The Presence of Periodontal Disease in Patients With Rheumatoid Arthritis

In this video, Dana Orange, MD, MSc, and William H. Robinson, MD, PhD, discuss the study, “Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis.” Drs Orange and Robinson talk about the connection between patients with rheumatoid arthritis (RA) and periodontal disease, how patients with RA and periodontal disease should be managed, and the impact of the study on the multidisciplinary approach in the treatment of patients with RA.

Additional Resource: 

Brewer RC, Lanz TV, Hale CR, et al. Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis. Sci Transl Med. Published online February 22, 2023. doi:10.1126/scitranslmed.abq8476

For more rheumatoid arthritis content, visit the resource center. 

Dana Orange, MD, MSc, is an associate professor of clinical investigation at Rockefeller University and an assistant attending rheumatologist at Hospital for Special Surgery (New York, NY).

William H. Robinson, MD, PhD, is an associate professor of medicine and chief of the Division of Immunology and Rheumatology at Stanford University (Stanford, CA).

TRANSCRIPTION: 

Consultant360: How did this research question come about?

Dana Orange, MD, MSc: My name is Dana Orange and I am a rheumatologist, physician scientist working in New York City at the Rockefeller University and Hospital for Special Surgery. And we're going to talk about a project that I've been working on with Will Robinson, who's also here to study the underpinnings of disease activity flares in rheumatoid arthritis.

And one of the curious things about rheumatoid arthritis is that it tends to have this waxing and waning course. So, patients might be feeling okay for some amount of time and then they might have a flareup. They might wake up one day and their arthritis is acting up and it makes them really, it makes it difficult for them to carry out their activities of daily living. And very little is understood about why that happens.

So, our group had become interested in that phenomenon and we developed a method whereby patients could participate in research from home. And we basically give them a little box of supplies so that they can collect their blood. And we use that to measure RNA expression from samples that they would collect weekly over the course of years. And if they had a flare, we could go back in time and see what was changing over time leading up to the flare.

And using that approach, we detected changes in the blood leading up to flares in patients with rheumatoid arthritis, certain immune cells like B-cell and a fibroblast like cell, which we call the prime cell that were increased prior to flare. But that study left us with so many questions about what might be triggering this immune activation that we were seeing prior to flares.

C360: Can you tell us about your study?

And so, in the study that we're going to talk about today, we collaborated with Rob Knights lab at UCSD who spent their time working on microbiome analysis. And we took our finger stick RNA samples and took all of the reads that aligned to the human genome and got rid of them. And in this analysis we analyzed the reads to see how they compared to the human microbiome project data. And using that approach, we saw that patients with rheumatoid arthritis and periodontal disease were having repeated episodes, many, many, many repeated episodes where they were having oral commensal bacteria was getting into their blood or at least their gene products were getting into the blood.

And when we looked at the human response, we could see that there was a human gene expression response to these events and it really overlapped with the type of inflammatory monocyte that can be seen in the inflamed RA joint. But of course, we modeled that experiment in vitro and confirmed that if you take oral commensal bacteria and culture them with blood samples in vitro, you can see the same gene expression response, that there's this inflammatory monocyte gene expression response. But that happens even in normal donor blood. So probably, patients with periodontitis, whether they have rheumatoid arthritis or not, are having breaks in their mucosal barrier in their mouth and it allows oral bacteria to access the blood and it causes some low level of inflammation that overlaps with the type of inflammation that you can see in an RA joint, but it's not entirely specific to rheumatoid arthritis because people without rheumatoid arthritis would have this as well.

So, to try and make sense of that and see if there's something that's more specific to rheumatoid arthritis, our group teamed up with Will Robinson's lab and I'm going to let him tell you about that side of the story.

William H. Robinson, MD, PhD: Yeah. So, I'm Will Robinson and I'm also a rheumatologist and I'm a faculty member at Stanford University, where we investigate the role of B-cells and antibodies in rheumatoid arthritis and other autoimmune diseases. And we have been sequencing B-cell repertoires and antibody repertoires in rheumatoid arthritis for several years. And we've noted several very interesting or intriguing features of the B-cell repertoire in rheumatoid arthritis. One, is that the B-cells that are activated are heavily mutated. Meaning, they have many mutations or what we call somatic hyper-mutations from germline. And second, that they persist in the blood for a many month or year long period, the same clones of B-cells. Which made us think that perhaps a mucosal activator could be driving them, because they're IgA in their isotype.

And so as a result, we've been studying all these B-cell that were heavily mutated, that were persisting over a many month or a year timeframe and that we're IgA. And that's really one of the key things that led us team up with Dana Orange and her lab to ask whether they were making antibodies and being activated by these oral bacteria that she was seeing in the blood. And the short version of a long story is that they completely are. So in essence, we think that these mucosal breaks of commensal oral bacteria are activating the anti-cyclin protein B-cells in rheumatoid arthritis.

C360: How does this study fill a current gap in our knowledge?

Dr Orange: So, it's been known for many years that patients with rheumatoid arthritis are more likely to have periodontal disease. Periodontal disease is incredibly common, but it's even more common in patients with rheumatoid arthritis and particularly patients who have these auto-antibodies, the CCP auto-antibodies. Not only is it more common in patients with rheumatoid arthritis, those who have rheumatoid arthritis and also have concurrent active periodontal disease are more difficult to treat, they they're less likely to achieve benefit from our immunomodulatory therapy. So I think what our study adds to these, the literature, is a mechanism to explain why patients with rheumatoid arthritis and periodontal disease might be more difficult to treat because they have probably these leaky gums that are allowing bacteria to get into their bloodstream, sort of sporadically, frequently and that's triggering an immune response that's relevant to rheumatoid arthritis.

C360: How does this study impact the multidisciplinary care of rheumatoid arthritis?

Dr Orange: Well, we're very interested to know whether you know better management of periodontal disease in patients with rheumatoid arthritis or even pre-rheumatoid arthritis or rheumatoid arthritis that are refractory to treatment, whether that could actually make patients easier to treat, more responsive to therapy.

Dr Robinson: It provides a key mechanistic link for how this association of RA with periodontitis and with people with RA and peritonitis having treatment refractory disease, the mechanistic basis for why that might be. And it has a lot of implications for how one might develop better periodontal care to thereby better treat RA. But that latter part, showing whether better periodontal care in fact results in less active RA has yet to be shown.

But obviously, that's a key next step. And in the old days, meaning many, many tens of years ago, one of the things they used to do in RA patients was extract their teeth. And it's not totally clear to what degree that provided benefit, it was anecdotally providing benefit. And presumably if they did that, they would've prevented further mucosal breaches. So, we're obviously proposing not that, but the modern day approach to that, meaning just better oral hygiene and better dental care such that the periodontal tissue is more healthy and thus robust and refractory to mucosal breaches.

Dr Orange: Yeah, I just want to add to that. We don't have a cure for rheumatoid arthritis, but there is a cure for periodontal disease. So, if it's true that improved management of gum disease could actually help patients with rheumatoid arthritis, then that would be a very feasible treatment plan.

C360: Will we see more communication between rheumatologists and dentists?

Dr Orange: I think as Will said, we really have to prove that it makes a difference before this is going to be widely adopted. It's expensive to pay for dental care for everybody to make sure everyone's gums are perfectly healthy. So, I think before it is really widely adopted, the onus is on us to prove that it actually makes a difference.

C360: What is the next step in research on this topic?

Dr Robinson: I think that there's multiple next steps in research. Interesting findings always spur many different, many new scientific questions. And obviously, further defining the mechanisms by which these bacteria activate, both inflammatory monocyte macrophage population as well as the B-cells is an important next step. But also further investigating through more clinical translational studies about whether some oral intervention that improves periodontal health might provide benefit in RA, would be another important next step.

Dr Robinson: Thank you for your interest in our work. I think for many, for millennia, infectious and diseases and microbes have been thought to trigger autoimmunity. But yet, it's been very difficult to actually demonstrate those triggers. And our work is showing a key role for oral periodontitis and mucosal fragility in allowing commensal bacteria to basically evoke an autoimmune and an auto-inflammatory response that's perpetuating RA. So this is a very cool finding, which we believe truly links a microbial trigger. In this case, commensal bacteria breaching through the mucosal barrier to the autoimmune disease, rheumatoid arthritis. 

Dr Orange: Okay. Well, I just want to thank Consultant 360 for the opportunity to speak with you all today. It was fun for us to participate in this video interview and we are going to keep working on rheumatoid arthritis and see what we come up with next.