New research in Nature identifies key molecules for rheumatoid arthritis

Using a new systems biology approach, scientists at UC San Diego School of Medicine further analyzed cellular roles and roles in rheumatoid arthritis (RA), a complex disease that affects more than 1 million Americans in ways that contradict
a unified treatment.

The findings, published in the October 20, 2022 issue of the American Medical Journal Nature Communications, show that the same molecules involved in rheumatoid arthritis have opposite functions in cells from different patients, which also helps explain why current targeted therapies respond differently in patients with the same diagnosis and similar symptoms
.

Arthritis includes more than 100 diseases
that affect joints, tissues around them, and other connective tissue.
It is estimated that more than 58 million adults (one in five) in the United States have been diagnosed with the disease
.

Osteoarthritis is the most common form and involves joint degeneration, usually in the hands, hips, and knees
.
Rheumatoid arthritis is less common but still affects more than 2 million Americans, mostly women
.
It is a systemic autoimmune disease characterized by long-term persistent or chronic pain
in the tissues of the affected joint.
It can also cause problems with other organs, such as the lungs, heart, and eyes
.

There are many causes and risk factors for rheumatoid arthritis, but they are not well understood
.
They range
from age, sex, lifestyle (such as smoking) to obesity and genetic characteristics.
There is no cure for rheumatoid arthritis, but there is a wide range of targeted therapies that can help slow disease progression, prevent joint deformity, and reduce pain and disability
.

"Although the clinical presentation of rheumatoid arthritis is similar between patients, the response to any individual treatment is unpredictable and requires a tried and wrong approach
.
This process is repeated until a drug is found that reduces disease activity in a particular patient," said
Gary Firestein, MD, director of the Ultraman Institute for Clinical and Translational Research and Associate Professor of Medicine at UC San Diego School of Medicine.

"The prognosis of many patients has improved, but a large proportion of patients do not
.
They have persistent inflammation
.
These different responses to treatment suggest that the same disease may have different mechanisms
.
”

The diversity or heterogeneity of diseases of different cell types in individual rheumatoid arthritis patients has prompted efforts to find individualized mechanisms to help better understand the nature of rheumatoid arthritis and reliably prescribe
effective early treatment.
In the new study, the UC San Diego team focused on fibroblast-like synovial cells (FLS), a special cell type found inside the synovial membrane of the joint, a soft connective tissue that lubricates joints and reduces wear
.
FLS plays an important role
in RA joint destruction.

By examining cultured primary FLS, the researchers identified specific transcription factors (proteins that regulate gene transcription or replication) that are associated with
cell lines from individual RA patients.
Through the analysis, scientists can divide these cell lines into at least two subtypes that predict different pathways of activation that can lead to inflammation
.

"Basically, we biologically validated these predictions of top subtype-specific transcription factors," said
co-corresponding author Wei Wang, Ph.
D.
, professor in the Department of Chemistry, Department of Biochemistry, and Department of Cellular and Molecular Medicine at UC San Diego School of Medicine.
"This study is the first to characterize
cell lines with unique transcription factor biology in RA patients by integrating transcriptome and epigenomic data.
"

Systems biology is a computational approach that studies the interactions and behaviors of all components in a biological entity, based on the understanding that the whole is greater than the sum
of its parts.
Using this approach, the findings may help pave the way for a better understanding of the heterogeneity of rheumatoid arthritis, while focusing better on existing and future individualized therapies
for individual patients, the authors write.