ACR20 - Day 3.4 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.

Hi. I'm doctor Janet Pope, a reporter at RheumNow coming to you from ACR twenty twenty, the virtual meeting or convergence. I want to talk about what I think is a best in class production. That is an oral presentation number fifteen oh eight from Doctor. John Hanley's group in Nova Scotia.

So it starts to me with a clinical question. When our patient with lupus is saying, I have headache, I'm not thinking clearly, I can't remember my best friend's date of birth even though I've known her a long time. Things like that. They're very non specific. I take them seriously but I don't know what to do about them.

To me this is a game changer abstract. So in 1508 abstract what they did was they looked at 65 people with SLE and nine controls and they were looking at leakage of the blood brain barrier and they had advanced imaging. And what they found in the lupus patients is that one in four or twenty five percent had significant or clinically relevant blood brain barrier leakage with advanced imaging. So one in four patients and they looked at where this was occurring and it seemed to be all over the place. It wasn't just say a frontal lobe as a for instance.

What was really interesting to me was there was no difference in neuropsychiatric events prior to this in those who had blood brain barrier leakage and those who didn't but you had higher disease activity as lead eye of four compared to 2.4 if you had leakage compared to no leakage. What they also went on to do was look at not just the structure as I explained but function. So there were more cognitive defects in those who have this leakage than those who didn't. What's the take home? Number one, take your patients seriously with SLE when they say they're not thinking right.

Number two, more work needs to be done to know how to treat it. I think though this will change the way I think about CNS events occurring in lupus. Please follow us at RheumNow and enjoy ACR twenty twenty. Thank you.

Hello everyone, I'm Richard Conway from Dublin, Ireland reporting from ACR twenty twenty. And I'm going to talk to you about a study by Doctor. Joshua and colleagues, which was presented on Sunday in Planar Recession three. And this study was entitled Citrulline Reactive B cells are present in the lungs of at risk or A and early untreated or

A.

So this is a very important topic. Rheumatoid arthritis, as we all know, is an autoimmune condition. And we don't really know why or how or where rheumatoid arthritis starts in the body. And perhaps part of the reason why we have had some difficulties in treating it is because of that lack of knowledge. And the lungs have been one of the main focuses as a potential trigger site.

And there's a number of reasons why we think the lungs could be important. There's a strong association with rheumatoid arthritis with smoking. And there's a high rate of interstitial lung disease as a manifestation of rheumatoid arthritis and ACPAs have been identified in the lungs of patients with rheumatoid arthritis. So it was in this setting that the authors of this study decided quite sensibly to look at people with the earliest stages of rheumatoid arthritis and see what they could find in their lungs. So this was a relatively small study.

They enrolled 12 patients. They enrolled patients who had seropositive arthralgia, so who didn't yet meet the criteria for rheumatoid arthritis. And then patients with early untreated seropositive rheumatoid arthritis and early untreated seronegative rheumatoid arthritis. And with these patients, they did a bronchoscopy on all of them and a bronchiolar lavage. So they did a washout of the lungs and gathered up the cells that are in the lungs, and then sorted these cells.

And specifically what they were looking for were B cells, and particularly CD19 positive B cells. And they identified these CD19 positive B cells at a significantly higher rate in those with seropositive arthralgia or seropositive rheumatoid arthritis compared to seronegative rheumatoid arthritis. They then went on and looked at what these B cells were doing. And they found that they were making pathogenic ACPA. So they identified pathogenic ACPA in these patients who had the CD19 positive B cells.

So the implications of this study, this supports the theory that the lungs may be a primary site of both initiation and propagation of rheumatoid arthritis. And as well as giving us knowledge of the pathogenesis, there may be clinically important implications to this. And if we want to try and prevent rheumatoid arthritis, especially in at risk people, then it may make sense to focus on the lungs and this data supports a strategy like that. So thank you. Follow me on Twitter at Richard P.

A. Conway and tune into RheumNow for more updates from ACR twenty twenty.

Hi, ACR Converge. I'm Doctor. Rachel Tate from West Palm Beach, Florida. Today, I am honored to be chatting with two of my friends, Doctor. Cassie Calabrese from the Cleveland Clinic and Doctor.

Mary Inoujos Mammet, PGY5, from Largo Medical Center, also here in Florida on the other coast. She's also the incoming chair of the ACR FIT subcommittee. Guys, thank you for being here today. I really appreciated it. I would just wanna talk to you ladies about COVID-nineteen, but more specifically regarding work and work life balance that you've seen with COVID-nineteen.

I'll tell you the pandemic has definitely changed the way I work. I have even scheduled patients for telehealth visits on days that I wasn't previously in clinic. So just to start us out, how has the pandemic changed your work or your workflow, Cassie?

Hi, that's a really great question. Like what is not different since the pandemic started which feels like a decade ago but I think a lot has changed. I work at the Cleveland Clinic so it's a large academic medical center tertiary referral center and we were really busy at baseline. And I think the most interesting thing about rheumatology and COVID is that our patients always need to be seen. We're an institution with ortho and, you know, they don't need their patients often can, you know, not come and our patients have chronic medical issues.

And so we never really slowed down, but we did a lot of virtual, which I'm, we've converted mostly back to in person, but I'm still finding a lot of patients who are very scared to come into clinic. I think our patients are like very aware of their health issues and for that reason are being uber cautious. But I feel like I'm even more busy virtually somehow and have struggled with balancing. You know, we fortunately didn't get struck down like with pay cuts or anything, but we were asked to work harder, and more, whether it's adding on patients. We were given free rein to pick the time.

Some people see patients at six in the morning. Some people see them on the weekends, some people see them, at the end of the day after work. So it's been busier in a different way and balancing has been a challenge.

Well, it's funny that you should bring that up. Mary just had a wonderful lecture. I mean, Mary, tell us

about it. Yeah, so I had the opportunity to moderate a lecture for the ECR convergence yesterday, Work Life Balance, and it was hosted by Doctor. Leanne Gensler. It was really interesting. I feel like there was quite a few, really good points, but, you know, there's at least three that really were take home for me and not necessarily in COVID because even before COVID work life balance is very challenging.

And, you know, one of the biggest things that, you know, as a fellow in training for me was that everybody has their own path, really emphasized. And, you know, making sure that what you're doing is making you happy. And as long as you're happy, that path that you're taking is the correct one. You know, there was another point that she made that really resonated with me, and that was not to hold others to your own expectations that you hold yourself to. And I think that that's really important in just recognizing and respecting everybody else's expectations and their own paths as well.

And then the third big one was it's okay to say no. And I think that that's important and especially important in the COVID era as we're trying to figure out how to do things because there's no right answer at this time. And as a fellow in training too, you want to say yes to all these opportunities that you have that will open other doors for you. But she made a really good point in regards to saying no also means that you're allowing for other opportunities, whether that's at home or at work, but, you know, you're allowing that time to something else that makes you happy. I think Cassie and

I can say one quick thing about that. That's not just for fellows.

Saying yes, I'm glad that you did. That doesn't go anywhere. Doesn't. No. I think it's harder earlier when we're younger in our careers but that has been a challenge for me since day one and getting asked to do so many things or to help with so many things can be exciting and challenging and you want to say yes to everything but the art is actually learning which ones to say yes to and what to say no to.

How's that been? Has that been really I'm sure that's been difficult with your expertise in infectious disease and rheumatology this year.

It's been a lot. It's been a lot of stuff. Been in it's all, you know, so exciting. And and for a while, I tried to do everything. And about, like, two months ago, I had to kind of re re take another look at what I was like doing with myself and my time and energy and it's been very good, but that can be really hard.

Well, do you have any tips that you learned two months ago? What's your secret? I don't know how to do this yet.

Well, ten years of not sleeping. Take moment. And, it's important, you know, things you say yes to range, you know, things you get asked to do range from, you know, patient care things to, you know, writing things, book chapters, things that are easier and harder, you know, getting asked to write like a book chapter in the midst of all this, is if you have not learned one of the most difficult things to do and time consuming things and kind of like lesser rewarding things, but also very intellectually stimulating and so putting a higher priority to COVID related things and always patient care related things and favors, but, it's still a challenge and a work in progress and I welcome any tips.

Oh yeah, me too. Well, Mary, do you have any tips for fellows? Do you have any tips for attendings? I think it's important right now, right? We're all shifting gears and we've had to learn quickly and adapt, which is something that we are pretty used to in rheumatology.

But as human nature, we don't want to adapt quickly. That's not what we do.

So Yeah, I agree. I think that, you know, I would just kind of echo what doctor Calabrese said, and that's triaging and, you know, picking and choosing those things that the time may be more appropriate for your schedule while you're still finding the balance for additional activities and in your personal life as well.

I think that's really important. I thought of a super good quick example of I took like a vacation vacation day a couple weeks from now. It's like one day. I was like, I need this day. And then just yesterday, I got asked to do something like super cool, like COVID related that falls on that day.

And I was like, oh gosh, like, I really should do this but I was like, I'm not gonna do this. Like, no, this is my day. I wasn't supposed to do anything on this day and I was proud of myself for saying no.

Well lead by example. Mary, has it changed a lot from being a PGY4 now to a PGY5 with the pandemic? What are you guys seeing?

So that's a really good question. I don't think necessarily going from PGY4 to five, I've seen differences. It's a nice flow in transition in fellowship. But in regards to education, COVID has made a difference. And I can't speak for all the fellowships around the country because everybody's had a different experience.

But there does seem to be a consensus in regards to concern about education. Are we seeing enough patients still? Are we doing enough physical exams, getting enough procedures? A lot of fellows have also had research projects put on hold. So those are some real concerns, but, I think what's really cool is the ACR is recognizing this.

And one of the big focus for them is something that they can make a great impact on, and that is the education part. So there's been these viral series lectures going on. A big one was the VIP lecture series that went on through July and August. And I know that there is some coming up here in the next half of academic year. I'm not sure how much I can say about that at this time, but, you know, it's really there for the fellows and it's there to help provide those resources and maybe some gaps that we have.

And it's great that everything's online and it's available still today.

Well, thank you for this very short period of time. What I've learned from us is that we're pretty ambitious. We're still young. We have problems saying no. But overall, that the ACR has some really great options for fellows, for support.

And as Cassie has said, we still advocate for our patients and we need to advocate and educate ourselves. So thank you so much for being here. Any last comments, thoughts? Mary, go first.

Yes. Thank you. I do wanna share that we did the ACR FIT subcommittee to do a survey of fellows in regards to the COVID impact. And that was back in the spring. We're gonna be talking about that as kind of a town hall, but it's gonna be during our fit reception.

That's tomorrow night, Monday the eighth at 7PM Eastern Standard Time. So I just want, you know, the fellows to know that that's available. We will talk about resources that, you know, some of our colleagues have been using to help cope with some of the difficulties.

Excellent. Cassie, any last thoughts?

I think I'll say just remember to take care of yourself. You have to take care of yourself and reserve even just a little time for yourself so that you can be there for your patients and your family.

Guys, that's wonderful. That's what we all need to be doing. So, well, thank you so much for being here. Stay safe and healthy. And for this and more information, check us out at roomnow.com.

Thank you.

Thank you.

Hi. I'm doctor Sheila Reyes from The Philippines reporting for RheumNow from ACR twenty twenty. Today, I'll be giving you an update on myositis, in particular, the results of the progress in dermatomyositis or ProDerm study, abstract number nine ninety five, which was presented by professor Rohit Agarwal during the abstract sessions. This trial investigated the efficacy, safety, and tolerability of IVIG in patients with dermatomyositis. This study is a phase three randomized placebo controlled trial that enrolled ninety five adult patients with active disease currently on standard immunosuppression or previously failed or intolerant to standard immunosuppression had a manual muscle test score of less than 142 over 150 with at least two abnormal core set measures.

Patients were stratified into mild, moderate, or severe disease. The study was divided into two periods. The first period, patients were randomized to IVIG two gram per kilogram every four weeks or placebo every four weeks up to week sixteen followed by an open label extension period of for up to week forty. For stable patients, there was an option to decrease the dose of IVIG to one gram per kilogram every week at week twenty four. And patients with confirmed deterioration anytime from week eight to week sixteen can be switched to an alternate treatment group.

The trial met its primary endpoint, which was the proportion of responders at week sixteen who had a total improvement score, or TIS, of more than 20 points. For a brief background, the TIS is a validated response criteria for both DM and PM based on six core set measures, including manual muscle testing, physician and patient global assessment, HAC, muscle enzymes, and extramuscular disease activity. So going back to the results, there was a statistically significant proportion of patients who had minimal improvement TIS of less than 20 points versus placebo at week sixteen. Similar results were also found for the proportion of responders who at least had moderate or major improvement. IVIG response was maintained for all efficacy endpoints through week forty and similar response rates were seen after switching to IVIG from placebo.

The mean test was also significantly higher in the IVIG groups. Sixty two patients developed treatment emergent adverse events, most common of which were headache, pyrexia, and nausea. Serious TEAEs were similar in both treatment groups with thromboembolic events being the most common. In conclusion, the ProDerm study showed the efficacy, safety, and tolerability of ten percent IVIG or ten percent Octagam in patients with dermatomyositis. What's my take on this?

The results are really good. Probably not yet my first line agent for dermatomyositis, but definitely an alternative option for patients refractory to treatment or those with contraindications to standard immunosuppressive therapies. Follow me on Twitter at RheumOrampa and tune into RheumNow for more videos and reports. Thank you.

Hi. This is Eric Ruderman from Northwestern University in Chicago coming to you again from ACR Convergence twenty twenty, bringing you some, discussion through RheumNow. In this meeting, like a lot of other meetings lately, there's been tremendous interest in the psoriatic arthritis space on measuring disease activity. Psoriatic arthritis, more so I think than rheumatoid arthritis, is a bit of a challenging disease because there's so many domains of disease activity and it makes it hard in an individual patient to figure out what's going to drive your treatment choices. If all treatments were equally effective for all the different domains of involvement, it wouldn't matter, but that actually is not the case.

And as we get new therapies, it's becoming increasingly important to sort through all of that so we can understand what's the right treatment for the right patient. That comes up in, guidelines, that's come up in the past, in the grapple guidelines, and it's part of the discussion as the, next iteration of the grapple guidelines are going, through the process right now. And one of the challenges is that there are a number of different, composite outcomes in psoriatic arthritis and yet it's not clear which one gets the information that we really need in an individual case to take care of our patients. So sort of stepping back, you know originally psoriatic arthritis trials used, outcomes that were sort of poached from rheumatoid arthritis, ACR response, DAS response, and in fact they still do, but it was recognized fairly early that they don't always capture the full spectrum of psoriatic disease, that patients with enthesitis, for example, may not have a very high score on a DAS score if it's focusing specifically on synovitis, and none of those, account for skin disease or nail disease. So one of the challenges has been to develop a composite that addresses all those things and yet does so in a way that's applicable to individual patients.

There are a number of these, the dapsa and the pastass, and most recently I think people have focused on a composite that is something akin to a clinical, remission, basically. And what's driving that, in many ways, I think, is the treat to target concept, which, you know, initiated in rheumatology, in rheumatoid arthritis, and is now moving into the spondyloarthritis arena, and the idea being that if you have a patient with active disease, you continue to monitor their disease activity, and then either change therapy or escalate therapy if they haven't achieved, a target. Now that's, I wouldn't say easy to do, but easier to do in rheumatoid arthritis when you have a very clear cut target. It's either remission or low disease. There's some controversy over which, you know, which, remission diagnosis you use, but it's the same idea because it really focuses on joint disease.

In psoriatic arthritis, it becomes a little bit more complicated, so, an outcome like the MDA, minimal disease activity, which takes into account joints and skin and enthesitis and dactylitis and pain and all the different elements of disease, seems on the surface, preferable. The problem is that the impact on an individual patient may differ. So some people are much more bothered by their skin disease than by their joint disease, and sometimes it's quite the opposite. And as a clinician, as a treating physician, or a practitioner, we have to sort of work on that with the patient because, know, as in all other aspects of our care, shared decision making is critical. So we have to understand what the patient wants, and one of the challenges is, you know, what's not controlled and how important is the part that's not controlled.

So there are a few abstracts at this meeting after I sort of wound through all this that sort of look at this. So there's a couple, eight eighty four for example, which looks at the corona, database, the corona spa registry, npsa registry, 323 which looks at some data from the park cohort, the psoriatic arthritis research cohort, and both of these look at the concept of what elements of disease are left if someone has achieved a target, if you will, by a composite measure. It seems that a patient in minimal disease or very low disease activity has the least active disease left in both of these. There's some data in abstract nine zero nine at this meeting from the EXCEED study, which compares adalimumab to secukinumab, which shows some of the same things, it looks at what's left. Those are important elements.

The question is how important are the individual pieces that are left? So for example, if a patient is well controlled in terms of joint disease and still has some skin disease, but is not terribly bothered by that, do we need to push on for more therapy? Do we need to change therapy, or can we accept where we are? And is that different, and in my mind it is, from a patient with significant joint disease, where I worry about long term damage in a way that I don't worry for skin disease. So patients who have persistent joint involvement, particularly if I know that they have destructive arthritis, I'm not going to be as happy leaving them there and leaving them alone.

So these are issues we have to confront. I think a lot of abstracts at this meeting have begun to look at that, and there are a lot of abstracts with newer therapies where this is going to come into play. So 2027 is the data on tildrekizumab, a new IL-twenty three inhibitor. A number of abstracts, three forty seven, five zero five, eight eighty eight, and others on guzelkumab, an IL-twenty three inhibitor that was bit that has been approved. And the question is, are these drugs going to address the same elements of disease that we've treated with IL-seventeen inhibitors, that we've treated with TNF inhibitors, or that we're looking at treating with JAK inhibitors.

There's another IL-seventeen inhibitor, bimekizumab. An abstract nine zero six is a phase two study from this drug that targets both IL-17A and IL-17F. Is that going to change the elements of disease? I don't have the answers to these questions, but I think they're important questions to ask as we move forward in care, and they're not trivial because they really impact sort of guidance. Whether or not you believe in guidelines and follow guidelines, the kind of guidance that we need on what treatments are going to treat which patients is important for all of us, even if you don't, follow guidelines strictly.

So stay tuned, the answers aren't here. Abstracts at this meeting begin to look at this question. We'll learn more, going forward, and it's an area we need to continue to look at. Stay tuned to RheumNow for more information on ACR Convergence 2020, and I'll see you later.

Hello, I'm Anthony Chan from Reading in The United Kingdom, and I'm a consultant rheumatologist reporting here at the ACR20, full stop. I've been covering and looking at the new treatments in axial spondyloarthritis. And there are two very interesting posters from today, which I'd like to kind of share with you, which describes new treatments in axial spondyloarthritis. And this is with the selective JAK1 inhibitor, upadacitinib, which I'm gonna call YUPPA. And this has kind of thought us about new things about this treatment.

Now the data was first presented last year, at the end of last year published in Lancet with the SELECT axis one study by Van Haider, which showed that LUPA compared to placebo was able to achieve an ASOS forty or fifty two percent versus twenty six percent in the placebo group. And this two are the posters today, kind of extends the data from the SELECT-one access study. The first is poster number three sixty nine, which looked at the issue of pain. Now we know that in patients with access spondyloarthritis, spinal pain and also peripheral joint pain can be quite significant factor that can affect their function. In this study, they looked at the aspect of pain and they looked at the groups which first received UPA and versus placebo as well.

They looked at different measures including patient global assessment and also BEST I. The BEST I, as you know, is the Bavankylosing Spondylitis Disease Activity Score, and then they looked at the various different questions such as question two and three. And what they showed was that there was as early as week two in the UPA group, they managed to achieve improvement in the pain levels. And also in the patients who switch after a period of placebo for fourteen weeks where they switched over to the upper group. That again, these patients also benefited from the switch to upper.

And this was seen up to week 64 where there was an improvement in their pain at 5070% of improvement of pain compared to baseline. So I think that is very interesting and also gives us a lot of hope for the future in regards to new treatment for our patients with axial spondyloarthritis. The next poster is poster eight eighty six, which looks at the aspect of the effect of WUPER on remission scores in patients with Axis Bondyloarthritis. They use the ASAS score called ASAS Special Remission, ASAS PR, and then also looked at how this correlated with disease activity scores. They used the ASTER score.

The ASTER score can be differentiated into low disease activity, or moderate disease activity or high disease activity. And what they found was in the group where they had UPA from the start, and assessment at week fourteen, nineteen percent of these patients achieve ASUS partial remission. And that's a very high score in terms of improvement compared to baseline. And in the placebo group where they switched over after fourteen weeks, and they reassessed them again at week thirty two. And they also found that thirty three percent of these patients again achieve ASAS partial remission.

Now the majority of these patients who achieve ASAS PR also achieve very low disease activity or inactive disease scores on their S test. Again, I think this shows us that the benefit of the treatment can be on an Axis Pondyloarthritis in terms of achieving high scores in terms of partial remission. Now these two posters today supplement the data that we heard last year about the effect of WUPPA. And for us, we are looking for new mechanisms of action in the treatment of of access spondyloarthritis. We have obviously biologic drugs, TNF inhibitors, TNF blockers, we have interleukin seventeen blockers.

So again, this opens up a new area for study, and obviously we'll need further studies. We'll need to look at the effect of JAK inhibitors beyond this study. But again, I think this gives us hope in terms of management of our patients with axial spondyloarthritis. I'm Anthony Chan, I'm reporting from ACR20. Thank you for listening today, and I hope to share with you further news from the conference.

Thank you very much.

Hi again, Michael Pillinger from NYU School of Medicine here talking about gout for RheumNow. So today is Saturday at the ACR Convergence meeting and it's been a fairly busy day for gout with a large poster session and several talks. Of course, I've got to choose something to talk about. So what I'd like to highlight here today is a bit of gout drug development. Over the past decade, there had been a lot of drug development in gout, but over the past few years, it seems to have petered off, particularly when it comes to urate lowering therapy.

Currently, we're really left with allopurinol as our go to drug, febuzostat for a limited indication and the spectacularly effective but not for everyone pegloticase. And I'll be talking more about pegloticase at an upcoming round table discussion. Meanwhile, I wanted to highlight a couple of abstracts about a new uricosuric under development called AR-eight eighty two. AR-eight eighty two is a potent selective URAT1 inhibitor and therefore a uricosuric drug and the company sponsoring it has brought two studies to this meeting. The first one, abstract number six seventy five is a phase one study by Shen et al.

This is a study of healthy subject volunteers. It's a ten day long treatment study and like all phase one studies, it's a dose finding study. So here the doses are twenty five, fifty and seventy five milligrams once a day. 30 adults participated and the serum urate decreased forty, sixty or 65% by dose respectively. So it appeared that the benefit of going from twenty five milligrams to fifty milligrams was very significant from forty to sixty percent but the benefit of going from 50 to 75 was less so from sixty to only an additional 65% decline.

Of course, since this is a uricosuric, the fractional excretion of uric acid increased in the urine. So this study helped establish doses and demonstrate the short term physiologic potency of AR-eight eighty two for urate lowering in a non gout population. What about in a gout population? That brings us to the second study, which is a phase 2A study by Ye et al. This is Abstract six ninety.

And in this study, the authors examined a group of patients with gout. They chose the fifty milligram per day dose, the one we talked about in the prior study as maybe the sweet spot and they administered it with or without either forty milligrams of febuxostat daily or three hundred milligrams of allopurinol daily or against febuxostat or allopurinol alone. The treatment period was one week but in a three week crossover study that allowed all patients to get three different regimens. They either got the AR-eight eighty two or they got the xanthine oxidase inhibitor or they got both. There were only 20 patients in this study.

Eleven patients got febuzostat as the comparator and nine got allopurinol. To get into this study, the patients had to have a serum urate greater than seven but the average starting urate for all the patients was about nine milligrams per deciliter. So it was quite substantial. In this study, AR-eight eighty two's urate lowering capacity was genuinely impressive. Ninety five percent of the patients getting AR-eight eighty two alone achieved a urate of less than five milligrams per deciliter, which was in this case a fifty three percent reduction.

In contrast, only 10% of the allopurinol and 25% of the febuzostat users got to less than five mgs per deciliter. The percent of subjects achieving a year rate of less than six, a higher bar, an easier bar to achieve rather, was also markedly greater in the AR8A2 group. In fact, it was even higher than ninety five percent of the patients reached that. Though not surprisingly, the traditional drugs were also better at hitting this easier target than the five milligrams per deciliter one. The combination of AAR-eight eighty two with either of the xanthine oxidase inhibitors was even more impressive, often getting down to below four milligrams per deciliter or even lower.

And AR8A2 was also effective in patients with mild renal disease. So this looks really promising. Now, while the author has correctly affirmed that allopurinol and febuzostat have their limitations, the case against them in this comparison was perhaps a bit overstated. For one thing, the doses of febuxostat and allopurinol used were not the optimal ones. So this comparison does stack the deck a bit in favor of AR-eight eighty two.

We may really want to know how AR-eight eighty two will stack up against allopurinol eight hundred milligrams or febuzostat eighty milligrams, their maximal doses. The authors state that allopurinol is only effective in a percentage of patients but the recent nurse led care study by Michael Dougherty's group has taught us that with proper dose titration, allopurinol can be made to work in almost anyone. And the ongoing VA stopgout study led by Jim O'Dell is comparing allopurinol and febuzestat in about nine hundred patients. And that study should provide us with additional information about just how good these two drugs are at lowering serum urate and reducing flares when properly prescribed according to ACR guidelines. The authors of the current study also point out that the use of febuxostat is limited by its black box cardiovascular warning and that's true, but it's also true that that warning is controversial.

And for more on that, I'd refer you to an editorial by Doctor. Arya Abelis and myself in ACR Rheumatology Open in 2019. More importantly, a study to be presented later this week will provide accumulating evidence about febuxostat's possible cardiovascular safety. Maybe I'll discuss that issue in a later video. So overall, these very early studies suggest that AR-eight eighty two is really effective at lowering serum urate and not grossly toxic in a small group of people.

Of course, we need to remember that a similar URAT1 inhibitor that was highly effective, lisinirad was approved but only at a low dose and along with a urate lowering agent because of associated creatinine rises. And that low dose wasn't potent enough to convince rheumatologists to embrace it So it went off the market. We'll need to see whether AR-eight eighty two avoids these problems. A new urate lowering agent with a different profile would be really welcome. Will AR-eight eighty two be that drug?

Let's stay tuned for phase 2B. And keep tuning into RheumNow for more reports and videos. Thanks for watching. I'll see you next time.

Hi, I'm David Liu, rheumatologist from Melbourne Australia reporting again for roomnow.com from ACR twenty twenty, the virtual conference. One of the of the abstracts which has really shaken things up, of course, is about COVID and about COVID and anti phospholipid antibodies presented in, the plenary session, really addressing a lot about the talk about thrombosis and COVID. There's been a lot of talk in even in the lay media about this. There's been series of patients with, COVID patients with positive anti phospholipid antibodies. And some of these quite severe COVID patients do appear to have a catastrophic anti phospholipid syndrome type picture.

So, what these investigators did, led by, doctor Kuo and, with Jason in Jason Knight's group, looked at one hundred and seventy two consecutive hospitalized patients and had a look at a series of different anti phospholipid antibodies, conventional ones, non criteria ones, saw that over half of them had positive anti phospholipid antibodies. Now the strongest association is actually with anti PSPT, which is non criteria antibody, which usually gets picked up as part of the lupus anticoagulant section. But also, it was notable that anti cardiolipin IgM also had a strong association. But more than that, the presence of anti phospholipid antibodies was associated with real functional impairment, reduced oxygenation, associated with increased calprotectin levels. And in a disease where otosis is so important, we saw it was associated with increased NET formation and NET release.

Finally, they took those anti phospholipid antibodies from the COVID patients, introduced them to mice, and formed thrombosis as well. So they're functional. They're definitely functional. So this has got enormous implications. I think every time we think that COVID and rheumatology don't meet, they do and they were increasingly getting that sense.

But really, what is the future as we see potentially another wave of COVID in the Northern Hemisphere? What's this going to mean in terms of anti phospholipid type syndromes in our COVID patients? For more on this and everything else to do with ACI twenty twenty, head along to roomnow.com.

Hello, I am Doctor. Jonathan Cave from the University of Massachusetts Medical School in Worcester here at the ACR Convergence twenty twenty. Well, I'm really in my office at home, having spent the past two and a half days looking at the absolutely fantastic sessions that have been presented virtually by the American College of Rheumatology. I miss the in person interactions that we have at the annual scientific meeting, but with the ability to zoom in and see other people virtually and watch the presentations from the comfort of my own home. I've been enjoying this meeting and hope that you have too.

I'm gonna focus today on presentation fourteen forty five, an abstract presented at the third plenary session by Doctor. Vijay Joshua from the Rheumatology Unit at the Karolinska Institute in Stockholm, Sweden. He talked about citrulline reactive B cells present in the lungs of patients at risk for and with early untreated rheumatoid arthritis. Interstitial lung disease and rheumatoid arthritis seems to be a theme at this meeting with a number of abstracts, posters and oral presentations about interstitial lung disease in patients with rheumatoid arthritis. On Friday, we saw the presentations by Jeffrey Sparks from the Brigham Women's Hospital in Boston, Massachusetts, where he talked about the increased prevalence of interstitial lung disease among older rheumatoid arthritis patients, where about five percent of them were found to have interstitial lung disease.

He also talked about the fine specificity of anti citrullinated antibodies to predict interstitial lung disease, especially antibodies against citrullinated fibrillin. Now, the citrulline reactive B cells have been identified in synovial tissue, synovial fluid from patients with rheumatoid arthritis. And interstitial lung disease has been noted both in patients with rheumatoid arthritis and also in patients at risk for rheumatoid arthritis. In the studies of the etiology of rheumatoid arthritis or SERA longitudinal cohort, which is comprised of first degree relatives of probands with rheumatoid arthritis, who also have anti CCP antibodies, they found that there was an increased prevalence of pulmonary abnormalities in seropositive individuals without arthritis, both by spirometry and high resolution chest CT scanning. They found that airway abnormalities were detected in seventy six percent of autoantibody positive subjects, but only thirty three percent of autoantibody negative controls.

These included bronchial wall thickening, bronchiectasis, central lobular opacities and air trapping. These data were published in 2012 by Demorell and colleagues in arthritis and rheumatology. They also identified rheumatoid arthritis related auto antibodies in the sputum of these individuals at risk for rheumatoid arthritis or with early rheumatoid arthritis. They obtained simultaneous serum and sputum samples from 21 healthy controls, forty nine at risk subjects without inflammatory arthritis, twenty three of whom were seronegative and twenty six seropositive, and then fourteen patients with seropositive rheumatoid arthritis of less than one year duration. They tested paired samples for anti CCP antibodies, rheumatoid factor, and total immunoglobulin G, M and A.

They found at least one autoantibody in the sputum of thirty nine percent of the at risk seronegative subjects, sixty five percent of the at risk seropositive subjects, and eighty six percent of subjects with early rheumatoid arthritis. The rate of positivity for anti CCP antibodies and the median number of autoantibodies was higher in sputum than in serum, suggesting that rheumatoid arthritis related auto antibodies may be generated or sequestered in the lung in at risk individuals or individuals with early disease. These data were published by Willis and colleagues in arthritis rheumatology in 2013. Now, given that background, the question is, what is producing these antisitrolated peptide antibodies in the lungs of patients at risk for or with early untreated rheumatoid arthritis? There have been anti citrullated antibody reactive cells identified in the lungs of rheumatoid arthritis patients in ectopic lymphoid structures, and in bronchial biopsies of ACPA positive rheumatoid arthritis patients compared to ACPA negative rheumatoid arthritis patients.

The aim of this study by Doctor. Joshua and colleagues was to look for citrulline reactive B cells in the lungs of individuals at risk for and with early untreated rheumatoid arthritis. Now these citrulline reactive B cells have previously been identified in synovial fluid, but not in bronchial alveolar lavage fluid from patients with early untreated rheumatoid arthritis or at risk for the disease. To look for this, they identified four at risk subjects who fulfilled the twenty ten ACR ULAr criteria, I'm sorry, who did not fulfill the ACR ULAr criteria, but who had musculoskeletal symptoms and were on no anti rheumatic drug therapy. They found patients who fulfilled the ACR UR criteria who were either ACPA positive, three individuals, or five individuals who were ACPA negative, all with symptom duration of less than one year.

And they performed bronchoscopy on these individuals, bronchial alveolar lavage, and obtained cells. They identified, they isolated and sorted the CD19 positive B cells, and then they analyzed the sequence from these individual cells for heavy and light chain variable region, amplifying these, and then transfecting the genes for the heavy chain and light chain into HEK293F cells. They then screened these cells, and they first found that there was a higher proportion of CD19 positive B cells in APA positive individuals, both at risk for rheumatoid arthritis and with early rheumatoid arthritis. When they looked for these cells, they found that by identifying cells that expressed immunoglobulin on their surface with mutations at end glycosylation sites or high variable gene mutations. This selected for ACPA cells or cells that were likely to be producing ACPA, and they found that there were two patients at risk for rheumatoid arthritis, and three seropositive patients with early untreated rheumatoid arthritis who had B cells that had ACPA on their surface.

And they then created monoclonal antibodies, or produced monoclonal antibodies from these lymphocytes. And they found that the specificity of these antibodies were for a number of different citrullated proteins, citrullated fibrinogen, and citrullated vimentin, and citrullated filagrin. Two of the subjects had B cells that made anti filigrain antibodies, and these are the antibodies that Sparks and colleagues identified as being predictive, perhaps for interstitial lung disease in patients with rheumatoid arthritis. They found that these monoclonal antisitronated peptide antibodies cross reacted to acetylated and carbamylated antigens, as has been found for ACPAs in patients with established rheumatoid arthritis. They then looked for functional characteristics of these ACPAs, and they activated neutrophils with Ionophore and found that several of these ACPAs bound to activated neutrophils, but not to non activated neutrophils, perhaps contributing to NETosis.

They also found that by challenging synovial fibroblasts, they were able to induce fibroblast migration with two of the four ACPAs that were produced from these patients' B cells. They also found that two of the four ACPAs promoted osteoclastogenesis when they incubated the ACPAs with macrophages in the presence of M CSF and RANK ligand, they were able to differentiate the macrophages into osteoclasts with ACPAs from two of these patients. So their findings were, for the first time, demonstrating that there were citrulline reactive B cells present in the lungs of early untreated rheumatoid arthritis, as well as patients at risk for developing rheumatoid arthritis. The ACPAs identified in the lung were similar in properties with high variable region mutations and mutations in Fab glycosylation to ACPAs from synovial B cells from patients with established rheumatoid arthritis. They found that these ACPAs cross reacted to acetylated and carbamylated antigens, and that there were variable functional properties binding to activated neutrophils, promoting fibroblast migration, and macrophage differentiation into osteoclasts.

So interestingly, B cells are present in patients with early untreated rheumatoid arthritis at risk for developing rheumatoid arthritis, which probably produce the ACPAs that have been identified in sputum and in saliva from these individuals in earlier studies. The specificity of some of these antibodies is for the citrullinated filigrin, which is similar to what Jeff Sparks and colleagues have identified as a risk factor for interstitial lung disease in patients with rheumatoid arthritis. And there are functional characteristics of these antibodies that may contribute to the pathophysiology of interstitial lung disease with fibroblast migration, neutrophil activation, resulting from these antisiphonated antibodies. So the story of interstitial lung disease in rheumatoid arthritis and at risk for patients for rheumatoid arthritis continues to develop. It looks as if the lung is the alpha and the omega of rheumatoid arthritis, where the earliest features of rheumatoid arthritis may originate in the lung, and interstitial lung disease may be an extra articular complication in established rheumatoid arthritis, leading to morbidity, cancer, and mortality in some patients with rheumatoid arthritis.

So here is a wonderful abstract presented from the Karolinska Institute number 1445, which demonstrates that the lung is the alpha and omega of rheumatoid arthritis. I'm Jonathan Kaye. For more information about this and other abstracts, please join us on RheumNow. And I look forward to seeing you again with our rheumatoid arthritis faculty panel tonight, highlighting the various rheumatoid arthritis abstracts from day three, Sunday, November 8 at ACR Convergence twenty twenty. I'm Jonathan Kaye.