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Abstract
Objective This study aimed to identify protein biomarkers associated with patient-reported symptom burden and health-related quality of life (HR-QoL) in patients with a systemic autoimmune rheumatic disease (SARD), positive for anti-SSA.
Methods Anti-SSA positive SARD patients were recruited prospectively. Baseline and 6-months HR-QoL were determined by patient VAS (0–100), and symptom burden by ESSPRI (0–10). Proximity extension immunoassays (OIink) were used to measure normalised protein expression (NPX) in sera across 88 inflammatory proteins. K-means clustering was applied to baseline NPX, and patient clusters were identified using unsupervised hierarchical clustering. Linear regression, adjusted for multiple comparisons, was used to identify significant proteins associated with patient and physician reported outcomes at follow-up.
Results We included 30 patients with Sjögren’s disease (30%), SLE (50%) and UCTD (20%); mean (sd) age 46 years (14); 97% female, and 13 healthy controls. HR-QoL and symptoms burden did not differ by diagnostic group. Clustering identified two clusters, each containing 15 patients, with downregulation (Cluster 1; ‘low expression cluster’) and upregulation (Cluster 2 ‘high expression cluster’) of inflammatory proteins with good separation and cluster assignment (figure 1a). These clusters were not associated with diagnosis, however, were associated with fatigue, pain, HR-QoL and physician VAS. Cluster 1 demonstrated higher symptom burden (dryness and pain) and more impaired HR-QoL (figure 1b). Cluster 2 was associated with lymphadenopathy (p=0.031) and a higher physician global VAS (p=0.051). These clusters are driven by protein networks implicated in IL-17 signalling, and viral protein interactions with cytokines and cytokine receptors. At follow-up, poor HR-QoL and high symptom burden were associated with downregulation of inflammatory proteins, whereas physician VAS was associated with upregulation of inflammatory proteins (figure 1c).
Conclusion In patients from across the Lupus-Sjögren’s spectrum with a common autoantibody, we identified patient clusters anchored by discrete symptom burden to distinct proteomic profiles. The identification of the novel protein networks driving symptom burden and poor HR-QoL will help elucidate aetiology, and identify novel targets amenable to therapeutic intervention.
Acknowledgements SD and MR are MRC Clinical Training Fellows based at the University of Manchester supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (Award Ref. MR/N025989/1), Roche Pharma, Eli Lilly and Company Limited, UCB Pharma, Novartis, the University of Liverpool and the University of Manchester. INB is a National Institute for Health Research Senior Investigator and is funded by the NIHR Manchester Biomedical Research Centre (NIHR203308). BP is supported by the NIHR Manchester Biomedical Research Centre (NIHR203308) and NIHR Manchester Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
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