EULAR 2026 RA Topic Panel Save

You're listening to a RheumNow podcast coming to you from London in UR twenty twenty six. Enjoy. Hello, everyone. Welcome to RheumNow. This is our post UR twenty twenty six panel discussion on rheumatoid arthritis.

I'm joined today by three of our faculty who were at the meeting in London with me we're all back home rested and have considered what we thought were some of the best abstracts and rheumatoid arthritis that we want to discuss for you today. So, I'm going to begin with introductions. I'm Jack Cush from Dallas, Texas. Janet?

Janet Pope from the other London, Ontario, Canada.

John.

Jonathan K from UMass Chan Medical School in Worcester, Massachusetts. And Bella.

Hi, this is Bella Mehta from New York.

Very good. Okay, so let's begin with Janet. Again, I think RA was very well represented. There was a lot of RA content at this meeting. It seems like the buzz always comes from CAR T and PSA and whatever.

But if you look at volume, I think the number was over 1,700, almost 1,800 RA abstracts. So we're going to hear eight of the best. Janet, you're first.

Great. So we always wonder about what's better than something else. So I picked a head to head trial. I'm not gonna give you the results of the head to head because I'm not sure I know them, but it's still a good trial. So this is called the Bach trial and it was OP0204 and basically the question here was what's better in rheumatoid arthritis CSD MARD IR randomizing a patient to Jack, in this case it was filgotinib, or randomizing them to TNF, and I think it could have been any TNF.

It was open label, a pragmatic trial done in the real world in a clinic setting. So that's what the question was. Now they also decided rightly so that they would collect the group of people who were eligible, who didn't want to be randomized, and look at their choices, and look at their satisfaction and see how they did. So it's a parallel universe. The the randomized people, they actually had, a sample size calculation and achieved it.

And interestingly, about a 100 per people were willing to be randomized versus a 101 not or something like that. Was about a 100 per group. So those randomized, about half got a TNF and half got FILGO. Of those not randomized, the choices were kind of similar between TNF and FILGO. So you go, okay, well what are they going to really answer here?

So what they told us were I think really a few important things is that the patients choosing did better with satisfaction. Well, think that might be expected because they made a choice. They did better though with retention when they chose the treatment, and they actually did a deeper dose or change in disease activity than the people randomized. And I thought, uh-oh, I do clinical trials all the time, and I thought people like to be randomized because they go, Doctor, if you don't know what's best, let's just go for it and kind of go, you know, that if we're in equipoise. So I thought it was kind of interesting in that the satisfaction didn't surprise me.

So they had a standardized thing. It was like a wee little video of a nurse saying, you could take this drug of or this drug, a Jack. In this case, it was filgotinib that the Jack would have been the people would have had access by usual care. Everybody was able to make a decision within twenty four hours of those who refu like, did not wanna be randomized. But, I think it has implications for future trials because we don't do this parallel arm of people refusing to be randomized and how they do.

So I thought that was really cool, but here's the bottom line. They didn't tell us how they did within the trial that was powered adequately to say what does better TNF or Phil go on, you know, rate of response, retention, satisfaction. So maybe they'll present that at the ACR. I don't know.

Yeah, open label. I think the results were going to be something just like Sunstar, something we were not going to present, but I'll say it here now, OP0205. That was the same trial, 200 something patients who failed a biologic or TNF, and then they were randomized to either receive, as open label, tocilizumab or abatacept, and they looked at a fifty two week outcome. And in the end, they all did well. They came in with C.

Dyes at 25 and they dropped their C. Dyes down to 10, and they all did well with no significant difference between them. Although it was designed to be a superiority trial for tocilizumab, it wasn't superior. Except unless you did some funny analyses or if you looked at tocilizumab monotherapy was better than abatacet monotherapy. When you added methotrexate, it didn't matter, which drug you got.

But it was the same kind of thing. And I think it goes to the point of ULAR guidelines, one and done. Once you fail a targeted synthetic or biologic, you change classes. And that's what happened in your trial, it's what happened in Sunstar, but the dangerous part is what you said, give patients a choice and they do better. Why don't we see that in clinical trials?

Because there's no choice in a double blind randomized placebo controlled trial. You got it. Right.

But the patients were I mean, they also knew about the black box warning, right? Which came in in the middle of the trial. So that might have changed the choices. Right?

There's a lot of factors at play, but they said the patients were quite the reasons that they chose were all over the map, my friend. Like, sometimes I wanted it. My friend was on this and liked it. Or I heard something bad about this one, so I want the other one. So there was no consistent reason why they chose.

Oh, I like an oral. Oh, I was on a needle, so I want another needle. Like, the choices were as varied as the patients in the, I refuse to be randomized group.

In a clinical trial, they gotta show A is better than B and your comparator can be placebo or an active comparator. It can't be patient choice because that's too outside the box and will screw up your results for, could very well screw up the results. And that's why you need studies like this to make this point, but you'll never see it in a drug registration trial. John, what do you think?

Yeah, I think it's an interesting trial. I don't quite know what to make of it. In terms of the outcome, I think they said that patients tended to prefer the JAK inhibitor because they like oral medications rather than needles. But there's a lot of expectation bias in that trial. It's such a completely different approach to trials that I really don't know how to interpret it.

If I was going to start all over in rheumatology, I would rename my clinic the High Expectations Clinic and we would be doling out a lot of placebos, and we would do just as well as everybody else in Dallas. Placebo is a very powerful thing. Let's move on. John, what did you have that you liked?

So there are a whole bunch of things I liked. I thought I'm gonna talk about OP-two zero nine, which was a negative trial that was presented by Ian McGinnis. This was a safety and efficacy trial, looking at balinatum balinatum fib. It's really a tongue twister. This is an oral TNF receptor one signal inhibitor that was studied in patients with moderate to severe rheumatoid arthritis.

This study, which is negative, was interesting to me for two points. One is that it's an oral molecule, a small molecule that binds to the TNF R1, the TNF receptor type one, and blocks binding of TNF to that receptor. So it's using a small molecule approach to block TNF signaling and not by blocking signal transduction. As you know, the JAK inhibitors don't block TNF signaling because TNF signaling is not mediated through Janus kinase. But anyhow, that's one reason why it was interesting.

The other was that it was a negative trial because the placebo response rate was so high. It was conducted all over the world, including South America, where there's a very high placebo response rate and also Eastern Europe. But the study was phase 2b twelve week multicenter randomized double blind placebo controlled dose ranging study looking at I'll try it again. Belin at Tunfib, two hundred milligrams twice daily, two hundred milligrams once daily, one hundred milligrams once daily, fifty milligrams once daily, placebo. And it was two to two to one to one to two randomization, so twice as many patients were on the two hundred milligram dose regimens and placebo as were on the one hundred milligram and fifty milligram dose regimen.

The primary endpoint was ACR20 response at week twelve. Key secondary endpoints included ACR50 at week twelve, changed from baseline to week twelve, and DAS28 CRP. Basically, the placebo response rate was so high that none of the clinical endpoints differed from placebo. They did look at the decrease in blood IL-six as a pharmacodynamic marker, and this decreased with each of the doses, suggesting that there was biological activity to the molecule. But in terms of the clinical trial, it was a failed clinical trial.

Interesting in that the molecule has a unique approach to blocking TNF signaling. And also the trial deserves to, the molecule deserves to be studied again if it can be studied without such a high placebo response rate.

I had to look it up. And you're right, it's hard. Come on, Jack, you can do it. No, no,

it's Ballinotun fib.

Doctor. Ballinotun fib. We're going to spend the rest of this podcast getting the name right. What's interesting about this is that Ian also presented another oral cytokine inhibitor in icotrokinra, which is the IL-twenty three oral agent from J and J for psoriasis that's being tested in psoriatic arthritis. So there's an oral IL-twenty three drug that does look good.

The other interesting thing about this, and I love that it's an oral drug, but I got my start in rheumatology. I went to a meeting, very first investigator meeting I went to was like in the Swiss Alps, had to take a train and whatnot. It was on Lenercept and Lenercept was Itanercept equivalent that targeted p55. And it failed for a number of reasons, not for efficacy, but a number of reasons. But that was the first TNF drug I ever saw, but it never made it to market and it had a lot of Achilles heels.

Maybe one of the issues here is that p55 may not be a really good target and they might have to find that out the hard way.

That's true. In terms of the high placebo response rate, probably about fifteen years ago at EULAR, I presented an oral abstract about a p thirty two map kinase trial, which had enrolled 200 patients. 100 patients were from Western Europe and the and North America. There was one from North America, 99 from Western Europe. The other 100 were from either South America or Eastern Europe.

The comparison was between North America, Western Europe versus Eastern Europe, South America. And there was a dose response in the Western Europe, North America group, 100 patients, but no dose response because of a very high placebo response rate in the South America, Eastern Europe group. So the company never wanted to go and publish it because they didn't want to offend potential clinical trial sites from those areas. But it was essentially a controlled trial looking at two different study site regions and the same trial, and it showed that there was a dose response in the North America, Western Europe sites, but not in South America, Eastern Europe. So the fact that this study was conducted at places where the placebo response rate was so high, it was somewhat doomed to fail.

Doctor. A sort of a question there. Like, how do they measure the placebo response? Is it patient reported outcomes or is it like objective, sole intended, joints? Because that makes a huge difference.

Oh, it's

ACR I'm sorry. It's ACR twenty. It's all of the outcome measures. The placebo response rate was high. But the problem is the question is, are the patients that are entered into the study truly on steady dose of methotrexate, or might they have been starting their methotrexate when they enrolled?

The charitable interpretation is that they became more compliant when they were in the clinical trial. I'll leave the other explanations up to people's imagination.

Okay. Let's move on to my selection, RA bridge, RA branch. I think this might have been the most important study in RA because it's an incredibly large study. It's a controlled study. It was FDA mandated.

You may not be aware of this. This is a LB009, that's three zeros and a nine, presented on the last day by Peter Taylor. And this was a post regulatory commitment by Lilly to study the risk of venous thromboembolic events, VTEs in patients receiving baricitinib. Baricitinib was approved by the FDA only at the lower dose because they were worried about problems with the higher dose. Was the first JAK inhibitor, actually the only JAK inhibitor that when it launched had a risk of VTE right from the start.

So like with tofacitinib, which had a regulatory commitment to do the oral surveillance study, they had this commitment to do a large, study. What they did was pretty much the same as oral surveillance. They had entry criteria for high risk individuals, and that was going to be people who had either a prior history of VTE over the age of 60, a BMI greater than thirty, or BMI twenty five to thirty with some other criterion. But just think about that, that's cardiovascular VTE risk and obesity and age, not that dissimilar from oral surveillance. And the people that went into the study were people who were either DMARRed, naive, or they could have actually received a prior biologic or target synthetic.

Two thirds were biologic or targeted synthetic naive. And they were randomized, over three thousand five hundred patients were randomized to receive either baricitinib two milligrams a day, four milligrams a day, or a TNF inhibitor. So there's three arms and they follow them, you know, until they got a certain number of VTEs that they could, adjudicate on. It turns out they didn't need to get to the end of the study. The study was about three and a half years, three and a half years of exposure.

And in the end, baricitinib at all doses two and four had significantly more venous thromboembolic events, DVTs or PEs, than did the TNF inhibitors. But unlike the oral surveillance study, the JAK inhibitor did not increase the risk of MACE events, major adverse cardiovascular events, mortality, arterial thrombosis, opportunistic infections. There was a significant but small risk of, serious infectious events with baricitinib over the TNF inhibitor. So that's the take home. It's different than oral surveillance.

It confirms, I think firmly stamps the risk of VTEs with these drugs. The question is, does it muddy up the concerns about cancer and cardiovascular risk? And you could say that, well, they're two different studies, oral surveillance in this study with two different entry criteria. Are they really that different? So I want commentary, but let me just go quickly go around and ask each of you, is this gonna change your thinking about oral surveillance?

Let me start with Bella. Yes or no and why?

A little bit, but I I think that this most importantly tells me that patient selection for JAKs is gonna be the key. There was another poster, zero one four five, POS zero one four five, which basically said obese patients don't do as well on JAKs. And there was this was, like, pooled trials from three three different trials. So, basically, it's just risk profiling, putting in the right patient for the right drug.

Janet?

I already think that Jacks are pretty safe, particularly in younger people, non smokers, etc, etc. So I think it didn't help that, like, it's not a nail in the coffin for Baricitinib because, of course, in North America, we can only get two milligrams anyway, and in US, you can only get it after TNF. So, I don't think it doesn't help, but I don't think it changes my mind on stuff, it's just it's kind of too bad. It's too bad that it was because the non non inferiority was almost reached on VTE, which is the primary outcome. It's the point estimate was where it should have been.

The confidence interval went a bit beyond that, and doesn't that sound like oral surveillance? The primary outcome was the same idea, that it was numerically higher on the MACE in oral surveillance, but the standard deviation was there, but it was a bit too far out on the bad guy end. So that's the problem with these trials, out the confidence interval around it, but numerically more infections, bit more cancer, cancer, more VTE, no increase in MACE, so it does depend on patient population.

Well again, the only thing that's not non inferior here is the VTE. And the non inferior margin, the upper limit was 1.8. So that was the case for the primary endpoint. A few of them did go higher than 1.8, MACE didn't, mortality didn't, ATE did, but it was really

Fair loss events,

so yeah.

And opportunistic was at really wide confidence interval. So again, I think this makes me feel better about what I do, which is I'm fairly liberal on this. Don't give it to really old people with heart disease and smokers. And that's like eight percent of my population who might get a Jack. Anyway, John, what do you think of this data?

Yeah, I think these data are confirmatory of oral surveillance other than for the VTE. My take on oral surveillance is that TNF inhibitors lower the risk of MACE and lower the risk of cancer. And that in that case, tofacitinib didn't lower it as much as the TNF inhibitors. So here, you know, I think it's also similar that the risks that are lowered by TNF inhibitors were not lowered more by baricitinib. Baricitinib is a different molecule from tofacitinib.

Tofacitinib is less selective. Baricitinib is a JAK1two inhibitor. Upadacitinib, which isn't even being talked about here, is a JAK1 selective agent. And then, the Chinese drug is even a more selective, JAK one inhibitor, and filgotinib is JAK one. So, you know, I I prescribe JAK inhibitors.

I take a JAK inhibitor. I'm not as worried about, JAK inhibition except in people who are who have lots of cardiovascular risk factors. But all the registry data seems to have gone against the conclusion of oral surveillance. So in the quote unquote real world, we're not seeing what is observed in these post marketing requirement studies.

You can't get a drug approved and you can't get a label change on registries and real world data. It could be part of the development plan, but it can't be the pivotal trial. I want to just clarify something that John said, which I agree with 100%, which is there's very, very good data that TNF inhibitors are very effective at lowering cardiovascular endpoint outcomes. And I don't know about cancer outcomes, we're going to talk about that next. But it's unclear that they lowered TNF inhibitors, lower the risk of VTEs.

I think VTEs are a separate phenomenon. And I think this study proved that really well by showing, I would argue the oral surveillance data, it wasn't that the JAK inhibitor was worse than the TNF, it's just that the TNF inhibitor was better than the JAK. And that could be a contrary argument that we go round and round about that you can't disentangle from design. But here, this was designed to look at the VTE and I think it shows it quite strongly. We could go on on this forever, let's not.

Bella, what's your big one for the day?

So talking about the right patients are doing well on the right drugs, this is abstract OP0112. This is looking at real world data, the RISE Registry, which is the ACR Registry of around sixty thousand patients with rheumatic conditions, and they looked at two GLP one receptor agonists, semaglutide and tirzepatide. And both of them are rapidly adopted in the past few years, as we all know. One thing that struck me was that around twenty one percent of rheumatoid arthritis patients were exposed to this, and then around thirteen percent of osteoarthritis patients were exposed to it at some point, especially amongst a population which has a a high baseline obesity around like BMI. The mean BMI was around thirty six of those who were exposed here and both agents caused or helped with clinically meaningful weight loss with tirzepatide achieving more reductions, which is known because it's because of the mechanism of action.

And even non diabetic patients were losing more weight than diabetic patients. Again, weight loss seemed to plateau at eight-twelve months and regained a little bit by eighteen months, you know, again that happens when either there is, you know, breaks in the way they're taking it and or some sort of resistance. But baseline disease activity burden was higher in these patients who were obese, diabetic. Patient reported outcomes were similar, but they also say that maybe there is improvement of patient reported outcomes as well as disease activity measures in patients who are on GLP-one medication. So I think that this just shows that, again, they didn't show all the data on pain function and all of that is I'm sure we'll see it see it at ECR because this is like they're sort of deep diving into this analysis Jeff Curtis and the group but what it shows is that we'll be prescribing these drugs along with all these DMARDs very very soon because in the right patient population, they might be game changing.

Yeah, we discussed this a few days ago in our panel on PSA that a high number of our patients are gonna be on this. You said twenty one and fourteen percent of-

Of that obesity group, right? Like, yes.

Oh, of the obesity group. Okay. Yeah. In The US, the general population, eight percent of adults are on GLP-one drugs. So I don't know how that equates to the obese RA and OA population, but it's still a high number.

And it says very clearly that you, the rheumatologist, need to know about these drugs, how they're to be used, whether they can be used in conjunction, and they can, with everything that you're doing and whether they will be adjunctive, and I believe that they will be. So I think this is all encouraging, but the company's got to step forward like Lilly stepped forward in doing the Together PSO and a Together PSA trial, a well designed controlled trial with an active control, that tells you what the impact of these drugs are and how safe they are. Without that, it's all anecdotalism. And we've been talking about GLP-one now for two years. So it's about time we get larger data, and this is good.

I mean, the RISE Registry is big, but I don't know how they're going to Could they do a target? If they have that many patients on drugs, could they not do a target emulation trial from the data set to make some kind of inferential message here? Again, it is not what it was designed to do. It's a little bit like looking at TriNetX large volume data. It's really hypothesis generating, but until we see the design trials, I don't know how else to proceed on this and whether I know I'm prescribing GLP-one drugs to my patients when I can get away with it.

Vast majority of rheumatologists are not, but some of us are. It seems like it's more in the PSA world than it is in the RA world. John, what do you think?

Well, to your comments about the PSA world, that's because more PSA patients are obese than rheumatoid arthritis patients, probably, because of the association between obesity and psoriatic arthritis. These drugs are amazing. They have pleiotropic effects. They're anti inflammatory. They lower cardiovascular risk.

They lower the risk of obesity associated cancers. They lower blood sugar. They lower blood pressure. They lower serum lipids. They change diet.

They change the brain. So I'm not at all surprised that patient reported outcomes are improved because of the cognitive effect of these drugs. Also, the patients are feeling better. They're more active. The biggest problem is that if the drug doesn't have an indication that the insurance company likes, they're not gonna cover it.

So patients who are being prescribed GLP-1s who don't have diabetes, it's very hard to get it covered. Even FDA approved indications like obstructive sleep apnea, insurance companies are saying, sorry, your hemoglobin A1c isn't high enough. You don't have diabetes. We're not going to cover it. The cost of all but the lowest two doses, two point five and five milligrams of tirzepatide on Lilly Direct, are $449 a month.

So for the vast majority of patients, that price is probably out of reach. I've had I've recommended GLP-one agonist to many of my patients, and those that have taken it feel great and they're really pleased with the results. Problem is once they're no longer covered and they have to stop it, they gain the weight back. So there really has to be societal reconsideration of these medications. They seem to be so good with the only real side effects being constipation and muscle loss, which can be addressed with frequent liquids, stool softeners, and weight lifting exercise and supplementary protein.

So, you know, this is a medication that is important to society. I don't wanna go off on a tangent and talk about single payer systems versus our system. But if we had a single payer system where the cost of treating the complications of all of these problems was the responsibility of the same payer who was paying for the GLP-one agonist, it wouldn't be a problem. That's why other countries are paying for them. But in our country, the average time on a given insurance plan is only a couple of years, which is why insurance companies make the business decision to not cover preventive therapies because they're not going to have to pay for the treatment of the complications.

Janet, how is this being handled in Canada?

So, it's highly variable because we have, global health insurance, we have multi payers. So the drugs are approved, of course, for weight loss. They're reimbursed in some private plans, not others. They're not reimbursed in the provincial plans, and the provincial funder is for the poorer people, the older people, and so people in the middle might or might not have coverage, so it's a big deal. But when we talk about the obesity epidemic, even in rheumatoid arthritis now in the brass cohort in The US and our Canadian early arthritis catch cohort.

One third of the patients are overweight, one third obese. So here's my question, which isn't really the question that you're asking me. But my question is, what about the patients that are normal weight without diabetes? Are they going to get the benefit, or is this all weight loss and because they're highly effective in weight loss? That's like the million dollar question.

It's a heavy question to answer, and nobody wants to do the studies in normal weight because that's not going to be an indication of, I don't think, of an adjunctive to DMARDs or to biological drugs in our patients with RA or PSA.

Yeah. Think, Janet, it depends on, you know, there are studies going on and they're trying to find there's receptors in the synovium, even in non obese patients. There is in RA

patients with the ubiquitous, right? Receptors are in Synovium. Somebody presented on that too on a biopsy study or something. But I think the receptors are all over. Like these small molecule peptides, or I'll call them gut hormones, are wavy on the gut, as Jonathan had just said.

Yeah.

Yeah. Yep. But, again, I talked to some colleagues from other countries, and it's $25 a month for semaglutide there, right? And this is out of pocket, not covered by Like, so there are a lot of cheaper options coming in in the market, so things might change. $25 or $30 a month is much, much more affordable.

And I I think that if I know these indications are not there right now, but in a few years, they will start coming in. I mean, if I have rheumatoid arthritis patients whose disease activity is completely you know, they're off meds because they're just better. So in in certain cases, it does work, like, phenomenally.

I had a patient with peripheral spondyloarthritis who didn't respond adequately to methotrexate alone, didn't respond to TNF inhibitors, was on an IL seventeen, anti IL seventeen antibody. I pushed that to the maximum dose with improvement, but still incomplete response. Even though she was normal weight, I put her on tirzepatide two point five milligrams weekly, and that pushed her over to responding to the anti IL-seventeen. So now that's an N of one anecdotal experience. But I think that the biology behind that makes sense, certainly with receptors on synovium, but also the anti inflammatory effect, which is probably more than just binding to receptors on synovium.

Problem is going to be that payers aren't going to be willing to pay for it.

Yep. I agree. And, also, as you get more and more of the the the double combo, I think there's even one that is proposed or maybe even out a triple combo where it's GLP one, GIP, and I forget what. They'll the, you know, the innovation will cost more money too. Yeah.

How about we we change over to maybe our rapid round, and and maybe I'll I'll start. So I was going to do OP0206. I think, Jonathan, you might have actually presented this in one of the room now things I'm covering for Ular last week. So this is the randomized controlled trial of split dose methotrexate twenty five milligrams a week split dose versus twenty five milligrams sub q once a week. I really kind of like this study because it answers a question.

So we already know that oral methotrexate at the higher doses isn't as well absorbed. We also know even though I forget to prescribe it this way, we know that split dose methotrexate divided over twelve to twenty four hours is better than the full dose at once, even though I forget to prescribe it that way. And there's been this thinking that once you're above fifteen milligrams of methotrexate, that SubQ will do better than oral. So this was a randomized controlled trial, six centers in India, I think two fifty two patients. And so it was to be a non inferiority where they said split dose methotrexate oral fifteen milligrams a.

M, ten milligrams p. M. Once a week should be about the same as twenty five milligrams sub q once a week. And you could add a DMARD at sixteen weeks if things weren't going well. So it was a very good pragmatic study.

So I guess the drum roll of the results is that twenty five milligrams Sub Q methotrexate was not non inferior, it was actually superior to fifteen milligrams a. M, ten milligrams p. M. Of oral methotrexate. So twenty five Sub Q was better on the primary outcome, so it wasn't inferior, it wasn't non inferior, it was superior.

But also some of the key secondary outcomes. You know what, in Canada there's a lot of Sub Q methotrexate. And I think it will change my practice because I often do oral methotrexate because they often start on combo CSD marts and I think it's a bit overwhelming. So, I liked it. I thought it was something that's a good take home message for me to maybe change my ways.

I agree. And I I did a RheumNow video while I was in London about this. There was a plenary presentation at the ACR meeting last year where they pointed out that split dose oral was better than not split dose oral. So with that plenary, that certainly changed my practice. And above fifteen milligrams and certainly above twenty milligrams, I go to split dose.

But this was really eye opening because split dose, I thought, was the answer. Patients would rather take oral methotrexate than give themselves a jab. And for a while, sub q methotrexate was unavailable, so I switched most people back to oral. But it points out that at doses of more than fifteen milligrams weekly, the receptors in the intestine for or in the stomach for the methotrexate are saturated. So just today, I had a patient on twenty milligrams of oral methotrexate once daily who was doing better but not completely better.

And rather than pushing her up to twenty five, I had her split her dose. So I had her take ten milligrams in the morning and ten milligrams in the evening based on this and the ACR plenary. So this certainly is one of those abstracts that changes practice.

I don't believe these results.

Do I believe them?

I don't because number one, there's so much data that shows that oral split dose is as good as parenteral. As far as actually, oh, there's a lot of very good PK studies that show on limited populations. And here the issue is, how do we know that the oral tablets were taken?

Well, that's what I was gonna say that I think that SubQ either took it or you didn't. My fear is when I have a patient on split dose, they're not going to I don't think we want them on taking it on Monday and Thursday. And so if they forget Monday evening and they go, Oh, Doctor. Pope said don't take it far later, that I wonder what the compliance is, not like the forgetful non adherence for the second dose. But I think in general, the idea makes sense.

The pharmacokinetics, even a split dose absorption or not, I mean, it's highly variable, that's the problem. It's not always obvious in

a patient. Not when you're talking at doses of less than when you're at 15, that's when the wheels are off the tracks as far as absorption. And if you're waiting for 20 and 25 to split your dose, you you missed the opportunity of 15. Anybody who's at fifteen should be on three pills BID Thursday, you know, with at least, you know, ten hours between. Because at seven and a half and 10, the absorption is very, very good.

Yes. And again, the PK studies, Arial and the Curve studies are really very, very clear about this. And so this open label in India where you're doing the 15 and the 10, think, anyway, that's just, by the way, that's the same design as the SMART study that John alluded to that was a plenary at ACR that showed that oral split dose was equal to parenteral.

No, that was equal it was superior to oral once a week. I don't they didn't do a sub q

oral. No. You're right. Right. It was this it was.

But that's why I think, you know, methotrexate old drugs sort of sometimes new ideas. I change my practice, then I don't. Like, I flip flop a bit, so I get where people are coming from.

Alright. We gotta move on. John.

So I'm gonna talk about another study where you might criticize where it was done. This is OP-two zero eight. This is a study that was done in China, randomized double blind placebo controlled phase three clinical trial that evaluated efficacy and safety of Zemprocitinib, which is a JAK1 oral small molecule drug. You know, why do we need another oral JAK? Well, we have upadacitinib, which is JAK1 selective in Europe, and the rest of the world, they also have filgotinib.

So this would be the third one. But according to the presenter, this is more selective, very highly selective for JAK1 with very little off target. It was a one to one randomization, twelve milligrams twice daily of the zempricitinib versus placebo in patients on stable conventional synthetic DMARD background therapy. And the primary endpoint was ACR 20 at week twenty four, and I think it was at week twenty four. Don't wanna anyhow, by week twelve, the there was clear separation with sempracitinib, much better response, rapid response compared to placebo, ACR 20, ACR 50, ACR 70.

DAS low disease activity or remission, C. Low disease activity or remission, DAS 28 remission. So, and the safety profile was comparable to placebo. So very positive study suggesting that this very highly selective JAK1 inhibitor is effective. I don't think it's gonna take off in The United States because people are so used to the JAK1 selective agent that we have, and the commercial market in The United States is much more complicated than that.

But it's nice to see that there's a trial where, active drug separates nicely from placebo.

Yeah, I mean, it's exciting and it's a lot like the other, I think it's the same molecule coming out of China, another JAK1 inhibitor that showed it was superior to tofacitinib, looking at ACR20 and fifty and seventy, but really, really high ACR20s. If they want real respect, they're going to have to do a global study. They're going to have to do this outside of China involving a lot of other populations. But right now, it's done, just as this is, why tell me about it if it's not going to be a tool that's going to be available worldwide? I don't know.

Think it's always a question of reproducibility always. There seems to be virtually no placebo effect, pretty safe, no dropouts or little dropouts in China compared to the rest of the world. So you're right, we've got to see something on other population to see if it's reproducible. But there you go, who knows?

So I want to present a great abstract POS that looks like 83 coming from Ascling and colleagues in Sweden. Prelude to this is many of you believe that there is a risk of lymphoma with TNF inhibitors. I don't believe that. It's in the package insert, but you weren't at the FDA hearing where they looked at the first three TNF inhibitors and showed that the risk of lymphoma, mainly non Hodgkin's lymphoma, B cell lymphomas, had an SIR or relative risk of two point five to six point three. They showed that that SIR, that increased risk with the first three TNF inhibitors was exactly the risk of RA patients developing lymphoma in the pre biologic era.

Hence, you've got enough inflammation to cause cancer, then it's a RA related risk and patients who are sick enough, inflamed enough to get on a JAK inhibitor, TNF inhibitor, it doesn't matter, they're going to have some signal there about lymphoma. And then to back that up, at the same time, there's a famous study by Baeklund, A E C K L U N D et al, showing that the risk of lymphoma in RA goes up with disease activity, disease severity by functional class and also by inflammatory load. And I'm talking like an odds ratio of seventy one with the highest levels of inflammation. So the question therefore is, if you would then control disease activity with effective therapies, especially TNF inhibitors, won't you lower the risk of lymphoma over time? And leave it to Asclean and their colleagues to do marvelous work using the, national Swedish registries, and they had, almost one hundred thousand RA patients matched by, birth year and sex to one to five to general population controls looking at lymphoma risk.

And they showed that the RA lymphoma risk was very high around two thousand, higher than the population, my fingers are apart. And then you look over time, the RA population stayed above the general population, and it kind of goes up and varies year to year. But the RA population was always more than the general population. And they did the hazard ratio, which was around two to three, kind of the same as relative risk odd ratio, relative SIR. And then they showed in different years starting in the mid 2000s, the rate of biologic use and it was going up and up and up.

They proved the point that greater biologic use didn't lower the lymphoma risk, but it didn't increase it either. So it doesn't give me the data I really expected, which was more effective therapy, lowers inflammation, lowers risk, that's not happening. There's other factors in play. But I'm going to play the advocate and say the exact opposite occurred here. By what they showed, they didn't prove in any other way, in any new way that biologics and TNF inhibitors increase the risk.

The risk stayed the same, even though the rates of drug use advanced biologic use went up. So this is I think a really interesting study. I still think you have to talk about lymphoma risk in your RA patients, and if you want to talk about when they go on TNF, go ahead and knock yourself out, but I'm not changing my therapy and what I want to use if there's a story of lymphoma involved. I let the patient make make up their mind and give them the information.

So you make a really important point there, Jack, that, lymphoma is a marker reflecting past disease activity, and biologic use is initiated in patients with high disease activity despite previous therapy. Eva Beckland's paper, which I think was Arthritis and Rheumatism around 2000, looked at the Swedish RA register and looked at lymphoma, and they divided them into deciles of disease activity. And it was that highest decile, the tenth decile, where the rate of lymphoma rose tremendously. I think you're right, 70 fold increase. And so the patients that are going to be on TNF inhibitors are the ones who have had high disease activity before they go on the TNF inhibitor, which is probably why you're seeing more lymphomas perhaps in that group.

But it doesn't mean that it's a causal effect. And in fact, the control of disease activity seems to lower lymphoma risk. So if you put those patients on TNF inhibitors early, you're probably lowering the risk of lymphoma. But the point that you bring up about lymphoma risk being associated with active inflammation and duration of active inflammation is most important.

I want to be clear with the audience that it doesn't affect my thinking because I have thought about this much, much more than most people. But you may be guided by the package insert, that's fine. And you could have that discussion about the risk of lymphoma with a TNF inhibitor or any drug. The good news for you is you got lots of options. And that's really the other good news.

Based on this study and what's going on before, is a very murky issue. Janet, you were going to say?

I was just going to say one we devil's advocate. It's probably also the HLA DR4 of some of our patients and whatever triggered their RA, so we'll just blame it on a virus. Because there are data of two things that non Hodgkin's lymphoma and MACE events have an elevated relative risk, highest in RA from a year before RA to a year after, but of course the cumulative effect goes up over time. So I think it's also whatever the in your body has possibly allowed you to get both a chronic autoimmune inflammatory disease like RA and has also allowed your B cells to go a little bit or T cells to go a little bit unchecked. So yes, cumulative high disease activity for decades has higher lymphoma, but getting RA, there's some kind of polygenic environmental thing that might increase your lymphoma even in our well controlled patients.

So, think we're always going have an increased risk in our RA population compared to the general population even when we get a lot of people into sustained remission. So just a wee devil's advocate way of looking at it as well.

That's fine. Bella, give us your last quickie.

So this is OP eleven. And, you know, I I especially thought of this because we're talking about all these drugs and how they help with patients, but fatigue is a big one. So, you know, this was a multicenter real world study with RA patients, and fatigue was highly prevalent affecting around forty three percent of the patients in this two hundred or three hundred patient group. And this was associated with high disease activity as well as comorbid depression. They did remove or exclude patients who had chronic fatigue syndrome.

Importantly, and that's what my takeaway was that there was no significant differences in fatigue prevalence across CSD mods, biologics or small molecules. So, suggesting that treatment class may not meaningfully impact fatigue levels, and maybe that's a whole separate pathway and a whole big problem that we are not completely addressing. And, again again, patients who had higher fatigue were patients who were on high glucocorticoids too. And, again, maybe that is also a marker of disease activity. But, overall, it just shows that we're treating sometimes inflamed joints, swollen joints, but, you know, fatigue, which is multifactorial and can be game changing for patients, still has an unmet needs in terms of even medications or even non pharmacological multidisciplinary management strategies.

Yeah, I mean, can be a real Achilles heel in patient management. Anyone who believes that they're treating fatigue when they say I'm treating RA and I'm using aggressive therapies has missed the boat because there's four other reasons why that patient is going to have fatigue. And they can be fixed with lifestyle and better sleep and counseling, and, you know, there's so much you have to deal with here. I think it's great when a company wants to say they have good PRO fatigue data on their, new drug in an RA population. But I'll remind you that two weeks before ACR, we had a report from a large lupus cohort, and it showed that fatigue and lupus had nothing to do with activity, it had to do with damage and depression.

And depression trumped damage big time. So it's sort of like the chronicity and severity of an overall disease and maybe like the moral distress that it causes on the patient, that it starts this other cascade going. As you say, there are many pathways into it. But, you know, in lupus where you'd figure it's got to be related to their SLEET I2K scores and their complement levels, and not at all the case. And I think that's true in all our diseases.

But anyway, John, how do you advise people about how they should address fatigue in their clinic?

Get a lot of sleep. And I I tell them be compliant with your antirheumatic drug therapy, but exercise oftentimes is helpful for fatigue. So I encourage aerobic exercise. I know you just got off of riding 10 miles on your bike, and that's terrific for fatigue. And then the usual sleep hygiene, you know, only go to sleep on a bed.

Don't take naps in the afternoon. Don't drink coffee before you go to bed. Put that iPhone away, before you go to sleep, and, don't wake up in the middle of the night and check your email. You know, those those common things. But, you know, disease controlling disease is the best I can do as a rheumatologist, but that's not enough, and patients need to maintain appropriate sleep hygiene.

In obese patients, obstructive sleep apnea is often ongoing. And patients who feel unrefreshed, what people call fibromyalgia, is oftentimes the manifestation of disturbed sleep pattern. GLP-1s are tremendously effective in helping patients who are overweight lose weight and improve their sleep apnea. It doesn't necessarily lead to resolution. But I have probably done more referrals to sleep specialists than any other specialist with my patients.

And patients who come in with chronic fatigue, chronic pain, the combination of the two, oftentimes are diagnosed with obstructive sleep apnea or if they're light, restless leg syndrome. My sleep specialist to whom I refer said that I have about a ninety nine percent accuracy rate in picking up obstructive sleep apnea based on those symptoms.

Yeah. All right, this is really helpful. I want to thank our panel for a great discussion on a lot of really important presentations from UR London twenty twenty six. Tune in for more of these panel discussions on RheumNow. Thanks everyone.