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

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.

Funding: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. VIDEO ABSTRACT.

Figure 1

Patient reported symptom scores for each cluster (A) Dendogram and symptom heatmap shows results of the cluster analysis of patient symptom scores from the ESSPRI and HADS scores for pain, fatigue, dryness, anxiety, and depression. The symptoms are colour-coded in the heatmap at the base of the dendrogram: teal is low, white is intermediate, and brown represents a high symptom score. (B) Median (IQR) patient reported symptom scores within each cluster. ESSPRI=the EULAR Sjogren's Syndrome Patient Reported Index. HADS=Hospital Anxiety and Depression Scale.

Figure 2

Chaussabel module activity scores Chaussabel module activity scores adjusting for batch differences for the UKPSSR and ASSESS transcriptomics datasets centred on the mean for each module. Shown are the top 31 modules with significant differences between subgroups in the UKPSSR and ASSESS cohorts. Negative values imply inhibition and positive values imply activation. The error bars represent 95% CIs. For example, the first module is activated in patients in the dryness dominant with fatigue and low symptom burden subgroups, but inhibited in patients in the high symptom burden. and pain dominant with fatigue subgroups. Of particular interest are the modules IFN Response, mature B cells, and T cells (highlighted red). Unadjusted p values were used in this analysis. Details of the modules including the adjusted p values are listed in the appendix (p 17). IFN=interferon.

Figure 3

Reanalysis of two clinical trials using symptom-based subgroups (A) ESSPRI scores for each subgroup for patients in placebo and HCQ groups in the JOQUER trial. Box plots show the median ESSPRI scores, quartiles, and ranges for placebo and hydroxychloroquine for LSB, HSB, DDF, and PDF subgroups. The step break indicates the mean ESSPRI scores of the placebo and hydroxychloroquine treatments for each subgroup. Although we found no overall treatment effect, we found a significant treatment by subgroup interaction. This consistency test is statistically significant (p=0·036). The p values shown are for the contrast within each subgroup. (B) Stimulated salivary flow for each subgroup for patients in the placebo and rituximab groups of the TRACTISS trial. Box plots of log transformed data show the median SSF and ranges for placebo and rituximab treatments for each subgroup. Data are shown for the LSB subgroup; however, statistical analysis was not done because of insufficient data in this stratum. Although the figures show group values at the end of the trial, the probability values refer to the statistical analysis on changes from baseline as per the original clinical protocols. LSB=low symptom burden. HSB=high symptom burden. DDF=dryness dominant with fatigue. PDF=pain dominant with fatigue. SSF=stimulated salivary flow.