EULAR2025 Topic Podcast RA1 Save

You're listening to a RheumNow podcast coming to you from Barcelona, Spain, and you are twenty twenty five. Hope you enjoy it. Hi. I'm Jack Cush. I'm coming to you from Barcelona, and you are twenty twenty five.

This is an early look at a new problem that we're dealing with and that is at risk RA, clinically suspect arthralgia, preclinical RA. The question is, when do you treat these folks? How do you treat them? So, we've had a few trials demonstrating the efficacy of a few drugs, but in general it's not that clear. There's a sort of a collision now of several sets of data that I think are somewhat instructive.

We reported this week on RheumNow the results of a twenty twenty five ACR ULAR risk stratification criteria. This is a paper that was published that gives us some insight as to maybe who should get treated with more aggressive therapies when they just have arthralgia and may be at risk because of ACPA or being positive, for family history. So, that paper says that the criteria, a point based system, is based on morning stiffness, patient reported swelling, inability to make a fist, C reactive protein, rheumatoid factor and ACPA levels. And there's high and low points for low levels of morning stiffness or high levels of ACPA and that seems to be a reasonable approach but that's very different than what's being reported here at EULAR. Specifically, are two important long term follow-up studies to the Epipra study and the ARIA study.

So, the ALTO study OP-four is a long term follow-up study of the Epipra study. Apipra was a two year trial where patients with at risk clinically suspect arthralgia, ACPA positive but a positive MRI or ultrasound, so they didn't have synovitis, right? Two hundred plus patients were either given abatacep subcutaneously or placebo for a year and then followed for a year off of that. In that study, we do know what the primary endpoint at week fifty two, six percent who received abatacep went on to develop RA but if they received placebo, it was twenty nine percent. But after a year, another year of follow-up off of drug, didn't seem to make much difference.

It was 30% 40%, small difference. They followed those people out to as long as six years and what they found in the two year study holds true in the six year study, and that is the patients who had the best responses were the ones with an extended auto antibody profile, meaning they had ACPA and rheumatoid factor, several ACPAs, and a number of different antibodies, anti acetylated protein antibodies, anti carbamylated protein, if they had all five of them, you were likely to have an extended response. In a two year study, it was fifty percent of the placebo patients went on to develop, RA but if you had this five serotype profile, only ten percent. That was at two years. That same result is carried out to two years and four years and as long as six years.

At four years, the extended autoantibody, it was forty seven percent of abatacept developed RA versus sixty seven percent. So, starts, there's still some protection is the point, and that's just with one year of treatment. So, the profile being not what the ACR ULAR risk stratification said but here it's being ACPA positive and really high titer plus five other autoantibodies for RA. This is a little bit different than what was shown in the ARIA study. The ARIA study was another abatacep study, about 100 patients were enrolled in a six month trial abatacep versus placebo and then they were followed for another twelve months.

At the end of six months, eight percent of abatacept and thirty five percent of placebo developed RA, and in this study, they followed them initially out to eighteen months where kind of the lines start to come together suggesting that the delay is being lost thirty five percent versus fifty seven percent. But what they found in their prolonged study at five point three years, the people who never developed RA were those who had lower SED rates, lower rheumatoid factor, lower pain scores, better functional status, meaning that the opposite of that might be the people who are at high risk, and maybe those are the ones that you do want to treat and maybe that you do want to treat them with abatassa. So, from these three studies, we're getting a picture of the people that we may want to treat more aggressively with abatacep, right? So the extended autoantibody profile and maybe the people who had high risk disease, not low risk disease, from the ARIA study. One more caveat and that is the TREAT earlier RA trial with methotrexate only showed in past publications that it worked only in seronegative, actin negative patients.

So again, these are sort of rules as to who may need treatment in this hard to manage group. Do you treat them, do you not when they have clinically suspect arthralgia but no arthritis. Tune in for more great abstracts and presentations from ULAR twenty twenty five.

Hi everyone, my name is Jiha Li and it's my pleasure to highlight an abstract from EULAR twenty twenty five, which kicked off today here in beautiful Spain, Barcelona. Today's abstract is one I found personally meaningful, but I think it's both inspiring and important for the rheumatology community as well because we're caring for an increasingly aging population. The abstract I'm going to discuss is POS0627. It is titled Examination of Clinical Outcomes by Treatment Duration of Biologics and JAK Inhibitors and Non Agenarian Rheumatoid arthritis. It is by authors Kuo Katayama and Hiroshi Ito from Japan.

So this study examines RA outcomes in non agent areas. And I have to admit, even as someone who specializes in geriatric rheumatology, I had to double check and look up what this word meant. And it actually refers to people aged 90 years and older. Now, this is a different concept than how we think about older adults in The US. Typically, we would categorize them as young or old between 65 and 74, middle aged between 75 and 84, or oldest old being more than 85.

So the patients in this study, they're at the very top of the aging spectrum, and they're the oldest of the oldest. And that's one of the things that makes this study very powerful and rare, because a systematic review by Palmosky et al. Showed that the average age of participants in RA studies is actually in the mid-50s. And actually about 30% of the studies exclude older adults just purely based on this age. And this pattern is seen also in observation and population based study.

What that means is there's a real gap in our knowledge of how best to treat for older adults with RA, even though this population are growing and older adults continue to be newly diagnosed with elderly onset or now better known as late onset RA. So a study like this that looks at real world outcomes in people over the age of 90, it's not only rare, it's essential. So, let's take a closer look. So, this was a single standard study out of Japan, and it included sixty six patients who were all currently in their 90s and were receiving treatment for the past two years. And this center took care of more than 3,000 patients and out of sixty six were over the age of 90.

They were divided into two groups. Group A, it included 25 patients who developed RA on or after the age of 84. So on average, they're about 88 at the time of diagnosis. And at the time of study enrollment, they had an average age of 92 and were on treatment for about four years. In comparison, Group B, it included forty one patients who developed RA earlier than 84.

So their average age at diagnosis was 76, at time of enrollment, similarly 92, and obviously they've been on treatment for a longer period of time for about sixteen years. And here's where it gets really interesting. The rate of use of biologic and JAK inhibitor was remarkably high. In group A, the older group, about just over half, so fifty six percent received advanced therapies with biologic or JAK inhibitors within six months of diagnosis. And in group B, just under fifty, forty six percent received biologics or JAK inhibitors.

But there was a little bit of a delay from the time of diagnosis, on average about seventy years, understandably because they were in their mid-70s when they were diagnosed and had probably less comorbidities and could tolerate step up therapy or had time for it. But just to put this in perspective, in The US on a Medicare based study, less than thirty percent of older adults diagnosed with late onset RA after the age of 65 are put on any treatment within the first year. And the rate of biologic use is less than ten percent. So the fact that the Japanese are more experienced and prescribing these treatment, I think is really remarkable. Moving on to the outcome.

So, importantly, clinical disease activity measures improved in both groups. But what this study asks is they absolutely also looked at functional outcomes, which is really important for older adults. So, A, the older group, the walking independence improved by about twenty percent from sixty four to seventy three percent. And that rate was similar regardless whether it was treated with biologics or non biologics. Now, what was a little bit perplexing to me when I was looking at this study in group B, the younger old, the walking function actually declined.

But it's important to note that they had a higher functional independence at the beginning of baseline. So for group A, the older older baseline was about 55 to 64. For the older old, it was 64 to 95. So there was very little room improvement. And it may have been having had disease for a longer period of time, more tolerant, they were more active.

And therefore, if anything, we were seeing declines. The decline actually was coming from higher rates of fracture in this group. And I think we'll see this in the manuscript, but likely more related to their social structures or their activity levels. But again, importantly, they looked at functional outcomes in addition to clinical outcomes and both improved. So yes, adverse events occurred, also including infections and malignancy and age can be an independent predictor.

But the overall takeaway is clear that with careful monitoring treatment is both feasible and beneficial, even at an advanced age into the patient's 90s. So, my message and the conclusion that I took away from this is that this study makes a compelling case for why older adults should and need to be included in clinical studies. We need data to inform our guidelines and that when we have guidelines to assure that we actually implement them in this growing population of older adults with RA. So non agentarians is a new word I picked up today. They not only tolerated biologics and JAK inhibitors, but they benefited from this.

So let's move beyond age based assumptions and commit to treating older adults with the same rigor and respect we give every patient. Thoughtful, effective RA care should be guided by need and not age. Thank you for watching. This is Chihuly reporting for RheumNow from Barcelona, San Diego, Spain, and there will be more highlights from EULAR twenty twenty five. Thank you.

Hi, everyone. This is Aurelie Najme reporting for RheumNow in sunny Barcelona, day one of the conference. A lot of very exciting content and science, And there's one abstract that particularly caught my attention today, amongst many really, that looked into a different way to assess methotrexate adherence and what it means for people living with rheumatoid arthritis who maybe stop their methotrexate when they start their biologics. So, it was posted from a team from Manchester, poster five sixty three. And we know very well from the points to consider for treatment in rheumatoid that were updated in 2023, that it's recommended by EULA for people starting biologic to remain on a conventional synthetic tumor, in particular methotrexate, pretty much regardless of the biologic and we could discuss that, but that's not the point.

They also recommend the methotrexate dose to be reduced to ten milligrams a week because we know it improves the outcome and potentially immunogenicity. But in a lot of studies, we look for methotrexate adherence, this is self reported adherence, which is prone to measurements bias. So they came up with this alternative way to measure methotrexate adherence. And I'm gonna have to read my notes here because this is very complex. This is high sensitivity liquid chromatography tandem mass spectrometry, LC MSMS.

And that's a very objective way of measuring. It looks for composites from the drug after it's metabolized. And so in their cohort of two fifty patients, they looked into whether the adherence measured by this objective method was dropping after starting in biologic and it does drop from ninety one percent to eighty one percent when people start biologic drug. So that's six months after starting the biologic. The two things here I wanted to say is that first of all, 91% is really good and so it's telling you that it's definitely a selected population that is willing to participate to research and so it's kind of biased there because I'm pretty sure if we were to do that same measurement objectively into the standard of care, secondary care population would probably have lower rates.

The other thing they looked into was whether this drop in adherence was associated with a less likelihood of reaching EULA response, at least if it was associated with EULA response or reaching EULA remission. And no there particular association. However, there was a trend towards an improved change in DAS28, but the numbers probably made it I mean, at least it wasn't significant statistically. There was no information as to whether this was associated with specific drugs in particular as opposed to other, but I think it's quite interesting. Obviously this is not something I'm going to use in clinical practice.

I don't think it's ready yet. We wouldn't use mass spec in clinical practice every day anyways, but I think it just brings a different perspective on a mastrexate adherence and this is certainly something to reflect on. So that was it for me today. I invite you to follow RheumNow for more content and to follow me also on X at AurelyRomo. See you later.

Hi guys, this is Aurelynej from Glasgow reporting live from Barcelona on day one of EULAR twenty twenty five. I saw a lot of really exciting science today, and there's one poster in particular that really caught my attention because it was about a topic that we just really never talk about with our patients, at least I don't, but I will after this. And it also comes together really well with this old saying that a laughter day keeps the doctor away. And so in Poster June, Suzuki and colleagues looked into laughter and rheumatoid arthritis. So they're not new to the topic because in 2024, they did publish a paper that was looking the association between laughter, frailty and depression in rheumatoid arthritis.

And they found out that people that had more frailty, higher frailty scores and higher depression scores had a less frequency of laughter. And it was a cohort of about 200 people and they wanted to increase the number and correlate laughter frequency with a lot more patient reported outcomes. So that's what they did in this study. So they interrogated over six seventy patients and they classified them in four different groups. So the first group was people who laugh almost every day, people who laugh one to five days a week, people who laugh more than one to three days a week and people who never or almost never laugh.

And it also made me wonder what category do I belong to? But I'm gonna let you guys guess that. So when they looked into correlating patient reported outcomes, in particular HAC TI, social fraternity scores and this is activity, they found out that the people, there was definitely an association between social fraternity and physical function. And in particular, people who had less frequent laughter had higher HACDI and higher social fratty scores, but there was no association with this activity. And in their conclusion, the authors suggest that future research should assess the impact of laughter focused interventions.

And I'm not sure what these would be, but it also is something that I wish I could have asked the authors, but I didn't find them at their poster. But certainly it would be really interesting to know if that could improve health outcomes in RA. With this, I am going to invite you to follow RheumNow on eggs for more content and follow me orillerymo. And I see you guys around.

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 should 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 EULAR twenty twenty five in Barcelona, Spain, go to RheumNow.

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 2005 and 2017 comparing anti TNF therapy with conventional synthetic DMARC treatment. They looked at one hundred and fourteen patients treated with anti TNF therapy and two twenty eight treated with conventional synthetic DMARTs.

And at five years, they found that fewer than one percent 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 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 twelve months 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 Kay from UMass Chan Medical School in Worcester, Massachusetts.

Hi, everyone. This is Doctor. Jihao Li reporting for RheumNow for ULR 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 Losothromide 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 losinomide. Now, this isn't a combination that many clinicians use, because of the 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 questions. First, does ever use of combining methotrexate and losafenamide 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 leflunomide.

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, FIB-four and APRI, which 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, statistically 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 glafunomide. 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 Jigalifa RheumNow from Barcelona, Spain covering EULAR twenty twenty five.

Thank you.

Hello, my name is Rinalini Day, and I am reporting from EULA 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 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 practise 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 for us at COPE. So this was the study looking at the ALTO trial, which was a follow-up to the Epiphora 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, 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 twenty five milligrams sub q 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 obadacept 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 baseline effects. And the primary endpoints we used were the same as Epiprat, 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 DMARC. And it's worth saying that in a PIPRA, all of the people meeting the primary endpoint met ACR EULA twenty ten criteria. So I think that's quite a good benchmark for future studies. And 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, 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 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 term data yet, but 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, someone who has one year upfront of a 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 inflammatory 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 could you tell us a bit more about risk profiling as well?

So I think risk profiling is essential for a couple of reasons. One is that we don't want to expose people 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, 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 and 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 have 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 and 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 sort of practical ways in which we might be getting a step towards a 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 redosing 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 flavor. So, these were people with palindromic rheumatism, they dosed for a year at full dose of Adacept, so that was the standard dosing weekly, and then in the second year, every other week. And their survival curves, I mean, it was almost flat in the Adacept 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.

And these are all sorts of studies that we need to do.

Great. Well, thank you so much for taking us through the ALTER 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. Thank you for listening.