EULAR 2024 RA Topic Panel Save
Moderated by Dr. Jack Cush and featuring Drs. Aurelie Najm, David Liew and Jonathan Kay
Transcription
Hello everyone. Welcome to RheumNow's review of Rheumatoid Arthritis at UR twenty twenty four. I convened a panel of friends and discussants, all of whom were involved in covering rheumatoid arthritis at the meeting, to hear their take on some of their favorite abstracts that concern rheumatoid arthritis and the drugs that we use in rheumatoid arthritis. We're going to go a few rounds, have an interesting discussion. I hope you've enjoyed these panel discussions.
I certainly have. I'm Jack Cush from Dallas, Texas. I want my friends to introduce themselves. Let's begin with Orly.
Hi everyone, I am Orly Naj from Glasgow. Nice being here with you tonight.
And David?
Dave Liu, Melbourne, Australia.
And Doctor. John.
Jonathan K, Worcester, Massachusetts, United States.
We are covering the globe as we cover rheumatoid arthritis. This is what RheumNow does, I guess. So, again, the rules are there's no bedding, there's no cursing, there can be drinking, you know, is after hours. There you go. John's got a glass that looks like it's full of vodka or water.
Water. Yeah. We know it's not one of your vices. Okay, let's begin with David Lewis. Well, let's begin with orally first.
All right, yeah. So I wanted to talk to you guys about the amplified study. I don't know if you've heard about the amplified study. The amplified study was following a smaller study, which was the ample study. It's a study in rheumatoid arthritis, and it's looking at patients that are inadequate responders to methotrexate.
But most importantly, it's those people that we do believe might respond back to some drugs, especially those carriers of the shared epitope and those people with drowsy or positivity. And so in that ample study which was not the one presented but the one that kind of gave birth to amplified. It seemed that people with carriers of shared Epitope and Drowsy or positivity would respond better to a better set. In a small head to head trial against adalimumab. And that gave birth to this phase three randomized controlled trial with over 300 patients.
All positive for both act as in rheumatoid factors and sixty five percent of them carriers of the shared epitope. And the idea was abatacept is gonna do better.
Before you get into the meat of it, I wanna do a little prelude. Yeah. That there have been, I don't know, five, six, seven studies that make the claim that if you're seropositive, you're going to respond better to apertussia than to comparator biologics, including TNS. And I would say there are a number of studies, majority studies, but they're not a double blind randomized control trial like amplified and ample work. And these are either observational cohorts, retrospective analyses, and a few open labels.
And then there are some data that actually argue this point. So the question of why amplified was done is to really nail home this issue that maybe you do get an advantage to use abatacept in patients who are strongly seropositive. Go ahead, Doctor. Nen.
Yeah, no, absolutely. From a physiological, physiopathological point of view, it does make sense, doesn't it? But yeah, so over three hundred patients, all jaws are positive, sixty five percent carriers of the shared epitope. And they looked at week 24 who were the best responders using ACR fifty and big disappointment actually because what we saw is that the response was actually very similar in both groups was roughly sixty percent. They did then look at the DAS response and again, there was absolutely no difference and so what it's telling us is that at least in these patients that are bio naive because you know, it might be that if you go to a population that has failed a few a few biologics, then you might have a different, you know, outcome but what it does seem like is that in this trial, at least there was no difference between a and and and and they did look, they did stratify by levels of ACPAs and they looked at that specific group that have very high levels that ACPAs have baseline and they did seem to respond better at least numerically but I think because the numbers were a bit a bit smaller that when they did they showed trends.
But you know, how high is high ACPAs? You know, is is the question as well.
Well, think the entry into this was maybe three times upper limit normal, which is not gigantically high, obviously. So I want to ask the others, has this study changing your mind at all about the abatrazole seropositivity story? David?
Yes. So I mean, I remember seeing these the high level numbers for this before the meeting and thinking, geez, well, that's really disappointing, isn't it? Because I think we were hoping maybe this might be one of the few biomarkers that we had accessible in terms of picking preferred biologic or targeted synthetic agent off the basis of the tests that we conventionally do right now. And that's, you know, simply was a swing and a miss. And I'm sure that orally we'll talk about synovial biopsies coming up.
And I think something like an R4RA has given us a little bit of hope that we might be able to do something else, but we're still chasing this elusive idea that maybe we can try and figure out which of the many different agents that we have might work better than another. And I feel like it's, you know, here we are fifteen, twenty years later after having had eight different biologic agents in rheumatoid arthritis, and we're still here. So I believe these data, I think, you know, you can stratify out, you know, the plausibility is there. And I did a video on this earlier in the week, you know, you can pin as much as hope as you want on the plausibility, but ultimately the data has to speak for themselves. I think the other thing that we can talk about related to this is a data from Erlangen with the rituximab plus a beta set with or versus just rituximab being a bust as well.
I think that speaks to the difficulties that we have.
Yeah, that's a sequential trial. Actually, a combination trial showing, again, as you said, no real benefit to that combination. John, what do you think of this data?
Well, I believe the data, but it's essentially a recapitulation of the AMPLE trial in terms of the seropositivity. Yes, it would be nice if there were a marker. But ACPA is a heterogeneous group of autoantibodies. There are fine specificities. And this study did not look at the fine specificities.
It certainly would be underpowered to identify a single ACPA, antisitroinated protein, specificity that might be predictive. But it might be that a subset of antisitroinated protein antibodies, might be predictive. So I wouldn't I wouldn't hang up the towel yet, on this approach, but it would be low yield to keep chasing after a dead horse. I think that what we've seen is that clinically abetacept and ailinumab are similar in terms of their efficacy. In terms of ample, every single outcome measure was superimposable at all time points over two years.
And we're seeing that here. This study, the shared epitope population was a subset of the patient population, and probably the study was underpowered to be able to detect superiority of shared epitope and certainly double dose shared epitope compared to shared epitope negative.
It was actually powered for the shared epitope population, but not for the double positive one, just for the one or two LLs.
Interesting. Again, disappointing in that it's a negative result. Doctor. Liu, what do you have?
I want to talk a little bit about, well, I mean, if I was going to really nominate my own highlights, I just want to make mention of the debate I had with Janet Pope. It's not every day you get to debate someone like Janet Pope at Yuli and we debated Jack Inhibitor Safety, which is a lot of fun. And I just want to reassure all of our listeners that Janet and I are still friends. We had dinner on Friday night. We hugged it out.
So despite the fact that yes, yes, I won, like the, that we hugged it out and it was all okay. But I wanna talk a bit about depression and rheumatoid arthritis. Well,
wait, wait, wait. Is it gonna say that you won? What view did you back that gave you a winning vote by the audience compared to Janet's? What were, again, what side did you take?
Well, I was saying that the warning wasn't, the data did not support the warning. And to be clear, so we had a vote at the beginning and the crowd thought it was fiftyfifty right on the dot and we swung it out to 60 something percent. And if we've learned anything in recent years from politics in recent years, it's that a couple of percent swing can mean all the difference. So I'm going to claim a victory here. I'm very much going to claim a victory.
Again, debate was to look at the regulatory recommendations from all the countries stemming from the oral surveillance and were they appropriate? And should we pay attention to them? That was Janet's point of view. Doctor. Liu got to argue that it's much ado about nothing.
I mean, there's a message there, but maybe it's overblown and the audience did sway a little bit that way. But nonetheless, I will say that in the voting that we did do, the audience did indicate that this is still a concern. And we know that this issue going on two, three years now out, it's still a concern that we still need to, I think, have frequent discussions on. But go ahead, David, you were going to say another report.
Yes. Well, this is Polish, there was a Polish cohort which looked at depression in rheumatoid arthritis patients. And I think it probably speaks to the issues that we've got. So under two percent had a formal diagnosis, but over twenty percent had low mood on HAC. But then you'd see as well that low mood is associated with and maybe this isn't news, but low mood is associated with higher DAS-twenty eight increased swollen joints and increased tender joints, of course, patient VAS scores.
What are we doing in practice to really try and identify low mood and depression in our patients and actually really try and you see that as something we can lever off in a world where we've kind of had diminishing returns, I think potentially on the incremental improvements we've had for rheumatoid arthritis patients. That I think is a question.
Yeah. I like these abstracts because they are reminders of this major problem. Was it last ACR that the abstract, I think from a Dutch group showed that there was an incredibly high mortality in RA patients who had depression. I think the point is that we don't do this. If Ted Pinkus and Fred Wolf beat you up in the 80s and 90s to do a health assessment questionnaire on every patient, every visit.
These data, seem to come up every other month, should be enough that you should be doing a short form screen for depression in all your patients at every visit. I know I'm hard at doing it. I think it's important.
In the presentation about the Canadian cohort that looked at predictors of difficult to treat rheumatoid arthritis, depression was one of the predictive features.
Sure. Yep. It's one of the key elements in other studies to this non inflammatory refractory RA population, Nira, as opposed to the other difficult to treat RA population called Pira, which is a persistent inflammatory. Meaning that if they're not responding, they either have information or they don't, and the ones that don't have depression, fatigue, widespread pain, a number of other factors that are in play. Yeah, I think we need to pay more attention to this.
I think it's good that you bring this out as an important abstract from the meeting.
If I can just highlight a presentation that I gave last year at Milan, presentation looking at women with postpartum depression. Women with inflammatory arthritis had a significantly increased risk of postpartum depression compared to matched controls, women without inflammatory arthritis. It's very important for us to address depression and to identify patients with depression and start treatment.
Agreed. Okay. All right. Doctor. K, what's one of your favorites?
Well, I have lots of favorites, but Kevin Winter wins again. Kevin is our infectious disease specialist to the rheumatologists, And he looked at vaccination with recombinant herpes zoster vaccine in patients with rheumatoid arthritis treated with upadacitinib and methotrexate, and found that without stopping the upadacitinib, both humoral immunity and cell mediated immunity were fine. He then looked at a population of patients, 35 individuals in a study who were of patients being treated with abadacept. And about, eleven of these thirty five patients were on concomitant methotrexate. The remaining, twenty four were not.
And they had no cell mediated immunity when they continued the abatacept at the time of vaccination. So contrary to the recommendations for COVID vaccination, where we're told to stop the methotrexate for one to two weeks after the vaccine to optimize immune response to vaccination and to hold the JAK inhibitor for seven days after vaccination, continuing methotrexate and upadacitinib after the vaccine dose seemed to have no deleterious effect. So it points out, first of all, we know that herpes zoster is increased in individuals taking JAK inhibitors, So it's very important to have them immunized. And even if you started the JAK inhibitor, you can go ahead and give them the two doses of recombinant zoster vaccine without having to stop the JAK inhibitor or their methotrexate and still achieve adequate, immune response. However, on abatacept, which is a drug that we've been talking about a lot, abatacept, because of its interference with T cell co stimulation, inhibits the cellular cell mediated immunity to the zoster vaccine and also reduces, but does not completely ablate the humoral immune response.
You know, I was on a panel with Kevin and a bunch of other rheumatologists to develop some teaching slides on vaccination practices. This would have been going back about eight or nine years ago, really before the JAKs appeared. The overwhelming takeaway from that panel was methotrexate is the bad player. That methotrexate really impairs cellular and humoral responses almost in every study. The other bad players would be rituximab and then very high dose steroids.
But all the other drugs including abetacept, IL-six inhibitors and all the TNFRs look great as far as vaccine response. They're mainly looking at pneumococcus and influenza were the main studies that we looked at. I've always been of the opinion that methotrexate is a big culprit here and the big surprise with Kevin's research is that not that they did well on OOPA, but that they did well on OOPA and methotrexate. And that I find surprising. But maybe an element here of the methotrexate plus the reason you're given methotrexate, meaning they're not well controlled and maybe if they're on a JAK inhibitor and a methotrexate, they get better, faster control and inflammation.
Control inflammation allows for better vaccine responses. Kevin did a report from last ULAR, I want to say that was on TOFA. No, it wasn't him. He had another report, but there was another report from, I want to say Norway, where they looked at patients on JAK inhibitors and showing that around thirty percent, forty percent who were on JAK and got a zoster vaccine did not have a good response. This is still a dicey area.
I find that this is encouraging, but I'm still going to hold for a week when I'm on methotrexate regardless of what vaccine I'm doing, mainly because of the park data that was a ACR presentation from plenary, and then his repeat data that showed you don't need to wait two weeks, you're going to just do one week. John, do you think that this data from Kevin is going to change your practices?
It makes me a little bit less uncomfortable if the patient continues their JAK inhibitor. If they're on abetacept, I will definitely instruct them to withhold it probably for two weeks after vaccine and to try to time the vaccine if they're getting it monthly halfway in between the two doses. I feel a little bit less uncomfortable with, vaccination in individuals taking a JAK inhibitor. I wouldn't say I feel more comfortable, but I definitely feel uncomfortable with the potential response of a patient's on abatacept and continues the abatacept around the time of vaccination.
I'm sorry to talk too much on this, but I get really excited on this subject. I know David is also chomping at the bit here. But the other important thing is that these people got vaccinated on a JAK inhibitor. They're already on the OPA and they got vaccinated. Isn't that right?
Yep, Which I make people very concerned. Do I have to stop the JAK and then give the vaccine? So I think that's an encouraging aspect of the study as well. David, And
I would just make the comment that because the JAK inhibitors in individuals who respond are so effective and stopping them leads to flare of disease relatively quickly, it's not great for the patient taking the JAK inhibitor to have to stop it from vaccination.
Exactly. Other comments?
Oh, mean, I think I would really love us to see data with JAK inhibitors plus withholding methotrexate. I know when you're doing a sub study in select compare, can't just go about randomly withholding methotrexate for things like vaccination sub studies. It would be clearly very useful data that would inform our practice with the idea that plausibly, you know, we've seen a lot of correlates between influenza vaccination and the patterns that we see there and COVID vaccination and possibly zoster vaccination as well. But I mean, surely, as much as you know, maybe we were a little bit surprised by the Batacet results, that lack of cellular, the complete lack of cellular response from a Batacet, I mean, that is really disappointing. We've got to try and find better ways.
You got to wonder whether withholding a Batacet for a week or two might not help to improve the immunogenicity. I wonder what people think about that.
Well, I knew I'd like to see the study rather than guess. Orly, does this is this going change your practices at all?
Yeah, well, I don't, to my opinion, it doesn't say anything about the metric state. I I would not take any conclusions from that for the methotrexate one, but definitely it just reassures me that anybody that I've already started on JAK that didn't get that, you know, I'm much more confident to give them the vaccine without withholding. But I was just having a look because there was another abstract looking at the pneumococcus vaccine as well, and there were, I was just trying to look into that, they were looking at also withholding metrics, no metrics, and the responses were also quite good. I think it's one of those ones. And also with methotrexate, it doesn't say, is there a dose?
Is there a cutoff dose that over it maybe it impairs the response maybe and they're not. Is there a difference between subcut, oral? That's some of the stuff that I would really like to know more about.
Yeah, the caveats here are many and the nuances in the design of the trials and how many arms you have. And that's why you probably don't see the data that you want because these are difficult trials to do. And you need a cohort of like 10 to 15, at least in each group to get something meaningful. All right, let me ask, go ahead, Orly.
Yeah, going to say I found the pneumococcus one actually. So it was Vaximera, that's how it's called. And they had two seventy patients, and they did vaccine at the time of methotrexate or vaccine and then start methotrexate one month later. And the humoral response, they didn't measure cellular response, was seventy six versus eighty eight percent. So it was good, but it was obviously better if you do vaccine and then you start Right.
Which people I mean,
you'd have to be brave to tell your new RA patient that I'm going to wait four weeks. Know that in the end, the data showed that the steroid utilization was the same. The disease, it should be the same after year. But jeez, I'm not telling my rude new RA patient. Let's just wait four weeks.
Some of methotrexate say, don't worry, guys. But getting me to talk about same.
David brings up a good point. Whenever I brought this up in clinic, we're going give you the influenza vaccine. Hold your methotrexate for two weeks was the message a few years ago. And the concerned look on the patient's face was like, what? Why?
So it got a little better when we said only hold it for skip one dose and a little less protest. But the patients who are doing well on methotrexate sometimes are not too happy about this. Takes a little coaching. Let me give you what I think is a novel little study. It comes from Andres Kirschbaum from Austria, where he studied the effects of geography on placebo response rates in clinical trials.
What he did was review rheumatoid arthritis, double blind placebo controlled clinical trials using an ACR 20 response rate, and they had to be placebo controlled trials. Going back to 1994 and all the way through to 2019, so they had a lot of trials. What they did in the poster was they showed you a map of the world. And in one half of the study, they showed you where all these trials were done. And in 1994, they were pretty much all done in North America, mostly US, a lot in Canada.
Then as you go from 'ninety four, 'ninety five, 'ninety six and go on all the way to 2019, you can see the spread of the clinical trials being done color coded to Western Europe, and then throughout all of the rest of the world, including USSR, Southeast Asia, Australia, and then ultimately even in South America. So it's a much more global. Those of us who do clinical trials know this to be so. It's gotten harder and harder to enroll patients from The United States, that's why companies have had to go global. But then the interesting part of the study is they showed the placebo response rate in all these trials against, and that's on the y axis, against the normalized gross national product of each country.
They had a slope like this such that the countries that had the poorest countries had the highest response rates as high as forty percent, and that the richer countries had the lowest response rate around twenty percent. When we started doing clinical trials back in the 90s, we would see 15%, 20%, 21% response rates. But now we see much higher response rate, 35%. We're wondering, well, that's because they're bringing in all those other countries in the rest of the world that are ruining it. Turns out that that is partially true.
The question is, how is GMP influencing the placebo response rate? My simple explanation is it's a surrogate measure for how many treatment options you really have. In a rich country, you've got a lot of treatment options. If you don't have treatment options, you're less likely to say, Ouch, when they're squeezing on MCP-two because you need to be on something because I don't have the money to afford the drugs in my poor country and whatnot. So I think it's a nice little explanation of what we've observed over time.
Absolutely. Back about twenty years ago, I had looked at a MAP kinase clinical trial that was done in Western Europe and North America for half of the patients, and the other half were in South America. And there was a dose response in the Western EuropeNorth America group. There was no dose response and an incredibly high placebo response rate of almost sixty percent in South America. Now, that might be that the patients there were not compliant with their methotrexate before the study.
And once they entered a clinical study, they were followed more closely and were more compliant with their background medication. Or it might just be the nature of the patients and their response to any kind of treatment.
Exactly. Yeah, this is an interesting phenomenon. Let's go around the horn again. Doctor. Neng.
Yeah, so I'm going to talk about a topic that is close to my heart. I do a lot of research on sinovial tissue. So obviously I couldn't not talk about this oral presentation from the Rome group that presented their study of synovial biopsy and so what they did that they biopsied over 300 patients that were naive, rheumatoid arthritis naive, and they were interested in looking at different levels. Because we know when we did the R4RA study back then, the London group presented and showed that maybe some patients with a specific pathotypes or with a specific type of cell infiltrating their tissue, they were maybe more likely to respond to this or that drug. It was not fully convincing, you know, and and so what they were interested to do in this study was to look first of all whether there were differences in the tissue if you're going to respond to your first treatment to me, you're to get in remission or not And so what they did is they did very basic staining and histology analysis and they did the score called the Kren score, which looks at the amount of inflammation that's in the tissue.
And so what they found makes sense, you know, the less inflammation you've got in the tissue, the more likely you are to respond at six months to your first treatment. Okay, well, until then, that's fine. They they looked into the pathotypes. So, you know, is there more myeloid cells in there? Is there more lymphoid cells in there?
Or is there more of nothing which is what we call the post immune pathotype. There's just not many cells infiltrating. And as opposed to what was shown before that you know the thinking was oh if there's not immune infiltrating the tissue if you immunosuppressive drugs, it doesn't work. Well, actually, they found the complete opposite. If there's not much inflammation and not much cell infiltrating the tissue, people are more likely to respond.
In fact, the response to conventional DMR is 60% as opposed to those with a lot of myeloid cells was with thirty six percent. So, know, we kind of almost doubled there. But they didn't stop there. They then disaggregated the tissue, and they did some flow cytometry and they looked into specific cells population that we know are associated with high chances of reaching remission. And so what they found is you've got a specific subset of macrophages in your assignable tissue, and you got above forty percent of these cells, your odd ratio to be in remission at six months is twenty four.
I mean, what biomarker do we have that gives us a prediction with an odd ratio of twenty four to reach remission? I've never heard of that before. So, you know, I think it's really interesting and I think it's promising. Obviously, it's not ready for clinics just now. But if we were able to, you know, identify some of these biomarker and translate that into bloods biomarker, for example, how powerful could that be?
So I think this is something that I found massively exciting personally.
How early were these patients in their disease course? Were these ten year established disease or were these people in the first four years?
Naive of any drug. So I mean, obviously it doesn't mean that the symptoms started yesterday, you know, but I haven't seen what was the duration of symptoms beforehand. But you can imagine they were pretty early in the course of their disease.
This is different than Petsalis study where they showed that there was a lot of non response basically and all that was related to fibroblasts and stromal cells. It turns out that histology the wasn't nearly as good as differentially expressed genes and that was maybe a little bit more predictive. But this I think is because I think you get them early enough that the synovial biopsy might be more predictive and tell you who's going to response. As you say, an odds ratio of twenty four is a powerful number that should be pursued. But I don't know in longstanding disease, established disease that the biopsy is going to be quite as helpful unless you're dealing with flare situations or whatever.
But this has always been like the Holy Grail of researchers. I played in this for a while as well and I had to move on to something else because I wasn't getting any fame out of that. But don't bang your head against this wall too hard is what I'm going to suggest that this is still what you're going to do.
Yeah. But to my opinion, we know now that the drugs that we give do impact the tissue. And so obviously, if you look at established disease that have already had two biologic, we look at something very different. But also most importantly, I believe that the tissue is fantastic to understand the biology. But I don't know that we're going to use that as a biomarker per se.
I think it's great to give us cues to then maybe move into something more achievable and The
holy grail is knowing a pathotype that predicts that relates to a phenotype, but the pathotype tells you where you need to go in targeted therapy. Because right now we're flipping coins and guessing about what we're going to do. John, what do you think of this data?
I think the data are really interesting. I think that the important thing is to come up with clinically relevant biomarkers. In clinical practice, the average rheumatologist is not going to perform a synovial biopsy and won't be close to a center that can disaggregate the tissue and do flow cytometry and, single cell SEEK or whatever is necessary to come up with this information. But possibly looking at these markers and then trying to understand using deep learning what clinical features might correlate. And we might actually come up not with a hazard ratio of 24, but maybe something like eight, which would be darn good.
So I think it's very promising that this is segregating patients into potential responders versus non responders. And then we should take this and go bring it closer to the clinic with, as you said, more accessible biomarkers.
All right. David, what's your second one for today?
I'll just make I know we're running short on time. I'll make a quick one quick as a clinical pharmacologist in my other life, I just want to make mention of the therapeutic drug monitoring debate. So therapeutic drug monitoring, that process of using drug concentrations to help guide prescribing is a really fascinating Yuli debate. I think all the Yuli debates were great this year. Desiree Van de Heide, who is not a TDM person, was thrown in on the negative side of things.
I think she made some really strong points, which I think probably go at the heart of some of the, I think reasons why TDM hasn't had the same traction in rheumatology compared to say gastroenterology to IBD, where we've seen it really become mainstream. And, you know, she asked questions about, you know, but why, especially when adverse events from TNF inhibitors are low, that we've got many drug choices in rheumatoid arthritis, that we've got low drug prices of biosimilars, and overall we have little to gain from trying to optimise drug dosing, especially when it comes to escalating. So Gochan Valpnik, who's I think the godfather of rheumatology TDM did say one way to get rid of TDM is to get more drugs and that's what we're doing. And it's true that, you know, we've had all these new drugs from rheumatoid arthritis that mean that the proportion of, we've had to work less and less hard for our outcomes in terms of choosing a therapy. Some of the outcomes outside of that are things that we need to be working on, but we just cycled through therapies instead of trying to optimise doses.
And that makes it a lot, I can think less appealing to do TDM. But potentially the benefits in my mind, and this is my kind of editorialisation of this, is I think there'll be other settings. Maybe, you know, if we are insistent on trying to reduce doses in some people of biologic agents, then one of the ways to do that might be TDM because you're coming down the sharp side of the concentration effect curve. You're kind of getting to the bits where actually concentration might make a difference. Things like that are going to make a lot of sense in terms of TDM.
But right now it's probably been hard for us to pitch in a reason why given that high concentrations haven't seen to consistently lead to better outcomes haven't seen seem to consistently lead to toxicity. And we're really struggling to be able to make an argument as to why you should do drug concentrations for your TNF inhibitor treated rheumatoid arthritis patients.
So I assume Desiree won the debate.
Yes, but by small percentages again, you know, but small percentages win, just to mention that to Janet once again.
Well, certainly wins elections. So we'll take it in debates as well. All right, that's cool. John, what's your last one?
So my last one is two posters from Thomas Hugo's department in Lausanne, Switzerland. Posters 451607. Four fifty one looked at finger pad or finger fold distance. And we have these folds over our fingers that go horizontally, the width of the finger and the distance between the folds increase, the distance increases with joint swelling. So for remote patient monitoring, it would be helpful to be able to take photographs using an iPhone or another digital device and then to analyze these.
And so Thomas Hugo, who's very involved with artificial intelligence in rheumatoid arthritis and other rheumatologic diseases, has developed this app, where they can take the photograph of the PIP joints of the second, third, and fourth digits, and then measure the distance between the finger folds and the ratio of the distance to the width of the finger fold and come up with numbers. It's not yet reliably predictive of joint swelling, but certainly is a start and promising as one of the potentials for remote patient monitoring. The other poster looked at their Mephisto program, which is an app where you take a brief video of a patient making a fist five times as rapidly as they can, and then that uses geographic localization of the fingers and measures flexion angles and rate of movement. And as patients have more inflammation, their ability to make a fist slows down and their angles are limited. And if their disease gets better, they can do it much faster.
And their excursion is a larger distance. So I thought that these were both rather clever and potentially applicable to remote patient monitoring. And as we go more to telemedicine and having the ability to directly examine the patient's joints with your fingers using these technologies may be useful in assessing disease activity.
It's very cool to watch these in play. It's almost like technology becomes the shiny rock that we're drawn to. The question is, will we actually use it and can you integrate the data? What was good about the Mephisto was that they actually did like a cohort from three centers, 80 patients, they did clinical assessments and then they did the range of motion like this. They showed good correlations, reasonable correlations with HAC scores and also with dash 28 measures as well.
Suggesting it could be a useful tool in outpatient assessment. The one thing I've heard especially during COVID and as a big believer in telemedicine is that most people, they didn't know how to assess patients by video or over the phone. I've got two videos on how to do the virtual joint exam that I think are highly instructive. It's not for everybody and every patient, but to say you can't do it and then not do it, you're missing out on opportunity. Here are tools that will make you better.
So this is cool. It's got a wow factor to it. That's all you can say. He showed you basically use a cell phone and to take the pictures for the finger folds and the cell phone to do this kinetic assessment of joint movement and flexion specifically. Again, measured PIP and DIP, not MCP activity all that well, but still.
Yeah. Remember I was sharing a session where he was presenting that last year at EULA and I was quite interested, you know, to know how discriminative it can be for osteoarthritis because these people also have kind of swollen in just a different type of swollen. So that's something I'd be because osteoarthritis is much more common than the RA. So that's something I'd be quite keen to kind of know.
But
that's an important point. And I don't see these tools as being used in isolation. I see them as being part of a panel of digital tools and with validation in patients with osteoarthritis and those with rheumatoid arthritis and those with both. A couple of different assessments will perhaps be able to ferret out what is osteoarthritis and what's rheumatoid arthritis.
The people
Can I just shout out Go
ahead, David?
I just wanna say, I just read an article on the RheumNow website about caution, how we approach new technologies and how we try and consider them and the caution that we need to have, the rightful caution that I think we need to have. And this is someone who is a believer and I think sees enormous potential in computer vision and trusts Thomas Hugo to be able to try and figure out the right path. But go check that out on the RheumNow website.
Okay. My last one is going be real quickie about palindromic rheumatism. The study from Leeds, one hundred and sixty one patients who were largely DMARR naive, followed for three years and as you know palindromic comes and goes. What they did show is that over time with a mean of three years follow-up, a third of patients progressed from palindromic disease to chronic inflammatory arthritis with about ninety plus percent of those meeting criteria for RA. One, it gives you a number.
Two, they also showed like a lot of the other preclinical RAs, clinically suspect arthralgia reports that we had from this meeting, that you can stratify patients by risk factors and there's a score. The score is based on whether you have, what your age is, whether there's rheumatoid factor, whether there's smoking, whether it's CCP, and you get a score in patients who have more risk factors for developing RA, guess what? Develop RA and with really high predictive value. I liked it because it's about something we don't talk much about. I liked it because after looking at this and scratching my head a few times, I thought palindromic RA really is preclinical RA.
We know patients and we always thought that if they're seropositive, that they're probably going to progress than not. It clears up for me what it was the enigma of palindromic rheumatism, and maybe it needs to be included. What we really need is a big nosology and classification system for preclinical RA, clinically suspect arthralgia, etc. Because we're certainly getting closer to developing the risk factors for progression to chronic inflammatory arthritis. Well, I want to thank our discussants for bringing to light some really hot topics in rheumatoid arthritis care.
We appreciate your tuning into these panel discussions and we'll do it again at ACR. David, Norley, John, thank you very much.
Thanks, Jack. Good seeing
everybody. Thanks everyone.
Right. Bye.
I certainly have. I'm Jack Cush from Dallas, Texas. I want my friends to introduce themselves. Let's begin with Orly.
Hi everyone, I am Orly Naj from Glasgow. Nice being here with you tonight.
And David?
Dave Liu, Melbourne, Australia.
And Doctor. John.
Jonathan K, Worcester, Massachusetts, United States.
We are covering the globe as we cover rheumatoid arthritis. This is what RheumNow does, I guess. So, again, the rules are there's no bedding, there's no cursing, there can be drinking, you know, is after hours. There you go. John's got a glass that looks like it's full of vodka or water.
Water. Yeah. We know it's not one of your vices. Okay, let's begin with David Lewis. Well, let's begin with orally first.
All right, yeah. So I wanted to talk to you guys about the amplified study. I don't know if you've heard about the amplified study. The amplified study was following a smaller study, which was the ample study. It's a study in rheumatoid arthritis, and it's looking at patients that are inadequate responders to methotrexate.
But most importantly, it's those people that we do believe might respond back to some drugs, especially those carriers of the shared epitope and those people with drowsy or positivity. And so in that ample study which was not the one presented but the one that kind of gave birth to amplified. It seemed that people with carriers of shared Epitope and Drowsy or positivity would respond better to a better set. In a small head to head trial against adalimumab. And that gave birth to this phase three randomized controlled trial with over 300 patients.
All positive for both act as in rheumatoid factors and sixty five percent of them carriers of the shared epitope. And the idea was abatacept is gonna do better.
Before you get into the meat of it, I wanna do a little prelude. Yeah. That there have been, I don't know, five, six, seven studies that make the claim that if you're seropositive, you're going to respond better to apertussia than to comparator biologics, including TNS. And I would say there are a number of studies, majority studies, but they're not a double blind randomized control trial like amplified and ample work. And these are either observational cohorts, retrospective analyses, and a few open labels.
And then there are some data that actually argue this point. So the question of why amplified was done is to really nail home this issue that maybe you do get an advantage to use abatacept in patients who are strongly seropositive. Go ahead, Doctor. Nen.
Yeah, no, absolutely. From a physiological, physiopathological point of view, it does make sense, doesn't it? But yeah, so over three hundred patients, all jaws are positive, sixty five percent carriers of the shared epitope. And they looked at week 24 who were the best responders using ACR fifty and big disappointment actually because what we saw is that the response was actually very similar in both groups was roughly sixty percent. They did then look at the DAS response and again, there was absolutely no difference and so what it's telling us is that at least in these patients that are bio naive because you know, it might be that if you go to a population that has failed a few a few biologics, then you might have a different, you know, outcome but what it does seem like is that in this trial, at least there was no difference between a and and and and they did look, they did stratify by levels of ACPAs and they looked at that specific group that have very high levels that ACPAs have baseline and they did seem to respond better at least numerically but I think because the numbers were a bit a bit smaller that when they did they showed trends.
But you know, how high is high ACPAs? You know, is is the question as well.
Well, think the entry into this was maybe three times upper limit normal, which is not gigantically high, obviously. So I want to ask the others, has this study changing your mind at all about the abatrazole seropositivity story? David?
Yes. So I mean, I remember seeing these the high level numbers for this before the meeting and thinking, geez, well, that's really disappointing, isn't it? Because I think we were hoping maybe this might be one of the few biomarkers that we had accessible in terms of picking preferred biologic or targeted synthetic agent off the basis of the tests that we conventionally do right now. And that's, you know, simply was a swing and a miss. And I'm sure that orally we'll talk about synovial biopsies coming up.
And I think something like an R4RA has given us a little bit of hope that we might be able to do something else, but we're still chasing this elusive idea that maybe we can try and figure out which of the many different agents that we have might work better than another. And I feel like it's, you know, here we are fifteen, twenty years later after having had eight different biologic agents in rheumatoid arthritis, and we're still here. So I believe these data, I think, you know, you can stratify out, you know, the plausibility is there. And I did a video on this earlier in the week, you know, you can pin as much as hope as you want on the plausibility, but ultimately the data has to speak for themselves. I think the other thing that we can talk about related to this is a data from Erlangen with the rituximab plus a beta set with or versus just rituximab being a bust as well.
I think that speaks to the difficulties that we have.
Yeah, that's a sequential trial. Actually, a combination trial showing, again, as you said, no real benefit to that combination. John, what do you think of this data?
Well, I believe the data, but it's essentially a recapitulation of the AMPLE trial in terms of the seropositivity. Yes, it would be nice if there were a marker. But ACPA is a heterogeneous group of autoantibodies. There are fine specificities. And this study did not look at the fine specificities.
It certainly would be underpowered to identify a single ACPA, antisitroinated protein, specificity that might be predictive. But it might be that a subset of antisitroinated protein antibodies, might be predictive. So I wouldn't I wouldn't hang up the towel yet, on this approach, but it would be low yield to keep chasing after a dead horse. I think that what we've seen is that clinically abetacept and ailinumab are similar in terms of their efficacy. In terms of ample, every single outcome measure was superimposable at all time points over two years.
And we're seeing that here. This study, the shared epitope population was a subset of the patient population, and probably the study was underpowered to be able to detect superiority of shared epitope and certainly double dose shared epitope compared to shared epitope negative.
It was actually powered for the shared epitope population, but not for the double positive one, just for the one or two LLs.
Interesting. Again, disappointing in that it's a negative result. Doctor. Liu, what do you have?
I want to talk a little bit about, well, I mean, if I was going to really nominate my own highlights, I just want to make mention of the debate I had with Janet Pope. It's not every day you get to debate someone like Janet Pope at Yuli and we debated Jack Inhibitor Safety, which is a lot of fun. And I just want to reassure all of our listeners that Janet and I are still friends. We had dinner on Friday night. We hugged it out.
So despite the fact that yes, yes, I won, like the, that we hugged it out and it was all okay. But I wanna talk a bit about depression and rheumatoid arthritis. Well,
wait, wait, wait. Is it gonna say that you won? What view did you back that gave you a winning vote by the audience compared to Janet's? What were, again, what side did you take?
Well, I was saying that the warning wasn't, the data did not support the warning. And to be clear, so we had a vote at the beginning and the crowd thought it was fiftyfifty right on the dot and we swung it out to 60 something percent. And if we've learned anything in recent years from politics in recent years, it's that a couple of percent swing can mean all the difference. So I'm going to claim a victory here. I'm very much going to claim a victory.
Again, debate was to look at the regulatory recommendations from all the countries stemming from the oral surveillance and were they appropriate? And should we pay attention to them? That was Janet's point of view. Doctor. Liu got to argue that it's much ado about nothing.
I mean, there's a message there, but maybe it's overblown and the audience did sway a little bit that way. But nonetheless, I will say that in the voting that we did do, the audience did indicate that this is still a concern. And we know that this issue going on two, three years now out, it's still a concern that we still need to, I think, have frequent discussions on. But go ahead, David, you were going to say another report.
Yes. Well, this is Polish, there was a Polish cohort which looked at depression in rheumatoid arthritis patients. And I think it probably speaks to the issues that we've got. So under two percent had a formal diagnosis, but over twenty percent had low mood on HAC. But then you'd see as well that low mood is associated with and maybe this isn't news, but low mood is associated with higher DAS-twenty eight increased swollen joints and increased tender joints, of course, patient VAS scores.
What are we doing in practice to really try and identify low mood and depression in our patients and actually really try and you see that as something we can lever off in a world where we've kind of had diminishing returns, I think potentially on the incremental improvements we've had for rheumatoid arthritis patients. That I think is a question.
Yeah. I like these abstracts because they are reminders of this major problem. Was it last ACR that the abstract, I think from a Dutch group showed that there was an incredibly high mortality in RA patients who had depression. I think the point is that we don't do this. If Ted Pinkus and Fred Wolf beat you up in the 80s and 90s to do a health assessment questionnaire on every patient, every visit.
These data, seem to come up every other month, should be enough that you should be doing a short form screen for depression in all your patients at every visit. I know I'm hard at doing it. I think it's important.
In the presentation about the Canadian cohort that looked at predictors of difficult to treat rheumatoid arthritis, depression was one of the predictive features.
Sure. Yep. It's one of the key elements in other studies to this non inflammatory refractory RA population, Nira, as opposed to the other difficult to treat RA population called Pira, which is a persistent inflammatory. Meaning that if they're not responding, they either have information or they don't, and the ones that don't have depression, fatigue, widespread pain, a number of other factors that are in play. Yeah, I think we need to pay more attention to this.
I think it's good that you bring this out as an important abstract from the meeting.
If I can just highlight a presentation that I gave last year at Milan, presentation looking at women with postpartum depression. Women with inflammatory arthritis had a significantly increased risk of postpartum depression compared to matched controls, women without inflammatory arthritis. It's very important for us to address depression and to identify patients with depression and start treatment.
Agreed. Okay. All right. Doctor. K, what's one of your favorites?
Well, I have lots of favorites, but Kevin Winter wins again. Kevin is our infectious disease specialist to the rheumatologists, And he looked at vaccination with recombinant herpes zoster vaccine in patients with rheumatoid arthritis treated with upadacitinib and methotrexate, and found that without stopping the upadacitinib, both humoral immunity and cell mediated immunity were fine. He then looked at a population of patients, 35 individuals in a study who were of patients being treated with abadacept. And about, eleven of these thirty five patients were on concomitant methotrexate. The remaining, twenty four were not.
And they had no cell mediated immunity when they continued the abatacept at the time of vaccination. So contrary to the recommendations for COVID vaccination, where we're told to stop the methotrexate for one to two weeks after the vaccine to optimize immune response to vaccination and to hold the JAK inhibitor for seven days after vaccination, continuing methotrexate and upadacitinib after the vaccine dose seemed to have no deleterious effect. So it points out, first of all, we know that herpes zoster is increased in individuals taking JAK inhibitors, So it's very important to have them immunized. And even if you started the JAK inhibitor, you can go ahead and give them the two doses of recombinant zoster vaccine without having to stop the JAK inhibitor or their methotrexate and still achieve adequate, immune response. However, on abatacept, which is a drug that we've been talking about a lot, abatacept, because of its interference with T cell co stimulation, inhibits the cellular cell mediated immunity to the zoster vaccine and also reduces, but does not completely ablate the humoral immune response.
You know, I was on a panel with Kevin and a bunch of other rheumatologists to develop some teaching slides on vaccination practices. This would have been going back about eight or nine years ago, really before the JAKs appeared. The overwhelming takeaway from that panel was methotrexate is the bad player. That methotrexate really impairs cellular and humoral responses almost in every study. The other bad players would be rituximab and then very high dose steroids.
But all the other drugs including abetacept, IL-six inhibitors and all the TNFRs look great as far as vaccine response. They're mainly looking at pneumococcus and influenza were the main studies that we looked at. I've always been of the opinion that methotrexate is a big culprit here and the big surprise with Kevin's research is that not that they did well on OOPA, but that they did well on OOPA and methotrexate. And that I find surprising. But maybe an element here of the methotrexate plus the reason you're given methotrexate, meaning they're not well controlled and maybe if they're on a JAK inhibitor and a methotrexate, they get better, faster control and inflammation.
Control inflammation allows for better vaccine responses. Kevin did a report from last ULAR, I want to say that was on TOFA. No, it wasn't him. He had another report, but there was another report from, I want to say Norway, where they looked at patients on JAK inhibitors and showing that around thirty percent, forty percent who were on JAK and got a zoster vaccine did not have a good response. This is still a dicey area.
I find that this is encouraging, but I'm still going to hold for a week when I'm on methotrexate regardless of what vaccine I'm doing, mainly because of the park data that was a ACR presentation from plenary, and then his repeat data that showed you don't need to wait two weeks, you're going to just do one week. John, do you think that this data from Kevin is going to change your practices?
It makes me a little bit less uncomfortable if the patient continues their JAK inhibitor. If they're on abetacept, I will definitely instruct them to withhold it probably for two weeks after vaccine and to try to time the vaccine if they're getting it monthly halfway in between the two doses. I feel a little bit less uncomfortable with, vaccination in individuals taking a JAK inhibitor. I wouldn't say I feel more comfortable, but I definitely feel uncomfortable with the potential response of a patient's on abatacept and continues the abatacept around the time of vaccination.
I'm sorry to talk too much on this, but I get really excited on this subject. I know David is also chomping at the bit here. But the other important thing is that these people got vaccinated on a JAK inhibitor. They're already on the OPA and they got vaccinated. Isn't that right?
Yep, Which I make people very concerned. Do I have to stop the JAK and then give the vaccine? So I think that's an encouraging aspect of the study as well. David, And
I would just make the comment that because the JAK inhibitors in individuals who respond are so effective and stopping them leads to flare of disease relatively quickly, it's not great for the patient taking the JAK inhibitor to have to stop it from vaccination.
Exactly. Other comments?
Oh, mean, I think I would really love us to see data with JAK inhibitors plus withholding methotrexate. I know when you're doing a sub study in select compare, can't just go about randomly withholding methotrexate for things like vaccination sub studies. It would be clearly very useful data that would inform our practice with the idea that plausibly, you know, we've seen a lot of correlates between influenza vaccination and the patterns that we see there and COVID vaccination and possibly zoster vaccination as well. But I mean, surely, as much as you know, maybe we were a little bit surprised by the Batacet results, that lack of cellular, the complete lack of cellular response from a Batacet, I mean, that is really disappointing. We've got to try and find better ways.
You got to wonder whether withholding a Batacet for a week or two might not help to improve the immunogenicity. I wonder what people think about that.
Well, I knew I'd like to see the study rather than guess. Orly, does this is this going change your practices at all?
Yeah, well, I don't, to my opinion, it doesn't say anything about the metric state. I I would not take any conclusions from that for the methotrexate one, but definitely it just reassures me that anybody that I've already started on JAK that didn't get that, you know, I'm much more confident to give them the vaccine without withholding. But I was just having a look because there was another abstract looking at the pneumococcus vaccine as well, and there were, I was just trying to look into that, they were looking at also withholding metrics, no metrics, and the responses were also quite good. I think it's one of those ones. And also with methotrexate, it doesn't say, is there a dose?
Is there a cutoff dose that over it maybe it impairs the response maybe and they're not. Is there a difference between subcut, oral? That's some of the stuff that I would really like to know more about.
Yeah, the caveats here are many and the nuances in the design of the trials and how many arms you have. And that's why you probably don't see the data that you want because these are difficult trials to do. And you need a cohort of like 10 to 15, at least in each group to get something meaningful. All right, let me ask, go ahead, Orly.
Yeah, going to say I found the pneumococcus one actually. So it was Vaximera, that's how it's called. And they had two seventy patients, and they did vaccine at the time of methotrexate or vaccine and then start methotrexate one month later. And the humoral response, they didn't measure cellular response, was seventy six versus eighty eight percent. So it was good, but it was obviously better if you do vaccine and then you start Right.
Which people I mean,
you'd have to be brave to tell your new RA patient that I'm going to wait four weeks. Know that in the end, the data showed that the steroid utilization was the same. The disease, it should be the same after year. But jeez, I'm not telling my rude new RA patient. Let's just wait four weeks.
Some of methotrexate say, don't worry, guys. But getting me to talk about same.
David brings up a good point. Whenever I brought this up in clinic, we're going give you the influenza vaccine. Hold your methotrexate for two weeks was the message a few years ago. And the concerned look on the patient's face was like, what? Why?
So it got a little better when we said only hold it for skip one dose and a little less protest. But the patients who are doing well on methotrexate sometimes are not too happy about this. Takes a little coaching. Let me give you what I think is a novel little study. It comes from Andres Kirschbaum from Austria, where he studied the effects of geography on placebo response rates in clinical trials.
What he did was review rheumatoid arthritis, double blind placebo controlled clinical trials using an ACR 20 response rate, and they had to be placebo controlled trials. Going back to 1994 and all the way through to 2019, so they had a lot of trials. What they did in the poster was they showed you a map of the world. And in one half of the study, they showed you where all these trials were done. And in 1994, they were pretty much all done in North America, mostly US, a lot in Canada.
Then as you go from 'ninety four, 'ninety five, 'ninety six and go on all the way to 2019, you can see the spread of the clinical trials being done color coded to Western Europe, and then throughout all of the rest of the world, including USSR, Southeast Asia, Australia, and then ultimately even in South America. So it's a much more global. Those of us who do clinical trials know this to be so. It's gotten harder and harder to enroll patients from The United States, that's why companies have had to go global. But then the interesting part of the study is they showed the placebo response rate in all these trials against, and that's on the y axis, against the normalized gross national product of each country.
They had a slope like this such that the countries that had the poorest countries had the highest response rates as high as forty percent, and that the richer countries had the lowest response rate around twenty percent. When we started doing clinical trials back in the 90s, we would see 15%, 20%, 21% response rates. But now we see much higher response rate, 35%. We're wondering, well, that's because they're bringing in all those other countries in the rest of the world that are ruining it. Turns out that that is partially true.
The question is, how is GMP influencing the placebo response rate? My simple explanation is it's a surrogate measure for how many treatment options you really have. In a rich country, you've got a lot of treatment options. If you don't have treatment options, you're less likely to say, Ouch, when they're squeezing on MCP-two because you need to be on something because I don't have the money to afford the drugs in my poor country and whatnot. So I think it's a nice little explanation of what we've observed over time.
Absolutely. Back about twenty years ago, I had looked at a MAP kinase clinical trial that was done in Western Europe and North America for half of the patients, and the other half were in South America. And there was a dose response in the Western EuropeNorth America group. There was no dose response and an incredibly high placebo response rate of almost sixty percent in South America. Now, that might be that the patients there were not compliant with their methotrexate before the study.
And once they entered a clinical study, they were followed more closely and were more compliant with their background medication. Or it might just be the nature of the patients and their response to any kind of treatment.
Exactly. Yeah, this is an interesting phenomenon. Let's go around the horn again. Doctor. Neng.
Yeah, so I'm going to talk about a topic that is close to my heart. I do a lot of research on sinovial tissue. So obviously I couldn't not talk about this oral presentation from the Rome group that presented their study of synovial biopsy and so what they did that they biopsied over 300 patients that were naive, rheumatoid arthritis naive, and they were interested in looking at different levels. Because we know when we did the R4RA study back then, the London group presented and showed that maybe some patients with a specific pathotypes or with a specific type of cell infiltrating their tissue, they were maybe more likely to respond to this or that drug. It was not fully convincing, you know, and and so what they were interested to do in this study was to look first of all whether there were differences in the tissue if you're going to respond to your first treatment to me, you're to get in remission or not And so what they did is they did very basic staining and histology analysis and they did the score called the Kren score, which looks at the amount of inflammation that's in the tissue.
And so what they found makes sense, you know, the less inflammation you've got in the tissue, the more likely you are to respond at six months to your first treatment. Okay, well, until then, that's fine. They they looked into the pathotypes. So, you know, is there more myeloid cells in there? Is there more lymphoid cells in there?
Or is there more of nothing which is what we call the post immune pathotype. There's just not many cells infiltrating. And as opposed to what was shown before that you know the thinking was oh if there's not immune infiltrating the tissue if you immunosuppressive drugs, it doesn't work. Well, actually, they found the complete opposite. If there's not much inflammation and not much cell infiltrating the tissue, people are more likely to respond.
In fact, the response to conventional DMR is 60% as opposed to those with a lot of myeloid cells was with thirty six percent. So, know, we kind of almost doubled there. But they didn't stop there. They then disaggregated the tissue, and they did some flow cytometry and they looked into specific cells population that we know are associated with high chances of reaching remission. And so what they found is you've got a specific subset of macrophages in your assignable tissue, and you got above forty percent of these cells, your odd ratio to be in remission at six months is twenty four.
I mean, what biomarker do we have that gives us a prediction with an odd ratio of twenty four to reach remission? I've never heard of that before. So, you know, I think it's really interesting and I think it's promising. Obviously, it's not ready for clinics just now. But if we were able to, you know, identify some of these biomarker and translate that into bloods biomarker, for example, how powerful could that be?
So I think this is something that I found massively exciting personally.
How early were these patients in their disease course? Were these ten year established disease or were these people in the first four years?
Naive of any drug. So I mean, obviously it doesn't mean that the symptoms started yesterday, you know, but I haven't seen what was the duration of symptoms beforehand. But you can imagine they were pretty early in the course of their disease.
This is different than Petsalis study where they showed that there was a lot of non response basically and all that was related to fibroblasts and stromal cells. It turns out that histology the wasn't nearly as good as differentially expressed genes and that was maybe a little bit more predictive. But this I think is because I think you get them early enough that the synovial biopsy might be more predictive and tell you who's going to response. As you say, an odds ratio of twenty four is a powerful number that should be pursued. But I don't know in longstanding disease, established disease that the biopsy is going to be quite as helpful unless you're dealing with flare situations or whatever.
But this has always been like the Holy Grail of researchers. I played in this for a while as well and I had to move on to something else because I wasn't getting any fame out of that. But don't bang your head against this wall too hard is what I'm going to suggest that this is still what you're going to do.
Yeah. But to my opinion, we know now that the drugs that we give do impact the tissue. And so obviously, if you look at established disease that have already had two biologic, we look at something very different. But also most importantly, I believe that the tissue is fantastic to understand the biology. But I don't know that we're going to use that as a biomarker per se.
I think it's great to give us cues to then maybe move into something more achievable and The
holy grail is knowing a pathotype that predicts that relates to a phenotype, but the pathotype tells you where you need to go in targeted therapy. Because right now we're flipping coins and guessing about what we're going to do. John, what do you think of this data?
I think the data are really interesting. I think that the important thing is to come up with clinically relevant biomarkers. In clinical practice, the average rheumatologist is not going to perform a synovial biopsy and won't be close to a center that can disaggregate the tissue and do flow cytometry and, single cell SEEK or whatever is necessary to come up with this information. But possibly looking at these markers and then trying to understand using deep learning what clinical features might correlate. And we might actually come up not with a hazard ratio of 24, but maybe something like eight, which would be darn good.
So I think it's very promising that this is segregating patients into potential responders versus non responders. And then we should take this and go bring it closer to the clinic with, as you said, more accessible biomarkers.
All right. David, what's your second one for today?
I'll just make I know we're running short on time. I'll make a quick one quick as a clinical pharmacologist in my other life, I just want to make mention of the therapeutic drug monitoring debate. So therapeutic drug monitoring, that process of using drug concentrations to help guide prescribing is a really fascinating Yuli debate. I think all the Yuli debates were great this year. Desiree Van de Heide, who is not a TDM person, was thrown in on the negative side of things.
I think she made some really strong points, which I think probably go at the heart of some of the, I think reasons why TDM hasn't had the same traction in rheumatology compared to say gastroenterology to IBD, where we've seen it really become mainstream. And, you know, she asked questions about, you know, but why, especially when adverse events from TNF inhibitors are low, that we've got many drug choices in rheumatoid arthritis, that we've got low drug prices of biosimilars, and overall we have little to gain from trying to optimise drug dosing, especially when it comes to escalating. So Gochan Valpnik, who's I think the godfather of rheumatology TDM did say one way to get rid of TDM is to get more drugs and that's what we're doing. And it's true that, you know, we've had all these new drugs from rheumatoid arthritis that mean that the proportion of, we've had to work less and less hard for our outcomes in terms of choosing a therapy. Some of the outcomes outside of that are things that we need to be working on, but we just cycled through therapies instead of trying to optimise doses.
And that makes it a lot, I can think less appealing to do TDM. But potentially the benefits in my mind, and this is my kind of editorialisation of this, is I think there'll be other settings. Maybe, you know, if we are insistent on trying to reduce doses in some people of biologic agents, then one of the ways to do that might be TDM because you're coming down the sharp side of the concentration effect curve. You're kind of getting to the bits where actually concentration might make a difference. Things like that are going to make a lot of sense in terms of TDM.
But right now it's probably been hard for us to pitch in a reason why given that high concentrations haven't seen to consistently lead to better outcomes haven't seen seem to consistently lead to toxicity. And we're really struggling to be able to make an argument as to why you should do drug concentrations for your TNF inhibitor treated rheumatoid arthritis patients.
So I assume Desiree won the debate.
Yes, but by small percentages again, you know, but small percentages win, just to mention that to Janet once again.
Well, certainly wins elections. So we'll take it in debates as well. All right, that's cool. John, what's your last one?
So my last one is two posters from Thomas Hugo's department in Lausanne, Switzerland. Posters 451607. Four fifty one looked at finger pad or finger fold distance. And we have these folds over our fingers that go horizontally, the width of the finger and the distance between the folds increase, the distance increases with joint swelling. So for remote patient monitoring, it would be helpful to be able to take photographs using an iPhone or another digital device and then to analyze these.
And so Thomas Hugo, who's very involved with artificial intelligence in rheumatoid arthritis and other rheumatologic diseases, has developed this app, where they can take the photograph of the PIP joints of the second, third, and fourth digits, and then measure the distance between the finger folds and the ratio of the distance to the width of the finger fold and come up with numbers. It's not yet reliably predictive of joint swelling, but certainly is a start and promising as one of the potentials for remote patient monitoring. The other poster looked at their Mephisto program, which is an app where you take a brief video of a patient making a fist five times as rapidly as they can, and then that uses geographic localization of the fingers and measures flexion angles and rate of movement. And as patients have more inflammation, their ability to make a fist slows down and their angles are limited. And if their disease gets better, they can do it much faster.
And their excursion is a larger distance. So I thought that these were both rather clever and potentially applicable to remote patient monitoring. And as we go more to telemedicine and having the ability to directly examine the patient's joints with your fingers using these technologies may be useful in assessing disease activity.
It's very cool to watch these in play. It's almost like technology becomes the shiny rock that we're drawn to. The question is, will we actually use it and can you integrate the data? What was good about the Mephisto was that they actually did like a cohort from three centers, 80 patients, they did clinical assessments and then they did the range of motion like this. They showed good correlations, reasonable correlations with HAC scores and also with dash 28 measures as well.
Suggesting it could be a useful tool in outpatient assessment. The one thing I've heard especially during COVID and as a big believer in telemedicine is that most people, they didn't know how to assess patients by video or over the phone. I've got two videos on how to do the virtual joint exam that I think are highly instructive. It's not for everybody and every patient, but to say you can't do it and then not do it, you're missing out on opportunity. Here are tools that will make you better.
So this is cool. It's got a wow factor to it. That's all you can say. He showed you basically use a cell phone and to take the pictures for the finger folds and the cell phone to do this kinetic assessment of joint movement and flexion specifically. Again, measured PIP and DIP, not MCP activity all that well, but still.
Yeah. Remember I was sharing a session where he was presenting that last year at EULA and I was quite interested, you know, to know how discriminative it can be for osteoarthritis because these people also have kind of swollen in just a different type of swollen. So that's something I'd be because osteoarthritis is much more common than the RA. So that's something I'd be quite keen to kind of know.
But
that's an important point. And I don't see these tools as being used in isolation. I see them as being part of a panel of digital tools and with validation in patients with osteoarthritis and those with rheumatoid arthritis and those with both. A couple of different assessments will perhaps be able to ferret out what is osteoarthritis and what's rheumatoid arthritis.
The people
Can I just shout out Go
ahead, David?
I just wanna say, I just read an article on the RheumNow website about caution, how we approach new technologies and how we try and consider them and the caution that we need to have, the rightful caution that I think we need to have. And this is someone who is a believer and I think sees enormous potential in computer vision and trusts Thomas Hugo to be able to try and figure out the right path. But go check that out on the RheumNow website.
Okay. My last one is going be real quickie about palindromic rheumatism. The study from Leeds, one hundred and sixty one patients who were largely DMARR naive, followed for three years and as you know palindromic comes and goes. What they did show is that over time with a mean of three years follow-up, a third of patients progressed from palindromic disease to chronic inflammatory arthritis with about ninety plus percent of those meeting criteria for RA. One, it gives you a number.
Two, they also showed like a lot of the other preclinical RAs, clinically suspect arthralgia reports that we had from this meeting, that you can stratify patients by risk factors and there's a score. The score is based on whether you have, what your age is, whether there's rheumatoid factor, whether there's smoking, whether it's CCP, and you get a score in patients who have more risk factors for developing RA, guess what? Develop RA and with really high predictive value. I liked it because it's about something we don't talk much about. I liked it because after looking at this and scratching my head a few times, I thought palindromic RA really is preclinical RA.
We know patients and we always thought that if they're seropositive, that they're probably going to progress than not. It clears up for me what it was the enigma of palindromic rheumatism, and maybe it needs to be included. What we really need is a big nosology and classification system for preclinical RA, clinically suspect arthralgia, etc. Because we're certainly getting closer to developing the risk factors for progression to chronic inflammatory arthritis. Well, I want to thank our discussants for bringing to light some really hot topics in rheumatoid arthritis care.
We appreciate your tuning into these panel discussions and we'll do it again at ACR. David, Norley, John, thank you very much.
Thanks, Jack. Good seeing
everybody. Thanks everyone.
Right. Bye.
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