Harnessing molecular signatures to deliver personalised B-cell targeted therapies in Sjogren's syndrome

Sjogren Syndrome (SS) is a persistent/long-lasting disease characterised by inflammation of the glands that produce moisture in the body. The signs and symptoms range from dryness, joint pain and fatigue affecting nearly all patients, to severe involvement of organs and systems, in a more limited group. The cause of SS remains unknown but is associated with defects in the immune system. Our preliminary research showed that specialised types of immune cells, called B and T cells behave more abnormally in adults with SS contributing to organ and tissue damage. We want to understand why immune cells and genes they transcribe are different in adults with SS and healthy controls (HC) of the same sex and age, and try to identify how we can influence the way these cells behave, which will hopefully lead to better treatments for patients with SS.

To be able to look into this, we established a collaboration with a pharmaceutical company, GSK, who run a study in patients with SS and treated them with two different therapies which target B cells, called Rituximab and Belimumab. They used these treatments alone as well as in combination and compared how effective they are versus normal treatment (which we call standard of care). In addition to assessing patient response, they collected blood samples and also salivary gland biopsies (small pieces of tissue removed to view under the microscope to help diagnosing SS).

What are our research aims?

Objective-1: Define the fingerprints associated with the genes that are transcribed by patients blood cells to look for differences between :(i) SS disease vs. healthy controls; (ii) SS disease which is active versus well controlled (iii) SS patients who responded to Belimumab and Rituximab versus non-responders (by looking at samples collected at baseline vs 24 weeks post B-cell targeting therapies/placebo).
Objective-2: Establish shared fingerprints between blood and salivary gland tissue that reflect disease activity (combining patients from the GSK trial and UCL cohorts) and potential response to B cell targeted therapies at the end of the the GSK trial

Research question: Can a "molecular signature" or "endotype" (defined as a combination of whole blood - WB and salivary gland tissue transcriptomic signatures) be more relevant than the diagnostic label in defining unique disease characteristics?

Importance: If such a preliminary "molecular signature" can be identified, this is likely to help (after further validation in larger prospective studies) better patient stratification and ultimately guide treatment selection for better SS patient outcomes. Subsequently, this will address the challenge of SS patient heterogeneity as likely contributor to many negative interventional clinical trials in SS.

We propose an exploratory study to investigate this research question, focused on transcriptomic signatures, which will generate preliminary data for further validation in larger prospective studies, as well as support further investigation of other omic-signatures in the same SS cohort (such as targeted proteomics analysis based on the transcriptomic analysis generated by this proposal).

Rationale: B cell targeted therapeutic strategies (Belimumab and Rituximab, alone or in combination) have been used/trialled in SS with varied results.
This proposal will investigate both peripheral blood and salivary gland (SG) transcriptomic signatures associated with SS in a combined cohort of SS patients (GSK patients, n=65 matched samples at baseline and W24 and UCL patient samples n=46, total n=111).

These transcriptomic signatures could provide new insight into SS disease pathogenesis in different tissue compartments and generate preliminary data for further investigation of potential predictive biomarkers for patient stratification for selection of B cell therapies