Inflammation Begins Long Before Symptoms

Researchers at the nonprofit research organization, the Allen Institute, in Seattle, Washington, together with scientists of the University of Colorado Anschutz School of Medicine in Aurora, Colorado, the University of San Diego in California, and the Benaroya Research Institute in Seattle, have discovered that people who are at risk of developing rheumatoid arthritis, undergo severe immune system changes long before symptoms occur. 

Rheumatoid arthritis is a debilitating, systemic autoimmune disease in which the body’s own immune system begins to attack healthy cells. It is mainly caused by a combination of genetic and environmental factors, and, once triggered, results in chronic inflammation of the joints and other parts of the body. If left untreated, rheumatoid arthritis can lead to the destruction of joints, as cartilage degrades and bones erode. 

Approximately 18 million people worldwide are living with rheumatoid arthritis, with the prevalence expected to increase to almost 32 million by 2050. While the number of affected individuals is expected to grow, the mortality is declining as treatments become more widely available and more targeted.

Once symptoms appear, patients can be treated with disease-modifying antirheumatic drugs (DMARDs). However, treatment failures and disease relapse remain a common challenge. Generally, the earlier the treatment intervention begins, the higher the chances of reducing disease activity and preventing or delaying damage to the joints and other tissues. 

Currently, two biomarkers—anticitrullinated protein antibodies (ACPAs) and rheumatoid factor (RF)—are used to diagnose the condition. People who are positive for the ACPA autoantibodies but are otherwise healthy are at risk of developing rheumatoid arthritis later on.

Researchers have suggested that an early intervention before disease onset could significantly slow down or prevent joint damage. However, until now, knowledge of the immunobiological state during the at-risk period has been lacking, preventing progress toward preemptive therapies. 

In their study, published in the journal Science Translational Medicine with the title “Progression to Rheumatoid Arthritis in At-Risk Individuals is Defined by Systemic Inflammation and by T and B Cell Dysregulation,” the researchers studied the immune states of 45 clinically healthy, ACPA-positive at-risk patients and 11 patients with early clinical rheumatoid arthritis, and compared their findings to 38 ACPA-negative healthy individuals. 

During the seven-year study, around one-third (36%) of at-risk individuals developed clinical rheumatoid arthritis. 

The researchers compared the proteins found in the blood plasma of individuals at risk and with rheumatoid arthritis with those of healthy individuals. They identified 272 proteins that differed between the two groups, while some proteins were also different between at-risk individuals and people with clinical rheumatoid arthritis, “suggesting that some molecular features of RA begin before clinical manifestation,” the authors wrote.

Other findings, based on single-cell RNA sequencing, showed that systemic inflammation was already occurring throughout the body of at-risk individuals, similar to that found in patients with active rheumatoid arthritis. 

At-risk individuals also had several immune cells with abnormalities: B cells went into a pro-inflammatory state, instead of producing protective antibodies, and T helper cells were overactive and greatly expanded beyond normal levels, triggering immune responses and revealing how the immune system begins attacking healthy tissues. 

Moreover, the research team discovered that in people who had been at risk and developed rheumatoid arthritis, “naive” T cells, which hadn’t previously encountered threats, showed changes on a genetic level. The cells were reprogrammed even before they encountered their first threat, making them more likely to attack the body’s own healthy cells. 

The team also found that at-risk individuals showed a similar type of inflammation in their blood as rheumatoid arthritis patients have in their joints. This, say the researchers, suggests that the disease process was already preparing to attack the joints. 

“Overall, we hope this study raises awareness that rheumatoid arthritis begins much earlier than previously thought and that it enables researchers to make data-driven decisions on strategies to disrupt disease development,” said co-senior author Mark Gillespie, PhD, assistant investigator at the Allen Institute. 

Co-senior author Kevin Deane, MD, PhD, professor at the University of Colorado Anschutz School of Medicine, added: “We expect that going forward the findings from this study will support additional studies to identify ways to better predict who will get rheumatoid arthritis, identify potential biologic targets for preventing rheumatoid arthritis as well as identify ways to improve treatments for those with existing rheumatoid arthritis.”