Gluten-related Disorders in Familial Mediterranean Fever Patients
Gluten-related Disorders in Familial Mediterranean Fever Patients
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.
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.
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