Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials
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- Jessica Tarn, Nadia Howard-Tripp, Dennis Lendrem, Xavier Mariette, Alain Saraux, Valérie Devauchelle‐Pensec, Raphaèle Séror, Andrew Skelton, Katherine James, Peter McMeekin, Shereen Al-Ali, Katie L. Hackett, Clare Lendrem, Ben Hargreaves, John Casement, Sheryl Mitchell, Simon J Bowman, Elizabeth Price, Colin Pease, Paul Emery, Peter Lanyon, John Hunter, Monica Gupta, Michele Bombardieri, Nurhan Sutcliffe, Costantino Pitzalis, John McLaren, Annie Cooper, Marian Regan, Ian Giles, David Isenberg, V. Saravanan, David Coady, Bhaskar Dasgupta, Neil McHugh, Steven Young‐Min, Robert J. Moots, Nagui Gendi, Mohammed Akil, Bridget Griffiths, Svein Joar Auglænd Johnsen, Katrine Brække Norheim, Roald Omdal, Deborah Stocken, Colin Everett, Catherine Fernandez, John D. Isaacs, Jacques‐Eric Gottenberg, Valérie Devauchelle-Pensec, Philippe Dieudé, Jean Jacques Dubost, Anne-Laure Fauchais, Vincent Goëb, É. Hachulla, Claire Larroche, Véronique Le Guern, Jacques Morel, Aleth Perdriger, Xavier Puéchal, S. Rist, Damien Sen, Jean Sibilia, Olivier Vittecoq, Joëlle Bénessiano, Sarah Tubiana, Karine Inamo, Stanie Gaëte, Djilali Batouche, Domitille Molinari, Mickael Randrianandrasana, Isabelle Pane, Adeline Abbé, Gabriel Baron, Philippe Ravaud, Jacques-Eric Gottenberg, Philippe Ravaud, Xavier Puéchal, Véronique Le Guern, Jean Sibilia, Claire Larroche, Alain Saraux, Valérie Devauchelle-Pensec, Jacques Morel, Gilles Hayem, P.Y. Hatron, Aleth Perdriger, Damien Sene, Charles Zarnitsky, Djilali Batouche, Valérie Furlan, Joëlle Bénessiano, Élodie Perrodeau, Raphaèle Séror, Xavier Mariette, Samuel M. Brown, N. Navarro, C Pitzalis, Paul Emery, Sue Pavitt, Joanne Gray
- Journal
- The Lancet Rheumatology
- Year
- 2019
- Citations
- 134
Abstract
BackgroundHeterogeneity 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.MethodsWe 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.FindingsIn 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.InterpretationStratification 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.FundingUK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIyOTUzMmExYmI4ZmUzM2U3MTY4OWEwY2RlZDgzZTgzMSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjQ3NDI0MjYzfQ.FPob_XBAgxz6D-GKyAA1qrbbBlFyZR-cvgsA51HscM66sOA7KC_ZBdSh1pCuKrWp_7WWQWES3d0s55x8EyByctqnBLy3e97Cbym1rL-8jIZJj_XjGQJFYygDXk8WclyNJtu9kAqUpyAcLnZdlmMVcAmm76mny0JyLP6dC3D6YNdwcCwMRbXHosz2ZfUlfhQ9Q-eMojRGvmI1joDMeUxd03joeO7_Hht9hcuI809_mhAfZu6SVKUo-qu6tHKNpszu8Me-M6bM2q149gSplGxObG0sBezPJZ2qbgm1tK8BSPuVpPPk9dbwMT7fg-cjpY4en6KurU1PsbVqQMvl01qjJw(mp4, (77.1 MB) Download video Symptom-based stratification of patients with Sjögren's syndrome