Rheumatoid Arthritis Faculty Panel Q&A Save

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We got tons of questions. We're going to take questions from the online audience and also in house. So in house, if you have would like to jump up to the microphone. Jeff, I'll start with a question with you about MUC5B testing. Who in RA should be MUC5B tested?

Does it have utility in diseases outside of RA?

Well, I think another question that needs to be answered is will it be paid for and what are the logistics? Know, things like the HLA B27 have a lot of the logistics for it. So there needs to be some logistical barriers overcome about how it gets paid for and clinically interpreted. I think in an ideal world, you'd have the data on everyone and it would help to inform your risk stratification. However, many of the models now have done it with and without the MUC5B promoter variant.

And I could see an intermediate step where people who are high risk, you then check the genetics. And then if they have the MUC5B promoter variant, might think about checking the CT scan.

And then the high risk stuff, you mentioned a number of them, and you're still working on maybe the ideal formula for them. But rule of thumb at this point, my rule of thumb's always been the 3S rule, but then there's more than that. Do you want to explain that?

Yeah, the 3S rule, which I think we came up right at five a. M. Right before ACR, because we were meeting then, it's smoking, male sex, and seropositivity. Those three factors are, seem to be some of the most important factors that put you at risk for ILD. So those are kind of an easy acronym to think about.

The other is to you know, age would be another one to think about. I think, you know, lower than 50 or 55, ILD is extremely low risk. And, you know, once you hit the age 60, that's another factor that could be, you know, easy to stick in your mind about age 60, which also happens to

have an S. Okay,

so this question could be for all of you, but maybe we'll start with Kristen. It's sort of a variant on the case, the Kate case. What happens if a young male, 16, presented because they went to orthopedics, they sprained their wrist playing volleyball, an MRI was done and showed erosions. Is this RA and how would you treat? So I mean, the story you kind of answered was if they were seropositive, what would you do?

But now what if you go one step further? Does this change your thinking?

Yep. That's a good question. I don't take care of 16 year olds. But, the I think the concept is important. Yeah, erosions on an MRI, it's hard to imagine that person didn't have symptoms.

And when I see that I do usually think there is some underlying rheumatoid arthritis. The, you know, certainly I see patients who haven't complained of symptoms and then something like this happens. But then as you talk to them, you know, maybe they did actually have symptoms, maybe they were subtle and they never raised to the attention of a provider. So yeah, I would certainly factor that in and without other context think that that could be urethritis. I think the other thing, erosions are a bit I guess more extreme.

I think one question that comes up to us more often perhaps is someone has symptoms, gets an MRI that has let's say tenosynovitis or maybe even synovitis, but clinically on your exam you don't find any joint swelling. Think that one's a little bit more tricky. Certainly if you scan just the general population with MRIs, there are people who have evidence of synovitis that don't have rheumatoid arthritis. So I think you have to be careful to assume that that is rheumatoid arthritis. But that being said, particularly if they were CCP positive, I think that is a time in which I may be more likely to consider that they're further along in truly having clinically diagnosable rheumatoid arthritis and may need treatment.

You know, before those EULAR guidelines on or the ARD paper on risk stratification for clinically suspect arthralgia, the factors and point system, I used to always quote Kevin Dean, who you worked with in Denver, about this ratcheting effect. The more you see that looks like RA, the closer you are to writing a prescription for RA and whatnot. But now we have it reduced to a numeric sort of way of looking at that. Another question was that was popular was what happened to positive predictive factors? Jeff, you were involved in guidelines in the past, early iterations of the ACR guidelines, treatment guidelines for RA had, if you have these positive predictive factors for a worse RA, it changes where you are in the algorithm.

That was there originally for ACR and for ULAR. It first went away for ACR and most recently went away for ULAR. Elena, what's thinking about, what's their role in how we treat RA when these one factor like extra articular manifestations is present or multiple are present?

Yeah, great question. So these positive predictors factors when we consider them at presentation give us potentially an outlook on how this patient will behave in response for treatments and possibly they will have a more severe disease. So upfront we can be a little more vigilant in terms of how soon and how fast we will advance the treatments without losing time and giving that cumulative inflammation buildup in the person to improve the outcomes going forward. So that's probably one aspect as to how to address this.

Jeff, what's your thinking on that?

Well, I think it just emphasizes the guidelines are a one size fits all solution and life isn't that easy in the clinic. There's some people where, you know, the guidelines aren't perfectly aligned with them. And some of them you're going to be more aggressive than the guidelines might suggest. Some of them you might be less aggressive. And I think those kind of factors in the real world are what drives some of those decisions.

So I kind of think it would be nice to have them back into the guidelines. But again, most of these guidelines are conditional in a way, they're kind of baked in from that standpoint anyway.

I'm going to ask a question, let's go to microphone first.

Thank you for the talk. So in the community, you know, our pulmonology colleagues refer a lot of ILD to us. Yeah. And when they see that they'll order the panels of myositis panels, CCP, RF, ANCA and you'll see positive factor of fifty, sixty, 100, whatever and they may not have RA but the ones with bronchiectasis. Can you speak to that and RA and how we should maybe look at that?

It's one of my other passion projects is looking at bronchiectasis and airways disease and it definitely folds into a lot of what Doctor. Demerrill is doing here. Yeah, I think you do get into this kind of volleyball with pulmonary when they definitely have ILD and they have some antibodies and they're saying, Is this your problem? Is this my problem? And I think there's so much nuance here, it's hard to, again, put a one size fits all solution.

I think certainly there are many patients who have ILD that are seropositive. Some of them have an undiagnosed rheumatic disease where us seeing them in clinic is really helpful because we know how to treat, you know, the organs that are being affected besides the lungs. Some of them truly just have ILD and they're seropositive. And I think, you know, we often say we're happy to monitor them because they are at higher risk of, you know, articular involvement. But if they have lung disease, and they're the lung doctor, we would support them to be treated.

For example, they have seropositivity without arthritis and ILD, you know, they might be treated very similar to IPF and start up front with an anti fibrotic. I think for the most part I would not support starting them on rituximab or other medications unless they truly had a rheumatic disease. And the bronchiectasis bit is, you know, really intriguing and I think we don't exactly have as much data to know what to do with those patients. And again, I think it does fold over into the mucosal pathway there that, you know, these patients are probably much more likely to go on to develop articular manifestations. But again, it's not really clear that any treatment there are some approved treatments for bronchiectasis granted, but certainly starting immune suppression in people that only have airway involvement is probably only going to increase their infection risk without really any certainty that they're going to improve any other clinical outcome.

So I would typically refrain from treating those patients.

So as moderator, I'm going to be very instructive here on this question that I just made up. I want each of you to answer the question, how hard should I look for the thing that you were addressing? So in Jeff's case, how hard should I look for interstitial lung disease? For Kristen, how hard should I look for mucosal involvement? And for Elena, how hard should I look for extra articular manifestations?

Do you take a macro view? It's painfully obvious that they have it and then I do something? Or do you take a more micro view? Should I look really hard for maybe what I don't see? Start with Elena.

Yeah, I can start. I think again one size does not fit all here and if a patient is seropositive patient, I will definitely look harder for exartical manifestations in this population. Obviously clinical exam is a must, but in terms of screening including CTs for high resolution CTs for the ILD presence, I would be even more driven to do that in a seropositive individual with rheumatoid arthritis.

Kristen?

Yeah, think at this point I don't think we go searching for the mucosal site that is inflamed perhaps in the pre aure individual, though we may get to that point in the future and that may be more informative. I think at this point, a clinically actionable item is whether or not to screen a person for anti CCP or rheumatoid factor positivity. I think at this point, while in Colorado we have done some kind of general population screening, and that is an option a person could have. You know, you screen every person, about two percent of people are CCP positive, probably one percent of them have rheumatoid arthritis, they do or don't know it. So I think there is information, as we talked about with the earlier question, that can be given to a person.

So maybe someone with a family history or someone with a nonspecific joint symptom I think is a good person to screen for CCP positivity in. But we're not quite where we would, you know, screen the whole population like we do with, say, cholesterol or blood pressure screening or something.

Kristen, do you foresee that there will be salivary CCP assay?

You know, I have tested that before as well. It might be more easy for some people than a blood test. I think there's a lot of translocation at that site, so you may be picking up what's in the blood. So in my view, salivary CCP could be a way to test people who don't have access to a blood draw easily. But I'm not sure if it's going to tell us if their oral mucosa is the site of their RA.

Jeff, you've already talked about this, but do you want to do one final word on how hard should

I look? Well my perception, maybe the audience can tell me, at the moment I think very few people screen all RA patients for ILD, is that true?

With a chest x-ray? Does that really, at Well,

mean chest x-ray is really not very helpful. But think rheumatologists are not convinced to screen all patients for ILD, and I'm convinced too. And interestingly, the ATS has recently released their guidelines that said that all rheumatic diseases, including RA, everyone should get a CT scan, which I feel like is definitely a stretch. So I definitely think we should hone in on a subgroup where the prevalence is around fifty percent. And I think we've already have pretty good data that we know many factors that could help risk stratify.

And the proof's in the pudding, I think. We're never going to convince all rheumatologists to screen all RA patients. So I think focusing on the subgroup where the prevalence is fifty percent or higher makes good clinical sense and probably has a favorable cost benefit analysis, although we do need to do formal studies on that.

We have a question in the audience, but I want to thank the virtual audience for upvoting the questions that are in there. That helps us to prioritize what's asked so that upvoting is very helpful. Go right ahead.

So on the heels of that, a subgroup that we might be able to look at easily clinically if this information is available is dental disease, significant gingival and dental disease, is there a direct correlation with interstitial lung disease? And independent of that, is there a direct correlation with mortality?

I think we need to put in a grant together for this one, right? I'll let Kristen. Yeah,

I don't know of a relationship between, ILD, but it's interesting, especially when you think that you may be aspirating things into your lung, and is that, you know, more inflammatory, oral mucosa with, you know, contributing to some lung inflammation. I think that's very interesting. I don't think there's a study out there. I think, you know, periodontal disease, as I mentioned, is associated with some individuals in the pre RA period, so it can be associated with a risk for developing RA. I think there's some studies, I think, currently going on in The United Kingdom that are quite intriguing where they're actually trying to intervene to treat the periodontal disease and see if it impacts the outcome.

I think in general it's good to have good dental hygiene so it's easy to tell a patient that they should factor that into their well-being. But at this point, you know, whether or not it actually prevents RA, we don't really know. But it's probably good overall. I assume it's associated with mortality probably, just as a general population. But yeah, so good thing to take care of, but I think we need more information on whether or not it's associated with the lung disease or the mortality specifically.

Doctor. Ribera?

Yeah, periodontitis. Thank you. Oh, In terms of mortality, periodontitis is associated with increased coronary heart disease risk and increased RA risk. So the major contributors are there. I believe it would be associated with overall increased mortality, although I don't have data on hand to support that, but the coronary heart disease is definitely one of the major drivers and RA association amplifies that as well.

Okay. Just a quick question about the use of ultrasound in the screening process for ILD. If we are concerned about the costs and the radiation that will accumulate over time with repeat CT scans, couldn't we use ultrasound as the deciding tool to then, if it's a positive ultrasound, I will proceed with a CT scan and so on, since the positive likelihood ratio is very good, as well as the negative likelihood ratio?

Yeah, thanks for bringing that up. And I debated putting that in, but we had a lot of content as you saw already. For those not familiar, lung ultrasound is also, you know, being used as a point of care test to screen or to identify ILD. I think this is a big opportunity. Obviously there's been a huge movement to do musculoskeletal ultrasound.

Many rheumatologists have ultrasounds in their clinics. And actually, from what I'm told I'm not an ultrasonographer myself but from what I'm told, it is not super hard to learn how to do that. And obviously you'd have to think about your clinic workflow. But there would be a lot of appeal to, if you have an ultrasound, to perhaps think about doing a lung ultrasound. Obviously it's there in the clinic, you could probably bill for it.

There's no radiation. You get an instant answer. And so yes, that is definitely an appealing process and I think that could be a very important tool. And actually, as part of some of our studies, we have incorporated lung ultrasound. And I think one of the questions is, you know, is it an intermediate step again?

Do you end up getting the CT scan anyway to confirm? Or do you just kind of go straight to the gold standard? So I think that's where the tension is with lung ultrasound. But overall, I'm pretty excited about it.

So I'm going to recall a quote from an episode of The West Wing, and Artie would like this because he knows Latin and I don't. Post hoc ergo propter hoc. What? It's a quote that means it's a logical fallacy that because event B happened after event A, A caused B. We have a lot of questions about, Doctor.

Sparks, what would you do if ILD develops? Will I stop the TNF? Will I stop the leflunomide? Should I stop the methotrexate?

Yeah.

Go ahead. Either explain the Latin or Oh try to figure out the

boy. Well first off, these are super complicated patients and, you know, our group has a multidisciplinary conference with pulmonary and radiology where we meet weekly to talk about these difficult cases. So unfortunately, my, you know, thirty seconds here is probably not going to solve this. But I will say that for my approach and with our pulmonologists, we do not typically stop methotrexate or TNF inhibitors unless we're really suspecting pneumonitis. Granted, those are very first line treatments for RA, and if the ILD has happened after those meds have been exposed, we don't typically circle back to them necessarily.

But for the most part, we are not stopping those medications because we think perhaps they're helpful for lungs, or they're at least neutral. The other question is do you shunt them onto abadacept or tocilizumab, which have positive data in some context related to lung health? And, you know, the easy answer is we need a trial. I mean, would be great if we did kind of a factorial trial of anti fibrotic plus abadacept versus, you know, placebo and TNF inhibitor, and that would give the ultimate answer. But for the most part, if RA is active, we're trying to intensify treatment.

And by RA I mean articular RA. And if their articular RA is in remission, sometimes we might switch around the DMARD to a more lung friendly combination like rituximab. And sometimes we would add an anti fibrotic and Neurodomelast is the newest tool. So I don't know if that's helpful at all, but that's my general approach to those big picture questions.

And I agree. I would never stop any of those three drugs because ILD alone might have other I need other reasons. Are, Kristen, there's a question about might you explain the tetracycline story in RA through the mucosal hypothesis?

Yeah, I mean, it's an interesting question. Guess the we'll never know. But yeah, I think many things influence our microbiome, whether it's your diet, or antibiotic use, or different medications that you take along the way. So yeah, I think it's very possible that there has been an influence on the microbiome over time with different treatments that maybe is helpful to know. I don't know if we'll ever know.

Will we get to the point where we're prescribing antibiotics for rheumatoid arthritis? I don't know if we'll if that will be the future. But I think the consideration for the microbiome and trying to understand that makes sense. I'll just lastly maybe say that I think as you saw there's many different microbes that have been associated with RA, and so I think it may be hard to, you know, pinpoint a specific one. So it may be kind of a more global approach to a healthy microbiome.

Yeah, again, the story was that Doctor. Brown had treated a whole bunch of patients with tetracyclines, and that led to the minocycline trial and And the thinking was that it was all probably mediated through metalloproteinases with a real small mention about microbiome back then. That's become more of the predominant story. But anyway, that's still interesting. A number of people asking, about, titers of, RF and CCP, how high is high.

Again, the story on that that everyone that was shown and that we all know is that highest titers are associated with greatest risk, multiple antibody associated with greatest risk. Anybody want to comment about that and how it either how that becomes clinically useful? Elena?

Great question. I think there's a dose dependent association to an extent with mortality. Some studies have shown very consistently that the higher the titer, the higher the mortality rate. For example, in rheumatoid arthritis. Other studies shown that there's no clear cut association with the titer, but just the antibody positivity.

In terms of the clinical presentation and disease severity, in my experience it does seem to certainly track with the titer and patients who are above two fifty for their CCP antibody and some who I saw above 500, they are definitely severe and more refractory terms of how their RA behaves. I don't necessarily take CCP titers below 40 as know, as predictor of very severe RA. But still, you know, if you were to dichotomize antibody positivity is informative for prognosis of RA disease presentation as well as outcomes.

Do those same besides those high titers, double seropositivity, triple seropositivity risk for developing disease, does that also exist in ILD, Jeff? That titers are become more important the higher they become, or the

more they become? Yeah, actually we are doing an antibody profiling project right now, and it's submitted to you, LAR. And actually we did the entire panel that pulmonary does, as well as the extended panel. So we're still kind of analyzing through those results. But as a general comment, the people with very high titers of the RA specific antibodies had much higher ILD risk.

I may add one point to the antibody discussion. Is it for the prediction of RA, different labs do different tests? And so you may be aware of the CCP3, in The United States it's usually either CCP3 or three point one. The 3.1 part adds an IgA antibody that's being detected whereas the three is only the IgG. Studies do show that that IgG anti CCP is more strongly predictive of getting rheumatoid arthritis and at higher levels as we discussed earlier.

Something to note as you interpret your results depending on your lab.

And I should mention our antibody profiling does suggest that the IgA subtype is much stronger associated with ILD which folds right into the mucosal origin hypothesis of RA.

So, a few questions about environmental pollutants. Actually important for each of your subjects. We had Karen Costabatter talk about this last year, but I'd be interested in each of you commenting on the role of pollutants and if you can do anything about it other than move to Arizona, where there's still pollutants.

I guess when it comes to risk, there have been some studies that have identified increased pollution risks associated with increased risk of rheumatoid arthritis. I think that ties into, you know, you inhale these things and so they may be activating some immune dysregulation perhaps in your lung as the first site, but then they're also likely, you know, become, you know, throughout your body could affect other sites. But certainly that's a factor that in some individuals that may influence lung inflammation during the preclinical period.

You know, this week we put up a report from Ontario about pollutants and PM, 2.5 levels, PM in particulate matter, less than 2.5 microns inhaled, fumes, dust, tobacco, whatever. And they did a population based study based on where you lived in Ontario showing that when you where there was going to be high PM2.5 levels, ANAs went up significantly. I thought that was really quite interesting.

Yeah, I'll mention that we're of course interested in inhalants and RALD risk, and there's recent papers showing PM2.5 and specific pollutants. Our group's also interested in respiratory infections as a trigger, and I think we've also mentioned silica exposure, miners, fire pit exposure, mold. So you can imagine anything you breathe in that disrupts the immune system at the mucosal surface has the potential to set off RA, ILD mortality. So certainly that seems pretty consistent.

And more globally in terms of impact of pollutants and mucosal irritants on the health in general including the autoimmune health, cardiovascular health, malignancy, all of that of course is not favorably influenced by these by the pollution and hence has adverse impact on mortality.

I guess I have to address this, although it's not the topic that we're on. A number of people asked about oral surveillance and you alluded to it. So first, my two cents on oral surveillance is that it's not that JAK inhibitors kill people more. I believe that it's because TNF inhibitors are better at preventing. You showed, you know, reduced mortality TNF inhibitors, maybe it's just not as good with JAK's, but maybe comments from the panel about how oral surveillance is affecting you, because it seems like a lot of people are still handcuffed by JAKs and risk, And they want to know if it's just in RA or is it really anywhere you might use JAKs.

Elena, you want to start with that?

Yeah, certainly. So the signal and the regulatory implications relate to the tofacitinib versus TNF inhibitor comparison. There hasn't been really strong evidence from observational studies to back that up from long term observational studies as well with long term follow-up or across the diseases or across the panel of the JAK inhibitors. So take it with a grain of salt, there's definitely a high risk category of patients that particularly showed that association. In my practice, and that was my first conclusion from the talk is that untreated RA is the worst RA, right.

So JAK inhibitors can help achieve control of rheumatoid arthritis including remission and sustained remission. And so you use it to the benefit. And those high risk population of older individuals with high cardiovascular disease risk, that's a separate discussion. But even then there is a balance in terms of their use for potential weighing of balance and benefit and risk for a particular patient. If they are a non responder to everything else and they are really set up to potentially respond to a JAK inhibitor, why not use it?

Okay. I'll mention for RAILD, this is a population that's enriched for oral surveillance risk factors. It's almost all older people. It's enriched for males, enriched for smokers. So this does come up quite a bit in RA ILD, particularly in patients with difficult to treat RA.

And I have to say, think rituximab's got a bit better data in ILD, so I've been favoring that, but there are some patients that have very refractory RA that I still do put them on JAK inhibitors, but by that point they've been exposed to TNF inhibitors, and the options have whittled below, but it definitely comes up often in talking with patients with our ILD about the oral surveillance results.

There was one question I think that you did answer. What DMARD or biologic would you not use in ILD patients? You said azathioprine is you shy away from anything else that you'd add to that?

You know, I think if it's a brand new patient, I might I think the question is like when to use anti fibrotic. This is not answering your exact question, granted, but I think that's been the clearly the trials are only with anti fibrotic and how you weave that into the sequence of therapies and whether you give the DMARDs six months to work or whether an early treatment with antifibrotics. So I think that's been kind of the more of the question as opposed to the choice of DMARDs when to add on an antifibrotic into their regimen.

Okay. Last quick question for Kristen. Your center where you're keen to this hypothesis of mucosal involvement, how are you using the dentist in your RA clinics? I guess Does we everybody go or only people, you know, who obviously have problems?

Yeah, it's a great point. Even at our center, wouldn't say that the routine recommendation is to go see the dentist. I think we do need more data before that, I guess, that comes top of line. But, but it obviously makes sense, yeah, to have them see that.

Okay. I wanna thank the panel for a great discussion and a great session. Thank you. If you enjoyed this podcast session, there are other RNL 20 '26 podcasts to listen to. Also, you can purchase unrestricted, on demand, full access to all of the RNL twenty twenty six content.

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