GCA PMR Panel From EULAR2020 Save

Hi everyone, I'm Jack Cush with RheumNow. I'm joined by three friends to discuss the polymyalgia rheumatica giant cell arteritis happenings at UR twenty '20. I'm joined by Doctor. David Liu from Melbourne Health, I'm sorry, Austin Health in Melbourne, Sarah Mackey at Leeds in The UK and Glenn Calabrese at the Cleveland Clinic. Good afternoon, good morning, good night.

We're in so many different time zones here. It is the way of the world. So we're going to discuss the some happenings on, the PMR GCA front. David, why don't you take the lead and introduce our first abstract?

Absolutely. Well, there have been some really exciting abstracts, I think, at this EULR that have challenged the way that we think. I think in particular, one of the things that has I think all of us would nominate as something which we'd be looking forward to seeing is the extension data from JECTRA. JECTRA, course of being the key registration trial for tocilizumab, angina, ciliar arthritis and what we saw at this conference was that some of the data that's come out from subgroup analyses or from extension data, so in fact going out to three years now. One of the key bits was that three year data which was presented by John Stone from MassGen, that's OP 27 with data looking at steroid utilisation and flare rate in the different groups of JAK, so that's a weekly, every two weeks and then the placebo group from that study.

I mean, I'd be curious to know, to to get some thoughts from the group about that. It's such an important study for our use of tocilizumab in giant cell arteritis.

Sarah, what do you think about that?

Well, think this three year data is really, really exciting. It's in a way even more exciting than the one year data, which resulted in the license of tocilizumab because it starts to answer the question whether good control of inflammation in the first year of treatment for giant cell arteritis matters for long term outcomes. And additionally, there's the relapsing subgroup. So if you then have one year of really good control of inflammation, does that then cause better long term control? So they did an intention to treat analysis and they looked at the percentage of patients remaining flare free through the whole years two and three of the study by their original treatment allocation, and they also looked at the median time to FLAIR.

It was really, really impressive that the patients who were originally allocated weekly tocilizumab had a much greater chance of remaining FLAIR three throughout years two and three compared to those who allocated placebo and then the two week ditosumab was somewhere in the middle. So this is absolutely fascinating because for a long time in inflammatory arthritis, we've had discussions about window of opportunity, about the importance of tight control. But until now, we haven't really had that kind of data in giant cell arteritis, that good control of inflammation actually then has long term benefits.

So Lenny, what do you think about G Acta and especially the long term data? Is it enough to change the habits and practices of rheumatologists? It's been slow on the uptake in actual

you know, I consider it a standard of care and, you know, I think that, we'll talk about steroid toxicity in a bit. But I was impressed that we've learned or reaffirmed, this is a chronic disease. It's not going away. And, the other thing that I would say, Sarah, I would say that, that the every other week is not in the middle. It's pretty darn close to the weekly.

And I've been using a lot of every other week, you know, trying to risk mitigate and, you know, I don't think we have the final answer right now on, you know how many people we can control but I'm in for the long run and if I can get away with every other week I'm very happy to do it.

David what about you in weekly versus every other week?

Well, I think that the relapse data from this extension in that three extension really has started to make me think maybe I should be thinking about weekly for my patients. Australia, we get one year in total of weekly dosing, so we get fifty two doses. And it's made I've often thought about well, some of my patients have been spreading them out, trying to do it every two weekly thinking about that data. But I think this has made me think a little bit more about that and also has made me think a bit bit about whether we really should be advocating for more atosumab access for our patients. Ultimately, it's a steroid sparing benefit and it's the benefit said early on.

I mean, what would you say to that one?

Let me be clear. I start with weekly and I'm talking about the long run now, year two, year three and beyond. I think there's a case to be made that we need to look more carefully at dose reduction in that group. And I think it works pretty good.

Mean, yeah.

David, what about the aspect on PET CT? Does that make us smarter in our management of GCA? Can you tell us about that?

Yes. And I particularly like this because it really this is work from sorry. This is sorry. I think it's showing up there. This is work from Peter Grayson at NIH with his group and and looking particularly at what happens after throughout the course of tocilizumab therapy.

So I think as as Len was mentioning, as as Len talked about this ongoing tocilizumab therapy there. They looked at 22 patients and they did I think what seems pretty remarkable to me in that they did a a PET CT at baseline and then every six every six months after that, which I don't think we'd necessarily do for routine care, we'd it gives us an idea as to what the kind of FDG vascular uptake, how that trends over the course of time. I think we're starting to understand that more and we're seeing that in a few of the other abstracts that that may well represent real disease activity, but what I think was interesting out of this was that they they tracked it over two years and we could keep on seeing that FDG uptake, scintigraphic uptake representing inflammation in the vessel keep on dropping over the course of time. And what's more, they looked some patients where they withdrew the tocilizumab and then they saw them flare as well. So, I mean, for me, that's quite a stunning finding to be able to see that there's benefit over two years.

But this isn't the kind, I've always thought once again, maybe because of my paradigm in clinical practice that a lot of that benefit comes from the first year, this is where we see the stereotypical benefit. But it does seem that this is something that keeps on going and going and going.

So is this just a research tool, Sarah, or is this something that has practicality?

I guess it's whether it's going to change your clinical decisions at the time. There is this disconnect between the systemic symptoms of giant cell arteritis, know, inflammatory markers of CRP and how patients feel and then what's going on in the vessel wall and without doing serial biopsies, really imaging is the only other way to monitor what's going on. I think other people have used serial ultrasound but clearly only you can only access limited number of vessels with that you can't to the aorta to see whether there's kind of ongoing disease activity there. So I think at present we're still finding a way as to how much vascular imaging monitoring is required in these patients. But I think when you get to clinical decision points imaging is often very helpful.

Lenny, at clinic you guys are one of the worldwide leaders in vasculitis care. Does FDG PET fit into your use and assessment?

Well, it sure fits into the diagnostic algorithm. I mean, nobody does bilateral temporal artery biopsies anymore. You have access to it diagnostically, I think it's very sensitive and helpful. I think that to me this abstract reaffirms, hey, this is a chronic disease, not going away. But as Sarah said, is this actually gonna change practice if you could do this?

And you know my knee jerk response is that no, it wouldn't change my practice. And the real question is what is the end game? What would it look like you know eight years out? I suspect there'll still be low grade inflammation there. And I think this is is Len being crazy that, you know, this is going to kind of anneal itself with chronic low grade inflammation of aging, Inflamma Ageing and I don't think it's ever gonna go away and, I, you know, these events of aortic aneurysms and stenosis, they're really rare.

Yeah, I mean, you know, this and all of these people demonstrate this. So I find this pathophysiologically fascinating and leaves me in a quandary as to how it would work as a clinical tool, but it also gives us great insight into inflammation and aging.

Let's move on to the abstract on on PMR and what may be lying underneath that in the form of vasculitis. David.

Absolutely. Well, this is one that, I first heard talked about, at at the PMR GCa study group, but I think has real implications. So, this is from a group, in Bonn, Valentin Scheffer's group in Bonn who they took PMR patients, 50 consecutive PMR patients presenting to their clinic and really tried to address this question, what's this relationship between PMR and GCA? And where does it sit and how many of our PMR well, we think eventually twenty percent of our PMR about one fifth of our PMR patients might go on to develop clinical GCA. But where does that relationship start at the at the beginning?

Is it there all along? Are we and we're we're not picking it up? How does it develop? So they they performed a vascular ultrasound on all of their 50 patient consecutive patients. So, you know, we wouldn't think that beyond what's getting coming into that tertiary center that it necessarily be selection bias.

And and what they saw was that twenty seven of those fifty had vascular uptake outside of outside of limits, would be consistent with giant cell arteritis. And of those twenty seven, seventeen had symptoms which which could be culpable, which could be attributable to GCA, which did sound high to me. But then another ten had no GCA symptoms at all, but still had an uptake. So I'm not really sure what this means, is this part of giant cell arteritis, this subclinical giant cell arteritis going on there? Does this become giant cell arteritis in the end or not?

I'm still uncertain where that relationship comes about and does it need it to hit to do PMI patients see that second hit to develop giant cell arteritis in the future or not.

So Lenny, this is another more sensitive way of finding what we've always been told in the past that it could be there but you don't necessarily treat it. Does this make you more inclined?

There is nothing new under the sun. This is the same question that's been asked for the past fifty years in this disease and you know I love Valentin. He's a very careful observer and this just reaffirms everything that I've ever thought about this disease.

So be careful what you ask for. So

I mean this is a question which I've been fascinated by since I first started PMR and GCA and Colin Pease and I looked in our leads data set looked at these patients who were originally diagnosed with polymyalgia rheumatica and then went on to develop giant arthritis later. And we were trying to work out did they always have giant cell arthritis that was just hiding or did they actually then develop this like a two hit this second disease? And was there subclinical giant salaritis? And of course, at that time, we didn't do routine vascular imaging diagnosis. And so we didn't know, we still don't know because in clinical practice, don't necessarily do that.

But I mean, this does would support the idea that at least in some patients, polymyogeomaatica patients do have a subclinical giant cell arteritis from the beginning that you can pick up if you look on ultrasound, and maybe these patients you would need the long term follow-up data to know, but maybe these patients are the ones which we're watching really, really carefully to see if they then develop clinical giant cell arteritis requiring high dose steroids. And we should maybe be treating polymyogeometric a lot more seriously as a pre disease state, not as a little category all by itself that could just go back to the primary care physician, but actually these patients are high risk for developing giant cell arteritis and we should be taking this seriously.

So this is in line with what Lenny was saying that this is a chronic disorder and you know we gotta we gotta be in it for the long haul in our assessment of these people. Let's end up with the aspect on PMR and steroids. Davis.

Absolutely. Well, this is it's industry initiated, but I think it has a really important, message. I think it's been done recently well. This looks at claims data, US claims data, in patients with a with a diagnosis of PMR, and then looked beyond that at that first year to see, what incident, potentially steroid related complications accrued in that period of time. So we're talking about some standard numbers of patients.

We're talking about because it was over twelve thousand patients. PMR patients had very well matched controls at that time and then they looked to see what complications they developed. And you can see right across the board that they kept on accumulating more and more complications. Now it's hard to know, is this disease, is this a steroid? As a guess that it's more likely to be the steroid but I can't say that for certain.

But I think what's really telling is that I think people often dismiss the fifteen milligrams of prednisolone that you might have for polymyalgia rheumatica not harmful. I think people perhaps maybe even undervalue PMR as a disease. Think of it as incidental or self limiting. It's still a disease we don't have steroid sparing therapies for that have been proven in a phase three trial. So we're left in a situation where these patients are getting more hypertension, more diabetes, more infections, more cardiovascular disease, more skin toxicity and neuropsychiatric disease, ocular disease, renal problems, things that we wouldn't, that might easily, get forgotten in terms of thinking that PMI is a real disease.

So this is the age old question in managing, especially PMR, you know, how can we minimize or avoid steroids? Are we going to get to the point where we could use, we should be using tocilizumab in PMR or the C5A inhibitor, avacopan, that was for the ANCA associated vasculitis? Should, should we hold tight to steroids or should we be looking to the future and substitutes? Sarah?

I think we desperately need some good trials of steroid sparing agents for polymyalgia rheumatica. This is not a benign disease, so for the patients that can get off steroids quickly and without complications, that's absolutely fine. But there's a substantial, so it's not even a minority, who require two or more years of systemic steroids and they accumulate the most awful panoply of side effects, some of them. And we just have no decent evidence as to what we should be giving these patients to help mitigate that. Should be going in much earlier, I think, and thinking about what to give them.

I think it's been challenging to get these trials funded. It's been challenging to get these trials designed because historically they have the classification criteria of polymyal dramatica, there were lots of different sets and it was confusing. Also some criteria for relapse and remission needed definition. But all these things are being worked on now and I think this just really underlies the need for a decent trial of something that can help our patients with polymyo dramatica.

Len, what's your perspective on this?

Prednisone is poison.

Many years ago I came

up I didn't say that, it's not my quote as you know, But

But many years ago I came up with a trial, greatest acronym I've come up with yet called the Prada trial. Polymyalgia rheumatica and adalimumab. And and, you know, we ran it around. It was obviously the companies loved it. But, you know, the old guard, you know, Harry Spire and a lot of the guys that are the PMR guys, they were like, what are you out of your mind?

You're gonna use a million dollar drug when you can spend 12¢ on prednisone. We still, this is what we're up against.

It sounds like. No, I agree. But I mean, there's been some great advances now in steroid sparing. You mentioned Avacopan and actually AbbVie has a bispecific antibody with adalimumab and an intracellular steroid antagonist that anneals to the same cell. I mean, yeah, these are expensive bioengineered drugs, but you know, I guarantee you that you know, five years from now, we're going to be doing something a lot different in this area.

We got to keep pushing. I'm so excited about the Avacopan I think that's just a total game changer it's going to be and it gives us no one would have dreamed of that a decade ago.

So David, why don't you just briefly go over that data because it was a highlight from the meeting.

Absolute. I mean, in my mind, was probably the the highlight of the meeting. So that's Avacopan. In that phase three trial, it also got presented at the European, Renal Meeting as well on Sunday by David Jane, Peter Merkel presented the data looking at patients with anchor associated vasculitis who were getting either rituximab or cyclophosphamide and compared in a double blinded randomized controlled trial way, steroid versus the vapacopan. And the outcomes are fairly stunning.

We saw that it was non inferiority at twenty six weeks. The patients went on had superiority at fifty two weeks, better renal outcomes, obviously less steroid toxicity. I mean, this is gonna be a great this is a great new advance and I mean, to be able to have the chance to to use this would be fantastic.

But unfortunately, it's gonna come at a price. That's the that's the big worry. Right? Anyway, this is really stimulating. I want to thank all of you for taking the time out to discuss these important abstracts.

There'll be more on you Laura to come, I assume. So good day, everyone.

Thank you

so much. Thanks.

Stay safe.