TNR Journal Club Dr Artie Kavanaugh Save

Hi, everyone. Welcome to Tuesday night rheumatology. This week, it's not grand rounds. It's journal club with Artie Cavanaugh from UCSD. Hey, Artie.

Hey, Jack. Glad glad to be here.

Yep. Wherever we are in the ethernet, you from San Diego, me from my office in Dallas. And you know, three four hundred of our best friends watching us and they're gonna join in the conversation. Folks, we're gonna get to Arty's journal article in a minute. And, but I wanna start off with a few items that we can discuss.

But when we do get to Arty's presentation, feel free to ask questions while we may, and we're gonna be talking about lupus and the use of steroids going forward. And that should be the bulk of your questions. But if you wanna ask us about tomorrow's weather in Wichita, we could take a stab at it, know, no reason to do that. So for that, you're gonna use the Q and A button on the bottom, not the chat button. Don't raise your hand, I'm not paying attention to it.

But we will get your questions and go through as many as we can in the last half hour. Artie, I wanna start off with, one of the reasons why we're here is, you know, life has changed, education has become difficult. You're at a major university with a major teaching program. How has education changed and how are you educating the fellows at UCSD?

Well, it's certainly a difficult time. And I think, as, Alan Matsumoto said, a couple of weeks ago on RheumNow, it's something that's a skill set we're learning. And we've gone, of course, I think as everybody has to virtual grand rounds, which actually don't they weren't pretty good. It's it's sure feels not as good as sitting there with people, but the grand rounds part of it seems good. I think the the clinics are taking a bit of a hit because there's a little bit fewer patients and because at the start we were really distant from each other.

Boy, you sure, it's hard to learn in that atmosphere. We have, I think a lot of traditional teaching clinics do, we have a big room and the attendings are there and the fellows come in and we talk about patients and say, Hey, what do you think about, you know, Hey, look at this x-ray. We're starting to get a little bit more back into that, trying to social distance while being close enough to each other to get that sort of camaraderie, which I think is an important part of this apprenticeship that is rheumatology education. We're heading back toward there. We certainly encourage the fellows to take advantage of all the resources.

The ACR put together a teaching program that has been very well received by the fellows. We still talk about the newest journal articles and what's coming out. So I think it's a scramble, but I think we're doing it and I think everybody else is probably doing the same.

So I know you to be a voracious reader and consumer of data and information, and you do all that while you're in the high skies traveling to wherever your next lecture is or meeting. That's where you get a lot of work done. Now, since you're working from home, has it changed how you read and cover the journals?

Well, in a way though, in a way, of course, it has. I mean, it's different universe but the good part about being on a plane was that you're alone, you had time where people weren't really bugging you and now with so much time there are large parts of the day where now whether it's reading journals or cleaning out the file cabinet or doing other things, there is a lot of time. And so I think that has replaced it. I keep up with the journals as good as I did when I was taking them on a plane. It was really the going to work part.

That was what got into interfere with the journal reading.

So we have a few reports this week, including today, two new reports about IL-six, and that they might work in patients with not necessarily cytokine storm, but in severe patients with the COVID-nineteen infection. These are in the JAMA open network publication. And then we had an early report from the VA center about hydroxychloroquine and another report about chloroquine having a higher death rate. And all of these are basically early reports, almost preprints, or really even news headlines. One that I wrote about today was from a French newspaper, and the author said, We have an obligation to put this stuff out there.

It's ethical for us to do this. We're gonna get it published, but we're putting our data out now. One hundred and twenty nine patients treated with tocilizumab. It looked like they did better if they were on tocilizumab than not on tocilizumab. But the idea is, I'm gonna bring up a quote from one of the editorialists who wrote, Amidst the torrent of data that's coming out right now, seems like the half life of information is making this really, really difficult.

So, you know, is it right to be reporting on these, you know, studies that are almost fully done? A lot of them actually are, they're interim analyses. And we're getting almost like a preprint. Is that right to put it out there, or should we be holding back and saying, I'm not believing it until I see the real study?

Yeah, it's a difficult one. I read on RheumNow, I read those reports, including the French one, and exactly as you said, they framed it in an ethical standpoint and said, it's too important. We can't not have this data out. But before instead, it it has a danger of causing more harm than good. So I think things are being rushed a little bit.

You see chloroquine was the savior, now it's the devil, then it's the savior maybe for a couple of people. Of course, same with the IL-six inhibitors, it makes a lot of sense that they could work. Premature data, I don't know that that necessarily helps us.

Yeah, I, you know, I think that's, it's like the days when you really can't get the results of how to treat inflammatory myositis. The best you can do is some kind of either claims data analysis or database analysis. You know, they're not proof of principle. They're hypothesis generating and help you to lean. But unless you have nothing else to lean on, it's the best you can do.

And that right now is the best we can do. Let's get to today's journal article. All right, go ahead.

But you know, things come and go in medicine. Remember magnesium sulfate, as a therapy. You get old like us, prednisone, you know, it's either saving sepsis or killing sepsis and then it's saving it and then things come back and forth hormone replacement. So these these high publicity anecdotes which have not been methodologically shaken out, they they're not the strongest data. And that's where that's the kind of data that gets overturned.

Okay. Yeah. We still are heavily reliant on real journal articles from real journals to give us our best guidance. Speaking of journal articles, this is our article for today. It's ARD.

The title of it is withdrawal of low dose prednisone SLE patients with a clinically quiescent disease for more than one year, randomized clinical trial by Matthijn Alexis et al. I'm going to turn the screen over to Arti. Actually, I'm going to be controlling the screen, and Arti's going to be narrating the slides as we go forward. So let's do that. Let me see.

Which one do I wanna show? I got too many open slides. Alright. Not that one. Oh, this is the one we want.

There we go. Alright. Here As we go,

you're, as you're getting the slides ready, Jack, let me take a little commercial, tangent here, which I wouldn't normally do, but I swear, hand to God, fifteen minutes ago, was cleaning out some old, files, and I am it's a mixture. You know, stuff that you you've saved over the years receipts, pay stubs, certifications, evaluations from 2006 and in that file, and I said, you know, if it wasn't fifteen minutes before the show I wouldn't have probably said anything about it but I found this. Ask the experts and look at that handsome young purple lad there. This is this is John J. Cush right there back in the day.

So I'm saving this bad boy. But it's amazing the stuff that you have in your files that you haven't looked at for a number of years.

So bonfire fire cell.

So speaking of old things, prednisone. Prednisone, it's the therapy that's defined rheumatology for more than half a century now and we're still arguing about what the most proper place of it is. This is an abstract that was presented at EULAR and now it's just been published in the Annals of Rheumatoid Disease, the withdrawal of low dose prednisone in lupus patients. Think prednisone, I always say it's the secret of rheumatologists. If you ask a rheumatologist how many of your lupus patients take prednisone chronically, we know the answer is not supposed to be a lot.

We know that we're supposed to get people off prednisone. That's what we're supposed to do. But if you look at our charts, it's probably sixty-seventy percent of people. I remember Jack and I were in the lupus clinic in UT Southwestern in Dallas and someone asked, well, what do you do with your prednisone? I said, we taper it.

This is how we taper it. Boom, and they're off, everybody's off by a year. And then you look in the charts and there's a lot of people who are still on it. So I think, you know, many of us would say, well, what is the, what happens especially when people are doing very well because you have the potential risk of the disease acting up versus the toxicity of the steroids. In registries there's sixty, seventy, eighty plus percent of patients who are on low dose prednisone and to me that rings true in that you you have Mrs.

Jones come and you want to get off the prednisone but just not right now because she's got a travel coming, she's going on a cruise, something else is going up, we always do it slower than we should. Our societies tell us we should be getting people off prednisone. The most recent EULAR recommendations in 2019 said withdrawal when possible. This study addresses that in very nice way. It's the cortical loop study.

It's single center. 01/2024 patients with clinically quiescent lupus for twelve months or more who are on five milligrams a day. What is clinically quiescent? Well clinically quiescent is pretty low disease. The SLED I2K less than or equal to four.

The BILAG which covers pretty much every aspect of lupus that could exist had to be a D or an E in all systems except some non significant hematologic manifestations like someone who's always lymphopenic, they could be lymphopenic. The physician global assessment had to be zero, very important. They were on prednisone five milligrams a day. They were allowed to be on other medicines, hydroxychloroquine, acythropin, but that had to be stable for a year or more. Now it is an open label study and they were randomized to either continue the prednisone or to withdraw.

A nice aspect of the study, especially because the people have been on this prednisone a while, is that they gave people hydrocortisone for the first month, twenty milligrams a day, just to make sure that adrenal insufficiency was being flagged as lupus flare. Tested They a few people and found that that was not the case. Primary endpoint of the study was any flare according to the revised Salina Sliedi FLAIR Index over fifty two weeks and it was powered to be a superiority study and with that they ended up saying they needed about just over 120 patients which is what achieved. The patients were evaluated every three months and looking specifically for signs and symptoms consistent with the flare. Treatment could be changed only for occurrence of adverse events related to the medicine or for a flare and they didn't consider isolated serologic changes of flare so changes in the dsDNA, changes in the complements were not considered a flare.

So who did they put in the study? Sixty three people ended up in the open label prednisone withdrawal group, sixty one patients maintained prednisone. The table one of the paper, really very comparable. Achieved, randomization worked, they had very comparable characteristics. The age mean was 42, ninety percent women, long disease, long duration of lupus, so more than twelve years.

They had been quiescent importantly for a long time so sixty two months was the mean duration of clinical quiescence and the mean SalinaSleeti was one point That's virtually as anybody who's used the SLETE eye form knows that basically gets you zero or one thing at all. There's not a lot. What did they have? A lot of patients had arthritis, eighty percent, sixty percent had dermatologic complications of lupus, lupus nephritis in thirty seven percent, serositis in twenty five percent, and then smaller numbers with the cerebritis etc. Low complements twenty eight percent at baseline, high double stranded DNA forty seven percent and both in sixteen percent of patients.

That's an interesting subset of people who, as the Canadians call them, would be clinically quiescent serologically active lupus. Treatment ninety two percent on hydroxychloroquine as you would have guessed in this group of patients with a lot of skin and joint stuff. Mycophenolate thirteen percent, azathioprine an additional three percent, and methotrexate ten percent. The steroids have been used for one hundred and forty one months, so almost twelve years. The data?

What did we learn from this? Well, the people who withdrew the prednisone flared more. Twenty percent of them, seventeen out of sixty three flared compared to seven percent or four out of sixty one which was highly statistically significant. They looked at of course at some secondary endpoints mild or moderate FLAIR was twelve patients versus three which was also statistically significant and severe FLAIR five patients versus one small numbers and not statistically significant. They looked at other definitions of flare using the bi lag, for example, and found very similar results.

Changes in serology were not very predictive of who would flare. They didn't find any difference in the damage index. The flares were very often what the person had had before. The patients had arthritis, many of them, so arthritis was the most common, skin disease the second most common, and glomerulonephritis were three patients of those who flare. There were no predictors of who would flare.

Serologically it didn't predict, duration of steroids didn't predict, concomitant medicines didn't predict, other than the withdrawal of prednisone. The key question in everybody's mind, well what about toxicity? Isn't it better to get off prednisone for considerations of adverse events? Well, they didn't have a lot of adverse events, which again sort of makes sense when you think about the long duration of treatment and the low dose. This is five milligrams that we're looking at.

They looked at the glucocorticoid toxicity index and changes in that index, worsening different between the two groups. In conclusions that they had is I think hard to argue with and that is that withdrawal of low dose prednisone in people who are pretty much rock stable for a long time, five milligrams of prednisone if we withdraw it, they are much more likely to flare and some of them mild to moderate and some of them severe. Now on the oh, and you know what, haven't haven't I haven't been adjusting the slide. So let's see. Let me let me back up.

Rookie mistake here. Let's go to the second slide, which has things I've just been reading off and talking about. This is the setup and said, why should you do this? Next slide shows the baseline characteristics which I read all of these very comparable, recombinant therapies. Then go to the next slide and this is the data slide that shows all the information.

Next slide. Here's the survival plots really showing the stark difference between those who and this is the main outcome, primary outcome, this is probability of flare patients who withdrew, many more of them flared compared to those who did not withdraw. The overall conclusion is that withdrawing low dose prednisone and people who've been on it for a very long time, very stable at that dose, be associated with a flare. An interesting aside also on the next slide as this journal club was posted, Cindy Aronneau reached out and said this is something I did years ago and she sent me an article that she had written, published in the Scandinavian Journal of Rheumatology which, wasn't picked up, should have been referenced by these authors but was not. This was a review they did back in the day, retrospective chart review.

'22 lupus patients who had a flare or two patients had more than one flare. They were in prolonged inactive disease, which was actually defined by use of low dose prednisone, and they were looking at them for CEHU flared, and again, flaring was defined by needing twenty milligrams or more prednisone for three consecutive months. Of these patients, six had major flares, eighteen did not. Again, these are people with active lupus that was treated. Now they're in prolonged inactive disease on very low doses of prednisone, presumably doing very, very well.

What they found is that fewer flares were associated with people who had been on a higher dose for a longer period of time of steroids when they were active. Concomitant azathioprine and hydroxychloroquine. Thirty three percent, use by those who didn't flare, seventeen percent by those who did, Plaquenil as well forty four percent, for people who didn't flare, seventeen percent who did, and interestingly five of the six people who were flaring had tapered off prednisone completely. Remember they were on zero to five most of them were on five when those who tapered to zero had much higher incidence it looks like of having a flare. It looks as if these data really go along with the data that we just said from the analyst rheumatic disease paper and that is that you may want to keep some people on long term prednisone and this they didn't find a dramatic difference in the tapering from the low dose steroids.

A little bit more in those who stayed on prednisone in terms of steroid related adverse events. So I really love that Doctor. AronNow forwarded this and it brought a warm fuzzy to my heart because I've been there when you've done a paper and nobody knows about it. And there was a study that we did at UT Southwestern and Jack remembers this one very well. This was the HELPS trial, the hydroxychloroquine effects on lipoprotein profile.

So we did this study, we set it up, did it all internally, drug and matching placebo from the manufacturer, and got an endocrinologist, Margot Genki, got a nutritionist, got statistician, really kind of putting their time in voluntary basis. It was an investigator initiated study with no money behind it and we did show that in a double blind study that in placebo controlled study that hydroxychloroquine had a significant benefit on decreasing lipoprotein levels. This was published in the Journal of Clinical Rheumatology in 1997. For any of you who want, and actually some investigators from, Quebec reached out to me last year and they found the paper and that just that just brought a tear to my eye, and they they asked me, if I could send them the data and I said I would love to send you the data, let me find the file for that and I did find the file for that on something that was like this, and for those of you who young youngins that are listening, public service announcement, you know when you save something on a computer and you see something that kind of looks like this and you wonder what the hell is that thing?

Well this is, we called them floppy disks. They're not floppy, they're pretty hard, but the ones before this were floppy, the five and a quarter inch. These are three and a half inch, this holds 1.44 megabytes so that's enough for a couple of files and maybe a very very poor quality picture these days. But anyway I tried to send the files, trouble is they were in a program called LOTUS 123 which only Jack knows because Jack was the LOTUS 123 Maven. But anyway, sometimes you do things and it's really nice to get to hear back that somebody paid attention to it years from now.

So bottom line on the next slide, if you will, is that if we go to there the withdrawal of low dose prednisone is in patients who are doing really well on prednisone for a really long time, very low disease activity. You stop that five milligrams of prednisone, they're gonna flare and What do you do with that data? I'm gonna ask Jack this. You could look at it and say, Well, seventy three percent of the patients didn't flare, so why don't you just stop the prednisone and see what it does? And other people may say, Well, why do that?

Why not just keep that low dose prednisone because the toxicity didn't seem to be a real tremendous burden, although it wasn't really assessed over a long period of time. Think very well done, beautifully done study. I really like this. I think it raises questions, and I'd love to hear discussion. Jack, what do you think of it, on this topic?

Well, think we're gonna a lot of questions on this. I wanna remind everyone next week, Glenn Calabrese is gonna do our grand rounds and he's gonna talk about IL-six and health and disease. But this week, it's still just you and I. And I like the paper too, because it fed a belief that I developed over many years of working with you and Peter Lipsky in the lupus clinic. You know, we had an incredible lupus clinic, lots and lots of patients at Parkland.

And I mean, I don't know that I would have done as well managing lupus if I wasn't allowed to keep people on two and a half or five or even seven milligrams of prednisone because it was the great equalizer. Otherwise everybody's in the hospital or we're using more consultants or whatnot. So this boils down to an old mentality, mine mentality of keep them on the prednisone supported by this data. I love this data. But if we had Michelle Petrie here, she'd be ranting about we don't need to use prednisone these days to manage our patients with lupus and that the goal should be steroid free management.

Yes, steroid plays a very important role, but can we really get around to steroid free management of lupus? What do you think?

Well, I think it's interesting you mentioned Michelle, because one of her other passions is hydroxychloroquine is very safe, as, which I believe as well, but these days, especially with the change in how the ophthalmologists consider this, I find myself with getting hydroxychloroquine taken off the plate for some patients because they go to the ophthalmologist and all they hear is blah blah blah blah blah, blind, blah blah blah blah blah and they won't take the medicine anymore. And that's kind of this population. Fifteen years of lupus, doing well with active manifestations in the past that would respond to hydroxychloroquine. So we have, you know, many other options do we have? We do have belimumab available to us now.

We have other options, but you know, you're to give somebody who is this kind of a a patient, like a phenolate, some of them are on it, you give them methotrexate. I think this makes me reevaluate writing at the bottom of every note, taper off prednisone next time.

The question is would these results have looked the same if this was a five year study? So, you know, we learned in RA that, you know, flares have a cumulative effect, right? And we tend to think of as flares and flare management as sort of a knee jerk response, If this, then that, give more steroids, get them over the hump and move on. But there's a cumulative effect to flares in RA, especially when you're relying on one agent only, which is steroids. I don't know that we know that we can afford to take them off and then manage a whole lot more flares.

Yeah, and I think that I agree with you a 100%. I think the same issue with lupus. You take them off five and they flare. Well, maybe they're miserable. And then what do you do?

Then you put them back. Generally, I think a lot of us would go higher and give them 15 or 20 or some people might even say higher to get that capture, get them doing well again, get them back to five. So in the meantime, for some people you're using more steroid than they you would have likely if they had just stayed on the five.

You know, the graph that you showed on the primary endpoint, in that last slide showed that the ones who stayed on steroids still had a flare rate, although it occurred at a lower level and it occurred late, right? Suggesting that over time, there's an inherent propensity for lupus patients to flare, we know that. But that taking them off the steroids just sort of accelerates that and magnifies it a little bit to the point where it looks bad on paper and it could be clinically bothersome to manage. And the question is what do patients want?

Yeah, and as you alluded to, I think you could say the same in rheumatoid arthritis. So we know the studies with the tocilizumab where if you looked at the people who were removed from the steroids very similar data in that a lot of people did well and did fine off the steroids but some of those flared more so than the ones who stayed on the prednisone. And it's the same thing. What is it gonna take to capture them to get them back under control?

All right, so let's go some questions here. Let's do some questions on this before we get to life in Corona. But do you believe in the BILAG scoring system? Does it have any utility for you? I mean, do lupus trials and you understand that the rest of us is like a bunch of nonsense that I don't need to know about.

But do you believe in it or other outcome measures of lupus?

Yeah, I am involved in a lot of lupus studies. Mainly because my colleague, Doctor. Ken Clooney, is a a renowned lupus expert, and so he's often the PI of the study, which means that I will sometimes have to do the BioLag, and it's awful. It's absolutely horrible. Wait, does this go internationally?

Just the above, above into Canada only. Not across The Atlantic.

No, I'm not telling, I'm not saying anything anybody hasn't already said. I mean, it's a, it's the Rube Goldberg assessments. And it has an inherent complexity that pretty much guarantees that you're going to have logical errors, you have to you can't go from you can't go from very severe to gone, You have to go to improving first. And then in a research study it's awful because you're really looking at this a year later and saying, Well, Mrs. Jones, she went from this to this and she didn't go into the in between.

And it is very comprehensive. I think it was a great idea to be able to really look at every potential facet of lupus and look at it in a way that the clinicians it is meaningful. Are you changing therapy based on this manifestation? But it's completely unwieldy, completely, I think, unpractical, never ever used in the clinic. When are they going to move as rheumatoid did to getting something that you really can do in the clinic so that you're not just looking at journal article and looking at an outcome and then saying, Well, I'm not doing that.

RA has kind of gone the other way, and I think lupus has got to go that way. I know a lot of people, including Ken and Cindy Erino, and a lot of people are working on trying to get something and it's difficult because it's a heterogeneous disease and in that way RA is a lot easier. But no, I don't think the BioLag has any use in the clinic.

Okay, so a number of questions on how fast were the steroids tapered? And Tony Russell says surely people who've been on steroids for twelve years, you need to tail down very slowly and not to stop them. So in this study, how are they tapered and what do you really do?

Well, were stopped, from that and they did think about, adrenal insufficiency.

It went from five to zero?

Yeah.

Okay.

Mean, I got the article. I got the article here. Yeah, they tapered them off, and they did give them, twenty milligrams of hydrocortisone for the first month and they did ACTH simulation tests on several people, like a handful of people, for whom there was a question, is this a lupus flare versus adrenal insufficiency? And it was not adrenal insufficiency. To find data on the prednisone withdrawal, you really have to go back a long ways in rheumatological history.

I remember looking this up many years ago as an allergy fellow. It's interesting because of course the history of steroids people use more and more and more. People are feeling fantastic. Then they went for orthopedic surgery to replace the crippled joint that was now holding them back because of the damage, not because the inflammation. They went in the hospital, no one knew about steroid withdrawal and boom that's when they found out about it.

I remember an article from the late 70s that actually looked at acutely stopping people on much higher doses and most people do not go into adrenal insufficiency. It's become standard practice for anesthesiologists to use replacement for anybody who's on certainly higher doses of prednisone. It's interesting though, the practice isn't necessarilyI think somebody on three or four, I've seen the anesthesiologist say, No, they don't need to do that. So I think we worry about the adrenal insufficiency always, but, I don't think it happens nearly as much, so, as we worry about.

So this study was an open label trial, meaning that those who were randomized to continue were okay, we're continuing, status quo. But those who are randomized to withdrawal, do you think that could have biased this? They might have thought themselves either as pioneers or being persecuted. And could that have changed the outcomes here?

Sure. And it's always something you think about an open study. I'm not gonna flare because I'm still on the prednisone. Whereas the other people, you know, you're taking away a medicine that I've been on for a while. I think that's always an issue in rheumatologic diseases.

The most common flares were the same things that they had before, the arthritis and the dermatologic manifestations. But some people had a flare of glomerulonephritis. It would have made that a perfect study if it was blinded with a prednisone placebo.

Andy Weinberger asks, what about the abrupt cessation? Would this study maybe have looked different if we had done a gradual taper as we would normally do, or would it just delay the inevitable?

Impossible to know, that's a great point. What about if you had gotten to, you know, do they need five? And it's interesting because I always look back to the work of Gus Escalante in UT San Antonio, who's done a ton of work on the toxicities of prednisone, looking particularly at the cardiovascular, and to say, What is the safe dose? I'm not sure exactly where I get it from. What I tell patients is three or four.

That you get down to three, I don't think there are side effects of the prednisone, so if you want to stay at three forever, God bless, especially if you're 70 years old and you have other issues going on. What if they had I mean, that's, you know, if you had gone, you know, if you'd gone slowly, what if some of the people went to 2 and a half instead of going to zero? Would two and a half have been in between or would have had the same staying power as the the five milligrams did? I don't you know and I don't think we know this. Those are interesting questions.

I personally I like to get people be below five. I'm happier at four than at five although I have trouble, and I can't support that with a lot of good data, that's for sure.

So again, this isn't, this is sort of mind bending nerve racking puts my brain in a pretzel. What's worse, the chronic toxicity of five milligrams of prednisone, which might be something, who knows, maybe in bad people would be something and maybe in good people wouldn't be so much versus the consequences of players being off. And then in the background you have, you know, mavens like Michelle telling us that we really need to manage our lupus patients more aggressively, and not rely more on steroids. This is again, it's a tough one for rheumatologists. And I think what I hope comes out of this is that everyone rethinks their strategy because being comfortable where you are may not be the right thing for the patient.

Yeah, you say, well, these patients, they should have watched them longer to see if there was less avascular necrosis in the people who discontinued. I find myself telling patients that prednisone is this sneaky drug. You could be on it for a while and pop up with a side effect, unlike most people are gonna have a side effect for a medicine that they have it really early on in the course. But prednisone does things that can sneak up on you. Shingles I didn't see reported specifically for this but low doses of prednisone always pop up as a risk for that.

So if they had followed them longer term, would they have found a difference for some of these, side effects that, you know, besides the bothersome ones about the weight gain and the Cushing white appearance and stuff?

Art So Weinstein points out seventy three percent of patients did not flare after withdrawal. So isn't the issue going to be here that we need to know who those people are and who the people who do flare are. So is there a you think there's a futuristic way of figuring that out? Is it gonna be the proverbial biomarker, which I'm tired of people talking about it and it not showing up like I need it. But, I mean, what do you think?

Can we ever predict who or is this just a taste test? You gotta do it and find it.

It'd be I think for right now, it's it's you know, you have to do it and see if there is a flare up. It'd be awesome if there was a test to do it, but think this discussion highlights one of the things about biomarkers is they have to be really strong and they have to apply to most of the population that you're interested in otherwise you don't care. Talked with Jeff Curtis and we looked at these in more in RA patients, but it has to apply to eighty five plus of the population that you're looking at otherwise you're not gonna do it it's if it's sixtyforty that's not worth that that test isn't gonna help you you're just as good just just trying it and see if it works. Yeah

Do you think that patients on certain regimens like Benlysta or, know, mycophenolate with hydroxychloroquine that are more apt to successfully withdraw or is it the same story, you just have to try?

Well, in this group, were well balanced, so well balanced that they couldn't dissect out that effect. In Cindy's old paper, which, there was, looked at it in a different way, they did find infective concomitant medications and those people on the azathioprine or the Plaquenil flared less than as did those who got treated more aggressively when their disease was active. So this study, because it was randomized, you didn't have that effect because the groups evenly matched for exposure to things. So that is, that's an important question. I think all of us would feel much better tapering the prednisone if they were on something else and able to stay on something else that was helping control their lupus.

Do you think there's any role, Tanya Donne asks, is there any role for using hydrocortisone with prednisone when you want to stop like this to cover adrenal insufficiency or is this just a facet of a clinical trial that has no clinical applicability?

I like it, just as they said to try to dissect out is this a flare. I think that's what we do, we tell our patients, don't we, when we're tapering prednisone. Prednisone like you know be cognizant that you're if you're tapering prednisone and you feel like your get up and go is gone that could be the steroid so maybe hang in there and see and if after a week or so you feel fine then continue the taper whereas if you have a new rash that's not a steroid adrenal insufficiency that's the loop is acting up because she had the rash before and was treated now it's coming back so I warn the patients I don't treat with the cortisone and I don't have a great reason not to accept that. I think that the adrenal insufficiency, it's horrible when it does happen, but it's really infrequent even on people who are chronically on much higher doses.

So to get back your giddy up, what dose of hydrocortisone was used here for the first month? Twenty. Twenty. Okay, interesting. Someone's asking, actually Martina Ziggenbein asked, what do you and I do, with our low dose prednisone long term?

I'll start out, you know, so, low dose prednisone long term, we're talking about lupus patients here specifically. I have always tended to rely on low dose prednisone. So my patients have serious disease, not a little bit of aches and pain and mild skin stuff, but people who have multi organ disease for which I'm going beyond hydroxychloroquine. I usually would strive to keep them, get them down to five or two point five a day and never change it. This paper sort of supports that, but I'm now swayed by some of the other evidence that says that maybe I should try to get them.

So I think that the idea, the protocol that here where people were in remission for six months, or in this case, twelve months, with a low dose activity state, I think that they're asking you, they're inviting you to make a change. And I think it, I'm gonna go back to my fellowship days of thinking like, I should get them off of steroids if I can.

Yeah, think that I would say still, I mean, how can you put in a chart, I'm just gonna keep prednisone forever? You you were always thinking we're gonna taper it. I probably people in in a population such as this, I'd probably chicken out and go to four and then go to three and then go to two thinking that, for, you know, missus Smith, she'll go to zero and do fine, but Mrs. Jones, she flares, if she can't get below three, and for some reason that makes me happier to be at three than at five.

You know, I'm actually much younger than I look. I have my hair colored this way. But, Richard Jones at UAB says, Graciela Alecon would not be ranting. She'd be congratulating us because she's often said during his fellowship and after that it's wrong to remove steroids from people with severe lupus. And a lot of people in the old school, Ted Pinkus was one of them.

I know that I've been one of them. Morris Ziff taught me. And I think that our whole plan was this way. Is this an artifact of aging and that we need a new refresher approach here? Is it better managed lupus going forward?

I think one of the differences for older folks and the younger folks, and I'll admit it readily, younger folks are way better about things like glucocorticoid induced osteoporosis. They're all over that, and if that's in the back of your mind, then the lowest the dose you can get to, the better. I think one of the things that's been, think shouldn't be surprising, I don't think it was surprising, but all the discussion of zoster, particularly around the JAK and IBS, and yet when you look at it, the prednisone is always a confounder in that. You look at, GI perforations, file six inhibitors, prednisone is always in there with that. So I think some people can't get off it, and certainly if they have no other alternatives, but I'd still probably, as Art just said, seventy three percent of the people could taper.

You know, your glass three quarters empty or three quarters full or a quarter empty or a quarter full.

Cindy Weaver asked about do we check, hydroxychloroquine levels in your lupus patients?

I haven't. I know Michelle has published a lot on that and there are very good correlations with levels and outcomes, but I think it's really, it's kind of a sneaky way of checking for compliance isn't it? Don't think there's there's not large genetic variations in how people metabolize not like azathioprine for example so I don't know, I always feel bad. I haven't really, I don't know that I've done it, with hydroxychloroquine because it's sort of a sneaky way to say, I know you're not taking it.

Yeah. And I mean, the numbers on, on lupus noncompliance by hydroxychloroquine are astounding. I mean, as much as eighty percent are noncompliant in some studies and as little as forty percent in most studies are noncompliant. Yeah, you'd be showing that. That's not who we're talking about in this particular study because people were, don't know about their compliance, we do know that they were in a very good state for over a year and compliance wasn't really the question.

In fact, they were doing so well they could stop the steroids and you might have made different studies to actually stop the hydroxychloroquine.

Well, that's another, that's a fascinating point, Jack, that you could raise about this study. I think all of us have the sense, and I think there is some data to support it in some studies in rheumatoid arthritis, when people get in the study, they behave better. And maybe there's better compliance with the ninety two percent of people who are on hydroxychloroquine. And maybe if they were not compliant, then the disparity in flares would have been that much greater. You don't know.

And compliance, other than those bubbles that tell you when they open the pill or some other fancy intrusive method, you're still just asking the patient if they're compliant.

Well, noncompliant patients are actually as smart as the rest of us. They find ways around that to fake the system. One of our, viewers is asking about their, our views on their concerns for low dose steroids being an increased risk factor for infection. My view on that is five milligrams of prednisone probably does not increase your risk of infection unless you're someone who's sick. Someone who's really sick with comorbidities and other reasons to, you know, have an infectious risk, uncontrolled disease, five milligrams of prednisone adds to your risk in my opinion.

But if you're someone's doing really, really well, there's very little evidence that five milligrams or less is going to add to an infectious risk. What do you think?

Yeah, think the problem is we don't have a ton of data and you will find data that says five milligrams and five milligrams is associated with an increased risk of infections. But it's sort of we don't have fine dosing data. Is three safer? Ten does seem to be worse, fifteen definitely seems to be worse. So I don't know if five is clear of any risk of serious infections, but I think that the comorbidities, that can come into medications are likely more important.

So based on this trial, you have someone and you say, oh, well, you know, you've been in remission now for eighteen months and you're on five milligrams of prednisone, four milligrams, would you be stopping it abruptly or would you, what would you do?

I'd probably still go to either four, for people who have a little OCD, have which to have to take four one milligram pills every day as compared to two and a half I would still probably taper I like the every other day taper as a gentle way. That way, to me, you're sorting out the adrenal insufficiency issues and you're really seeing if there is any benefit to them being on a low dose lower than than five. So I'd probably still not just stop abruptly.

Okay. Let me ask you a question about practice. You know, I don't know about you guys but, in our group at UT Southwestern we're talking about the days of returning to normal and what is the clinic gonna look like in June, July, or whenever that's going to be. So one of our viewers asked, how will you be restructuring your clinic? For instance, how much telemedicine, how much face to face visit once we get back to normal business?

And what would you advise people as far as keeping patients and staff safe during that era?

Well, think telemedicine definitely has a place, and I was a skeptic, being a bit of a technophobe, Luddite, as I am, but think it think it has a nice place and I think it's gonna replace a lot of my my charts where someone asks an essay question in five parts and you know like well you don't want to be a bad person not answer them but it takes a very long time that's a televisit that's a telephone visit or a video visit in the future we're also starting to open up again I think a big problem that all of us are gonna have is that, outside of concierge medicine, waiting rooms are not designed for social distancing. They they stack them in like, like the f train in, in our clinic. You certainly can't do that now, so their plan is to bring in new patients and still try to keep the video visits for the return patients for a little while, either till things blow over completely or we sort out a better way to do it so that people aren't sitting packed into a small room.

Yeah, we're making plans for how patients are gonna come in. Very few people in the waiting room, you know, and how you run flow to accommodate that. We're looking at a hybrid where we're going just like you're saying, a certain amount of telemedicine, it's going to naturally fall to those who are good at it and can make it profitable. And those that really want the face to face and wanna bang on a keyboard and touch every joint, then it's gonna work out in the future. But I believe it's gonna be a mixed model as we go forward.

Andres Casano, one of my partners here at Southwestern asked, which do think is worse, the cumulative damage incurred by steroid use or the organ damage incurred by either low activity or flares of activity? Wish, if you had to bet.

Well, problem is for some patients it's A and some patients it's B and that's what you're pointing out, Jack, is we don't know. You sure, if a patient had a flare of glomerulonephritis because she stopped a small dose of prednisone, boy, you'd not be happy with that. But if someone got AVN and you think, Geez, if I could have stopped the prednisone earlier, maybe they wouldn't have gotten it. But we don't know which is which patient. Both things can be possible and both things can be very serious.

Neil Stahl asks about QOD, prednisone dosing. A blast from the past, a goody but oldy. No adrenal suppression, works for me. Am I treating my patient or myself? He thinks the patient, what do you think?

Well, doesn't matter who you're treating, it matters who you're billing. So don't be billing yourself. That just that no, there's no win in that.

No, it makes sense.

No. I I love the every other day. And I guess that if if I if I just have somebody on five when I and I wanna taper them, I'll ask them and say, we can go to four and then three and then two. And sometimes you get that look like, yeah. And so okay, what about five one day, two and a half the next, five, two and a half, five, two and a half, and go to it every other day.

I think there's, I love that regimen.

Yeah. Another question of whether we think this data is generalizable to populations who are on more aggressive therapies like everybody's on mycophenolate. I don't think we learned anything from this particular study about who you can best do this in.

No. They had the the they had did have some people on mycophenolate. I'm gonna pull the numbers to see what the percentage was, like thirteen percent or something like that, that were on that stayed on the the microphenolate. Ten percent were on methotrexate, three percent were on, azathioprine. So there were a small minority of people who were on those.

But, yeah, if if someone was if one hundred percent of the patients were on microphenolate, would you be more successful tapering?

Our buddy David Borenstein in Washington says in 1993 wrote a paper, he provides a citation, American Journal of Medicine, volume 94, page two fifty eight, about the recovery of the HPA axis in RA patients on steroids. Every patient on five milligrams or less had an intact axis. Patients between five and a seven and a half were marginal. Everybody at 10 had a suppressed HP access.

I get to see that paper. See, I know. Another old paper that would, you know, you gotta bring them back from the archives. That's actually great. I wanna see that.

That's very useful information.

1990 You're going to have to look on that floppy disk you were talking about earlier to find that one. Let's see. FB3, that's meant for me. The question is worse. Which is worse prednisone or the disease?

Boy, isn't that like narrowing it down? Thank you, Danny, for asking that question. I think in the end, lupus is worse than prednisone, but boy, they're neck and neck, aren't they? When things are bad.

Yeah, it's individual patient, could be either.

Vivian Sue, New Jersey asks, what do you do with younger patients below age 40 who have osteoporotic fractures on the spine to the long term steroid use, do you push as hard to get them off steroids? Could you do this kind of experiment in people like that?

Well, think it'd be it'd sure be hard in someone with osteoporosis to do anything but have as your goal to get them off the steroids. I think it's, you know, the steroids are so bad for bone health in so many different ways from calcium absorption through vitamin D processing through the effect on the osteoblasts and the osteoclasts. They're bad all the way. Are they this bad? Is there a dose of four or three that would be safe?

We don't know. We're not knowing that in that person, that's such a big risk. I think you really do have to push.

So E. Scopolitos writes, and Bob Dylan wrote how many roads muscle lupus patient walked down before it'll burn out. Do you believe that lupus burns out?

I think that I think that it does. And I think it's interesting in this study, the mean age was forty two ninety percent were women. I think as they go a little longer in the disease duration, when they go through menopause, there's two things. One is the hormonal change of menopause. The other is that many of them will have had lupus now for twenty five-thirty years.

And I think you can see, you certainly can see some activity still, but I think mostly if it does become quiescent. Is it the hormonal change or the burnout, because they've had it for three decades? But I think it does become less active over time.

Is this right that the NNT on this is five to prevent a flare? Seems about right.

Yeah, I'd have to get out my pencil and

Slide roll, pencil, the whole deal. Phillips Theo says that Michelle used an in house whole blood hydroxychloroquine assay. She believes that the commercial assays that are out there are not reliable. And that's one of the problems. I think we should be using more hydroxychloroquine monitoring of blood levels.

The question is, are they available and are they reliable and can use the commercial ones? Well, I think Philip and Michelle are telling us that you gotta be really careful about what you ask for here.

Yeah.

John Goldman says, p is for prednisone or is it for poison? Okay. Do you think the time release chronic steroids are better in lupus or any other condition for that matter? Or is steroid steroid the cheaper the better?

Yeah, I've not been convinced that, I mean, this is older than you and I, which is saying something. How much time in rheumatology has been spent looking for a safer prednisone? The trouble is because the side effects are not actually super common, the biggest ones that we worry about and they take longer times to develop like the osteoporosis we don't know that we have a safer one it'd be great if we did but I'm not convinced that you can really just dissect or dissociate the good effects of prednisone from the the same mechanisms resulting in the toxicity.

Let's see. Joe Flood asks, how much do we worry that even five milligrams of prednisone is at risk for post op infection? Where is the risk benefit ratio? Is mild flares worse than post op or infections.

It's tricky and gets back to the, you know, the individual patient.

Yeah. When Nancy Lane is asking about Denosumab and tapering glucocorticoids. I mean, I think in patients who you have with glucocorticoid induced osteoporosis, they're on denosumab, you obviously are gonna try tapering, but I haven't seen data about the hazards of that, have you?

No. And it would be tough because there's just in those few variables, there's dosing and other issues. So it'd be tricky to be a big study to answer it. The interesting question for sure.

Yeah. Let's see, I think we got maybe a few more questions here. One question that's got nothing to do with this study but has to do with COVID infection. Do you have any comments about our patients on TNF inhibitors or on IL-seventeen inhibitors? Do you think that it's any different than being on hydroxychloroquine or Actemra at this point?

I don't know. Think we're all gonna learn when we see the data, especially from Italy where they've had a lot of cases and a very similar approach to the treatment of patients as we have in The US and in Europe. You're not hearing a lot of really bad outcomes, But, I I I think we will learn we have to see the data. Wouldn't be surprised that it's not a tremendous risk, but we have to see the data.

Okay. Alright. That comes us to the close of the hour. I wanna thank Artie Cavanaugh for joining us and presenting this great paper. Artie, thanks a million.

We're going to get you again to the Journal Club in another few months. Tune in next week, everyone. We're going to have a great session with Len Calvary talking about IL-six and health and disease coming to you from the Cleveland Clinic. So until next week, folks. Take care.

Okay.