Individualized Care in the Management of Patients With Lupus Nephritis
In this video, James Matera, DO, discusses a patient with a malar rash, diffuse polyarticular arthritis, and abnormal renal function laboratory test results. He includes insights into the shared decision-making process in selecting the most effective treatment agent for this patient. This is part one of a two-part series.
Additional Resources:
- Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021;397(10289):2070-2080. doi:10.1016/S0140-6736(21)00578-X
- Saxena A, Ginzler EM, Gibson K, et al. Safety and efficacy of long-term voclosporin treatment for lupus nephritis in the Phase 3 AURORA 2 Clinical Trial. Arthritis Rheumatol. 2024;76(1):59-67. doi:10.1002/art.42657
- Furie R, Rovin BH, Houssiau F, et al. Safety and efficacy of belimumab in patients with lupus nephritis: open-label extension of BLISS-LN study. Clin J Am Soc Nephrol. 2022;17(11):1620-1630. doi:10.2215/CJN.02520322
- Kidney Disease: Improving Global Outcomes (KDIGO) Lupus Nephritis Work Group. KDIGO 2024 Clinical Practice Guideline for the management of LUPUS NEPHRITIS. Kidney Int. 2024;105(1S):S1-S69. doi:https://doi.org/10.1016/j.kint.2023.09.002
Watch part two of this two-part series on patients with lupus nephritis here.
TRANSCRIPTION:
James Matera, DO: Good afternoon. This is Dr James Matra. I am a nephrologist and the Chief Medical Officer at Central State Medical Center, part of Atlantic Health System. We're in Freehold, New Jersey. And today we're going to do a couple of videos regarding lupus nephritis. I'm going to do this through case presentations and show how we approach treatment for these patients.
The very first one I'm going to start with is a 30-year-old African American female who presented to the renal clinic with a three-month history of a malar rash, diffuse polyarticular arthritis, and abnormal renal function labs. She was seen initially by her primary care physician, and there she reported these new onset issues. Upon getting some blood work done, she had some significant abnormalities, including a creatinine of 1.9 and a urinalysis that showed 4+ proteinuria and 2+ hematuria. Subsequently, because of her arthralgia, she was started on nonsteroidal anti-inflammatory agents for about two weeks. And then upon return to her primary care physician, several things happened. Number one, she had a little bit of worsening of her renal function with a creatinine that was now up to 2.1, and interestingly enough, no improvement in her symptoms of arthritis and arthralgias with the nonsteroidals. So, at that time, further laboratory testing was done, which showed that she had a markedly positive ANA and an anti-double-stranded DNA. And at that time, the primary care physician chose to refer her to a rheumatologist. The nonsteroidals were stopped, which is always a good thing with the renal function. And they did a 24-hour urine, which showed that her protein excretion was over six grams in a 24-hour period.
So, this is a woman who has some significant renal function abnormalities in association with what appears to be lupus. So at the visit with the rheumatologist, she was diagnosed with systemic lupus erythematosis and was started at that time on hydroxychloroquine. It was suggested because of renal abnormalities that a kidney biopsy be done. That's when she was referred to me. So this is a typical presentation that we see often in a patient who's suspicious or has been diagnosed with lupus. And then we start to look at issues with the kidneys, such as lupus nephritis. So when we look at this, we know that the incidences of lupus nephritis in any lupus patient can range from about 20 to 60% once they're diagnosed. And there is a predilection for certain demographic types. For instance, Asians, African Americans, people from the Caribbean nations, and also Hispanics tend to have a higher incidence of lupus nephritis.
Also, younger patients. When they're diagnosed at a younger age, they tend to have more aggressive lupus nephritis than someone who's diagnosed perhaps in their late to early thirties, or so. So these are things that we always want to pay attention to as we start to determine the diagnosis and then how we're going to treat this patient. So, due to this patient's history and the rapid progression of her renal disease, she agreed to a percutaneous renal biopsy, which we performed. And during that time, it came back that she had a stage 4 lupus nephritis. And in our second presentation, I'll go into a little bit more about that, but you also had 25% crescents, which is a bad sign of acuity. And when we look at different things on a biopsy, I really want to determine if this is an acute, type of lupus nephritis or a more chronic type. The latter would predispose itself to not responding to therapy. So she had a very high acuity index and a low chronicity index. So that really bodes well for potential treatment.
Now we're faced with a young woman who has rapidly progressing renal disease affecting her kidneys, and she's at substantial risk if we don't treat her. So we must start to do some decision-making. And what are our options and what are our goals for therapy? So number one is we want to try to lower the inflammatory risk that she's at right now and try to stabilize or even reverse some of the adverse effects that we're seeing with her kidneys, especially in lieu of the fact that she has a very active case and not a lot of interstitial fibrosis or atrophy, which would indicate more of a chronic disease. We want to look at why we're doing these things, and actually just published now are what's called the 2024 KDIGO or Kidney Disease in Improving Global Outcomes just came out at the end of last year with some guidelines for how we would treat lupus nephritis and other kidney diseases in 2024.
The basic tenant is when we're looking at a patient like this, to reduce inflammation, corticosteroids have to be in our armamentarium, and then everything else is in conjunction. We know, though that steroids alone don't often lead to a very good outcome, and I'll explain a little bit more about that in a minute. So, for a class 4 patient, we want to use steroids and either mycophenolate or CellCept, which has become a big proponent recently, or low-dose cyclophosphamide. And I'll get into the pros and cons of that. There is a monoclonal antibody called Belimumab, which has gained interest over the last few years. Now remember, these are, again, in addition to our corticosteroids, and for people who can't tolerate that, we would try something like a calcineurin inhibitor. The two that we know of are tacrolimus, which we use primarily in transplants, and a new agent called voclosporin, which can also have a positive effect on lupus.
When we're looking at which regimen to choose here, we want to balance the risks, benefits, and adverse effects of the medication and the best possible outcome that we can have for this patient. So despite steroids being the mainstay of therapy dating back to the 1960s, that's been good, but there's been no impactful improvement in long-term outcomes. So steroids do taper or attenuate the acute, but it has not, they have not been shown to be alone capable of reducing chronic kidney disease. So that's why we always have to use another agent. So the advent of combination therapies started to improve the outcomes of lupus nephritis. In the past, this consisted of high-dose cyclophosphamide, which led to improved outcomes in chronic kidney disease. However, there's a lot of toxicity associated with cyclophosphamide, and that adds things like bladder cancer, infertility, especially in a young woman, and often profound and significant immune suppression in leukopenia, which can limit the therapy.
Back when I started practice, that was the mainstay of therapy. But towards the early 2000s, we started to see MMF or mycophenolate come into play as a potential agent for reducing lupus. And MMF initially started as an adjunct for transplant patients, and then it was tried in a multitude of kidney diseases as well because of some, uh, less toxicity. So we would look at studies from the mid-2000s, 2012 to about 2016, they found that the use of mycophenolate, which is an oral agent, had equal efficacy to the cyclophosphamide, but also had a reduction in adverse effects. And who wouldn't want that for our patient? So this combination has become the focus of much of lupus nephritis recently. I'll talk briefly about a couple of the other things we talked about. So again, with the advent of transplant, we started to get away from cyclosporine in the 80s to tacrolimus, which proved to be a little bit better and was used, but now a second-generation calcineurin inhibitor named voclosporin has been added.
There's a big study called the AURORA Study, which was published in 2019, which showed that response rates were higher in patients who took voclosporin. And again, this is in addition to usually MMF and steroids as well. So it's not a sole therapy, but they found that at both 24 and 52 weeks compared to placebo, there was a lot better improvement in those who took voclosporin. Study AURORA 2, which was just published last year, also showed that it seems to stabilize renal function as well. Long-term outcomes, however, are sparse in this. So it's definitely there as a potential when we look at the immune system. In another way, we know that B-cell activation and accelerated activity play a big part in the inflammatory component.
A human monoclonal antibody named belimumab has been accepted way back in 2011 as a potential adjunct for lupus. When we look at a study published in the New England Journal, which was called the BLISS Study, we find that in over 440 patients followed for a two-year period, so a long period, Belimumab showed superiority and efficacy in response compared with the placebo. So, as you can see, we have a lot of choices for our patient here, and we want to make the best decisions. We must always keep in mind that we want to have shared decision-making. The patient is very important in this. We want to understand the social determinants of health. Again, in an African American patient, we may be looking at more adverse effects down the road, and we want to take the future consideration before we make any decisions. We cannot forget that when making decisions, the initial choice must take on a personalized component. This is not cookbook medicine.
We have to adapt to everything that we want to do for our patient. We want to balance so many things. We want to know the short-term efficacy, especially in this patient, we want to try to stem the tide of acute kidney injury. But we also have to remember the cost, quality of life, long-term efficacy, which may not be proven in some of these drugs, the adherence to the therapy, and also how long and how many adverse effects are we willing to accept, if you will. So one consideration can be that while the calcineurin inhibitors like tacrolimus and voclosporin may have an improvement, sometimes when you stop those medicines, particularly tacrolimus, you have a rebound or a flare. So, these are all things that we have to put into our basket when we're making a decision. While steroids are not known to be the best long-term outcome, they are essential in the early phases.
And as an adjunct to what we're talking about here, they're going to be your best friend in trying to reduce inflammation right off the bat. However, you're going to get more bang for your buck, but long term, you're going to have more adverse outcomes. So let's go back to our patient, and I'll tell you how we chose to proceed with this patient. So, my first thought was, again, to try to stem the tide. She already has a GFR that's on the lower side. She has a progression of her chronic kidney disease. So, I chose intravenous methylprednisolone as a pulse dose over three days. I used 1000mg/day, and at the same time, I did choose to start her on mycophenolate, and I started at 1g/twice a day, which is pretty standard for the regimen. You can go up to 1.5g/ twice a day.
But usually, I start at one gram, taper up if I need to, or taper down based on side effects. After she had the pulse methylprednisolone, I started her on prednisone and I chose an alternate-day regimen, 1mg/kg every other day. And I set up a, not aggressive, but about a 3-to-4-month taper of her steroids to get her down to the lowest dose. So, why did I choose this regimen for her, given the fact that I've given you others? Well, I think this is important when we make decisions in practice, I chose this because MMF or Mycophenolate has data for the short-term efficacy that is equal to cyclophosphamide, but yet fewer adverse effects. I think that's an important decision point. Most of our patients who get started on MMF are going to have GI side effects, and there is a lower dose that you can use to try to minimize those.
In this case, I did not think that that was going to be a good choice because I really wanted to limit the inflammation as much as possible. So, the combination of MMF and corticosteroids was my choice. MMF does seem to transcend some of the racial and ethnic considerations that we have in our patients. A few studies have shown a response, although not statistically significant in African Americans, but it was significant in patients like Hispanic patients that have at least as good of an efficacy and a decreased amount of inflammation in those early stages. Interestingly enough, in Asian patients that initial response tended to favor cyclophosphamide. But again, you have to weigh the weigh the risks and benefits of that. Also, the fact that MMF, we don't have gonadal suppression.
So, fertility in a 30-year-old is still important, although that brings up the prospect of how a patient who has significant lupus, whether or not we want to advocate for pregnancy. Also, the hematological malignancies appear to be fewer with MMF. So, based on this, even though I know they may have a higher infection rate, I feel I can monitor that, which is the reason for that decision-making. The key take-home point here is lupus nephritis therapy, especially early on, and depending on the class needs to be individualized, we must take into account all of these drugs and what they expect and what we want to see for our outcomes when making those choices. I will tell you that after 3 months of this regimen and following after 6 months, the patient did well, but did not go into a complete remission.
A complete remission would be the complete dissolution of protein. But what we did see was a decrease from about six grams of protein to about one and a half, and the renal function stabilized. It didn't revert back to normal, but our estimated GFR when we started the therapy was 39. It's now 48. So I think we have a good start to this patient maintenance therapy will be very important. And one of the important things about MMF is we don't know how long we treat patients. I usually treat them over a 2-to-3-year period of time, reassessing as we go, and then a decision point on whether to taper or not. So I hope this gave you some good insight into this particular patient with acute kidney injury, and I look forward to our, uh, next presentation on lupus nephritis. Thanks again.