ACR 2025 SpA Topic Panel Save

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Hello, everyone. Welcome to the spondyloarthritis panel discussion. We, as a group, were at ACR twenty twenty five in Chicago. This group was covering spondyloarthritis. We're convening post meeting.

We've had forty eight hours of rest, to, get our brains back in order and to think about the important items from this meeting and that's what we're gonna talk about in this panel discussion. I'm Jack Cush from Dallas, Texas. I'm joined by colleagues and friends, Anthony.

Hello, I'm Anthony Chan, a rheumatologist from the University of Reading in United Kingdom. And Atul.

Yeah. I'm Atul Devdar. I'm joining you from Portland, Oregon. I work at Oregon Health and Science University.

And Marina.

Hi. I'm Marina Magre. I'm joining from Cleveland, Ohio. I work at Case Western Reserve University Hospitals. I'm very excited about this podcast.

Yeah, me too. And to be joined by three people who are really the ones I look to when I have SPA and AS questions, this is a great group. So what we're going to do in this session, we're going to go around the horn, hear from each of our experts on what they thought was important from this meeting and we'll give some feedback on that. Let's begin with Doctor. Chan.

Yes. I have a poster fourteen thirty four, which is a study that came from Philadelphia. And it's the question about whether NSAIDs, anti inflammatories are safe to use in IBD. Of Of course we know that up to ten percent of our XBA patients can have IBD but sub clinically even as high as thirty percent. So the question was whether IBD made their sorry the NSAIDs made the IBD worse and they looked at two outcomes firstly IBD related hospitalization and the secondary outcome was all cause hospitalization or GI surgery.

This was a non inferiority study and what they found is that there was no increased risk for IBD related hospitalizations particularly in the ulcerative colitis group but there was a slightly higher risk in the Crohn's disease group and also for GI surgery and all cause hospitalization there was a slight increased risk. I think this this study kind of opens a kind of new chapter whether we should be rethinking our concept of blanket ban of NSAIDs use in IBD particularly in these patients who also have joint problems such as XBA. So it's an interesting study I think one that worth a revisit and maybe further research into.

Yeah, I think that our opinion is obviously different than the GI and to me it seems like the exception, the rare event became the rule for GI with the mechanisms being quite uncertain, changes in intestinal permeability, mucosal immunology with nonsteroidals. It all seemed very suspect to me and I paid no attention to their guidance about nonsteroidals. And I like to see, you know, at least a good systematic approach to the problem. What's, how have you handled this, Atul? And RheumNow, with Atul.

Yeah, at my university, I've discussed this with gastroenterologists and they allow me to use celecoxib. They and they go by, of course, being gastroenterologist, the American Gastroenterology Society or college or whatever they they have their association. They actually say that, nonsteroidals should not be used in patients with IBD, complete blanket, no. Our gastroenterologists say that celecoxib is safe, and that's what I have used. This one is interesting that they are saying that any nonsteroidals can be used.

And as Anthony was saying that subclinical IBD is very common and this was shown by the work from Ghent when they did the biopsies of completely asymptomatic people sixty-seventy percent of people might actually have, inflammatory, bowel disease type of pathological change. However, non steroidal is the first line of treatment in ankylosing spondylitis. If non steroidals are really going to cause problems then all these patients would have flared but it doesn't happen. So, I tend to believe what Anthony was saying and what they are finding that they are not non steroidals are not that dangerous.

Marina, this information change what you do?

Definitely. I'm very evidence based. I was very intrigued by these data. I think after looking at it, what they showed was that overall hazard ratio was I think one point zero nine for both Crohn's disease and ulcerative colitis. For ulcerative colitis, actually there was not any increased risk.

That made me feel very comfortable that at least I know in my UC patients, should be able to use it judiciously, you know. I think, Atul, as you were mentioning, celecoxib, if I remember correctly, I think twenty percent of patients in this study also had used celecoxib. I I think how they looked at it is it was a I think it was from Optum database and they actually were looking about prescriptions who had between this study period of two decades who had gotten a prescription for a non steroidal and those who had never gotten a prescription were included or had never used the medication. So definitely it made me feel very comfortable to use it in the patients.

I think the number I want to see is an NNT. How many you need to treat to get this event? I assume that that was not provided. I haven't heard that discussed.

Yeah. I think we can calculate it from the the abstract. So I did some calculation. The n n h, which I came up with is hundred 37. Number is 137.

So it's a modest I mean, I'd like to see 200, 500, 600. So there is a small risk there. And I guess it may be the message should be you can use it, but there's gotta be a good reason to use it and maybe no alternatives. But I'm glad that they did this research. It's important.

Yeah. All right. Let's go with Atul. What's your first one you want to discuss?

Yeah, I'm going to discuss the classic study. This I think was perhaps the most important one in the SPAR field. This is abstract number eight fifty four. This was a plenary session, abstract presentation. And the classic stands for classification of extrasporal arthritis inception cohort study.

And all of this relates to that the 2,009 classification criteria, the ASAS classification criteria had low specificity. And that's why, especially for their, clinical arm, And there was a worry that non radiographic extra spondyloarthritis patient entering into the clinical trials would probably have fibromyalgia or might actually have just mechanical back pain. And, FDA was very concerned about this. And that's the reason why they added on their own either positive MRI or high CRP has to be there in this classification criteria. Plus, we were forced to do fifty two week placebo controlled studies.

So that is the background why SS and Spartan came together. And this study was started in 2016. And it took us nine years to complete the study. And most of the study, in fact, was done during pandemic and huge study ten fifteen patients from 61 centers, 27 countries, half of these patients five zero four were enrolled in North America, US, Canada, and Mexico, and the remaining 500 plus patients in the rest of the world. And the idea was these were patients referred to rheumatologists with the suspicion of extra spondyloarthritis.

And we did everything that we would generally do. Take the history, do the physical exam, do the x-ray, do the MRI of the sacroiliac joint, get the CRP, HLAB27 etc. And then the rheumatologist was asked at every stage after physical examination and the what do you think this patient has excess spondyloarthritis or not etc. And the very final diagnosis was made after the rheumatologist had all the information including MRI read centrally. And based on that the lasso coefficients lasso analysis was used.

Lasso is like it's like it's basically a way that Euler and ACR and Euler have developed their previous classification criteria and this lasso logistic regression gives you SPA variables some kind of coefficients and you multiply that and get some number. So for example MRI has MRI has the highest points and x-ray is number two and then HLA B27 is number three and inflammatory back pain is number four etc. And then you add those numbers and if you have got 11 points then you can say somebody is classified. And so this was done. There were two models were developed.

There was some voting done and it was very close voting 158 to 151. And, ultimately the final model has sensitivity of 79.5% and specificity of 90.4. And this was a priori decided that if the classification criteria are to be revamped, then the new classification criteria need to have 79 more than 75% sensitivity, more than 90% specificity. And I think this is an important one, this classification, the new classification criteria, because all the new studies will be using these classification criteria going forward.

Now, is just applicable to, radiographic axSpA or also to non radiographic?

Also non radiographic. This is that radiographic non radiographic we don't even talk about this. Are going calling it the SS Spartan axial spondyloarthritis classification criteria. And the difference from the old classification criteria is that we actually have added mimics excluded in the stem. So patients with diagnosis of excess spondyloarthritis, and I want to stress this that classification criteria should not be used to make a diagnosis, you already diagnosed some patients mimics excluded, plus history of chronic back pain more than three months age of onset less than 45 years, then you apply this.

And we don't talk about non radiographic radiographic I mean and you you could, get somebody with negative MRI and negative x-ray. However that is going to be quite difficult. You need HLA B27 which has got four points and inflammatory back then has three points but you need 11 points. So you practically need everything else like uveitis and inflammatory bowel disease and peripheral arthritis and heel enthesitis etc because the imaging is so very important in axial spondyloarthritis that negative imaging excess model if you want to really classify somebody then you really have to have a very solid case. But to answer to your question, Jack, there is no classification criteria.

Don't say anything about radiographic, non radiographic.

Yeah, I like this because it allows to get earlier patients obviously into clinical trials. That's a good point. And these criteria can be applied by AI to find people for clinical trials.

I just want to add one quick thing, the MRI positivity. Previously, we were only concentrating on the active lesions on this and structural lesions were completely, not considered. And in fact, what we found out was when the expert readers when they were looking at the MRI sequences, they were in fact giving more importance to the structural lesion and more structural lesions positive MRI were counted as positive by the experts. So MRI indicative of axial SVA in the sacroiliac joint by global evaluation needs both active and structural lesions.

Marina, what do you think?

It's a great study. We have all participated in it. One thing which Atul was trying to elucidate here was that in order for a patient to be included in a clinical trial, and if they are HLA B27 negative, because one arm is HLA B27 positive, the clinical arm, if they are HLA B27 negative, we definitely need to have some imaging evidence of inflammation before we include them into clinical trials, because many people were questioning, how are people who are HLA B27 negative? They may not get included in the trials, but we often see these patients who come to us with inflammatory back pain. They are HLA B27 negative.

We look for other manifestations in these patients in order to make a diagnosis. Forget about classification, but ultimately we rely on imaging. And in the classic study, it showed ultimately when the diagnosis had to be made after four assessments by the clinician, they would sway towards what the imaging had shown. So, does play a big role in this disease. Atulam, is that correct?

Absolutely. Spartan is coming up with positive. What is positive MRI definition? This is there is a huge big confusion, and we will hopefully publish that paper along with this because that is very important. MRI as exactly as Marina said, imaging is so important, and we need to educate people what exactly is positive MRI.

Anthony, do you think this is going to lead to more imaging and more MRI in people with back pain?

I think it's a very important study because of the very high prevalence of a background back chronic back pain and what we see in this study is that these the main thing is the specificity has gone up from eighty four percent in the previous guideline to now more than ninety percent. So the ruling out aspect is going to be more important now. I think this is supported by many other studies take for the the early cohort from the space study which showed that you can diagnose XBA early and the one single thing that doesn't change over the two year period is the imaging more than some of these clinical features. So I think this is in line with the right use of imaging and also very important because this is not diagnostic criteria diagnosis is clinical but for recruitment into for evaluation of clinical trials we need this otherwise we will get you know impact from other diseases that are affecting our results.

Yeah. Alright. Atul that was that was great. Thanks for bringing that up. I think it will be important going forward.

Marina what's your first one?

So I'm going to present this abstract, which is very clinically relevant. It's an abstract number l b zero nine, rotation or change of biologic after TNF blocker treatment failure for axial spondyloarthritis. This was actually a prospective trial that was done out of France from 31 centers, and what they were basically looking at was that they call this steady rotation or change of biologics. Should we rotate the patients to a different TNF after the inadequate response to first TNF, which they define as those patients who had been on a TNF inhibitor for ninety days. And then they randomized them, either they switched to a different TNF blocker or they went to an IL-17A blocker.

So what they found was the primary endpoint was ASAS40 response at week twenty four, and they did not find a statistically significant difference between the two groups. It was for IL-17A, the ASAS40 response was around fifteen percent, and for the TNF inhibitor group, was about fourteen point five percent. So they showed there was no superiority of switching to an IL-17A inhibitor after the first TNF failure. There was a trend that patients who had psoriasis or those patients who were HLA B27 negative or had low CRP, they responding better to switching to an IL-seventeen, but overall there was no difference. So we, you know, ASAS put out guidelines in 2022 about management of axial SpA, and they mandated that if a patient has inadequate response to biologics, switch them.

They did not mandate a particular order to switch. Now, this data, whether this is going to change when we write future guidelines, that should we first try. I also feel that in my own practice, I don't like quickly switching classes because I don't want them to quickly finish all the, you know, whatever is available out there. So I usually go from one class to next. If a patient fails a TNF inhibitor, I usually will switch them to second TNF inhibitor.

If that doesn't work, then definitely I switch classes no more than two. And there are some, you know, even in the ASAS recommendations, there are some guidelines saying that those patients who have psoriasis, they may be switching to an IL-17A inhibitor may be a better option. That's what was the, you know, I thought this was an interesting abstract.

Anthony, what do you think of this data?

Very interesting. I think the evaluation needs to take into account whether it's a primary or secondary failure to the TNF inhibitor. We know that secondary failures the switching back or cycling can still work. In primary failures we probably should consider switching mode of action. The one thing I think with the new guidelines is a new thing that's come in every new guideline is revise review the diagnosis Every time the patient hasn't respond before we switch is just to reconsider whether the diagnosis is correct particularly in those challenging cases B27 negative, no CRP.

The imaging is probably going to be quite important before we either switch a cycle.

And Atul, are you concerned at all about the with this cycling or switch that pretty low response rates? Fifteen percent. Of course, the bar is high here. It's an ASAS 40. What do you think?

You know, when this happens in my clinic and when the fellow comes and says that he's presenting me a case and says that this drug is not working, say, what does it mean by not working? I mean, this is an important question. What does it mean? I mean, we are inflammation doctors. Are we treating here inflammation?

Or are we treating here nosyplastic pain? Or is this mechanical pain? Has the patient taken it correctly? I mean, what exactly do you mean this is not working? I mean, what is the expectation here?

I mean, this switching and in the same class or outside the class I mean you're changing the drug but important to go back and ask the patient what do you mean it's not working I mean and then finding out whether this is the CRP high is the MRI positive of the sacroiliac joint I mean I'm going to discuss one abstract after this about mosieplastic pain and this leftover pain and then you might switch, you might cycle, you might do whatever, but then the response is going to be poor, obviously, because Jack, you have a very good, difficult to treat RA and you know this very well. And this is the same thing applies to everywhere that whether you cycle or you switch, nothing is going to work because you're not treating inflammation. You're treating their mechanical back pain or their nociclastic pain by switching or cycling.

Also sometimes we do, patients do lose response. They may be doing good on a TNF for some time. And what do you do in that situation?

I completely agree. And I mean, I agree that this primary failure and secondary failure, but this is something that is important, especially for the fellows to understand.

So, know, and you are a lot of discussion about difficult to treat disease, both for PSA and for SPA. I didn't hear so much at this meeting. Was it discussed or is it still being worked out? Where does it stand now?

I think there were a couple of abstracts I saw from different countries, like from other countries similar to what was presented at EULAR. I think all of them are showing that everybody is using that ASAS has developed a definition for difficult to treat axSpA and saying those patients who have been on at least been treated on by two different biologics, two different classes of biologics and then those that tend to have an inflammation, either an elevated CRP or elevated inflammation on an MRI of the SI joint, or where a patient or the physician's perception that the disease is not quiescent, or they're having impaired quality of life. So there were a couple of abstracts presented there, you know, difficult to treat, and all of them show the same thing, that these are more females, these are patients who have high BMI's, they have comorbidities. So ultimately, how to manage these patients, that's gonna be an important study which we, I think, down the road need to do.

So that is more like complex to manage rather than difficult to treat. Yep. Right.

Because yes. It's a terminology preference. Who who wants to be called difficult? I'm often called difficult and I I wear it as a badge of honor. Others would be offended.

So, you know, who let's let's let's just move forward. Alright. Doctor Chan, what's your next one?

So the next one is a real world study. This came from the group in The US. It's fourteen forty four. Now we don't have head to head studies with JAK versus TNF versus IL-seventeen. So we have to look at some of these real world studies.

This is a study looking at TOFA versus TNF I versus IL-seventeen in XBAR. This was looking at claims based data and they use propensity score matching to correct for the baseline differences. And essentially they didn't find any significant difference between TNF versus TOFA or IL-seventeen versus TOFA. They were about similar in terms of their efficacy. Of course this is real world data it can be biased by selection of the drugs based on people's choice.

But I think it was just a nice interesting study to show that they work equally well across the mode of action.

Yeah to choosing amongst these choices is not going to be easy and we want evidence that helps us. Was this a TriNetX study or just claims not?

It's a claims based commodal health health locks I think that was where it came from.

Yeah. And of course, the you know, this kind of data isn't not is not proof of principle. It is it supports hypotheses and hypothesis hypothesis generating. But when you don't know how to approach the problems, sometimes it's the best you're gonna get. Atul, what do you think?

So I heard this. I mean, I wasn't this an oral presentation or was it a poster? No. There was something like this, and there was my question is the JAK inhibition at least in The US you cannot use JAK inhibitor unless they have failed TNF inhibitors whereas TNF inhibitors and IL-seventeen can be the first line treatment. So you are comparing the first line treatment for two drugs versus a drug which has been used being used on patients who have failed at least the TNF inhibitor, and those patients are generally difficult to treat.

So this is the end. So if that

is one of the limitations of claims based data real world data similar to our registry data that we have here as well. It's in it's there's a confounding by indication so you put them on because of practice or because they are second line. I think it was overall look at the efficacy across the different modes of action.

Okay.

Because if that is the case then I think JAK inhibition they are being used in patients who are difficult to treat whereas the other two drugs are being used in patients who are not so difficult to treat because those are first line drug.

Yeah. The results are good as at face value and then when you start getting into it, interpretations can go all different ways. So, but it it does add to our body of knowledge and hopefully will lead to better studies. Atul, what's your next one?

This is abstract number one four three five, and this is about this leftover pain, and this actually has been the theme in this meeting as well. This particular thing is upadacitinib. I mean, it's interesting that I'm speaking after Anthony and about JAK inhibition. Impact of treatment with upadacitinib on non nociceptive pain. And by non nociceptive, they mean neuropathic or nociceptic pain and its relevance for the presence of residual symptoms in external spondyloarthritis results from multi country observational study.

So this was a study called UPstand. This is a twelve month multi country non interventional observation study on patients who are being treated with upadacitinib for excess spondyloarthritis. And they used all kinds of questionnaires here to differentiate between neuropathic pain and for that you use a questionnaire called PainDetect. And their scores go up to more than 18 and if more than 18 it's very high score. And PainDetect is a questionnaire that will tell you about neuropathic pain.

And then there are these nocciplastic pain and for that you use this symptom severity score SSS and WPI which is widespread pain index. Combining these two will give you some idea about their nocciplastic pain. And so those patients were treated and this was done at the baseline and at twelve weeks and then at week twenty four. And the long and short of this is patients with excess bone arthritis who were treated with upadacitinib. Their non nociceptive pain which is neuropathic pain went down.

Their nocciplastic pain also went down but they found out that those patients who actually had high levels of these non nociceptive pain at baseline, those were the people who were difficult to treat or, you know, complex to manage or whatever we want to say it. They had persistent back pain, nocturnal back pain, fatigue, etc. Was a little bit left over and you can predict that by looking at what actually what happened at week twelve is what they so, non nociceptive pain at week twelve was associated with residual symptoms anxiety depression poor sleep etc etc and I just want to add that I also went for another session which was whole session was on pain and there something similar was shown in patients with rheumatoid arthritis and there they showed that patients who have these non nociceptive pain at baseline were the people who do worse later on and I think it stands to, you know, reason that yes, these are the people who probably have a little bit of fibromyalgia ness. And, those are the ones who are not going to do that well.

In this UPA trial, was there a comparator drug, an active comparator, or was it just UPA exposure?

Just UPA. This was observational trial. This was not really, this was, yeah, just an observational non interventional, but, yeah, study.

So, you know, past studies have always, especially with JAKs, always looked with a comparison drug and shown that JAKs do well with residual pain.

Yes.

Which is, as you say, going to be sort of nociplastic and fibromyalgia like. And I guess the whole thing here is to recognize what the pain is so that you know what to do going forward and you're not switching biologics, but instead having other strategies to help manage that pain. Marina, what do you think of this data?

I thought about when they were, how they were measuring this nociplastic pain, they use this WPI, widespread pain index, that area. But I don't think they actually use the second component of WPI, the symptom intensity scale. I asked a question. I said, you only have used half of the questionnaire, not the other half. But if you look at that questionnaire that was developed by Doctor.

Wolf several years ago, it has two components and one component was missing. Is that right? Or did you see the same thing?

You're right. You have to take both of those. And that's called fibromyalgia.

Fibromyalgia symptom intensity scale and pain.

But you need both.

And what I would wanna know is how does that translate? This is a research tool that we're not gonna use in practice. Are is there a reasonable facsimile what for what we do in practice? Can you get this from the hack in their in their pain scale?

So, can I jump in here? I just there is somebody called Mohammed Bittar, and I interviewed him on your channel, Jack. And Mohammed Bittar works with me at OHSU, and his whole he got a grant, to look at this leftover pain, residual pain and he does fancy stuff. He does functional MRIs and he does quantitative sensory testing and etc. And you can actually and these are just starting things.

This is early on. But then we are looking at, he's looking at I should say more than me at patients with excess spondyloarthritis who have got pain because of active inflammation and when all the inflammation is gone and which parts of the brain light up and the default mode network the DMN and then the salience network and this is we're just scratching the surface but this is a large amount of stuff going to come out. Also there was an abstract about fatigue, leftover fatigue and pain. I mean, in today's world, people get disabled because of pain and fatigue, not because of bamboo spine. Rarely anybody gets to bamboo spine.

But this is very important part for from patients point of view.

And I think it's going to be really important as we get into more research on complex to manage, spot, and knowing what to do, based on this kind of research with some of those patients is gonna be very important. All right, our last report's gonna be from Marina.

This you know, every time I go to ACR for the last couple of years, I've been we don't we haven't had many recent like, any new phase three clinical trials going on in EXPA. So last year I went and was looking for something that could be going to phase three trial or at least some beginning trials. And this year there was this abstract eight eighty six, first in class biologic selectively targeting HLA B27 reactive T cells in ankylosing spondylitis. It's targeted therapy for axial SpA. We have cytokine inhibitors, but this one was looking at some targeted therapy.

So what this this abstract taught us was they have genetically produced genetically engineered HLA B27 fusion proteins, and these fusion proteins then they bind to these autoreactive T cells and are able to block them. So they did this study both in vitro and also they took PMBCs from patients with axSpA and showed that they're able to completely they bind to them, the binding is pretty strong, and also they're able to then these auto reactive T cells. So raising some hope for us that maybe down the road, there will be some, you know, clinical trials going with this fusion protein and giving us some good response. Last year, I think there was a similar study which looked at a subset of T cells which are present in these patients. They're called like beta variable chain T cells and showed that blocking them would also be effective in patients with Axial SpA.

So this was keeping up with that same direction, but a different, you know, molecule.

Right. That was presented at EULAR. So this is building on that. Anthony, what do you think of this?

Yeah. It's further on from the the presentation at EULAR looking at more cell specific therapy in Expo. I think it's a really expanding area for some very nice reviews come out in the last year about this as well. So it's nice to have this type of treatment in in Expo really.

Atul, is there hope for precision therapy in SPA?

Yeah, this actually is very precision because even the previous one, the TRBV9 monoclonal antibody, that antibody would eliminate and people are trying to, these are CD8 positive T cells, and they have this TRBB9 on their beta chain of the T cell receptor. And those are 3% of our all CD8 positive T cells. So rather than eliminating 3% of your CD8 positive T cells, these people thought that we will eliminate only those T cells which are recognizing the auto antigen presented in this HLA B27 molecule. And there is not the CD8 positive T cells, which actually react to this HLA B27 presenting the auto antigen are not just TRBV9 positive. Their TRBV9 negative T cell receptor T cells also recognize that.

So they have this very novel thing that as Marina was saying they did actually HLAB27, they created HLAB27 in the lab and put in an autoreactive thing and then two of these and then a sort of very interesting thing with FC and then some cytotoxic thing and that goes and only it goes to the it's only recognized by these auto reactive T cells whether they're TRBB9 positive or not And those are eliminated. And these are only 0.1% of CD8 positive T cells. So this is really targeted, as you were asking, Jack. And this is, of course, all in vitro currently, but very exciting to do this, kind of work and we have totally neglected CD8 positive T cells all along. Were in spondyloarthritis just blocking TNF.

Yeah. So

those strategies have largely been targeting the amplifiers. The things that make the disease worse and more damaging and more symptomatic. This is obviously getting more to the core, which the question now is gonna be, when to use these drugs? Can it be used at any stage of disease or only at the earliest stages of disease? So that remains to be seen, but this is very exciting.

Anyway, I wanna thank panel for a great discussion and their hard work at ACR where they were all over the place, finding the really interesting content that we covered here today. Tune in for more of these panels at RheumNow. Atul, Marina, Anthony, thanks so much.

Thank you.

Thank you. Bye.