RheumNow Day 4 Recap ACR Convergence 2024 Highlights Save

RheumNow, our daily panel. I have with me two other participants. Doctor. Liu, can you say who you are and where you're from?

Yes. David Liu here from Melbourne, Australia.

Wonderful. So quite a different time zone. And Doctor. Sood, where are you from and what do you do?

Yeah, so I'm Akhil. I'm a rheumatology fellow at Stanford. I'm in Palo Alto.

Wonderful. And I'm Janet Pope. So I'm still here in Washington, but I practice in Western University, London, Ontario, Canada. So what we're going to do and thank you for attending our audience. What we're going to do is a bit of a daily recap.

We'll go a little bit in-depth, then we'll do a round robin, and then we might say some other highlights. So, David, I'd like to start with you. Tell me about what you found interesting.

Oh, there's so much to I always feel like last day gets a bit of a bad rap, but I love the last day because late breakings come on the last day and there's always the abstract sessions always crammed with some, you know, really interesting stuff. So it's hard to pick, But the late breaking session that you chaired, Jana, I think had some really interesting things. Maybe we should talk a little bit about dapirilizumab, which I think we knew about in late September having a positive phase three and monitoring severe lupus. And we obviously only got to see the details today. I think it's

a Phase bit two, David, but yep, keep going.

Yep, sorry, apologies. Yeah, I think it's a well, a phase three, isn't it? It's a phase but anyway. Is. Phase two, Phase three, I mean

three, it's all good.

We're having and I think whatever the case is, we're getting more options to in lupus in a way that we perhaps didn't anticipate before. I think we realised that with the lupus nephritis ACR guidance that got released as draft version in this meeting. I think, you know, and that's had to be we've had to really have a bit of a frame shift on that because we've had new agents incorporated. And that doesn't even that was in lupus nephritis, that doesn't incorporate a number of other agents that have come out well, that are relevant to lupus subsequent to then. Anifrolumab obviously as well.

We've had announced binotuzumab with lupus nephritis as well. And then this dapirilizumab. It's a pretty nowadays, I guess lupus trials are getting more standardised registration trials, which is always pleasing, But forty eight but so, Phoenix goes, the name of the study, forty eight weeks. And so, for the loopologists out there and I'm obviously not a loopologist, but I can you know, the numbers look decent. Sorry, four sixty to forty one.

Bicola response was forty nine to thirty four. Severe bile egg flares eleven versus twenty three. So, exactly the kind of things I would expect to see in a good response category. It looks to be really well tolerated. I should say it's a CD4 ligand inhibitor and we're starting to see, I guess, a lot more interest in the CD4 ligand mechanism of action, not just in lupus, in Sjogren's, and I think it'll probably have some other applications as well.

We're starting to realise the importance of CD4 ligand. So, you know, we'll take new agents in lupus. I think, you know, obviously we all it's easy to get too excited about it, about any new agent in lupus, but at the same time, having new options is clearly something that we desperately need.

Right. And what I would add to it is they also had better steroid tapering in the active treatment. So this was getting a superior response on less steroids over time. So, David, here's my dilemma. Mhmm.

Belimumab, safe, modest benefit. We have anamfrelimab, pretty safe, maybe a bit more benefit, maybe in my mind. Where then belimumab? Where will this fit in in your armamentarium when we know there's CAR T and BiTE trials coming up?

Yeah. And I mean, I feel like I need to be asking you this question, but my simple mind is that we still do need to find better biomarkers in a heterogeneous disease like lupus. And yet we still don't really know, I guess, CAR T by where they're going to land in terms of how we're going to incorporate them into our treatment algorithm. I think that's a big disruptor, right? I think all these others slot in in a way in which you can imagine probably similar to what we do in inflammatory arthritis, where we're cycling through non responders, and that potentially we might find some broader biomarkers based on our Routine KED numbers, know, what's happening to the complement, you know, what's, you know, maybe we'll get some sense as to whether it's more likely to have high interference signature or not.

We might get some general senses like that. But clearly, CAR T depending on how effective it truly is, how well tolerated it truly is, and then how accessible it is, that's going to be what comes in either over the top or as a last stitch therapy. But I mean, I'd really love to know your opinion, I'd like to know Akhil's opinion. Right,

so I'll say what I think because who really knows its only opinion right now and then we'll also ask Akhil. So I think really it looked pretty safe. It's pegylated so there's a possibility that they might do studies in women desiring pregnancy which would be a real asset to know about. Of course once their lupus is stable you wouldn't want them to try to get pregnant until they were doing well. And then I really think the CAR T, the B, well, the T cell engagers, bispecific are probably for a different kind of population.

So I don't know where it'll fit in, but if we get access like anything and if we think it's safe and effective, we're apt to use it. Akhil, what do you think? Do you think you'd get using a drug like this with the responses you heard about?

Yeah, I think those findings are quite promising and very exciting. And definitely I would love to see the long term efficacy of the data as well, past the one year mark, the two year mark, and beyond that as well. And I think even just thinking of populations within lupus that it would benefit, as you mentioned, Janet, the women who are designing pregnancy in the near future, especially with the way the drug is manufactured and designed. I think that can be a really promising, exciting as well. I think CAR T, you know, the results are really interesting, especially where we're seeing patients going into disease remission with the samples that we've seen to date.

But I think, know, when we look at the lupus and the population that affects the females of young reproductive age, think I that would definitely be a really interesting and very exciting avenue to look into in the near future and seeing the long term efficacy. But I even think that the dependence on steroid, I think that's a big finding. And I think that with that minimizing the use of steroid could be of huge benefit and impact as well for this patient, for this population.

Right, and I think the bottom line is time will tell. We have to see their next phase three trial. If the results are consistent, they will, I would suspect, get a drug to market. Hopefully, we'll have reimbursement, and then we'll get a feeling of although no biomarker orientation on this, but who might be this kind of biologic or this kind of advanced therapy or another one. So wonderful.

Thanks, David. Akhil, what do you want to tell us about?

Yeah. There are a few abstracts just also in the realm of lupus today that I thought were really interesting. I guess just kind of going along the lines of identifying this lupus, drugs, armamentarium drugs are expanding and it'll now come down to choosing these drugs wisely. I think one of the abstracts that I thought highlighted really key and a very important point that I think for patients to consider, it's abstract 2,682 that looked at the indirect cost in lupus. Traditionally, when we look at healthcare resource utilization, we look at the direct costs such as ER visits, hospitalizations, frequency of clinic appointments, the total cost in healthcare expenditures.

But one of the things that we don't really look at is the indirect cost. And what do indirect costs exactly involve is missed workdays, being present at work, but being impaired, and even just the opportunity costs, meaning they're doing work but not getting paid or they're unable to work. In this abstract, they had a cohort of lupus patients in Canada composed of men and women, and they looked at the indirect cost of lupus care and how it varied by gender as well. And what they really found was that there a higher opportunity cost among women compared to men. For women, the opportunity cost due to unpaid labor was 40%, but for men, the opportunity costs were lower at 20%.

And while lupus does affect women more than men, there is still quite a striking difference in the indirect cost of lupus, indirect costs as it relates to their underlying lupus. And when it comes to being absent from work or being present at work due to impairment or even just the opportunity cost, I think it's really important that we kind of think more broadly of the drugs that we use to treat lupus, whether it's subcutaneous infusion form, and now even CAR T, how is this going to affect their ability to be at work or get paid from work and just the broader implications in society as well.

You know, these are all good points you've brought up. So, work disability in SLE is at least twenty five percent. A lot of these are fairly young people. I mean, age might be 40, but a big weight range around it. So that brings them into poverty and things like that.

So I think that that's really important. The other thing is if we're trying to look at CAR T, we don't know how long if something was transformational. Are they gonna get deep remission and for how long? So I think that's really important. When we talk about work, the the absenteeism is missing work.

We're used to that. And what you were talking about is presenteeism. So they're there and kind of not functioning at the highest level. And that gets people not promoted, sometimes fired. The coworkers are mad at them.

And it's because they can't do as much if they're active disease, fatigue, pain, etc. Going to more doctor's appointments isn't quite absenteeism, but that costs time and money as well. So I think that's really helpful. So I thought it might be interesting to talk about some things that might change my practice. So we heard about the Depralizumab, which was L20.

I kind of did a bit of a summary of what's up with PMR because PMR we all see in our standard of care was always glucocorticoids checking for their BMD and going from there. So as you know in The US, cirmab was approved for GC sorry, for PMR that was repeat. So you couldn't get them off glucocorticoids or they had flared. Now there's a whole bunch of studies. So these are abstracts.

I'm just going to give you a whole bunch. Sixteen ninety eight, 1,700, sixteen ninety seven, o eight five eight, sixteen ninety six, and seven six four. What's the bottom line? So don't stop tocilizumab and PMR at six months or most people flare. So that's after an RCT, the semaphore trial when they stopped tocilizumab was IV eight milligram per kilogram monthly.

So quite soon after they stopped, there was a really high flare weight rate or maintaining remission didn't really work out. So, cirolimumab was better than methotrexate and a head to head comparison. Methotrexate did not work compared to no methotrexate and an actual RCT. There was zero steroid sparing. So I think in PMR, there was really no evidence with the last two studies I've talked about for helping that.

Baricitinib had a positive RCT in PMR four milligrams a day, two and no steroids two milligrams a day and then write off at thirty six weeks without a big flare after. And there was a tofacitinib study, I think out of Asia, maybe China or somewhere, I can't remember, a year or two ago, presented at one of our meetings, and it basically said tofacitinib was equal or superior to glucocorticoids without any glucocorticoids and PMR. So I think the JAKs are gonna have a role to play, but the IL-six already do. We go to GCA. There's just a couple topics that I would talk about.

So tocilizumab plus methotrexate. So I just said methotrexate is not working in PMR. This is tocilizumab plus methotrexate had less development or worsening of aortitis than tocilizumab alone in GCA. So the problem with aortitis and GCA is obviously far far more than PMR. It's more PMR with GCA or GCA alone.

It was also another group looked at. It was rare to have a first failure of treatment with tocilizumab in GCA, but we still have a dilemma of how long does it work for, who to choose, maybe a Jack like Guppa or Tocilizumab, and when do you stop. And then really I think that these are the dilemma that I have every day when I'm treating patients with GCA and PMR. We have nice products to help our patients. We don't know sometimes a dose, we don't know for how long, and we don't know with glucocorticoids or without, and how fast do we taper them.

So these are kind of dilemmas. We've had tocilizumab around for a while. Cirulimumab will probably get approval in Canada next year for recalcitrant PMR. So can't get the glucocorticoids down or a recurrence, and The US already has the data. So Akhil, do you have any experience with advanced therapies in either GCA or PMR or what the group that you train with, do you know what their algorithm is?

Yeah, no, definitely, especially with the PMR, have considered the use of a cerulimab given the FDA approval. And even in my clinic as well, I've had the challenge of some cases of refractory PMR or difficulty tapering steroids below five milligrams. And we had a patient with the IL-six inhibition, but had difficulty tapering. And now I'm kind of looking back at kind of the other options in the JAK inhibitor, And one of the things is, I think the findings for the JAK inhibitor are really promising and really exciting, but then I think kind of more broadly as well as the FDA black box warning with JAK inhibitor and then the population of GCA PMR patients as well as being older, comorbidities, underlying cardiovascular comorbidities. And while I'm really keen on considering JAK as a next step in the algorithm, I do also kind of am cautious and worrisome with cardiovascular risk profile as well.

Maybe you and or David also have had similar encounters or have you gone about that in your practice? It would be interesting to hear.

So David, much experience in Australia with any advanced therapy in either PMR or GCA?

Yeah, so I mean, we do PMR clinical trials and see it's my interests. I think it's clearly an exciting time for PMR therapeutics. It's nice to have options. I think we're at the point that we need to try and understand, you know, we've got one agent who's had, you know, a successful randomised, a phase three randomised controlled trial and I think we're happy that works for refractory disease. And the rest, I think it's still variable evidence.

We're still not sure how to make comparisons. And so, I guess I'd just make two points here. I think, firstly, taking I think it's a different paradigm between newly diagnosed disease and established disease based on I mean, thinking about I think we all know about PMRs, natural history, that you've got this and the treatment paradigm that we have that there's a stage at the beginning where usually we're giving slightly higher dose steroids. And I think trying to influence things at that point is quite different to the refractory persistent disease when the patient's stuck on prednisone seven and it's a bit more a persistent kind of phenomenon. And I think that's really relevant to the methotrexate thing now.

Open disclosure, we're doing a large trial of methotrexate in PMI between The UK and Australia. But that's in a refractory disease as opposed to in what this small Dutch trial, Dutch RCT looked

at. Exactly.

Very hard to and I guess it's a difference between induction and maintenance that we might see in say, you know, patient

with hepatitis or Precalcitrant, recurrent, high OP, high, like, cataracts, other risks that might make you not wanna use so much glucocorticoid. I agree. I think it's a puzzle. And then IL seventeen is in clinical is in clinical trials as well. I don't know if it's GCA or GCA and PMR.

So, yeah, it's it's a it's a dilemma of riches the way we also had in the lupus that we just talked about. Okay, David and Akhil, let's go fast now. Tell me what might have been something you're interested in from today or recent. David?

Yeah. Well, I think, I mean, there's once again so much. There's let me talk about Late Breaking 20, which is another one from that session that you chaired, Janet, about looking at what I think a lot of people have talked about, which is kind of artificial intelligence and ultrasound. Now, I mean, fundamental issue that we have with ultrasound in rheumatoid arthritis, and in fact, other inflammatory arthritis is that ultrasound is very useful. It's clearly got a lot of benefit for the way we practise.

And we had the guidance earlier in the meeting about musculoskeletal ultrasound from the ACR. What I think is difficult is the consistency to try and so much which is operator dependent on that, and unless you've got expertise, if you're better at it, clearly you get better outcomes. A lot of us are not better at it and in fact then how do you work it in? And then time. It takes a lot of time and and we've got a workforce shortage.

How do we actually dispute our time?

Right. And the cool thing on this was an AI module where it's a robotic arm doing the ultrasound. The patient puts their gel on. The patient's guided through. The robotic thing is actually programmed to talk to them.

Actually looked at the comparison of ultrasound experts, a gold standard of external ultrasound people like experts, and the AI. The AI did pretty darn well. They're programming for o a. We don't know the overlap or false positives right now, but really, really exciting. I just don't know where I'd use it because I do not want this in the mall and you screen, and then you end up with a whole bunch of erosive OA Yeah.

Or maybe mild CVPD referrals when you're trying to find RA. But I thought it was pretty cool, and it really it's self guided. You don't really need even a technician the first time they get one. The rest of the time they just do it. Pretty cool.

Akhil, does your group do ultrasound?

Yeah. Yeah. We we have an yeah. Large ultrasound program here. So yeah.

We have a right. But it's time consuming. Very valuable. There's often not necessarily a fee for it.

Mhmm.

And this thing anything with AI that's trained enough is I'm going to not be cynical. I'm gonna say we'll probably outperform what many of us do. So pretty cool. Akhil, any rapid discussion of something that you were interested in?

Yeah, another abstract from today was abstract 2679. It was looking at fractures and lupus patients. It was out of the Hopkins cohort, about a thirty five year longitudinal data of patients with SLE. They looked at the total number of fractures as well as the rate of the fractures per year, and they found that there was nearly three hundred fractures in this cohort at a rate of zero point one per person year. And what I think was really striking, was really interesting, was looking at the factors that are associated with the increased fracture risk.

So the expected factors would be is that females and low bone density are higher risk, and then even stroke was a risk factor. But one thing that I found was really interesting and tying back to multiple abstracts that I saw at ACR was the prednisone exposure. Steroid exposure, whether it was present exposure, past exposure, and incremental increases of five milligrams, ten milligrams, fifteen milligrams, was associated with the increased risk of fracture in patients with lupus. And I think just tying it all together is that we saw a lot of, there were several other abstracts at ACR looking at the cumulative steroid exposure or looking at steroid exposure in different cohorts. And they found that despite new biologics and new therapies that have been come out, steroid discontinuation and reduction is still unchanged over the past few decades.

And that was abstract 2421 looking at the Lupus Midwest Network out of Mayo. And then there are other abstracts that we've highlighted that the role of biologics are key, especially early introduction. And that's been associated with quicker tapers off steroids, especially newly diagnosed lupus. So I think this kind of points out is that we need to minimize steroid use. I think the guidelines that came out, that released yesterday for lupus nephritis may be pointing us in that direction that with triple therapy at the time of induction and even quicker steroid taper, we may be seeing less steroid exposure and hopefully fewer fractures in the future among our patients with lupus.

Right, and you're raising a really good point because possibly the stroke might be risk of falls, it's hard to say. Absolutely. But I think the bottom line is it's very difficult if you had a 45 year old woman with lupus because everything then even the prevention of glucocorticoid induced osteoporosis at seven point five milligrams a day or more is kind of off label because she's so young. So the risk of fracture can be present, but the BMDs have a lot of standard deviation around the T and the Z score for them. So really good.

I think it's something we need to keep in mind and not prescribing as much steroids are the way to go possible and disease activity is strongly linked. Inflammation like in this case lupus but RA, other high inflammatory conditions increase basically not just periarticular osteopenia but frank osteopenia throughout. That's really cool. So I'm going to tell you about it quickly. Something that will change my practice even though it's a rare condition.

This was presented yesterday, I think, so it's 1696. It was a really interesting RCT in Takayasu's Arteritis because we don't really know what to do. It was two:one randomization, 150 people took a few, I think four or five years to enroll, but they randomized patients to MMF if tolerated two grams a day, methotrexate fifteen milligrams once a week. So not full dose, but combo from the beginning when you can't get the steroids down compared to cyclophosphamide induction with azathioprine one hundred milligrams a day, maybe less if they're according to body weight per day as maintenance. And there was a very strong signal of equal to better safety and better effectiveness or efficacy and the patients on MMF plus methotrexate.

I've never been shy to use that combination. We use it in inflammatory myositis. We kind of use it but often as add on therapy in some of our CTDs and vasculitis like Takayasu's. So when I treat my next Takayasu's, I will indeed start methotrexate plus MMF at the beginning instead of serial monotherapy or adding when you're a failure. So I really liked it, and although it wasn't today, I thought it will change my practice.

Any last words of wisdom or something that really caught your eye before we call it to a close?

I'll throw in one abstract from the RA abstract. Basically about steroids and about how long the harm lasts after even if you stop them. It's Canadian data, so of course I've got to mention this, right? It's from

BC database. Yes.

Yeah, absolutely. Well, so basically the longer the short of it is you think that your risk from low dose steroids would end when you stop the steroids. But actually what they found in their study was if you're on it for six months, you've got another one point five years of risk as far as cardiovascular deaths are concerned, and as infection's concerned, two point five years. If you're on it twelve months, it's another three and a half years risk. And if you've got twenty four months of steroids, you're gonna have ten years of risk.

And so I probably use more steroids than I should in inflammatory arthritis. I'm gonna take a good long hard look at myself in the mirror. Obviously there's the risk of residual confounding, but I think it's still a shake up for me.

Right, right. And just for the audience, it's confounding. Our worst patients in inflammatory arthritis get glucocorticoids. So it's a patient it is, inflammation, not responding as potentially or not tolerating drugs, as well as the actual steroids themselves. That is very concordant with what Doctor.

Brian England did last year as a plenary at the ACR showing in the big VA cohort that once you stop glucocorticoids at various doses, it was a dose response. But even six to twelve months later, your risk of not risk, actual MI and MACE were still elevated and very, very something that I think we have to think about. And then we have to think of all the cardiovascular risks if we're going to use long term steroids. Because hardly ever do you prescribe long term, but those scripts just keep going. Akhil, any other words of wisdom?

No, I think those were all great points, especially I think steroid exposure, it's been the early treatments and one of the early discoveries in rheumatology, now we have so many new therapies out and also looking at the toxicities and what the effects has been in our patients, I think just have really large implications. I think it's really interesting just to see is that we need to be more judicious and cautious just about use of steroids in our patients with rheumatic disease. Especially as David pointed out, I think even in inflammatory arthritis, if we can try to minimize the use of it, even the short term or long term, I think it can be for the greater benefit. Though, obviously, you wanna consider the patient's pain and minimizing risk of irreversible damage in the long term as well. But I think those are all really important findings.

I think the bottom line is steroids were transformative but that's almost like almost a century ago. TNS were transformative in RA and then some of the other molecules. And now we're get getting as we talk today transformative treatments including lupus, vasculitis, etcetera. And therefore we found over many decades of use that the steroids can do good and they can do harm as well. So with that, I would love to call this to a close.

Thank you to our listeners and keep following us for more of our discussions that we'll have over the next week or so at RheumNow. Thank you very much.