Stratified medicine in primary Sjögren’s syndrome

Concept

Primary Sjögren’s syndrome (PSS) is a chronic complex immune-mediated rheumatic disease with no effective treatment to date. PSS affects 0.05-0.1% of the adults. A key barrier to therapeutic development is the marked heterogeneity in clinical manifestations and pathobiological profiles among PSS patients. We have recently described a strategy to stratify PSS patients into four subtypes with distinct clinical phenotypes and transcriptomic signatures.

Facts and figures

Project lead
W-F Ng
Newcastle University
Wan-Fai.Ng@ncl.ac.uk
FOREUM research grant: € 600.000
2018–2021

Meet the team

W-F Ng
Newcastle University
D Lendrem
Newcastle University
J-E Gottenberg
Strasbourg University
R Seror
Université Paris Sud
V Devauchelle-Pensec
Brest University
A Saraux
Brest University
S Bowman
University of Birmingham
F Barone
University of Birmingham
B Fisher
University of Birmingham
G Nordmark
Uppsala University
U Landegren
Uppsala University
R Omdal
Stavanger University Hospital
M Bombardieri
Queen Mary University London
P McMeekin

Objectives

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

1. To understand the natural history of the different PSS subtypes.

2. To validate the transcriptomic signatures of the PSS subtypes and re-calibrate (if necessary) for non-UK cohorts.

3. To further characterise the underpinning pathobiological profiles of the four PSS subtypes

4. To explore whether the four subtypes respond differently to treatments by reanalysing data from two clinical trials (JOQUER (hydroxychloroquine) and TRACTISS (Rituximab)

Patient voice

A patient partner advisory board (PPAB) has been set up – comprising 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.

Interim results

  • 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

Publications

Tarn JR, Howard-Tripp N, Lendrem DW, Mariette X, Saraux A, Devauchelle-Pensec V, Seror R, Skelton AJ, James K, McMeekin P, Al-Ali S, Hackett KL, Lendrem BC, Hargreaves B, Casement J, Mitchell S, Bowman SJ, Price E, Pease CT, Emery P, Lanyon P, Hunter J, Gupta M, Bombardieri M, Sutcliffe N, Pitzalis C, McLaren J, Cooper A, Regan M, Giles I, Isenberg D, Saravanan V,  Coady D, Dasgupta B, McHugh N, Young-Min S, Moots R, Gendi N, Akil M, Griffiths B, Johnsen SJA, Norheim KB, Omdal R, Stocken D, Everett C, Fernandez C on behalf of Leeds CTRU†, Isaacs JD, Gottenberg JE on behalf of the French ASSESS cohort†, Ng WF on behalf of the UK Primary Sjögren’s Syndrome Registry. Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials. Lancet Rheumatology. 2019 Oct 1;1(2):PE85-E94. doi.org/10.1016/S2665-9913(19)30042-6
Read more

Goals/Milestones

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

Lay Summary

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.