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Biomarkers of salivary gland disease in Sjögren’s syndrome

Student thesis: Doctoral ThesisDoctor of Philosophy

Sjögren’s syndrome (SS) is a systemic, chronic, autoimmune inflammatory disease that affects the exocrine glands. The absence of early diagnostic markers contributes to delays in its diagnosis. Furthermore, SS patients have an increased incidence of lymphoma and there is a need for biomarkers to identify its development. To enable a better understanding of disease activity and progression, the following aims were undertaken; 1. Investigate the potential use of the salivary gland assessment tests (whole flow rates (WFR), parotid flow rates (PFR), clinical oral dryness score (CODS) and ultrasound score (USS)) in discriminating SS and non- SS sicca patients as well as to differentiate between the different subgroups of SS. 2. Determine the diagnostic accuracy of USS. 3. Complete a longitudinal study on dry mouth patients at 5 and 10-year time-points. 4. Identify salivary markers of disease activity and progression in SS; MALT-L risk and MALT-L subgroups. Methodology: Clinical parameters (WFR, PFR, CODS and USS) of 244 patients involved in the cross- sectional study were recorded for SS of different subgroups as well as for disease controls and ROC curves were constructed to determine an optimal cut- off USS. Five-year follow- up of 80 patients was done while only 16 were involved in the 10-year follow- up. Salivary (parotid) proteomic analysis was done followed with initial candidate biomarker selection (S100A8/A9) and verification via immunoassay (ELISA) involving SS of different subgroups, disease and healthy controls (n=83). Salivary (parotid) cytokine array analysis was done followed by further screening of cytokines via multiplex bead- based assay on 76 samples and verification of the cytokines with significantly altered levels via a more sensitive multiplex bead- based performance assay on 82 samples. Results: 1. All parameters (WFR, PFR, USS and CODS) of the overall SS group showed a significant difference when compared to the disease control group. This was attributed mainly to the advanced subgroups of SS (SS at risk and MALT-L groups) (p<0.0001 for all parameters). 2. USS would be an ideal non-invasive test to differentiate and monitor SS patients in general; an optimal cut- off of 4 yielded 81% sensitivity and 94% specificity and odds ratio of 70.5% with a negative predictive value of 66% while the positive predictive value was 97%. 3. The follow- up of patients over 5 and 10 years has proven that in patients with a longer disease duration SS is a slowly progressing disease where all the parameters remained relatively stable, although some individuals may display flare ups and remissions as in any other rheumatic diseases. S100A8/A9 ELISA analysis of parotid saliva showed significant differences between the overall SS group and both disease and healthy controls (p=0.001 and 0.031 respectively). SS at risk of MALT-L and those with MALT-L also demonstrated increased levels when compared to healthy controls (p=0.019 and 0.014). IL-1α, -4, -6, and MCP-1 were significantly different in the overall SS group when compared to the disease control group but only IL-6 was increased when compared to the healthy control group. Further verification via more sensitive assays revealed that IL-6 and IL -4 continued to show significance compared to the disease control group and IL-6 compared to the healthy group. Conclusion: the results of the above-mentioned studies suggest that several clinical parameters can aid in differentiating between SS and non- SS sicca especially the subgroups of SS (MALT-L risk and MALT-L sub groups) with attention to USS as a valuable diagnostic tool. Salivary biomarkers showed differences between SS and the other groups as well.
Original languageEnglish
Awarding Institution
Award date2017


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