Rx Update - Lupus Nephritis Save

Our next speaker is well known as well, Doctor. Michele Petrie from Hopkins and the Hopkins Lupus Clinic. I heard her eight years ago in Dubai say crazy things about lupus, but it's changed. And now there's new rules on lupus. Let's hear what Doctor.

Petrie has to say about new rules on steroids in lupus.

Hi, I'm Michelle Petrie and I'm going to be talking about new steroid rules for lupus. Here are my disclosures. So here's the first subject. We find the metabolic side effects of steroids early, and those are things like the cholesterol going up, diabetes, hypertension. But the permanent organ damage often isn't found until later.

Here you see the organ damage plotted by organ in my African American patients on the left and my Caucasian patients on the right. The letter M stands for Musculoskeletal System and you see that's the most common organ damaged in both races, representing mostly osteoporotic fractures, but also osteonecrosis. Obviously that's almost completely driven by corticosteroids. Now the second most common organ damage is different in the different races. So in African Americans on the left, you see it's R for Renal.

But for Caucasians it's N for Neurologic. And that's mostly represented by strokes. We have proven in this prospective analysis that cardiovascular events, meaning myocardial infarction and stroke, are independently predicted by the prednisone dose. So if the prednisone maintenance dose is ten mg, the risk goes up 2.4 fold, and if the maintenance dose is twenty mg, the risk goes up five fold. These models included not just the disease activity, but also the traditional cardiovascular risk factors.

In another prospective longitudinal analysis, I actually looked at the mean daily prednisone dose. But what's key about this model is that we were able to adjust for confounding by indication because obviously there was a reason I prescribed the prednisone and that was to control the lupus disease activity. If the prednisone dose is kept below six mg, there was only a sixteen percent increase in permanent organ damage. But the minute it got to six mg or more, there was a fifty percent increase. And you can see if the maintenance prednisone dose is above eighteen milligrams, there's over a 2.5 fold increase in later organ damage.

So let's put all this together in a simple way that you and I can apply in clinic with just simple arithmetic. So this looks like a really complicated Cox proportional hazard model. It's the time to organ damage. And you can see there are lots of risk factors, aren't there? Including disease activity.

But I just want you to look at the last line. So if you or I decide to increase prednisone by one milligram, there will be a three percent increase in later organ damage. So you can do this easily in your head. If you decide to increase prednisone by ten milligrams, there will be a 30% increase in later organ damage. I think this is enough to make you feel guilty and enough to look around for a different path forward.

So here's my second subject. Some recommendations are never going to be implemented in real world practice, but the UR 2023 guidelines will be. So the previous UR guidelines for lupus had accepted seven point five milligrams of prednisone as the daily goal. But now that's changed. Now I was on this committee, but I promise you I didn't have to strong-arm the other members.

This is a unanimous recommendation. The maintenance prednisone should be five mg a day or less and if at all possible withdrawn entirely. Now it is permissible to use pulses of intravenous methylprednisolone to control disease activity. And I would actually add to this using an intramuscular triamcinolone injection, as we'll discuss later. Now how are we going to do this?

Obviously we're going to have everybody on hydroxychloroquine, right? But the key here is if we're unable to taper glucocorticoids to five milligrams or less, These guidelines clearly state we need to introduce immunosuppressive or immunomodulatory drugs and or biologics. You see that keyword there? Or? This means you don't have to do a step approach of having the patient fail multiple immunosuppressive drugs before you go to biologics.

If the biologic is the right choice for that patient at that time, you can go directly to it. Now the problem with guidelines, of course, is there are traps. I'm going to call these corticosteroid traps where you and I end up using corticosteroids and there's going to be a consequence for the patient. So the first example is bridging. Now I know a bridge sounds like a good idea, doesn't it?

It sounds like this is the Biden infrastructure plan and there should be bipartisan support. The problem is the way physicians use the term bridging is we mean giving corticosteroids while we're waiting for our best therapy to take effect, meaning an immunosuppressant drug and or a biologic. So how long can you bridge? Well, I hope this will shock you. This is our prospective analysis of osteonecrosis.

And it turns out that just one month of forty or sixty milligrams is enough to increase the risk. Or more than one month, like six weeks, at twenty milligrams. So you cannot get away with bridging for longer than a month at these doses of glucocorticoids. And what about flares? Because that's an obvious trap.

Gosh, I see this happen all the time and I know you do. When your patient goes to the emergency room, they get on an astoundingly high dose of oral corticosteroids and you often don't hear about it until a subsequent follow-up visit when it's too late. So when your patient is facing a flare, and I mean something that's non life threatening, like a skin flare, a joint flare, a serositis flare. We did this randomized trial, randomizing patients to a methylprednisolone dose pack or intramuscular triamcinolone one hundred milligrams. And by one month the great majority of patients were doing fine on either therapy.

So I think it's possible for most flares to treat with a small burst and not to increase the daily oral corticosteroid dose. But my fourth topic is truly real life and my statement here is prednisone a necessary evil? And I'm afraid lupus nephritis is still that major hang up. So here is an analysis recently published by Ali Duarte et al. This is a meta regression of the placebo groups of multiple randomized lupus nephritis trials.

Now first in red, you see that patients who receive pulse methylprednisolone are more likely to achieve a complete renal response at one year. Well, that's an important take home message, isn't it? And remember the UR 2023 guidelines make it clear that pulse methylprednisolone is allowed. But what you see in blue is clearly stated that as the oral prednisone dose goes up, so does the complete renal response at one year. And this includes, by the way, that sixty mg dose, which is pretty much the one mgkg.

But as you know, the UR lupus nephritis guidelines have recommended zero point five mgkg as the top dose, so for most patients, let's say twenty-twenty five mgday with rapid taper. Why can we get away with less oral corticosteroids? Well, if we also follow the ACR lupus nephritis guidelines so we don't use mycophenolate alone. When we first diagnose lupus nephritis, we need to add one of the other FDA approved therapies such as a calcineurin inhibitor or a BAF inhibitor. Now the fifth topic is why patients often say, I don't want to reduce my prednisone.

The last time we tried, I didn't feel well. Or this happened or that happened. So why isn't it always successful? Well, think the first problem is the background therapy better be present and the patient better be taking it. Hydroxychloroquine non adherence or non adherence with our oral immunosuppressive drugs is very frequent.

And here is one study that a whopping twenty nine percent of adolescents and young adults with lupus had undetectable hydroxychloroquine levels. Undetectable! Now even in my patients, we found that fifty percent were subtherapeutic when we first introduced hydroxychloroquine whole blood levels. So I think this is like Reagan when he said, Trust but verify about nuclear weapons. Now what's the worst thing that might happen when you taper prednisone?

And I think the worst thing that's going to happen is a chance of flare. So I think we need to know how often that happens and we need to tell patients as well. So in a systematic review, it happened twenty four percent of the time. But the systematic review was very reassuring that these flares tended to be mild. However, I don't want to hide from you a very large randomized clinical trial of what happened when people were on prednisone five mg a day and were further randomized to taper.

Twenty seven percent had a FLAIR. But, five of the seventeen FLAIR's were severe. So again, if the patient has had severe lupus nephritis, for example, the past, severe thrombocytopenia, severe whatever, I think we need to make sure that the background therapy is sufficiently strong that they are not going to flare as we taper the prednisone. So I wanted to end with how I'm doing. Because the problem when people give talks is often they state what the goals are and they don't make it clear that it's not possible with today's armamentarium to always reach those goals.

So here in green you see my patients that I've been able to taper off prednisone entirely. And then in the very light green, you see the patients that are below five milligrams. So let's say about seventy percent of my patients are reaching the UR goals, but thirteen percent of my patients are on five to seven point four milligrams. Remember those would have reached the twenty nineteen goals, but aren't really at where I want them to be. But then I have eighteen percent of my patients, the ones in red, where their maintenance prednisone dose is above seven point five.

Now, I always think I have a good reason for it, right? But no excuses. I need to do better in those eighteen percent. And maybe I can't do better quite yet. Maybe I can get some of them from ten to nine, for example.

Remember, every one milligram counts. You'll never forget now how easy it is. Every one milligram multiplied by three, that's the increase in permanent organ damage. Thank you very much for your attention.

Hello, ladies and gentlemen. My name is Hans Joachim Anders. I'm a nephrologist from Munich, Germany of the Ludwig Maximilian University, and I'm practicing in lupus and lupus nephritis since many years. So today I was asked to speak a bit about chronic kidney disease in patients with lupus nephritis, and to clarify maybe some misunderstandings in that context. So a patient with lupus nephritis usually comes in with an acute inflammation, the biopsy is done, and when there's decision taken for acute therapy, then this always involves immunosuppressant therapy, and then the patient gets that label SLE, lupus nephritis, and one may not think so much about kidney function up to when kidney function has ended and we have to talk about dialysis transplantation, but there's a misconception here.

Chronic kidney disease doesn't start with the end, it doesn't start when kidney function has ended. Chronic kidney disease starts from the very beginning. So we have in nephrology an institution, it's called KDIGO, that sets global definitions of diseases, and KDIGO already twelve years ago has defined chronic kidney disease as anything that lasts more than three months in the kidney, and we know that lupus nephritis lasts more than three months almost always, and from re biopsy studies, we know very well that almost all patients that had an acute lupus nephritis have irreversible damage no matter how well the treatment was, the patient may undergo complete remission, proteinuria disappear, kidney function seems great, but if a biopsy is being done, we see there is some irreversible damage, and this already fulfills the criteria for chronic kidney disease. So, of course, chronic kidney disease can come in different stages, and there are some people that have mild chronic kidney disease, no doubt, and the risk for all the consequences of chronic kidney disease are low, but there are patients, especially those that have repetitive episodes of lupus nephritis, second flare or relapse three times, four times, where every time something gets lost in the kidney.

So this is what rheumatologists know as damage accrual. So the damage accumulates over time, and obviously every episode of lupus nephritis adds some more damage, and this, at a certain point, also impacts on kidney function. In the beginning, the kidney is able to compensate the function even though some parts got lost, but on the long run, also kidney function will decline, and this is what worries us because that means the kidney won't last anymore as long as it should be, ideally up to the end of life without having any health problems out of that. But if a person has a lupus nephritis episode at age 20 or age 30, it's it's will be not so easy to make sure that the kidney will last another sixty years without ending function because we all lose kidney function as we grow older, and if there was an injury earlier in life, this comes on top of the aging process. So what we have to do for these patients?

Well, we have to inform them to avoid any further damage to the kidney, like toxins, certain drugs that can affect kidney function, that we have to be very careful with the kidney. We should avoid overweight or obesity. Diabetes has to be treated very carefully in case it occurs because diabetes basically increases kidney workload, and those people that have reduced kidney function struggle with such increases in workload. We have to tell young males not to eat protein supplements in the gym, or we have to keep an eye on blood pressure. And there are many things that we can improve to reduce kidney workload, for example, reducing salt in the diet.

This is not the usual thing a rheumatologist does in the lupus clinic, but that's what a nephrologist does in the CKD clinic. So that's why the main message of my short presentation today is go to a nephrologist, also in addition to the rheumatologist, let's have a nephrologist take a look at that and maybe something could be improved to make sure the kidneys last as long as possible. Thank you.

Hello, I'm Nathalie Costeudois Alimeaux from Paris, and I will speak about hydroxychloroquine blood levels and adherence treatment. So, I have no specific conflict of interest.

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patient with a lupus should be on hydroxychloroquine because it prevents SLE flares, it protects against damage including renal, diabetes, somatic events, dyslipidemia, and it has been shown to improve survival with several studies now. Also, maybe it prevents congenital heart block. So, it is recommended by all the treat to target ACR, EULA and the European Renal Association. And my friend, Fred Ocho, also says that that's a good reflect of how the patients are well treated, the percentage of patients on HEQ in a cohort. It is also highly recommended during pregnancy and lactation.

Regarding side effects, the main one is this one, the severe ophthalmological toxicity, which is very rare with one out of one thousand patients. You should never see that, providing you follow the recommendation to screen for ophthalmological toxicity. And you will stop the treatment way before the real clinical toxicity. You can also have discoloration on the skin, which is not so nice. That's why some patients will stop it.

And you have cardiomyopathy and myopathy, which are quite rare, and I won't speak about it for the sake of time. So, hydroxychloroquine has an excellent benefit risk ratio in patients with lupus. And an additional benefit, it's long half life with the availability of its blood assay. You can measure it in the blood. And you will have levels that vary widely among individuals, as it's true also for many other drugs.

We have measured ETQ levels in patients and some other teams also. And we found that mean blood levels range between 801,000 nanograms per milliliter in patients treated with two tablets a day. And we found that low levels are associated with higher SLE activity and are predictive of flares. We also note that at very low levels, you can take the threshold you want, but when it's very low, it means that the patients are severely nonadjuvant, meaning they don't take their treatment at all or just from time to time. And it represents seven to twenty nine percent of the patients, depending on the series.

This leads us to advance to treatment. So, it's defined by the WHO at the degree to which the person's behaviour corresponds with the grid recommendations from the healthcare provider. So, adherence is about treatment, but also to recommendations of diet, physical exercise and non smoking, and as you can guess, that's difficult for some patients. Valuating nonadvanced is very difficult. And if you look at the studies, the non advanced ranges between three and eighty five percent.

And with such a wide range, you can guess that there are some issues. Indeed, it depends on the methods used, subjective like self questionnaires, which underestimate non adherence, especially severe, and objective like rates of fulfilling prescription when you compare what is prescribed and what is collected in the pharmacy, And also drug levels which can find out severe non There are two patterns of non adherence indeed, one which is the patient doesn't take anything, it's severe non adherence or just one tablet from time to time, and drug levels are perfect for that, or made non adherence, meaning you forget from time to time and you need other methods to find out that. Here is an example of what a young patient is supposed to take for her lupus with some comorbidities. And of course, you can imagine how hard it is to take this one day, two days, one week, one month, one year. We had a very nice study on non adherence.

This one was on pharmacy refill information with more than ten thousand patients with lupus, and you can see that eighty five percent of them were classified as non adherent. And if you take all these patients, the overall mean proportion of the cohort, meaning what they collected in the pharmacy, represented only forty two percent of what they should have collected. So, you can see that's a huge problem. And here, to show you that there are many consequences and that can be a real issue for our patients, in this SLEC cohort, we measure hydroxychloroquine blood levels at the beginning of the study at inclusion for incidental lupus in six sixty patients. We found out that seven percent were severely nonadjuvant, they did not take their treatment, and we know that it will increase over time to adjust the beginning, and that was associated with SLE flare in the next year with early damage until three years and with five year mortality, so just by measuring HEQ levels, you can discover a very severe non adherence that you would not have known usually, and you can try to improve that and to see with your patient what can be done.

So, that's the main benefits of measuring HQ in our patients. That's it. I hope you enjoyed this talk and are interested by non aviolence. And I'll tell you bye bye.

Hi, everybody. My name is Maria DeLera from UC San Francisco, and I'm joined today by my friend and colleague, Michelle Petrie from Johns Hopkins. And we are going to discuss some of the concepts in the 2024 ACR guideline for the screening, treatment, management of lupus nephritis. Thanks for joining us. Point number one, we're going to talk about screening.

The ACR guideline recommends that in patients with SLE without known kidney disease, we recommend screening for proteinuria at least every six to twelve months or when the patient is experiencing an extra renal failure. Michelle, what do you think about this recommendation?

Maria, I don't think it goes far enough because within twelve months, someone who's developed diffuse proliferative lupus nephritis may already be in renal failure. So what we've done in the Accelerated Medicines Partnership is to emphasize the high risk patient. So that's the non Caucasian patient, the patient with low complement or anti DNA, or if someone's able to measure it, C1Q. So I think every chance we get is the best answer about when to screen for lupus nephritis.

And Michelle, I have to agree with you on this. I think that screening is left to the clinical judgment of the treating clinician. And I think that most of us who take care of lupus patients will screen our patients for the onset of lupus nephritis when we have them in clinical care. And I think the voting panel here wanted to give some flexibility for those patients who are so mild, they might be in clinical remission for twenty years, not have any of the high risk characteristics that you mentioned, maybe only come in to see you once a year and that's when you would screen them. But I think your point is very well taken that in patients with those high risk features that have had any activity in the recent past, we would want to screen them more often.

I think that's a very good point. I think your points Michelle are very well taken. And I think that in patients who have high risk clinical characteristics, as you mentioned, or recent activity, either in various extra renal manifestations, those are people who we're gonna be seeing in the clinic and we would of course want to screen for the possibility of lupus nephritis. Okay, and here is the crux of the guideline. And this introduces the concept of triple immunosuppressive therapy.

And we've seen an evolution in the nomenclature for how we think about the treatment of lupus nephritis. We've moved away from these discrete phases of induction and maintenance or initial and subsequent, and now moved on to continuous combination therapy. The term used in the ACR guideline is triple immunosuppressive therapy. And this means glucocorticoids plus two additional immunosuppressive or targeted biologic agents on a background of hydroxychloroquine and inhibitors of the renin angiotensin aldosterone system. And the two options are either a belimumab based regimen or a calcium urine inhibitor based regimen.

And as we all know, we have two FDA approved therapies with belimumab and voclosporin. So Michelle, what is your reaction to this overall guideline recommendation?

I like to rephrase it as mycophenolate plus. And I think the clear message here is that mycophenolate is insufficient on its own for the majority of patients, because only a twenty percent complete renal response is achieved at twelve months. But the part I don't like is calling it triple therapy and including oral prednisone up to forty milligrams. Now, course, we're all aware that the Toronto cohort showed that people who got high dose oral prednisone had higher complete renal response at twelve months. And the Mayo group headed by Ali Duarte did a meta regression showing increased complete renal response with higher oral doses, in fact, to sixty milligrams.

But I want to compliment the voclosporin trial design that limited prednisone to twenty to twenty five milligrams, and still showed double the complete renal response over prednisone alone. I don't think we have to continue to use high dose oral therapies anymore, especially now that the AMP group is trying to push the idea that we need to biopsy before people hit five hundred milligrams. If we can hit people early, why do we need the prednisone? Prednisone?

Agree, and I think that we are moving towards a place where we are using lower and lower doses of glucocorticoids. What I like about this recommendation for glucocorticoids in the guideline is that it's stated as less than or equal to zero point five mgs per kg with a maximum of forty. So to your point, Michelle, the goal is to use as low a dose as possible and then taper in an expedited fashion. And the guideline recommends less than equal to five milligrams a day by six months. Now I think you and I would agree that we would even want a faster taper, but that gives at least some guideline to practicing rheumatologists, nephrologists in terms of how to manage this.

But I agree that we need to move to a point where we can minimize glucocorticoids. And I'm hopeful that that day will come that we will have a substitute for glucocorticoids, something that will act as rapidly and have similar anti inflammatory and immunomodulatory properties. Agreed. Okay, class five. And I know that this can elicit a lot of contention because I think this is a confusing area and an area in which we don't have great data.

So I would love to hear your opinion, Michelle. This is how the guideline came out. In patients with active newly diagnosed or FLAIR of pure class five LN with proteinuria of less than one gram, we conditionally recommend treatment with glucocorticoids and or immunosuppressive therapy over no immunosuppressive therapy alone. And then the second point is in patients that have proteinuria of greater than or equal to one gram, we conditionally recommend treatment with a triple immunosuppressive regimen. And again, that's similar to the class three, class four.

So the differentiation here is that threshold of one gram of proteinuria helping us think about how best to treat. But how do you think about this?

There's something different about class five. For example, the group with class five did the worst in both the belinumab and the voclosporin trials. Class five is not as inflammatory, and it doesn't reach renal failure as quickly as the proliferative group. And for that reason, I don't think that these guidelines fit. And in fact, I think it was somewhat of a shock for many nephrologists and rheumatologists who treat a lot of Class five because we tend not to use steroids.

And I think one of the things we should really take to heart is that old adage, above all, do no harm. So I want us to think in particular about the class five patients who are nephrotic, because this is what class five is known for. And the nephrotic patients are more likely to be hyperlipidemic, hypogammaglobulinemic and hypercoagulable. The hypogammaglobulinemia because we have the patients lose globulins in the urine, and the hypercoagulability because they lose components of their coagulation pathway in the urine. And what does prednisone do?

Well, of course, prednisone makes hyperlipidemia worse, hypercoagulability worse, and of course infection risk higher. So I think it's very possible to treat class five without steroids. And I might have actually favored a comment here that the favored therapy for class five should be the calcineurin inhibitors, which through their podocyte action act quickly to reduce nephrotic syndrome.

I agree on all accounts. And I think some additional points to make here was it's very interesting when we reviewed the literature on class five lupus nephritis, even going back to that original small NIH trial looking at glucocorticoids alone versus glucocorticoids with cyclosporine or glucocorticoids plus cyclophosphamide. There were always glucocorticoids and every trial since then, our large scale phase three trials with belimumab and voclosporin that included pure class five and actually including OMS, which included pure class five. All of those trials included glucocorticoids even with the pure class five. So we didn't have a robust evidence base to help us understand if we could use less amounts or even no glucocorticoids with class five.

And that was one of the major challenges that we faced here. And that is why we ended up keeping in the group of corticoids because we didn't have the data to do otherwise. Two other points I'd love to hear your thoughts on Michelle, because I struggle with this as well. Mean, you and I take care of a lot of these patients and I struggle with this. With class five, as you said, these are patients who often have higher levels of proteinuria than our class three or in class four.

Not always, but often. And what I struggle with is that we know any level of proteinuria is toxic to the renal tubules. And so anything that we can do to bring down that proteinuria more quickly will impact kidney outcome. And that's why I think your point about the calcineurin inhibitor is excellent. I could not agree more that that is an agent that will bring down proteinuria quickly because of the direct action on the podocyte, as you so beautifully stated.

But that's a struggle as well. And then the other thing that's interesting to me, it's intriguing, and this is very close to you because you are doing this work with the AMP, is I seem to recall an abstract that was presented, I want to say two years ago at the ACR, showing that there were myeloid cells in the biopsy of the pure class 5s. So showing us that there may be more inflammation there than we originally thought of with pure class five. I thought that was very intriguing data. I haven't seen that yet in the full publication, but I seem to recall that abstract.

So people can get to class five in two ways. They might have been class five from the get go, but there are other patients who have had lupus nephritis for a while and their initial lupus nephritis was proliferative. And then on a subsequent repeat biopsy, they now have class five. And so I think it makes a big difference. How did you get to the class five?

So I'm assuming that these guidelines are initially going to be for fresh lupus nephritis. I'm not sure if we're always going to know though, exactly how an individual patient got to classify. But yes, the Accelerated Medicines Partnership is working on trying to describe what happens in lupus nephritis. And the early phase may be driven by myeloid cells. And the later phases may be driven by lymphocytes, but it's very complicated.

More to come.

The last thing I'll just mention here, I agree, thank you. The last thing I'll mention here before we get to our last slide is this just, your comments about how glucocorticoids can exacerbate some of the metabolic toxicities that we see with nephrotic syndrome and some of the hypercoagulability that we see with nephrotic syndrome. Such an excellent point. And it makes me think about the potential down the road. This is very early days.

But for agents like the GLP-one receptor agonists being used in coordination with glucocorticoids to mitigate some of those metabolic toxicities for a short period of time until we can get those glucocorticoids off. But your comments stimulated that thought in my brain, again, thinking about the future and where this field is headed. But I agree that we have to try to minimize glucocorticoids at all costs in these patients. Okay, and this brings me to our last slide here. And this recommendation deals with inadequate responders.

And this is how the recommendation is written. In patients of any class of LN who have not achieved at least a partial renal response by six to twelve months, we conditionally recommend escalating treatment to triple therapy if initial treatment had been dual therapy, the alternative triple therapy if the initial treatment had been triple therapy, or consideration of adding an anti CD20 agent. Michele, take it away.

So I would rather rephrase this as mycophenolate plus plus So if it was mycophenolate plus belimumab and the patient's not responding, add a calcineur inhibitor. If it was mycophenolate and a calcineurin inhibitor, add belimumab. But where should anti CD twenty fit in? And this is very important because our European colleagues use a lot of anti CD20, but the one they use is rituximab. And I actually think if we're going to bother to do clinical trials, we should pay attention to the results.

And the LUNAR trial did not show sufficient benefit of rituximab to want to continue to use it. But obinutuzumab is an entirely different story. Obinutuzumab was glyco engineered to be a better B cell depleter, that's been proven. And the phase three trial did show complete renal responses above 40%. But the forest plot in the Obenetuzumab trial showed that it clearly worked best in fresh lupus nephritis.

So I would want to actually rewrite the ACR guidelines, even though they just came out. And so I think we should talk about triple therapy as being mycophenolate plus or minus belimumab plus or minus a calcineurin inhibitor plus or minus obinutuzumab. And make it very clear that if we're going to use an anti CD20, we want to use it early when the patient is most likely to benefit from it. So this is like every guideline, as soon as it's out, it's already behind.

Well said. I agree. And I wish that we had had the Regency trial data when this ACR guideline was being developed. But as you said, we didn't have it. And I think that we will have these data for the next iteration of the guideline.

But I think what you said, Michelle, is spot on that now we have these various options of targeted therapies that have demonstrated efficacy in these large scale trials. And the question is which agent for which patient, which combination of agents for which patient. And this is where we are headed is trying to understand that. And I think the work that you and others are doing with Accelerating Medicines Partnership is going to help us hopefully personalize this approach based upon blood biomarkers, tissue biomarkers, urine biomarkers. But until we have those biomarkers, I think we have to think about our patients holistically and clinically when we decide how to use these therapies.

But it's a challenge, it requires our clinical judgment as we go along. But an exciting time that we have these agents available for us to use.

Yes, and I think the clear take home message is, it can't be mycophenolate alone anymore. And that's been proven by the protocol kidney biopsies that were in Anna Malvar's study, that the activity is actually slow to respond, and chronicity is increasing in the first ten months. So you can't do this step up stuff where you're going to add things later. You have to add something more than Mycophenolate from the very time of the biopsy. Marie, I want to thank you.

I know that you and all the other authors of the guidelines did a tremendous amount of work. And you'll forgive me for rephrasing it as mycophenolate plus.

Well, thank you, Michelle. It's always a pleasure speaking with you and hearing your insights. I think this has been a great discussion and I appreciate all of the audience out there listening to our discussion and please let us know if you have any comments. Thank you.

Hello everyone. I'm Brad Rovan. I'm the Chief of Nephrology at Ohio State University, and I'm coming to you from Columbus, Ohio. I'd like to discuss how a nephrologist like myself manages, patients with lupus nephritis, in our clinic. So one of the things that has impressed me most about patients, with lupus is the multisystem involvement.

So the first thing that, we try to do, here at Ohio State is make a combined clinic with nephrology and rheumatology so that our patients can see both of us at the same time or within the same visit day. We find that this is really helpful in trying assess and manage all of the issues that patients with lupus and lupus nephritis have. Obviously, I focus on the kidney involvement for patients with lupus. And the philosophy of the nephrology side of the clinic is to run the clinic very much like our colleagues in hematology oncology do. That is to say, a great deal of progress has been made in the cancer world, because the physicians who are seeing the patients have taken a proactive role and interest in putting patients into clinical trials to develop novel therapies.

And so using that approach, we've taken the position that we would like to evaluate all patients with lupus, kidney disease, for a potential clinical trial to see if we can move away from the traditional medications and the traditional general way of immunosuppression into much more specific therapies and also therapies that have far fewer side effects. I think one of the big problems with treating patients with lupus nephritis is that many of the medications we use can be quite toxic. And these side effects can be severe enough that even if the patients are doing better on paper, for example, or their laboratories are doing better or their their kidney function is improving. They don't feel well and and we're not really eating our obligations to make the patient really, in my opinion, get back to a normal lifestyle. So, in my clinic, patients are assessed when they come in.

And we do try to see if they would potentially qualify for a clinical trial, and also discuss what clinical trial may be best suited for them. Another sort of philosophy of our practice is to understand the individual patient and what their needs may be, and also push forward this concept of personalized or precision medicine, which is really putting the right drug with the right patient to control their disease in a way that is efficient and safe. So, that overriding philosophy permeates the group that we've created, which is our glomerular diseases group in our nephrology division. And we all do that in our clinics. The other overriding philosophy in our management approach to patients with lupus nephritis is that we want to preserve kidney function because by and large, these are young individuals who have an entire lifetime ahead, and we really want to avoid the need for coming to require kidney transplantation or kidney replacement therapy like dialysis.

And so that's our overarching concern. We do look at a lot of parameters when we're approaching the patients. And yes, most patients will realize that we focus quite a bit on urine protein loss. And that's because that's a biomarker of how the kidney is doing. And we do try and target reducing proteinuria, which will be an important part of every patient's visit.

But that's something that we do in concert with watching kidney function and trying to modulate how the kidney is doing and really to preserve function over time. Our other goals are really to address the overall lifestyle needs of our patients. As I noted before, many of our patients, most in fact, are young women, and lupus is occurring at a particularly important time in their lives. A lot of folks are either in school or they're out in their career, they're developing jobs, they're working on families, and the drugs and the disease really put a damper on all of those things. So one of my goals is to also really try to get to know the patient and what their life goals are.

Many of my patients are concerned, rightly so, as to whether or not they might be able to have children in the future. And so this is a big part of our discussion. It's a little bit risky to become pregnant when you have floridantly active kidney disease. And so we try to counsel our patients that this is indeed our goal for the future, but we have to get the disease under control. We want our patients to be able to develop their careers or finish school.

And so we try to design regimens that work with the patient. Some patients, for example, might not have access to a medical center where you would get intravenous medications. And so for those patients, maybe self injected medications at home subcutaneously or pills would be a more appropriate approach. But I I think I've given you the idea that our our example is to assess where the patient is in their life, what they need to sort of get back to a normal life while having a chronic illness, and then to try to work with the patient and their family, that's very important as well, to provide therapies that will actually get them to where they want to be in their lives. Our ultimate goal, as I noted, is to preserve kidney function over time.

And we are fairly successful at that. There's been a lot of developments of novel therapies for lupus nephritis and we try to offer our patients the cutting edge therapies whenever possible. We also know that sometimes after lupus nephritis, patients are left with chronic damage in their kidney and so, once we're weaning down the immunosuppression to reasonable levels, we know from our other chronic kidney diseases that there are medications and procedures we can sort of do to preserve kidney function outside of immunosuppression. So, we're big proponents on that. We talk about diet.

We talk about salt and protein intake quite a bit. We talk about blood pressure control and how important that is to preserving kidney function. And then we also talk about lifestyle, good eating habits, good weight habits, avoiding smoking. All of these things sort of seem like they're distant perhaps, to the main problem of lupus and lupus nephritis, but all of these things could actually impinge on kidney function. And so I think, again, the idea is to look at the patient holistically and say, what can we do for the kidney in the broader context of the patient's overall health?

And as I said, we do this in partnership with our rheumatology division and those physicians in rheumatology that are interested in lupus. And this is really a great partnership because we can address both the kidney issues as well as the extra renal manifestations of lupus and really try to get our patients back to a normal lifestyle as quickly and as safely as possible.

Hi. I'm Jack Cush reporting to you from Vienna and EULAR twenty twenty five. It's the first day of the meeting. A lot of interesting things. I heard a message several times today and the message being our thinking on steroids and lupus is changing.

One such abstract where that's portrayed is this abstract, OP 59. It was an oral presentation, in a lupus session, presented by, doctor Askenazi with other authors being Ken Colounian and Maria Delara talking about how we treat lupus nephritis patients. This is a reanalysis of data already presented. One study being the ALM study and two other studies, were the AURA LV study and the AURORA-one. In this study, they did a propensity matching, and they compared the ALM study to one hundred and seventy nine patients to one hundred and seventy nine in the ORA LV plus AURORA one study.

And they wanted to look at outcomes, renal outcomes, which is the primary endpoint, but also side effects and whatnot. The main differences were a, in the immunosuppression. The study received either up to three grams per day of mycophenolate or IV cyclophosphamide and a higher dose of steroids starting out at sixty milligrams per day, lowering every two weeks until they got to ten per day, but with, not a lot of success and a lot more overall steroid exposure in the ALM study. That was compared to the ORA LV and the AURORA-one where the patients received, two grams of mycophenolate plus voclosporin, the lower daily dose, plus steroids starting at twenty five milligrams per day, and then decreasing down over sixteen weeks to two point five milligrams a day. That second group, the Oral V or Oral one had less steroid exposure, but also had the addition of the voclosporin.

They called that triple therapy. I don't know if I agree with that. Mycophenolate and voclosporin, that's double therapy. Adding steroids to that, I don't I don't think that we're using enough steroids to consider this to be truly immunosuppressive, but they called it triple, with the third big drug in there being steroids. The end result of this was that, you know, there were more side effects, AEs, in the ALM study than in the other two.

SAEs were the same, serious adverse events were the same. But the AURORA LV and the AURORA one, AURORA LV and AURORA one had urinary renal endpoints and that being a 50% reduction in UPCR and whatnot, and overall had less steroid toxicity. So yeah, it makes sense to use combination immunosuppressors and lupus nephritis. But I think that you're going to hear at this meeting as you get from this particular trial, that limiting steroid use is going to be important in the overall success. And success is not just measured by getting to that renal endpoint, but also how much toxicity you're going to incur along the way.

Anyway, that was an interesting one from EULAR twenty '25. Tune in for more at RheumNow.