Trends and Innovations from Barcelona (6.2 Save

It's 06/20/2025. This is the RheumNow podcast. Hi. I'm doctor Jack Cush, executive editor of rheumnow.com. This is our EULAR wrap up.

This is where I get to wax and wane on things that I thought were important, hence the title, Trends and Innovations from Barcelona. Today, I'm gonna talk about a number of things around rheumatoid PSA guidelines, MAS, osteoarthritis, and large database studies. So I'm kind of winging this without exact data. I want to talk about what I think are the trends and the things that are new and that I see happening in our field. Again, like past recent ACRs and URs, a lot of abstracts presented trying to use machine learning, deep learning, AI to do something important.

I didn't see one of them that did anything important. You know, there was the usual ones of AI being better at reading X rays, And so that's fine, but that's been done before. There are way too many abstracts and presentations on the outcomes of withdrawing therapy. I've said it before, that's a special kind of stupid. Why would you spend your whole career and life trying to control these horribly difficult inflammatory and autoimmune mediated conditions only to try to stop therapy when things look good for six months?

That's nuts, and I'm gonna get to that under guidelines. So let me start with, what I think was a nice trend and, starting to evolve takeaway message on preclinical RA, at risk RA, or or, not yet RA with arthralgia, or what's better clinically suspect arthralgia. At this meeting, we had, long term follow-up of three really important studies that have defined this area of research in the last several years. The Epipra study with abatacep presented its six year follow-up. The, ARIA study, which was a six month abatacep versus placebo, is, and first reported with eighteen months follow-up, now has up to nine years of follow-up, but they're reporting four years long term data, and the treat earlier is giving you the sixty month data on methotrexate versus placebo.

Throw in with that the new one called PALABA. This is patients with palindromic rheumatism who receive either, abatacept or hydroxychloroquine. Let me get right to that one. That was a two year study, head to head, blinded, showing really that the hydroxychloroquine group had no benefit where twenty eight percent at two years developed RA, and the ABBA group showed some protection with only nine percent developing RA at two years. No long term extension.

But the other ones, two with abatacep and one with methotrexate, have take home messages. So let's go with what is their take home message? And should these drugs be used? As you know, TREAT earlier was a methotrexate versus placebo in patients who had subclinical arthritis and arthralgia. They could have been seronegative or seropositive, and you know their primary endpoint was not met, meaning methotrexate did not prevent or delay the onset of RA when you looked at all patients.

However, in their sub analyses, which they've reported in the literature, it's the seronegative patients who have high risk for progression, so they have high risk features, but they happen to be seronegative. They're the ones who showed, significant benefits out to sixty months or five years where the lines weren't getting close, suggesting that if you're seronegative and you have other risk factors for progression from CSA to RA, methotrexate looks like it might work. Also, they published last year that it was cost effective. So I like that result. Seronegatives, high risk methotrexate works.

But there are other trials where methotrexate didn't work, and methotrexate didn't work in aqua positive individuals. In the treat earlier, ACPA negative people, some of them were rheumatoid factor positive, but they were a minority. What's to take home from the APIPRA study? A two year study, one year of Avatacep versus placebo, second year everybody's off all drugs, and at one year it was something like thirty five versus nine percent, and it stayed significant out to two years, although the lines are starting to come together. Their four year follow-up shows that the lines do come together, but that there's a significant period of benefit and delay of RA onset if you receive one year of abatacept.

And who were these people? They were arthralgias, and ACPA plus They did not have to have subclinical synovitis on imaging. But what the take home message on that study was that if you had heightened autoimmunity, meaning if you had five autoantibodies that are associated with rheumatoid arthritis, and that included two ACPAs, one rheumatoid factor, you know, a carbamylated P antibody, and acetylcholine antibody of some sort, that basically said an autoantibody, extended autoantibody profile, or the five profile had benefit out to six years, and really no separation between the lines until six years, that you got a better response. So, strongly seropositive, double seropositive, high titer seropositive with RF and ACPA, or you could do all the other autoantibodies, then abatacept seems like it might one year of treatment will give you maybe four or five years of benefit. Great.

What about the ARIA? That was another abatacept trial where they got six months of placebo or six months of abatacept, followed for another year out to eighteen months, showing benefits. When they followed them out to four years, there was still a benefit to the people who received abatacept for just six months. But the predictors of long term benefit were people who at baseline had all the things that you associate with BEDRA risk, meaning many joints, a lot of pain, you know, acute phase reactants, etc. Functional deterioration or functional scores that were high.

So again, now we're getting a profile of who we might want to treat. And I think that the treatment trials thus far, backed up by the PALABA study showing hydroxychloroquine doesn't work, Backed up by the STOP RA trial from last year, hydroxychloroquine doesn't seem to work, right? Methotrexate may not work unless you're seronegative with high risk factors. Abitacib seems to work in many trials. But are you going to use it?

Is it going to change your therapy? Are you seeing enough of these people for this to even matter? That's really the question. Another innovation I think from this trial was the return of vagal nerve stimulation, as you know that was presented I think ten, twelve years ago by Mark Genovese with to much fanfare and an uncontrolled early phase two trial. Then other trials were done including trying to stimulate the, vagus by, electrodes in the earlobe.

That failed. Now we're back to implanting a stimulator near the carotid, near the vagal nerve by a neurosurgeon. It's the size of a vitamin pill. Half the group got an active stimulator that stimulated for one minute a day every day in this two year trial, or in the first, twelve weeks there was a pill there that was inactive, that was a sham, that wasn't stimulating, and they compared the outcomes and the outcomes looked good. You know, at six months, the results were, sorry, at twelve weeks, the results were only about thirty four percent for those that were on the stimulator versus twenty something percent on the sham.

If they stayed on the stimulator for another twelve weeks out to twenty four weeks, now the ACR 20s went up to 51, 52%, and the placebo crossover, sham crossovers sort of caught up. So kind of a slow onset of effect, but a gradual onset of effect. Again, the rationale here is that stimulating the vagus nerve leads to a reflex where you have a reduction in pro inflammatory cytokines, mainly TNF, but also other ones like IL-six. And maybe this is a way of doing this. There were some reactions or adverse events related to the neck and, you know, hoarseness and whatnot, but those were all none of those were permanent.

The safety looked okay. This was an, again, a solid phase two. They're gonna need to do a much larger phase three for this to go somewhere. The other big news from EULAR was the, update of the 2022 EULAR guidelines by doctor Joseph Smolin. They update those every three years.

Largely they were the same, but there were several take home messages. One, they reduced the number of guideline statements and recommendations by consolidating and simplifying. Two, they stressed the importance of prednisone from the outset in newly diagnosed RA, and that it should be low dose and that you should wean them off once you have them on effective therapy. Two, they affirm their allegiance to methotrexate as first line therapy for everyone by itself, maybe in some people you could add other drugs, but honestly really it's by itself. The next thing was that if you fail a conventional synthetic DMARD, methotrexate, if you can't take methotrexate you take buffalinamide or something else, if you fail one of those, just one conventional DMART, in the past guidelines, whether you got another conventional DMART or whether you went on to biologics as an add on was based on the presence of positive predictive factors The ACR had done away with those in their guidelines.

The Ulor had them in twenty twenty two but they're gone now in 2025, and they're saying that if you fail methotrexate, whether you have positive predictive factors, and that would be erosions, high titers, functional deterioration, many joints, that sort of thing, that you immediately go on to adding a biologic or targeted synthetic and an asterisk for the targeted synthetic meaning that you don't want to use a JAK inhibitor if they have risk factors for JAK inhibitor adverse events including the cardiovascular malignancy ones. So they're pretty much recommending biologics, in some people JAKs if that's allowable. So it's pretty much one and done, and that kind of flies in the face of what's currently going on, but they showed some data that really sort of supports that, you'll have to look at the paper. And lastly, it comes to people who are in remission for an extended period, six months or one year, they say you can change the dosing interval. Well, first off, you can't change the biologic or the DMAR therapy until you withdraw steroids.

If you can withdraw steroids, then you can change the biologic by changing the interval or changing the dose, but they underscore exclamation point, a few, capitalizations that say you don't stop therapy. Going to my earlier point, it's a special kind of crazy to want to stop therapy in someone who's had active RA for one, two or three years. Chances of true disease free, drug free disease remission off drugs is way less than ten percent. I don't know why you'd do it. Kudos to EULAR for their very aggressive approach to guidelines.

They had guidelines on ILD and RA, ILD in connective tissue diseases, physical activity for those, with arthritis, guidelines and recommendations for APL, anti phospholipid syndrome management, patient education. They did their update to lupus nephritis. It's kind of the same, but it is a little different and worth a look. They had, criteria for, and management of familial Mediterranean fever. Criteria for the antisynthetase syndrome, classification criteria for hemochromatosis, and points to consider with difficult to treat psoriatic arthritis.

So I'm going to talk about that for a second. Difficult to treat PSA. Actually, it was tackled by two different groups, by the GRAPA group, who's got great guidelines on PSA management, and a EULAR multidisciplinary group. And they kind of did the same thing. They did something different than what's going on in RA, where difficult to treat RA are people who failed two or more biologics and had an active disease, and patient and doctor were in agreement they weren't doing so good, and then they move on, Right?

And then so we've seen a lot of studies in the D2TRA world, and we've seen some clarity in the D2TRA world by basically saying that if you are D2TRA, you should be classified as MIRA or Pira. NEARa is non inflammatory persist persistent, refractory RA. Pira is persistent inflammatory refractory RA. The persistent inflammatories have signs of inflammation, swelling, MRIs, acute phase reactants, etcetera. NEARa are people with obesity, depression, fibromyalgia, poor sleep, and functional problems, right?

So at EULAR, both GRAPA and the EULAR group came up with two classification screens. The bigger one is called c two c two m, complex to manage, that's the GrappaLit name, or d two m, difficult to manage. GrappaLitinJews, difficult to manage because it's politically incorrect to call patients difficult. They're gonna get their lawyer after you, that won't end up well. But this is a larger group.

It could be in different series as large as thirty percent, in some series fifteen percent. And then there's a smaller group of difficult to manage patients called treatment refractory PSA. And by the same, same terminology here, it was also discussed and presented for SPA at the meeting. Complex to manage, difficult to manage, and then a smaller group, one third or less of the bigger C2M group, are refractory to manage, and in that group they supposedly have to have signs of acute phase reactants being elevated, measures of inflammation, along with MRI evidence of synovitis. Same thing for the spondylitis patients.

So, you might have ten percent with C2M and PSA, but only two or three percent with refractory, or in other series where it's twenty thirty percent with C2M, you know, third of those, maybe ten percent are gonna be refractory. The point is the refractory, the inflammatory ones, are kinda like the Piras with D2T RA, the difficult to treat RA patients. They have signs of inflammation, and those are the ones you're gonna use your new therapies, aggressive anti inflammatory or immunomodulatory therapies, your expensive biologics. But in the larger group, you've gotta treat the whole patient. You've got to go towards managing comorbidities.

You've got to manage sleep, you've to manage pain, you've to manage depression and anxiety. And that's where this is going. My problem with the PSA and the spondylitis rework of what they did in RA is that because someone has a positive MR, doesn't mean that they're gonna have or gonna be responsive to the sixth biologic that you're trying, the fourth biologic you're trying. Once you fail a biologic, you're likely to fail the second, third, fourth, and fifth. So how do you ensure a better response?

Just because they have a high CRP doesn't mean that they're going to respond. CRP never predicted IL-six responsiveness in any disease that I know of. And there's a large subset of patients with inflammatory arthritis that have normal SED rates and CRPs. So a lot of this has got to be worked out in clinical trials. Good luck to these groups, I'm sure they're in fact going to do this.

Hemochromatosis guidelines I thought were very cool, worked through a look, look at what we covered in RheumNow on this. It's a point system, most of the criteria had one point, you had to have five or more points out of a total 11 points, you got two points for being age less than 50, two points for having no DIP involvement, and then you got one point each for the iron fist. Iron fist was when you make a fist, knuckles two and three are higher than knuckles three and four due to owing to the bony hypertrophy. So it kind of sticks out like rabbit ears, if you will. That's the iron fist sign.

And then the the next criterion was involvement of MCP two, three, or four, not just two, two, three, or four. Two points for hip or ankle surgery, I don't know why that was there, but that was there. JSN, joint space narrowing in either MCPs, hip or ankle, gets one point, and hook osteophytes in those joints gets you one point. I thought it was a great presentation. The innovation, there are a lot of new drugs that are getting closer, to marketability, especially in psoriatic arthritis where we don't have enough sore- wait, wait, I think we have too many drugs, do we not, in psoriatic arthritis?

Well, there's supposedly an unmet need out there, and most of you are crying for these new drugs, so be careful what you ask for or cry about. Tucavacitinib, which you know is approved as a TYK2 inhibitor in psoriasis, is getting closer with this phase two trial, the POET YK PSA1 study was presented by Desiree Vanderheide. The, results were impressive as far as an ACR 20 of fifty percent and a delta over placebo of more than twenty percent, with good outcomes in all other measures, MDA, PROs, dactylitis, enthesitis, she presented the X-ray data, which their initial analysis was negative, but they wrongly considered the analysis, and when they did the right analysis with the right patients, it showed significant x-ray protection for those treated with the TYK2 inhibitor, ducravacitinib, compared to placebo at sixteen weeks. Not easy to do, but it was significant at that point. Was it clinically meaningful?

We'll see, but that's a positive, making that drug on its way probably to FDA approval in the next year. The other, IL-17AF inhibitor, you know, there's there's bimekizumab, there's, the, SKYRIZI one, which, the name just alludes me right now, and then there's another one from Moon Lake called Sonalicimab. It's an AF inhibitor that also showed good phase three data, and I think that's exciting. The other innovation is icotrokinra, which is for a drug study from J and J. This is their oral IL-twenty three inhibitor.

They only have trials at this point in psoriasis, plaque psoriasis. I would assume down the line we'll be seeing, the oral IL-twenty three inhibitor in PSA trials. I'm sure that those are underway. A great presentation by, a trio of great investigators on MAS, led by Fabrizio De Benedetti who really went over the biology of MAS largely in STILS showing the importance of CD8 cells, IL-eighteen as a predictive variable, you've got more than 45,000 picograms per ml, it predicts that you're gonna get MAS in with systemic JIA or STILS, and then gamma interferon driving the whole process coming from those activated CD8 cells. You can't measure gamma interferon, you can measure CXCL9, the chemokine, as a surrogate measure, showing great data for the gamma interferon inhibitor emapalumab, but also other, measures to target these three drivers of MAs, targeting CD8 cells, that would be with etoposide and calcineurin inhibitors, maybe even with JAK inhibitors.

IL-eighteen binding protein would be probably very effective in this, and we do know that emapalumab is probably up for FDA consideration in Still's disease. There were, there are three new drugs for OA that are in development. They're all gene therapy. Single gene injections into an OA knee, Kelgan grade two, three or four, and the gene that they're injecting, either with a adenovirus vector or sort of a pseudo vector, delivers a dose of IL-one receptor antagonist that stays in the joint, and is in the joint in these three trials. One was recently published, one was presented at EULAR and another one, is out there, also available with, the information.

Again, trials from nine patients to sixty patients, but this looks very very promising. Study, I saw the data that said that the IL-one RA is released in the joint for beyond a year, as long as three years, and that it is released in response to IL-one being released. So, it kind of matches what's going on. As you know, IL-one and inflammation is an intermittent event in osteoarthritis and probably a driver to some extent, probably not the full extent, to what is clinically manifest OA of the knee. These will be significant, but they're very early in development.

We now need to see some large solid phase two and then phase three trials. I want to speak, quickly about, TriNetX, and Jackpot. These two names appear in a lot of abstracts, and they do because the numbers are incredible. TriNetX is a worldwide network of registries based on EMR data. So, you'll see a TriNetX report looking at a 100,000,000 people and they found, you know, four thirty with a rare, rare, rare condition and they got a control for it, and they're gonna make a claim.

You can go and play with Trinetics and do your own research and do your own propensity matching, but that's like the street version of it, which isn't very good in my opinion and fraught with all kinds of problems. The same can be said for a jackpot. Jackpot is a worldwide set of registries up to 20 registries, up to 20,000 patients with up to 60,000 treatment courses in RA. The jackpot was started after the Jack's hit the market and is sponsored by, I don't know, five, six, seven different drug companies, and a lot of data gets presented. So at this meeting there was a jackpot presentation, tremendous numbers, know, I think it was, it was twenty six thousand people on TNF inhibitors and three thousand five hundred on a JAK inhibitor, and they looked at cancer rates, in this jackpot, basically showing no increased risk of cancer with JAK inhibitors compared to TNF or compared to other MOA mechanism of action biologics.

But I don't know that this is, for either of these that this answers any question. First off, the Jackpot study on cancer was meant to be modeled after what the inclusion criteria for oral surveillance was, so as to refute oral surveillance. You can't refute oral surveillance, which is a five year double blind randomized placebo controlled trial with over 4,000 patients, you can't refute it unless you got your own double blind trial. When you do a target emulation or one of these jackpot emulations, you know, the best you can do is come up with a hypothesis. So these are at best hypothesis generating, not proof of principle in any way.

So my point is look at such data with a little bit of doubt and a jaded opinion. I'll give you two more nuggets that I think were important. And one comes, bottom line, rheumatoid factor should be measured in patients with EGPA, the eosinophil with granulomatosis and polyangiitis. You know, why? In their study, they reported on eighty five patients, in whom they had data on and they had noticed just generally in practice that that EGPA patients who are rheumatoid factor positive seemed like they were doing worse.

So, they went back into their data set, found two hundred EGPA patients, they found eighty six of them in whom rheumatoid factor was measured, usually as an initial test done when patients were being newly diagnosed, newly considered, alright? They weren't being done as part of EGPA management. They had eighty six and they showed that the ones who were rheumatoid factor positive were more likely to have relapses, were more likely to have higher CRPs, and were more likely to not do so well. So I found that really interesting. It might go to what I was talking about earlier with rheumatoid factor and clinically suspect arthralgia.

Heightened immunologic activity may mean that you're at greater risk, right? And the last thing was a resubmission of the MODE study that was presented at you at ACR in November 2024. The MODE study was a 58 patient study showing those on methotrexate versus placebo in the treatment of PMR showed no benefit. Wait a second, they had a misclassification error they discovered after the meeting. They resubmitted their abstract with the same patient, same design, with the correctly classified patients, and now they show a significantly better response with methotrexate.

According to their primary endpoint was the PMR activity score being less than 10 and being off of glucocorticoids. I think it's a little not so clean that it clearly works, and I think the area of whether you should use methotrexate or not in patients with PMR is still a muddied one. But this was an important reclassification and resubmission of the data, and I look forward to actually reading the paper. Hope you enjoyed this podcast. Tune in next week.

We'll be back in action post EULAR.