Abstract
SummaryBackgroundHeterogeneity 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 Symptom-based stratification of patients with Sjögren's syndrome
Highlights
Primary Sjögren’s syndrome is a chronic, immunemediated inflammatory disease, characterised by ocular and oral dryness, musculoskeletal pain, profound fatigue, and an increased risk of lymphoma.[1]
In the UK Primary Sjögren’s Syndrome Registry (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)
There were no significant differences in age, med ian EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), or EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) scores between the three cohorts
Summary
Primary Sjögren’s syndrome is a chronic, immunemediated inflammatory disease, characterised by ocular and oral dryness, musculoskeletal pain, profound fatigue, and an increased risk of lymphoma.[1]. Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (J R Tarn PhD, N Howard-Tripp MBBS, D W Lendrem DPhil, A J Skelton MSc, S Al-Ali PhD, K L Hackett PhD, B Hargreaves BSc, J Casement MSc, Prof J D Isaacs PhD, Prof W-F Ng PhD); Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK (N Howard-Tripp, B Hargreaves, S Mitchell BSc, B Griffiths MD, Prof J D Isaacs, Prof W-F Ng); Université Paris-Sud, AP-HP Université Paris-Saclay, Hôpital Bicêtre, Department of Rheumatology, INSERM UMR1184, Le Kremlin-Bicêtre, France (Prof X Mariette PhD, Prof R Seror PhD); Lymphocytes B et auto-immunité, Inserm U1227, University of Brest, Brest, France (Prof A Saraux PhD, Prof V Devauchelle-Pensec MD); Centre Hospitalier Régional Universitaire de Brest, Brest, France (Prof A Saraux, Prof V Devauchelle-Pensec); Interdisciplinary Computing & Complex BioSystems Research Group, School of Computing, Newcastle University, Newcastle upon Tyne, UK (K James PhD); Faculty of Health and Life Science, Northumbria www.thelancet.com/rheumatology Vol 1 October 2019 e85.
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