Dissertation committee:
Αθανάσιος Τζιούφας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Παναγιώτης Βλαχογιαννόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ευσταθία Καψογεώργου, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μιχάλης Βουλγαρέλης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Δημήτριος Φωτιάδης, Καθηγητής, Πολυτεχνική Σχολή, Πανεπιστήμιο Ιωαννίνων
Κλειώ Μαυραγάνη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Ανδρέας Γουλές, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Introduction: Primary Sjögren's syndrome is a complex, autoimmune disease with distinct clinical phenotypes and variable outcomes. The systemic form of the disease is characterized by immune complex-mediated manifestations and is complicated by lymphoma as a result of a polyclonal B cell hyperactivity that is evolving into B cell malignancy. The clinical phenotype of Sjögren's syndrome can vary from person to person, and its symptoms can range from mild to severe. Since Sjögren's syndrome can have such a diverse range of clinical manifestations, one of the primary goals of research in Sjogren is to revolutionize the way we stratify and classify pSS patients based on clinical phenotypes and novel useful biomarkers.
Methods: Cumulative clinical, laboratory and histologic data of consecutive SS patients who fulfilled the 2016 ACR/EULAR classification criteria and were followed up, in 5 centers from Greece (University of Athens, Harokopio University, University of Ioannina) and Italy (University of Pisa, University of Udine) (UPAHI group), were collected, integrated, and analyzed in a unified dataset according to each project of the PhD thesis [both study group(s) and control group(s)]. For the prognostic models the Fast-Correlation based feature selection (FCBF) algorithm was applied on the unified datasets to identify potentially independent variables for constructing a logistic regression (LR) model with the appropriate feature of interest as an outcome. Statistical analysis for categorical data was performed by χ2 test with Yates correction or Fisher exact when cell counts <5 patients and for numerical data t test or Mann-Whitney, after Shapiro-Wilk normality test. CXCL13 levels at serum and saliva samples were measured by a commercially available ELISA (sensitivity: 1 pg/ml; Abcam) according to manufacturer’s instructions.
Results: Male SS patients carry an increased risk of lymphoma development. Although statistics showed no difference in classical lymphoma predictors compared to females, data-driven analysis revealed gender and lymphadenopathy as independent lymphoma-associated features. Furthermore, Focus score evaluated at the time of SS diagnosis, is an independent lymphoma associated risk factor and may serve as a predictive biomarker for the early diagnosis of SS-associated lymphomas. A second minor salivary gland biopsy is patients with a FS ≥ 4, 4 years after SS diagnosis and in those with FS < 4 and a history of SGE, at 9-years, may contribute to an earlier lymphoma diagnosis and a better prognosis. Patients with combined seronegativity [triple seronegativity anti-Ro/SSA(-), anti-La/ SSB(-), RF(-) and ANA(+) and quadruple seronegativity [anti-Ro/SSA(-), anti-La/SSB(-), RF(-) and ANA(-)] accounts for almost 9% of total SS population and is associated with a milder clinical phenotype, partly attributed to the absence of rheumatoid factor. Serum levels of CXCL13 were associated with histologic, serologic, and clinical features indicative of more severe pSS while saliva levels did not reveal clinically significant correlations. MALT lymphomas constitute the majority of lymphomas (92/121, 76.0%) followed by diffuse large B-cell lymphomas (DLBCL) (11/121, 9.0%) and nodal marginal zone lymphomas (NMZL) (8/121, 7%). The 10-year overall survival and event free survival rates were 79% and 45.5% for MALT, 40.9% and 24.2% for DLBCL and 46% and 31% for NMZL. Cryoglobulinemia, focus score and the total EULAR SS Disease Activity Index (ESSDAI) composite index at SS diagnosis were proven independent MALT lymphoma predictors. In addition, it was shown that patients presenting non-lymphoma related stable lymphadenopathy constitute a subgroup of younger individuals with B-cell hyperactivity while pSS patients without sicca complaints constitute a distinct phenotype involving younger patients, sharing common immunopathologic mechanisms with typical sicca patients.
Conclusion: In the context of Sjögren's syndrome (SS), the presence of male gender, a high focus score, non-lymphoma stable lymphadenopathy, and cryoglobulinemia collectively represent a cluster of characteristics that often manifest in SS patients with a more severe clinical phenotype related to future lymphoma development. Conversely, seronegativity and a low focus score tend to be associated with a milder clinical presentation. Conversely patients who exhibit seronegativity and a low focus score tend to experience a milder clinical manifestation of the disease. This practice of categorizing patients based on easily attainable clinical parameters, a process referred to as clinical phenotyping, holds considerable value for healthcare practitioners entrusted with the care of individuals diagnosed with Sjögren's Syndrome. Such categorization aids in risk assessment and contributes to more informed clinical management decisions. This PhD thesis is centered on the clinical phenotyping of patients with Sjögren's Syndrome.
Keywords:
Sjogren's Syndrome, Clinical phenotype, CXCL13, MALT lymphoma, Cryoglobulinemia, Salivary gland enlargement
