ACR20 - Rheumatology Roundup Save
ACR20 - Rheumatology Roundup by Dr. Cush
Transcription
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.
To get transcriptomics. So they looked at the cells and then looked at the expression. Interestingly, they found a unique population of cells. There was a CD8 subset which represented 80% of the T cells. It was CD38 high, CD127 negative and PD1 positive.
They did have an increased expression of cytotoxic genes and they did have a interferon signature. They did, which you wouldn't think of as being, I mean, happens in RA, happens in PSA. You think of it being associated with lupus, but they found that in over transcription of genes downstream from the type one interferon. So I think this was fascinating. First of all, the ability to do the work where they can look at individual cell types, which are, even though if they're the same type of cell, they might have differences at the expression level.
They found the population, maybe this will translate into something we can use therapeutically. We have guidelines on immune checkpoint inhibitor arthritis, but not a lot of data. So maybe this is a promise.
Yeah, there's certainly a lot at this meeting about checkpoint inhibitors and stuff that affects us. And it's a growing concern for rheumatologists because most of us are seeing this. And short of using steroids, the next step is really concerning. And then other steps about like how long we're gonna have to treat them for and when do we you know how are going to communicate with the oncologist about when they can resume their, you know, their, their checkpoint therapies and whatnot. It's still seems to be a fair amount of push pull but thank God we have research like this.
Again, the authors didn't take this to the next step and postulate on how this could be used therapeutically, did they?
No, and it was just a number of people, but I think this finding really did surprise them. And maybe we should be thinking more of alternative therapies. As you say, one of the problems is anything we're gonna use via inflammatory arthritis, you sure don't wanna interfere with the ability to kill the tumor. That's why they're on the checkpoint inhibitor in the first place. In the clinic, it's, boy, it's tough, isn't it?
Because they're on these for the long haul, the checkpoint inhibitors. There's no, sometimes, you know, you'll see, well, maybe if you're still doing well next year, we'll think about stopping it, but they're on them for the long haul. So this is something we certainly need more information.
So I wanna talk about vaccination, and specifically vaccination in patients who are receiving tofacitinib. So there were two abstracts that were presented, late breaking for LL4, granted by Kevin Winthrop and then, a Shingrix vaccination in TOFA, that was 1997. Kevin presented this data on the drug development program with tofacitinib in 21 trials and at a low number of patients who receive the influenza vaccine. And the point of this was, could they get the influenza vaccine? Was there any real issue in there?
And the bottom line was there was not. There was no greater, and of course they had patients who were on placebo in their trials and on methotrexate and on adalimumab and also on tofacitinib. And the numbers of you know, actual influenza events or even worse hospitalizations, or serious events, those are like less than one or one and a half percent across the board. The bottom line was it looked pretty good. So that's good news for you, especially now as we're getting into the flu season, and worrying about when we're gonna get the COVID vaccine.
Can you do this in your patients on tofacitinib? The answer is yes. But wait, there's this other abstract that was presented by Calmark from Sweden. And it was a study to look at the of the immunogenic potential of the new shingles subunit vaccine, the one that's on the market now the Shingrix. And in that study, they studied 40 patients and they basically had a bunch of controls and they showed that the controls had a good antibody response and the topacitinib patients also had a good antibody response and they had, you know, mild to moderate symptoms, no big deal.
But the caveat worth mentioning here is that twenty five percent of patients on tofacitinib did not have an antibody response, which I'm sending all my patients that are going on a JAK inhibitor to receive the Shingrix vaccine. And even the ones who are not old enough to get it, I'm trying to implore them to get it because this class of drugs does impart a three to four to five fold higher risk shingles. And if you can avoid it with a ninety five percent effective drug, why not? But this says that maybe like methotrexate for people who are on and it's maybe because this is not really what the intention of the study was, but maybe like methotrexate for people who you're gonna give Shingrix to, maybe they should suspend the use of tofacitinib for, I don't know, a week or two. What would you do with this data?
The problem is we don't know what they mean. So presumably your cell mediated immunity is more important for the control of viral infection such as zoster. This is a nice surrogate looking at the antibody production, but we don't know as much about what that means. It may be possible that they have perfectly good ability to control it, control the zoster, or it could be that they need a booster. You know, the zero and then two to six months later, very reasonable and certainly that seemed to be quite efficient in the general population, but maybe it's not in these people.
We don't have a great readout because we don't care about antibodies. We care about cases of zoster. There's Jeff Curtis who writes in and says, Kevin and Winthrop and I are starting a larger Shingrix trial in RA next year. Awesome. Well, thank you, Jeff.
And yeah, I mean, we wanna see events. That's what we really wanna know. That's one of the difficulties, even I think in infections where the antibodies are more reliable in terms of to predict, you still want events. You're preventing the disease. That's what you want to say.
So I also want to give, I saw Jeff's tweet about this and I said, Oh, I gotta go look at that abstract zone. Thank you, Doctor. Curtis for steering me towards something kind of important. Arti, what's your next one?
Well, before we go to the next one, me, hey, there was a comment on the checkpoint inhibitor commenting, could you comment on the TNF and IL-six inhibition? I've had more experience with the TNF inhibition. And I think it's my level of comfort and the oncologist level of comfort with what they're okay with me doing. I haven't really used IL-six inhibition much, but it makes perfect sense. The trouble is we're just all dealing with anecdotes.
And I I go with what I had more experience with and I can't say that that's the right way to go. Jack, do you have a preference or?
Steroids, TNF inhibitors, IL-six is certainly possible. I think you stay clear of abatacept because of CTLA-four. But other than that, that's been my general rule. I've only had one patient who clearly had this and one who maybe had this. So I was not seeing that not as many as like Lenny or David Liu or some of the other people I know have seen a lot of this.
Yeah, I think we're all gonna see many more of them. So my next is fourteen eighty four, which isn't very sexy. I mean, the number, but the Time
to go to the refrigerator folks.
Because it's a negative study. But I think sometimes negative studies give us good information just like positive studies could. This is efficacy of tocilizumab in patients with hand osteoarthritis. So boy, there's been, every year it seems like there's a study or every other year there's a study on pretty much all the drugs that we have and pretty equivocal data and then differences in the study design. Mostly they're negative though.
There was a review in the Rheumatology Oxford two years ago and looked at this and maybe there was a hint of a positive signal for hydroxychloroquine, but I think this is an important issue. I think when we see osteoarthritis patients, boy, it gets harder and harder to say we got nothing, But if you come back, you get RA because I got 20 therapies, and if you have PSA, I got 15, and if you have lupus, I have six. So this was, I think, a nicely designed study. Not so big, one hundred and four patients. And eighty of the patients completed the study.
They didn't find a difference. So the primary outcome was the visual analog scale for pain, which had to be above 40 at the start. The delta was minus 7.9 in the tocilizumab group and minus 9.9 in the placebo. So the p value as you can imagine is 0.7. So absolutely no difference about that.
Also no difference in the secondary outcomes. And as you would expect, a little bit more of a signal with adverse events in the treatment group. So still a big unmet need in osteoarthritis, particularly the inflammatory kind, I think, what do we do? We sort of treat them with the agents that we have for rheumatoid arthritis. We treat them methotrexate, we give them hydroxychloroquine, at least until this year when I had to I like to use hydroxychloroquine for inflammatory hand away, but all of them had to develop rheumatoid arthritis in the chart so that I could get the drug for them because they weren't getting it this summer.
Or COVID.
It was COVID, COVID related arthritis CRA. But it was a negative study, nicely done study, negative study. And especially when you think about the tolerability issues, that of course weighs in our decision to use any treatment.
So the therapeutic pessimist likes to talk about all the drugs that have failed in scleroderma, they should change that to all the drugs that have failed in osteoarthritis, especially of the hand and doesn't even have to be inflammatory OA. All of our DMARDs have failed multiple times. All of our biologics have failed. But you know, the rationale behind this is not unreasonable, meaning that there is a component of inflammation that drives, you know, early events in cartilage degeneration. That is one of the earliest steps in development of OA.
The cytokines are often mediators of pain, you know, involved in pain signaling. So why not, you know, but again this didn't work and I was again disappointing. I'm not surprised I would say still my, my go to drug for osteoarthritis the hand is acetaminophen and cohesive tape for problematic joints, I wrap up fingers and immobilize them. And then I give them maybe two milligrams of prednisone for a short period I could possibly get away with. Other than that, I don't have a lot.
It's really disappointing. So my next one is, IL-sixteen and lupus nephritis. This was actually a presentation, a plenary session presentation, done on the second day, presented by, Andrea Fava from Boston. This is abstract nine thirty six. This is a proteomic study where they looked at urinary proteomics as a way of looking at lupus activity or lupus disease correlates, making the point that you know what do we do to best assess lupus nephritis patients, we have biopsy, we have sampling issues with that, it's not always available, we have proteinuria which actually can be somewhat helpful or can be misleading.
And the idea here is that in multiple studies that they did looking at, cytokines in the kidney, they actually showed that IL-sixteen is like the second most common cytokine found in the kidney. So they actually took thirty lupus patients over 110, urine samples, they did proteomic sampling on that, to see what they could come up with. And they basically showed that lupus patients who have class three and class four proliferative glomerulonephritis have a strong correlation with high urinary IL-sixteen levels, that those levels do correlate with histologic activity scores, but not chronicity scores, and that those levels will go down as the patient clinically improves on therapy. That IL-sixteen level was independent of urinary proteinuria. And that was sort of another key feature.
Then other studies that were sort of adjunctive to this looked at IL-sixteen staining in the kidney in renal biopsies and showed that a lot of IL-sixteen, especially around the glomerulus, but even within the glomerulus. IL-sixteen is a CD4 ligand, but actually has a lot of downstream effects that clearly would make it a good immunologic target or immunologic activator I guess in this situation. So they showed that this was very predictive. It was easily obtained at some point I guess it could be easily obtained. Again, to me if I found it novel, and I thought it was a really well done study that covered all its bases, looking at, many different markers, but they again was shot was sort of stood out amongst all the others was the IL-sixteen.
Yeah, it was definitely well done. And there's been a kind of a hint at looking at urinary biomarkers in lupus nephritis, which in some ways makes sense, of course, because you're downstream from the target organ, literally downstream from the target organ. And but you you also wondered because the obviously, proteinuria is part and parcel of the disease. So you have kind of a gimmish of proteins. You have the tubular, the tam horse sprawl proteins.
You have proteins that are leaked out from, patients who have any sort of membranous involvement with their lupus, but you also have, potential biomarkers of disease activity. That would just be that would just be absolutely outstanding to have something like that. I think in the clinic know what the biopsy is and of course we teach the fellows to not just take the number like three because three could be one proliferative glomerulus among 50 with a little bit, or it could be just barely a four with a bunch of crescents and a lot of chronicity. So we desperately need something as a biomarker. I think, especially the more therapies that we have available to us, now with the positive data, we're looking for belimumab.
With the other CD20 therapies, not just rituximab, which didn't work, but obinutuzumab, which is much more efficient at depleting. So yeah, a biomarker lupus nephritis would be just outstanding. Plus you could collect it remotely. You can literally mail it in and you can have many, many sampling points and you can't do a biopsy that often. I think sometimes it's hard to get them done.
They're expensive to get done. So this could be really a tremendous advance to not only the clinical care, but also of the research studies into lupus nephritis. Absolutely. So I'm gonna go into psoriatic arthritis or should we take the chats, Jack or?
Yeah, there's a bunch of them.
Well, Nancy Lane gives us a shout out. Keep the faith for OA treatments. Hopefully we certainly need them for so many patients. Gosh
right. Let's see Gary Botstein anecdotal avatars of treating CPI induced Myocarditis New England Journal. You Gary from Atlanta. What else we got?
Is it now standard to add belimumab? I don't know that it's standard. I think some people still come into terms with that data. That data was presented by Rich, did a great job presenting it, presented it earlier at UR, looked at some subset analyses here, which was the new part of the study, the blimumab study. I have to look to catch the number of that presentation.
But it showed that it worked actually, If it had lesser effect, it seemed like it was in membranous. Whereas in three and four, actually looked very solid. And he promised in the presentation today that he would get back to us about some of the other analyses that they're doing on that data to really help refine. So I don't know that I would say it's a standard of care because the effect size was pretty, it was small for sure, but it was absolutely clear. So to me, what I wanna say as well within that, if you have an improvement with one therapy or another of fifteen, twenty percent, that's small, but who are the people for whom it really makes a difference?
I think that's what we need to see. They also looked at race in that one and it looked, there were smaller numbers, but it didn't look like there was a lack of effect among African American patients. So not a standard of care, but I tell you that data still surprised people.
It's encouraging data, but it's certainly far from Doctor. Bazavariju who's here in Texas and that's taking care of one of my lupus nephritis patients and does it done a great job. She points out this, you know, what's the standard. I think it's encouraging data can't be misconstrued as a standard right now I think we still have to rely on the drugs that have been good for us so far, mycophenolate, when necessary, the Euro, cytotoxin protocol, that seems to work really well for a lot of patients. But it's very encouraging.
I think they just have to follow-up on it. And it was also very encouraging all the trials being done right now where lupus nephritis is the primary endpoint, as opposed to trying to get a global lupus, indication. Yeah,
that abstract number by the way, Richie Furies was fourteen forty one. It was kind of an update that's been published in New England Journal just earlier this year, but the new parts are the sub analyses according to the histopathology of the kidney and also the analysis by the race. And it was interesting when he gave his presentation, someone asked about the cost benefit because when you say, when do you use the different therapies? Well, it's the tolerability, it's the clinical effect, it's the cost. So all those things go into the equation.
So I'm gonna go into psoriatic arthritis and there was a late breaker L03. Phil Meiss was the first author in this one. This one was ducravacitinib, which is a molecule that we've seen studied in skin psoriasis. And it's one of the JAK inhibitors, but it's really much more of a TYK2 inhibitor. And if the immunology makes sense, which it doesn't always make sense, it's really easy to predict the past, I think that's what we do with the immunology.
That's why we know IL-one isn't really important in RA because blocking it doesn't work. But if you drew out psoriasis and psoriatic arthritis, you might say that those cytokines that use the JAK signaling molecules, that TYK2 might be a very useful target. And this is a relatively selective TYK2 inhibitor. And of course, the flip side of that is, are there going to be differences in safety? Is it gonna be any different compared to the other JAK inhibitors?
But of course, first they have to prove efficacy. So this is a study in PSA. Typical criteria, they looked at two different doses, six and twelve, and they met their primary endpoint was the ACR20 at week sixteen. And then they got that in fifty three percent of the lower dose, sixty three percent of the higher dose compared to thirty one, thirty two percent of the placebo. They also saw impact in functional status and in quality of life.
Actually nice distinction in and the site is as well. They didn't see a bunch in side effects. Now of course, it's psoriatic arthritis where the generally things, the patients are younger and generally fewer comorbid conditions. So they tend to do well with a lot of therapies and we need to see more. We want to see what the skin effect is because that's one of the things that people had hoped was maybe this would have a better skin effect than the other Jack and Ems, but it was a positive study.
And I think that's intriguing and we certainly look forward to more data on that.
So are you do follow the psoriasis literature and you run the same circles as those skin dermatologists? What's the take on on TYK2 inhibition in skin disease? You know, they did think they had like a big paper about this last two years ago. I know it's out there as far as the research is being further studied, does this is this going to stack up against IL-seventeen and IL-twenty three and those other new
That's a interesting question. The, you know, the dermatologists are, they're giddy with success with the 17s and the twenty three inhibitors. So as I like to say, they, you know, they talk about the PASI 75, the PASI 90, the PASI 100, the PASI 120 where you get completely clear and your sister gets 20% clear. You know, this is not that this is not that level of response, but it's much higher than what has been seen previously with the JAK inhibitors. Remember a couple of years back, Tofacitinib went to the agency, and I think part of why they didn't get approved at that time was that the higher dose was definitely much better than the lower dose, and it wasn't in league with what the dermatologists were seeing.
I think the attitude goes, well, why do we need this? Now they are super hot on Jakinibs, not only in psoriasis, but boy, you almost, you name it. And they're looking at Jakinibs for the therapy for a whole manner of immunologic skin diseases and there's a lot of orphan diseases in dermatology that don't get a lot of study, hidradenitis, the bullous diseases and there's a bunch of interest in JAK inhibitor. So I think they are pretty high on these. And we seem to be worrying more at least as of now about the tolerability issues and the VTE issues with JAK inhibitor.
Dermatology is very high.
Yeah, I think it's great that the ticks are being developed and we'll see what their range of efficacy is gonna be, but it's gonna get a really crowded on that JAK inhibitor floor. Now that the ticks are gonna be in there and filgotinib after it sorts out its problems with the regulatory agencies might be on the market as well. I wanna move on to another difficult disease treat and that is systemic sclerosis. Dinesh Khanna had a podium presentation today about a novel compound called zerotaxostat. The name of the study is the Novesa study.
I have to get you the numbers on that. Don't have it right here, but it's the Novesa study. And this is a study using this new drug which is an autotaxin inhibitor. The idea being that there are a few main pathways that can lead to skin fibrosis, but autotoxin is one of them, and as is IL-six. And those two are somewhat interrelated.
So this makes for a fairly attractive target. And that's what xerotaxostat is supposed to do. They studied it in patients with early diffuse systemic sclerosis. I believe it was this is like an early phase two study. They enrolled, 21 patients on zerotaxostat and, 12 on the placebo.
The primary endpoint here was going to be the modified Rodman skin score. And the patients, the groups matched up really well. There was slightly higher skin thickening with modified rodent or 27 in the zero tax stat group 22 in the placebo group. But after, I guess twenty four weeks which is the primary endpoint. The study drug did much better than placebo minus eight, versus minus five.
And that was significant at both week sixteen and week twenty four. They have a biomarker that showed significance so again, this is this is great in that phase two, but phase two a lot of things look great in phase two will it pan out and phase three is what we need but they are going further with this investigation so I think that's encouraging.
Yeah. But they're they, you know, they used to say like the Cubs, but I guess you could say like the Mets now. You know, every the start of every season, it looks promising, you know, in spring training, they they are gonna win the World Series this year. And I think unfortunately scleroderma is sort of like that. There's, I think back over the years, so many therapies that not only made sense if you look at the mechanism, you say, well, that's an interesting mechanism.
You know, That's something all that could work. Think back to relaxin from decades ago, where it worked in phase two and actually had a biomarker, had increased bleeding because it increased menstrual bleeding because that was part of the mechanism of it, failed dismally in phase three. How many other therapies are there? I hate to be negative about scleroderma, but you have your hopes up so many times by so therapies that should have worked. So is it the outcomes?
We looked at EULAR. There was a study looking at skin ultrasound as perhaps a more objective way of looking at skin. We desperately need some therapies. There's some hints of positives. And of course, Dinesh, he spins a great tale.
You got to be a believer, and it makes sense. But I think we really do need to see the longer term data.
Right.
So my next one, I think speaking of an unmet need, I really liked seeing this because I think just over the past couple of weeks, I interestingly have had a few people with giant cell arteritis, one of whom just refused to take steroids, which is an interesting patient And another one who took the steroids, but is just you know, he said his wife wanted him on the steroids because he cleaned the whole house by 5AM because he was so manic. But what do we have? Well, we have IL-six inhibitor, have tocilizumab and presumably cirilimab, but this is a late breaker abstract LO-six for marvelimab, maverilimab, which is a GM CSF directed monoclonal antibody that have been studied and had some positive results in rheumatoid arthritis. This is in giant cell arthritis. And I think, know, as we're just talking about for scleroderma, there is a scientific rationale looking at histopathologic expression within the inflamed vessel wall and patients with giant cell arthritis that you could make a case that it could be effective.
So this is a study, a 70 patient study with either new or recurrent giant cell arteritis. They had a fixed tapering plan for the corticosteroids and of course corticosteroids are the mainstay of therapy, but then it was maverilimumab or placebo randomized and flare was the primary outcome. And what they found out that disease flare by week twenty six, which is the time period over which they were also doing the steroid taper, had forty six point four percent of placebo and nineteen percent of maverilimumab. Overall, the tolerability seemed to be pretty good sustained remission. This is eighty three point two percent of maverilimumab versus fifty percent of those on placebo.
It was both new and recurrent patients. Tolerability seemed to be relatively good. Not a lot of AEs, not a lot of SAEs. Of course, these are people by definition, they're older and they have a lot of stuff going on. So they're gonna have some AEs no matter what you treat them with.
But I think this was interesting and promising. And I just, I said, I literally just thought of it because the, you know, the in the clinic, yeah, we get steroids. We have IL-six inhibitor. I'm not a, I don't know about you, Jack. I'm not a methotrexate believer.
I don't think methotrexate is a really viable option in giant cell arise I don't think it works I think we use it because we're rheumatologists and we use methotrexate for everything so I was, I was excited to see the possibility of these data.
Yeah, it's certainly in the holster and ready to use it all at all times and I have used it but not with a lot of great hope. And IL-six inhibitors seem to work really well in GCA, problematic GCA in the uncontrolled clinical trials that are out there. So that's certainly an option, but getting it approved, getting it paid for it could be another issue. I do wanna see more development. I mean, there's a lot of patients in this country and all around the world with GCA.
So you know, and even more with PMR. But interestingly, you know, as much as there's a great need here, there isn't a lot of people using the approved IL-six inhibitor here. So I'm not sure what the reluctance is. Maybe like we're too married to methotrexate, we're also too married to continuing that steroid at ten milligrams, twelve milligrams, fifteen milligrams as opposed to using a biologic. But I think it's a great study.
And I mean, so good that one of the faults of the study was one of the secondary endpoints was time to flare and they really couldn't calculate it for the maverolimumab group because they didn't really have any flares, which is like a great thing.
Yeah, it's a funny population because they're older people with by definition, they're sick people like you're talking about the gout population before. And I think there's a reluctance. I think if you look hard enough, you could talk yourself out of a biologic that in somebody who's over 60 and has some other comorbid conditions. But in those populations, methotrexate, is that going to be a go to? And to me, I think if you use methotrexate you want to use it, you got to use it 25 or more even if you're going to do steroids sparing with it so.
Yeah I was excited excited to see the data and the anecdotal data, as I know it for the TNF inhibitors has not been as great, even though I think the anecdotal data are very good in Takayasu's. I don't think the anecdotal data in giant cell are that good.
Yeah, so a few comments, but not much JAK inhibitors in GCA given IL-six effects theoretical but not studied well enough to even talk about it here. And there's a concern about GI perforations, a very low risk event with both tofacitinib and even IL-six agents, JAK inhibitors and IL-six inhibitors as well.
Yeah, I think, I mean, the GI issue I think is, everybody who's gonna qualify for this study has degenerative disc disease. Everybody has diverticular disease because all humans do by the time they get old enough to get giant cell arthritis.
Right, right. Alright, so my next one is the results of a afternoon session where it was sort of understanding auto inflammatory diseases and Dan Kastner presented this sort of like you know what to do with undifferentiated auto inflammatory. But you know, you almost really should watch this presentation because Dan Kastner gets very demonstrative in this thing. He's playing super sleuth and he's banging on the table and it's a really, really good scientific story. And it's a story of vexus.
Vexus is a new syndrome, V for vacuoles, E E1 ubiquitin activating enzyme, X being X linked, A auto inflammatory and S for somatic mutations. The story goes he had a patient, patient was with an auto inflammatory like presentation, and they did a bone marrow and the pathologist at the NIH was going over the bone marrow and said, you know, there's these very strange vacuoles in the cells within the marrow. And she said, I wanna study this further, come back. And they came back two days later and she said, there's two other patients so I had to look up. I remember this happening before.
You need to look up these people and see if they have the same problem. And sure enough, they did have the same kind of presentation. And sure enough, all three of them were known to have or found to have this UBA1 somatic mutation. It's an X linked somatic mutation. So they did further investigation.
It turns out some of those patients had relapsing polychondritis like symptoms. They did further investigations and they found out that in their center they had 21 males. They investigated them, they all had this UBA-one. All male, middle aged, high fever, sweets like rashes, neutrophilic like lung involvement, chondritis, VTEs, macrocytic anemia. They had a lot of other diagnoses, most of them, more than half of them were relapsing polychondritis, a lot of them were sweets or myelodysplasia, a few were polyarteritis nodosa.
But they were all ultimately unified by the UVA1 mutation and the other clinical features here. So this is a new syndrome. It's going be a rare syndrome, but it is a nice sort of scientific who done it that's got a happy ending and a new syndrome being described.
I think the key to any new anti auto inflammatory syndrome is the acronym. You have to have a cool acronym, DIRA.
Efficiency of IL-one receptor antagonist.
Yeah, or all the auto inflammatory syndrome.
Yeah, there's whole bunch of them. Other thing I want to really underscore here is that Kastner said, and now they're famous for their auto inflammatory clinic. They got Raphaela Golbakmanski and a bunch of other people are just fabulous there. They have about three thousand patients they follow in their auto inflammatory clinic, but only one thousand of those people have a firm genetic diagnosis. Two thirds of their audience, they're not so sure, but they're following them, they're treating them symptomatically, a lot of them are on biologics, they're doing a lot of sampling to see if you know where they can find like syndromes amongst the 2,000 or unrecognized.
So don't be frustrated if you can't quite figure it out. I think genetic testing is a little bit more available. If you wanna do genetic testing and what you think is an auto inflammatory periodic fever, go to invitae.com, invitae.com. You know, the patient can pay $100 now it's $250 cash and get like 77 genes tested for. And you don't have to be writing letters to medical directors to try to get, you know, the FMF gene tested for, you can get all 77 done.
So just think about that.
Yeah, and it gets so complicated because you have somatic mutations. These are not inherited diseases as of yet because, they just started. And then also some some of those are lineage dependent. So you have a somatic mutation only in myeloid cells, which makes it incredibly hard. Mean, Dan, of course, it can do the deep sequencing that you need to find those mutations in different cell populations.
But if you just looked broadly, like with the genetic tests, they would show up normal. So yeah, maybe worth sending them over to Dan and maybe Dan will name the disease after you.
No, it was already Cushing syndrome. All right, got, already we got about ten minutes left. It's lightning round. Why don't you do a mulligan? Tell us about your research at the meeting.
Well, actually I'm gonna, I have another one teed up. So I'm gonna do that one. Okay. That's abstract 40, and this is a whole blooded RNA expression in clinically suspected arthralgia. And this is from The Netherlands, and of course, they do fantastic work there with the early arthritis clinics, including people who don't have inflammatory arthritis.
Those who have arthralgias, maybe seropositive, of course, they collect these folks and follow them. There's great information, including at this meeting about the how likely are they to develop inflammatory arthritis and shocking numbers, they're actually pretty low. Like if you're CCP negative, basically by two years, you're only fifteen percent of you who have clinically suspect arthralgia are gonna have inflammatory arthritis. If you're CCD positive, maybe that's thirty, forty percent. So this was from one of those clinics that contributed to several of the abstracts of the meeting.
This is abstract 40, and this looked at whole blood RNA expression. So again, transcriptomics, expressionomics, or proteomics, looking at the RNA level. And what they did is take a couple 100 patients from the Leiden, clinically suspect arthralgia cohort, followed the patients up through two years or until they developed inflammatory arthritis, looked at 135 genes in innate and adaptive immune system and said, can they detect who is going to develop inflammatory arthritis? So of the cohort of two thirty or something, twenty percent developed inflammatory arthritis. And interestingly, the one hundred and you think one of the problems when you look is multiple, multiple analyses and you're gonna find something.
What they did find is that there were six genes that really stood out after controlling for multiple testing, which is what you have to do. If you're gonna look at a thousand variables, some of them are gonna be significant. So they found six, interferon gamma, PHX, insulin like growth factor one, IL-seventeen receptor, CD-nineteen and the chemokine receptor CCR7. Looking at linkage, what they ended up with was that two, IGF-one and IL-seventeen receptor were most differentially expressed than those people who went on to develop inflammatory arthritis. So the data doesn't make sense necessarily because it doesn't fit with our story of how people develop inflammatory arthritis, but the data were pretty clear.
And of course, one of these biomarker studies, they always predict the past and we need to predict the future. So we'd love to see something like this validated, but it was nice, crisp data that said that maybe we can find out that we go to clinic next week or this week, somebody whose joints ache and they're CCP positive, but they don't have arthritis and maybe get an ultrasound and they have a little power Doppler signal, what's gonna happen to them and how can we know? And if we did know, that gets the whole idea about early arthritis or early treatment of arthritis, which could be that much better than waiting longer.
The other abstract that sort of ties in with this is the one that you and I looked at four eighty one, which is about patients with suspicious synovitis, meaning that they don't have any swollen joints, have a few tender joints. And, but they have an ultrasound signal for synovitis. And that was a fairly large three cohorts like two or three hundred people in each cohort. And they looked at predictors of developing rheumatoid arthritis. And the bottom line was fairly low level just like you said.
But if, if you were CCP positive and didn't tell us about high or low CCP, that your positive your chance of developing RA went up from like less than twenty percent to almost fifty percent on average. And that's sort of what I think the practice is. But the question is, if you have an ache and a pain but no swollen joints, but ultrasound synovitis and you're CCD positive, should you be on a DMARD? The authors on that study said no. And I think that currently is the standard but there are a lot of people that are being swayed into treating those people right now.
And I think you can treat them symptomatically but I'm not going to treat an MRI and I'm not going to treat a lab and I'm certainly not going to treat a little power Doppler signal. Think you really have to treat swollen joints at this point.
Yeah, absolutely. You'd over treat a lot of people which is you know I think that gets to the idea what are you gonna treat them with? I think everybody thinks Plaquenil is pretty safe but that's not super super effective. So what do you treat them with?
I got a quickie, my sixteen oh seven, this was done by one of the fellows from Doctor. Chang from UC Irvine, and this was a retrospective study of their clinics and looked at those gout patients receive dietary counseling. That was like thirty patients compared to gout patients that received that did not receive any dietary counseling and they showed when they followed them out two years that the people who received dietary counseling, gee, they had less, they achieved target more frequently. And that was both at six months and at two years, they had less flares overall. This is something we talk a little bit about, You know, first off diet is important or not.
I got yelled at in Boston when I said not so much in my clinic, he said, Oh my God, shellfish up here is a gigantic problem. So I learned something in my trip to Boston. But you know, I don't think we spend any time doing this. And this to me says, we probably should spend a lot more time counseling people on diet.
Yeah, if it could have a benefit, I mean, I think that was, that's part of the excitement for the studies on the microbiome and absolutely the, there's an answer. And I tell people there's an answer, I just don't know what it is. Should you eat nothing but yogurt? Should you avoid all yogurt? Should you, I think there are some things that you can tell them and maybe we should be trying to tell them a little bit more, but it's hard to know, hard to say that we know what we're doing when we're telling them to manipulate their diet outside of some conditions for gout, yeah.
Yeah. All right, what's your next?
Last one I think I'll do is the number 507. So this is an analysis of the XSEED study. Remember the XSEED study was in psoriatic arthritis and it was secukinumab head to head with adalimumab. And they both did very well. In fact, the secukinumab were very respectable responses, almost made it to be better than the adalimumab in the joints and did make it to be better in the skin.
This looked at the sex response. And what they found is that overall, the female patients with PSA and memory in PSA studies, it's about half and half that, you know, the it's not ankylosing spondylitis, where it's mostly men or rheumatoid arthritis, it's mostly women, It's evenly distributed, but they had greater baseline disease or severity. And they did a little bit differently than the men did. We tend not to think of sex in the outcomes, I think, as we think of studies. Wait,
wait, you're telling me that sex was an outcome in this study? That
sex affects the outcomes. I don't think we Oh. We we don't pay much attention to it. The the men tended to have higher responses across the board for skin and and really remarkably for the the higher levels of response. So I think there's definitely differences between men and women.
I don't know if we've talked about that, Jack, but you can measure the various aspects of the immune system are different, and yet we lump them together. We say you got this disease, you got this disease, you got 10 joints, so does he, you're the same. And that may not be.
Yeah, disparities by sex are kind of a big theme at this meeting, especially a on spondyloarthritis as well. Playing on the theme that women tend to be diagnosed later and yet have more severe disease and more pain and whatnot. So yeah, that's surprising. I was not aware of this particular abstract. My last one is going to be a quick mention of Michelle Petrie's three abstracts, twelve sixty one, twelve sixty two and twelve sixty six.
They all deal with the issue of testing for anti phospholipid syndrome. As you know, she runs a fairly large lupus cohort at the Hopkins Lupus Clinic. I think they have 800 patients. They had a total of about 88 thrombotic events in their clinic, both arterial and venous. And in her testing, she shows that the one that is hands down the best test and outperforms all the other tests even combined is lupus anticoagulant.
The patients who have lupus anticoagulant outperforms either, the anti phospholipid, any of the subtypes, or being double or triple positive. She showed the lupus anticoagulant. If you have that, you have a threefold higher risk of arterial thrombosis and a fivefold higher risk of venous thrombosis. And of course, these thrombotic events tend to be multifactorial. There's a lot of other things that are in play in these lupus patients that add to it.
But then you fold that into the other story that she had in abstract twelve sixty six comparing, MI and stroke events in their lupus cohort. That, turns out that you could stroke real early in lupus, but MI not so much. That stroke and in all of its forms was related to lupus activity by complement and also to lupus anticoagulant. Where the same could not be said for MI. MI, the risk of MI and lupus in her cohort seemed to be very multifactorial and very time dependent.
So, why that is she found curious and she basically throws that out for anyone to consider that wants to research this but it's obviously something that she's concerned about.
Yeah, and I think we sort of had had that as one of the things that we had learned I thought over the years that lupus anticoagulant was the strongest correlate of course that test, which one are you using? Is it the hexagonal phospholipid? Is it the dilute Russell Vipervanum? Do they perform the same?
And I
know when this comes up in the clinic, nothing I hate more than uninterpretable result on the test where it's like, it should be yes or no. You should correct the with the dilute Russell Vibram should correct or it shouldn't. Sometimes it's like, well, it kind of corrected and then you don't get an answer with that.
All right, that brings us top of the hour. We want to thank everyone for tuning in to Rheumatology Roundup. That's it for this year. We hope to see you in 2021 in San Francisco or again at the dining room table, wherever it's gonna be. Maybe we'll just have, Artie, you have a Facebook chat room that people can go to.
I've heard of the Book of Face, but I have not yet partaken.
Oh, okay. Well, that's another. We can talk about both sex and Facebook after we close this meeting. Thank you very much everyone. Have a good night.
So we've stopped recording. I don't know if I stopped the meeting. I'm going to stop it now. So, that was good. Thanks.
To get transcriptomics. So they looked at the cells and then looked at the expression. Interestingly, they found a unique population of cells. There was a CD8 subset which represented 80% of the T cells. It was CD38 high, CD127 negative and PD1 positive.
They did have an increased expression of cytotoxic genes and they did have a interferon signature. They did, which you wouldn't think of as being, I mean, happens in RA, happens in PSA. You think of it being associated with lupus, but they found that in over transcription of genes downstream from the type one interferon. So I think this was fascinating. First of all, the ability to do the work where they can look at individual cell types, which are, even though if they're the same type of cell, they might have differences at the expression level.
They found the population, maybe this will translate into something we can use therapeutically. We have guidelines on immune checkpoint inhibitor arthritis, but not a lot of data. So maybe this is a promise.
Yeah, there's certainly a lot at this meeting about checkpoint inhibitors and stuff that affects us. And it's a growing concern for rheumatologists because most of us are seeing this. And short of using steroids, the next step is really concerning. And then other steps about like how long we're gonna have to treat them for and when do we you know how are going to communicate with the oncologist about when they can resume their, you know, their, their checkpoint therapies and whatnot. It's still seems to be a fair amount of push pull but thank God we have research like this.
Again, the authors didn't take this to the next step and postulate on how this could be used therapeutically, did they?
No, and it was just a number of people, but I think this finding really did surprise them. And maybe we should be thinking more of alternative therapies. As you say, one of the problems is anything we're gonna use via inflammatory arthritis, you sure don't wanna interfere with the ability to kill the tumor. That's why they're on the checkpoint inhibitor in the first place. In the clinic, it's, boy, it's tough, isn't it?
Because they're on these for the long haul, the checkpoint inhibitors. There's no, sometimes, you know, you'll see, well, maybe if you're still doing well next year, we'll think about stopping it, but they're on them for the long haul. So this is something we certainly need more information.
So I wanna talk about vaccination, and specifically vaccination in patients who are receiving tofacitinib. So there were two abstracts that were presented, late breaking for LL4, granted by Kevin Winthrop and then, a Shingrix vaccination in TOFA, that was 1997. Kevin presented this data on the drug development program with tofacitinib in 21 trials and at a low number of patients who receive the influenza vaccine. And the point of this was, could they get the influenza vaccine? Was there any real issue in there?
And the bottom line was there was not. There was no greater, and of course they had patients who were on placebo in their trials and on methotrexate and on adalimumab and also on tofacitinib. And the numbers of you know, actual influenza events or even worse hospitalizations, or serious events, those are like less than one or one and a half percent across the board. The bottom line was it looked pretty good. So that's good news for you, especially now as we're getting into the flu season, and worrying about when we're gonna get the COVID vaccine.
Can you do this in your patients on tofacitinib? The answer is yes. But wait, there's this other abstract that was presented by Calmark from Sweden. And it was a study to look at the of the immunogenic potential of the new shingles subunit vaccine, the one that's on the market now the Shingrix. And in that study, they studied 40 patients and they basically had a bunch of controls and they showed that the controls had a good antibody response and the topacitinib patients also had a good antibody response and they had, you know, mild to moderate symptoms, no big deal.
But the caveat worth mentioning here is that twenty five percent of patients on tofacitinib did not have an antibody response, which I'm sending all my patients that are going on a JAK inhibitor to receive the Shingrix vaccine. And even the ones who are not old enough to get it, I'm trying to implore them to get it because this class of drugs does impart a three to four to five fold higher risk shingles. And if you can avoid it with a ninety five percent effective drug, why not? But this says that maybe like methotrexate for people who are on and it's maybe because this is not really what the intention of the study was, but maybe like methotrexate for people who you're gonna give Shingrix to, maybe they should suspend the use of tofacitinib for, I don't know, a week or two. What would you do with this data?
The problem is we don't know what they mean. So presumably your cell mediated immunity is more important for the control of viral infection such as zoster. This is a nice surrogate looking at the antibody production, but we don't know as much about what that means. It may be possible that they have perfectly good ability to control it, control the zoster, or it could be that they need a booster. You know, the zero and then two to six months later, very reasonable and certainly that seemed to be quite efficient in the general population, but maybe it's not in these people.
We don't have a great readout because we don't care about antibodies. We care about cases of zoster. There's Jeff Curtis who writes in and says, Kevin and Winthrop and I are starting a larger Shingrix trial in RA next year. Awesome. Well, thank you, Jeff.
And yeah, I mean, we wanna see events. That's what we really wanna know. That's one of the difficulties, even I think in infections where the antibodies are more reliable in terms of to predict, you still want events. You're preventing the disease. That's what you want to say.
So I also want to give, I saw Jeff's tweet about this and I said, Oh, I gotta go look at that abstract zone. Thank you, Doctor. Curtis for steering me towards something kind of important. Arti, what's your next one?
Well, before we go to the next one, me, hey, there was a comment on the checkpoint inhibitor commenting, could you comment on the TNF and IL-six inhibition? I've had more experience with the TNF inhibition. And I think it's my level of comfort and the oncologist level of comfort with what they're okay with me doing. I haven't really used IL-six inhibition much, but it makes perfect sense. The trouble is we're just all dealing with anecdotes.
And I I go with what I had more experience with and I can't say that that's the right way to go. Jack, do you have a preference or?
Steroids, TNF inhibitors, IL-six is certainly possible. I think you stay clear of abatacept because of CTLA-four. But other than that, that's been my general rule. I've only had one patient who clearly had this and one who maybe had this. So I was not seeing that not as many as like Lenny or David Liu or some of the other people I know have seen a lot of this.
Yeah, I think we're all gonna see many more of them. So my next is fourteen eighty four, which isn't very sexy. I mean, the number, but the Time
to go to the refrigerator folks.
Because it's a negative study. But I think sometimes negative studies give us good information just like positive studies could. This is efficacy of tocilizumab in patients with hand osteoarthritis. So boy, there's been, every year it seems like there's a study or every other year there's a study on pretty much all the drugs that we have and pretty equivocal data and then differences in the study design. Mostly they're negative though.
There was a review in the Rheumatology Oxford two years ago and looked at this and maybe there was a hint of a positive signal for hydroxychloroquine, but I think this is an important issue. I think when we see osteoarthritis patients, boy, it gets harder and harder to say we got nothing, But if you come back, you get RA because I got 20 therapies, and if you have PSA, I got 15, and if you have lupus, I have six. So this was, I think, a nicely designed study. Not so big, one hundred and four patients. And eighty of the patients completed the study.
They didn't find a difference. So the primary outcome was the visual analog scale for pain, which had to be above 40 at the start. The delta was minus 7.9 in the tocilizumab group and minus 9.9 in the placebo. So the p value as you can imagine is 0.7. So absolutely no difference about that.
Also no difference in the secondary outcomes. And as you would expect, a little bit more of a signal with adverse events in the treatment group. So still a big unmet need in osteoarthritis, particularly the inflammatory kind, I think, what do we do? We sort of treat them with the agents that we have for rheumatoid arthritis. We treat them methotrexate, we give them hydroxychloroquine, at least until this year when I had to I like to use hydroxychloroquine for inflammatory hand away, but all of them had to develop rheumatoid arthritis in the chart so that I could get the drug for them because they weren't getting it this summer.
Or COVID.
It was COVID, COVID related arthritis CRA. But it was a negative study, nicely done study, negative study. And especially when you think about the tolerability issues, that of course weighs in our decision to use any treatment.
So the therapeutic pessimist likes to talk about all the drugs that have failed in scleroderma, they should change that to all the drugs that have failed in osteoarthritis, especially of the hand and doesn't even have to be inflammatory OA. All of our DMARDs have failed multiple times. All of our biologics have failed. But you know, the rationale behind this is not unreasonable, meaning that there is a component of inflammation that drives, you know, early events in cartilage degeneration. That is one of the earliest steps in development of OA.
The cytokines are often mediators of pain, you know, involved in pain signaling. So why not, you know, but again this didn't work and I was again disappointing. I'm not surprised I would say still my, my go to drug for osteoarthritis the hand is acetaminophen and cohesive tape for problematic joints, I wrap up fingers and immobilize them. And then I give them maybe two milligrams of prednisone for a short period I could possibly get away with. Other than that, I don't have a lot.
It's really disappointing. So my next one is, IL-sixteen and lupus nephritis. This was actually a presentation, a plenary session presentation, done on the second day, presented by, Andrea Fava from Boston. This is abstract nine thirty six. This is a proteomic study where they looked at urinary proteomics as a way of looking at lupus activity or lupus disease correlates, making the point that you know what do we do to best assess lupus nephritis patients, we have biopsy, we have sampling issues with that, it's not always available, we have proteinuria which actually can be somewhat helpful or can be misleading.
And the idea here is that in multiple studies that they did looking at, cytokines in the kidney, they actually showed that IL-sixteen is like the second most common cytokine found in the kidney. So they actually took thirty lupus patients over 110, urine samples, they did proteomic sampling on that, to see what they could come up with. And they basically showed that lupus patients who have class three and class four proliferative glomerulonephritis have a strong correlation with high urinary IL-sixteen levels, that those levels do correlate with histologic activity scores, but not chronicity scores, and that those levels will go down as the patient clinically improves on therapy. That IL-sixteen level was independent of urinary proteinuria. And that was sort of another key feature.
Then other studies that were sort of adjunctive to this looked at IL-sixteen staining in the kidney in renal biopsies and showed that a lot of IL-sixteen, especially around the glomerulus, but even within the glomerulus. IL-sixteen is a CD4 ligand, but actually has a lot of downstream effects that clearly would make it a good immunologic target or immunologic activator I guess in this situation. So they showed that this was very predictive. It was easily obtained at some point I guess it could be easily obtained. Again, to me if I found it novel, and I thought it was a really well done study that covered all its bases, looking at, many different markers, but they again was shot was sort of stood out amongst all the others was the IL-sixteen.
Yeah, it was definitely well done. And there's been a kind of a hint at looking at urinary biomarkers in lupus nephritis, which in some ways makes sense, of course, because you're downstream from the target organ, literally downstream from the target organ. And but you you also wondered because the obviously, proteinuria is part and parcel of the disease. So you have kind of a gimmish of proteins. You have the tubular, the tam horse sprawl proteins.
You have proteins that are leaked out from, patients who have any sort of membranous involvement with their lupus, but you also have, potential biomarkers of disease activity. That would just be that would just be absolutely outstanding to have something like that. I think in the clinic know what the biopsy is and of course we teach the fellows to not just take the number like three because three could be one proliferative glomerulus among 50 with a little bit, or it could be just barely a four with a bunch of crescents and a lot of chronicity. So we desperately need something as a biomarker. I think, especially the more therapies that we have available to us, now with the positive data, we're looking for belimumab.
With the other CD20 therapies, not just rituximab, which didn't work, but obinutuzumab, which is much more efficient at depleting. So yeah, a biomarker lupus nephritis would be just outstanding. Plus you could collect it remotely. You can literally mail it in and you can have many, many sampling points and you can't do a biopsy that often. I think sometimes it's hard to get them done.
They're expensive to get done. So this could be really a tremendous advance to not only the clinical care, but also of the research studies into lupus nephritis. Absolutely. So I'm gonna go into psoriatic arthritis or should we take the chats, Jack or?
Yeah, there's a bunch of them.
Well, Nancy Lane gives us a shout out. Keep the faith for OA treatments. Hopefully we certainly need them for so many patients. Gosh
right. Let's see Gary Botstein anecdotal avatars of treating CPI induced Myocarditis New England Journal. You Gary from Atlanta. What else we got?
Is it now standard to add belimumab? I don't know that it's standard. I think some people still come into terms with that data. That data was presented by Rich, did a great job presenting it, presented it earlier at UR, looked at some subset analyses here, which was the new part of the study, the blimumab study. I have to look to catch the number of that presentation.
But it showed that it worked actually, If it had lesser effect, it seemed like it was in membranous. Whereas in three and four, actually looked very solid. And he promised in the presentation today that he would get back to us about some of the other analyses that they're doing on that data to really help refine. So I don't know that I would say it's a standard of care because the effect size was pretty, it was small for sure, but it was absolutely clear. So to me, what I wanna say as well within that, if you have an improvement with one therapy or another of fifteen, twenty percent, that's small, but who are the people for whom it really makes a difference?
I think that's what we need to see. They also looked at race in that one and it looked, there were smaller numbers, but it didn't look like there was a lack of effect among African American patients. So not a standard of care, but I tell you that data still surprised people.
It's encouraging data, but it's certainly far from Doctor. Bazavariju who's here in Texas and that's taking care of one of my lupus nephritis patients and does it done a great job. She points out this, you know, what's the standard. I think it's encouraging data can't be misconstrued as a standard right now I think we still have to rely on the drugs that have been good for us so far, mycophenolate, when necessary, the Euro, cytotoxin protocol, that seems to work really well for a lot of patients. But it's very encouraging.
I think they just have to follow-up on it. And it was also very encouraging all the trials being done right now where lupus nephritis is the primary endpoint, as opposed to trying to get a global lupus, indication. Yeah,
that abstract number by the way, Richie Furies was fourteen forty one. It was kind of an update that's been published in New England Journal just earlier this year, but the new parts are the sub analyses according to the histopathology of the kidney and also the analysis by the race. And it was interesting when he gave his presentation, someone asked about the cost benefit because when you say, when do you use the different therapies? Well, it's the tolerability, it's the clinical effect, it's the cost. So all those things go into the equation.
So I'm gonna go into psoriatic arthritis and there was a late breaker L03. Phil Meiss was the first author in this one. This one was ducravacitinib, which is a molecule that we've seen studied in skin psoriasis. And it's one of the JAK inhibitors, but it's really much more of a TYK2 inhibitor. And if the immunology makes sense, which it doesn't always make sense, it's really easy to predict the past, I think that's what we do with the immunology.
That's why we know IL-one isn't really important in RA because blocking it doesn't work. But if you drew out psoriasis and psoriatic arthritis, you might say that those cytokines that use the JAK signaling molecules, that TYK2 might be a very useful target. And this is a relatively selective TYK2 inhibitor. And of course, the flip side of that is, are there going to be differences in safety? Is it gonna be any different compared to the other JAK inhibitors?
But of course, first they have to prove efficacy. So this is a study in PSA. Typical criteria, they looked at two different doses, six and twelve, and they met their primary endpoint was the ACR20 at week sixteen. And then they got that in fifty three percent of the lower dose, sixty three percent of the higher dose compared to thirty one, thirty two percent of the placebo. They also saw impact in functional status and in quality of life.
Actually nice distinction in and the site is as well. They didn't see a bunch in side effects. Now of course, it's psoriatic arthritis where the generally things, the patients are younger and generally fewer comorbid conditions. So they tend to do well with a lot of therapies and we need to see more. We want to see what the skin effect is because that's one of the things that people had hoped was maybe this would have a better skin effect than the other Jack and Ems, but it was a positive study.
And I think that's intriguing and we certainly look forward to more data on that.
So are you do follow the psoriasis literature and you run the same circles as those skin dermatologists? What's the take on on TYK2 inhibition in skin disease? You know, they did think they had like a big paper about this last two years ago. I know it's out there as far as the research is being further studied, does this is this going to stack up against IL-seventeen and IL-twenty three and those other new
That's a interesting question. The, you know, the dermatologists are, they're giddy with success with the 17s and the twenty three inhibitors. So as I like to say, they, you know, they talk about the PASI 75, the PASI 90, the PASI 100, the PASI 120 where you get completely clear and your sister gets 20% clear. You know, this is not that this is not that level of response, but it's much higher than what has been seen previously with the JAK inhibitors. Remember a couple of years back, Tofacitinib went to the agency, and I think part of why they didn't get approved at that time was that the higher dose was definitely much better than the lower dose, and it wasn't in league with what the dermatologists were seeing.
I think the attitude goes, well, why do we need this? Now they are super hot on Jakinibs, not only in psoriasis, but boy, you almost, you name it. And they're looking at Jakinibs for the therapy for a whole manner of immunologic skin diseases and there's a lot of orphan diseases in dermatology that don't get a lot of study, hidradenitis, the bullous diseases and there's a bunch of interest in JAK inhibitor. So I think they are pretty high on these. And we seem to be worrying more at least as of now about the tolerability issues and the VTE issues with JAK inhibitor.
Dermatology is very high.
Yeah, I think it's great that the ticks are being developed and we'll see what their range of efficacy is gonna be, but it's gonna get a really crowded on that JAK inhibitor floor. Now that the ticks are gonna be in there and filgotinib after it sorts out its problems with the regulatory agencies might be on the market as well. I wanna move on to another difficult disease treat and that is systemic sclerosis. Dinesh Khanna had a podium presentation today about a novel compound called zerotaxostat. The name of the study is the Novesa study.
I have to get you the numbers on that. Don't have it right here, but it's the Novesa study. And this is a study using this new drug which is an autotaxin inhibitor. The idea being that there are a few main pathways that can lead to skin fibrosis, but autotoxin is one of them, and as is IL-six. And those two are somewhat interrelated.
So this makes for a fairly attractive target. And that's what xerotaxostat is supposed to do. They studied it in patients with early diffuse systemic sclerosis. I believe it was this is like an early phase two study. They enrolled, 21 patients on zerotaxostat and, 12 on the placebo.
The primary endpoint here was going to be the modified Rodman skin score. And the patients, the groups matched up really well. There was slightly higher skin thickening with modified rodent or 27 in the zero tax stat group 22 in the placebo group. But after, I guess twenty four weeks which is the primary endpoint. The study drug did much better than placebo minus eight, versus minus five.
And that was significant at both week sixteen and week twenty four. They have a biomarker that showed significance so again, this is this is great in that phase two, but phase two a lot of things look great in phase two will it pan out and phase three is what we need but they are going further with this investigation so I think that's encouraging.
Yeah. But they're they, you know, they used to say like the Cubs, but I guess you could say like the Mets now. You know, every the start of every season, it looks promising, you know, in spring training, they they are gonna win the World Series this year. And I think unfortunately scleroderma is sort of like that. There's, I think back over the years, so many therapies that not only made sense if you look at the mechanism, you say, well, that's an interesting mechanism.
You know, That's something all that could work. Think back to relaxin from decades ago, where it worked in phase two and actually had a biomarker, had increased bleeding because it increased menstrual bleeding because that was part of the mechanism of it, failed dismally in phase three. How many other therapies are there? I hate to be negative about scleroderma, but you have your hopes up so many times by so therapies that should have worked. So is it the outcomes?
We looked at EULAR. There was a study looking at skin ultrasound as perhaps a more objective way of looking at skin. We desperately need some therapies. There's some hints of positives. And of course, Dinesh, he spins a great tale.
You got to be a believer, and it makes sense. But I think we really do need to see the longer term data.
Right.
So my next one, I think speaking of an unmet need, I really liked seeing this because I think just over the past couple of weeks, I interestingly have had a few people with giant cell arteritis, one of whom just refused to take steroids, which is an interesting patient And another one who took the steroids, but is just you know, he said his wife wanted him on the steroids because he cleaned the whole house by 5AM because he was so manic. But what do we have? Well, we have IL-six inhibitor, have tocilizumab and presumably cirilimab, but this is a late breaker abstract LO-six for marvelimab, maverilimab, which is a GM CSF directed monoclonal antibody that have been studied and had some positive results in rheumatoid arthritis. This is in giant cell arthritis. And I think, know, as we're just talking about for scleroderma, there is a scientific rationale looking at histopathologic expression within the inflamed vessel wall and patients with giant cell arthritis that you could make a case that it could be effective.
So this is a study, a 70 patient study with either new or recurrent giant cell arteritis. They had a fixed tapering plan for the corticosteroids and of course corticosteroids are the mainstay of therapy, but then it was maverilimumab or placebo randomized and flare was the primary outcome. And what they found out that disease flare by week twenty six, which is the time period over which they were also doing the steroid taper, had forty six point four percent of placebo and nineteen percent of maverilimumab. Overall, the tolerability seemed to be pretty good sustained remission. This is eighty three point two percent of maverilimumab versus fifty percent of those on placebo.
It was both new and recurrent patients. Tolerability seemed to be relatively good. Not a lot of AEs, not a lot of SAEs. Of course, these are people by definition, they're older and they have a lot of stuff going on. So they're gonna have some AEs no matter what you treat them with.
But I think this was interesting and promising. And I just, I said, I literally just thought of it because the, you know, the in the clinic, yeah, we get steroids. We have IL-six inhibitor. I'm not a, I don't know about you, Jack. I'm not a methotrexate believer.
I don't think methotrexate is a really viable option in giant cell arise I don't think it works I think we use it because we're rheumatologists and we use methotrexate for everything so I was, I was excited to see the possibility of these data.
Yeah, it's certainly in the holster and ready to use it all at all times and I have used it but not with a lot of great hope. And IL-six inhibitors seem to work really well in GCA, problematic GCA in the uncontrolled clinical trials that are out there. So that's certainly an option, but getting it approved, getting it paid for it could be another issue. I do wanna see more development. I mean, there's a lot of patients in this country and all around the world with GCA.
So you know, and even more with PMR. But interestingly, you know, as much as there's a great need here, there isn't a lot of people using the approved IL-six inhibitor here. So I'm not sure what the reluctance is. Maybe like we're too married to methotrexate, we're also too married to continuing that steroid at ten milligrams, twelve milligrams, fifteen milligrams as opposed to using a biologic. But I think it's a great study.
And I mean, so good that one of the faults of the study was one of the secondary endpoints was time to flare and they really couldn't calculate it for the maverolimumab group because they didn't really have any flares, which is like a great thing.
Yeah, it's a funny population because they're older people with by definition, they're sick people like you're talking about the gout population before. And I think there's a reluctance. I think if you look hard enough, you could talk yourself out of a biologic that in somebody who's over 60 and has some other comorbid conditions. But in those populations, methotrexate, is that going to be a go to? And to me, I think if you use methotrexate you want to use it, you got to use it 25 or more even if you're going to do steroids sparing with it so.
Yeah I was excited excited to see the data and the anecdotal data, as I know it for the TNF inhibitors has not been as great, even though I think the anecdotal data are very good in Takayasu's. I don't think the anecdotal data in giant cell are that good.
Yeah, so a few comments, but not much JAK inhibitors in GCA given IL-six effects theoretical but not studied well enough to even talk about it here. And there's a concern about GI perforations, a very low risk event with both tofacitinib and even IL-six agents, JAK inhibitors and IL-six inhibitors as well.
Yeah, I think, I mean, the GI issue I think is, everybody who's gonna qualify for this study has degenerative disc disease. Everybody has diverticular disease because all humans do by the time they get old enough to get giant cell arthritis.
Right, right. Alright, so my next one is the results of a afternoon session where it was sort of understanding auto inflammatory diseases and Dan Kastner presented this sort of like you know what to do with undifferentiated auto inflammatory. But you know, you almost really should watch this presentation because Dan Kastner gets very demonstrative in this thing. He's playing super sleuth and he's banging on the table and it's a really, really good scientific story. And it's a story of vexus.
Vexus is a new syndrome, V for vacuoles, E E1 ubiquitin activating enzyme, X being X linked, A auto inflammatory and S for somatic mutations. The story goes he had a patient, patient was with an auto inflammatory like presentation, and they did a bone marrow and the pathologist at the NIH was going over the bone marrow and said, you know, there's these very strange vacuoles in the cells within the marrow. And she said, I wanna study this further, come back. And they came back two days later and she said, there's two other patients so I had to look up. I remember this happening before.
You need to look up these people and see if they have the same problem. And sure enough, they did have the same kind of presentation. And sure enough, all three of them were known to have or found to have this UBA1 somatic mutation. It's an X linked somatic mutation. So they did further investigation.
It turns out some of those patients had relapsing polychondritis like symptoms. They did further investigations and they found out that in their center they had 21 males. They investigated them, they all had this UBA-one. All male, middle aged, high fever, sweets like rashes, neutrophilic like lung involvement, chondritis, VTEs, macrocytic anemia. They had a lot of other diagnoses, most of them, more than half of them were relapsing polychondritis, a lot of them were sweets or myelodysplasia, a few were polyarteritis nodosa.
But they were all ultimately unified by the UVA1 mutation and the other clinical features here. So this is a new syndrome. It's going be a rare syndrome, but it is a nice sort of scientific who done it that's got a happy ending and a new syndrome being described.
I think the key to any new anti auto inflammatory syndrome is the acronym. You have to have a cool acronym, DIRA.
Efficiency of IL-one receptor antagonist.
Yeah, or all the auto inflammatory syndrome.
Yeah, there's whole bunch of them. Other thing I want to really underscore here is that Kastner said, and now they're famous for their auto inflammatory clinic. They got Raphaela Golbakmanski and a bunch of other people are just fabulous there. They have about three thousand patients they follow in their auto inflammatory clinic, but only one thousand of those people have a firm genetic diagnosis. Two thirds of their audience, they're not so sure, but they're following them, they're treating them symptomatically, a lot of them are on biologics, they're doing a lot of sampling to see if you know where they can find like syndromes amongst the 2,000 or unrecognized.
So don't be frustrated if you can't quite figure it out. I think genetic testing is a little bit more available. If you wanna do genetic testing and what you think is an auto inflammatory periodic fever, go to invitae.com, invitae.com. You know, the patient can pay $100 now it's $250 cash and get like 77 genes tested for. And you don't have to be writing letters to medical directors to try to get, you know, the FMF gene tested for, you can get all 77 done.
So just think about that.
Yeah, and it gets so complicated because you have somatic mutations. These are not inherited diseases as of yet because, they just started. And then also some some of those are lineage dependent. So you have a somatic mutation only in myeloid cells, which makes it incredibly hard. Mean, Dan, of course, it can do the deep sequencing that you need to find those mutations in different cell populations.
But if you just looked broadly, like with the genetic tests, they would show up normal. So yeah, maybe worth sending them over to Dan and maybe Dan will name the disease after you.
No, it was already Cushing syndrome. All right, got, already we got about ten minutes left. It's lightning round. Why don't you do a mulligan? Tell us about your research at the meeting.
Well, actually I'm gonna, I have another one teed up. So I'm gonna do that one. Okay. That's abstract 40, and this is a whole blooded RNA expression in clinically suspected arthralgia. And this is from The Netherlands, and of course, they do fantastic work there with the early arthritis clinics, including people who don't have inflammatory arthritis.
Those who have arthralgias, maybe seropositive, of course, they collect these folks and follow them. There's great information, including at this meeting about the how likely are they to develop inflammatory arthritis and shocking numbers, they're actually pretty low. Like if you're CCP negative, basically by two years, you're only fifteen percent of you who have clinically suspect arthralgia are gonna have inflammatory arthritis. If you're CCD positive, maybe that's thirty, forty percent. So this was from one of those clinics that contributed to several of the abstracts of the meeting.
This is abstract 40, and this looked at whole blood RNA expression. So again, transcriptomics, expressionomics, or proteomics, looking at the RNA level. And what they did is take a couple 100 patients from the Leiden, clinically suspect arthralgia cohort, followed the patients up through two years or until they developed inflammatory arthritis, looked at 135 genes in innate and adaptive immune system and said, can they detect who is going to develop inflammatory arthritis? So of the cohort of two thirty or something, twenty percent developed inflammatory arthritis. And interestingly, the one hundred and you think one of the problems when you look is multiple, multiple analyses and you're gonna find something.
What they did find is that there were six genes that really stood out after controlling for multiple testing, which is what you have to do. If you're gonna look at a thousand variables, some of them are gonna be significant. So they found six, interferon gamma, PHX, insulin like growth factor one, IL-seventeen receptor, CD-nineteen and the chemokine receptor CCR7. Looking at linkage, what they ended up with was that two, IGF-one and IL-seventeen receptor were most differentially expressed than those people who went on to develop inflammatory arthritis. So the data doesn't make sense necessarily because it doesn't fit with our story of how people develop inflammatory arthritis, but the data were pretty clear.
And of course, one of these biomarker studies, they always predict the past and we need to predict the future. So we'd love to see something like this validated, but it was nice, crisp data that said that maybe we can find out that we go to clinic next week or this week, somebody whose joints ache and they're CCP positive, but they don't have arthritis and maybe get an ultrasound and they have a little power Doppler signal, what's gonna happen to them and how can we know? And if we did know, that gets the whole idea about early arthritis or early treatment of arthritis, which could be that much better than waiting longer.
The other abstract that sort of ties in with this is the one that you and I looked at four eighty one, which is about patients with suspicious synovitis, meaning that they don't have any swollen joints, have a few tender joints. And, but they have an ultrasound signal for synovitis. And that was a fairly large three cohorts like two or three hundred people in each cohort. And they looked at predictors of developing rheumatoid arthritis. And the bottom line was fairly low level just like you said.
But if, if you were CCP positive and didn't tell us about high or low CCP, that your positive your chance of developing RA went up from like less than twenty percent to almost fifty percent on average. And that's sort of what I think the practice is. But the question is, if you have an ache and a pain but no swollen joints, but ultrasound synovitis and you're CCD positive, should you be on a DMARD? The authors on that study said no. And I think that currently is the standard but there are a lot of people that are being swayed into treating those people right now.
And I think you can treat them symptomatically but I'm not going to treat an MRI and I'm not going to treat a lab and I'm certainly not going to treat a little power Doppler signal. Think you really have to treat swollen joints at this point.
Yeah, absolutely. You'd over treat a lot of people which is you know I think that gets to the idea what are you gonna treat them with? I think everybody thinks Plaquenil is pretty safe but that's not super super effective. So what do you treat them with?
I got a quickie, my sixteen oh seven, this was done by one of the fellows from Doctor. Chang from UC Irvine, and this was a retrospective study of their clinics and looked at those gout patients receive dietary counseling. That was like thirty patients compared to gout patients that received that did not receive any dietary counseling and they showed when they followed them out two years that the people who received dietary counseling, gee, they had less, they achieved target more frequently. And that was both at six months and at two years, they had less flares overall. This is something we talk a little bit about, You know, first off diet is important or not.
I got yelled at in Boston when I said not so much in my clinic, he said, Oh my God, shellfish up here is a gigantic problem. So I learned something in my trip to Boston. But you know, I don't think we spend any time doing this. And this to me says, we probably should spend a lot more time counseling people on diet.
Yeah, if it could have a benefit, I mean, I think that was, that's part of the excitement for the studies on the microbiome and absolutely the, there's an answer. And I tell people there's an answer, I just don't know what it is. Should you eat nothing but yogurt? Should you avoid all yogurt? Should you, I think there are some things that you can tell them and maybe we should be trying to tell them a little bit more, but it's hard to know, hard to say that we know what we're doing when we're telling them to manipulate their diet outside of some conditions for gout, yeah.
Yeah. All right, what's your next?
Last one I think I'll do is the number 507. So this is an analysis of the XSEED study. Remember the XSEED study was in psoriatic arthritis and it was secukinumab head to head with adalimumab. And they both did very well. In fact, the secukinumab were very respectable responses, almost made it to be better than the adalimumab in the joints and did make it to be better in the skin.
This looked at the sex response. And what they found is that overall, the female patients with PSA and memory in PSA studies, it's about half and half that, you know, the it's not ankylosing spondylitis, where it's mostly men or rheumatoid arthritis, it's mostly women, It's evenly distributed, but they had greater baseline disease or severity. And they did a little bit differently than the men did. We tend not to think of sex in the outcomes, I think, as we think of studies. Wait,
wait, you're telling me that sex was an outcome in this study? That
sex affects the outcomes. I don't think we Oh. We we don't pay much attention to it. The the men tended to have higher responses across the board for skin and and really remarkably for the the higher levels of response. So I think there's definitely differences between men and women.
I don't know if we've talked about that, Jack, but you can measure the various aspects of the immune system are different, and yet we lump them together. We say you got this disease, you got this disease, you got 10 joints, so does he, you're the same. And that may not be.
Yeah, disparities by sex are kind of a big theme at this meeting, especially a on spondyloarthritis as well. Playing on the theme that women tend to be diagnosed later and yet have more severe disease and more pain and whatnot. So yeah, that's surprising. I was not aware of this particular abstract. My last one is going to be a quick mention of Michelle Petrie's three abstracts, twelve sixty one, twelve sixty two and twelve sixty six.
They all deal with the issue of testing for anti phospholipid syndrome. As you know, she runs a fairly large lupus cohort at the Hopkins Lupus Clinic. I think they have 800 patients. They had a total of about 88 thrombotic events in their clinic, both arterial and venous. And in her testing, she shows that the one that is hands down the best test and outperforms all the other tests even combined is lupus anticoagulant.
The patients who have lupus anticoagulant outperforms either, the anti phospholipid, any of the subtypes, or being double or triple positive. She showed the lupus anticoagulant. If you have that, you have a threefold higher risk of arterial thrombosis and a fivefold higher risk of venous thrombosis. And of course, these thrombotic events tend to be multifactorial. There's a lot of other things that are in play in these lupus patients that add to it.
But then you fold that into the other story that she had in abstract twelve sixty six comparing, MI and stroke events in their lupus cohort. That, turns out that you could stroke real early in lupus, but MI not so much. That stroke and in all of its forms was related to lupus activity by complement and also to lupus anticoagulant. Where the same could not be said for MI. MI, the risk of MI and lupus in her cohort seemed to be very multifactorial and very time dependent.
So, why that is she found curious and she basically throws that out for anyone to consider that wants to research this but it's obviously something that she's concerned about.
Yeah, and I think we sort of had had that as one of the things that we had learned I thought over the years that lupus anticoagulant was the strongest correlate of course that test, which one are you using? Is it the hexagonal phospholipid? Is it the dilute Russell Vipervanum? Do they perform the same?
And I
know when this comes up in the clinic, nothing I hate more than uninterpretable result on the test where it's like, it should be yes or no. You should correct the with the dilute Russell Vibram should correct or it shouldn't. Sometimes it's like, well, it kind of corrected and then you don't get an answer with that.
All right, that brings us top of the hour. We want to thank everyone for tuning in to Rheumatology Roundup. That's it for this year. We hope to see you in 2021 in San Francisco or again at the dining room table, wherever it's gonna be. Maybe we'll just have, Artie, you have a Facebook chat room that people can go to.
I've heard of the Book of Face, but I have not yet partaken.
Oh, okay. Well, that's another. We can talk about both sex and Facebook after we close this meeting. Thank you very much everyone. Have a good night.
So we've stopped recording. I don't know if I stopped the meeting. I'm going to stop it now. So, that was good. Thanks.
If you are a health practitioner, you may Login/Register to comment.
Due to the nature of these comment forums, only health practitioners are allowed to comment at this time.