Dissertation committee:
Κλειώ Π. Μαυραγάνη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Παναγούλα Αγγελογιάννη, Αναπληρώτρια Καθηγήτρια , Ιατρική Σχολή, ΕΚΠΑ
Αντώνης Χατζηγεωργίου, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μάρα Σιμοπούλου, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αρμακόλας Αθανάσιος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Φιλίππου Αναστάσιος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Παληκαράς Κωνσταντίνος, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Rheumatoid Arthritis (RA) is a chronic, systematic, autoimmune syndrome with an evolutionary character that predominantly diminishes joint health, being one of the major causes of disability worldwide. The disease presents with the classical findings of joint tenderness and swollenness. Although any joint of the human body can be affected by the disease, radiocarpal and phalangeal joints of the hand are most commonly affected, typically in a bilateral way. Characteristic disease symptoms include periarticular swelling, stiffness and reduction of range of motion, which appear after periods of rest and somewhat improve with light movement.Sjögren Syndrome (SS) or autoimmune epithelitis is another chronic evolutionary disease affecting the exocrine glands, mainly salivary and lacrimal glands. Autoantibody staining of exocrine glands causes the typical symptoms of xerostomy (dry mouth) and xeropthalmia (dry eyes), while lymphocytic invasion of exocrine glands on biopsy is the gold standard for the diagnosis. Although multisystem involvement occurs less commonly in SS than RA, it can affect different organs of the human body, including pulmonary, renal and central nervous system, as well as predispose to increased lymphoma risk compared to the general population.Cardiovascular disease and its complications appear at an increased rate in RA and SS patients compared to the general population, while increased atherosclerosis has been proposed as a probable pathogenetic mechanism. Even if traditional risk factors, such as hypertension, diabetes mellitus, hyperlipidemia, smoking, obesity and physical inactivity are found more frequently in the patient group, this imbalance does not seem to substantially explain mortality rate differences. Large cohort studies showed an up to 2-fold increase for acute myocardial infarction and up to 48% more cardiovascular events in RA patients comparing to healthy adults.A constantly increasing number of studies in the recent years occupy in engaging B-cell activating factor (BAFF), a cytokine of vital significance for the maturation, proliferation and differentiation of B-cells, as a common participant in the pathogenetic pathways of autoimmunity and atherosclerosis. BAFF concentrations appear increased in serum of RA and SS patients, while at the same time BAFF serum levels positively correlate with autoantibody production and disease activity.Bibliography already showcases how RA and SS patients appear with increased rates of atherosclerotic plaque within large- and medium-sized vessels as compared to examined adults without rheumatic disease. As media for subclinical atherosclerosis, carotid intima medial thickness (CIMT) and aortic/carotid pulse wave velocity (PWV) have been used.BAFF and BAFF receptors, as well as their genetic variance have been associated with a plethora of diseases, with specific polymorphisms appearing commonly in patients with autoimmune disease or predisposing to adverse effects of studied diseases. Furthermore, single nucleotide polymorphisms (SNPs) of the BAFF gene have been associated with the presence of subclinical atherosclerosis in patients suffering from rheumatic diseases, such as Systemic Lupus Erythematosus (SLE) and Sjogren’s syndrome.Taking the above observations into account, the purpose of the present study is first to confirm increased cardiovascular burden among the patient groups and then explore possible etiologic association of BAFF gene polymorphisms with subclinical atherosclerosis, as well as to define possible factors participating in this augmented burden.In 166 RA and 148 SS patients fulfilling ACR/EULAR diagnostic criteria, a full demographic and medical history was taken during their visit at a Hospital Outpatient Rheumatology Clinic and full hematological, biochemical and immunological profiling was performed. In addition, bilateral ultrasound examination of carotid and femoral arteries was performed and intima medial thickness of both vessels was noted as a non-interventional evaluation measure of arterial wall thickening and subclinical atherosclerosis. Finally, after obtaining written informed consent, peripheral blood samples were kept, for which quantitative reverse transcriptase-polymerase chain reaction technique was adopted to define genetic sequence of five BAFF gene polymorphisms (rs1224141, rs12583006, rs9514828, rs1041569, rs9514827). For comparison of BAFF genetic polymorphisms blood samples from 200 otherwise healthy adults were used.Atherosclerotic plaque was detected among RA with greater rates than SS patients (80.7% vs. 62.2%, p-value < 0.001), while no difference on IMT measurements or arterial wall thickening was observed. Moreover, RA exhibited greater rates of cardiovascular disease (CVD) family history compared to SS patients (20.7% vs. 14.6%, p-value < 0.001) as well as increased inflammatory markers, and were receiving greater steroid doses at the time of the study.Each patient group was subdivided into subgroups based on presence or not of atherosclerotic plaque and presence or not of arterial wall thickening, in order to compare traditional risk factors and disease characteristics. Among RA patients, arterial wall thickening was positively correlated with age, body mass index (BMI), hypertension and disease activity index DAS28, while atherosclerotic plaque presence was positively correlated with age, BMI, hypertension and erythrocyte sedimentation rate (ESR). Among SS patients, arterial wall thickening was positively correlated with family CVD history and ESR, while atherosclerotic plaque presence was positively correlated with age and xeropthalmia as a clinical complaint.BAFF genetic variants were examined to assess susceptibility to each of the two diseases as well as atherosclerotic risk within each disease group. Genotype TT of BAFF gene variant rs1041569 was found to affect RA susceptibility in codominant and recessive model, with haplotype TTTAT emerging as protective and haplotype TTTAC as increasing RA susceptibility. The same genotype affects SS susceptibility in codominant and recessive model, with haplotype TTTAC increasing SS susceptibility.Lastly, an attempt to connect subclinical atherosclerosis with BAFF gene variants was made. Genotypic alterations of BAFF gene variant rs1224141 were found to modulate risk for arterial wall thickening and atherosclerotic plaque formation in codominant, dominant, overdominant and log-additive model. Furthermore, genotypic alterations of BAFF gene variant rs1041569 were found to alter risk for atherosclerotic plaque formation in the recessive and overdominant model among RA and SS patients respectively. Haplotype analysis revealed haplotype GTTTT and protective against plaque formation but not arterial wall thickening among RA patients. Within the SS group, two distinct haplotypes, TATTT and TTCTT were found only among SS patients with arterial wall thickening.The current study brought to light new associations of CVD with RA and SS patient profiles, being a stimulus for clinical research of anti-BAFF treatments in RA and SS, with the goal of first- and second-line prevention of CVD mortality.
