Author Interview - Professor Andrew Cope, 2026

Hello, everyone. Thank you for joining us today for what we hope will be an interesting

and informative discussion around the latest data in rheumatology, my name is Fischer Peter

National and Griffith University in beautiful downtown Brisbane. And today I'm delighted

to be joined by Professor Andrew Coat. Andrew worked for a very short period of time in Southport

and he's doing a sabbatical all over the place, Monash. He's now in Brisbane, he's

off to Japan soon and we really look forward to our discussion on one of his recent papers,

which is the long-term outcomes of a intercepted individual that risk of developing rheumatoid

arthritis. The ALTO study, a randomized double blinded sabbatical trial work, Andrew, can you

just tell us a little bit about yourself and where you're currently working and what you're up to?

Yeah, Peter, so listen, thank you very much for the invite. It's great to be back on the pod,

I should say. So I'm an arthritis doctor based in London so I work out at the Centre for

Amatic Diseases at King's College London and my clinical practice is at Guy's in St Thomas's

Hospital, both on the Guy's campus and over at St Thomas's Hospital. And I'm having the best time

at the minute, the first phase of my sabbatical, I've been in Melbourne for a couple of weeks,

up in Brisbane for a couple of weeks and off to Japan and the US. And the main thing is really

having a little bit of downtime, read papers, talk to my collaborators, come up with some

crazy new ideas about how we can really push the boundaries in people at risk of RA in particular.

And that's fantastic. So this study is all about prevention of RA in high-risk people

and I'm old enough to remember Paul Emery's 2009 study, The Adjust Study, which took people who

already had inflammatory arthritis with Ciro Paws, gave them six months of a batterset and showed

some reduction in progression and even some x-ray change. And so now we roll forward to your

apipra study, which we looked at in the previous podcast. People have tried our Droxychloric

and metatrexate. Prairie was one dose of retux. So that's the background. So can you fill us in

on how you did the alto, which patients you took from apipra, because people say our selection bias

and whatever. So just to listen on the inclusions for the alto, which is the long-term follow-up of

those patients. Yeah, so Peter, just to remind folk, the Piper was a phase 2 BRCT and we recruited

213 individuals and we randomized them to receive either standard dosing of a batterset for 12 months

or placebo and then monitored them for another 12 months. And we documented 54 events in total.

So these were people who progressed to RA from this at-risk phase or stage, which was

anti-CCP with a without room to add factor and inflammatory joint pain. I think that's the key thing

here. And we published the results in the last at 2024 and we demonstrated that those who received a

batterset, the rates of regression were less. Now, we wanted to recruit all of the individuals or

invite all those apipra participants into the follow-up study and guess what? The COVID pandemic

rocked us. So there was a gap. There was a gap. We wanted to take people right from the end of

a Piper straight into alto and get all 213 in. We were not able to do that in the UK. I don't know

how it was in ours in the US, but in the UK, we were not allowed to do anything except for COVID

studies. So there was just total shutdown of everything. So it was a disaster. We were, however,

able to encourage 143 out of those original 213 Piper study individuals. There was no bias at all.

It was bring it on to get as many people in as we could. And by chance, the arms were really well

balanced in terms of age and gender, smoking status. And more importantly, those who had already

met the primary endpoint in apipra because we wanted to not just collect more events,

but we wanted to look at safety. We wanted to look what the impact of those who hadn't met the

primary endpoint was over the years, as well as those who had met the primary endpoint and were

on standard of care. And what we were able to do because of this gap is to collect data

and follow up for between four and eight years. So that, that was really key. So this really

is a long-term follow-up study. And so people who say that that 30% didn't go in,

were the people not doing well or doing very well. It was just a chance recruitment to be recruited.

Totally random. Now, can you just tell us the other thing that I've read about in the editorials,

is that you chose three ways of time to disease. And one of them was the commencement of a

DMAD, or was there any recommendations across the group on who you should start a DMAD in,

or was it at the doctor's recommendation? Yeah, so Peter, this is a key question. In a

paper, we were just looking at ACR ULA criteria, or three or more swollen joints, those were the

criteria. Because of this gap between a paper and alto during the lockdown, we came up with the

idea of using time to first DMAD, any DMAD, including steroids, as the third outcome,

for the very simple reason that we could go back to electronic health records during that interval

and get a very precise date around when DMAD are treated. So imagine you got someone in a

paper that do okay, they don't meet the primary endpoint. And before they get into alto,

they flare up, they develop RA, they're given treatment. So we were able to record that as the

third outcome. And it's in fact that blip on the survival curves that is explained by that third,

that that third endpoint. Otherwise, we probably wouldn't have been able to collect precise data

during that interval. And tell us a little bit about the stratification for ACPA and rheumatoid

factor, et cetera, at baseline. So we can get ahead around that and share depotov, et cetera, et cetera.

Yeah, so I think this was probably the biggest surprise of the study. So no surprise, perhaps,

that those with high levels of anti-CCPR ACPA were more likely to progress. That was a, that was

a no-brainer. What we also did was to look at people who had multiple auto-antibodies

at baseline. So this included rheumatoid factor, two different isotites of ACPA, so IGG and IGA,

as well as antibodies to carbaminated proteins, anantiacetylated proteins. So in all,

five auto-antibody subtypes. So we call that the extended auto-antibody type or the five

serotypes. And we call them serotypes because in fact, these assays are detecting probably hundreds

of different auto-antigenic specificities. So if you have high ACPA, so greater than 340,

in most clinical lab cells, off the scale, or you have five serotypes, these people, they

progress real fast. The surprise was that those were the individuals that responded best. And if

you look in the paper, at the cap of myoplots, those with the five serotypes, they got no disease

progression on drug, and then delay beyond six years. In fact, the survival curves don't even cross

in that particular group. So higher risk, progress more, but respond better to study drug.

So two questions, no shared epitope. Would that have made a difference? And

do you believe ACPA is pathogenic in rheumatoid or an epiphenominin rheumatoid?

How long have we got? So shared epitope question is an easy one. The problem with stratifying

by shared epitope here is that the high acupoteters, which we saw in 78% of individuals,

enriches for shared epitopes. I would say that the majority of people will have one copy,

at least, of the shared epitope. So we can't use that as a risk stratifying. In population-based

studies, we may be able to do that. And people like, as you know, poor memory of use, this is part

of their risk stratification tools to try and increase risk prediction. Is ACPA pathogenic?

I think so far, we're seeing a strong association. That's all I'm going to say. And the reason

why I'm saying that is that there is a very clear link between match duration of that ACPA

response and progression to disease. Two things. Vitamin glycosolation. So modification of the

phag fragment of ACPA, which increases the affinity, very strong predictor of risk. And if you do

clonal profiling, and this is what's been done by Renatoz and colleagues in Liden, that shows

again, although you've got expansion of the antibody repertoire, you're seeing some

oligoclonal expansions associated with progression to disease. The reason why we can't demonstrate

that it's pathogenic is because this test is responding to multiple autoentages. That's the

problem. Probably hundreds of modified proteins, same with anti-copy and anti-protein-sublated

proteins. So it's a really good diagnostic. It's a great predictor. Does it tell us anything

specific about disease pathogenesis? Not sure yet. We got a lot of work to do around that.

And I think I'm on your side. I think it is pathogenic. And we're being approached weekly

by B-cell depletors, T-cell engages to get rid of that, not in lupus anymore, but in the R-A

population that are ACPA positive. And they will really seriously deplete B-cells, even at the

tissue level, which retucks couldn't do. So it'll be interesting to see where that research goes.

Yeah, and I think Peter, one other area which people are exploring is this idea of trying to

block or prevent citrination. So these patterns are inhibitors. And I think, I mean, who knows

whether that's going to work, but it's a great experiment to do. And it will tell us how this

modification is contributing. And I was interested if you look in your paper, which for everyone is in

Lancet Rheumatology 2026, January the 20th, 60% smokers, 20% current smokers, and a small percentage

who were never smokers, driving those nice patterns, arms to sit to load all those peptides.

Well, welcome to London Birmingham and Leeds.

Was there any cirroconversion? And if you did, cirroconvert, were you more likely to be a

responder? Yeah. So we've seen very modest reductions in all 20 body levels on drug, no cirroconversion.

And I think that's because of the mechanism action of the CDLA 4 molecules compared to the B-cell

the pleaters. So excellent. So tell us a little bit about what your findings were. And if we need

to think about any of the methods given that it was many centres around the world, both Netherlands

and I like the idea, it was all from early arthritis clinics, which not many places in

ours as far as I'm aware have. Ranjini's got one, but I'm not sure that that many early arthritis

clinics, and we live in virus arthritis country. So those cirronegs are very tricky and we have

to be a bit cautious, but we don't have many early arthritis clinics.

Yep. So Peter, I think you raise a really key point here, even with people who look from the end

of the bed, like RERA or RERA, seronegative, different disease, really, really clear.

So I think the trip with the early arthritis clinics that the primary care physicians have picked

up is that if they do a CCP test and it's positive, those people will get seen in clinic quicker.

So it's as pragmatic as that. And I think that's why, you know, in the UK and the Netherlands,

we were in a strong position to be able to pick these up. People have tried screening, you know,

you find the first second degree relatives of people with RERA, the pickup rates very poor.

Kevin Dean's done a huge amount of work in the US looking at health affairs, testing people with

anti-CCP. And the issue is that these people often don't have symptoms. They have very low levels

of anti-CCP and their progression rates, their conversion rates are very low, sort of 10%, which makes

trials kind of kind of difficult to do. So the main, I think if you were to summer the results of

the combined studies and what a PIPRA has helped us, there are three things. Prevention on drug.

So if people continue to take a bata set for years, I think those cappular microbes will be quite

interesting. And there's one study that was reported at the ACR where they looked at people

with palindromic RERA. So it's a slightly different at risk group. But they're given two years

and they're cappular mice of survival curves. Those on a bata set, spectacular. So that's one thing.

So prevention on drug. The auto study tells us that we see up to four years of delay

on a bata set. So one year treatment three years off, we can still see a difference, but then

the survival curves merge. And the other thing I think for people who are at risk, they feel crappy,

they're tired, they're joints hurt, they've got all sorts of symptoms, mental health's not great,

they stop going to work. On drug, there is reversibility of these symptoms. So these people feel

better. But you stop drug and within six months, the symptoms all come back. So that's telling us

two things. If you want to make people feel better, you've got to continue the drug. And secondly,

it's telling us something about sort of systemic auto immunity or adaptive immunity,

because the bata set is taking away the systemic, the systemic effects. I'm going to throw some

of the out for you, Peter, a provocative thought. I'd love to get your reaction on this.

You wonder whether we are defining non-articular RA, right? Acpa, joint pain, feeling crappy. It's

reversible with drug. And then for whatever reasons you get this trigger, stuff goes into the joint

and you get inflammatory. I thought, that's articular RA. Now that's super provocative, but it does

mean that if we're going to be able to treat these people, we're going to have to maybe

rethink definitions, because the regulators are going to get concerned, the pairs are going to

get concerned. And when you've got people at risk, where maybe only 50% progress over a couple of years,

the big concern is over treating people who are at risk, who are never going to get the disease.

So trying to get all these things balanced and in line, I think it's going to be the big

challenge for the coming years. So I've been pushing for years, we should eliminate the term

rheumatoid arthritis and call it acpropositive arthritis, like an compositive vasculitis.

So that seronex can turn into a lot of different things, but they're clearly a different disease,

even though they respond pretty well in every trial with 20% included a seronex.

The rate of progression I think you were saying is critical. In your study, the placebo's

was at 30 or 40% didn't progress, and that you've enriched them for pretty high risk factors. So

that's exactly what you're saying, the risk of over-treating compared to the risk of being

aggressive early, but the good news is, tell us about the safety, because there was a lot of safety

and no really nasty safety signal from a year and maybe longer.

Yes, so Peter, we were interested in efficacy, but the second most important thing was looking

at safety, and we deliberately focused on the three things that you might be particularly twitchy

about. Not just for a bad accept, although it's relevant for a bad accept, but you know,

relevant to any other sort of treatment or opality. Infection, cancer, cardiovascular,

these are the things we worry about in our day job, and the signals look pretty good in a

pepperer, and you know, six to eight years down the line, no differences. So I think that's very,

reassuring. We don't see any, any, and I think having that time period gives us the opportunity

for looking at things you might not pick up in a short trial and cancers, obviously one of the

big ones, but no, no signals, no differences between arms, which I think is really short.

One other question, I don't think you'd be surprised that stopping drug leads disease to come back.

If the antibodies are still there, and we're trying to save the pathogenic,

were these a bad accept people mostly on metatrixating combination?

No, so in the trial, it was monotherapy. It was a bad accept nothing else.

Once they hit the primary endpoint, then because of the guidelines for standard of care in the UK

and the Netherlands, then they would go on to to metatrixate. And we hear from some of the PIs

that a lot of people who actually had received active drug say, well, I don't want this weekly

thing that makes me feel shitty. Give me, give me back the good stuff. Fair enough,

fair enough. So any other findings you want to highlight and what might be the take home message

for the clinician, as far as prevention, and then tell us where you're going to next with this research.

Yeah, so I think that the take homes are people who are at risk are willing to take drugs.

In the same way that people with hypolibidemia, you know, hypertension, and I think this concept

of risk and the opportunities for interception is fundamental. And, you know,

you look at people who are looking at studying people with psoriasis, who's going to get psoratic arthritis.

You're looking at people with family history of Crohn's and a positive fecal care protecting,

you know, these need to be treated. You look at the connective tissue disease teams, you know,

lupus, scleroderma, funny auto-antibody, bit of reynos, you know, all of these groups are

looking at this kind of stuff. So I think we are now in the era of interception. I think the other

really key things here we need to sort of emphasize is getting this risk stratification better,

because I'm really worried about over. I think we over-treat in our rheumatology clinics,

anyway, there are probably people out there who don't need chronic multiple demat and biologics,

and we know from the experience, trying to understand who to taper, who to withdraw is super

difficult with very high flare rates. So I think trying to get that right, and we're learning that

the combination of clinical factors with things like MR and ultrasound imaging help, but you know,

you're still only getting 60, 70% prediction over time. So there's a big gap. Now whether that's

immunology, whether it's looking at serum proteome, combining that with collagen at risk scores,

I mean, these are all sort of things that I think we need to look at. And then I think the other

thing looking ahead is do the drugs that we use in a stablished disease? Are these going to be

the same drugs that are going to work in an at-risk population? I suspect not. I mean, people are

interested in looking at maybe targeting type 1 interferons, because we get a type 1 interferon

signature very early. We keep seeing IL-17 and IL-23 signatures, free disease. It's not about.

Targeting those drugs in a stablished disease just really do a whole lot. So we need to understand

that early phase, looking at what contributes to mucosal breaches in the lung, in the skin,

in the gut, your agenda for the tract, all of this kind of stuff to really come up with something

maybe new and a little bit more, a little bit more innovative. So heaps to do, but I think we're on

a journey. And your next plan? Well, I think aside from the risk stratification, and we've got

huge numbers of biological samples to drill down and try and identify these biomockers.

For me, we're talking in the community about a sort of Bayesian trial design, where we have a

standard at risk treatment, and a bad asset will be one example of that. And then any

academic investigator or someone in the private sector could come on and say, right, let us

interrogate your at risk cohorts, and we will try these drugs. For fixed period dosing, see if you

see a signal, time out, bring on the next drug. And I think there's a lot of enthusiasm for this.

And we have to encourage industry to get involved, because I think established R.A.

is super crowded, but I think there's still a lot of work to be done in this at risk phase.

And you mentioned Peter Carti, outside of the risk, and the risk benefit here in this population

is a major issue. I think there's some potentially very exciting opportunities here to really

perturb the immune system before the disease starts, so that we can genuinely prevent

rather than delay. And Rangini is working on tolerance to aqua, using the patient's own

aqua antibodies and et cetera. Do you think that'll be difficult because you're talking of

hundreds of different antibodies to different antigens? So I think what's attractive about the

sort of antigen-specific immunotherapy is that if you can define a common citrinated peptide

that will target multiple patients with different HLA, DRB1, different shared epitope,

but target a population of cells, which you can see, and you get tolerance, and you get

bystander times. And this is what she's doing with a vermentin peptide. It could even be off the

shelf. And because it's so safe, it's so targeted, this is a sort of population, if you can prove that

the stuff is safe in very early RAP people in remission, for example. I think you're absolutely right.

I think this is the way that we might be able to go. So in juiced tolerance, and maybe dosing

once a year, every six months or so is all you need, almost vaccine-like.

Excellent. And with biosimilar, abaticept, and things that it takes cost out of the equation,

it might be a whole new world. So that sounds very exciting. We thank you very much for your time.

We greatly appreciate it, Andrew, and we hope you enjoy your sabbatical around the planet.

If you'd like to know more about this paper, and others uploaded to the immune-mediated

inflammatory disease forum website, you can get detailed slidesets are available at imidforum.com.

Please subscribe to this podcast on Spotify, iTunes, or other podcast media. Let us know what you

think. You can also watch us on the immune-mediated inflammatory disease forum on YouTube. And finally,

you can follow us on Twitter, LinkedIn, and Facebook to keep up with all the new immune-mediated

inflammatory disease content, which is coming soon. Andrew, thank you so much for your time. We

greatly appreciate it. Thank you so much for inviting me and be

really good to see you, man.