Minimizing Steroids in Lupus Sponsored by AstraZeneca Medical Affairs Nov 01, 2024 Save

Thank you so much for joining us today as we discuss the need to minimize steroid use in patients with systemic lupus erythematosus and clinical perspectives on how to do this. This discussion is sponsored by AstraZeneca Medical Affairs and is intended for healthcare providers. Both speakers have been compensated for their time. My name is Doctor. Liana Wise from the University of Southern California Keck School of Medicine, and I'm an assistant professor of medicine in the Division of Medicine and affiliated with Los Angeles General Medical Center.

I am joined by Doctor. Michelle Petrie, who will introduce herself.

I'm from Johns Hopkins University, where I've run the Lupus Center for the last thirty six years, and I'm the principal investigator of the Hopkins Lupus Cohort, a longitudinal study of outcomes in lupus.

Thank you for joining us today, Doctor. Petrie. I'd like to talk a little bit about the UR recommendations, were recently updated in 2023. One of the key updates in this UR recommendation is the prompt initiation of treatments for lupus that ideally aim at doris remission or LLDAS, which we'll talk about in a minute. This is based particularly on the fact that both remission and LLDAS have been extensively validated and proven to reduce the risk for damage and other adverse events in patients with SLE or lupus.

Studying these outcomes in patients with lupus has been a focus of yours throughout the years. Can you comment on this further?

We don't use the SRI four and the BICLA in clinic, even though those are the FDA accepted outcomes in our clinical trials. So the reason LLDAS and DORS remission are useful treat to targets is that they actually define low or virtually no activity, but also require that the prednisone dose be low. So let's first take LLDAS, Lupus Low Disease Activity State, developed by the Asia Pacific Consortium. I studied it in our lupus cohort. Now, in LLDAS, disease activity is low, which means that SLE disease activity has to be four or less.

On the Physician Global Assessment, it must be mild, one or less. There can't be anything new that's flaring. There can't be any major organ involvement, like renal or CNS. And the prednisone requirement is seven point five mg or less. Now, if my patients could stay in this state for 50% or more of their visits, they had a fifty percent reduction in permanent later organ damage.

Organ damage is always defined using the SLIC ACR damage index. And important kinds of organ damage were reduced, like myocardial infarction and end stage kidney disease. DORIS remission is stricter because, obviously, remission should mean no disease activity. There's a little wiggle room, though. The physician global assessment must be less than 0.5, where one is mild.

The sleep A must be zero. And now the prednisone requirement is stricter. It's five milligrams or less. Now, yes, the person can be on immunosuppressive therapy, biologics, and of course hydroxychloroquine. And so, of the different remission definitions, the one that is more clinically useful is remission on treatment or ROT for short.

Now, when we studied this in our cohort, on average, the median time to reach remission was one point eight years. That doesn't sound so bad, but it's the second part that's bad. The median duration of remission was three months, which means people would enter remission but then flare and come out of it. So that's not very useful. Right?

We need durability of remission. We particularly studied risk factors for not being able to reach remission. No surprise, if you started out with very high activity and needed a lot of treatment, it's going to take a long time to reach a remission. Some of the other things just make intuitive sense. It's harder for our African American patients and patients with hematologic lupus, as well as our patients with active serologies, like low complement and high anti DNA.

Great. Thank you so much. And I think that these ideas that are borrowed from other rheumatic diseases make sense for our lupus patients, especially when we think about all the new treatment modalities we have out there. Going back to this idea of LLDAS and remission, though, and bringing this back to the clinical setting for the everyday rheumatologists, with the formal ULAR recommendations, do you think these universal concepts can be put into play in the clinical setting? Are these reasonable targets for the everyday rheumatologists to aim for?

I think LLDAS is very reasonable. I think remission is much tougher with our current armamentarium. But there's a little space in between, isn't there? Because I think that five milligram goal, which is now incorporated into the EULAR 2023 guidelines, could make LLDAS a little bit stricter. I think it's fun listening to patients, isn't it?

My patients come in and they say to me, doctor Petrie, you've been my doctor for years. When are you gonna put me in remission? And I sometimes, like a good politician, have to change the subject a little bit to say that my goal is to have the lupus under good control on medications which are well tolerated.

I think that's going to be a great segue. Taking the patient's perspective and looking to see how they understand their disease activity, how they understand their treatment regimen is a major cornerstone of therapy. I'd like to jump back to the ULAAR 2023 guidelines though before we move on. One of the key updates from 2019 was reducing the steroid dose, the prednisone dose or oral prednisone equivalents from seven point five to five milligrams a day or less or even withdrawn if possible. Can you comment on why that was a big deal?

Well, I was on the committee, and this was really a unanimous decision that it was time to update the 2019 guidelines that said seven point five was acceptable. It's just not. By the way, not even five milligrams is acceptable. But maybe five milligrams is the best we can reasonably accomplish right now. So I thought the EULAR management guidelines were incredibly brave, not only to make this new standard for prednisone, but also at the same time to make it very clear that the way to achieve this is often going to be earlier introduction of immunosuppressive drugs and or biologics.

And not requiring a step, you know, not requiring that someone fail multiple immunosuppressive drugs before you go on to a biologic. I think this is going to embolden rheumatologists now. This is an awful disease with frequently awful outcomes. We can be more aggressive.

Can you highlight some of your data in particularly that drives home the risks of steroids?

Reliance on prednisone as a maintenance therapy is a major issue in lupus management. And this is because fifteen years after the diagnosis of lupus, Gladman and the Toronto group showed that eighty percent of the permanent organ damage was directly or indirectly due to prednisone. So one of the most important studies we did in the cohort was with a wonderful biostatistician named Mae Famer. And she was able to do longitudinal regression adjusting for confounding for disease activity because, of course, there was a reason I was prescribing the prednisone. And that was the study that showed the clear cutoff at five milligrams.

If the maintenance dose was six milligrams or higher, there was a fifty percent increase in permanent later organ damage. Now, we then went on and looked very carefully at that seven point five milligram cutoff, the part that's in LL DAS. And we did that with Cox proportional hazards analyses. And we found that if there was a one milligram increase in prednisone, it led to a three percent increase in permanent organ damage. Very easy to use in clinic, isn't it?

So if you've increased the prednisone by ten milligrams, you've just increased the risk of permanent organ damage thirty percent. And we did find that that prednisone seven point five cut off was important for cardiovascular events. They are not just due to lupus activity or traditional cardiovascular risk factors. In another analysis, we found a dose response. At ten milligrams of prednisone, cardiovascular events go up 2.4 fold.

At twenty milligrams, they go up five fold. But we looked at other outcomes too. And I wanted to particularly comment on bridging, because I think often we say, well, we're just gonna use prednisone as a bridge until the immunosuppressive drugs kick in. But bridging can be dangerous. So we found for osteonecrosis, I still call it avascular necrosis, more than twenty milligrams for one month or more was enough to statistically increase the risk of avascular necrosis.

And although we now separate type one inflammatory manifestations of lupus from type two non inflammatory things like chronic pain, fatigue, depression, we found a prednisone tie in with depression. So if the prednisone dose ever gets to twenty milligrams or more, there's an increase that is statistically significant in later depression. But, by the way, this is not just a lupus story. So I think a real key study is one from the Swedish population. So this is from their population registry.

Anybody who got five milligrams or more of prednisolone for more than twenty one days, and that doubled mortality. At the highest levels, the causes of death which stood out were sepsis. Well, nobody's surprised about that. But also pulmonary emboli because prednisone has a prothrombotic effect.

I think that all drives home the point very well. Prednisone is necessary at times, but the less, I think, long term clearly is better. And we have many good options for our patients now. We need to start that conversation sooner. So I think bringing that back to the clinic, bringing that back to our clinical rheumatologists, how could we address some of the challenges in tapering prednisone and also hitting LLDAS in remission for our patients?

How do you look at this when you have a patient in front of you, and you're trying to treat the patient well, getting the prednisone off, and also trying to meet LLDAS in remission?

I think one difference between how physicians approach chronic disease and patients is that physicians dwell on long term results, and patients focus on how they're feeling today. So, I think we have to educate on the long term problems from prednisone, so that patients will understand where we're coming from. And we also have to be very careful because when we're talking about prednisone use, we mean for those type one inflammatory lupus manifestations. Patients think that everything that happens to them must be from active lupus and won't understand, unless we take the time to talk about it, that their Type two symptoms, like the fatigue, the pain, will not respond to prednisone or lupus medications. And as I discussed, some of these will get worse on prednisone, not better.

So we don't want the patient thinking that they need to be on prednisone for type two manifestations. Those require a different approach. The bottom line is, TAPR is not going to be successful if the patient already has some disease activity that is noticeable to them, meaning rash or joints or pleurisy, something like that. We must get those under control before we start a prednisone taper. A prednisone taper will never work if the patient's not adherent to their background medications like their hydroxychloroquine, they're immunosuppressive, and or they're biologic.

So I do think it's very important to have the adherents talk early when we first meet the patient and to repeat it. I really like the comment that a former Surgeon General made that no medicine will work if the patient doesn't take it.

Agree with all of that. If the medication stays in the pillbox in the cabinet, nothing's going to happen. It's not going to do anything. And I think a lot of times it comes down to multiple conversations over multiple visits. It's not usually something that's going to happen at the first visit or the second visit.

And at least from my discussion with patients and research, I think it is education that needs to happen at the level of the patient and highly individualized. I think prednisone is pretty ubiquitous, and that maybe gives it a safety profile that is not deserved. We see it given out for asthma and allergies. And I think a lot of patients think that it's relatively safe. Do you think rheumatologists should do a more aggressive job of explaining the safety profile?

Do you think that's something we can improve upon?

Well, yes, of course. You know, there are not enough hours in the day for everything we want to teach our patients so they can be our equal partner. They'll understand where we're coming from. But I think also there's a control issue. I know that some of my patients stockpile prednisone because they want to be able to take it without consulting us.

And I think, you know, that can be dangerous. It's the patient, for example, who will say, well, I had four or five flares over the last month. And immediately, I'm gonna ask them, what do you mean by flare? Because it's probably unlikely those were lupus manifestation flares. They may have been fluctuation in their type two symptoms.

So we all need to speak the same language. We need to listen to the patient. They need to be taught adequately by us so they understand the lupus terminology.

Right. And I think along the lines of language is also education, making sure they understand the time and place for immunosuppressants and biologics, and how those are actually more targeted for their disease specifically rather than using prednisone that's just kind of a blanket, let's put out the fire everywhere with a lot of side effects. So I think, again, coming back to language, education, individualizing for the patient is very, very key. I like to encourage my patients, hey, I'm giving you a lower dose of prednisone. This is the two point five dose or whatever it is.

Please throw out the rest of your bottles. They might not always listen to that, but at least I'm telling them that. But I do realize, yes, sometimes patients stockpile and we want to encourage them not to do that. So even though we have a lot of recommendations about getting prednisone to lower than five milligrams, we don't have a lot of data on how to do that in clinical practice. There's no clear guidelines as to this is exactly how you taper in your patients.

This is going to be a very individualized journey. Can you share some of your clinical guidance as to how you'd recommend tapering for patients?

Well, let's start with data. So there is a systematic review and meta analysis that was done by Gee and colleagues. And it showed something that I hope is self evident, that, yes, some patients will flare when we taper their prednisone. And so in that meta analysis, it was twenty four percent of patients who were tapered flared, and it was a one point three eight increase over the group that did not. And, again, you know, we have to make sure the patient is adherent to their background medications, but a FLAIR on prednisone taper is not the end of the world.

It means that we need to increase their background medication so the next time we taper, we're more likely to be successful. It was really driven home to me that prominent rheumatologists in the lupus field had patients on prednisone who didn't necessarily need to be on it. This goes way back to the PRASTERO randomized clinical trials. Half the patients who were enrolled because they were supposedly necessarily on prednisone were able to be tapered without flaring. So we won't be successful all of the time, but we will be successful the majority of the time, provided we follow those rules about making sure the activity is under control.

We start and the patient is adherent.

Are there any particular comments or ways that you advise your patients as you taper prednisone other than compliance to other medications?

Well, I like buzzwords, you know, my sound bites. But this one, I have to give credit to Doctor. Ruiz Aristorsa, who in an editorial said that the take home message on prednisone taper was to taper rapidly, but to withdraw slowly. And I thought, yes, those are words of wisdom. So if the patient is up sixty milligrams and their disease is under control, let's go down to forty right away.

If they're on forty and they're under control, let's go down to twenty right away. But then you kinda like slow things down a little bit. And when they're on five milligrams, maybe you're only gonna reduce by one milligram a month. Because when you get down to those low doses and you're tapering, a one milligram reduction is like a 20% reduction. And you don't want the patient to have too much prednisone withdrawal.

That's like the aching kind of symptoms. And you sure don't want to have a patient suddenly have adrenal insufficiency problems. So everyone will remember forever, taper rapidly, but withdraw slowly.

Thank you for that. I would say, generally speaking, a theme or an undercurrent that's coming out here is just good patient clinician communication and education. And again, I don't think this is going to happen all in one or two visits. I think this is something that has to occur with every visit over time. And I know it's much easier said than done when you have only a twenty minute visit or less.

So I think some major things that are coming out here are, we know we want to get patients on low doses of prednisone. We know we want to consider using other steroid sparing therapies, getting our patients to less than five milligrams of prednisone, if not off of prednisone, into that state of LLDAS or remission. And we really want to individualize patient treatment plans. This is important. We want to get to those low disease activity states to prevent flares and prevent organ damage.

But overall, I think more data is needed. We need some practical guidance for our patients and for the clinicians who treat them. Doctor. Petrie, do you have any other last thoughts about tapering prednisone, clinical pearls you'd want to share about doing this when you have a patient looking at you in the eye and saying, Doctor. Petrie, I think I'm nearly in remission.

I'm on a little bit of prednisone. Any last words of wisdom?

I think the most important thing is some patients are reluctant. We need to listen to them. This could be a patient who had had an organ threatening or life threatening flare and just doesn't wanna take a chance on it happening again. We may need to hold their hand. We we may need to give them that confidence that we're gonna do it very carefully and respond immediately if they do flare.

But I think the most important message for the rheumatologist is sometimes management guidelines come out, and you never even bother to read them. You know, there's maybe the committee care, but nobody else does. I think the UR twenty twenty three guidelines are so important. I think they're going to change our field. Remember that the five milligram rule is there, but also the guidance statement that to achieve that, you will often need to introduce immunosuppressive and or biologic treatment early, and that you're not required to fail multiple steps before you get to biologics.

I think that's the kind of confidence that we need to give rheumatologists.

That's great. Thank you for that. I think from working with my patients here in my faculty practice, and actually at county hospital as well, I think visualizing their lupus activity and also medication side effects has gone a long way. Just turning the computer screen around to them, letting them see the trends of their complements over time or their double stranded DNA, even though they may not understand that biochemically, I think seeing this value is low, this value is high, these are blood counts that are low or normal, goes a long way with helping them understand this is where you've been, this is where I want you. I think that helps drive the disease home and brings them into being a partner for their care.

Similarly, there's a lot of good graphics out now that show side effects from steroids. And I think when you describe what avascular necrosis or osteonecrosis is, that is a huge first step. And then actually showing what a cushionoid person is and a graphic also brings that home as well. So that's just one thing I've tried to do is show these are the short term side effects of steroids versus long term side effects. I think I'm a visual person.

I kind of presume some of my patients are visual people as well. And that has helped me explain to my patients the medications we have now are so well targeted. We have medications that are going to help you get off of these steroids, hopefully avoid some of these side effects short and long term. Let's start to explore what those options are. So there are things out there that we can use.

We don't have to rely on prednisone ten milligrams anymore. And I think you've really driven home why we can address these with our patients earlier rather than later and not be ignoring or in doubt about the EULAR guidelines. Thank you, Doctor. Petrie, for all those remarks. I'm going to summarize what we talked about today in this podcast.

I really want to drive home the idea of LLDAS and remission as our treatment goals for taking care of patients with lupus. These are treatment goals that are possible to achieve, and they are associated with better long term outcomes for our patients, less damage and less mortality, and we want this for our patients with lupus. We want to minimize prednisone use. This is apparent in the EULAR recommendations, and we can do this with minimizing the prednisone and introducing more targeted therapies for our patients. We've also discussed better patient and clinician education on the risks and benefits of prednisone use and now we have new therapies such as biologics for helping our patients get off of prednisone.

Overall, for treatment landscape, we do need to have more data and more guidance on how to taper and withdraw prednisone in clinical practice. Yes, there's some data there, but we need a more individualized approach and more information on how to tailor this to meet our individual patient needs. Doctor. Petrie, thank you so much for joining us today.

Thank you.

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