The standard approach for treating patients with rheumatoid arthritis (RA) is based on trial and error. When patients fail initial treatment, permanent joint damage can occur.
"The longer someone takes a drug that’s not working for them, the greater the risk of permanent damage to their joints," says rheumatologist Vivian Bykerk, MD. "Finding the right medication early in the course of the disease is important."
Scientists at HSS are using cutting-edge laboratory techniques to make sense of RA at a cellular level, with the hope of cultivating a more targeted treatment approach and advancing drug development.
In 2018 and 2019, Laura Donlin, PhD, co-director of the Derfner Foundation Precision Medicine Laboratory, and a team of collaborators published research characterizing the full range of immune cell types found in the joints of people with RA. The research revealed new clues about why not everyone benefits from the same drugs and suggested an approach in which treatment selection could be personalized.
In one study, published in Nature Immunology, the researchers studied tissue samples from 36 people, including from joint replacement surgeries at HSS. They used advanced sequencing technologies to define the immune cells at the single-cell level and ultimately gain an understanding of the cells that drive the damaging inflammation characteristic of RA. They identified 18 unique cell populations in RA joints, including two types of fibroblasts that appear to be highly enriched. Work can now begin to determine how these cells may impact RA and whether medications targeting them can be a new therapeutic direction.
A second study, published in Science Translational Medicine, focused on a subset of macrophages that appear to be abundant in RA-afflicted joints. These white blood cells play a major role in the destruction of bone and cartilage, and thus irreversible joint damage, in people with RA. Using patient samples, they gained insights into how these disease-associating macrophages are most effectively targeted by medications. "We plan to do a more detailed study to look at possible connections between the differences in the cells found in patient tissues and variations these patients have to medications," Dr. Donlin says.
Both studies were part of the Accelerated Medicines Partnership in Rheumatoid Arthritis and Lupus Network, an innovative public-private collaboration created to find promising biologic targets in rheumatic disease. HSS is a major contributor to this effort.
"This research could lead to a more direct way of predicting drug response," says rheumatologist Susan Goodman, MD. "Although more research needs to be done to validate the findings clinically, it has the potential to be valuable."
It is also part of a broader effort to study patient samples rather than using lab models — an area in which HSS can make unmatched contributions. "To get results that are statistically significant, we need to be able to look at the detailed cellular and molecular pathways in hundreds of patients," Dr. Bykerk says. "We have one of the largest populations of RA patients anywhere. This will enable us to take advantage of this resource."
The collaborators expect to eventually conduct clinical trials testing different drugs for patients based on the specific populations of cells in their joints.
Back to HSS Annual Report 2018-19