Research on the pathogenesis of rheumatoid arthritis (RA) is revealing that cell interactions are driving the disease and the epidemiology of pre-RA stages and may shed light on delaying or preventing the onset of RA. Collaborative team efforts are expected to yield significant breakthroughs in the near future.

Our understanding of RA is advancing through a team science approach in which basic scientists are partnering with clinical researchers, drug companies, and the Foundation for the National Institutes of Health (FNIH) to assemble a group of people who may have different alignments but are all working together to get answers. This is what is exciting now in RA, because we are going to get answers about what is going on in the joints of patients with RA. It is not immediately apparent what those answers will be, and it will likely take another 2 to 5 years before we really understand what is occurring.

There are 2 areas of RA research that are interesting and exciting right now. The first is looking at the cell types in the synovial membrane of patients with RA and how the cells are interacting with and relating to one another. This is being done with highly sophisticated techniques. Using spatial transcriptomics, for example, we can actually see individual cells in a 3-dimensional space and how they interact with one another over time. This type of direct information is obtained from ultrasound-guided techniques for tissue biopsies. So, we have new ways of accessing the tissue and looking at individual cells using highly sophisticated, single-cell techniques.

The second equally exciting area of RA research relates to epidemiology and prevention. Several studies have examined whether we can identify RA in the early stages, or what we call pre-RA, before it becomes active, becomes aggressive, or causes damage. We might then attempt to intervene with a relatively safe medication that targets a cytokine, a cytokine effector molecule, or a B-cell/T-cell interaction to potentially prevent the disease from evolving over time into something more serious.

The recent APIPPRA study utilizing the drug abatacept was conducted in patients who had early biomarkers of RA and joint pain without obvious swelling but did not yet fulfill the criteria for having established disease. Researchers were then able to show that you can actually delay the development of RA in such patients for over 1 year with abatacept therapy, and, if it does occur, it occurs in a milder form.

Over the past decade, we have identified molecular risk factors for RA using epidemiologic methods, by taking blood samples that were previously collected for epidemiologic surveillance reasons. A certain percentage of the individuals will develop RA. When that happens, you go back in the freezer, pull the samples from the affected individuals, and see which disease markers occurred years earlier. That research defined what we call pre-RA.

At the same time, we have also identified environmental triggers for RA, such as cigarette smoking and air pollution. Studies on these environmental triggers are even more interesting because if we know that something like cigarette smoke or air pollution contributes to RA, what is the mechanism? It appears to take place in the lung, but what cells and what parts of the lung actually do this? We are not sure, and this is under active investigation.

Finally, an exciting study (again, contributed to by team science) has extended our understanding of anti-citrullinated protein antibodies (ACPA), a biomarker that could predict one’s susceptibility to RA. Investigators studied patients with RA with or without periodontitis, showing that breaks in the oral mucosa from periodontitis were associated with oral bacteremias. The bacteremias could lead to flares in RA disease activity through mechanisms involving the activation of ACPA-producing B cells. This new area of research could help us understand why some patients have more severe RA and worse outcomes, and it could have implications for disease prevention.