Biologic Milestones & Future Treatment of RA Save

Hello everyone. Welcome to Tuesday Night Rheumatology. I'm Jack Cush with RoomNow. Tonight, we're going to be discussing what's happened in the last two decades as far as treatment of RA, what we're calling biologic milestones and future treatment of RA. And I'm joined by a great group of friends, panelists who will be helping us sort of decipher where we've been and where we're going.

I'm going to ask each of us to introduce ourselves. I'm Jack Cush in Dallas, Texas. I'm joined by Katherine.

Hi everyone, I'm Katherine Li. I'm a rheumatologist at Brigham and Women's Hospital, VA Boston Healthcare System and Harvard Medical School.

Stan. Yeah, hi, I'm Stanley Cohen. I'm a rheumatologist in Dallas, Texas like Jack and I'm at Presbyterian Hospital in Dallas and run the teaching program for the residents.

And Jeff. I'm Jeff Curtis.

I'm a rheumatologist at the University of Alabama at Birmingham.

Okay. In this TNR, we're going to look at what you've done to help us discuss this issue. To do that, we have done surveys of rheumatologists to ask their opinions. I'm gonna show you some of them to start with. Actually, before we actually did the surveys with the RoomNow audience, I did a Twitter poll overnight and I asked, what's the greatest healthcare advantage in the last twenty years?

And your answers were sort of very much in favor of biologics. And this was just meant to be a general medical kind of question to a rheumatology audience. But clearly, biologics have been at the forefront of what we've been doing and how we practice. Biologics are important part of the DMARD arsenal that we have. So what we did, the objectives of this particular program was to survey rheumatologists about what's happened since biologics have been introduced, what's happened to your practice and whatnot, and then ask you how you practice and maybe where you're going in the future.

So we did three weekly surveys on RheumNow. The first one was at the July and the next two were early August. And you can see the first one had four fifty eight responses, almost half from The United States. The next two had either two forty two or two thirty three responses. And that's just with one email one day with over 60% being from The US.

And you can see we're getting a range of possibilities here as far as what topics we're gonna cover. And it turns out when I did all the analysis on these survey results, not much difference between US and outside of US, okay? So here's the demographics of those who responded bottom left, 61% male, sort of a bimodal distribution, two thirds were either kind of old and kind of young, 43% were in practice more than twenty years. That's me and Stan. And then 20% or 15% were less than five years up to ten years.

That's Catherine. Jeff, you're in that group, I would assume. So you can see we have a fairly good representation. Where are they from as far as practice? Two thirds are from private practice, a quarter from academic centers.

And then where were they in the world? A third or 36% were outside The US, but of the two thirds in The US, you could say it was mostly really where the distribution of rheumatologists is, which is sort of Northeast, East Coast, West Coast and a little bit in the middle. So it's Southeast, Southwest, West And Mid Atlantic makes up the majority of people. The vast majority of respondents were rheumatologists, but in different surveys, was three-six percent were nurse practitioners. Then when I asked the rheumatologists, do you use nurse practitioners?

This is what they answered. Half of them are working with one to two nurse practitioners in their group or their practice. Only 15% have no nurse practitioners or physician assistants. There's 12% that's got five or more. I would assume those are big centers or academic centers.

But I find this is a big shift in what has gone on in the past, where 30 to 40% of people in practice weren't working with advanced practice providers. And then we asked you, the audience about where you were in your career. A third said that I'm at a point where I'm really seasoned, I have greater knowledge and experience. Unfortunately, 23% said that they're burnt out. And 20% are just getting started and the other 13% were just starting to grow a practice.

So again, there's kind of a diverse representation here, which is kind of what I was hoping for. And now we're going to get into some of the questions and whatnot. But anybody have a comment on the demographics of the respondents? Not much to talk about really. All right.

So I wanted to get into what are the big things that have happened in the last twenty years? And before I show you the questions on that, I want you to know that when I was a fellow in 'eighty eight, was this guy at Stanford named Jim Fries, who is famous for the RMS database and patient reported outcomes. Jim did a survey of almost 500 rheumatologists, think it was. He called it milestones in rheumatology. In 1988, the milestones as chosen by your peers, which would have been Stan and I, was the greatest things that changed outcomes in RA was joint replacement, early aggressive treatment, methotrexate.

Methotrexate being the new thing on the block, having been introduced in 'eighty '4. 2008, that changed. I repeated this. Now the top aggressive treatment TNF inhibitors and methotrexate. Joint replacement dropped to actually ninth place.

We asked this question of our audience and we said, what advancement has had the greatest impact on RA care? And biologics, just like that previous survey was sixty one percent, methotrexate thirty one percent, and everything else is just a drop in the bucket. Is anybody surprised by these results, Dan? What do you think?

No, I mean, there's no question that the sea change that happened in 1998, 1999 dramatically improved outcomes for our patients. Prior to that, we did a very poor job. And prior to the 1980s when we first started playing with methotrexate, was a real problem to manage these patients. So I totally agree. Biologic targeted therapies have made a huge difference.

And the other thing was the early aggressive treatment. We've delayed treatment back when I was a trainee. My chief of rheumatology told me to hold treatment, which turned out to be totally incorrect. So I think those are the two major advances over the last many years.

What do you think of the fact that, joint replacement surgery is no longer held in high regard by rheumatologists, Jeff? I mean, it really the biologics that are to blame or are they really not that important?

No, I expect so that we can credit the biologics with that. I think physicians who trained in a different era have a different expectation of normal. And if you trained in a pre biologic era, it wasn't that uncommon that you saw a whole bunch of people in wheelchairs and that had, you know, assistive devices and that were on their second or third artificial joint. And I think people who have been trained and grown up with biologics just aren't used to seeing that. And some of the extra articular manifestations that, you know, rheumatoid cachexia, that's not much of a common thing anymore.

So I think that or joint replacement surgery, obviously not a thing of the past, but much less common. And I think biologics are largely due as to be credited for that change.

In both 1988 and in 2008, and those other surveys, cost of care was a major disappointment for all rheumatologists. It's still on the list on the right being maybe the second most common, but they're really split on what is most disappointing. One is no predictive genomics or biomarkers was the most common unpredictability as far as drug responses and lack of timely referral. Catherine, what do you think about these opinions? Are they really representative?

Yeah, I think so. If I were to talk about research, a lot of effort in rheumatoid arthritis right now is finding predictors of treatment response. And I think the field is changing. I think there's a lot of promise, maybe you'll talk about it later in the types of data we now have available to us. To comment on the cost of care, I'd say I agree with that.

One of the big changes that came out was the introduction of biosimilars, but we did not see costs come down after that.

Yeah, we're gonna talk a little bit about biosimilars, but does anybody wanna address the issue? Clearly we have a growing use of biosimilars now and we have many, many choices and they ultimately become adopted. But do we have clear data about how much money we're saving on biosimilars or whether it's really expanding the use of biologics like it was supposed to?

I think it is in the rest of the world, Jack. But it's very hard to follow the money in our arcane health care system. I mean, you would expect with the reduction in the cost of these medications that the only way we're going to see, number two things, patients should have no copay if the medication costs less, which is not the case. And our premiums should come down, which is never going to happen. So at least in The United States, the answer is we don't know.

But the rest of the world, clearly, the cost has come down substantially in those countries where governments buy the medication and distribute

Jack, although Jack, I might quibble a little bit. Who is the we even in The United States? I think biosimilars have probably saved money for somebody, just not patients, and they certainly haven't made rheumatologists lives easier. If anything, it's more complicated because we need to know, you know, what's the adalimumab biosimilar du jour that your patient's insurance company wants them to be on this month or this quarter. But I do think probably some cost savings have been realized, but it's mostly for insurance companies and not the people who maybe were most interested in it saving money for which is patients.

And we do need to know what the Dejure biosimilar is because we have to explain it. We have to explain those four letters after adalimumab. We have to explain why it was one pharmacy sick last year and now it's a new pharmacy this year, but it really is the same drug. Oh my goodness, complicated. Next survey question has to do with what's changed and how we treat RA and what changes have you seen?

Here's some historic data both from the world of juvenile idiopathic arthritis and RA and Jeff has been involved in these studies and as a co author on them. But you can see the trends and they both go from 2,000 to roughly 2022 or 2021. And the top line is always the DMARDs, conventional DMARDs. Again, leflunomide methotrexate hydroxychloroquine. Obviously they dominated the market at the turn of 2000, but they have steadily come down and dropped either 40, 30 points here in JIA and in RA, it looks like they've dropped at least 20 points as well.

And why? Well, it's obviously the growth of a biologic DMARC class in both JIA and also here in RA. And then the advent of JIA, we see other biologics, this other dotted line down here starting in 2005. But then really the advent of JAKs, which slow uptake in JIA, but bigger uptake in adults. So now we ask the question of the audience, that two to four fifty in the last twenty years, what drug are you using more of?

And they say biologics, methotrexate and JAKs. This is sort of according to script. I do think that that's kind of true. I'll tell you there's another question I asked the audience, which is, what's the last RA patient you treated, what drug did you prescribe? Sixty percent said methotrexate and then ten percent each it was an IL-six inhibitor, a JAK inhibitor or another biologic each.

So this is kind of representative, although I think it may overstate the patient to patient important to Jack, but that's what people are answering. So I thought that was interesting. Then we asked them, how has your biologic or new therapies changed in the last year? Like how are you using these drugs differently? More than half said they use it earlier, biologics earlier.

Almost twenty percent say, I know how to use these drugs, like trust me, I know what I'm doing. And nine percent say they're using less TNFs and more MOAs. So it's not so clear that there's a lot of jump to other MOAs. But anyway, Katherine, what's your opinion of this data?

Yeah, I think it really reflects what we've been seeing and it reflects what the data are showing, earlier aggressive therapy, earlier biologic use. And based on society guidelines, it's usually methotrexate followed by TNF.

Jeff, do you think that this reflects some of the claims data analyses that you've been an important part of?

Well, I think it does, but honestly, I was a little bit bothered by this. You know, why are CSD marks flat or even going down? And that's been shown in this study and I think in some others, you know, the more lines of therapy that somebody fails, the more likely it is that they are not on concomitant methotrexate. And in fact, if you're on your second, third, fourth, etcetera, biologic or JAK inhibitor, the prevalence of methotrexate use, you know, drops to, you know, near fifty percent, meaning almost half of our patients on a biologic or JAK are not on concomitant methotrexate. And yet I'm not seeing strong evidence that we're getting so many more people to remission.

And so I'm a little disturbed that combo therapy with methotrexate and one of these advanced therapies doesn't seem to be increasing the ceiling of getting people into remission or close to it. And if anything, methotrexate use is declining a bit over time.

Before I get a comment from Stan, I wanna remind the audience that you can ask questions by using the Q and A box. You can put your questions in and we'll address them as we go along. It's important that you're a part of this discussion as well. Stan, do you have an answer as to why everyone's bailing out on CSD marts? Is it the grand quest for either monotherapy or no therapy?

Well, I think patients prefer monotherapy and methotrexate, which is a great drug, still has aggravating side effects in some people. And so we know that IL-six inhibitors, you know, monotherapy is quite good in those patients. We know in JAK inhibitors that more than fifty percent of them are not on a concomitant CSD Mart and do very well. And then I think that people who have more refractory disease have been there, done that with methotrexate, and they haven't really responded and they're we're trying salvage therapy and doing other things and they're not willing to continue on. So I think that's why you see somewhat of a drop off in the use of those anytime.

But I agree with Jeff that, you know, clearly the data shows that these with TNF inhibitors, most certainly the monoclonals, and even atenorcept, that methotrexate provides additional benefit. But I think the patients themselves, if they will vote with their feet, would prefer to be on monotherapy if they could.

Does anybody think Jim Dowd asked the question that does toxicity drive down, not toxicity, but concomitant liver issues like fatty liver disease and whatnot? Is that driving down methotrexate use? Or is that responsible for less methotrexate use? I don't know.

I think it may play a modest role. If we have someone who has steatosis, we'll often ask have the liver service to follow them with us. So it comes a little more complicated. So if we're able to get them into low disease activity remission without methotrexate, it makes life simpler for everybody.

You can just treat their steatosis by putting on a GLP-one drug and just driving up the cost of care and avoid the liver consult. But no one's gonna go with that recommendation. I think it is the quest for monotherapy by patients and also by the companies who are developing these drugs. Want to say that our drug works great as monotherapy. I've had arguments, Stan, going back to the days when we were meeting with the developers, product managers and CEOs of companies who were trying to tell us how excited they were about monotherapy and I'd raise my hand and say, you mean that your magical drug, one drug by itself can treat a disease that I have not been able to control in my career and that I need multiple drugs to control.

I mean, why is your drug magical? And I'm demeaning them. But that's how I feel. I think that I don't know who's gonna respond. So I'm going to use combination drugs and I'm not a big believer in patients that want to withdraw therapies.

I don't know, Katherine, how do you handle the patients that want to get off of therapy even though they need therapy?

Yeah, that's a tough question. I totally agree with the comments before that everybody wants to be on monotherapy. I tell them the goal of this early aggressive treatment and just the comments, I came on, I went through training when early aggressive treatment was the thing. And I saw the patients with established disease, but then transitioned to these early RA patients who never progressed to those type of joints. And I tell them that.

I said, the goal is to prevent joint destruction that is irreversible. And our goal is to get your disease completely under control. When we get to that point, then we can talk about tapering off drugs. And that has helped me to prolong how long they're on multiple therapies. But if a patient doesn't want it, they'll come off anyway and they'll tell you at the next visit.

All right. I got two more methotrexate questions and then we're going to move on. Does anybody want to handle the issue of the SubQ methotrexate work better than oral methotrexate and do you use it preferentially? Does anybody use SubQ methotrexate preferentially like they do in JIA?

Well, I mean, clearly the data has shown that in some patients, SubQ methotrexate can salvage patients who've been on oral methotrexate and haven't responded by better bioavailability. You know, in certain parts of the world and Canada and places, like that, where they're strong, advocates for SubQ methotrexate. You know, most people don't want to inject themselves every week. So, you know, my practice has always been to start oral methotrexate. If there is toxicity and they've had a clinical response, I'll go to sub q methotrexate.

Since I tend to be more aggressive, I'm not one of those people and go to biologics. I'm not one of those folks who will take someone who's not responding very well and try sub q methotrexate first. But I know some people do.

Liko Barbosa makes the comment that most a lot of insurers require patients to be on methotrexate if you're going start an expensive biologic. So that may be how you start out. But she also throws in the other caveat. There's also always the alcohol issue in methotrexate and that maybe you can't use it because of alcohol. Jeff, what's your policy on alcohol and methotrexate?

I'm going to ask each of you to declare and I'm going to bet that I have the most eyebrow raising policy. Jeff, go ahead.

So I'm going to go with the Greeks, the nothing in excess, in moderation. So the first principle is please just tell me the truth. You know, I'm not your dad, I'm not your pastor, I'm not your priest. Just like tell me what you're doing and let me be your advocate. If you're a six pack a day on weekends kind of guy, okay, just let me know so I can be the doctor to you that I can and help you do things safely.

So I guess I want to know what patients are doing, but secondly, you know, in moderation, you know, a couple of glasses of alcohol a week, I'd be fine with that. As long as your LFTs are being carefully monitored and you're reliable. I know others may feel more conservative, but I'm okay with some as long as it's not a lot. And I realize that's a bit subjective.

Anybody, Artie Cavanaugh says don't drink more than your rheumatologist. And that's too high a bar I think actually. Anybody have a different opinion than Jeff? I agree with what Jeff says. I'm very permissive because the data doesn't really back it up.

But the vast majority of rheumatologists are like, if you're drinking, admitting to alcohol, I guess we assume that they're not telling the truth, then we're gonna bail. We're not gonna use methotrexate. I don't wanna be, does anybody

have- allow moderate alcohol. The only time I've been burned by methotrexate has been psoriatic arthritis in patients with morbid obesity. I will not use methotrexate in those patients. I didn't sort of believe the literature, which I should have. And I've had a couple of people, LFTs were normal forever.

And then they have a diagnosis of cirrhosis twenty years later. So it's really been these obese patients in moderate alcohol, as long as we're monitoring their LFTs, have not been a problem. And Jack, why they just point out this as, so I was on a call yesterday with a pharmaceutical company, and they were trying to figure out the future of biosimilars and their drugs. And they said all of the employers are trying to figure out with their insurance companies how to pay for GLP-one agonists, and they want to lower the cost of biologics when you mentioned the GLP-one agonist. Because that's taking up such a great amount of their expenditure in health care that they're trying to get more people on biosimilars rather than originators, the cost of their healthcare insurance.

Well, it sounds like a nice narrative for the biosimilar companies as to why they should use them to save money. The GLP-1s, I'm all for that. And I'm a big believer in biosimilars, but we need trials that show that GLP-1s really do work other than what's been observational up to this point. Let's move on to the next set of questions. Here we go.

Compared to twenty years ago, how does it about decision making? I make RA treatment decisions based on more than half said clinical trials and guidelines. And then more than a third personal experience, that's almost 90% of the decisions are made with only eight percent admitting to formal RA metrics helping to guide their decisions. Jeff and I did a survey over ten years ago and we documented that fifty four percent of rheumatologists measure something, but they're all over the map and how much they use it and decision making wasn't very much. Obviously the treat to target hasn't driven this very far.

Then the second question gives the same answer. What resource most influences you're prescribing in your treatment? Again, published guidelines, big meetings and conferences, and maybe some online education. But between online education, CME and conferences, you're still looking at maybe 25%, 24%. So guidelines and trials, I found that surprising.

Was anybody else surprised by that? Katherine, what do you think?

No, I guess I'm surprised. I'm wondering why you were surprised. Well, okay, so I'll say one thing. Only have the guidelines and trials, particularly the trials, tell us treatment effectiveness. Usually the older trials is versus placebo, and now they have comparative effectiveness trial.

I think where we still have a hole where you brought up earlier is which drug will work best for which patients. So what resonated with me is that you do have to use some personal experience there to fill in that gap because you have all these options. But I am curious to know why you were surprised by evidence base.

I don't think people read newspapers or read articles anymore. Maybe they just read RheumNow or maybe they just listen to presentations. Don't know. Mean, there was an era back in the 2000s when you could have stopped any one of us who were doing clinical trials and we could have recited for you what the exact response was at twenty four weeks in the ATTRACT trial or in the methotrexate TNF inhibitor trial. We knew those numbers and stats because we were living them because they were like hot off the presses.

But I will tell you that I shouldn't be surprised by that because on RheumNow, things that get read a lot is any title that's got methotrexate in it, and any title that's got guidelines in it. So people are, I guess, cognizant of guidelines. Jeff, what do you think?

I would argue that maybe rheumatologists, like most doctors are really good at taking tests and the clinical trials and guidelines seem to be the right answer. What clinical trials is it that people are thinking of to pick the drug for the person who's failed three or four or five or more biologics or JAKs? Like which trials would that be? Because I can think of, you know, so few trials I can count them on my fingers, maybe on one hand fingers. We just don't have trials for people that are that refractory that have bad difficult to treat RA.

So I guess I would challenge that a little bit that we don't have trials for people that are as refractory as the patients that you and I and all of us see in the real world that are much more commonplace that there are no trials for.

Stan, you've done all those trials that people are pointing to. What do you think?

No, I mean, listen, I'm pleased that, this is what they responded. They, actually, you know, listen to the guidelines and the trials that are out there. Clearly, experience makes a big difference. But we can say that at least with the web and all that, that this data is disseminated. It's there.

You can pick it up. You can go to chat GPT or Perplexity. You can get all this data now. So I think it's it's improved. Now I can't speak to what the rheumatologist in Teaneck, New Jersey does.

But I mean, it looks like the group that you polled here really does adhere or at least follow the trials and the guidelines. I think that's a tremendous improvement over time.

I think it has been an evolution. A little bit more about decision making comes on the next slide. Here we're going to ask, your patient's been on a biologic and almost always that's in the TNF inhibitor class. The first question, an RA patient who's failed one TNF or actually one biologic, let's say, what factors guide you with your next choice? Switching to another MOA was their top answer.

Guess that means that it's available to them. Hard to know. Usually when you're doing this question, the dominant answer is whatever managed care forces me to do. And that's the number two, but half as prevalent as the fact that I have options, which is what another MOA means. Efficacy data safety concerns makes up 25.

Then how many TNF inhibitors will you try before you go to another MOA drug, meaning a non TNF biologic. Half of them say they'll try one and switch, the other half say they'll try two and switch. I find those answers. I think that this is a trend towards maybe switching, not going through all five TNFs or three TNFs at least, but maybe switching to other therapies. It may be that we have enough other MOA drugs and other class drugs like JAKs that people are comfortable with that.

Jeff, what do you think?

Yeah, would agree with you. I think TNF cycling, even though perhaps there's some evidence against it, there's still some evidence for it and people are clearly doing it. Sometimes it's mandated by insurance. I think that was another question that you asked. So perhaps in the future, you'll ask not just how many will you try, but, you know, if insurance were not a constraint, how many do you think is warranted?

But I think that TNF cycling, and I think we're starting to even see Jack to Jack cycling, that's pretty common, but I think some of that is externally imposed on us by what payers will pay for and fail first and even fail second policies are unfortunately still pretty common.

John Tesser brings up the point that patients entering clinical trials, he points to the recent RESET Bagel nerve stimulating trial where two thirds of patients were on two or more drugs. The definition of refractory disease to get into a trial, the definition of refractory disease to be called D2T RA, difficult to treat RA, means that there's still a lot of patients out there on two or more before they switch. Catherine, what's your policy on this? How long will you stick with a class of biologic before you change? Will you go through one or two?

Yeah, it really depends. So when somebody starts on a TNF, so we actually did an observational study on this where we went back and tried to understand why did people switch and where did they switch to? So there are maybe four groups after TNF. Well, you have a group that has a good response to TNF, responders who response for a year or two and then they lose efficacy, people with partial response and those with no response at all. So I'll say for me, those with a good response, whether it's like a year or two, I do like to give TNS another try because it's promising.

It looks like it's something that has to do with antibodies against the drug. Whereas the partial or the non responders, I'll switch MOAs. And after that, how I pick the MOAs is really based on comorbidities. So we have more data now on what drugs might perhaps be helpful for cardiovascular disease, such as data on IL-six inhibitor and reducing cardiovascular risk. So if I have a vascular path where I need to switch off a TNF, I might think about an IL-six.

The best data on switching MOAs comes, I think from the ACCELERATE trial that Stan was a part of. The ACCELERATE trial was a head to head of two TNF inhibitors in early disease. If you didn't respond at twelve weeks, you switched to the other and ACR 20 responses went down by 50%. The best they were going to do when they switched over was still half as good, really speaking strongly for moving on after a primary non response. Anyone else have any other opinions about this?

No, I think this substantiates that people might be reading the guidelines because they do generally suggest switching to a different MOA after lack of efficacy with a TNF inhibitor. So maybe that substantiates your previous data.

Yeah, and I'm gonna show you that. I'll show you the UR guidelines in the next Oh, here they are right here. So the UR, I mean, Joseph Smallen just presented UR guidelines at Barcelona in June, as an update of the 2022 EULAR guidelines where there weren't many changes. But in the guidelines, they say that if you don't respond to a conventional DMAR like methotrexate, you add a biologic or a JAK only after the JAK has been assessed. And then you reassess for three to six months and if they're responding great, if not, you change.

They're kind of suggesting that you change like you're one and done and you move on to another class. But print actually is that if a patient fails a biologic or targeted synthetic, you should consider another. If it's a TNF inhibitor or an IL-six receptor inhibitor, you can go to a second one. They put that in the text. I know why they are preferentially, I guess they have enough data to support that, but I don't believe it's well designed controlled trial data.

I think that's observational data at best. But then again, these are guidelines. Guidelines are conditional recommendations, often expert opinion, not necessarily strongly grounded in fact. But again, the guidelines kind of suggesting what Stan said and what I like to practice, which is pretty much one and done. Let's go on to important point has to do with comorbidities.

Actually, Leica Barbosa makes a comment that fibromyalgia OA chronic pain can confuse assessments in RA and knowing what to do. But I think that's really a strong endorsement for what rheumatologists do. We can spot those secondary issues and not confuse them with the need for another biologic going forward. So I wanted to ask people about comorbidities. Fifteen, twenty years ago, we were starting to talk about comorbidities and the overwhelming opinion of rheumatologists was, Yeah, it's important, but don't ask me to manage it.

That's what they got primary care doctors for. I don't have time. I got twenty minutes, I got 23 things I got to do, including people want me to do the leads, enthesitis index now or too many things. But I think these answers reflect the change in how they consider comorbidities. Let's look at the first two.

What are you most worried about? They say cardiovascular disease, forty three percent infection, twenty nine percent and lung disease, almost twenty percent. Then when I asked them, which comorbidity are you more likely to manage without referring it to a PCP? I didn't give them the option, must say, of I won't do this. So my mistake in not giving them I don't do this as an option.

But I found it interesting that they're willing to take a stab at these comorbidities led by managing infections and managing smoking and lung disease. Rheumatologists are pretty good at managing smoking disease. Jeff, why don't you start addressing this because you've worked on this many times in your career, looking at what rheumatologists actually do when it comes to comorbidity management and health maintenance management, and how deficient we might be.

Well, I think that the question isn't like which are we willing to manage it, but which are we willing to manage? So I find the delta is most interesting. What do you worry about in that left hand pie chart? Then the middle one, like, what are you willing to do? For infections and lung disease, that difference isn't that great.

But in cardiovascular disease, that delta is pretty substantial. Like, 43 said they're most worried about CV, but then if you said, well, what are you willing to do your own self? It drops to less than half. I know I've been part of some projects where we were trying to focus on improving cardiovascular disease management in RA, A lot of rheumatologists got very uncomfortable and said, Look, don't make me responsible for that. If I have to focus on it or measure lipids, I'm out.

I don't even want help with that because then you put it into my domain. No. Thank you. Although they mostly said that quite quietly when it was a discussion with their peers. So I think that's the one that people are most uncomfortable with because don't ask, don't tell still seems to reign supreme in some people's practices.

Just they're busy and they don't want that to be within their domain of their scope of practice.

Kathryn, you run a cardiology rheumatology combined clinic. So this has got, is this distressing to you or encouraging to you?

Yes, have to say I was tickled by the same numbers that Jeff had just pointed out, how they're worried but don't really want to deal with it. And I think it's real, but actually I would say I'm encouraged that rheumatologists are willing to think about it. So we are in Boston here, we have a very big PCP shortage and our patients see us regularly. So my thinking is it's good for the rheumatologist to know it's an issue and perhaps get the process started. So that's what I'm thinking.

When I talk about the, so I co direct a cardio rheumatology clinic here, and there is just, as Jeff mentioned, this big gap in patients who should be on a statin, who aren't on a statin, and how do we close that gap? And my hope is that since rheumatologists know that this is such a big problem, cardiovascular risk is the leading cause of death in patients with rheumatoid arthritis, that they will pass that on to the patients, perhaps get the patients started with checking the lipids and then pulling in the PCP or cardiologists afterwards, if they're understandably not able to manage the lipids.

On the left panel, you'll see that only some really low number, one point five percent, that purple slice are interested or worried about cancer and nobody is managing cancer. This is interesting to me because I get lots of how do I treat someone who has cancer questions. Most rheumatologists are very, very afraid of this issue and punt to the oncologist when I don't think you really should, but that's really reflected in this data. I don't know that we've evolved on that. Have we evolved?

You've heard lots of talk so far on our responses so far on where JAKs sit right now and how they've come on the scene. We asked the question, how has the oral surveillance data and the JAK inhibitor warnings affected your prescribing of JAKs? And if you look at the numbers, especially Stan, you're very much involved with this and the safety of JAK inhibitors. The blue is some decrease in JAK use. The orange is a major decrease, that's now forty nine percent.

And then the thirty three percent is a more selective use of JAKs. If you think about it, that's almost eighty percent of people who are on caution mode either in a major way or a minor way in rheumatology. And I was surprised at this. I thought most rheumatologists were still gung ho on JAKs, whereas I can tell you dermatologists are totally wigged out about the warnings and whatnot. It really changed some of their use.

At least that's what I've heard from dermatologists. Stan, what do you think of this data?

No, I think it reflects what's going on in Rheumatology. And I think you show that data that Jeff was one of the authors on and it shows that JAK inhibitors going down and be a little flat in as far as prescribing. Yeah, no, I think again, because of the guidelines and the concerns and the VTE signal as well as a MACE and malignancy, there's something going on. We haven't figured it out, you know, and I think that it is a class effect, you know, not just limited to to one of the JAK inhibitors. So yeah I think we're careful and what it reflects Jack is you know we have multiple options to treat the patients.

It's not like we have two drugs so we can select what we want to do, do shared decision making, look at the comorbidities and decide who have good cancer. Listen, JAK inhibitor growth has been exponential in all so many different diseases. And we know that the other diseases, there's not much of a signal to this. Patients are younger, less cardiovascular risk in general. So again, we just have to be careful in this elderly population of RA patients.

I do want to say that something like what Jeff said earlier, and that sometimes when we answer these surveys, we give what we think is the right answer, maybe not exactly what we do. I think some of that's an operation here because last year at ACR, or was it UR, I chaired a session on, should we as rheumatologists be worried about the JAK data? We had a debate and really the vast majority of, I don't know, 1,500 people in the audience voted and said, Yeah, we're okay using JAKs. That's not really reflected here. Jeff.

Yeah, I can't help but want to comment on the middle panel about obesity. So I just came back from a real world evidence conference earlier today, and it's multidisciplinary, not rheumatology focused, but I felt like every fourth abstract was on GLP-1s. So I was intrigued that the orange group, that obesity was something that rheumatologists in the survey said they're comfortable managing. And I'm very interested to know, does that mean that rheumatologists that answered the survey or US rheumatologists are comfortable prescribing GLP-1s? And is that going to be something that's now par for the course?

I can tell you I've started prescribing that and have increasing comfort with that. But, you know, obesity and treating obesity might solve a whole lot of things. But if rheumatologists are willing to have that be part of their remit and what their scope of practice entails, that might actually be great for patients, but definitely would be something novel compared to what rheumatologists are used to managing. So I'm curious whether you or other panelists or people in the audience are turning to prescribing GLP-1s themselves.

I have. I think that they're a significant advantage, especially for the obese where obesity just adds to all kinds of problems. And sometimes I can't prescribe because I'm not an endocrinologist and the managed care will restrict me that way. But I've done appeals and whatnot, and I've gotten free drug. So I think there's a minority of people and I think it's going to be furthered by their clinical trials right now in progress where patients with psoriatic arthritis and maybe rheumatoid arthritis are going to be treated with biologics and with a GLP-one or not.

The question is, is that safe? Is that reasonable? Forget about what its cost is, but does it The real question is, is all the benefit of those drugs from weight loss alone or is there an inflammation component to GLP-one use? I don't know. We don't know the answer to that.

Everyone keeps hinting that there's an anti inflammatory or immunomodulatory effect. We don't really know that right yet. Catherine, do have a view on this at all?

I have not been prescribing GLP-one just because even my patients who are on it can't access it. They're on it, they lose insurance, there's not enough supply. So I have to say, and in our practice, we haven't really taken it on.

Jack, we're certainly prescribing it. And I think with the rheumatologist, we're going get their foot in the door because it's the only good drug for osteoarthritis. And that's a disease that's our biggest unmet need. So they'll be comfortable with GLP-one agonist. As you know, there's going to be many, many different formulations, oral formulations coming.

So I think we will be prescribing that for inflammatory arthritis as well as osteoarthritis.

Jim Dowd, who again, I used to work with in Dallas, says insulin resistance is epidemic and drives up inflammation, which really fuels a lot of these comorbidities and hence drugs that will attack that are going to be advantageous. Christian Diquette makes the comment that primary care doctors don't understand the role of these comorbidities and our disease or our disease and their comorbidity, and hence they're less likely to be adequately treated because of that fear and lack of knowledge, which is another reason maybe why we should get into this. But I think there has been, based on what I said earlier that when I was doing this fifteen years ago, everyone was like shutting down the discussion. I'm not considering any of this. I think that in fact they do now.

Maybe they could do better. So What does the future look like? We asked them, in the future, be treating RA with more what? Again, you blame me for these answers I gave them as choices, but they jumped at combination biologics, which we were always told that's a no no and it's in the package insert for most of the biologics not to combine it with other biologics. But there is some data that especially in the psoriasis and psoriatic arthritis and in GI world of combination biologics without added toxicity.

The second most was biosimilars. That's I think a surprise or maybe a welcome answer. JAKs have a healthy answer, non TNF 11%. Again, they're not going be relying maybe as much on TNF inhibitors in the future. Anybody surprised by this answer?

Well, it's interesting with all our great therapies and sea changes that we had, we do have a ceiling, the sixtyfortytwenty. So we do need, you know, for the refractory patients, the ones who cycle through multiple therapy, we need something new. I mean, combination biologics is, as you mentioned, you mentioned the data in other disciplines, other diseases. We had bad luck in RA many years ago using combinations. But I will tell you, since I consult for a number of very small biotech companies getting started phase one, phase two, combinations high on their list in RA, psoriatic arthritis, and other diseases.

So it will come. It certainly hasn't been proven out so far. We just had our latest failure with BTK inhibitors with the JAK inhibitor. But I think it's certainly sexy. Biosimilars, there's no question the growth is going to continue to, I mean, we have greater growth with those as well.

If I'm gonna be prescribing combination biologics like I'd like to, I'd want to see data, and then I'm gonna need coursework on how I can convince payers to pay for it, either hypnotism or hostage negotiation kind of coursework. I think that those might work. How about these answers? What's the next major advance in RA management? These two questions, future guidelines need to address what?

Both lead answers is either linking specific biomarkers to the choice of therapy or precision medicine, what Katherine was talking about earlier. These are high on the list of people going forward. Now I'm a little distressed in the middle question that the second choice for major advances, CAR T cell therapy for which I don't think we have any indication for use at this point. But you can see the answers here, but again, people want better guidance. They want biomarkers, precision tools, something that's got predictive value as opposed to what we're currently doing, which is experience and maybe guidelines.

Katherine, what do you think?

Yeah, I was actually really excited to see regarding the precision medicine or personalized medicine. I think that it's been a promise for a long time, but I do think that we're getting very close because we have so much more granularity in the data, all types of data, genomic data, clinical data with electronic health record, what we're able to get out of that with the large language models and other technologies that Jeff also is very familiar with, such as natural language processing. And then from the synovial tissue with projects such as Accelerated Medicine Partnership, we're really understanding what kind of cell types are in there and cell types that we may not have thought about as important for RA that haven't been targeted yet. So, but what would that give us? I think one thing will not be the answer, but with all of these together, we may have a better way of understanding predictors for treatment response.

And then also within that sphere in that with this knowledge, we may also identify new targets for RA.

Jeff, are you surprised at any of these answers?

I'm not, although I do think that that middle panel, you know, what will be the next major advance, people were most optimistic about specific biomarkers to predict treatment response and yet harkening back to one of the earlier surveys, like that was one of the things that people were most disappointed at. So it's interesting that enthusiasm remains high, even though we've had a lot of disappointments up to date. But I agree with Cath that I think we're probably close. There's a number of different groups and companies that are still working on this. So I'm happy to see enthusiasm remains relatively undiminished because I do think this is where the greatest need is.

I don't know that we need more drugs. We need to get smarter about how we're using the current therapies. We'd probably be a little bit remiss to mention that it may not all be drugs or may be devices like vagal nerve stimulation. You know, John Tesser, who's on this webinar who led a trial of VNS that just got FDA approved. So there may be interesting use of devices like that or even combinations where about twenty percent of those people had vagal nerve stimulation plus a biologic or a JAK, we may see those sorts of novel combinations with devices that we haven't seen heretofore.

Stan, do you want to give us some wisdom on how you might not and I'm not saying that you have done this, but if you were thinking conceptually, I'm making this very fuzzy so you don't have to admit to nothing. How you would use a combination biologic because I have some comments that people are combining drugs, including things out of the cabinet, both in dermatology and rheumatology and GI. What's your obligation? How do you handle this?

Well, I don't think it's feasible right now with the biologics that we have, but, there are things in development, science that I wouldn't even aware of in looking such as, going after soluble TNF rather than, the whole TNF class membrane bound as well, may be safe and you will be able to give it to other patients on other biologics and combine it. So I don't think we have the combination therapy exists now. I'm not going to put T cell inhibitor with the TNF. We've done that, failed that. But the bottom line, it's coming.

So I think there would and again, we're talking about a disease we've always described phenotypically. Kat talked about the AMP efforts and whatever. We need to come up with some type of cell free DNA circulating biomarker that tells us what's really going on in the tissue and directs our therapy. At that point, we could come up with more targeted and possibly combination therapy. So in a long winded way, didn't answer your question.

But I think in the future, there are going to be other biologic therapies that are preclinical that we will be able to combine. We need to figure out what to do with that ten-thirty percent of patients, however we define them as refractory.

Yeah, I think what you said and I would thoroughly endorse is don't do it. If you do happen to do this, I think you're obligated to tell the patient and document you told the patient that this is off label use.

Absolutely.

And that for medical legal reasons, it's very important to do that. The last question on the future, a few of us are very interested in and that includes both Katherine and Jeff. Where does artificial intelligence going to inform future treatment? I want to go around the block on this, but the audience said that AI will assist individualized treatment decisions as the number one choice, 44. And everything else is less than half of that.

Earlier identification and referral of patients to you or automated assessments and documentation done by AI, and then 10% saying better education of the patient and interface with the patient. Catherine, where do you see artificial intelligence helping RA management in the future?

Yeah, I guess when I think of that question, I think about how far in the future are you thinking more the immediate or the long term future? So AI is very good at summarizing a lot of data and what we have now is a lot of data, but we need to know how that data helps us to treat patients earlier. So I would say the low hanging fruit is, let's say we do find predictors for response, and I mentioned there may be different buckets, genomic, biomarker, clinical, It's gonna be hard for us as rheumatologists to be able to see and summarize all that data, that AI will summarize that data and help us to make a decision there. So that's one way I think it can help us in the nearer term.

Jeff, you've done a lot of work on this in this area and very interested in this. What do you think?

So I would agree that all these use cases for AI are legitimate. And I do think that there's a role. The one that I saw that seemed really important that I felt was missing was deprescribing. Sense is that most rheumatologists are pretty uncomfortable taking away biologics or JAKs, even for people that are doing quite well, remission or close to it, because the chance of success is relatively modest, you know, maybe one third, one half depending on disease duration, and you can mostly recapture them, but we don't know who's in that one third or one half. That's a legitimate role for AI to be able to predict who can stop or deescalate and still do very well.

That's going to save somebody a ton of money. And I think that's an untapped role for AI that could be really helpful for those patients that are doing quite well, that are willing to think about that.

I want to say that I think that the answer that AI can answer right now, that would be the biggest effect on RA, is the ability of RA to find patients and refer them. Large population databases, it can identify with great certainty who the RA patients is and get them to you earlier. Right now, we're all very passive in how we receive RA. Unless you've got a practice like Stan does, where anyone who calls for appointment can get seen this week. The vast majority of rheumatologists have three, six, nine month waiting lists, which means you're not seeing RA soon enough.

That could fix that problem real easy by your hospital system. Stan, you've done a lot of trials and still are doing a lot of trials and advising. Do you see AI playing an important role in future clinical trials?

I assume it will. I mean, it's such a powerful weapon. So I would hope that it might allow us to, you know, find candidates for trials because that's the biggest problem in North America and Western Europe and so forth. So again, I think it's got unlimited potential. Mean, one group that I'm working with right now, they think they have the ability to save us time.

So we see these people, they have medical records out the wazoo. And they think they can summarize all their medical records in two to three pages, which would help us see patients more efficiently quicker, and we could actually see more patients if we needed to. The answer is it's unknown, but clearly it's going to play a major role.

I'm going to end with three questions. We have a lot of comments about the future that people are liking, including the vagal nerve stimulator combinations, cellular targets and PCSK9 plus RA biologics. I don't even know what that is. Here are final questions. I'm going to ask my panelists, answer whichever question you want to answer in the last three minutes.

And I'll begin with Jeff Curtis.

Yeah, so I think the future will be determined by drug development or smarter use of existing drugs. I think it's the latter. I think we need to get smarter about what we've got, not just more of the same where we have the same ceiling, and I think that's where we need biomarkers and omics. And the one last comment that I would make that I think needs to play in to that is some of the mental health and some of the comorbidity issues, not just chronic pain. We touched on obesity, you know, anxiety, depression.

You know, sometimes people assume that, Oh, I just need a new RA drug, when in reality, if I had access to it, you just need a pain psychologist and some of the wellness behavioral interventions that unfortunately I don't have much access to, but that I think might be another role where AI sort of quote therapists or chat bots, maybe with a human in the loop. But I think there's some interesting developments in mental health that might be very useful to help people manage chronic pain that may not be inflammatory.

AI can definitely fill in a lot of the things that we need to do but that we're not very good at doing. Then I like those examples that you point out. Stan, do you want to answer one of these questions about the future?

Well, I mean, I think that we're going to take a phenotypically described disease and better understand it and that's going to allow us to target our therapies better and hopefully improve with the present ceiling that we have. And Kat's an expert on comorbidities and targeted LOA to targets. I'll let her speak to that.

Yeah, it's hard to be the last. I agree with everything that's saying. I think that's been discussed. Sub phenotyping, while it's a clinically defined disease, it's a heterogeneous disease. And so maybe I'll move away from AI and just weave in some of our other discussions is that maybe it will be more holistic.

So for example, the GLP-1s hold a lot of promise in reducing inflammation. So maybe it will be our RA treatments with something else. And it'll be GLP-1s with something different that's on the pipeline that would be very helpful that manages comorbidities that are perhaps driving disease activity like obesity. So that was just something I was just thinking out of the box as we were having this discussion in terms of just thinking in different ways that we might target this disease and manage it.

Yeah, I think my final comments are that we still need to ask the hard questions about RA. We're very good at doing what we do and doing it even with limited tools. We're very effective at therapy despite a lack of certainty around these therapies that we will employ. But we need to continue to ask hard questions about how we can do better because I think we can do better. I think other disciplines have done better by introduction of maybe the right drugs or different practices and whatnot.

Certainly we can do better going forward. So anyway, I want to thank our panel for their great insight on this. I want to thank the sponsor of these three surveys, which was Bristol Myers Squibb for their contribution to this activity and look forward to more Tuesday night.