Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease, with
autosomal recessive transmission, secondary to the mutation of the MEFV (MEditerranean
FeVer) gene. Several mutations have been identified as responsible for the dysfunction of
pyrin, a protein involved in the regulation of inflammatory processes. The resulting
inappropriate inflammatory response generally manifests with recurrent and short-lasting
episodes of fever, associated with inflammation of the serosa (FMF "attack"). Among the
most commonly reported symptoms during an acute attack, abdominal pain prevails, which is
often the first symptom to appear. The most fearful complication of this pathology is
amyloidosis. Currently, the first-line treatment for symptom control and prevention of
amyloidosis is colchicine. However, despite treatment, FMF attack may still occur
following exposure to some triggers, such as, for example, infections, trauma, physical
activity, and stress. Various researchers have also evaluated dietary habits and the
intake of certain foods, such as, for example, a diet rich in fats, cow's milk, and
wheat, as possible triggers of the FMF attacks.
Little is known about the trigger effect of foods on the exacerbation of FMF and the
evidence from the few studies in the literature appears to be controversial. The results
relating to the protective effect of a low-fat and a low-salt diet on the exacerbation of
symptoms in patients with FMF are conflicting. Furthermore, in a prospective study,
conducted on a limited sample of patients with FMF, it was demonstrated that the
ingestion of wheat could be responsible for both the clinical (with worsening of the
disease activity score), and the immunological reactivation of the disease [with evidence
of increased levels of serum C-reactive protein (CRP), serum amyloid A (SSA), and
circulating cluster of differentiation (CD)14+/IL1Beta+ and CD14+/TNFalpha+ monocytes].
The macronutrients in wheat potentially responsible for activating the immune system
could be gluten and/or alpha-amylase/trypsin inhibitors Amylase-Trypsin Inhibitors
(ATIs). Some researchers hypothesize that these protein components of wheat are also
responsible for an alteration of the intestinal microbiota, which, in turn, by alteration
of intestinal permeability and translocation of bacterial products, can lead to the
activation of the immune system, both innate and adaptive, at a local and a systemic
level, and, therefore, to the worsening of the inflammatory state of patients with
autoinflammatory/autoimmune diseases. Indeed, in patients with FMF, several studies
evaluated the relationship between modifications in intestinal microbiota and disease
activity. For example, one study demonstrated the presence of mucosal damage
predominantly affecting the jejunum and terminal ileum in approximately half of a group
of 41 patients with FMF undergoing endoscopic examinations. This finding would determine
the translocation and dissemination of molecules associated with pathogens and mucosal
damage (Pathogen Associated Molecular Patterns (PAMPs), and , Damage Associated Molecular
Patterns (DAMPs)) capable of triggering the acute attacks of the disease. Furthermore, it
has been shown that the overgrowth of intestinal bacterial flora (better known as Small
Intestinal Bacterial Overgrowth (SIBO), causing the blood diffusion of bacterial
metabolism products, can alter the response to colchicine and cause poor control of
disease activity, thus suggesting that the gut microbiota can modulate both the clinical
expression and the therapeutic response of FMF. In turn, in these patients, alterations
of microbiota and, consequently, of intestinal permeability, could depend both on the
chronic inflammatory state of the disease itself and on extrinsic factors (i.e. dietary
ones).
To date there are only few data regarding the relationship between ingestion of wheat and
other foods and the flare-ups of the FMF and the prevalence of gluten/wheat sensitivity
not linked to celiac disease or IgE-mediated allergy to wheat Non-Celiac Gluten/Wheat
Sensitivity (NCGS/NCWS) in patients with FMF. Therefore, the aims of this study are:
To evaluate, in patients with a definite diagnosis of FMF, the prevalence of the
trigger effect of wheat or other foods other than wheat, defined as the appearance
of symptoms and signs, identifiable as reactivation of FMF, after ingestion of wheat
or other specific foods.
To identify possible demographic, clinical and genetic differences between FMF
patients without and with reported trigger effects of wheat or other specific foods.
To evaluate, in patients with a definite diagnosis of FMF, the prevalence of
self-perception NCGS/NCWS, defined as the appearance of gastrointestinal and
extraintestinal symptoms caused by the ingestion of gluten/wheat, compared to a
control group [subjects of the vaccination center of the University Hospital 'Paolo
Giaccone'" of Palermo, Italy].
To identify demographic, clinical, and genetic differences between FMF patients
without and with self-reported NCGS/NCWS.