ACR20 - Day 4.4 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 at RheumNow reporting on the virtual ACR twenty twenty. Welcome to Washington or wherever we all happen to be. So I'd like to talk about number eighteen twenty five and that's looking at risk factors for antimalarial retinopathy. So between EULAR and ACR there have been a lot of abstracts looking at the safety of antimalarials including not prolonging the QT interval but also in looking at the safety of antimalarials with respect to retinopathy.

There are new guidelines over the last few years that we should dose five milligrams per kilogram per day of actual body weight or less of hydroxychloroquine to decrease retinal toxicity. So this study and I am one of the authors on it so true disclosures. We wanted to look at retinal toxicity and define would it be different in SLE versus other treatments such as rheumatoid arthritis adjusting for confounders? How common is it and is there a dose or a time response? So the first thing was it does appear that comparing other groups of patients that lupus has more retinal toxicity.

Maybe it's adherence, maybe it is because we use it for longer, but when we adjusted for duration of use and dosing and body weight we still found this to be the case. The next thing we wanted to look at was is there a timeframe? So some guidelines recommend that you don't do your eye exams until five years and beyond. In Canada we tend to do annual retinal eye exams with visual field and also often a retinal photograph or a CT of the back of the eye. What was found was that there was virtually no proven retinal toxicity before five years.

So I think that that is still a safe dose. The final thing that we found was that confirmed or suspected dose retinal toxicity was not necessarily increasing with time or dose. There was a hint but when we adjusted it really didn't come out. So there's probably a threshold above five years where some retina are at higher risk than others. The final thing and this has changed my practice is that the patients using Chloroquine instead of hydroxychloroquine routinely dosing at two fifty milligrams once a day had the highest retinal toxicity.

And it was very sobering and fortunately while we were doing this study, there was a shortage of Chloroquine in Canada. It's on permanent back order and that's even before the COVID-nineteen thought of using Chloroquine or Hydroxychloroquine. Therefore I did change all my patients from Chloroquine to Hydroxychloroquine and if their rash, it was often cutaneous lupus features. If the rash was worse, I actually would end up using other background immune suppression. So I will not use Chloroquine long term anymore in any of my patients.

Thanks for listening. This is At Room Now and enjoy the rest of ACR twenty twenty. Thank you.

Hello, I'm Doctor. Jeff Curtis at the University of Alabama at Birmingham. I'm missing you and others in person at the ACR Convergence meeting that's now being held virtual, but I did want to share something with you that caught my eye. It's late breaking abstract L08. It's the results of the FAST trial that compared the cardiovascular safety of febuxostat versus allopurinol for the treatment of gout.

As you're probably well aware, the CARES safety trial reported in 2018 in the New England Journal that the cardiovascular safety of febuxostat for its primary outcome was non inferior to allopurinol. That's the good news. The somewhat concerning news was that two key secondary outcomes that were pre specified, cardiovascular mortality as well as all cause mortality, had a thirty four percent and a twenty two percent, respectively, significant increase compared to allopurinol. The other methods issue that was also a cause for concern was that the dropout rate in the CARES trial was very, very high. It was close to fifty percent, which for a safety trial, some might consider rather unacceptable.

So that's where things stood until the late breaker reported today. Today, we've learned the results of the FAST trial, a pretty equally sized trial of more than 6,000 individuals, and the trial was enriched for those with cardiovascular risk factors. Median follow-up was approximately four years, much like the CARES trial. The event rates were approximately two per one hundred patient years, and the FAST trial reported that febuxostat cardiovascular event rates were numerically lower and statistically non inferior compared to allopurinol. This is quite a contrast with the prior CARES trial.

The study was conducted in The UK and other parts of Europe and was conducted under the aegis of the University of Dundee. It was pharmaceutical funded, but according to the authors, the pharmaceutical company that was the sponsor didn't have direct involvement in the conduct or the execution of the trial, which might give some people additional reassurance about the rigor and the independence of the investigators that ran the trial. So bottom line, I think we have a new trial, very large, and was randomized, controlled, open label with regard to treatment, but blinded with respect to endpoint assessment, which I think is quite consistent with the notion of a large pragmatic trial that I think gives us a very different answer than what we've had heretofore. Namely, febuxostat is probably on equal cardiovascular footing from a safety perspective compared to allopurinol. And I think that gives me and probably most clinicians much more reassurance that we haven't had up to this point that febuxostat won't put people in harm's way with respect to the safety profile and is a very reasonable treatment option for gout, not just to control their gout, but also from a safety perspective, it doesn't have an adverse event profile that's any worse than allopurinol.

Thanks for your interest.

Hi everyone, I'm Jack Cush with RheumNow and I'm here with good friend and past ACR President and Rheumatologist Par Excellence, Doctor. Stanley Cohen. How are you, Stan?

Great, Jack. Thanks for having me.

Yeah, I wanted to bring Stan on because he had a really great presentation, this week at ACR where he was talking about comorbidities and Stan, you were asked to talk about liver disease and RA. Now, no one really thinks of liver disease and RA, but it happens all the time. What was your take as you set out to talk about this?

Well, this was a session on difficult RA cases and, you know, my task was looking at the RA and liver diseases. And as you know, in clinic, both of us deal a lot with the folks who have metabolic syndrome, obese with nonalcoholic fatty liver disease is probably one of the most common dilemmas we have about which therapies to choose. Later this morning, we're going to hear about the new ACR recommendations for pharmacologic treatment. This will be addressed there again. We frequently deal with issues of transaminitis related to our therapies, whether it be handsets or whether it be methotrexate, leflunomide, or even our biologics or targeted synthetic DMARDs.

We rarely see, infectious, diseases such as CMV, which can affect the liver. I've had a few couple cases of amoebic abscess and so forth. And then we have the autoimmune syndromes which rarely occur in RA like primary sclerosing cholangitis, primary biliary cholangitis that can be seen. In North America we infrequently have to deal with patients who have been exposed in the past to hepatitis B. It's a real big problem worldwide and there's a big problem with reactivation of hepatitis B in patients who receive immunomodulators.

So I presented a case of actually one of my associates, who was a lady who came with active rheumatoid arthritis and was found to be hepatitis B, surface antigen, positive and hepatitis core antibody positive without hepatitis B surface antibody. She had very low levels of hepatitis B viral DNA and as per recommendation from the ACR recommendation twenty fifteen, the patient was appropriately sent to a hepatologist who evaluated her with other serology such as hepatitis B E antigen, which was negative, the E antibody was positive. And so this is a chronic hepatitis B carrier. And if this patient is going to receive, immunomodulatory therapy, they may need to be on antiviral therapy. So, the patient was reluctant, she refused and stayed on salicylazate hydroxychloroquine and did not have a good result, as far as managing the RA.

So, the guidelines have been pretty well established, by the American Association of Society of Liver Diseases. Every several years, they update their recommendations. And, you know, clearly for someone with hepatitis B surface antigen positive and core antibody, if they're going to go on target DMARDs to biologics, they need to be on antiviral therapy. If they're core antibody positive with those types of therapies, can generally monitor the patient, check their hepatitis B viral DNA, check their LFTs frequently every three to six months. But if Rituxan is being used, which is one of the drugs that we use frequently these days for vasculitis as well as RA, even if they're just core antibody positive, then they should be on antiviral therapy, and then they may be on antiviral therapy for a year after you discontinue the Rituxan, as well.

So, again, the ACR pharmacologic recommendations to be presented later today, this will also be addressed again.

So the Rituxan's an interesting issue. Certainly the history of Rituxan, you did all the clinical trials developing Rituxan, is that viral reactivation is a real possibility with that drug. But when I looked at this last, patients who are core antibody, first off, Hep B surface antigen positive, they don't go on any of our drugs unless they're on antiviral, too high a risk of reactivation, which is what, you know, the guidelines that you pointed out said. But core antibody positivity meaning they have a resolved infection, but they're B surface antigen negative, there's a lot of leniency there but you're saying with Rituxan no. Are there actually case reports of reactivation in those people when Rituxan is used?

Yes, and I think it's really more in the hematological literature. So, know, and there are multiple therapies. So it's unlikely, and the other thing we've commonly faced in clinic, Jack, is we'll have these false positive hepatitis B core antibodies. People have never had any history of having hepatitis That occurs. It's less likely than it was in the past.

But so I think you just have to be diligent. Know, with a lot of the information we use in rheumatology was taken from, oncology, hematology. So you just want to be careful in those people. And the biggest surprise was this, paper that, from the RISE registry, which showed how little screening was done. And I was shocked in some of the questions we got in the polling is, do I need to screen for hepatitis B before I go on biologic therapy?

And was,

you what do you mean? That's what we do in every patient before we do methotrexate. We check hepatitis B serologies.

Yeah. So again, you're right. There are lot of studies that have shown that before too, that we're not as good as we should be at that. And so everyone check your Hep B, Hep C before you start any of these drugs. But again, the battleground, the one that I think needs more clarification is, either, where there's drug specific risk, most of our drugs, not so much of a risk, when you're B surface antigen negative, core antibody positive, but the literature does show a two percent chance of reactivation of those people.

So you got to watch them, right?

You got to watch them and also the other problem is, you know, if you go off the therapy, you could have this immune reconstitution syndrome where you're longer suppressing the immune system, and then there's a viral DNA around, you get a fulminant hepatitis. That's and I've had one case of that in my forty two years of doing this.

So what are your there are two issues I want to end with. One is what are your guidelines for referral to the hepatologist for further evaluation and management?

Well, it depends on how conservative you are. I mean, you know, certainly we have recommendations for us, but I'm very liberal in my referrals. I feel comfortable having someone looking over my shoulder who's a hepatologist who spends a lot of time doing this. And sometimes they'll be your real partner and they'll assist you and they'll have the patient come back and they'll do the monitoring for you, sometimes they won't. So, you know, again, I think that, bringing another set of eyes to take a look at the situation is always helpful.

Someone's core antibody positive, and I'd like them to really drill down and do other serologies, which I normally don't do, like hepatitis B, antigen, antibody, things of that nature to help better define, what's going on.

So there are two new classes. Obviously, all our drugs can cause liver enzymes and whatnot. Two newer classes in the last newer, last 20. The IL-six inhibitors and the JAK inhibitors where liver enzymes are sometimes an issue. What's your take on that?

Especially, you know, the JAKs now. Is that much of a concern?

Well, first of all, as far as hep B issue with JAKs, all those patients were excluded from clinical trials. So we don't really have any data. But as far as the liver itself, I don't think the JAKs are a major issue, certainly in monotherapy. Most of the LFT elevation with the JAK inhibitors is in combination with methotrexate. So now having said that, if I had someone who has chronic liver disease, drugs that inhibit IL-six may not be my first choice since IL-six is somewhat homeostatic for liver cell integrity.

So if I had alternatives, I would go to alternative therapies.

Excellent. All right. So end with what are you looking forward to seeing on the last day here at ACR?

Well, I'm part of the pharmacologic recommendations that update. Did a little, you know, five minute to how you would use these in a clinic. So I'm looking forward to see, the presentation and how they're going to be received.

Thanks. Warmly, I'm sure. Stan, thank you for your time as always. You're very helpful.

Thank you, Jack.

Hi, I'm David Lu, rheumatologist in Melbourne, Australia reporting for RheumNow for ACR twenty twenty. Just want to tell you a little bit about one of the really interesting abstracts from the plenary session about interstitial lung disease and pregnancy, in particular, rare interstitial lung disease secondary to rheumatic disease. Some really interesting data from Duke, from Megan Claus' group. And it really gets to this question about what to do with these patients, especially when we know that the diseases that cause interstitial lung disease often affect women of childbearing age. Women often want to have children.

But we've always been taught that interstitial lung disease and pregnancy are bad. We know that there are pulmonary changes which can be problematic and the oxygenation can get compromised, but there are circulatory changes as well, and patients with ILD can decompensate really quickly. So the paradigm has always been when you're talking to an ILD patient about pregnancy that you should really talk about considering do they actually want to get pregnant. There And have always been questions about maybe even we should be considering elective terminations to some people. So it's all quite extreme.

We really lacked real world data. Me, Claus's group, have described the biggest cohort so far to date. And they've narrowed it down to the rheumatic disease patients and they've got ninety four babies in that cohort. What's really interesting out of that is looking at the pregnancy, the foetal outcomes and the maternal outcomes. So the foetal outcomes, especially for severe interstitial lung disease, not so good really.

We saw lots of complications in that severe ILD group for interspersers and lots of fetal loss, in fact. In the seven patients from the severe ILD side of things, four of them unfortunately were non live births and there were complications right throughout. What was interesting though was that the maternal outcomes were really good. No deaths, no real complications, only one ICU stay in someone with mild IOD and that was from asthma flare. And so it really speaks to this idea that actually perhaps there's not an enormous amount that's going to be lost from trying to get pregnant or go ahead with pregnancy, that these women actually are safer than themselves and really the risk is a fetal risk.

So I think that's really changed the way I think, and I think that's changed the way a lot of people think. So for that, plenty more on pregnancy in rheumatic diseases and all of what's happening at ACI twenty twenty. Go along to vroomnow.com for our ACI twenty coverage.

Hi, everyone. Coming to you live on RheumNow from ACR Convergence twenty twenty. I hope everyone's having a good virtual conference so far. There continues to be a plethora of spondyloarthritis abstracts I wanted to share and discuss an important but sometimes forgotten population, which is our female patients with axial spondyloarthritis. There are many interesting abstracts, but I wanted to also focus on a very important topic for our young female patients with axSpA and that's pregnancy and pregnancy outcomes.

So the first abstract is abstract fourteen ninety eight, and that was actually an oral presentation by Doctor. Mabler. And this actually involved four prospective cohort studies in Europe. And they looked at pregnancy outcomes and health of children and women with axSpA. They looked at over three hundred, they looked at three twenty eight pregnancies and they actually had some favorable outcomes of the pregnancies.

Three percent had preeclampsia, six to nine percent had gestational diabetes, and preterm birth rates ranged between zero to five percent. And that was actually pretty similar to the WHO general population rate of nine percent in Europe. The next abstract is 1323, and that was a systematic review and meta analysis. Reviewed over 18 studies with over 3,000 women analyzed. There was an increase in both preeclampsia with an odds ratio of one point three and increase in intrauterine growth restriction with an odds ratio of one point one seven.

There is also a statistically significant increase in c sections with NOD's ratio of one point eight five, which I don't think is highly irregular. And there was actually a disease activity variation with actually forty eight percent reporting increased disease activity during pregnancy. Unfortunately, there was not much data on medication use in pregnancy in this meta analysis. I think it's interesting because we tend to think our patients with inflammatory arthritis have an improvement of symptoms during pregnancy. But this review showed that almost fifty percent had increased disease activity.

And the last abstract is abstract thirteen twenty four. And this was another prospective study looking for adverse pregnancy outcomes in two European centers. This included patients with psoriatic arthritis, axSpA, and undifferentiated spondyloarthritis. The most common adverse outcomes was small for gestational age. They did note that inflammatory bowel symptoms and aggressive disease phenotype, which they classified as requiring two or more either conventional or biologic DMARDs and active disease before or during pregnancy increased the risk for adverse outcomes.

However, they didn't find any difference in age or use of steroids. Overall, I think it's, you know, been really nice to see an abundance of data on pregnancy outcomes this year, especially focusing on axSpA, especially so much prospective data because most studies thus far have been very heterogeneous in retrospective. I think a few things we can take away is one, I believe the old adage still maintains, which is healthy mom, healthy baby. Number two, in the prospective data, we're seeing a lot of positive signs in terms of adverse pregnancy outcomes in our female patients with axSpA. And lastly, I think we just need to continue to build more registries and obtain more prospective data, especially given the use and the introduction of newer biologics in this population.

So thank you for tuning in. I hope you continue to follow RheumNow for the latest coverage of ACR Convergence twenty twenty. Again, this is Doctor. Robert Chow and follow me on Twitter at DoctorRBC. Thanks.

Hi, Michael Pellinger here for RheumNow discussing crystal disease reports at the twenty twenty ACR Convergence meeting. So up till now, I've been discussing research presentations about gout. But today I'd like to tell you about a really terrific state of the art talk that I saw on calcium pyrophosphate deposition disease. The talk was given by Doctor. Ann Rosenthal, the Chief of Rheumatology at the Medical College of Wisconsin and one of the great important contributors to the science of this disease.

Doctor. Rosenthal divided her talk into three sections. First was clinical picture, the second was pathogenesis and the third was treatment. In the clinical picture part, she discussed the evolving nomenclature of the disease, the risk factors and triggers including a possible entanglement that I didn't know about between osteoporosis and CPPD and the increasing use of imaging including ultrasound and CT being helpful, MRI not useful at the present time, although stay tuned. She also talked about a joint project of the ACR and EULAR for new classification criteria, should say for classification criteria because we don't have any that I think would tremendously help advance the field.

Most interesting I think though was her discussion of pathophysiology. Doctor. Rosenthal reminded us that the processes of inflammation induced by CPP crystals are quite similar to those we see and are increasingly understanding, in response to gout crystals. But where things differ of course are in the crystals themselves,

how

they get there and how they form. Urate and calcium crystals are very different. It turns out interestingly that cartilage has lots of factors that inhibit mineralization and yet in CPPD deposition still occurs. Now CPPD can be hereditary, sporadic with aging, secondary to metabolic diseases such as magnesium abnormalities and secondary to trauma. But the hereditary form I think has the most to teach us since two genes, one called CCAL1 and the other CCAL2 have been most strongly associated with CPPD and understanding what they do may be a key to understanding a lot of this condition.

The CCAL2 gene encodes the protein named ANK, A N K H, H for human, in mice it's just A N K. ANK is the transporter that moves ATP or pyrophosphate out of chondrocytes and into the extracellular fluid. And in some patients with CPPD, gain of function mutations in ANK therefore result in extracellular excess pyrophosphate which can encounter calcium and form calcium pyrophosphate crystals. Conversely, in experimental models, silencing ANK reduces pyrophosphate in the extracellular space. In contrast, the CCL1 gene turns out to encode osteoprotegerin, the competitive regulator of RANK ligand that is well recognized in the osteoporosis field and this may be an explanation for why osteoporosis and CPPD disease may be linked in some way.

So loss of function mutations lead to decreased osteopetegrin expression and are associated with risk of CPPD. The biology here isn't complete but it looks as though the loss of osteoprotegrin leads to increased numbers of osteoclasts and that some unidentified secretory product of the osteoclasts may then drive the chondrocytes to extrude ATP or pyrophosphate and there you go, you begin to get the risk for crystallization. So these discoveries hold out promise for new treatments for CPPD disease, CPPD. For example, ANK inhibitors could reduce extracellular pyrophosphate and reduce CPPD risk. There are in fact are already examples of weak ANK inhibitors including probenecid that stand as proof of principle that ANK inhibition should be possible.

And strategies to restore osteopetergeron homeostasis could also be a potential strategy. So overall, we all know that CPPD is a slowly progressing disease and honestly, have been times when the science of CPPD has seemed to evolve equally slowly. But thanks to people like Doctor. Rosenthal, progress is ongoing and progress is certain. Tune into RheumNow for more reports on ACR convergence.

Hi, I'm Doctor. Janet Pope. I'm a reporter at RheumNow. My Twitter handle is janetburdeaux. I hope you're enjoying the ACR twenty twenty convergence meeting.

This is a neat abstract. It is number 1466 and it is data from the RISE registry, which is a large U. S. Registry. And the question here was who has more comorbidities, which are now called multi morbidities?

And they looked at patients with osteoarthritis, rheumatoid arthritis, looking at psoriatic arthritis and looking at gout. So the first thing to note was that osteoarthritis patients that at least were seeing rheumatologists had the least amount of comorbidities or multimorbidities. In RA it was just edging out a few more problems than psoriatic arthritis. And gout surprisingly to me had the most comorbidities or multi morbidities. So number one, gout has the most.

Number two, they were a little bit different so that some comorbidities clustered more say with RA and some clustered more with PSA or with gout. And so what is the take home? When I see a patient with gout, I am aware from this meeting of elevated cardiovascular risk. So I think to take a full history and review of systems, even in the days of telemedicine, is important so that we can decrease their multi morbidity problems and help their gout in general. Hope you're enjoying the virtual meeting.

Talk to you and go to AtRoomNow. Thank you. Bye.