From the Journals

Bacteremia, antibodies link periodontal disease to RA development and activity



Bacterial proteins in the bleeding gums of patients with periodontal disease (PD) and rheumatoid arthritis (RA) enter the bloodstream and trigger immune responses that may contribute to RA pathogenesis and disease flares, a new longitudinal study suggests.

The results suggest that PD involves repeated oral mucosa breakdowns with the release of citrullinated oral bacteria into the bloodstream and that these bacteria activate inflammatory monocytes in the inflamed RA synovium and in the blood of patients with RA. The bacteria also activate anti-citrullinated protein antibody (ACPA)–positive B cells, promoting affinity maturation and epitope spreading to citrullinated human antigens, the authors wrote.

“Our study discovered frequent and repeated episodes of oral bacteria in the blood of patients with periodontal disease and rheumatoid arthritis,” senior study author Dana E. Orange, MD, associate professor of clinical investigation at Rockefeller University, New York, said in an interview. “We saw that these bacteria were triggering an inflammatory [monocyte] response that is similar to what we see in the inflamed joints of patients with RA.

“RA patients are less likely to benefit from RA treatment if they have concurrent periodontal disease,” she said.

“RA patients tend to harbor cyclic citrullinated peptide [CCP] autoantibodies. Many groups have noted that CCP antibodies are very highly mutated, a signature of a B-cell/antibody response that has been stimulated over and over again,” Dr. Orange explained. “We found that CCP antibodies also bind the same oral bacteria we detected in the bloodstream. That patients with PD experience frequent, repeated episodes of oral bacteria in the blood is consistent with the very high level of mutation burden of CCP antibodies.”

Periodontal disease is a large problem among older adults

Periodontal disease ranges from gingivitis with swollen, red gums that may bleed, to periodontitis with gums pulling away from teeth, bone loss, and loose or lost teeth. PD is very prevalent in the United States, with some form of it occurring in 47% of people 30 years of age and older and in 70% of those 65 years and older, according to the Centers for Disease Control and Prevention.

PD is more common in people with RA who have detectable ACPAs, and that link implicates oral mucosal inflammation in RA pathogenesis.

Investigating whether PD leads to RA

At Rockefeller University, Dr. Orange and her colleagues followed five female patients with RA who were seropositive for CCP over the course of 1-4 years. Two had severe PD, and three showed no signs of PD. Each week, participants provided finger-stick blood samples for RNA sequencing and B-cell repertoire sequencing, reported changes in their medication and dental work, and completed questionnaires. They also underwent monthly physical exams that evaluated tenderness and swelling in 28 joints, and they provided additional samples during self-reported flares.

At Stanford (Calif.) University, researchers isolated plasmablasts from blood samples collected from 12 donors with anti-CPP+ RA and healthy donors. They also analyzed synovial fluid samples from 65 RA and OA patients.

In addition, University of Colorado researchers collected plasma samples from patients with RA and healthy donors, and they classified the gingival health of participants.

The researchers found that the patients with PD also had repeated flare-ups of oral bacteria in the blood, mainly from the Streptococcaceae family, suggesting that the oral mucosa repeatedly broke down and introduced bacteria into the bloodstream. In the blood, inflammatory immune cells targeted the bacteria and released ACPAs, which have been linked with RA.

“Even without dental procedures, patients with RA and periodontal disease experience repeated episodes of bacteremia,” Dr. Orange said. “While dental procedures are known to be associated with dissemination of oral bacteria into the bloodstream, we didn’t expect to see this happening so frequently and independent of dental procedures. We also had thought that people with oral bacteria in their blood would have symptoms such as fever or malaise, but they were asymptomatic.”


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