Blood vessels in the soft tissue between joints, during a rheumatoid arthritis flare-up. CREDIT Laboratory of Molecular Neuro-oncology at The Rockefeller University

It’s a well-documented medical mystery: Patients with gum disease are less likely to respond to rheumatoid arthritis treatments. But new research may help explain this link between gum disease and an otherwise disparate condition. The findings, published in Science Translational Medicine, suggests that breaches in damaged gums allow bacteria in the mouth to seep into the bloodstream, activating an immune response that ultimately pivots to target the body’s own proteins and causes arthritis flare-ups.

“If oral bacteria are getting in and repeatedly triggering immune responses relevant to rheumatoid arthritis, that could make it harder to treat,” says Dana Orange, a professor of clinical investigation in the laboratory of Robert B. Darnell at The Rockefeller University. “When doctors encounter arthritis patients who do not respond to treatment, it would be worth it to make sure they aren’t missing an underlying gum disease, which is quite treatable.”

The Darnell lab had been following a small group of arthritis patients over the course of several years, collecting weekly blood samples and looking for changes in gene expression to help explain why painful flare-ups occur, when they noticed a surprising trend. Two of their patients, who had moderate to severe periodontal disease, had repeated episodes of oral bacteria in their bloodstreams, even when they weren’t having dental work.

Orange knew that rheumatoid arthritis patients generally have autoantibodies in their bloodstream (rheumatoid arthritis is an auto-immune disease, wherein antibodies attack the body’s own proteins and peptides). In many cases, autoantibodies take specific aim at proteins bearing the signs of citrullination, a process by which one amino acid in the protein is converted into a different one.

Upon further examination, the team discovered that the oral bacteria they detected in the blood are also citrullinated in the mouth, much like the proteins targeted by autoantibodies in arthritis. They then demonstrated that the same autoantibodies that take potshots at the body’s citrullinated proteins activate in response to citrullinated bacteria.

The results may explain why arthritis treatments do not work as well in patients with gum disease. If the gums are continuously releasing immune triggers into the bloodstream, treating arthritis without first solving the periodontal problem is like trying to haul water out of a ship without first plugging up its leaks.

“Gum disease is quite curable; rheumatoid arthritis can be much more difficult to treat,” Orange says. “Our results indicate that periodontal disease leads to leaky gums that allow oral bacteria to enter the blood repeatedly. This level of oral bacteria in blood doesn’t cause obvious symptoms, so the patients were not aware this was happening, but they do trigger inflammatory and auto-antibody responses that are highly relevant to rheumatoid arthritis.”

These findings also demonstrate the importance of conducting long-term research to better understand chronic diseases. The present study would not have been possible without a unique initiative, pioneered by Orange and Darnell several years ago, that empowers arthritis patients to collect their own blood samples at home with a finger-prick kit and mail weekly samples to Rockefeller. The lab now has several years of data to help track what happens in the blood right before an arthritis flare.

“Without having weekly blood samples for at least a year, we wouldn’t have been able to find out what was happening before the patients had symptoms of their flares,” Orange says. “Our study revealed a plausible mechanism to explain why rheumatoid arthritis patients with periodontal disease do not respond well to treatment—something very hard to capture without long-term monitoring.”

Scanning electron micrograph of biodegradable microparticles that reprogram immune cells to protect joints against inflammatory arthritis. Imaged at UC San Diego’s Nano3 facility, Jacobs School of Engineering.
David McBride, UC San Diego

A team led by engineers at the University of California San Diego has developed a biodegradable polymer system to treat rheumatoid arthritis, an autoimmune and inflammatory disease, by working in concert with the power of the human immune system.

The research builds on increasing clinical interest in modulating the immune system to treat cancers and autoimmune diseases, as well as previous work with all-trans retinoic acid (ATRA), which is produced naturally in the body and helps cells grow and develop. By approaching these challenges from the perspective of a biomaterials engineering lab, the team adds two key innovations to previous methods: local release and harnessing the joint microenvironment for sustained effectiveness.

With this method, encapsulated ATRA is injected directly into a joint affected by rheumatoid arthritis, where it remains in effect for at least several weeks. During that time, ATRA transforms disease-causing cells into disease-stopping cells, known as regulatory T cells, which can treat or prevent the disease elsewhere in the body.

“Essentially, our system turns the disease site into a factory that produces regulatory T cells,” said David A. McBride, a chemical engineering graduate student at UC San Diego supervised by nanoengineering professor Nisarg Shah. “It uses a biodegradable biomaterial to facilitate the timed release of ATRA, which reprograms T cells so they can treat disease.”

The research was published in the March 8, 2023 issue of Advanced Science. McBride is a coauthor on the paper.

“This is a very promising line of research utilizing the latest and greatest technology in immunoengineering to combat arthritis,” said Iannis Adamopoulous, an associate professor of medicine at Harvard’s Beth Israel Deaconess Medical Center, Department of Medicine, Division of Rheumatology.

What is ATRA?

ATRA is a small molecule currently FDA approved to treat acute promyelocytic leukemia (APML). Research over the last two decades has suggested that it also has promise in treating autoimmune arthritis and relieving inflammation. However, that method relies on ATRA traveling freely throughout the body, which can cause immunosuppression and potentially significant off-target toxicity, along with other unwanted side effects.

“Previous work established that ATRA has potential in treating autoimmune arthritis, but the route of administration precluded the work from being relevant to clinical translation,” said McBride.

When ATRA is encapsulated using biodegradable materials, it can be injected directly into joints at therapeutic concentrations but as it diffuses out of the joint, it enters circulation at much lower concentrations, minimizing or preventing unwanted effects. Without the controlled release afforded by the biomaterial encapsulation, patients would require multiple injections per day to achieve the same effects, which would be impractical in most cases.

How it works

When the human immune system functions properly, helper T cells patrol the body in search of disease-causing pathogens. When a pathogen is detected, a helper T cell can recruit additional cells to help fight it. “It’s kind of similar to how you might have police cars roaming the city, and when one sees a crime occurring, they call for backup to get the situation under control,” said McBride.

Many autoimmune diseases result from cases of “mistaken identity,” in which these cells attack a perceived danger target that is in fact a part of normally functioning cells in the body. The subsequent proliferation of such pathogenic T cells, which McBride calls “bad apples,” can result from a combination of genetic and environmental factors and wreak havoc on the body when they summon large teams of immune cells for unnecessary standoffs.

For example, “in type 1 diabetes, you have bad apples that call in reinforcements against your pancreas,” said McBride. ”In multiple sclerosis, it is against your neurons. In rheumatoid arthritis, it is against your joints. So, your immune system recognizes this as something to be attacked, and it goes and recruits a bunch of additional immune cells to these places and fights a war until all the pathogens are gone. Except that, in this case, it’s not attacking pathogens, but healthy parts of the body.”

Many current approaches block the chemical signals that immune cells use to communicate, effectively preventing the pathogenic T cells from calling in reinforcements without eliminating the “bad apples.” Time-released ATRA reprograms them to act as regulatory T cells, or “good apples.” These cells still have the ability to recognize and activate in the joints, but rather than calling in additional immune cells, they help to resolve the inflammation. In areas such as joints, which aren’t recommended for repeated injections, the sustained-release formulation allows sufficient therapeutic exposure to flip the balance.

ATRA makes lasting modifications to the ability of cellular machinery to read cell DNA, improving the function of the anti-inflammatory regulatory T cells. This treats T cells at the site of disease and generates regulatory T cells specific to that diseased tissue. Then, when these cells move to other disease locations, they can help resolve inflammation and promote healing. Because the cells are specific to the disease, they don’t interfere with normal immune function, allowing them to supplement existing therapies or provide alternatives for patients who need them.

“The coolest part about this is that the treated site of disease, where the bad apples were previously proliferating, now becomes a place that can generate regulators that can now go patrol the body and actually prevent disease,” said McBride.

The limitations of existing approaches

Patients with rheumatoid arthritis are frequently treated with disease-modifying anti-rheumatic drugs (DMARDs) and in many patients this approach works well. However, about a third of patients don’t adequately respond to front-line DMARDs, and they come with some significant disadvantages. 

First, while using DMARDs, some patients become more susceptible to infectious disease and exhibit weaker responses to vaccines. In this regard, “the COVID-19 pandemic has brought a lot more understanding on the risks of immunosuppression into public awareness,” said McBride.

Additionally, because most immunosuppressives currently used to treat rheumatoid arthritis stay in the system for up to two weeks, there is no option to discontinue treatment if a dangerous infection occurs. This is compounded when patients use two or more treatments simultaneously, which is not uncommon due to the complexity of the disease. Using multiple powerful immunosuppressants can exacerbate the risks of infections or cancer.

“If you can instead have a treatment option that doesn’t have an immunosuppressive effect, you can really reduce the risk for patients that need multiple treatment modalities to keep their autoimmune disease in check,” McBride said.

Finally, for some patients, immunosuppressives work well for a time and then lose their effectiveness. This can happen when their bodies develop antibodies that neutralize the medications or new disease pathways emerge. New treatments like this one could potentially supplement DMARDs, compensating for waning effectiveness or requiring lower doses to start with.

“In well controlled patients, reducing or eliminating the need for immunosuppressive drugs is desirable,” said Shah. “However, when it is attempted, studies have shown that the disease can flare up again. So having a non-immunosuppressive option could go a long way.”

Research methods, challenges and next steps

The team tested its biomaterial-encapsulation method using a combination of mouse and human cells. After this achieved positive results, they transitioned to mouse models of autoimmune arthritis, coming closer to simulating the remarkable complexity of a real-life case of autoimmune disease in a human subject.

The work required multiple models of disease, each designed to demonstrate a specific aspect of the team’s hypothesis, as well as rigorously tracking the cells from their origin points at injection to the other locations where they recirculated and proved effective in fighting disease.

Currently, the researchers are actively working toward commercialization. “As this is my first experience with something like this, it is difficult for me to estimate, but we are currently targeting approval to start clinical trials within five years,” said McBride. To evaluate possible commercialization routes, McBride has participated in the UC San Diego Institute for the Global Entrepreneur (IGE) NSF I-Corps and MedTech Accelerator programs.

The power of a multidisciplinary approach

When he entered graduate school at UC San Diego, McBride was focused on modeling complex signaling patterns in biological systems, for which rheumatoid arthritis provided many intriguing examples. He became more engaged as he gained awareness of the human side of the disease.

“I’m always surprised at how many people know someone fighting an autoimmune disease or are struggling with one themselves,” he said. “These experiences have really moved it from an interesting problem on paper that I’m trying to solve to a real, difficult problem in the lives of friends and family,”

In this video, discover 10 practical tips to help you live better with rheumatoid arthritis. Learn how to manage your symptoms and improve your quality of life with lifestyle changes and effective treatments. Whether you’re newly diagnosed or have been living with RA for a while, this video has valuable insights and strategies to help you thrive.

Discover the top 10 foods to avoid if you have rheumatoid arthritis and learn healthy substitutes that can help manage your symptoms. Join me for expert tips and advice on nutrition and lifestyle changes that can make a difference.

People with rheumatoid arthritis (RA) know all too well the inflammation and pain of the disease. Although there’s no “RA diet” that treats the condition, some foods can lower inflammation in your body. And because they’re good for you, these foods — including fruits and vegetables, whole grains, olive oil, and fish — may help you feel better overall. Is There an RA Diet? No. But research shows that the Mediterranean diet’s tasty fare — like olive oil, fish, greens, and other vegetables — can lower inflammation, which is good for your whole body. In one study of women with RA, those who took a cooking class on Mediterranean-style foods and ate that way for 2 months had less joint pain and morning stiffness and better overall health than those who didn’t take the class.

Aim to eat a healthy diet with:

Lots of whole grains, vegetables, and fruits. They should make up two-thirds of your plate. Low-fat dairy and lean proteins, which should make up one-third

Small amounts of saturated and trans fats

A little sugar