Can Gluten/wheat or Other Foods Be Responsible for FMF Attacks

Familial Mediterranean Fever (FMF) is a chronic hereditary autoinflammatory disease caused by mutations in the MEditerranean FeVer (MEFV) gene which codes for pyrin. Dysfunction of this protein determines an inappropriate response to inflammatory stimuli. The clinical course of the disease is characterized by recurrent episodes of fever and inflammation of the serous membranes, which manifest with chest, abdominal and joint pain. Several studies suggest a possible association between acute FMF attacks and dietary triggers, including wheat. However, it is still unclear to what extent wheat is responsible for the reactivation of FMF and if, between one acute attack and another, patients with FMF experience other symptoms, both gastrointestinal and extraintestinal, characteristic of gluten/wheat sensitivity not linked to celiac disease or immunoglobulin E (IgE)-mediated wheat allergy (i.e. Non-Celiac Wheat Gluten/Sensitivity, NCGS/NCWS).

Therefore, this study aims to evaluate the appearance of symptoms compatible with an acute attack of FMF following the ingestion of wheat or other foods, and the prevalence of self-perceived gluten/wheat sensitivity in patients with FMF.

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:

1. 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.
2. To identify possible demographic, clinical and genetic differences between FMF patients without and with reported trigger effects of wheat or other specific foods.
3. 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 \[subjects of the vaccination center of the University Hospital 'Paolo Giaccone'" of Palermo, Italy\].
4. To identify demographic, clinical, and genetic differences between FMF patients without and with self-reported NCGS/NCWS.

Eligibility Criteria:
Inclusion Criteria:

* Patients, of both sexes, aged between 6 months and 80 years, affected by FMF, classified according to the Eurofever/PRINTO criteria.
* Patients able to understand and complete the questionnaires independently (or, in the case of pediatric ones, analyzed through the answers provided by parents).

Exclusion Criteria:

* Patients aged \<6 months and \>80 years.
* Patients unable to provide informed consent or complete the questionnaires.