporting a NCWS. The study will be done after a period of gluten-free diet, administering wheat flour or placebo for 15 days. 2. To identify possible immunologic markers (histological features, expression of cytokines and other constitutive mucosal proteins from peripheral blood mononuclear cells and mucosal lymphocytes) that may explain the mechanism underling FMF abdominal attack and wheat ingestion.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Diagnostic
Official Title: Gluten-related Disorders in Patients Affected With Familial Mediterranean Fever
Actual Study Start Date : September 1, 2018
Actual Primary Completion Date : March 1, 2019
Actual Study Completion Date : April 1, 2019


Arm Intervention/treatment
Active Comparator: Wheat flour
Wheat flour will be administered blindly versus placebo for 7 days
Other: Wheat flour
Wheat flour will be administered once daily for 7 days
Other Name: Active Comparator

Placebo Comparator: Rice flour
Placebo will be administered blindly versus wheat flour for 7 days
Other: Placebo Comparator
Placebo will be administered blindly versus wheat flour for 7 days
Other Name: Rice flour




Primary Outcome Measures :
  1. Fibromyalgia symptoms evaluation [ Time Frame: Change from baseline at 1 week ]
    Fibromyalgia symptoms of patients, evaluated by the International Severity Scoring System for Familial Mediterranean Fever (ISSF), will be scored before and after 1 week of wheat (or placebo) ingestion

  2. Gastrointestinal symptoms evaluation [ Time Frame: Change from baseline at 1 week ]
    Gastrointestinal symptoms of patients, evaluated by the Gastrointestinal Symptom Rating Scale (GSRS), will be scored before and after 1 week of wheat (or placebo) ingestion


Secondary Outcome Measures :
  1. Leukocytes cell surface antigens expression [ Time Frame: Change from baseline at 1 week ]
    There will be evaluated some leukocytes cell surface antigens expression, i.e. CD45, CD56, CD117, NKp44, CD3, CD19, and CD14, from peripheral blood mononuclear cells and rectal mucosal lymphocytes before and after 1 week of wheat (or placebo) ingestion

  2. Cytokines production [ Time Frame: Change from baseline at 1 week ]
    There will be evaluated some cytokines production, i.e. IFN-γ, TNF-α, IL-22, IL-17, and T-bet, from peripheral blood mononuclear cells and rectal mucosal lymphocytes before and after 1 week of wheat (or placebo) ingestion



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients, both genders, with age between 18-65 years, affected with FMF, diagnosed according to clinical criteria designed by Livneh et al ("Tel-Hashomer" criteria), self-reporting a relationship between their symptoms (especially gastrointestinal) and gluten assumption, improving on a gluten-free diet and worsen on a gluten containing diet
  • Patients testing negative for celiac disease (anti-tTG and EMA negative, and with biopsy Marsh 0-1) and wheat allergy (serum specific IgE for wheat negative)

Exclusion Criteria:

  • Subjects diagnosed with celiac disease (positive anti-tTG and/or EMA, and positive histology, with Marsh 2 or above);
  • Subjects diagnosed with wheat allergy (positive serum specific IgE for wheat)
  • Subjects with Inflammatory Bowel Diseases (Crohn's disease or ulcerative colitis)
  • Subjects with Helicobacter pylori infection and other gastrointestinal infection
  • Pregnancy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03563300


Locations
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Italy
Department of Internal Medicine, Giovanni Paolo II Hospital of Sciacca
Sciacca, Agrigento, Italy, 92019
Department of Internal Medicine, University Hospital of Palermo
Palermo, Italy, 90129
Sponsors and Collaborators
University of Palermo
Investigators
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Principal Investigator: Antonio Carroccio, PhD University of Palermo

Publications of Results:

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Responsible Party: Pasquale Mansueto, Clinical Professor, University of Palermo
ClinicalTrials.gov Identifier: NCT03563300     History of Changes
Other Study ID Numbers: ACPM21
First Posted: June 20, 2018    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Fever
Brucellosis
Familial Mediterranean Fever
Hereditary Autoinflammatory Diseases
Body Temperature Changes
Signs and Symptoms
Gram-Negative Bacterial Infections
Bacterial Infections
Genetic Diseases, Inborn
Skin Diseases, Genetic
Skin Diseases