Study Probes Heterogeneity of Rheumatoid Arthritis

Researchers at University of California San Diego (UC San Diego) School of Medicine have identified new cellular players in rheumatoid arthritis (RA), a complex disease that affects more than one million Americans and has defied development of uniform treatments. The findings notably show that the same molecules involved in RA can have opposite functions in cells obtained from different patients. This information that could help explain why current targeted therapies evoke different responses in patients with the same diagnosis and similar symptoms.

“Although that RA arises with similar clinical appearance between patients, response to any individual treatment is unpredictable and requires a trial-and-error method. This process is repeated until a drug that decreases disease activity for that particular patient is identified,” says co-corresponding author Gary Firestein, MD, Distinguished Professor of Medicine and director of the Altman Clinical and Translational Research Institute at UC San Diego School of Medicine.  “Many patients have improved outcomes, but a significant percentage do not. They have persistent inflammation. These variable responses to therapy indicate the same disease can have diverse mechanisms.”

Encompassing more than 100 conditions that affect the joints, tissues around the joint and other connective tissues, arthritis affects one in five adults in the US. Osteoarthritis is the most common form, involving degeneration of joints, often in the hands, hips, and knees. RA is less common and affects primarily women. It is characterized by long lasting or chronic, painful tissue inflammation in affected joints. It can also cause problems in other organs, such as the lungs, heart, and eyes.

The heterogeneity of RA, with varying cell types in individual RA patients, has driven efforts to find personalized mechanisms that would help to better understand the nature of RA and reliably prescribe effective, early treatment. The UC San Diego team focused on fibroblast-like synoviocytes (FLS), a specialized cell type found inside joint synovium, a soft connective tissue that lubricates joints and minimizes wear-and-tear. FLS play a major role in RA joint destruction.

Examining cultured primary FLS, the researchers identified specific transcription factors that are involved in individual RA patients’ cell lines. The analysis allowed scientists to stratify those cell lines into at least two subtypes with different predicted activated pathways that could contribute to inflammation.

“Essentially, we biologically validated these predictions for the top subtype-specific transcription factors,” says co-corresponding author Wei Wang, PhD, professor in the departments of Chemistry, Biochemistry and Cellular and Molecular Medicine at UC San Diego School of Medicine. “This study is the first to characterize groups of cell lines from RA patients with distinctive transcription factor biology by integrating transcriptomic and epigenomic data.”

The study used systems biology, a computational approach that studies the interactions and behavior of all components of a biological entity.  In taking this approach, the authors wrote, the findings could help pave the way toward a greater understanding of RA’s heterogeneity while providing better focus on existing and future therapies personalized to individual patients.

The findings were published recently in Nature Communications.