In a new study, symptom-based stratification of patients with primary Sjögren syndrome (pSS) revealed the existence of endotypes that differ with respect to their clinical and biological characteristics and response to therapy. “To our knowledge, this is the first report showing distinct subsets of an immune-mediated inflammatory disease and linking clinical and pathobiological heterogeneity, with direct clinical implications,” reports corresponding author Wan-Fai Ng.

Credit: A-Digit/DigitalVision Vectors

Heterogeneity in the clinical presentation of pSS presents challenges in the design of new treatments and in their evaluation in clinical trials. Understanding the differences between patient subgroups could influence pSS management.

In the study, a team of biostatisticians, bioinformaticians, data scientists and clinicians first undertook exploratory clustering analysis of symptom scores for pain, fatigue, dryness, anxiety and depression reported by 608 patients in the UK Primary Sjögren’s Syndrome Registry (UKPSSR). The analysis identified four distinct subgroups: low symptom burden, high symptom burden (HSB), dryness dominant with fatigue (DDF) and pain dominant with fatigue. A multinomial logistic regression model was then used to develop a tool to stratify other patients with pSS into these four symptom-based subgroups.

Comparison of the subgroups in the UKPSSR cohort revealed substantial differences in salivary flow, ocular dryness, serum IgG concentrations, peripheral blood lymphocyte counts and prevalence of anti-SSA or anti-SSB antibodies; whole-blood transcriptomic profiles also varied across the subgroups. These differences were also observed in two independent validation cohorts of patients in Norway (n = 62) and France (n = 334).

“A vital lesson that we have learned is the importance of collecting patient reported outcomes, not only because they matter to the patients, but also because they help us to do better research,” Ng says.

Application of the symptom-based stratification scheme in a reanalysis of data from two placebo-controlled phase III trials in pSS showed that treatment response varied across the subgroups. In the TRACTISS trial, patients in the DDF subgroup showed improved salivary flow in response to rituximab treatment, and in the JOQUER trial, patients in the HSB subgroup showed improvement in symptoms in response to hydroxychloroquine treatment, whereas no treatment effect was seen in the other subgroups.

“We believe that our findings have key implications for drug development, particularly in clinical trial design, as well as informing molecular targets,” says Ng. “Knowledge of these subtypes will also help us to develop a more personalised management plan for individual patients.”