Gluten-related Disorders in Familial Mediterranean Fever Patients
Condition: Not-celiac Wheat Sensitivity (NCWS); Familial Mediterranean Fever (FMF)
MeSH terms: Brucellosis; Familial Mediterranean Fever; Hereditary Autoinflammatory Diseases; Fever
Study type: Interventional

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.
    

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.
    

Intervention name(s): Wheat flour; Placebo Comparator
Intervention type(s): Other; Other
Intervention description(s): Wheat flour will be administered once daily for 7 days; Placebo will be administered blindly versus wheat flour for 7 days
Other intervention name(s): Active Comparator; Rice flour
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Diagnostic