Pioneer in B-Cell Function and Therapeutic Targeting in Autoimmune Disease Will Share Cutting-Edge Research on RA Synovitis

A deeper understanding of the pivotal role of B-cells in autoimmune disease pathogenesis has enabled development of B-cell-targeted therapies. Even as the armamentarium of new B-cell-targeting agents and their indications expands, the B-cell saga in autoimmune diseases has new characters and plots yet to be revealed.

In the session SOTA: Busy Bs: Deciphering B Cell Contributions to Rheumatoid Synovitis, being held on Tuesday, Nov. 19, from 9:30–10:30 a.m. ET in Room 144ABC of the Walter E. Washington Convention Center, Jennifer Anolik, MD, PhD, Professor of Medicine at the University of Rochester Medical Center, will speak about the latest findings on rheumatoid arthritis (RA) pathogenesis and progression obtained via detailed characterization of patient-derived synovial tissue samples. The session will be available on demand within 48 hours for registered ACR Convergence 2024 participants.

“Our work, and that of many others, has started to characterize, with state-of-the-art high-dimensional tools, the cells and molecular pathways that are perturbed in the synovium of patients with RA,” Dr. Anolik said. “We are particularly interested in B-cells, one of the adaptive immune cells that play an important role in autoimmune diseases.”

Although the reasons and mechanisms underlying formation and perpetuation of characteristic pathogenic autoantibodies — such as anti-rheumatoid factor (RF) or anti-CCP antibodies in RA — have not yet been completely elucidated, antibody-producing plasma cells and B-cells are enriched in the synovium of many patients with RA, Dr. Anolik said.

She will speak about the B-cell states and factors in the joint microenvironment that may promote autoreactive responses. She will also highlight work from the Accelerating Medicines Partnership Autoimmune and Immune-Mediated Diseases (AMP AIM) program, launched in 2021 as a collaborative initiative from the National Institutes of Health (NIH), the U.S. Food and Drug Administration (FDA), pharmaceutical companies, and other stakeholders. AMP AIM has been extending research conducted via an earlier initiative focused on RA and lupus — AMP RA/SLE — to now include other autoimmune conditions, such as Sjögren’s syndrome.

AMP AIM investigators seek to apply high-resolution technologies, such as single-cell RNA-seq, to decipher unique features in affected tissues and the tissue microenvironment. Dr. Anolik said this work is also querying spatial relationships of cell populations in affected tissues, in addition to characterizing their transcriptional and functional states.

“We have learned that there is quite a bit of heterogeneity in the types of cells present in the synovial tissue,” Dr. Anolik said. “Some RA patients have a paucity of pathogenic B-cells in their synovial tissues, while others have many. There is a spectrum of B-cell infiltrates in synovial tissue among patients with RA. We are now beginning to speak about this heterogeneity as RA synovial endotypes.”

The foundational hypothesis is that the responses of patients to different therapies and their outcomes over time will be impacted by the tissue endotypes. For instance, patients lacking altered B-cells in their synovium may be less likely to respond to B-cell-targeted treatments.

Dr. Anolik will also share insights on how the microenvironment may promote recruitment, selection, and/or retention of specific autoantibody-producing B-cells in the synovium and other features and functions of pathogenic B-cells in RA-impacted synovial tissues.

“We have data that B-cells can activate monocytes within the synovium, leading to tumor necrosis factor (TNF) production, which can contribute to joint inflammation as well as adverse outcomes,” Dr. Anolik said.

She alluded to data from multiple groups suggesting that B-cell signatures in synovial tissue are one of the strongest predictors of progressive erosions over time.

“We are trying to understand what these B-cells are doing that might be promoting joint damage,” she noted.

In addition to leveraging longitudinal analyses of samples from patients, which she said can provide powerful insights into pathogenesis and disease progression, animal model studies can further reveal mechanisms of disease. These complementary approaches can facilitate discovery of biomarkers — that can guide treatment choice and response — and uncover potentially new therapeutic targets, she said.

“I am a rheumatologist as well as a basic researcher with a focus on B-cells,” Dr. Anolik said. “My aim is to provide information on these state-of-the art studies that is clinically relevant and is going to be accessible to rheumatologists and other providers who are taking care of patients, and to provide insights into how these new high-dimensional tools and approaches for studying patient-derived samples are informing the next generation of therapeutics and biomarkers.”