Hello Raphaele, thanks for talking to us about NECESSITY today! Tell us a little bit about Sjögren’s disease – why do we need better treatments for this disease?
Sjögren’s disease is an autoimmune disease where the immune system reacts against the body itself. This disease is characterised by the disruption of certain glands such as those that produce saliva and tears – but it can also affect all the organs in the body. More than nine out of ten cases are women. Symptom-wise, some people are only affected by dryness, pain and fatigue, which affect their quality of life but are not life threatening. But on the other end of the spectrum, 5-10% will develop a malignancy, more specifically a lymphoma. This is the most feared complication of the disease.
What’s the situation today for somebody with Sjögren’s? As a patient, what is the treatment like?
As of 2024, no treatment has been marketed specifically for Sjögren’s disease. Typically, we compare the predominant symptoms to other autoimmune diseases, and treat the Sjögren’s patient with immunomodulatory drugs known to work in patients with those autoimmune diseases. For instance, if a patient has symptoms that are similar to arthritis – like joint pain – then we use a treatment that is used for arthritis.
How are scientists addressing this problem?
Worldwide, there are more than 20 clinical trials and 10 drugs that are in development for Sjogren’s. Some of them are finishing their phase 3 trials shortly and there are three or four pathways that have shown promising efficacy.
Within the NECESSITY consortium, a large clinical trial is ongoing across 8 European countries that is evaluating combinations of drugs that are already available for treating rheumatoid arthritis and lupus, and we are assessing their effect on patients with Sjögren’s.
What was the focus of the present study on clustering Sjögren’s patients ?
We tried to decipher if we could better map the patients into subgroups based on their individual characteristics, and then we aimed to determine if each subgroup had different outcomes and prognoses (for instance, whether the patients in one subgroup had a higher risk of organ complications or risks of lymphoma).
When you examined the patients to divide them into different subgroups, was it just the symptoms you were looking at or were other biological features considered?
That’s what we wanted to evaluate, that’s why we ran this particular method - which is called unsupervised clusterisation. We provided the machine with a large number of patient characteristics such as clinical symptoms, demographic features or even the presence of auto-antibodies (antibodies that are pathogenic and attack the body’s own proteins). The machine then classified the patients according to these variables.
We used 26 variables that reflected many things, like demographics, patient-reported outcomes, organ complications and some biological features that we believed reflected the activity of the disease. Based on this analysis, we identified 3 distinct groups, and these results were reproducible in two separate independent cohorts of patients.
Can you tell us more about these three clearly identifiable subgroups?
When we compare these three clusters of patients, we can see different presentations of the disease.
One cluster has high symptoms and no complications in the organs. This group was called ‘low systemic activity with high symptoms’ and they will not develop any complications, or very rarely.
Another group already had complications in the organs and a high level of symptoms like dryness and fatigue, and we called this group the ‘high systemic activity’ group. We observed that we had more men than usual in this group – about 20% of the patients were men, whereas normally it’s about 5%. This group also had more people with African ancestry, which is known to be associated with more severe cases of many autoimmune diseases, including Sjögren’s.
The last cluster is the one we called ‘B cell activity with low symptoms’, and this group was mainly composed of younger patients. They have a high amount of B cell activity in blood test samples, which are one of the major cell types involved in the pathogenicity of the disease. This group have a lower level of symptoms and dryness compared to the others.
When we analysed the results, we observed that the cluster with ‘high systemic activity’ was the one with the highest risk of lymphoma. The ‘B cell activity with low symptoms’ cluster also developed lymphoma sometimes and more frequently evolved complications in the organs. We believe that this cluster is at an earlier stage of the disease, and these people will probably progress to the cluster of ‘high systemic activity’ patients eventually. We saw no lymphomas in the last cluster which had a high symptom burden but low systemic activity.
What will this result mean in terms of how we treat these patients?
For the cluster with low systemic activity, the treatment is currently symptomatic. They can use tear drops and other treatments that help with the production of saliva. But usually for these patients we don’t need to use any immunomodulatory or immunosuppressive drugs.
On the other hand, the patients with high systemic activity frequently require an immunosuppressive drug.
The question is, for those patients with high B cell activity in the blood but not necessarily systemic complications yet, do we need to treat these patients or not? If we treat these patients, do we prevent the evolution of the disease and the risk of lymphoma and systemic complication? We do not know the answer yet.
Are the results already being used in clinical trials?
This study on clusterisation was conducted only with academic partners, but now we are working with the industrial partners of the NECESSITY project to apply those results to nine clinical trials, some of which were previously conducted by the industry, and some by academics.
We are going to apply this clusterisation approach to the results of these nine trials to see if we observe a better response to treatment once the patients are clustered. This could help researchers when designing future clinical trials, because they can focus on the cluster that is more likely to benefit from a specific treatment under investigation.
What are the next steps?
We completed another study where we analysed the biological markers in these three clusters, and we observed different molecular signatures in each. For example, the cluster without systemic symptoms had no increase in certain proteins that indicate the activation of the immune system. Whereas the two other clusters had big changes in these proteins, reflecting the activation of some pathways of the immune system. This is an important result – we observed that there is really a biological background behind each cluster, and we will write another manuscript based on these results.
NECESSITY is supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.