RA expert updates latest pathologic findings from Accelerating Medicines Partnership

Recent AMP RA/SLE Network findings

Recent work by the AMP RA/SLE Network has shown that stromal fibroblasts can become highly inflammatory in RA.

“What’s becoming clear is that these are more than just lining of the joint or structure of the joint, they actually play an active role in the disease,” Dr. Anolik said.

There is a lot of diversity in these fibroblasts but they broadly fall into lining or sublining subtypes. Those that are proinflammatory tend to express markers such as HLA-DR and CD90, and one that is of notable interest is a subgroup of sublining fibroblasts that express Notch3. Indeed, it has been shown that the higher the number of Notch3-expressing fibroblasts there are in the joint, the greater the level of inflammation. Also, mice lacking Notch3 seem to get less arthritis than those with Notch3. This makes Notch3 an interesting potential target that no one had thought of before.

Dr. Anolik noted that some evolving concepts about T cells include evidence showing CD8-postive T cells are more abundant in the joint tissue than previously thought and, together with natural killer (NK) cells, are an important producer of interferon-gamma.

“There are some very interesting CD4 T-cell populations, including an expansion of T peripheral helper cells that may be very important in driving B-cell activation,” Dr. Anolik said. There are also many other clusters of T cells and NK cells that have unknown roles.

Over the past years, Dr. Anolik’s research had focused on the role B cells play in autoimmune disease, and one of the cells of interest are known as age-related B cells, or ABCs. High percentages of ABCs have been found in the RA synovium, and these seem to be related to disease activity as measured by the Disease Activity Score in 28 joints (DAS28). These cells also seem to cluster with some of the T helper cell populations found in the joint. Another interesting target could be B cells expressing a transcription factor known as T-bet. Work in mice suggests that the absence of T-bet B cells could be associated with reduced levels of arthritis.

“One of the things that we’re really interested in about B cells, in addition to their production of autoantibodies, is that they may be important for some of the structural damage that occurs with rheumatoid arthritis,” she said.

T-bet B cells seem to have an effect on both osteoclasts and osteoblasts – activating one while inhibiting the other to have a negative effect on bone overall, she explained. However, knocking out T-bet seems to resolve this, again suggesting that T-bet B cells may be another interesting subpopulation to target.

“Overall, the AMP has been a really interesting approach. This is a massive data set. We are putting the data together now to publish, and it will be available in the public domain,” Dr. Anolik said.

Members of the AMP RA/SLE Network include: AbbVie, the Arthritis Foundation, Bristol‐Myers Squibb, the Foundation for the NIH, the Lupus Foundation of America, the Lupus Research Alliance, Merck Sharp & Dohme, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer, the Rheumatology Research Foundation, Sanofi, and Takeda Pharmaceuticals International.

Dr. Anolik had no disclosures.