Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Jessica R Tarn, Nadia Howard-Tripp, Dennis W Lendrem, Xavier Mariette, Alain Saraux, Valerie Devauchelle-Pensec, Raphaele Seror, Andrew J Skelton, Katherine James, Peter McMeekin, Shereen Al-Ali, Katie L Hackett, B Clare Lendrem, Ben Hargreaves, John Casement, Sheryl Mitchell, Simon J Bowman, Elizabeth Price, Colin T Pease, Paul EmeryPeter Lanyon, John Hunter, Monica Gupta, Michele Bombardieri, Nurhan Sutcliffe, Costantino Pitzalis, John McLaren, Annie Cooper, Marian Regan, Ian Giles, David Isenberg, Vadivelu Saravanan, David Coady, Bhaskar Dasgupta, Neil McHugh, Steven Young-Min, Robert Moots, Nagui Gendi, Mohammed Akil, Bridget Griffiths, Svein J A Johnsen, Katrine B Norheim, Roald Omdal, Deborah Stocken, Colin Everett, Catherine Fernandez, John D Isaacs, Jacques-Eric Gottenberg

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Abstract

Background
Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response.

Methods
We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab.

Findings
In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo.

Interpretation
Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases.
Original languageEnglish
Pages (from-to)e85-e94
Number of pages10
JournalLancet Rheumatology
Volume1
Issue number2
Early online date25 Sep 2019
DOIs
Publication statusPublished - 1 Oct 2019

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