Sjögren’s syndrome can be classified into four distinct groups based on symptoms, and these groupings may be suggestive of differences in underlying biology and even response to treatment, a new study suggests.
The study, “Symptom-based stratification of patients with primary Sjögren’s syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials,” was published in The Lancet Rheumatology.
Sjögren’s syndrome is a heterogeneous disease and symptoms differ from individual to individual. These differences can complicate clinicians’ ability to manage the disease, and they pose a challenge in developing effective treatments, since some people might respond to therapies differently than others, presumably due to differences in the underlying biology of their disease.
“Conventionally, patients with primary Sjögren’s syndrome are thought to consist of two subtypes — those with predominantly glandular symptoms and those with extra-glandular (systemic) manifestations,” the study noted. “However, many patients do not fit neatly into these subtypes and no consensus criteria exist for such classification.”
Researchers set out to divide Sjögren’s patients into subgroups based on their symptoms. Creating such groups, they hypothesized, could allow for a better understanding of the disease at all levels — from dissecting the basic biology to identifying likely therapy responders.
To create these subgroups, researchers first used data from the UK Primary Sjögren’s Syndrome Registry (UKPSSR), then confirmed their findings with data from the French Assessment of Systemic Signs and Evolution of Sjögren’s Syndrome (ASSESS) cohort and the Norwegian Stavanger cohort. In total, this included clinical and biological data on 1,004 people with Sjögren’s syndrome.
The team sorted individuals based on five common disease symptoms: pain, fatigue, dryness, anxiety, and depression. At the simplest level, the sorting was done by feeding symptom data into a computer program, which grouped individuals with similar symptoms together.
This resulted in four subgroups, which the researchers dubbed: low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF).
As the names suggest, the LSB and HSB groups were characterized by relatively low and high scores, respectively, for all five symptoms. The DDF group was characterized by high dryness and fatigue scores but low anxiety and depression scores, while the PDF group was characterized by high scores in pain and fatigue and low scores for anxiety and depression.
Researchers then looked for meaningful differences between these groups. All four showed no significant differences in terms of disease activity, age, sex, disease duration, or use of immune-suppressing medication.
However, significant differences were seen between the groups in terms of saliva flow, tear flow, levels of antibodies in the blood, and white blood cell counts.
The groups also showed significant differences based on transcriptomics analyses. Transcriptomics is the global study of genes that are being transcribed in cells — basically, an assessment of which genes are ‘off’ and which ones are ‘on.’ By looking at these changes as a whole, several notable biological differences were identified.
For example, the DDF subgroup had the highest levels of genes related to the activity of B-cells, the immune cells responsible for making antibodies. This was also one of the groups with higher levels of anti-SSA and anti-SSB antibodies — the autoantibodies causing Sjögren’s — and the group with the poorest function of the salivary and lacrimal glands.
The researchers then used these subgroups to re-analyze data from two previous Phase 3 clinical trials, the JOQUER trial (NCT00632866), which tested hydroxychloroquine in Sjögren’s patients, and the TRACTISS trial (ISRCTN65360827), which evaluated rituximab in Sjögren’s. Results of both of these trials were described by the researchers as “initially disappointing.”
Importantly, the biological differences mentioned above allowed the researchers to make predictions about treatment response. “In the TRACTISS trial,” they wrote, “because rituximab is known to target B cells, we hypothesised that the DDF subgroup was more likely to respond to rituximab than were the other subgroups because the DDF subgroup had the highest mature B-cell transcriptomic modular score.”
Indeed, when the researchers looked at only individuals in the DDF subgroup who took part in the TRACTISS trial, those on active treatment had significant improvements in stimulated and unstimulated salivary flow after 48 weeks.
In the JOQUER trial, likewise, a clinically significant reduction in disease activity was identified for the HSB subgroup, although the underlying biological reasons are less clear.
These data provide a proof-of-concept for using these or similar subgroups to identify individuals with Sjögren’s syndrome who are most likely to respond to a given therapy, the researchers said, although they urged caution in interpreting the results.
“The original trials were not powered for a stratified analysis, however, and further validation of these findings is needed,” they noted.
“[O]ur data show that symptom-based stratification is a robust and clinically meaningful approach, addressing the clinical heterogeneity of patient experience and reflecting differences in pathobiological profiles and therapeutic responses,” the researchers concluded.