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. 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.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.
Background Primary Sjögren’s syndrome (pSS) is a multisystem autoimmune disease characterised by salivary and lacrimal gland inflammation leading to glandular destruction. The pathogenesis of pSS remains unclear, and research into pSS is made more challenging due to the heterogeneous clinical phenotypes among pSS patients. Several serum cytokines and chemokines have been linked with pSS pathogenesis, but their role in the various clinical manifestations in pSS have not been fully explored1,2. Objectives In this study, we examine the serum samples of a large cohort of clinically well-characterised PSS patients3 in order to determine whether serum cytokines and chemokines may be used to differentiate PSS patients from healthy controls, and if so, the relationship between these serum abnormalities and clinical phenotypes. Methods Serum levels of 24 different cytokines, chemokines and adhesion molecules for 150 pSS patients and 30 healthy controls were measured using Cytometric Bead Array.PSS patients were further classified into the following subsets: 1) Lymphoma; 2) No Lymphoma; 3) High systemic disease activity (ESSDAI score >12); 4) Low systemic disease activity (ESSDAI <1); 5) High residual glandular function (Oral salivary flow (OSF) >10ml/15min and Schirmer’s test >10cm); 6) Low residual glandular function (OSF <1ml/15min and Schirmer’s test <1cm); 7) Anti-Ro and Anti-La positive; 8) Anti-Ro and Anti-La negative. The relationship between analyte levels and clinical and laboratory parameters of PSS was examined using multivariate analysis and Mann-Whitney U testing; p-values were Bonferroni corrected for multiple comparisons. Results There were marked differences in the levels of many cytokines and chemokines between PSS patients and healthy controls, with a p value <0.001, statistically significant after Bonforroni’s correction for multiple comparisons. Serum IL4 and IL17 were found to be significantly higher in patients versus controls. Chemokines such as MIG (CXCL9), MIP1a (CCL3) and MIP1b (CCL4), IP10 (CXCL10), were also measured at higher levels in patient serum. Serum levels of IFNa, LTα and TNFα also differ significantly between patients and controls. Differences in cytokine levels were observed between patient subsets which were no longer significant after Bonferroni correction. Conclusions Differences in blood cytokine and chemokine levels between primary Sjogren’s patients and controls can be detected in serum. Serum MIG (CXCL9), MIP1a (CCL3) and MIP1b (CCL4), IP10 (CXCL10) IFNa, LTA and TNFa levels differ significantly between patients and controls. Our observations raise the possibility that these analytes may be important in disease pathogenesis. References Baturone, R. et al. Scand. J. Immunol. 2009;38:386. Szodoray, P. et al. Scand. J. Immunol. 2004;59:592. Ng, W.F. et al. Rheumatology 2010;50:32. Disclosure of Interest None Declared
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