EULAR 2025 - Day 3 podcast Save

You're listening to a RheumNow podcast coming to you from Barcelona, Spain and ULUR twenty twenty five. Hope you enjoy it.

Hello. This is Eric Ruterman coming to you, for RheumNow from the ULUR meeting, in Barcelona. I wanted to talk about, a semi new drug, a drug called ducravacitinib, a TYK2 inhibitor, that's been approved for about a year now for treatment of psoriasis. And we've seen phase two data in psoriatic arthritis and assume that eventually this is a drug that would become available. At this meeting, two abstracts are presented with the two large phase three clinical trials of about 700 patients in each one.

Looking at dukravacitinib versus placebo to treat psoriatic arthritis. The upside of this drug is that it, is an oral agent. It's given once a day. It's very specific, for tick two as opposed to other members of the Jack family, which seems to reduce the risk of toxicity. Certainly, it seems to reduce the risk of some of the laboratory abnormalities that can see be seen with other Jack inhibitors and so far, it has not been associated with some of the other issues, the cardiovascular issues and so forth that have been associated potentially with other JAK inhibitors.

They presented two large phase three trials at this meeting. Both run-in parallel and and largely similar protocols. One compared ducravacitinib to placebo, and they included a safety reference arm of a premilast, not for efficacy, but just to look at some of the safety. Dugravis, it was effective. It was statistically better than placebo, though the placebo response interestingly was quite high in that trial.

It was more effective, at least nominally than a premilast, though it wasn't powered to really, test that statistically. And it did have actually fewer side effects. It did not have the GI side effects that are, often seen with, premilast, the nausea and the diarrhea. The second trial looked at ducravacitinib versus placebo and selected for patients who were at higher risk for joint damage. These are patients who had at least one erosion upon entry into the trial.

And they were able to look at x-ray data in the trial. The pre specified x-ray analysis did not meet its endpoint, but they presented some secondary analyses that have looked at that and suggested that, looked at another way. This may in fact, halt or at least slow radiograph progression. What I don't know is where this drug is going to fit It it appears to be effective. We really have no comparative data, including no really statistically valid comparative data against the premilast.

It does seem to be effective. Is it, more effective than a premilast? Probably. Is it as effective as, some of the other biologics we're using? Don't know.

Probably not, but we don't know. And I think it'll be really interesting, when this gets to the clinic, which it will at some point, probably within the next year based on these trials for psoriatic arthritis. It'll be interesting to see where people want to fit this in. It's intriguing to think about a once daily oral medication with very few side effects and and sort of stack that up against some of our other options, other oral drugs that may have more side effects or require more monitoring like methotrexate or against injectable drugs. I think that as people begin to use it, where it fits in will become more clear as they try to understand, you know, which patients respond, which patients seem to want an oral agent.

So, it's an area to stay tuned in, but I think it was really intriguing at this meeting to see the phase three data, to see that this is a drug that's going to work. And it's definitely a drug that I think will become part of our toolkit, where the toolkit it fits has yet to be seen. And, with that, this is Eric Ruderman again, coming to you for room now, from Barcelona, the EULAR meeting.

Hi, everyone. This is Adela Castro from Memphis, Tennessee, reporting from EULAR here in Barcelona. And I want to summarize a little bit of the How to Treat session today in the updates of asthma management, particularly in the lessons learned from uveitis. It is important to remember that up to forty percent of patients with uveitis present before the diagnosis of axfa and uveitis itself has been associated with longer time to diagnosis in patients with axfa. Regarding treatment, it was reported a network meta analysis of 44 clinical trials that showed that all standard of care, including TNF inhibitors, IL-seventeen inhibitors, and JAK inhibitors, are effective for management of anterior uveitis and are actually protective against uveitis in patients with asthma.

Something that was also noted here in this session was that there were very low rates of uveitis in patients with bimekizumab, which means that bimekizumab could also be protective against anterior uveitis. For more, follow-up over here at RheumNow.

Hello, I'm Anthony Chan. I'm reporting, from Barcelona, EULA twenty twenty five for RheumNow. And there have been a lot of, important discussions about difficult to treat in the field of spondyloarthritis at this meeting and today I'm delighted to have, Marina Margreave from Cleveland, USA who presented a very nice work, looking at, risk factors for the detection of a difficult to treat in ankylosing spondylitis. So Marina, welcome and I wonder whether you could tell us about your poster.

Thank you for inviting me for you know to present this abstract And you know, this we have all faced in our clinical practice these conundrums of some patients that do not respond to treatment or some that have difficult to manage. So in order to look at some risk stratification, we explored a database called TriNetX. It's a large global database. It has information from 86 healthcare organizations with about 125,000,000 patients. And we use the ICD-nine or 10 code for ankylosing spondylitis.

And then we looked at those patients, you know, using the ASAS definition for difficult to treat, which was published recently. So those patients that had actually failed two or more of biologic DMARDs and also had an elevated CRP. So we tried to take a very stringent patient population, those which had active inflammation and had failed at least two biologics from two different classes. So we found there were about ninety one thousand patients. And out of that, the prevalence for difficult to treat was actually very small.

It was about two thousand two hundred patients, which were difficult to treat based on that definition. So the oral prevalence was low. It was lower than there were a lot of other abstracts that were presented at EULAR this year regarding difficult to treat from different countries and ours was the lowest prevalence. And the reason for that was because we used the stringent criteria of elevated CRP and these patients median CRP was high. So, when we looked at their baseline characteristics, these patients who were difficult to treat, they were more females and they were actually had high BMI, they were obese, they had a lot of extra articular manifestations, psoriasis, inflammatory bowel disease, comorbidities were there, and then we used multi variable regression analysis to identify those factors at baseline, which increase the risk of these patients being difficult to treat.

And these patients were HLA B27 positive females, mainly they were the high BMI's obese and had a comorbidity of depression. So, I felt it is important for us as a clinician to understand this because these may be the patient when we see them in our practices start thinking about the response to treatment and educate them at the very beginning that there may be some modifications, lifestyle modifications they may need to do in order to respond better, maybe try lose weight. And if there are any comorbidities, we need to handle them too, so that the response to treatment increases.

Very nice work. A lot of patients in your analysis as well. Were there any particular factors that were you know waiting strongly or more independent for the prediction of a D2T?

Yeah, so we tried doing like, you know, some sensitivity analysis to avoid confounders between since the two groups are so different in N numbers and the only three things that in the end that stood up was BMI, obesity and depression and HLA B27 positivity.

And how about, you know, sex, male or female? Was there any

There was, yeah, females were obviously larger in number in the difficult to treat patients. And that's kind of, you know, shown by all the abstracts that were presented there. Hewlett, every one of them had the risk was higher in females than males. And it's an interesting question in terms of, you know, response to treatment also differs and it's usually delayed in females compared to males and we still haven't been able to nail it, nailed it further, whether it's because of biological difference. Is it because you know central sensitization in females that the we are not able to get the pain under control?

Is it a different disease phenotype?

Yeah, that's very interesting and wonder whether we should have a different outcome measures sometimes for different groups of population. What's the next step from here? I mean, you've done some great work. You've identified this cohort. What would you be sort of thinking of doing in in sense of following up from this study?

We are actually that's a very important question you asked, and we are actually trying to see if we could do some transcriptome studies to see if there is a difference in you know some genetic differences between these two groups and looking for other like you know inflammatory pathways that may be driving this inflammation in these patients who are difficult to treat.

Yeah, I think that will be very important for us, especially when we are thinking of the treatments as well, and how we are moving from one treatment to the other, and trying to identify the patients who are at most at risk. Are there any plans to you know look at the other cohort which is what we call it difficult to manage where maybe they have less objective or less inflammation and more non inflammatory pain?

You know, this database actually doesn't give us that kind of, you know, information like about what was the patient's perception of their disease, patient reported outcomes to look at that, whether other than that's why we use the stringent criteria, but in, you know, we do have a registry at our institution where now we may be able to look at that group separately and see if there is, because we have been collecting longitudinal data for some time now. So we do have some longitudinal data seeing how the patients are perceiving. We give them questionnaires, patient reported outcomes to do them at home after every visit. So that may help us to understand if there is some other factors that are impacting this.

Yeah, I think that's one of the challenges that we have seen here at EULA twenty five, the some of the other known inflammatory factors that sometimes can affect the outcome measures that we are using. So Marina thank you very much for your time and thank you for sharing with us your great work. So everyone this is a poster zero one hundred seventeen presented on the poster tour at Eula twenty twenty five. I'm Anthony Chan presenting for RheumNow. Thank you very much.

Thank you, RheumNow. You guys are doing a great job in disseminating all this information from EULA.

Good. Thank you. Bye.

Bye bye.

Hi, everyone. This is Adela Castro from Memphis, Tennessee reporting here from Euler in Barcelona, and I'm gonna discuss the abstract OP zero three ten. And in this abstract, this is data from the state cohort, which analyzes the difference between structural lesions on MRI of the spine between patients with early asthma and patients with non asthma and chronic back pain for two years. The patients on this study underwent imaging at baseline and two years follow-up. And it was found that at baseline, both groups were similar in conventional S rays.

However, two years later, patients with asthma had significant difference compared to baseline, predominantly showing a little bit of undermines on the fat lesions. And this was not observed in patients that did not have asthma. So this is what's shown that, you know, the significant change on fat lesions can be a potential signal of structural lesions in patients with asthma. For more, follow-up in and in now.

Hello, I'm Jonathan K from UMass Chan Medical School in Worcester, Massachusetts, reporting for RheumNow from Barcelona, Spain at EULAR twenty twenty five. Today there were several posters about JAK inhibitors, and the first was one from the jackpot registry, which is a combination of registries from several European Union countries that looked at use of JAK inhibitors and correlated it with various events, such as the FDA boxed warning about cardiovascular and malignancy risk, similar warning from EMA, the presentation of the oral surveillance study at the American College of Rheumatology meeting. And what this found was that there was a drop off in prescription of JAK inhibitors after each of these events, but one that recovered. The largest proportion of JAK inhibitor prescriptions in the European Union tends to be for baricitinib, with a smaller proportion and a decreasing proportion of tofacitinib and an increasing proportion of upadacitinib and also filgotinib. So this was the jackpot study, poster 150.

And then right adjacent was a presentation by Roy Fleishman on behalf of AbbVie, looking at the combined safety data for upadacitinib, looking at various adverse events and correlating them with disease activity. The oral surveillance study, which identified increased cardiovascular and malignancy risk in tofacitinib compared to TNF inhibitors, or at least did not identify a similar or lower risk than the anti TNF therapy. The upadacitinib data looked at correlation between disease activity and the various adverse events and found that cardiovascular events, major adverse cardiovascular events, venous thromboembolic events, and malignancies increased with higher disease activity, as would be expected, because inflammation predisposes to these adverse events, whereas herpes zoster was not increased based upon different levels of disease activity. And the final presentation, the poster 157, was one which looked at the safety of JAK inhibition in patients with underlying interstitial lung disease, comparing that of JAK inhibitors to abatacept, which is a biologic DMARD that is considered to be fairly safe for use in patients with underlying interstitial lung disease. This presentation found that the efficacy of JAK inhibition in patients with rheumatoid arthritis and interstitial lung disease was comparable to that of abatacept over time and found that there was no increase no worsening of interstitial lung disease in patients treated with JAK inhibitors, similar to that which has been observed in the past in patients treated with abatacept.

So these three posters taken together show that JAK inhibition is safe in patients with underlying interstitial lung disease. The degree of underlying inflammation in rheumatoid arthritis tends to correlate with the risk of developing major adverse cardiovascular events, venous thromboembolic events, and malignancy, but not herpes zoster. And finally, that the announcement of boxed warnings by regulatory agencies or the presentation of data raising some safety concerns about JAK inhibitors caused a transient decrease in the prescription of JAK inhibition in the European Union countries. And the overall prescription of tofacitinib has decreased over time, whereas that of upadacitinib and filgotinib has increased, and baricitinib remains the predominant JAK inhibitor used in this European Union registry. For more information about this and other presentations at ULAAR twenty twenty five in Barcelona, Spain, go to RheumNow.

And this is Jonathan Kay from UMass Chan Medical School in Worcester, Massachusetts, and I look forward to seeing you again soon on RheumNow. Hello. I'm Jonathan Kay from UMass Chan Medical School in Worcester, Massachusetts, reporting for RheumNow at EULAR twenty twenty five in Barcelona, Spain. Over the past two days, there have been a number of abstracts about what's called difficult to treat rheumatoid arthritis. Difficult to treat rheumatoid arthritis has been defined as patients with active disease despite at least two biologic or targeted synthetic disease modifying antirheumatic drugs.

This population constitutes about twenty percent of patients with rheumatoid arthritis. There have been a number of posters about difficult to treat rheumatoid arthritis characterizing the response of these patients or lack of response to various therapies and also looking at some of the factors that predispose to having difficult to treat rheumatoid arthritis. The first abstract that I'll talk about is poster 27, which came from Leeds in The United Kingdom. And this was an analysis of three rheumatoid arthritis trials conducted between 2,005 2017 comparing anti TNF therapy with conventional synthetic DMART treatment. They looked at one hundred and fourteen patients treated with anti TNF therapy and two twenty eight treated with conventional synthetic DMARDs.

And at five years, they found that fewer than 1% of anti TNF treated patients met the criteria for difficult to treat rheumatoid arthritis. And at ten years, anti TNF treated patients were two and a half times more likely to be on a single biologic DMARD and not meet criteria for difficult to treat rheumatoid arthritis and were twice as likely to be in sustained remission than those who had been treated initially with conventional synthetic DMARCs. Another poster, poster 28, looked at musculoskeletal ultrasound in patients with difficult to treat rheumatoid arthritis. And they defined a population of subclinical persistent inflammatory refractory rheumatoid arthritis as those individuals with ultrasound evidence of synovitis but no swollen joints. They found that the highest prevalence site of inflammation by musculoskeletal ultrasound in these patients was the risks in nearly fifty seven percent of patients with persistent disease and in fifty two percent of those with subclinical disease, ultrasound evidence, but not clinical evidence of a swollen joint.

In patients with subclinical disease, they found that involvement of the ankles and metatarsophalangeal joints was frequently observed in nearly forty three percent of patients. And most interestingly, they observed tendon involvement in both groups and more frequently in those without swollen joints but with ultrasound evidence of synovitis. So they concluded that musculoskeletal ultrasound is a useful modality to detect joint and tendon inflammation, even in patients with difficult to treat rheumatoid arthritis and without clinical synovitis. There was another study presented, poster 185, from the group in Torino, Italy, who looked at clinical and ultrasound predictors of difficult to treat rheumatoid arthritis in patients using musculoskeletal ultrasound. And they confirmed that the presence of active tenosynovitis in any joint in difficult to treat rheumatoid arthritis patients was associated with higher global disease activity scores and suggested that tendinous inflammatory disease is important in determining the difficult to treat rheumatoid arthritis phenotype.

In terms of prediction of who is going to have refractory rheumatoid arthritis, the group from Manchester, UK, in poster 30 looked at two thousand and fifty nine patients from a United Kingdom cohort of patients with inflammatory immune mediated diseases. And they found 13 significant predictors of refractory rheumatoid arthritis using stepwise logistic regression from an initial pool of 83 factors. And they identified or confirmed established risk factors, low financial status, a history of arthroplasty, chronic use of steroids, and chronic use of NSAIDs. But they also found, surprisingly, some independent factors that predisposed to difficult to treat rheumatoid arthritis, cardiovascular comorbidities such as hypertension, hyperlipidemia, and atrial fibrillation, a history of cancer, and most interestingly, obsessive compulsive disorder and reduced participation in leisure activities. So this raises the question, did the obsessive compulsive disorder and reduced participation in leisure activities contribute to the refractoriness?

This was addressed to some extent in a poster presented by the group from the Canadian Early Rheumatoid Arthritis Cohort, or CATCH RA, who looked at patients with symptoms of rheumatoid arthritis of less than one year duration between 2017 and 2022 who had active disease on methotrexate monotherapy or on a conventional synthetic DMARD combination. And these patients underwent standardized clinical assessments and completed the PROMISE 29 questionnaire at zero and three months. And they identified anxiety, depression, fatigue, and pain interference by having a PROMISE score of at least 55 compared to those with a lower score. And they compared these two groups based by symptom status. And they found that more than twice as many patients who were anxious at three months compared to those who weren't anxious were on advanced therapies at 12, fifteen percent compared to seven percent, and observed a similar trend at twenty four months, eighteen percent compared to ten percent.

The advanced therapy use did not differ significantly by pain, fatigue, or depression status at three months, but only by anxiety status. So they determined that the optimal model to predict the need for advanced therapy by twelve months included anxiety and disease activity, as assessed by the Clinical Disease Activity Index, or CDI, at three months after adjusting for age, sex, race, education, smoking status, obesity, comorbidities, serology, and symptom duration. And patients who were anxious at three months had five times the odds of being on an advanced therapy at one year, with a similar trend at twenty four months, where the odds ratio was three times greater for individuals with anxiety. So the conclusion of this study was that anxiety at three months, but not depression, fatigue, or pain, predicted worse clinical disease activity, patient reported outcomes, and a three to fivefold greater odds of requiring advanced therapy use by twelve and twenty four months. So that suggests that anxiety, obsessive compulsive disorder, and reduced participation in leisure activities contribute to refractoriness to therapy in patients with rheumatoid arthritis.

So these studies put together suggest that anti TNF therapy early on may reduce the likelihood of refractory rheumatoid arthritis. The identification of tendon involvement or active tenosynovitis predicts a difficult to treat rheumatoid arthritis phenotype when looking using musculoskeletal ultrasound. And then risk factors, especially and surprisingly, including obsessive compulsive disorder, reduced participation in leisure activities, and anxiety contribute to the refractoriness to therapy for rheumatoid arthritis. So this population of patients with difficult to treat rheumatoid arthritis, which constitutes about twenty percent of patients with rheumatoid arthritis, may be predisposed to by certain personality attributes as well as by tendon inflammation. For more on this and other topics presented at ULAr twenty twenty five, tune into RheumNow, and I look forward to seeing you again soon.

This is Jonathan K from UMass Chan Medical School in Worcester, Massachusetts.

Hi, everyone. This is Doctor. Jeeha Li reporting for RheumNow for ULUR twenty twenty five in Barcelona, Spain. Today, I'm sharing new real world data that may challenge our assumptions about conventional synthetic DMARC combinations in RA treatment. This is abstract number 0P or OP0195.

It is titled, Is the Association of Methotrexate and Losartan A Safe Strategy? A Cross Sectional Analysis of the REAL Study, REAL. So as the title alludes, this is a multicenter observational study from Brazil that evaluated the long term safety of methotrexate plus losartanamide. Now, this isn't a combination that many clinicians use, because of this safety concerns, particularly regarding hepatotoxicity. And I personally can attest I've never really used this combination.

But the authors ask, are these concerns really justified? And they set out to answer three fundamental question. First, does ever use of combining methotrexate and losfonamide increase the risk of liver fibrosis? And is it reflective of cumulative long term dose? That's their second question.

And as the third question, they were asking, does current use of this combination signal active drug toxicity? So to answer this, they analyzed data from more than 1,000 patients with RA. They consisted mostly of women, average age of 57, and their median disease duration was twelve years. At the time of analysis, about two thirds, sixty six percent were on methotrexate, a third were on lefronomide. What's interesting is that in this population, one in four or twenty five percent had ever used the combination of methotrexate or lefronomide.

Even more striking, sixteen percent were currently on this combination. Now that really surprised me because as I mentioned before, this is an uncommon strategy and it's not something that we commonly see in real world practice. So what did they find in terms of safety signals? So to assess for liver fibrosis, they use non invasive biomarkers, FIV-four and APRI, which are commonly used in hepatology to screen for liver fibrosis using routine lab work. Importantly, there were no significant differences in fibrosis scores between users and non users of the combination of methotrexate and leflunomide.

So that's a really strong signal to show that long term use may not carry the liver risk that we thought was there, and I believe was previously shown in psoriatic disease and, older studies. They also found that there was no correlation between the amount of duration or exposure on this combination and degree of fibrosis. Now, when they were looking at signs of current drug use, the combination and toxicity, the ALT was slightly higher in current users. But you really need to look at the numbers because the ALT was 27 compared to 22. Now, it was statistically significant, but the value in and of itself was still within normal ranges.

So really no increased risk of hepatotoxicity. Now, what's even more, the current combination users had fewer hospitalizations. Now, they didn't specify whether this was for all cohorts or RA, but the rate was lower at three point three percent among the combination users, to seven point nine or eight percent among the non users, again, significant. So this shows that perhaps there's compelling evidence that this combination is safe, that it actually may lead to lower health care utilizations. And this was reaffirmed in multi variable models, where they, again, looked at liver toxicity and health care utilization and adjusting for other covariates, the findings held out.

And why does this matter? Well, it's because there was a debut of a session that they called Fishbowl at ULUR twenty twenty five for the very first time where they had a panel and audience to engage in meaningful conversation. And one of those topics was about the cost of biologic drugs and treatment decisions because biologic drugs or cardiac synthetic drugs are costly, and it's not equitably available in all countries or resources. And it's dependent on regulatory considerations, cost restrictions, formularies, insurance hurdles, and whatnot. So if this combination of relatively cheap conventional synthetic DMARs of methotrexate and leflunomide is well tolerated and safe, it presents quite a viable cost effective alternative potentially to areas that are resource limited.

So maybe we need to think about whether to dismiss this combination entirely from our practice. I think after having some very frank conversations about risk versus benefit and understanding patient preferences, I myself might trial this combination in my patients who are really adamant about not doing self injections or are concerned about out of pocket costs. So that said, some caveats to take away to keep in mind. In the abstract, they didn't mention the amount of methotrexate dose, but this was raised in the Q and A sessions. And the authors did mention that on average, patients were on 17, which is fairly typical.

And again, signals that they're using a fair amount of methotrexate in combination with glufemide. This is an observational study, so causality can't be determined. And there may be some channeling bias of patients who are safer to take combinations being placed on this treatment. And again, this combination, whether it's safer or even more effective than being on biologic, is yet to be determined. But as I mentioned before, in certain circumstances where the needs are met and the risk assessment is adequately performed and monitored, it's a viable option to consider.

So for clinicians in certain constrained environments and for patients with limited access or strong preferences, this combination may be a pragmatic and reasonable option. It'd be interesting to see if more data emerges from this. So thank you for listening. And again, this was Chihali for RheumNow from Barcelona, Spain covering ULAr twenty twenty five. Thank you.

Hello, my name is Rinalini Day and I am reporting from ULA twenty twenty five in warm and sunny Barcelona for RheumNow. And today I'd like to highlight abstract that's being presented on the Wednesday of the Congress on June 11. And this is work that's come out from the Mayo Clinic looking at VTE risk in patients with rheumatoid arthritis. And it's a study that's been conducted over forty years of data, so really quite substantial. Now, we've known for quite some time that people with rheumatoid arthritis are at higher risk of VTE, venous thromboembolism, but this study aimed to clarify how that risk has changed over time and what disease features might contribute to it.

So the researchers at Mayo analysed data from over 2,800 individuals, and that was split evenly between people with rheumatoid arthritis and matched controls without. And what they found was that people with rheumatoid arthritis had a more than two fold higher risk of DVT and a one point six times higher risk of PE, it was quite substantial compared to controls, even after adjusting for things like age, sex, smoking, and obesity. The elevated risk remained in place relatively consistently across decades with no clear evidence of decline after the 2000s, which of course is when those biological therapies started to emerge. And in fact, the PE risk actually increased in rheumatoid arthritis patients diagnosed after the millennium, particularly in those who were seropositive, so had a positive rheumatoid factor or CCP status. Interestingly, the same upward trend in PE was also observed in the non RA population, so this may indicate that broader environmental or healthcare related factors may also be contributing to the risk.

The study also identified key predictors of VTE in rheumatoid arthritis. So for DVT, the risk was higher in patients with older age, obesity, comorbidities, rheumatoid nodules, extra articular disease, and those who were treated with a biologic in the first year of diagnosis. And for PE, the risk factors included smoking, obesity, rheumatoid nodules, large joint involvement, and again, early biologic use as well. Importantly, achieving remission in the first year was linked to a lower risk of pulmonary embolism. So that kind of underscores the value of treating early and treating to target.

So why is this study important? So firstly, this study confirms that rheumatoid arthritis continues to be a significant risk factor for PEs and DVTs, even in the modern treatment era where we've got such good biologic treatments. And while some of that risk appears to be linked to rheumatoid arthritis severity or systemic features, so those extra articular features, achieving remission may actually help to reduce it. So these findings do call for a heightened vigilance in monitoring for VTE risk, and perhaps suggest that future research should maybe focus on how we can better protect these high risk patients. So it's certainly something I'm going to be taking away from my clinical practice when I'm seeing my patients with rheumatoid arthritis.

And it's a really interesting piece of work that I think will be of great impact to the audience who are there tomorrow to watch this. So if you'd like to know more about what's going on at the EULA twenty twenty five Congress, you can check out the RheumNow website, or you can follow us on all of the usual social media handles. You can follow me on Twitter, drminiday, and I'll see you soon for the next video.

Hello, my name is Rinalini Day, and I'm reporting for RheumNow from EULA twenty twenty five here in Barcelona. And today I'm delighted to be joined by Professor Andrew Cope, who will be chatting to us about the abstract OP-four, which was presented on the first day of the Congress. Thank you for joining us, Professor Cope. So this was the study looking at the ALTO trial, which was a follow-up to the Epipra trial, which was published last year, looking at one year treatment with Abatacept, which showed a delay in progression to RA. So I wonder, for the audience, it would be great if you could just summarize the APIPRA trial briefly first of all, please.

So, this was a randomized controlled trial, multicenter, placebo controlled parallel arm. Two thirteen at risk participants recruited, so these were people with positive anti CCP antibodies or ACPA, with or without rheumatoid factor, and all had inflammatory joint pain. Now, this was at a time when we didn't have the clinically suspicious arthralgia definition, but we're pretty close. It's the Gestalt, we know what inflammatory joint pain looks and sounds like, and they were randomized to receive one year of licensed abatacept one hundred and twenty five milligrams subpu weekly or placebo, cold turkey stop at twelve months and then follow-up for just twelve months after that. And the bottom line from those is that on treatment we see, I would say, important impact on symptom burden, so by standard PROs, HAC, EQ5D, joint pain, fatigue, as well as a whole bunch of other things, you know, work instability and other symptoms, you know, poor sleep, mental, physical function impacted.

On stopping drug, we see progression of a subset of individuals on the abatacept, so they progress, it's almost like the survival curve shifts to the right, but at the end of the study, we still see separation of the survival curves. And it was for that reason that we wanted to do the follow-up to look at long term efficacy, so durability of one year of abatacept, and also to collect safety data.

Great. So that leads me very nicely onto my next question. So it'd be great if we can just talk a little bit more about the results you presented on Wednesday.

So from a design perspective, the biggest challenge we had was not being able to take everybody from the end of a PIPRA and enroll them immediately into Alto. And the reason for that, as you know, Minnie, that we had the COVID pandemic and the R and D departments were saying no studies. So that was a technical issue. We invited all APIPRA study participants who had received one dose of study drug to enroll and we recruited 143 of the two thirteen, very balanced in terms of those who received placebo and abatacept and who'd had primary endpoints during the Epipril phase and reasonably well balanced in terms of gender and age and sort of baseline effects. And the primary endpoints we used were the same as a PIPRA, so it was progression to three or more swollen joints or fulfilling the ACR ULAr twenty ten classification criteria.

And in addition, because of that gap in the middle between the studies and we wanted a hard third endpoint that we could use to really capture from health records those endpoints, we included first DMARD treatment excluding corticosteroids. So whichever was met first, three or more swollen joints, ACR ULA twenty ten and time to first DMARD. And it's worth saying that in epiphora, all of the people meeting the primary endpoint met ACR EULAR twenty ten criteria. So, I think that's quite a good benchmark for future studies. The effects were, we saw a durable effect of drug until just beyond four years, so we see more convergence of the survival curves.

But applying restricted survival times, which is like area under the curve capturing data points throughout the timeline, we see statistically significant differences in favor of abatacept up to four years. But what we didn't see associated with those primary events was durable effects on the symptom burden. So we see an effect of delay which appears to be durable. But once you come off drug, symptom burden is very similar to that that we've seen in the placebo group.

Yeah, no, it's quite exciting data and there's quite a lot of studies. It's an increasing area of research and there's quite a lot of studies being presented here as well and previously at ACR about delaying RA with the use of biologics. From my personal perspective, I've got an interest in comorbidities, so obviously there is what do you think are the we don't have the long long term data yet, but what's what do you think would be the lasting effects and the impact of this work, do you think, in the future?

So I think the questions that are still unresolved is exactly that. In other words, who has one year upfront of biologic, what are the downstream effects? There are a bunch of ways that we can look at that. I mean we can just look at disease activity over time. I think biologics use is another good outcome and then looking at comorbidities cardiovascular infection and other things cancer as well because we know these are risk issues in people with immune mediated diseases.

In our study, we had a look at that, again the numbers are really small, but we found that over the six year period that the number of individuals requiring a biologic, I think it was thirteen and fourteen in each of the groups, so hardly any difference. Numbers are very small.

And can you tell us a bit more about risk profiling as well?

So, think risk profiling is essential for a couple of reasons. One is that we don't want to expose people unnecessarily to drug. We saw sixty percent progression over the six year period in the study group as a whole. That means that forty percent didn't progress, some of whom received drug and that's an issue. So, ways we're going around that is to look at the serological profile, so autoantibodies.

And what for me was probably the most unexpected result was that if you see people who have five serotypes, so we're talking rheumatoid factor plus IgG and IgA agfa, and antibodies to both acetylated proteins and carbamylated proteins, so five serotypes, so a more mature autoimmune response, these people are at much greater risk of progressing. But unexpectedly, these are the people that respond better to abatacept. If you look at the survival curves there, the separation is sustained beyond four years, in fact doesn't even cross up to six years although the numbers are very small. If you take people who've only got two or three different serological profiles, the abatacept and placebo survival curves are almost superimposable from eighteen months. So, there's a big difference there.

So, that's one area and then we've started to dip our toes into the epigenetic landscape, so looking at three d chromatin changes. And work that we presented very preliminary data at the ACR last year seems to suggest that you can see signatures that identify those that are going to progress to RA with pretty high sensitivity and specificity. I mean, so high that we're really making great efforts to validate the data and to be able to show that these are true. Because what it would mean in the clinical setting, you've got

a person

with high levels of NCCP, they've got arthralgia, you could do an additional test to give you some confidence that the risk is up to ninety-ninety five percent. That's going to help us immensely. And the same will apply down the line with identifying epigenetic changes that relate to the drug response too, because the signatures we're getting are related to important immune related genes and how they operate in the at risk stage.

It's really exciting to hear practical ways in which we might be getting a step towards personalized medicine, essentially, which is great. My final question would be around sort of future work, and particularly one thing I was wondering was, any chance maybe re dosing or tapering these patients might increase that delay effect? Yeah,

so I think what we've heard at this meeting, the PABALA study, which is a really interesting one, now they took a slightly different population but with a similar flavour. So, were people with palindromic rheumatism and they dosed for a year at full dose of Adacept, that was the standard dose weekly, and then in the second year, every other week. And their survival curves was almost flat in the abadacept groups, so very few people progressing. What that's telling us is that in both the ARIA and the PIPRA study, we're just not dosing for long enough to see the really long term effects. Whether in the long term, we end up approaching people at risk in a way that we treat people with cancer, you know, we induce remission or immune homeostatic state, follow these people and if necessary, redose again.

I mean, these are all sorts of studies that we need to do.

Great. Well, thank you so much for taking us through the ALTO trial, Professor Cope. If you'd like to know more about what's going on here at ULAr twenty twenty five, don't forget to check out RheumNow and follow our coverage.

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