The findings could lead to more effective therapies for the incurable autoimmune disease, which affects roughly 1.5 million Americans, according to the Centers for Disease Control and Prevention.

“Our discoveries point to the importance of the tissue environment in worsening rheumatoid arthritis and driving resistance to antirheumatic medications,” said Nunzio Bottini, MD, PhD, director of the Kao Autoimmunity Institute at Cedars-Sinai, professor of Medicine and corresponding author of the study.

Rheumatoid arthritis causes chronic inflammation in the joints. In other forms of autoimmune arthritis, inflammation can be relieved by targeting a protein called interleukin-17, one of several that can contribute to joint inflammation.

In experiments involving human rheumatoid arthritis tissues and laboratory mice, investigators showed that, over time, the immune cells that produce interleukin-17 gradually stop making it. This finding helps explain why IL-17-targeted treatments do not work well against established rheumatoid arthritis.

“These immune cells can also change in ways that make them more aggressive and able to sustain inflammation even without interleukin-17,” Bottini said.

Changes to the immune cells appear to be driven by synoviocytes—nonimmune cells that produce the lubricating synovial fluid in the joints, according to the study.

Bottini said that the Department of Computational Biomedicine at Cedars-Sinai, particularly the laboratory of Kyoung Jae Won, PhD, played a key role in the study by contributing critical work in spatial biology, an emerging field that studies how cells function within their tissue environments.

The findings carry significant implications for treating rheumatoid arthritis, according to Joyce So, MD, PhD, chief genomics officer at Cedars-Sinai and medical director of the newly established Center for Genomic Medicine at Cedars-Sinai Guerin Children’s.

“This important new insight contributes to shifting the paradigm of how we understand rheumatoid arthritis progression and why IL-17 treatments haven’t worked as well as expected,” So said. “Only with a precise understanding of the biological mechanisms of disease can effective, precision therapies be developed. In the meantime, clinicians can help patients in early or presymptomatic stages make the most of treatments that may lose effectiveness over time.”

Additional Cedars-Sinai authors include Kensuke Suga, Amara Seng, Sanaz Panahandeh, Myungja Ro, Yizhou Wang, Hyobin Kim, Zhiping Paul Wang and Jason H. Moore.

Other authors include Martina Zoccheddu, Mattias N. D. Svensson, Paramita Dutta, Hadijat-Kubura Moradeke Makinde, Zbigniew Mikulski, Katarzyna Dobaczewska, Francesca Ingegnoli, Ruth Minsha, John F. Seagrist, Mary Carns, Kathleen Aren, Salina Dominguez, Mohammad Daud Khan, Angela Denn, Roberto Caporali, Pietro Simone Randelli, David A. McBride, Arthur M. Mandelin II, Carla Marie Cuda, Nisarg J. Shah, Deborah R. Winter, Ferhat Ay and Harris Perlman.

Funding: The study was supported by UCSD and CSMC Institutional funds and NIH grant R21 AI154964 and R01 AR066053 to N.B., a joint LJI-UCSD pilot grant (to N.B. and F.A.) and LJI Institutional Funds (F.A.). A.S.is funded by NIH T32 HL170963. We wish to acknowledge support by the following NIH S10 instrumentation grants awarded to LJI: OD021831 (Zeiss LSM 880 microscope); RR027366 (FACSAria II Cell Sorter); OD025052 (NovaSeq 6000). The human RA tissue collection was supported by the Italian Ministry of Health grant RF-2018-12365439 to F.I. and P.S.R.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Cedars-Sinai investigators will share research findings designed to improve the prevention, diagnosis and treatment of rheumatic diseases, which affect nearly 60 million adults in the U.S.

On Saturday, Nov. 11, Daniel Wallace, MD, associate director of the Rheumatology Fellowship Program at Cedars-Sinai, will receive the Distinguished Clinician Scholar Award. The American College of Rheumatology gives the honor to a rheumatologist who has made outstanding contributions in clinical medicine, clinical scholarship or education.

Cedars-Sinai Presentations

Racial Variability in Immune Responses Only Partially Explains Differential Systemic Sclerosis Disease Severity    
Francesco Boin, MD, chair of Rheumatology and director of the Cedars-Sinai Kao Multispecialty Scleroderma Program

• Largest systematic analysis of autoantibody responses sheds light on why Black people with scleroderma may have more severe disease presentation than white patients.

Topological Proteomic Differences in Fibrotic and Unaffected Skin in Scleroderma  
Irene Choi, MS, Francesco Boin, MD and Nunzio Bottini, MD, PhD, director of the Kao Autoimmunity Institute 

• Laser-assisted microscopy technology improves understanding of the complex structure of skin affected by fibrosis and may pave the way to new therapeutics for scleroderma patients.

Inflammatory Markers and Left Ventricular Dysfunction in Systemic Lupus Erythematosus (SLE) 
Audrey Hagiwara, MD, Mariko Ishimori, MD, and Caroline Jefferies, PhD

• Among women with lupus and chest pain but no diagnosis of coronary artery disease, 40% did have undiagnosed coronary microvascular dysfunction.

Cumulative Infections by Week 52 Among Patients With SLE: A Summary of Data From Placebo-Controlled Belimumab Studies    
Daniel Wallace, MD

• Findings further support the favorable safety profile of belimumab for the treatment of systemic lupus erythematosus (SLE).

Circulating CTHRC1 Levels Are Associated With Disease Severity and Predict Survival in Systemic Sclerosis 
Francesco Boin, MD

• Circulating CTHRC1 levels are increased in systemic sclerosis patients and exhibit a significant association with more severe skin disease, pulmonary arterial hypertension and worse survival.

Single Cell RNA-seq of Myeloid Cells From Systemic Sclerosis Patients Identifies Circulating Monocyte Population With Interferon Signature Associated With ILD
Richard Ainsworth, PhD, Nunzio Bottini, MD, PhD, and Francesco Boin, MD

• Interstitial lung disease (ILD) is a major cause of morbidity and mortality in systemic sclerosis (SSc). Investigators identified features of circulating immune cells associated with SSc-ILD, which could lead to the development of biomarkers and treatment targets of the disease.

NOTE: A full list of Cedars-Sinai’s research presentations at the conference is available upon request.

Expert Interviews Available

During the conference, Cedars-Sinai rheumatology experts are available to comment on research they have presented as well as a wide variety of clinical and scientific topics in the field of rheumatic diseases and patient care. For interviews, please contact Cedars-Sinai Communications Specialist Laura Coverson by phone, at 310-562-1112, or by email: Laura.Coverson@cshs.org.