Stratified medicine in primary Sjögren’s syndrome

The proposal aims to further characterise the clinical significance and the underpinning pathotypes of 4 PSS subtypes. The specific objectives are:

• To understand the natural history of the different PSS subtypes.
• To validate the transcriptomic signatures of the PSS subtypes and re-calibrate (if necessary) for non-UK cohorts.
• To further characterise the underpinning pathobiological profiles of the four PSS subtypes
• To explore whether the four subtypes respond differently to treatments by reanalysing data from two clinical trials (JOQUER (hydroxychloroquine) and TRACTISS (Rituximab)

• Task 1: Obtain regulatory approval / Patient recruitment & blood sample collection / Data analysis
• Task 2.1: Complete RNA sequencing & data analysis / Validate ± recalibrate transcriptomic signatures
• Task 2.2: Complete serum profiling (discovery phase) / Validate candidate serum protein signatures
• Task 2.3: Identify pathobiological differences in salivary glands between PSS subtypes / Validation of findings
• Task 3: Obtain trial data / Re-analysis of trial data

• Finalised PROM set and a new questionnaire the Sjögren's Work and Life Questionnaire (SWLQ), translation in different languages completed
• Validated the transcriptomic signature of the 4 PSS subtypes
• Identified 3 candidate proteins that were differentially expressed between the subtypes. Expanding discovery work
• Additional experimental work performed on mRNA and RNA for sequencing
• Re-analysis of clinical data on effects of hydroxychloroquine (HCQ) and rituximab (RTX) carried out
• Collaboration planned for storing data on a shared platform

Fore more information download the publication indicated below.

Primary Sjögren’s syndrome (PSS) is a condition typically causes dryness, pain and fatigue, with many patients also suffers from anxiety and depressive symptoms. The severity of these symptoms and the long-term consequences of the disease vary greatly among individual PSS patients. Similarly, pathological changes detected in PSS also differ between individual patients. There is currently no effective treatment for PSS and the diversity of symptoms and pathologies make it hard to find effective treatment.

Using clinical and biological data from over 1000 PSS patients from the UK, France and Norway, we identified four different subtypes of PSS. Furthermore, after reanalyzing the data from two previously published clinical trials of two different drugs (hydroxychloroquine and rituximab respectively), it was found that hydroxychloroquine helped one subtype of PSS patients and rituximab helped another subtype, with the remaining two subtypes did not benefit from either treatment.

The study is now trying to find out more about the underlying pathology of these four subtypes of PSS patients. There will also be investing whether patients can switch from one subtype to another and whether the medium to long-term consequences of the four subtypes of PSS are different. The results of this project will make a step change to the way we develop treatment of PSS patients, potentially making the process much more personalized and effective.

• Tarn, Seror, R., McMeekin, P., Al-Ali, S., Hackett, K. L., Hargreaves, B., Price, E., Pease, C. T., Hunter, J., Gupta, M., Sutcliffe, N., Regan, M., Giles, I., Isenberg, D., McHugh, N., Young-Min, S., Akil, M., Stocken, D., Everett, C., … Dubost, J. J. (2019). Symptom-based stratification of patients with primary Sjögren’s syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials. The Lancet. Rheumatology, 1(2), e85–e94. https://doi.org/10.1016/S2665-9913(19)30042-6
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• Tarn, Lendrem, D., McMeekin, P., Lendrem, C., Hargreaves, B., & Ng, W.-F. (2022). Primary Sjögren’s syndrome: Longitudinal real-world, observational data on health-related quality of life. Journal of Internal Medicine. https://doi.org/10.1111/joim.13451. PMID: 35018685
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A patient partner advisory board (PPAB) has been set up – comprising 4 (originally 7) patient research partners from 4 participating countries - to advise on what information to collect to best describe the burden that PSS brings to their daily lives. The activities are being coordinated by Dr Peter McMeekin, a health economist. 3 patient research partners have joined the steering committee.