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Mouth and Other Bacteria May Trigger RA

Studies increasingly highlight the role of microbes in rheumatoid arthritis and other inflammatory diseases.

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A century ago, it was widely believed that gum infections were the source of many inflammatory diseases, including appendicitis and rheumatoid arthritis (RA). The treatment for so-called oral sepsis was total tooth extraction – which rarely improved symptoms and was unpopular with patients – and by the 1930s, the oral sepsis theory had largely been discredited.

Now, however, the link between RA and oral bacteria is attracting serious attention, bolstered by research on the complex interactions between the immune system and microbes in the mouth, lungs and digestive tract.

Collectively referred to as the microbiota, the trillions of bacteria that live on and in the human body are generally beneficial and protective – aiding digestion and guarding against pathogens and inflammation. But it is becoming increasingly clear that in certain circumstances, these bugs may lead to the development of RA and other autoinflammatory disorders.

"We used to think that the bacteria [in our bodies] were benign partners, helping us out while we provide them with food and other nutrients. But when we alter the relative composition of [bacterial communities], can that trigger an immune response targeting the body's own tissues? At least in animal models, the answer seems to be 'yes,'" says Jose Scher, MD, director of the Microbiome Center for Rheumatology and Autoimmunity at New York University Langone Medical Center Hospital for Joint Diseases in New York City.

The answer also seems to be yes in some human studies. In the last few years, a great deal of research, aided by DNA sequencing techniques, has shown an association between the germs that cause periodontal disease and RA.

As early as 2009, researchers from Case Western Reserve University in Cleveland reported in the Journal of Periodontology that patients with severe RA had less joint pain and swelling and better overall health when they received treatment for gum disease in addition to arthritis medications. The researchers also noted that bone erosion and tissue destruction in both diseases are caused by similar inflammatory processes.

A 2010 epidemiological study, also in the Journal of Periodontology, found that RA patients were twice as likely to have gum disease compared to others (without RA) and their periodontal disease was more severe. Other studies have found an even higher incidence of gum disease in people with RA.

In a 2013 study, researchers at Massachusetts General Hospital in Boston showed that patients newly diagnosed with RA were far more likely to have antibodies to Porphyromonas gingivalis, a bacterium that causes gum disease, than healthy controls or people with other autoimmune disorders.

Patients who had the antibodies were more likely to be rheumatoid factor positive (a sign of more-aggressive disease), and to have more inflammation and greater dysfunction than RA patients who didn't. After a year of treatment, the P. gingivalis patients continued to have worse disease and were 50 percent less likely to be in remission. The results appeared online in Arthritis Research & Therapy.

So what is going on here? Sheila Arvikar, MD, a rheumatologist at Massachusetts General Hospital and lead author of the study, explains that P. gingivalis contains a unique enzyme that alters proteins – in a process called citrullination – so the body perceives them as a threat. This can lead to the production of antibodies against the proteins in the joint lining, causing inflammation and eventually RA. The autoantibodies are strong disease markers and can be detected in the blood years before symptoms appear.

Recently, researchers from the University of Louisville School of Dentistry in Kentucky and the European Union's Gums and Joints project reported that P. gingivalis may lead to earlier onset, faster progression and significantly increased bone and cartilage destruction in RA patients.

The lungs, too?

Meanwhile, Kevin Deane, MD, an assistant professor at the University of Colorado School of Medicine in Aurora, suggests that bacteria in the lungs might trigger RA in some people.

According to a pilot study published in the October 2013 issue of Arthritis and Rheumatism, Dr. Deane and colleagues found that people considered at high risk of RA had elevated RA-related autoantibodies in their sputum, but not in their blood, suggesting that the lungs may also be a source of an immune response that triggers RA.

Dr. Deane notes that immune cells and proteins "move around in the body," which may cause different people to have different sites of RA-related autoimmunity – "some in the gums, others the lungs and still others the gut mucosa" where changes in bacteria are associated with RA.

Future RA prevention and treatment

Evidence about the role of bacteria in diseases like RA has sparked intense speculation about future treatments. Stephen Paget, physician-in-chief emeritus of rheumatology at Hospital for Special Surgery in New York City and an expert in autoimmune diseases, has suggested that therapies for autoimmune disease may need to focus on enhancing immunity, via our bacterial communities, rather than suppressing it. Other experts argue for restoring healthy gut communities with probiotics or fecal therapy. And still others think treating gum infections might cure a variety of systemic diseases. What is almost universally acknowledged is that more research – probably a lot more – is still needed.

Dr. Scher is especially cautious. "Rheumatoid arthritis is very complex and multifactorial. Maybe it will be possible to identify some metabolites produced by bacteria that we can target that have an effect on arthritis, but we are at such a preliminary stage," he says. "What we are learning is that there is something happening between the mucosal surfaces in the mouth, lung and gut and the inflammatory response. We have seen in animal models that there is a clear connection. But how that translates into human disease needs more investigation."

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