ACR20 - Day 5.1 Save

This is the RheumNow podcast, and you're listening to highlights from the ACR twenty twenty virtual meeting. Our faculty reporters have been doing videos and recordings so that you could stay up to date. Hope you enjoy these and our panel discussions.

Hello from RheumNow. This is doctor Eric Dine reporting from Baltimore, Maryland. We just concluded the final day of ACR convergence. It's been a wonderful meeting here at the ACR and a lot of great information, a lot of great posters and abstracts. Right now I'm here to talk about one of the abstracts in our final day session and this was abstract 2,001.

And the study was adverse effects of low dose methotrexate looking at hematologic outcomes in a large randomized double blind placebo controlled trial. So many of the readers listeners should certainly know the CERT trial. It was the low dose methotrexate study looking in a non rheumatologic patient population, looking to see if there's any cardiovascular advantage. People who are familiar with that study will know that that did not show that endpoint. But there was this was a large study of nearly 50 of nearly 5,000 patients.

And so there's a lot of information that we could go back and learn a little bit more about the use of methotrexate based on this study. So this abstract comes from up in Boston, Doctor. Solomon is the senior author on this, and they look at low dose methotrexate, so fifteen to twenty milligrams per week. So in that rheumatic range, non oncologic dosing, and they looked at again, a non rheumatologic patient population and comparing to placebo. So what this group wanted to go back and do is take a look and see what were the hematologic effects of putting this many patients on methotrexate and following them closely as part of this study.

And really what the main find away is not a whole lot in terms of hematological side effects. You know, when you think back to what methotrexate used to be, it used to be a major problem. Two percent of patients would have pancytopenia, it was often quite fatal. But today, that's not the case. Folic acid has really revolutionized the treatment with it.

So in our patients that we found in the cert trial, again, there was low dose methotrexate, which was a mean of right about fifteen milligrams per week compared to placebo. Cytopenias were rare. So two line cytopenia was very rare in both groups. It was four percent in low dose methotrexate, three percent in placebo. That was not a significant number, although did trend a little bit more to be higher in the methotrexate group.

Pancytopenia was even more uncommon, very low numbers, but a little bit more common in the low dose methotrexate. So thirteen, which is zero point five percent in low dose methotrexate, versus six in the placebo, which is zero point three percent. Who were these patients that became cytopenic? So the thirteen people on methotrexate that became pancytopenic. They were median age of 70 years old, which is just slightly older than the general methotrexate group in general.

They developed it as soon as four months after starting methotrexate as late as three and a half years after starting the methotrexate. It's really hard to draw any statistical significance based on this patient group just because we have very small numbers, but it's important to keep track of who these patients may be and think about what made them a little bit different. In terms of single line cytopenias, white blood cell count and platelet counts did not change over time in the low dose methotrexate group. Hemoglobins over time, they decreased just slightly in both arms, but a little bit more in the methotrexate arm. There's a zero point four gram per deciliter decrease in the methotrexate arm as compared to zero point one gram per deciliter in the placebo arm.

So what do you make of all this data? Well, I think the takeaway here is that there's not a whole lot of hematologic side effects when you give the general population, non rheumatic patients methotrexate, what happens to their bone marrow and their hematologic labs, you find that there's a little bit lower of hemoglobin potentially, but white blood count, white blood cell counts and platelets on the whole do not change very much. When you look at cytopenias on multiple lines, two line cytopenia, we're talking about four percent and possibly some significance, possibly some trend, but no statistical significance compared to placebo, with pancytopenia being exceedingly uncommon. So when you're talking to patients, there's a number of things to counsel them with in terms of methotrexate, certainly making sure that they're taking folic acid to prevent these complications. But if they're taking that supplementation correctly, it's very reassuring that hematologic abnormalities are very rare on methotrexate at the doses that we prescribe for rheumatological care.

That's all for ACR coverage for RheumNow. It's been wonderful covering ACR twenty twenty. This is Eric Dine checking in from Baltimore, Maryland, and I look forward to chatting with you again soon at the next meeting. Take care.

Hello. I'm Jonathan Kay from the University of Massachusetts Medical School in Worcester. Welcome to RheumNow. I'm here at ACR Convergence twenty twenty on Monday, the last day of the meeting, and I am sitting in my home office where I've been watching, videos of the various sessions. I was impressed with an abstract this morning that was presented by Siyang Kim, from the Brigham Women's Hospital Pharmacoepidemiology Group on cardiovascular risk in rheumatoid arthritis patients treated with methotrexate or hydroxychloroquine.

Now, there have been data suggesting based on observational data that the increased cardiovascular risk that's observed in rheumatoid arthritis is decreased with methotrexate therapy. Hyun Choi published a paper a number of years ago showing that methotrexate therapy decreased mortality in patients with rheumatoid arthritis. Paul Ridker published a study, a large study of about 5,000 patients with stable atherosclerosis, who were treated with low dose methotrexate, in the New England Journal of Medicine in February 2019. This study was stopped prematurely after about two point three years because the incidence of cardiovascular events was not lower in those treated with low dose methotrexate compared to placebo. So this raises the question, how does this apply to patients with rheumatoid arthritis?

Since that study was conducted in nearly five thousand patients with stable atherosclerosis, but who did not have rheumatoid arthritis. So to study the effect of methotrexate on cardiovascular events in rheumatoid arthritis patients, the investigators performed a claims database cohort study using data from Medicare Parts A, B and D between January 2008 and the December 2016, and linked the Medicare database with the National Death Index. They included patients all of whom were older than 65 years because they were on Medicare, and they enrolled rheumatoid arthritis patients who newly started methotrexate or hydroxychloroquine. They excluded patients who previously used any DMARDs, patients who had recently been hospitalized for myocardial infarction, unstable angina, stroke, transient ischemic attack, heart failure, or coronary revascularization during the previous sixty days prior to beginning either methotrexate or hydroxychloroquine. The date of starting therapy became the index date, and then patients were followed until the end of the study.

The primary endpoint was the occurrence of a major adverse cardiovascular event with a composite endpoint of myocardial infarction, stroke, or cardiovascular death. And then secondary endpoints were individual events, myocardial infarction, stroke, heart failure, cardiovascular death, or all cause mortality. Now, so assess patients for many different covariates, including demographic features, rheumatoid arthritis related medication use, use of corticosteroids, use of non steroidal anti inflammatory drugs or COXIBs, which might increase the cardiovascular risk, comorbidities, the Charlson Comorbidity Index, a frailty index, other medication use and healthcare utilization. Patients were censored at the end of the study period or when they discontinued drug, had an outcome or died. They analyzed the data looking at patients controlled with propensity score matching based on baseline characteristics, and they calculated incidence rates for each of these events in the propensity score matched cohorts, calculating hazard ratios and 95% confidence intervals with a Cox proportional hazards model.

They enrolled a final cohort of nearly 60,000 patients, thirty five thousand six hundred and ninety nine on methotrexate, twenty three thousand six hundred and thirty who were starting hydroxychloroquine. Patients were well matched for age, sex, and comorbidities, including atrial fibrillation, heart failure, coronary artery disease, stroke, or transient ischemic attack, hypertension, hyperlipidemia, peripheral vascular disease, diabetes, chronic kidney disease, and chronic liver disease. In terms of any oral glucocorticoid use, cumulative prednisone or equivalent dose, and use of NSAIDs or COXIBs, these were also matched as well as use of drugs for treatment of cardiovascular disease or diabetes. The primary analysis, the incidence rate per 1,000 patient years for methotrexate therapy in terms of major cardiovascular events, that's cumulative myocardial infarction stroke or cardiovascular death, the incidence rate per thousand patient years was twenty three point three nine for methotrexate, and for hydroxychloroquine, it was twenty four point three three. So the hazard ratio was zero point nine six for methotrexate compared to hydroxychloroquine with ninety five percent confidence intervals across unity.

And the cumulative incidents over time, was not different, not significantly different for the two drugs. In terms of the secondary analysis, however, they found a lower hazard ratio of 0.8 for myocardial infarction and a 0.06 zero for heart failure, and a higher hazard ratio for stroke of one point three three, all of which had confidence intervals, ninety five percent confidence intervals that did not cross unity. So the secondary analyses revealed a significantly lower incidence of myocardial infarction or heart failure among patients with rheumatoid arthritis treated with methotrexate compared to those treated with hydroxychloroquine, but a higher incidence of stroke. Interesting in that this is a paradoxical observation of different cardiovascular outcomes. So this study concluded that in this large observational study of older rheumatoid arthritis patients enrolled in Medicare, they found no difference in the risk of major adverse cardiovascular events, the cumulative MACE grouping between patients who newly started methotrexate and those who newly started hydroxychloroquine.

However, the secondary analyses, as I just mentioned, showed a greater stroke risk, but a lower risk of myocardial infarction and hospitalized heart failure among those treated with methotrexate compared to those initiating hydroxychloroquine therapy. No substantial difference in all cause mortality between the two groups. So perhaps methotrexate therapy in rheumatoid arthritis patient lowers the risk of myocardial infarction and heart failure, but at the price of a perhaps slightly higher risk of stroke. These are interesting data, and it will be interesting to see whether these findings are borne out in an analysis of another claims database looking at individuals younger than age 65, and then perhaps an interventional study might be conducted in rheumatoid arthritis patients to try to assess the validity of these findings prospectively. I'm Jonathan Kaye, and I welcome you to go to RheumNow website to look at other abstracts and other panel discussions and look forward to seeing you again on RheumNow.

Hi there, Doctor. Kevin Winthrop, I'm back. Some discussion about COVID today at the late breaker prompted me to want to just finish this conference with COVID, because we all have COVID on the brain. We're trying to keep it off our brain, But it's, overwhelmed us in so many ways, of course. And, Jack wanted me to just answer a couple questions for you.

First, I'll highlight the Late Breaker poster by Doctor. Sterling Boyd from Boston. This was a cohort study, between, multiple health care centers. They found PCR positive cases, and looked at rheumatic disease patients that were positive and compared them to control patients who were positive, one hundred and forty three rheumatic disease patients, and six eighty eight, non rheumatic disease patients, all with COVID. And they looked at their outcomes, and what I think is the answer to the first question Jack wanted me to, address was, what they found.

And what they found was the rheumatic disease patients seemed to be at about the same risk of being in the hospital as the non rheumatic disease patients with COVID. And once in the hospital, their outcomes are largely the same. Their death rate is largely, what we see in, the general population. There's a few experiences, and in this one, the rate the percent that ended up on mechanical ventilation was fifteen percent versus nine percent for the controls. But I've seen other data where those are more similar.

And again, this is a pretty small study, and that difference wasn't driven by too many numbers. In terms of the percent in the ICU and the percent of death, it was equal between the groups. And I think that's the answer to the first question. Are rheumatoid arthritis patients or other autoimmune disease patients at higher risk? And so my answer, Jack, is, I don't think they are, at least not what we've seen.

If you look at the CDC overall hospitalization data for COVID, about two point eight percent of patients in the hospital in The US with COVID have an underlying autoimmune disease, which is probably, not too far off from what the background population prevalence of autoimmune disease is. In fact, it's probably higher than that if you add in all sorts of things. So I think to me it appears that they're at no higher risk of having it and no higher risk of being hospitalized should they have it, than the general population. So why is that? I think one reason, and I've seen survey data to support it, that I think these patients in general are more risk averse and they are taking more precautions in terms of masking, distancing, and avoiding potential, high risk situations.

That's one issue. Number two, perhaps some of the drugs they're on are protective in some ways. So if they do get it, and they end up in the hospital, perhaps some of those drugs prevent progression or ameliorate already progressed disease. And of course, there are a number of RCTs we talked about the other day looking at the value of actually even using some of those drugs in the hospital therapeutically. But for people who end up having COVID who are already on those drugs, I'd say the observational studies so far, both in IBD, the Secure IBD Registry, as well as the Global Alliance for Rheumatology data, so far suggests that those drugs aren't really increasing the risk of having a poor outcome.

And if anything, there's some data from those two sources suggesting again, it's observational, but suggesting maybe being on a TNF blocker is somehow protective from a more advanced or a worsened outcome. Number two question, what DMARC or biologic drugs should be stopped? And I've been part of that ACR work group, and we've published, some of our musings and decisions that are as database as they can be. They're increasingly more database as more data is known. But, in general, we're saying, hey, if you get COVID, you should consider all these DMARDs similarly.

You should stop them. And that would be how we advise around any serious infection, and given the potential for COVID becoming serious, should you have it, I think stopping those drugs temporarily is very reasonable. Prior to that, I don't think you need to stop them. Now, of course, if you're a contact to a case and you think you probably have it, then, again, you would stop it just as if you were a documented case. But again, this may change.

It's a fluid situation. But for right now, I think that's pretty reasonable based on the data that we've seen. What's the story with prednisone? Is it bad if people on prednisone get COVID? I just, I think, address that.

I think the data, again, this observational data, would suggest people who are infected who are on high dose steroids seem to be more likely to have poor outcomes. Of course, I don't know if that's the high dose steroids or if that's some other, or just a marker for, you know, worsened underlying disease or other factors that aren't being controlled for in those analyses. In the Global Rheumatology Alliance cohort study initially, they did do a multivariate analysis. So they did try to control for differences in underlying disease and comorbidities, and they did see that SILs association. And I've seen that in other data as well, although not as well modeled.

But I think it's probably a real association. In terms of dexamethasone, obviously this is a different story. We're using this now as a standard of care in the hospital. If you look at that data, though, it's really only supposed to be used starting at a certain point. In patients who are not receiving oxygen support or they're receiving, quote unquote, regular or low dose oxygen support, there's really no clear evidence that the dexamethasone helps you at that point.

In fact, the discovery data would or the recovery trial would suggest that, you know, starting it earlier might even be detrimental. If you remember those survival curves, they didn't look favorable in those early patients. So it was really the patients on high pressure oxygen and beyond, those on BiPAP and mechanical ventilation, ECMO, etcetera, that was where the mortality benefit was seen, and really being driven for in the dexamethasone data. So that's really where Dex is, indicated. Number four, should my patients get the vaccine?

What's the vaccine landscape? I go into that because it's about a forty five minute talk. You saw today very exciting news from Pfizer. It was just a press release. There was no data attached to it whatsoever other than saying, an early look at our vaccine trial suggested ninety percent efficacy.

Now, that's way beyond my wildest dreams. I think most of us were thinking these vaccines are going to come in the fifty to sixty percent range, might luck out, get a little higher, but ninety percent is really high. So whether that holds up with further analyses when the study's done, we'll see. I would be tickled, if it did, and that'd be fantastic. Now, of course, that's an mRNA vaccine.

It's got to be kept really cold, so there's always these storage and transportation issues around those types of vaccines. So might complicate delivery, etcetera, and giving to a large population. But in that initial report, I think, is really hopeful. So I hope it holds up and I hope the other vaccines look that good too. Should you get vaccinated?

Sure. Yeah, you should when we have vaccine and when you can actually get it. It's gonna be a while, but but I definitely, I I think it's unlikely we're gonna see many safety concerns from these vaccines. And like I said, the the efficacy may may be better than than I was anticipating. We'll have to see.

I suspect the efficacy will be different for different types of vaccines, but we're still months away from that. Number five, drum roll please. How long will the pandemic continue? I might have said this the other day, but I think it's going to just keep going for a long time. I mean, think this virus has become endemic.

I think we're going to probably see a seasonality to it. And, it'll be several years before we get enough people in the world with immunity, either naturally or by vaccination. We also really still don't know how long immunity lasts. I mean, we do know people are getting reinfected after three months. So for some people, obviously, immunity doesn't last that long.

And in some of those cases they've had worse infections the second time around, which is counterintuitive. So, so I we don't know, and I'm going answer this question again for you in like three months when we have a lot more data. But for right now I think we should just prepare to, do things that Doctor. Fauci, told us all to do, during his, ACR talk. Wear our masks, stay distant, or somewhat separated, live our life as, to the fullest as we can, but avoid large gatherings and do the right thing in terms of, washing our hands and infection control.

So, for now, that's our best, preventive, effort. And unfortunately, we weren't all able to get together at ACR, but maybe next year we will be. We'll just all be wearing masks. I don't know. And I think wine should be involved too, because I definitely I'm optimistic about that.

Anyway, I hope you guys had a great conference. I did. I actually really enjoyed cruising around the website, when I could find stuff, to look at it. And I thought some of the sessions went really well. So thanks very much, and, have a great holiday season, everyone.

Cheers.

People I'm going to interview today. So I have Doctor. Tom Appleton, whom I work with. He's an OA leader in the field doing basic sciences. He gets it clinically as well.

He's an MD PhD. And I have with me the newly minted professor Peter Nash. He's from Griffith as well as many other universities around the coast including Brisbane area. So, and as you all know, Peter Nash has been very busy on seronegative and some seropositive things at this meeting, as well as dabbling in many other things. So I thought if I may, Tom, if you can give me what you think are the highlights for OA, then we'll cross over to PSA and then we'll have some more dialogue.

So Tom.

Thanks very much, Janet. It's a pleasure to be here. Thanks for inviting me. I think actually it was a great year for osteoarthritis. And actually year over year, I get more and more excited about all the things that are in the works.

It seemed like for a while there, there was quite a dry period, but there's been a lot. So probably the biggest thing is the updates on the Tanezumab story. So anti NGF therapy for osteoarthritis. And important to point out, this isn't a demode per se, but it's aimed at improving symptomatic outcomes and looks like a quite a positive story. I think overall, the Tanezumab story is essentially two stories in one.

The first is on benefit. Tom Schnitzer reported in a pooled phase three analyses that at week sixteen, there were more patients who hit clinically meaningful endpoints in terms of Womack score, not just at all, but at 30% improvement, 50%, 70% cutoffs compared to placebo. So good early responses across the board. There was another abstract presented by Tahina Neogi subcutaneous Tanezumab two point five or five milligrams. For those who had a good early response, we're actually able to sustain that out to fifty six weeks of follow-up.

So good long term profile as well. On the other hand, the other part of the story or the flip side of the coin, if you will, is really the safety one, and people have been following this story very closely. John Carino reported on Abstract fourteen eighty two, the integrated safety analysis. And so there's this new composite joint safety outcome for joint safety events, and that's comprised of rapidly progressive OA of two types. The first type is the most common by far, RPOA2, osteonecrosis, spontaneous insufficiency fracture as well.

So there were events in all groups and they happen more in the tanezumab groups and certainly a dose response effect. So, there certainly is something to follow here. It'll be interesting to see how the FDA handles this. It's already before the FDA. I think in the future, it'd be nice to see comparison against joint injections.

So corticosteroid injections, this was another theme that came through loud and clear this year is potential concern about corticosteroid injections and what that means for safety. Think it's way too early to know for sure. We need well controlled studies to look at that, so probably more to come there. But overall, two stories, benefit and safety, it works, but potential downsides as well. So we'll have to see where this goes.

So I have two follow-up questions for this. So I saw the one set of data over 3,000, think 3,100 patients or something, but at the end, and it wasn't all that long a study, there was only over a thousand that they were analyzing. Like, is this what happens in long term OA trials or what's with that?

You mean just in terms of the total number of patients?

Yes, yeah, there was a huge dropout on one of the abstracts and I didn't clearly understand why.

Yeah, I actually tried to read into that as well. I couldn't get all the details. It wasn't all in the abstract, but I certainly see there's quite a few people who did not meet the primary endpoint at sixteen weeks, and so they were excluded from a number of these analyses. So I think it's important to point out that in the long term studies, they're really looking at the people who did well, so you're more likely to do well in the long run if you already met the early endpoint, but those are the data. Great.

And I had trouble with this Tanezumab stuff because the higher dose seemed the most effective. The two point five wasn't anywhere near as good as the five but the five had all the same vascular necrosis and I love the way they rename things rapidly progressive OA as if it's a normal natural thing. It's really AVN and insufficiency fractures so you know the most effective dose had the most adverse events so I'm just a bit sceptical about Tanezumab.

So I guess too, I mean this has been a long time we've been waiting for a demode. I guess if we're going to consider this maybe an analgesic, an enhancement to standard of care for those who fail standard of care, you do think there's going to be really a market at the type of cost of drug development for something like that? For sure there's unmet need but do you just think that something can be costed in an area that will help our patients?

Well, I think we always have to keep in mind just how large the osteoarthritis market is. So there'll be some economies of scale that way and probably the closest correlate would probably be the osteoporosis market as well. Know, things are able to be marketed at a lower cost just because the market is so large. So that's a consideration. Think it's also important to point out that not every patient is gonna be a candidate for this, and I think you're alluding to that.

I think the thinking is right now that if people have really failed a lot of conventional therapies for quite a while, and this is something that they're looking at, there will be a risk benefit kind of discussion that has to happen. Another group that comes to mind though is people who may be eligible for joint replacement but for multiple good medical reasons are not good candidates for that. And so, you know, you're sort of asking yourself, well, what other options might there be and your threshold for risk might be a bit higher there. So those are some of the clinical discussions I think that would end up happening. But again, we can't get ahead of ourselves.

This is not approved, it's still being reviewed.

Great. Peter, can you tell me what you think are some of the highlights looking in the PSA area on either our evolution of thinking or in trials as well?

Well the big things in the PSA field and trying to establish which PSA patients go on to get PSA and Jose Scher and Joseph Marola have been doing a lot of work looking at risk factors, which patient will go on and which patient won't and there's some nice abstracts looking at PSO patients treated with aggressive biologic therapy for their skin, does it prevent them developing PSA subsequently and from my reading I reckon it's about halves the risk of going on to get PSA. It doesn't get rid of it but it does reduce it and I think those long term studies will be very interesting. We now have a plethora of treatment choices, two or a couple of extra IL-seventeen inhibitors, one from China, one from Russia, so we'll have at least five to play with and Bredalumab didn't make it so that would have been the sixth. The JAKs are now in the PSA space and the upadacitinib data is very impressive because it covers all the domains and it has excellent skin response which the Filgo and Topher don't have quite as good skin response as the OOPA does. No new safety signals in the PSA world from JAKs.

Here in the skin cancer capital of world, we're very cognizant of whether you're going to add non melanoma skin cancer issues to all the biologics including the JAKs and there doesn't seem to be any issue or signal there. So all the domains including skin are covered and the risk doesn't seem to be any different to what we're used to in RA. There's an interesting SECU paper where there's differences between the genders in baseline disease activity and how they respond to therapy. So there's talk of stratifying people going into PSA studies based on their gender now. The thing that they didn't look at which I'd have been interested in, do genders have different adverse effect profiles as well?

Are there different issues we should be looking at? For example, the JACs, are we going to see HPV as an issue in our younger women that needs to be looked at given that there's a zoster signal across the class. So there's lots of interesting treatment choices now that P1923 inhibitors looking very impressive. First study ever maximized which looked at PSA axial disease, so there's a lot happening.

Great, can I ask you though on the gender was it that women just start worse so they end worse so they have more pain and suffering and therefore the delta is kind of the same and they end worse or does it really look like a different kind of response?

No, I think we just don't know. I think you're probably right with what you're saying but no one's looked at it before so and we've got so much clinical trial database to look at maybe we should look at it in other therapies as well.

Yes, makes a lot of sense and please because we have the placebo arms as well. So in RA in general women start with higher pain sometimes in the RCTs higher burden of disease and the Delta seems to be the same. So if you start a bit worse, you end a bit worse on average but it is tough to know if it's just the dynamics of where you start or if there's a difference. So what about the TYK2? So is TYK2 with the phase two trial was presented, I think it was a late breaking poster by Phil Meese, do you have any opinion on that Peter?

Well Well it looks nice, it works very well in PSO and this is the first study to look at PSA and I think it'll find a place as well. It's interesting that it's a different mechanism, it's not that reversible JAK inhibition that we used to, it's a covalently bound, permanently bound and so that's when we have to make sure that there's no downside from a side effect point of view. I mean the VTE thing is one of those things that we still haven't settled with the JAKs. Is it a class effect or is it a JAK-two inhibition effect? I'm not sure it's adequately worked out yet.

Right, so lots will come and I think stratifying how we're going to treat PSA is probably going to change dramatically over the next three or four years because we just have such a plethora. I know there was a talk about dactylitis being higher risk for erosions and maybe I would have guessed that polyarthritis was as well in PSA but I might not have fully guessed that. So I think we're going to learn more. So can I open this up to both of you? There were several articles at this meeting on the value of intra articular corticosteroids that in one it was superior to hyaluronic acid, well that's not quite true and one it was equal on two large cohorts of over seven hundred patients equal joint space narrowing or need to go on to knee replacement in primary knee osteoarthritis for those who got one or more IA methylprednisolone injections versus so it didn't seem to accelerate cartilage loss.

There is another one, a nice RCT looking at intra articular steroids plus lidocaine versus lidocaine alone showing KOS, K O O S, some outcome measurement was better and they're going to do some interesting sub analyses and strongly, strongly positive with the small n. And I know Tom, some of your data that the gait improved post primary knee OA intra articular steroid injection and maybe helped the quads as well. So with those things in mind, I think that there's been a lot of backlash in the media that intra articular steroids accelerate cartilage loss are not so good. And there also there's a meta analysis as well I guess that analgesics such as lidocaine can also accelerate cartilage loss. So can I have both your takes on what do you tell patients?

Do you think we need more data or do you think we have enough data to keep doing what we're doing and feel comfortable with it?

Well, I'm happy to chime in on that. I think there's certainly a lot to discuss, but I also am, optimistic that over time we'll be talking about corticosteroid injections less and less in this area, which will be really nice to be able to do at some point. So yeah, so you're absolutely right. Really mixed effects. And I think that just underscores the pleiotropic effects of corticosteroids.

They have atrophying effects on some tissues. They're potently anti inflammatory. They're also anti pain for non inflammation related reasons and probably have a little, you know, at high doses, it can also have some effects on cell death as well. One of the things that I often think about is, okay, how much and how often and in which patients? So we have to be careful in a lot of the cohort studies that are either uncontrolled or potentially subject to channeling bias where, you know, these people might have progressed anyway.

And unless we have a really good controlled arm, ideally with randomization, we're not really going to be able to answer the question very clearly. And so I always refer back to the study that Tim McElinden did. It was published in 2017, so a few years ago now, where they had a randomized trial for two years of corticosteroid injection, same dose, compared to saline injections every three months for two years, and regardless of whether the patients really needed it at that moment or not, they clearly needed it to get into the study, but they didn't necessarily need it every three months. But that was the protocol. And yes, they did have a little bit more cartilage thinning point one millimeters after two years of repeated injections, but it wasn't worse than that.

And both arms progressed regardless. So I think number one steroids don't cure away. And they clearly don't, you know, stop your joint from progressing structurally. They have a short term transient benefit and that's clearly reflected in the guidelines. And that's usually what I talk about with patients and then hopefully we'll have something that'll be better than steroids in the future.

But possibly more expensive.

Yeah, Peter, go for it.

Well for me, steroids just temporary symptomatic relief and in the new molecules group we're looking at a couple of very interesting new there's a modified human angio poitin like three protein in neoA which looks very interesting at preserving cartilage and one injection is very long lasting. The Tanezumab stuff we're looking at again and another one if I pronounce it correctly Spreferment which led to prevention of loss of cartilage over time, didn't really do a lot for symptoms but that if you combine it with a symptom relief like some NSAIDs or an injection of steroid and then use the D mode, I mean I think that'll be our approach because FDA guidance says not only do you have to improve symptoms, you have to do something structurally as well. So I think we'll use a combination on the symptomatic side and on the cartilage preservation side. So it looks exciting in the OA area now.

Excellent. I think my last question, Tom, you had mentioned there's some intra articular anabolic thing. Can you tell me about that?

Yeah, so just as Peter was just referring to, so spiframine, which is a recombinant human FGF18, not only slowed the progression, but actually caused cartilage thickening. So this is really a game changer. This is the first time that we have seen an increase in cartilage thickness as a result of a treatment for osteoarthritis. And what they showed was that not only was that thickness dose responsive, so the higher dose more frequent was able to thicken even more compared to placebo, but over a five year follow-up that the difference between the treatment group that was most effective and the placebo maintained that same distance so that the cartilage thickness was sustained. So really a true anabolic in that sense.

And I think it's very exciting to see where this will go, probably phase three coming very soon. But Peter's absolutely right. Combination therapy is the rule. And if you think about it, that's the rule in most of our diseases. So why would it be any different here?

Just being an old greach, the Stromerefin was the increase over five years was 0.05 millimeters. So it's like a paper thickness over time, but at least stopped loss.

No, you're absolutely right. Although if you look at 0.1 millimeters as essentially a change in grade of Kellgren Lawrence grade, so that's actually potentially meaningful. But even more important for me, that group thickness went up while the placebo group went down. So it sort of stopped progression over that period of time. But to your point, Peter, I'm also skeptical because after the two years, it started decreasing in thickness again.

It's just that you kind of separated the two groups and they stayed separated. So we haven't yet figured out how to turn off osteoarthritis.

Induction maybe, maintenance, something else. So I did say final question but there is a burning question and it comes up at every other ACR. So from India again a methotrexate study primary knee OA but they had to have a knee effusion. They got methotrexate versus I think it was glucosamine and they did the stats pre post instead of between groups differences but a sizable enough and very, very strong statistics. So should I be dishing out some methotrexate?

Maybe it'll prevent psoriasis which will prevent psoriatic arthritis but should I be doing that in a swollen knee osteoarthritis not clinically CPPD, not probably hydroxyapatite, apatite, not uric acid, where they're failing a lot of stuff and maybe too young to move on to a replacement.

Yeah, so I think people have been using methotrexate off label for this purpose for quite some time. The story continues to evolve. I'm not sure this is a slam dunk just yet. You're right. It was compared to glucosamine and as a three month response.

So there was a statistically significant response within group in terms of the Womack pain, but we didn't actually see the stats compared to the glucosamine group. So I'd like to see that fully reported out. I'll also just mention that Phil Conahan's group has been working on the PROMOTE trial, which was a reasonably sized RCT of methotrexate that did show clinically meaningful improvements, small to moderate, but still clinically meaningful improvements in the methotrexate group. And we're waiting to see that ultimately published as well. So I think there's more to the methotrexate story, probably more evidence that we need to generate.

There was also a hand osteoarthritis trial that showed slower progression in terms of bony damage as well reported at last year's ACR. So I think it's been more successful in these studies than hydroxychloroquine for sure. And maybe some cautious optimism there.

Great. Peter,

I think OA is not one disease. Right. And that erosive OA in the hand which is so symptomatic will be very different to you know Heberden's and Bouchard's we see commonly because you know and then even in the knee you know one group of OA patients will have a high white count not so high but clear evidence of inflammation the next one won't. So I just you know I think that if you're going to have efficacy of things like methotrexate we really need apples compared to apples and if you just take a big group and lump them all together I don't think we're going to have much success.

Great, excellent. So thank you both for joining us, please follow RheumNow and I'm Janet Pope, my Twitter handle is JanetBurdope, enjoy ACR twenty twenty. Thank you.

Hello again, Michael Pellinger here from NYU School of Medicine talking about gout for RheumNow. Today is Monday. It's the day of late breaking abstracts at the ACR meeting. And I'd like to talk to you today about the infamous black box warning on febuxostat in the context of late breaking abstract L01, a report of the so called FAST trial. Just to remind you, when the FDA initially reviewed the phase three trials and approved febuzostat, they noted a non significant increase in cardiovascular risk.

Accordingly, they requested that the sponsors follow-up with a trial to further assess risk in a phase four study. That trial was called CARES and included about seven thousand patients with gout and cardiovascular disease. Subjects were treated with either allopurinol or febuxostat and the trial found no difference between the two in terms of its primary composite endpoint of all possible cardiovascular outcomes basically. But it did find in a secondary outcome, a significant increase in cardiovascular and all cause mortality, small but significant. Accordingly, in 2019, the FDA issued a black box warning highlighting the cardiovascular risk and restricting febuxostat to patients who had failed or who couldn't take allopurinol.

While the decision was prudent on the FDA's part, the trial that they based that decision on, CARES was deeply flawed. Among the issues with CARES are the fact that only about half of the patients actually completed the study, a really low number. Most of the events that were found in the study actually occurred after the study was already over and patients were off the drug. And patients who took aspirin in the study as high CV risk patients probably ought to do, experienced no increase in mortality in the febuzostat group. And perhaps most importantly, since the study lacked an untreated placebo arm, even if the difference was meaningful, it was impossible to know whether fubuzestat actually raised risk or maybe even just lowered it less than allopurinol.

Moreover, there were already two large studies that contradicted cares. The first by Zheng et al was a retrospective study of about a 100,000 Medicare patients and it showed no increased febuxostat risk. The second study, the prospective so called freed trial may have had some flaws of its own but it also found no increase vabuzestat risk in about one thousand patients, not with gout in this case but with asymptomatic hyperuricemia. But what everyone has been waiting for was a study mandated by European Medicines Agency, essentially a European equivalent of CARES. And now that study is here presented by Thomas McDonald and his group.

FAST, the febuxostat versus allopurinol streamlined trial was a prospective randomized open label blinded endpoint study, a so called probe study of about six thousand patients with gout. Subjects were 60 and had either cardiac disease or at least one cardiac risk factor. Subjects entering the study had all previously been treated with allopurinol and were now randomized back to allopurinol or to febuzestat after a washout and then titrated to a urate of less than six milligrams per deciliter if they weren't already there. They were then observed for a composite outcome of non fatal MI stroke and cardiovascular death and the data was assessed in a non inferior design. So what happened?

In contrast to CARES, about ninety five percent of the subjects completed the trial after being followed for a median of four years which was much longer than CARES. Overall, there was no significant difference between the two groups for the primary endpoint of composite outcome and no significant difference in mortality. In sum, with the exception of CARES, no meaningful study to date has identified an increased risk of cardiovascular events or death when taking febuzostat and CARES was deeply flawed. Will the FDA reverse its black box warning? Probably not.

Should we be using febuxostat as a first line drug? Probably not if only for cost reasons. But the ongoing VA stopgout trial will give us the first evidence as to whether allopurinol or febuxostat is actually one superior to the other or equivalent. In the meantime though, when as practitioners we do see the need to prescribe febuxostat, we can all sleep a little easier knowing that fast and freed have failed to reproduce the results of CARES. Keep tuning into RheumNow for more reports and videos and thanks for watching.

I'll see you next time.

This is Doctor. Catherine Dow reporting for RheumNow. I'm at the ACR twenty twenty virtual meeting, And I think this is the year when they really talk about women's health and pregnancy outcomes. There's this really good, meta analysis of axial spondyloarthritis, psoriatic arthritis, over four thousand pregnancies. And they found that in these patients, they're at increased risk for preterm labor, small gestational age, as well as for C sections.

But rarely there's no change in miscarriages, stillbirth or gestational diabetes. So that's actually reassuring. In another study, and this is Abstract '17 62, they were looking at very, very young rheumatic disease patients. So these are patients who are 21 who get pregnant. What are their outcomes?

Do they have higher complications risk or what happens to them? So it's interesting. This is a study by UCSF and UCSD and they looked at seventeen hundred, a little bit over seventeen hundred pregnant women 25 and three ninety four of them actually were 21 years old. And they found that the younger women, so the ones 21, they had less risk for gestational diabetes and less risk for C section, but they did have an increased risk for preterm labor. All right, so these young patients can actually get pregnant and do pretty well, but you got to monitor them for a preterm labor.

And then Doctor. Michelle Petrie presented her abstract seventeen seventy. And what she looked at is that, sometimes it's hard for patients with lupus to achieve complete remission before they get pregnant. So she wanted to see whether or not just low lupus disease activity might actually, be okay. And so she followed these patients, who had low lupus disease activity, and actually there wasn't really an increased risk for, maternal or fetal mortality.

And these patients actually did very well. Low lupus disease activity may probably be a more realistic pre pregnancy clinical goal, compared to remission, which might be difficult to achieve. So there you have it, pregnancy and rheumatic diseases. This is Doctor. Catherine Dow reporting for RheumNow.

Follow me on Twitter kdao2011.

Hello, this is Leanne Gensler reporting on the last day of ACR twenty twenty for RheumNow on the topic of spondyloarthritis. I'm in San Francisco, and today's session there was a lot of spondyloarthritis both in terms of abstracts, but also a couple of sessions. So I am going to report on a couple of these items that I thought were novel and interesting today. The first abstract that I'm going to present on was actually one of the posters, and this was abstract number eighteen eighty three, and this was a poster by Jean Liu from Boston University where she really looked at outcomes of access spondyloarthritis, specifically disease activity, and the influence of BMI and exercise on that outcome. So really important as we holistically think about caring for our patients and optimizing their outcomes.

And so she is the cohort of axial spondyloarthritis patients, and what she was able to show was that BMI had a direct effect on disease activity and there was a smaller contribution that came from a mediation through exercise. So the take home from this abstract for me was that really we want to encourage our patients to both keep a healthy weight but also to exercise. They're both important for controlling disease activity in addition to all the other options that we offer them in terms of pharmacologic therapy. In terms of additional sort of abstracts that I thought were helpful today, in particular in thinking about diagnosing axial spondyloarthritis, so oral abstract number twenty fourteen was entitled The Relative Diagnostic Utility of Inflammatory Back Pain Criteria in an Inception Court of Patients with psoriasis, iritis, and colitis, and this was from the SASBIC cohort, and it was presented by Georg Kuber from Denmark. And so what they showed interestingly was that we put all this weight in inflammatory back pain.

We talk about it being the hallmark feature of axial spondyloarthritis, but when you really disentangle it from the rest of the features of spondyloarthritis, when you really ask all those questions and you're blinded to knowing that a patient has sacroiliitis or is HLA B27 positive, what they found was that the performance of the inflammatory back pain criteria were far weaker or poorer than has previously been described, with worse both sensitivity and specificity and coming up with a likelihood ratio of about half of what has been reported in the past and in fact worse in patients with psoriasis. That part is not so surprising in that patients with psoriatic arthritis and axial involvement can present more atypically and have less inflammatory type back pain. So I think it's important for us to consider that IBP is not all of what we expect it to be and we should still consider the diagnosis in patients that don't have classic inflammatory back pain. Today there was a dedicated MRI session on thinking about how to use MRI for the diagnosis of axial spondyloarthritis. I was one of the presenters at this session, and Rob Lambert from Canada presented.

He's an expert musculoskeletal radiologist and Xenophon Baraliakos also presented, who is both an expert reader and also a rheumatologist. So I actually wanted to clarify, I think it was an excellent session. There was a lot of very good pearls there, but some of the social media exchange after the session suggested that we might be able to diagnose and treat patients that don't have any completely negative imaging. So I want to just clarify that I might be comfortable with a clinical diagnosis of axial spondyloarthritis, but I would not treat a patient with biologics that has no objective signs of disease activity and no damage. So in a patient that has absolutely no damage to the joints and no bone marrow edema to suggest inflammation, I'm not sure that I would be comfortable giving that patient a biologic, particularly if the CRP is normal.

So I do perform imaging studies always to confirm the diagnosis, though I think you can come up with a clinical diagnosis without those imaging studies. Would not I would be careful. I think it's dangerous to diagnose patients just based on soft features so that inflammatory back pain, endothelial tenderness, and a family history, that could put you in a dangerous place. Then even if you add HLA B27, though that may be helpful, it actually isn't additive on top of these other features because family history is actually not independent from HLA B27. In terms of big impact pharmacologic studies today, we have to talk about the late breaking abstract that was L11, and this is Pfizer's study of tofacitinib in ankylosing spondylitis presented by Atul Diadar.

In this study, this is a phase three placebo controlled, randomized controlled trial of two sixty nine patients that were randomized to either placebo or tofacitinib, five milligrams twice a day. These patients obviously were bio naive, and they nicely showed at sixteen weeks that they met their primary endpoint and key secondary endpoints, and actually interestingly, so fifty six point four percent of patients in the tofacitinib group met the OSS-twenty versus twenty nine percent in the placebo group, and for the OSS-forty endpoint, forty point six percent of the treated group patients met the primary endpoint compared to twelve point five percent of the placebo treated patients, all of that being significant. So obviously not head to head data, this is a different place and time. However, if you think about many of the other biologic trials, we think about sixty percent of patients having a twenty percent response, forty percent of patients having a forty percent response, so quite similar there. The final abstract I wanted to talk about was a mechanistic result that I think is really important to think about.

This was abstract 2,022. This was an oral presentation by Xenophon Baraliakos looking at 16 patients with active ankylosing spondylitis that were starting a TNF inhibitor, and these patients were refractory to the usual two courses of an NSAID, and what they did in this study was they performed imaging studies before treatment and then at four months of follow-up of treatment using 18 plus MRI, and so this really is getting at what happens to not just inflammation with treatment, but what happens to new bone formation or osteoblast activity on that PET scan. And so what they showed is they looked at SI joints and the spine and they were able to show that, as we might expect, the bone marrow edema decreases on the MRI, but very interestingly, so does the osteoblastic or 18 fluoride activity of the osteoblast on the PET scan. They didn't comment on what happened to NSAID use in follow-up, and this might be interesting to think about. This is a small number of patients, of course, but it is interesting to think that NSAIDs may also have an effect and how that may interact with the exposure to the TNF inhibitor.

So I would love to see those results too, but very interesting to see disease modification potential from biologics in a very causal way, though of course this was short term follow-up and longer term data would be interesting. So this is Leigh Ann Gensler reporting for RheumNow. For more information, please go to RheumNow, we will see you next year in 2021.