‘Definitely not expecting this’: Bacteria from ‘leaky gums’ may trigger RA flares
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Patients with rheumatoid arthritis and periodontal disease may experience flares due to bacteria from “leaky gums” moving into their bloodstream and causing inflammation, according to recent findings.
Although periodontal disease incidence is generally elevated in individuals with RA, it is particularly common in those who have anti-citrullinated protein antibodies (ACPAs), according to study authors Dana Orange, MD, associate professor of clinical investigation at Rockefeller University, and assistant attending in rheumatology at the Hospital for Special Surgery, and William H. Robinson, MD, PhD, professor of medicine at Stanford University.
Together with their colleagues, they suggest that this may implicate oral mucosal inflammation in RA pathogenesis.
In the current study, which has been published in Science and Translational Medicine, the researchers gathered blood supplies from patients with RA and conducted a paired analysis of human and bacterial transcriptomics.
Results demonstrated that patients who had both RA and periodontal disease “experienced repeated oral bacteremias associated with transcriptional signatures of ISG15+HLADRhi and CD48highS100A2pos monocytes,” the researchers wrote.
These signatures are also found in the inflamed synovia of patients with RA.
Additional findings suggested that the oral bacteria in the blood were “broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPAs encoded by RA blood plasmablasts,” Orange, Robinson and colleagues wrote.
The findings led the researchers to conclude that periodontal disease can cause “leaky gums” that enable citrullinated oral bacteria to translocate to the blood and activate inflammatory monocytes in RA. Moreover, these oral bacteria activate ACPA B cells, which, in turn, may yield affinity maturation and epitope spreading to citrullinated human antigens, according to the findings.
Healio sat down with Orange and Robinson to discuss the background of their study, their surprise at the findings and what the results may mean for practicing rheumatologists.
Healio: What was the background for studying the association between periodontal disease and RA?
Orange: Our group had been studying RA flares. Like many common, chronic inflammatory diseases, RA has this fluctuating course where patients can be doing OK and then they can have a flare-up of their disease activity. Why that happens is poorly understood. We had developed a study to try to gain insight into that by having a small group of patients send us blood samples on a frequent, regular basis.
Healio: How frequently and how regularly?
Orange: The samples consisted of three drops of blood, which the patients collected at home and mailed to us once a week for years. If they flared, we could go back in time and see what was changing in their blood leading up to a flare.
Healio: Why did you focus on the activity surrounding an RA flare?
Orange: We had published a prior paper showing that we could identify these really interesting immune activation signatures around the time of flares. Specifically, those results showed us that 2 weeks prior to flare, there was a B-cell signature and then a fibroblast-like cell, called the PRIME cell, signature.
At these times, the patients were feeling well, they were not having symptoms, but they were about to have a flare. That left us with a lot of questions about what would trigger these B cells and PRIME cells. We hypothesized in the prior paper that it was possibly some kind microbial trigger could activate this type of response.
Healio: So those findings led you to this paper.
Orange: Yes, in this paper, we went looking to see if there was a microbe that triggered flares. The way we did that was remove all the reads that aligned to the human genome and analyze what was left over. Then we compared those reads to data from the human microbiome project. We used that data to deconvolute our blood gene expression data and infer which bacteria were coming from where.
What we saw was that patients with periodontal disease were having repeated, frequent episodes where an array of oral commensal bacteria, not just one dominant bacteria, but basically all the bacteria that are normally present in the mouth, were making it into the blood. Although the patients with recurrent oral bacteremia were undergoing dental procedures for their periodontal disease while they were on our study, these episodes were independent of the dental work.
That told us that patients with periodontal disease have leaky gums that allow oral bacteria to get into their blood frequently, more than we originally realized. Patients do not have symptoms when this happens, so they don’t know it is happening.
Healio: At this point, was the goal to try to connect that to RA?
Orange: Exactly. To figure out why this had to do with RA, we compared the oral bacteria inferred load in the blood to the human gene expression response, and we saw that there was this robust human gene expression that overlapped with a type of inflammatory monocyte that we see in rheumatoid arthritis-inflamed joints.
Healio: Were you expecting to find this when you started collecting the blood samples? Or were you expecting something else?
Orange: We were definitely not expecting this. If anything, we were expecting a viral trigger. We thought if there was a microbial trigger, that it would be a single microbe, but that’s not at all what we saw. Patients never had just one oral bacteria species in their blood — they had almost all of the oral bacteria in their mouths in their blood, and the abundance in the blood reflected their abundance in the mouth.
When we saw that there were these samples with oral bacteria, and that they were coming from patients we knew were having repeated dental procedures, we decided to chase it down. In addition, this is in the context of our understanding that periodontal disease is more common in people with rheumatoid arthritis.
Robinson: At the most simplistic level, Dr. Orange was studying human gene responses associated with flare and mapping them out really elegantly. Of course, she saw the B-cell signature and the PRIME-cell signature, but it was striking when she looked at the non-human genes and found multiple bacterial genes that mapped to commensal oral bacteria. The possibility that we would identify oral bacterial genes in RA blood was highly unexpected.
Healio: Once you made this discovery, what was the next step?
Orange: We wanted to make sure we could validate what we were seeing with this human gene expression response. We validated it by taking oral commensal bacteria and putting it with normal blood. When oral bacteria get into anybody’s blood, there will be this inflammatory monocyte gene expression response. That made us wonder about the association between periodontal disease and rheumatoid arthritis.
We reasoned that patients with rheumatoid arthritis must have additional more specific immune responses to oral bacteria to explain this association. This is how we ended up collaborating with Dr. Robinson’s lab. He has been studying the B-cell response in patients with RA, which is very specific.
Robinson: We had been sequencing B-cell responses in RA for many years, and finding in addition to IgG B cells, there were also prominent IgA B cells that were already heavily mutated. Additionally, the same IgA B-cell clones were persisting for many months or years. We thought that there could be some kind of mucosal triggers. So, one of the first things we did when Dr. Orange identified certain oral bacteria in RA was to ask whether the antibodies encoded by these persistent IgA B cells bound these same bacteria.
Lo and behold, they did. That was one element that convinced us that what we were studying was potentially real. The second element was that when we saw these bacterial RNAs in the blood, they were associated with human RNA inflammatory macrophage gene expression. They were linked not only to the B cell but also to the innate immune activation cells.
Healio: Does this give any indication of causality one way or the other? Does this tell us whether oral bacteria in the blood can lead to RA, or vice versa?
Orange: It is difficult to establish causality with observational data. We were studying patients with established rheumatoid arthritis, so we can’t say anything about causes of events in RA. However, three studies have shown that patients with RA and periodontal disease are more refractory to treatment.
Our findings provide a plausible mechanism to show that if you have periodontal disease and leaky gums, that bacteria are constantly getting into the blood and triggering an immune response of RA. It can help understand why it would be an uphill battle trying to treat this particular subset of rheumatoid arthritis patients.
Healio: What are the implications of this finding for the average practicing rheumatologist?
Orange: The right thing to do is perform some studies to see if eradication of periodontal disease is going to make refractory RA easier to treat.
Healio: What is a study like that going to look like?
Orange: We are still working on those details.
Robinson: Periodontal disease is complex. It is not just the periodontal bacteria itself, but the mucosal fragility that it gives rise to that we think is causing the breaks that induce RA activity.
The whole dental industry has tried to develop more effective therapies for periodontitis. There are mouthwashes and better ways to brush and floss, but there are also more aggressive approaches like grafting gums and shaving teeth. They seem like pretty radical approaches for RA. However, it is just not clear what types of interventions might be most applicable in a broader population and then find the benefit we need to provide for our RA patients.
Orange: The other part of it is that rheumatoid arthritis is not curable, and it can be debilitating and expensive to treat. Periodontal disease, on the other hand, is quite treatable. The onus is now on us to prove that changing periodontal disease activity can make a difference in the life of a patient with RA.
References:
Brewer RC, et al. Sci Trans Med. 2023;doi:10.1126/scitranslmed.abq847.
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