AGE and CALLY Index in Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent episodes of fever and serositis. Although clinical attacks are intermittent, persistent subclinical inflammation may continue between attacks and contribute to long-term complications such as amyloidosis and increased cardiovascular risk.

Advanced glycation end products (AGEs) are bioactive molecules formed through non-enzymatic glycation and oxidation of proteins and lipids. AGEs accumulate under chronic inflammatory and oxidative stress conditions and may perpetuate inflammation via activation of the AGE-RAGE signaling pathway. Increased AGE burden has been associated with chronic inflammatory and metabolic disorders.

Skin autofluorescence (SAF) is a validated, non-invasive method for assessing tissue AGE accumulation using the AGE Reader™ device (DiagnOptics Technologies B.V.). This method provides a rapid and painless measurement without requiring blood sampling.

The C-reactive protein-albumin-lymphocyte (CALLY) index is calculated using CRP, albumin, and lymphocyte count and reflects systemic inflammation and nutritional status. It has been investigated as a prognostic marker in several inflammatory conditions.

This single-center, observational, cross-sectional case-control study aims to:

Evaluate the association between SAF-measured AGE levels and the CALLY index in FMF patients.

Compare AGE levels between FMF patients and age- and sex-matched healthy controls.

Assess associations between AGE levels and inflammatory parameters (CRP, ESR, serum amyloid A).

Explore relationships between AGE levels and metabolic parameters (HbA1c, lipid profile) and renal involvement markers.

Eligible FMF patients aged 18-65 years who meet the Tel-Hashomer diagnostic criteria will be included. Healthy volunteers matched for age and sex will serve as controls. No treatment assignment, intervention, or randomization will be performed.

All laboratory parameters will be derived from routine clinical assessments. AGE measurements will be performed once at baseline using the skin autofluorescence method. The study poses minimal risk, as it is non-interventional and involves only non-invasive measurement procedures.

Inclusion criteria

For FMF Patients:

• Age between 18 and 65 years
• Diagnosis of Familial Mediterranean Fever according to Tel-Hashomer criteria
• At least 6 months of clinical follow-up
• Available routine laboratory data (CRP, albumin, lymphocyte count)
• Not in an acute FMF attack at the time of assessment
• Ability to provide written informed consent

For Healthy Controls:

• Age between 18 and 65 years
• No history of chronic inflammatory, autoimmune, metabolic, or renal disease
• Ability to provide written informed consent

Exclusion criteria

• Diagnosis of diabetes mellitus
• Chronic kidney disease stage 3 or higher
• Active infection
• Malignancy within the past 5 years
• Dermatologic condition affecting the forearm measurement site
• Use of high-dose antioxidant or vitamin supplementation within the past 3 months
• Any condition that, in the opinion of the investigators, may interfere with study participation