The Mucosal Hypothesis of Rheumatoid Arthritis. Dr. Kristin Demoruelle Save

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Our next speaker is Kristen Demerall. Kristen comes to us from the University of Colorado where she works with a number of researchers who are dedicated to knowing RA before it becomes RA, And we've asked her to talk about this mucosal hypothesis.

Thank you. Thanks to the organizers for inviting me to talk on this topic today. These are my disclosures. These are the learning objectives that were in the pre learning materials that we'll cover today. So I'll start with a clinical case that's not uncommon to my practice.

Kate is a 32 year old woman who comes in complaining of bilateral wrist pain. She states she doesn't have any joint swelling that she's noticed. She does have about forty five minutes of stiffness in the morning in her wrists. She doesn't have difficulty making a fist. She previously smoked but quit five years ago.

And when you do your exam she doesn't have any swelling or tenderness or synovitis that you can appreciate. But her labs come back with an elevated anti CCP of 82 units, an elevated rheumatoid factor of 45 units. She has a normal ESR and CRP. You get hand x rays and hand MRI, and those are unremarkable without any inflammation. And so you tell her she doesn't have rheumatoid arthritis.

Her joints are normal. And she asks you, well if my joints are normal and I don't have RA, then why are these antibody tests for RA so high? And I'll start by mentioning the twenty ten ACR ULAR classification criteria. And while these aren't diagnostic criteria, they can be helpful in assessing patients for rheumatoid arthritis. Notably these are designed to be assessed in patients who have joint inflammation or clinical synovitis.

And so these type of criteria wouldn't apply to our patient Kate. But what we know now from years of work is that individuals come into the clinic with swollen joints, they're diagnosed with arthritis. But if we looked back several years prior, we would find that most of them have antibodies associated with rheumatoid arthritis present in their blood many years prior. Dare I try a pointer. So in this figure individuals are diagnosed with rheumatoid arthritis at time point zero.

And these individuals had blood stored for up to fifteen years prior to that diagnosis. And when it was tested for rheumatoid factor and anti CCP, you can see that a large number of individuals had these antibodies present in their blood years before they developed rheumatoid arthritis. This has been shown in a number of studies now with anti CCP or ACBA antibodies as well as rheumatoid factor. There's also some more recent studies that have looked at other RA associated antibodies that are less used clinically, but things such as anti carbamylated protein antibodies or anti MA antibodies also being present in the blood years before individuals develop joint inflammation and are diagnosed with rheumatoid arthritis. So there's a number of these retrospective studies that again look back at someone's blood that preceded their onset of joint inflammation.

And we know that a large number of these individuals had these antibodies present early on. Importantly, we've got more information in the last decade or so looking at the prospective nature of these antibodies, which I think is really helpful and important. So if you have a person like our patient Kate who has anti CCP positivity but doesn't yet have inflammatory arthritis, what are her chances of developing RA? And so I'll go through a few studies that give us a little bit more information for the prospective nature of these antibodies. In the study on the left, individuals had nonspecific joint symptoms and they were stratified by anti CCP positivity in red or being anti CCP negative in blue.

And you can see that as they were followed, oops, as they were followed over time, at twelve months forty two percent of the CCP positive individuals developed rheumatoid arthritis. And the figure on the, oh that's your left. I'm not good with other people's right and left, but maybe I'll point instead. So in this figure you can see that these people were CCP positive, all of them. They also had musculoskeletal symptoms.

And when these individuals were followed over time for up to three years, at the end of three years thirty eight percent of them had developed rheumatoid arthritis. I think we can also get helpful information from several more recent prevention studies, which I'll talk about more at the end of the talk. But if we focus just on the placebo arm of here two of these prevention studies where individuals were enrolled and some received placebo, some received treatment to try to prevent RA. If we look at just the placebo group, for the Epipras study here, individuals were CCP and rheumatoid factor positive and had symptoms of inflammatory joint pain. In this study twenty nine percent developed rheumatoid arthritis at 12 and thirty seven percent at two years.

In the STOMP RA study here, these individuals only had to have CCP positivity at a slightly higher level, so two times the upper limit of normal for the positive cutoff. And they could or could not have joint symptoms. In this study, in the placebo arm, eighteen percent developed RA in twelve months and thirty three percent at three years. And so I think these numbers are helpful to answer questions that come up such as the one our patient asks, what's her risk of developing RA if she doesn't have it now and she has this anti CCP antibody positive? And so with the data I showed you the risk is, or the rates are eighteen to forty two percent of individuals will develop RA in twelve months.

Thirty three to thirty eight percent in three years. There's higher rates in the next twelve months if a person has arthralgias present or joint symptoms. And I think this tells us, and things that may be helpful to communicate to patients are that anti CCP positivity is not one hundred percent predictive for developing RA. So some people won't. And that can be reassuring to some patients.

But I think it's also important to highlight that their risk is markedly elevated compared to if they were CCP negative. If they were CCP negative it would be less than one percent. And so these rates in the thirty to forty percent range are quite a bit higher than what it would be otherwise. And so this leads to a model of RE development that's shown in the figure here. Where individuals start with genetic risk, encounter environmental factors over time.

And this can lead to inflammation at mucosal sites, which we'll talk about. They can expand over time. Maybe people have arthralgias at this time point. But then some individuals will transition to inflammatory arthritis that may be unclassifiable or classifiable by some of the criteria we have. I'll be focusing on this pre RA period prior to the onset of joint inflammation.

And so the title of the talk is the mucosal origins hypothesis of RA. And that's really based on two key factors to mention. First is what we talked about in the previous slide, that individual that circulating RA associated autoantibodies are detectable years before clinical inflammatory arthritis is present. There's also a number of studies that have found that joint imaging and even synovial tissue from biopsy studies don't have inflammation present in individuals who have pre RA or these systemic antibodies in the absence of clinical inflammatory arthritis. I'll just note this figure here is from a study, not good with the pointer, looked at MRI of the hands in individuals who were either ACPA or CCP positive compared to healthy controls.

And in these MRIs you can see that and they had no clinical synovitis on exam. There are a number who do have tenosynovitis or synovitis, as well as erosions and osteitis. But for this talk, the point is to look at the white spots. So there's quite a number of individuals who don't have any tenosynovitis, no synovitis, and yet are CCP positive. So when we put these things together, antibodies are present circulating in the blood, the joints are normal in a number of people.

This tells us that RA is not originating in the joints, but the question is where. And so this raises mucosal sites. We know that with autoimmune diseases like rheumatoid arthritis, genetic susceptibility is present. People encounter environmental exposures and this leads to a loss of tolerance. Mucosal sites are key sites where immune environmental interactions occur on a regular basis.

They can initiate local inflammation that can become systemic. And this happens for infections, but can also happen with autoimmunity. And so NRA, the mucosal origins hypothesis describes that autoimmunity related to rheumatoid arthritis originates at mucosal sites with these environmental interactions with the immune system and genetics. These are four mucosal sites that have been associated with RA. And I'll tell you a little bit more about the top three that have the most data.

So we'll start with the lung, my favorite mucosal site. There's multiple studies that link lung inflammation and immune dysregulation to this preclinical period of RA. And without going through all of these and just kind of summarizing some of the key findings here, we know for many decades that smoking, as well as other inhaled antigens such as silica exposure, are strong risk factors for developing RA. So those are environmental exposures coming in and affecting the lung. Our group a while back showed that there were inflammatory airways on individuals who were CRMCCP or rheumatoid factor positive, but didn't have inflammatory arthritis.

And we could look at high resolution CAT scans of the lungs and see that there was a higher prevalence of airways inflammation in those individuals with antibody positivity. Studies have also shown that lung diseases such as asthma, emphysema, interstitial lung disease, which you'll hear more about next, are more prevalent in individuals who later develop rheumatoid arthritis. Our group has shown that the antibody CCP and rheumatoid factor can be produced in the lung. This has also been shown by other studies. But this can be present in individuals who are at risk for RA.

And notably in some individuals who are serum CCP and rheumatoid factor negative, they have evidence of these antibodies in their lung, suggesting that it's not simply translocation from the blood, but actually may be originating in the lung in some individuals. Our group has also showed that lung derived neutrophils are more prone to undergo NETosis, or neutrophil extracellular trap formation, which correlated with anti CCP antibodies in the lung, and I'll touch on that on the next slide. There's also been studies using bronchoscopy that have identified aqua generating B cells from within the lung in individuals at risk of RA. So a large number of studies that support the lung can be a source of inflammation and immune dysregulation in this preclinical period. When it comes to the lung NETs or process of the immune system, it may be particularly relevant in the lung.

And so we proposed this hypothesis in the lung. But neutrophils are obviously present in the lung. They can be activated to undergo NETosis through a variety of exposures, including some that are associated with RA risks, such as smoking. Neutrophil netosis exposes the immune system to extracellular citrullinated proteins, which is relevant to the generation of ACPA in these patients. And so when NETs externalize citrulline proteins that interact with the immune system, they could trigger antibody generation to the citrulline proteins or ACPA.

Our group has also shown there may be a decreased clearance of NETs in the lung in particular that may be relevant to increased exposure to these citrullinated protein antigens. And so this may be one pathway by which in the lung the ACPA can be originally generated and then later go on to become systemic in this preclinical period. The gut mucosa has been an area of much research in the preclinical space. And a lot of the work here has really focused on the microbiome. So just to summarize a large number of studies, there have been some studies that have identified specific microbes that may be particularly relevant to the development of rheumatoid arthritis when it comes to the gut.

Those include things like Prevotella Coppari and what can be called S. Dido, which was identified by our group. The important things to consider here are that these specific bacteria have been associated with certain immune activation pathways such as molecular mimicry, BNT cell activation, altered metabolism. And these different components that are occurring in the gut mucosa may contribute to the development of rheumatoid arthritis in this preclinical period. Outside of these specific microbes there have been studies that have just looked at the gut microbiome in general and found that in individuals who have pre RA, they have a lower diversity of their gut microbes in general.

And one study interestingly did a fecal transplant of pre RA stool to mice, which led to intestinal inflammation, permeability, and increased Th17 cells in the gut. Suggesting that some of these microbial interactions with the gut mucosa may be contributing to the immune dysregulation in the preclinical period. Similarly in the oral mucosa there's also been a number of studies that have looked at certain bacteria has been a focus there. Porphyromonas gingivalis is a bacteria associated with periodontitis that can actually citrullinate proteins and so has been considered as a particular bacteria that may citrullinate proteins leading to act regeneration. More recent studies have looked at a set of streptococcal microbes from the oral cavity that were associated with RA flares, and were able to activate the immune system in a variety of ways, including B and T cell activation.

And so these different microbes in the oral mucosa may also be contributing to some of the preclinical inflammation in these mucosal sites. Interestingly in the oral mucosa there is an older study that did find in individuals who had periodontitis and did not have rheumatoid arthritis, they could identify the generation of anti CCP antibodies at that mucosal site using testing of gingival curricular fluid. This study also found increased citrulline proteins, pad enzymes that can citrulline proteins, and again these anti CCP antibodies locally being generated in the oral mucosa. So you know each of these mucosal sites that I mentioned kind of have their own flavor of what's going on. Some are more microbial driven, at least in the studies that we have, maybe less so in the lung.

And so we take that all together to describe that it may be that as an individual develops rheumatoid arthritis, kind of thinking back to the figure I showed you earlier on sort of this model of RA development, perhaps at this early stage individuals may have different endotypes based on the mucosal surface that they have activated. And there may be different features that are associated with an oral endotype early in the preclinical period, lung specific endotypes, and gut specific endotypes. And perhaps when they're occurring at these mucosal sites they may be somewhat unique, but then ultimately come together for common pathways of act degeneration, T cell activation, and then ultimately individuals developing joint inflammation and rheumatoid arthritis. And so I would answer this patient's question that, you know, what we understand so far is that these antibodies likely develop from inflammation at mucosal sites. And that this can happen years before joint inflammation.

And while she doesn't have RA now, these antibodies do increase her risk for developing RA in the future. Her next question is, what are my chances of getting RA? And I will try this poll. So what do you think her chances are of RA based on her initial presentation of having high titer CCP and rheumatoid factor, no joint inflammation on exam? Okay, all right.

So the majority of people think somewhere between twenty and fifty percent, which is correct. And so based on the prospective studies we talked about earlier, individuals with CCP positivity have somewhere on the order of twenty to forty percent risk of developing RA. I'd like to mention that there have been recently some new RA risk stratification criteria that have been published, which I think are really helpful for a patient like Kate in helping to understand what her risk is in a more individualized way. And so these risk stratification criteria, similar to the RA classification criteria, are a point based system that includes key features that are associated with risk of RA, including how long someone's morning stiffness is, if they report joint swelling, if they have trouble making a fist, increased CRP, rheumatoid factor and ACPA, with more points for higher titers of rheumatoid factor and ACPA. This point system then is associated with a little scale here that tells more granularly what a person's risk of developing RA is.

And so if we go through our patient Kate, she has forty five minutes of morning stiffness, no joint swelling, no trouble making a fist, normal CRP, high titer RF, high titer ACPA. And so her risk of developing RA is fifty three percent based on this criteria. But if you had a patient who also had joint swelling, also had trouble making a fist, they could have a risk of developing RA if they had over 20 points of much higher at seventy one percent. And so I think these criteria are quite nice for really individualizing a person's potential risk. These criteria also include MRI if that was performed.

And so if a person had MRI they have a separate little scoring system with different point cutoffs and different risk prediction. And so for our patient Kate, in addition to her clinical and serologic characteristics, if we add her negative MRI findings she would have a forty seven percent risk of developing RA. And so I think these risk stratification criteria are quite helpful, particularly with sort of gauging what an individual person's risk might be. Notably they don't include musculoskeletal ultrasound, which has been shown to predict risk in some individuals. But overall for these criteria, I think with some heterogeneity of who's performing it and things like that, it didn't make it into these criteria.

I also just told you about the mucosal sites that could be involved in RA in the preclinical period. And this doesn't include those, consideration for mucosal factors. Perhaps maybe that will change over time. Our group looks at sputum as a way to measure antibodies in the lung. And we've shown that in individuals who are serum CCP positive, if they're also sputum CCP positive, their risk for developing RA over time is much higher and is a good bit lower if they are sputum CCP and rheumatoid factor negative.

So maybe that in the future we also are able to add biomarkers from other mucosal sites to help really increase our prediction of who's going to get RA. Kate next asks, should I do anything or take any medications to prevent RA? This will be our second question. Should she start hydroxychloroquine, start methotrexate, start rituximab or maintain a healthy lifestyle? A well educated audience.

Okay. So a lot of us know, but just to kind of summarize here, there's been a lot of work in the area of RA prevention, is very exciting. There's been a number of studies that have been published over the last ten or so years where different interventions have been applied to different at risk populations with a goal of trying to prevent RA. We know that when a person has joint inflammation and comes to the clinic, we can't cure them. And so hopefully we can find a way to identify the right person, the right intervention, and prevent them from the long term damage of rheumatoid arthritis, as well as the increased mortality that we heard about recently.

And so this is a quick summary of some of the main studies in this space. First is the Prairie study, which included CCP and rheumatoid factor positive individuals who had joint symptoms and also had either an elevated inflammatory marker or imaging of inflammation on MRI or ultrasound. They received one dose of rituximab. And then the outcomes of developing rheumatoid arthritis at twenty nine months were thirty four percent in the rituximab group and forty percent in the placebo group. Their conclusion was that it delayed but did not prevent RA.

STAPRA was a study that used atorvastatin in individuals who had high titer CCP or CCP and rheumatoid factor positivity and also joint symptoms. This study at three years found a rate of development of RA of twenty nine percent in the group that got atorvastatin and nineteen percent in the placebo group, concluding that atorvastatin did not prevent RA. Treat earlier was a study that enrolled individuals with recent onset arthralgia and they had to have MRI joint inflammation. They could or could not have CCP positivity. They received methotrexate for twelve months.

And at two years there was no difference in the rates of who went on to get rheumatoid arthritis. Notably when they looked at the CCP positive group compared to the CCP negative group, there was a delay in the CCP positive group of developing RA but not prevention. STOP RA was a study done in The U. S. That enrolled, as I mentioned on an earlier slide, CCP positive individuals with a slightly higher positivity level.

They received hydroxychloroquine for twelve months, and at three years there was no difference in the rates of developing RA. So it did not prevent RA. Aria and Apipra both used abatacept. Aria was a bit shorter, abatacept for six months, outcomes at eighteen months. And in this study thirty five percent on the abatacept group developed RA compared to fifty seven percent in the placebo, concluding that short term rates were reduced for RA with abadacept.

And then Apipra used abadacept for longer at twelve months, and their two year conclusion was that it lowered the rates of RA at two years with twenty five percent, developing RA compared to thirty seven percent. I'll just mention the APIPRA study a little bit more. The original publication, this was they got for a year, two years looked at outcomes. And in the original publication there was some suggestion of possible prevention as the group that got abatacept did not develop RA as fast or as much as the group that got placebo. However, recently published their long term outcomes, and you can see that by six years these lines cross.

So they their conclusion is that it delayed rheumatoid arthritis, perhaps up to four years, but did not fully prevent it. Just based on the mucosal origins hypothesis, I think it's interesting to consider that maybe some of our prevention trials could target these mucosal sites in unique ways. And we'll see what that looks like over the future. And so yes, there's no medications currently to prevent RA, but modifiable risk factors could include smoking cessation if needed, maintain a healthy weight and diet, and perhaps good dental hygiene. And so in conclusion, extensive data supports inflammation and autoimmunity in RA originated mucosal sites prior to joint inflammation.

RA may be driven by distinct mucosal sites that differ across individuals. And because autoimmunity in RA begins before the joint disease, I think there's an opportunity for prevention, but we're not quite there yet. And I'll thank you for your attention.

We have time for a few questions. I want to jump on APIPRA data that you showed and Alto, the four year extension. You know the caveat to that is the subgroup of patients who had the extended serotypes, they had five autoantibodies associated with RA, which you would think would give you worse disease, They showed better separation and continued prevention of disease. Could you would you want to postulate on what's going on in the lung of those individuals with the five serotypes?

Yeah, it's a great question. Yeah, because everyone had CCP positivity or rheumatoid factor positivity, many of them, and then some of these extended antibody types were more likely to be prevented. I guess it maybe suggests a person whose immune system is a little further along in the development and maybe more responsive to treatment. This therapy is obviously targeting these interactions with T cells, and they have more antibodies, so maybe that's a particular feature of their immune dysregulation that's more engaged. I think it's a great question, and yeah, you would think maybe they're too far along, would be less likely to have prevention of RA, but perhaps we're seeing that their immune system is engaged in a way that is responsive to abatacept.

I think the big takeaway I have from all these studies is that I wonder if we need to target either target specific pathways in specific individuals, because everyone may not have the same sort of immune dysregulation that leads to what we call the same thing of clinical RA at the end. Or perhaps these are just sort of pathways that are further along the development of RA. And maybe there's some dysregulation earlier on that hasn't been targeted yet that we really need to consider in these prevention trials.

Certainly more questions than answers. Microphone, go ahead.

Bob Turcot, Tableau Hoy. Really nice talk. One of the things going on in The United States is this functional health exam with lots of biomarkers, and people sign up and they spend hundreds of dollars per year. And CCP is one of the things in the panel. What's your view on that?

Is that a great thing or is that a, you know, problematic thing or both?

I think it's a good thing. I think we can tell a person they have a different risk of RA in the future based on that test. I think it could be arguable that if you can't actually do anything about it, you know, is it helpful to know? So I think probably like many of the biomarkers in those assessments, there's a lot of counseling that needs to happen to the patient after. And so, you know, I think it is helpful information, but it may not be as actionable.

And hopefully people don't become overly worried about it. And then hopefully in the future we do have things that we can do for them. But you're right, it is a question of if it's helpful if you can't do anything, but I think, you know, maybe if they are smoking you do tell them, like, you will really need to stop smoking or, you know, maintain a healthier lifestyle.

Two quick questions, Artie?

Thank you for the talk. I think this is so important, we all see these patients, and what I do, and I want you to tell me how crazy it is, if I see somebody just like you said and their CCP is 40, I'll say, yeah, you know, let me come back in six months or let me know. If it's $2.50, I'll say, why don't you come back in twelve weeks and we'll reassess. Is there any data though? I think that's a natural reaction, but it's not, I don't think it's data that supports that, or is there?

Yeah, mean, think higher titers of CCP and CCP in addition to rheumatoid factor are associated with increased risk for RA. And that's kind of outlined in that risk stratification criteria where you get more points. So I do exactly as you say, where I probably see them a little sooner if that level is quite a bit higher. But we do know that even at a level of 40 you could develop RA. My approach is to more education for what to look for, because I think some individuals, especially, I know I see this more in younger people, but they'll kind of blame it on other things.

Like, oh I worked out too much and that's why my hand hurts. And so you're really trying to help them know this is when you need to come back to me. These are symptoms that really matter, think can be helpful. Great question. Thanks for the excellent talk.

Quick question, is there a role of probiotics in preventing RA? There is no current data to support that that would prevent RA. But as I mentioned, yeah, there are microbes that are associated with potential RA. So hopefully there will be some studies that look at that. Can we intervene in the microbiome either with probiotics or, you know, targeting certain bacteria that could be helpful?

I think there's many people that hope that's the case, but yeah, at this point not so much. Thank you.

Yeah, the probiotic data is, what is out there is pretty weak, but kind of positive. So I think that, yeah, we'd like to see more on that. Alright. Thank you so much. It was great.

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