What does it mean when scientists say they want to “prevent” a disease? “For the last 10 years or more, we’ve been making exciting discoveries that lead us to conclude that we can sBRI President Jane Buckner, MDtop autoimmune diseases before they start in people who have a high risk of getting the disease,” says BRI President Jane Buckner, MD.

While Benaroya Research Institute at Virginia Mason (BRI) continues to look for the best therapies to treat autoimmune and allergic diseases, BRI researchers agree that the best way to cure diseases will be to prevent them from taking hold in the first place.  Preventing type 1 diabetes is fully underway and rapidly making progress. BRI leads Type 1 Diabetes TrialNet  ̶  an international network of researchers dedicated to the prevention of type 1 diabetes through risk screening of high risk people and innovative clinical research studies to slow or stop the disease.

Now prevention work is quickly advancing in rheumatoid arthritis (RA). How do scientists plan to prevent RA? “We can now identify people at high risk of getting RA, and we are studying them to learn what occurs to trigger the disease,” says Dr. Buckner, leader of this work at BRI. “Then we will find ways to intervene, so they don’t get it.”

The ultimate goal, she explains, would be to develop a simple blood test that could be used routinely in the doctor’s office to determine a patient’s risk for the disease. For those at high risk, an individualized therapy would be provided to prevent RA from developing before symptoms occur.

Two studies are critical in making progress to identify individuals at risk of developing RA. The first, now completed, is SERA (Studies of the Etiology of Rheumatoid Arthritis) and the second, recently launched, is TIP-RA (Targeting Immune Responses for the Prevention of Rheumatoid Arthritis).

People considered at high risk for the RA research studies are people who have a parent, sibling or child with the disease as there is a genetic connection. In the general population, 1 in 100 people1 in 100 people have RA, but for people with a close relative with arthritis, as many as 1 in 20 have the disease. have rheumatoid arthritis, but for people with a close relative with arthritis, as many as 1 in 20 have the disease.

RA is an autoimmune disease in which the body’s immune system mistakenly begins to attack its own tissues, primarily the synovium, the membrane that lines the joints. Because of this autoimmune response, fluid builds up in the joints, causing joint pain and systemic inflammation. This can lead to destruction of the cartilage, bone, and ligaments, causing deformity of the joints. The disease is progressive and is a major cause of disability. RA can also cause inflammation and injury in other organs in the body.

During SERA, a study led by the University of Colorado which BRI participated in, Dr. Buckner and others followed volunteers who gave their medical histories and donated blood over time. They analyzed people before and after they developed RA. They also studied people who were at high risk but didn’t develop the disease.

Scientists learned that people develop autoantibodies called anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) up to 10 years before symptoms of the disease begin. CCP and RF are proteins that are part of the immune system that attack the joints.  They are good biomarkers or indicators for RA, appearing in the blood years prior to the diagnosis of RA.  Researchers also discovered that more of these autoantibodies are produced six months to a year before the disease occurs and that the immune system becomes more active.

“Our findings show there is an opportunity to intervene in this disease before it develops,” says Dr. Buckner. “Now we’ve started a new study, TIP-RA, to increase the number of people observed and to use new tools we’ve developed to understand disease. We’re also looking in-depth at people’s lifestyle and environment.” TIP-RA also includes new collaborators, bringing many perspectives to the work: 

University of Colorado, Denver

Experts at how the outside environment affects the immune system such as diet and medications. They are also exploring what might trigger the disease such as viruses.

University of California, San Diego

Experts on how genes are turned on and off and how that might contribute to RA or be used to eliminate RA.

Stanford University

Experts at understanding the immune system’s B cells that make the antibodies that precede RA and target the joint, CCP and RF, and how they develop and change as RA develops.

Benaroya Research Institute

Experts at how T cells contribute to RA. T cells are important in the immune system response because they tell the other immune system cells what to do in response to a virus or bacteria. They are key when the immune system makes a mistake and causes an autoimmune disease.   

“We know T cells are important to RA because the most important gene linked to RA is the gene that determines how T cells function,” says Dr. Buckner. Building on work from BRI’s Gerald Nepom, MD, PhD, and Bill Kwok, PhD, a team working with Dr. Buckner and her colleague Eddie James, Phd have developed the ability to identify and isolate the cells that are targeting the joints in RA called citrilline-specific T cells.

“We have the capacity to take a small amount of human blood and look in-depth at these T cells, so we can understand what makes them become harmful and attack the body. We think these are the cells that cause RA. With these new tools, now we can make incredibly rapid progress with our samples from our generous volunteers. Once we understand what starts RA, then we can develop approaches to stop it before it takes hold.”

While scientists are looking in-depth at the immune system response, they are also studying the environmental issues around RA. Volunteers in the study fill out detailed questionnaires about their lifestyle including diet, smoking, medications and vitamins.

“We’ve found exciting and valuable information about what people can do to protect themselves,” says Dr. Buckner. “Through our research and that of others we’ve learned that smoking significantly increases your risk for RA. If no one smoked, 30 percent of the people with RA wouldn’t have it. Oral contraceptives appear to be protective and people who take omega 3 fatty acids (fish oil) appear to have a lower risk. These are just some of our group’s findings and we’re looking forward to identifying more.”

Fighting Diseases

November 29, 2017

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