March 8, 2017
Jennifer Abbasi
JAMA. Published online March 8, 2017. doi:10.1001/jama.2017.0764
The mouth may seem like a strange place to search for a culprit in a disease that primarily affects the joints. But a recent collaboration by a group of multidisciplinary researchers suggests that one type of oral bacteria may be an important trigger in about half of rheumatoid arthritis (RA) cases.
The findings, published in Science Translational Medicine late last year, appear to confirm something that’s been suspected for at least a century: In some cases, gum-disease causing oral bacteria may set off a cascade of events that leads to the autoimmune form of arthritis.
It’s long been known that patients with RA are more likely to have periodontitis. In 1 nationally representative sample, participants who met 4 out of 6 American College of Rheumatology criteria for RA had a 4-fold higher risk of periodontitis compared with those who didn’t meet that threshold.
In both conditions, chronic inflammation destroys hard tissue—teeth-bearing bone in periodontitis and the joints in RA. Researchers have implicated several species of bacteria in gum disease, but what causes RA is still a mystery. Because periodontitis and RA often go hand in hand, researchers suspect that oral bacteria could be involved in RA.
To pinpoint the right bug, investigators have been searching for an oral microbe that can trigger the production of autoantibodies seen in patients with RA, said Maximilian F. Konig, MD, lead author of the new study and resident physician at Massachusetts General Hospital. Konig’s study, conducted when he was a postdoctoral fellow at the Johns Hopkins University School of Medicine, has moved the field closer to that goal.
The most accurate marker for RA—found in the blood of 76% of RA patients—is anticitrullinated protein antibodies (ACPAs). These autoantibodies target citrullinated proteins that are expressed by immune cells such as neutrophils.
Citrullination is a normal process that changes the structure of proteins, altering their function. Felipe Andrade, MD, PhD, senior author of the study and associate professor of medicine in the division of rheumatology at the Johns Hopkins University School of Medicine, likened citrullination to small costume changes—the addition of a mustache or a hat, for example. These changes cast proteins into new roles. “[How] you’re dressed defines your function,” he explained.
These protein modifications are necessary, and they usually fly under the radar of the immune system. But too many of them can raise alarm bells.
In patients with RA, hypercitrullination, an abnormal buildup of citrullinated proteins, triggers the immune system to generate autoantibodies that attack these modified self-proteins, inducing joint-destroying inflammation.
Konig, Andrade, and their coinvestigators found a mouth bug with a tongue-twisting name—Aggregatibacter actinomycetemcomitans (Aa)—can cause these runaway protein changes and drive RA-specific autoantibody production, key steps in the path to RA.
The Missing Link
The investigation began at Johns Hopkins, where Andrade’s group has been studying possible links between periodontal disease and RA. In collaboration with the National Institute of Dental and Craniofacial Research at the National Institutes of Health, the researchers collected samples of fluid from the gums of patients with and without periodontitis.
Using mass spectrometry, they found patterns of citrullination in these samples mirroring those found in RA-affected joints, but only in participants with gum disease. Of the 6 species of bacteria associated with gum disease that were detected in periodontitis samples, only 1—Aa—had the ability to induce hypercitrullination in neutrophils.
Calcium is required for citrullination. In the study, Aa produced a toxin that punched holes in neutrophil membranes, allowing calcium to flow into the cells in greater-than-normal amounts. The excess calcium amplified citrullination, resulting in the patterns of hypercitrullination seen in RA.
Another discovery bolstered the findings: Nineteen of the modified proteins induced by the toxin are known autoantigens targeted by autoantibodies in RA. “It may be that many more on our list are RA autoantigens, but they have not been systematically characterized and studied in RA,” Konig said.
Crucially, the researchers also found that 47% of patients with longstanding RA had Aa toxin antibodies in their blood, compared with just 11% of healthy controls.
Taken together, the findings suggest that the bacterium “could be the missing link” between gum disease, the generation of RA-associated antibodies, and the development of RA, said Gary S. Firestein, MD, director of the Clinical and Translational Research Institute at the University of California San Diego Health Sciences, who was not involved with the study.
Moving Toward the Clinic
The case isn’t closed just yet. The researchers said their findings must be replicated by different groups and in different patient cohorts. Animal studies will be needed to directly demonstrate that Aa can induce RA autoantibodies and RA. And more work must be done to parse out the temporal association between the bacteria and RA. Does Aa trigger the disease or just worsen it once it’s already established?
“Since it can take over a decade to go from the production of anticitrullinated protein antibodies to symptomatic RA, it may give us a window of opportunity to possibly prevent rheumatoid arthritis by taking away the driver,” Konig said. “This could be through Aa eradication by antibiotic therapy, nonsurgical periodontal treatment, or even targeted therapies that inactivate the bacterial toxin in the gums.”
Time will tell if targeting Aa can modify established RA. There are data suggesting that treating periodontitis can decrease RA disease severity, and Konig noted that several large prospective trials are currently under way to further investigate this possibility.
It’s also almost certain that other bugs are involved. After all, only around half of patients with RA had signs of Aa in their blood in Konig’s recent study.
“This particular pathway is important but probably one of several ways that you get to that common clinical phenotype,” said Firestein, whose research focuses on the pathogenesis of RA.
Many species of bacteria produce pore-forming toxins, Andrade added. Researchers suspect that these bacteria on other mucosal surfaces—specifically the lungs, gut, and urinary tract—may also trigger RA. Cigarette smoking is strongly associated with RA, and bacteria with pore-forming toxins in the lungs of smokers could explain the link, Andrade said.
Genetics emerged as another important factor in the study. The strongest known genetic risk factor for ACPA-positive RA and RA overall was only positively associated with autoantibody production in patients who had evidence of Aa infection.
“Our data suggests that you need to have both a genetic susceptibility to develop rheumatoid arthritis…and infection with Aa to develop anticitrullinated protein antibodies and possibly arthritis,” Konig said.
In the future, interventions to prevent RA, such as the use of antimicrobials, could be directed toward those who are at highest risk.
“Identifying people that have the predisposition to develop the disease and at the same time are infected with the bacteria might be an excellent group to target, in [whom] it might be possible to modify the evolution of the disease,” Andrade said.
For now, he cautioned that it’s too soon to prescribe antibiotics to treat or prevent RA: “It would be a big mistake.” Instead, he advised, “take care of your teeth and see what happens.”