1 Step Closer: Study Examines Factors That Lead to RA in Hope of Developing Prevention Strategies

What if patients at risk of developing rheumatoid arthritis (RA) could be identified before they became symptomatic?

Through ongoing research, Kevin Deane, MD, PhD, associate professor of medicine, Division of Rheumatology, Department of Medicine at the University of Colorado Denver School of Medicine, Aurora, Colo., believes the field of rheumatology is getting closer to discovering how to stop autoimmune diseases, such as RA, before they start.

Although clinical outcomes for RA have improved due to advances in therapy, Dr. Deane says some patients continue to respond inadequately to treatment. Over the years, he has devoted much of his research to exploring factors that increase susceptibility to RA.

“Through blood testing, we can now identify individuals who are at risk of developing RA before they develop full-blown inflammatory RA,” Dr. Deane says. “By identifying and treating RA earlier, we may ultimately be able to prevent RA, or delay its onset and severity.”

Dr. Deane

In his latest study, Dr. Deane and his colleagues examined the timing of elevations of autoantibody isotypes prior to RA diagnosis.¹ By using the Department of Defense Serum Repository, researchers identified 214 RA cases and 210 matched controls to evaluate patterns of elevations of the two most commonly used diagnostic markers of RA: rheumatoid factor (RF) and measured IgG, IgM and IgA isotypes for anti-citrullinated protein antibodies (ACPA).

“The presence of the different antibodies in serum of RA patients can be detected years before the onset of the actual disease,” Dr. Deane says. “We looked at the blood tests of patients who had ultimately developed RA to see which biomarkers were present and how they changed over time.”

Dr. Deane notes serum antibodies, including RF and ACPA, as well as systemic inflammation, have been shown to be abnormal prior to the development of clinically identifiable synovitis and a diagnosis of classified RA.

“In our research, we saw signs of an abnormal immune system in the years prior to an RA diagnosis that may lead to the development of RA,” Dr. Deane says.

In some cases, Dr. Deane says abnormal antibodies were present up to 17 years before patients began to experience symptoms, such as swollen joints.

In particular, Dr. Deane and his team noted IgA autoantibodies, which may reflect processes that occur at the mucosa, became elevated around the time individuals transitioned to a diagnosis of RA. “This needs more study, but this finding could mean in some individuals that mucosal factors are important in driving a transition from pre-RA to arthritis,” he says.

Additionally, the researchers found antibodies rising very late or very early before a diagnosis of RA, indicated different forms or endotypes of the disease.

“Differences in patterns of elevation of autoantibody isotypes can help us understand what factors drive initial autoantibody elevations compared with later increases in autoantibodies,” Dr. Deane says. “For example, individuals who had antibodies rise early in the course of the disease more often had manifestations of RA, such as dry eyes and mouth, and lung disease.”

In terms of broader effect of studying how RA develops, Dr. Deane says, “Currently, RA is only established after someone has been diagnosed with arthritis. But we may need to start identifying those in a pre-RA period during which blood tests show abnormalities in the immune system, sometimes years before patients report symptoms or full-blown arthritis develops.”

Dr. Deane says pre-RA could be used in the same way pre-diabetes is used to describe someone with higher than normal blood sugar levels, or pre-hypertension, where blood pressure levels are above normal or optimal levels.

“The key is letting people know they are at risk of developing RA,” Dr. Deane says. “By identifying and modifying risk factors, such as obesity, smoking or other factors in pre-RA, we may be able to prevent progression of the disease in vulnerable individuals.”

Right now, a diagnosis of RA is forever, but Dr. Deane says detecting the disease at the preclinical phase, before the onset of joint damage, may protect joints and allow doctors to treat patients with less toxic immunomodulatory therapies and/or risk factor modification to prevent future onset.

“In the same way blood tests reveal high cholesterol, blood-based tests can now identify patients before they get full-blown RA, opening new avenues for screening and possible prevention strategies,” Dr. Deane says.

Additionally, researchers found antibodies rising very late or very early in RA indicated different forms of the disease.

“Differences in patterns of elevation of autoantibody isotypes can help us understand what factors drive initial autoantibody elevations compared with later increases in autoantibodies,” Dr. Deane says. “For example, patients who had antibodies rise early in the course of the disease seemed to have better clinical outcomes when they underwent more aggressive therapy.”

Clinical Trial Tests a Possible Prevention
Dr. Deane also serves as the principal investigator of the StopRA clinical trial, short for Strategy for the Prevention of Onset of Clinically-Apparent RA, the first clinical trial in the U.S. of a drug that may prevent RA. Launched in 2016 and funded by the National Institutes of Health, the study is testing whether hydroxychloroquine, which is already used to treat patients with established RA, can also be used to prevent RA.²

Designed at Colorado University’s Anschutz Medical Campus, which is also the lead site for the study, along with 18 other institutions across the country.

“We’re continuing to enroll subjects in the study, and we expect to have answers within the next several years,” Dr. Deane says. “Those who have a family history of RA or elevated RA-related biomarkers are encouraged to enroll in our study.”

To learn more about the RA study or how to enroll patients, visit Stop-RA.org.

Linda Childers is a health writer located in the San Francisco Bay Area.

References

1. Kelmenson LB, Wagner BD, McNair BK, et al. Timing of elevations of autoantibody isotypes in rheumatoid arthritis prior to disease diagnosis. Arthritis Rheumatol. 2019 Aug 29. doi: 10.1002/art.41091. [Epub ahead of print]
2. National Institute of Allergy and Infectious Diseases. Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis (StopRA) [NCT02603146]. ClinicalTrials.gov. 2020 Apr 1.