Rheumatoid arthritis patients who fail one treatment after another are currently offered new drugs largely by trial and error, but a new approach using joint biopsies could change that. The problem is that a significant number of people with rheumatoid arthritis do not respond to B-cell-depleting therapies like Rituximab, even when their joints are packed with B-cells. The R4RA clinical study found that Rituximab works poorly when no B-cells are present in the joint, but even when they are abundant, only half of patients respond. The researchers have now identified a likely culprit: high levels of type I interferon—a molecule normally used to fight viruses—in the B-cells of non-responders. In the lab, they recreated this by growing B-cells with joint fibroblasts, which triggered the same interferon release. This project aims to map exactly how B-cells and fibroblasts communicate, then build a panel of markers that could predict which patients will respond to Rituximab before treatment begins. If successful, it would replace trial-and-error prescribing with a biopsy-guided strategy—similar to how cancer treatments are chosen. Because drugs that block type I interferon are already approved for lupus, the findings could also open a direct path to testing those drugs in rheumatoid arthritis patients who currently have no good options left.
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Rheumatoid arthritis (RA) is one of the most common inflammatory disorders. It is an autoimmune disease where the immune system mistakenly attacks the joints, causing pain, stiffness and swelling of the joints. Despite effective treatments compared to 20-years ago, a sizeable subset of individuals with RA fails several therapies with different mechanisms of action and continue to experience pain, joint damage and disability. Differently from cancer, where it is common for diseased tissues to be analysed (biopsy) prior to the selection of the correct treatment, in RA treatment decisions are largely based on a “trial and error” approach. Our group has pioneered the use of ultrasound-guided joint biopsies, where a small piece of joint tissue is obtained from an inflamed joint using a needle under a local anesthetic, as a tool to guide the choice of the right treatment to the right patient. The most successful of our studies, called R4RA, has shown that Rituximab, an approved treatment for RA which target a particular type of immune cells called B-cells, works very poorly when there are no B-cells in the joint. However, also in patients with plenty of B-cells in the joints we observed a meaningful clinical response in only 50% of those treated with Rituximab. A deeper analysis of responders vs non-responders to Rituximab has identified a new mechanism associated with lack of clinical response which decisively points towards a role for interferon type I (a group of factors normally involved in protection against viruses) in driving the resistance to drugs like Rituximab. We specifically observed high levels of interferon type I in B-cells from the joints of individuals with RA who do not respond to Rituximab. We were able to recreate similar conditions in the lab by growing B- cells together with another cell type which is resident in the joints called fibroblasts which were able to trigger B-cells to release interferon type I and behave in a similar way to those B-cells of patients who failed treatment with Rituximab. In this application, we first propose to better understand how B-cell and fibroblasts talk to each other. In order to do so, B-cells will be isolated from the blood and cultured with fibroblasts isolated from the joints. Later, the same cells will be identified in blood and joints and deeply characterized to clarify their involvement in the inflammatory process. The results of these analysis will allow to build a panel of markers specific for these B-cells that will be used to interrogate data from previous clinical studies, allowing us to predict individuals with RA who will respond to Rituximab from those who will not. Importantly, therapies blocking interferon type I are already approved in other autoimmune diseases, such as systemic lupus erythematosus, and we propose that a similar approach could be used in RA patients who do not respond to Rituximab. We will test potential drug candidates in a preclinical model of RA to determine if there is sufficient evidence to support a future trial in RA patients.
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