Unraveling Immune System Changes Before Rheumatoid Arthritis Onset

With her RA Research Program award, Dr. Elena Hsieh will focus on the immunological determinants that drive the conversion from “at risk” rheumatoid arthritis to symptomatic RA. 

By Vandana Suresh | Feb. 29, 2024

Dr. Elena Hsieh

In many ways, rheumatoid arthritis (RA) has met its match through a variety of medications that can suppress the immune system from attacking the joints. However, gaining a better understanding of the pathological changes in the immune system that lead to RA is one of the many goals of understanding the disease’s onset and developing targeted treatments to deter RA.

In that effort, the Arthritis Foundation has awarded $450,000 over three years to Elena Hsieh, MD, associate professor in pediatrics at the University of Colorado. With this funding, Dr. Hsieh and her team will investigate the immunological drivers of inflammatory arthritis that convert patients from pre-symptomatic RA to symptomatic RA. Addressing this knowledge gap will help in developing treatments that are geared toward RA prevention rather than managing symptoms after an RA diagnosis.

Rheumatoid Arthritis Prevention

“There is a lot of emphasis and research into treatments after the onset of inflammatory disease,” said Dr. Hsieh. “But in this grant, we are focused on studying the immunological events that happen a step ahead of clinical RA onset so that when we intervene for disease prevention, we do it in those individuals who are more likely to develop RA and will consequently benefit from the intervention.”

A hallmark feature of RA is the swelling of the small joints of the hands and feet, although most other joints are affected, too. The inflammation is caused by a variety of inappropriately activated immune cells damaging the tissues of the joint. These immune cells are often activated by the circulating cyclic citrullinated peptide (CCP) antibodies. In fact, a CCP antibody test is routinely used to diagnose RA when an individual has joint pain and inflammation. 

“Just like in diabetes, where elevated fasting glucose levels are an indication of pre-diabetes and increase a person’s likelihood of getting full-blown diabetes; in RA, there are likely to be some telltale immunological changes before the person starts to get symptoms,” said Dr. Hsieh.

Immune System “Soldiers”

However, while RA patients are most often CCP autoantibody positive, not all individuals positive for CCP autoantibodies end up with RA. This observation suggests that there could be immunological variations between people that are positive for CCP autoantibody and develop RA versus those who test positive but do not develop RA. Dr. Hsieh’s team will explore the differences in the immune cell types and function in these two groups using blood samples collected from CCP-positive and CCP-negative patients whose joint health was followed over time.

“Think of the immune system as an army with different soldiers. If you count them all, you will know how many you have of each type. That’s some useful information. But what my team really cares about is what each soldier or immune cell type does. How is its function altered in the individuals that convert to RA versus the non-converters?” said Dr. Hsieh.

She also noted that her team’s Arthritis Foundation-funded research will lead to better forecasting of whether a patient will develop RA and identify predictive blood-based biomarkers that could be used in clinical trials testing medications to prevent RA.

“I think working in the area of disease prevention is like being ahead of the game,” said Hsieh. “If we can actually identify these at-risk patients early and think about potential interventions before they develop symptoms, we can markedly improve their quality of life in the future, which is, of course, one of the major goals of the Arthritis Foundation.”

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