Empowering Patients in the Management of Lupus Nephritis

Click here to view video highlights from this interview.

AJMC^®: What measures can be taken to enhance comprehensive screening efforts for the early diagnosis of lupus nephritis in patients who have systemic lupus erythematosus? How do you screen for lupus nephritis in your practice?

WISE: All patients with systemic lupus should be screened fairly frequently for lupus nephritis. I screen all of my patients with a urinalysis and a spot urine protein creatinine ratio on a semifrequent basis, at least every 3 months. I’ll screen patients with risk factors maybe even a little more frequently, maybe like every 2 months or so. These would be patients with risk factors such as ethnic minority patients [(eg, Black or Hispanic individuals)], maybe patients who are a little on the younger side or even [male patients]. All of these individuals have been linked to maybe higher rates of lupus nephritis. But at the bare minimum, for my patients with systemic lupus, I’m screening at least every 3 months with the measures that I mentioned. A urinalysis, spot urine protein to creatinine ratio, and then, of course, we’re looking also at other biochemical profiles that may suggest active nephritis, such as complements, double-stranded DNA. But really the best markers are going to be urine studies at this time.

AJMC: How does the treatment of lupus nephritis influence the overall management of systemic lupus? And how do these considerations affect disease management in your patients?

WISE: The treatment of lupus nephritis will affect the overall management of systemic lupus, because lupus nephritis is 1 of the most severe manifestations of lupus in general and, unfortunately, also 1 of the most common. When I’m looking at a patient with lupus, my thought process immediately goes to whether…they have a history of lupus nephritis or ongoing lupus nephritis. Because I will tailor my treatment to…this patient’s most severe manifestation of their lupus, and then I’ll tailor the treatment to that. There are other severe manifestations of lupus. It’s not that lupus nephritis is the only scary manifestation, but because it is so common, and it is 1 of the more severe end-organ manifestations. If that’s present in a patient or if it’s occurred in the past, I will hone my treatment paradigm into the lupus nephritis pathway. It just helps me tailor the treatment. Of course, I take into consideration the patient’s other complaints, their concerns, but it helps me to focus my treatment modalities onto this 1 specific manifestation, because it is 1 of the most severe manifestations of lupus with very high morbidity and mortality.

AJMC: Describe your approach to the management of lupus nephritis. What key factors do you consider when you’re choosing between the different treatment options (eg, monoclonal antibodies, calcineurin inhibitors) for lupus nephritis?

WISE: My management for lupus nephritis will depend on a couple things. First and foremost, I do want to get a biopsy, and I want to see what class it is. I’ll also take into account the degree of proteinuria that the patient has. I want to also know what therapy they’ve tried in the past for their lupus in general and also for their lupus nephritis. I want to also know other comorbidities that they may have. Each patient with lupus is an individual, and I have to take into account all these things. It’s not going to be a 1- or 2-minute conversation necessarily with the patient, but I think some of the main things I want to think about [to start] are the class and the degree of proteinuria.

From a class perspective, if it’s class III, IV, or V, and they have active proteinuria and hematuria, I want to [throw] on aggressive immunosuppression—going up on steroids and then also adding steroid-sparing agents. This would be anywhere from belimumab, mycophenolate, [or] calcineurin inhibitors [to] some combination of these. A big paradigm in rheumatology in general is how…we spare long-term steroid use. Steroids, of course, are very helpful for controlling acute inflammation, but we don’t want patients on steroids [for the] long term if we can avoid it. We want to control the inflammation acutely, yes—but we want to avoid a lot of the long-term steroid [adverse] effects. A big thought in all autoimmune conditions is how can we use our steroid sparing agents, our disease-modifying antirheumatic drugs (DMARDs) to get patients off of steroids quickly and safely and also control the underlying rheumatic disease—in this case, lupus nephritis.

We do have good options for treating lupus nephritis. I think a big component of treating lupus nephritis nowadays is combination treatment. We’re starting to move away from just using [a] single disease-modifying agent, and we’re realizing that probably the best approach is to use multiple drugs in combination. A backbone of treatment would definitely be to use steroids but not to use them at high doses for very long. We’re also going to be adding hydroxychloroquine, and then there [are] recent studies looking at mycophenolate along with either a calcineurin inhibitor, such as voclosporin, which was FDA approved, or belimumab, [which was] also FDA approved for lupus nephritis.^1,2 There are subtleties in each patient’s case as to which [of these therapies] I’m going to use. If I have a patient with very high proteinuria, I’ll probably be leaning more towards a mycophenolate-voclosporin combination. If I have a patient with proteinuria on the lower side and a lot of articular disease and skin and mucosal disease, I might be doing more of a mycophenolate and belimumab combination. A lot of it depends on the patient’s history, what they’re on currently. They may have been on a certain regimen when the lupus nephritis actually became active. For a disease that itself is very heterogeneous, you have to look at each patient as an individual and then make the best treatment plan with the patient in the office in front of you and then move forward with that.

AJMC: Please provide insights into the efficacy and safety of FDA-approved belimumab and voclosporin in treating lupus nephritis and within the context of the broader systemic lupus treatment paradigm.

WISE: Belimumab has been on the market for the treatment of systemic lupus for many years, and it’s a very good drug for individuals with systemic lupus, particularly [for those] who have a lot of skin and musculoskeletal disease. But when it was first developed, the clinical trials did not include individuals with active lupus nephritis. And so we weren’t quite sure, based on the data, if it would actually be a good treatment for individuals with lupus nephritis. Then along came the [results of the] BLISS-LN trial [NCT01639339], in which belimumab did appear to be effective for individuals who had proteinuria.¹ When we look at the data closely, it looks like it is a good fit for individuals who have relatively lower proteinuria—not individuals who have high-grade proteinuria, looking at 9 or 10 [g/d] of protein—but it is effective for lupus nephritis.³ I like using it. It’s very safe. It has a fantastic track record in systemic lupus as a whole. If I’m looking for something for a patient with really bad arthritis, bad skin involvement, belimumab looks like it would be a good fit, especially if their proteinuria is on the lower side.

Voclosporin is a relatively newer drug. It’s a novel calcineurin inhibitor [that is] very similar to cyclosporine but with a much safer [adverse] effect profile. [In the results of] studies with voclosporin, [this drug] seems to be much more effective in patients who have a higher degree of proteinuria.^2,4 The [adverse] effect profile might be a touch more problematic, though. If I have a patient with poorly-controlled hypertension, perhaps a history of PRES (posterior reversible encephalopathy syndrome) or a known chronic kidney disease or they’re on a pretty extensive drug regimen and I’m concerned about some drug-drug interactions, I might be a little more careful with the use of voclosporin. Again, I think it’s a testament to the fact that I do need to be careful and thoughtful in how I individualize the lupus nephritis regimen for each patient. I’m not using either of these as monotherapy. I’m using them, at least according to the clinical trials, with a background treatment of mycophenolate and also, preferably, with hydroxychloroquine.

AJMC: How do you perceive the importance of tapering steroid use in lupus nephritis treatment?

WISE: Tapering steroids is very important in any autoimmune disease. Regardless of how you look at the literature, long-term steroid use—even 15 or 20 [mg/d] of prednisone—has been associated with a variety of end-organ damage. We see this for sure in our lupus nephritis patients, especially because we tend to keep them on a good amount of steroids, medium and long-term. There have been several studies looking at even the harmful effects of lower doses of prednisone, and it looks like no dose of prednisone is technically safe. There [has] been more and more of a push by lupus experts these days to try to spare steroids. This is, I think, appreciated by patients, because we’re minimizing the cosmetic effects of steroids—such as weight gain, the Cushingoid [appearance]—but we’re also minimizing the more insidious downstream [adverse] effects like osteoporosis, cataracts, [and] peptic ulcer disease. There could also be neuropsychiatric [adverse] effects, such as insomnia and irritability….Steroids can be lifesaving, but they’re also horrendous, and they can kill. We cannot take the use of steroids lightly. Yes, they can save the kidneys. They’re great at controlling acute inflammation. We cannot be good rheumatologists without using steroids, but we have to be very, very careful when we use them.

I think even [during] the past 5 to 10 years, the way we have viewed steroids has actually started to shift and change. I think we’re really starting to be more judicious and cautious with leaving patients on long-term steroids, and we’re no longer doing prednisone 60 [mg/d] for a month and 50 [mg/d] for a month and 40 [mg/d] for a month. We’re starting to realize maybe we can get away with tapering steroids a little faster, even in the setting of lupus nephritis, because we’re able to start a combination regimen for their active nephritis from the get-go.

AJMC: How might your treatment approaches for lupus nephritis differ from those of nephrologists, considering your holistic view of a patient with systemic lupus?

WISE: My treatment approach for lupus nephritis may differ a little bit compared [with that of] a nephrologist. I don’t know if it would differ substantially. I think a nephrologist might actually be a little better at getting tight blood pressure control. I do think that’s an area [in which] they may shine a little bit compared [with] a rheumatologist, [because] we might focus a little more on the extrarenal manifestations. I think that is a point as to why a patient with lupus nephritis may benefit from seeing both a rheumatologist and a nephrologist. I think there are components that we both can add, and I think a nephrologist can initiate treatment for lupus nephritis without a rheumatologist and vice versa….But I don’t think it’s an either/or [situation]. I think we can each add something to the picture. I think rheumatologists perhaps can be better at blood pressure control. But sometimes [rheumatologists are] so focused on managing immunosuppression and paying attention to the extrarenal manifestations…I do appreciate when the nephrologist can focus on the nitty-gritty of blood pressure control and electrolyte management. We both have something to offer for the patient.

AJMC: What strategies do you employ to effectively coordinate care with nephrologists and other specialists for lupus nephritis management?

WISE: We do have some strategies for coordinating care for lupus nephritis patients within rheumatology and nephrology. It’s not always easy and streamlined. It does help sometimes to have them within the same health care system, whether it’s an academic system or a certain group practice, but it’s not always perfect. And I do encourage these patients as much as possible to be proactive, really even from the get-go. With or without lupus nephritis, I encourage the patients to have a family member or a friend…involved in their care if they’re comfortable with that. I think this helps to advocate for the patient and just remove a little bit of the burden from the patient in terms of managing their health care.

I think most of these patients are on the younger side. Having a chronic disease, in general, is very exhausting, but I think especially when you’re a young individual and in school or having a family or trying to have a career, it’s just very exhausting to also manage a chronic disease. If there’s a second person who can help advocate for the patient and talk to doctors and help with that cross communication between different specialties, I notice this seems to help with outcomes. I’ll encourage them if they can have a significant other or a friend, a mom or dad, even [a] brother or sister, to help [me when I] say, “Hey, can you take this note that I’m going to print out to your nephrologist and just keep them in the loop…that I’m going down on the steroids?” Or, “I’d like to get your biopsy results.” Or, “We’re starting this new medication or stopping this other one.” I think that can help a lot.

AJMC: How do differing perspectives enhance patient management for lupus nephritis?

WISE: When patients with lupus nephritis see nephrologists and rheumatologists, I think we can focus on different aspects of their care. Nephrologists can help with managing immunosuppression, but they tend to focus more on blood pressure control. In my experience, the rheumatologist will usually manage the immunosuppression a little more. But that being said, I always appreciate the nephrologists not only managing the blood pressure but also maybe [helping to manage] some electrolyte imbalances. Calcineurin inhibitors were recently FDA approved via voclosporin for the management of lupus nephritis, and that’s actually a medication that was kind of grandfathered in from the realm of nephrology, so they’re actually really familiar with using calcineurin inhibitors. I like nephrologists to see these patients. They’re familiar with calcineurin inhibitors from the world of renal transplants. I think that the different perspectives can help quite a bit, and I appreciate my nephrology colleagues weighing in with my lupus nephritis patients.

AJMC: What challenges or obstacles may patients encounter when trying to access lupus nephritis therapies, and what resources are available to address these issues?

WISE: There are a lot of challenges with the treatment of lupus nephritis and lupus nephritis therapies. I would say the biggest…is just managing a chronic disease that can be on the silent side. Patients can have active lupus nephritis and be relatively asymptomatic….I think is tough to tell someone to take a large handful of medications on a daily basis when [they] have very few symptoms—possibly fatigue and some changes in urination. Sometimes you can be almost asymptomatic. We’re telling patients to get [laboratory results], we’re telling patients,…”Go eat and drink a certain way, go pick up your medication, go get your blood work and your urine work done frequently.” I think the main thing is to make sure that the physician and the medical team has, from the very beginning, formed a very solid partnership with the patient. As cliché as it sounds, just having a good patient rapport and making sure they’re on the same page with the patient [is valuable so that] the patient understands the gravity and the importance of treating this disease early and aggressively. I try to do that myself with my patients. I think I’m fairly successful with that, but there are definitely times when I think it is hard for young individuals to grasp how serious this is.

In terms of resources, I have some websites [that I recommend] and handouts that I give my patients. Some of the drug companies have some decent handouts that I’ve implemented here and there, but I point my patients to the American College of Rheumatology’s handouts. I think they’re solid, as well, and then [there] also [are] some local support groups [offering assistance} online that have been good. Lupus LA (https://lupusla.org/) for the Los Angeles area, I’ve used before. I’ve heard by patients that they also connect via social media on Facebook and other local support groups. That’s usually what I’ll hear [that they] start with. I think social support is important, just because maybe the first week or month or 2 after diagnosis, it’s like, “We can do this, let’s get through it.” But then after a while, living with a chronic disease becomes very exhausting, and the social support is important. That’s what I’ll recommend for my patients.

AJMC: How do you empower patients with lupus nephritis to manage their condition proactively and maintain their overall health and well-being?

WISE: When I have a patient with lupus, especially [during] the first couple of visits, I will try to sit down with them and preferably [a family member or other support system] and make sure that they understand how serious this condition is. A lot of times they’ll ask, “Is it going to go away? Is this temporary?” I try to help them understand that, no, it’s not. This is not going to go away. This is chronic, but you have the best chance of living as normal of a life as possible if you are proactive with taking your medications, getting this condition into remission as soon as possible, and keeping other issues at bay or quiet, as well. And what I mean by that is controlling blood pressure, keeping a normal weight, addressing other things such as mental health, things like that.

I will encourage my patients to do things such as staying away from tobacco use [and to exercise and eat healthy foods]. I try to be very specific about these things, not just telling them, “Oh, you know, make sure you exercise, make sure you eat healthy.” Personally, I have handouts that I give my patients on anti-inflammatory eating in the setting of lupus based on what the clinical evidence and what prior studies have shown—maybe some specific things to eat and specific things to avoid in the setting of lupus and lupus nephritis. Again, [if you just say], “Well, make sure you eat healthy,” [then] patients say, “Well, what is that? Does that mean, you know, eating a Mediterranean diet or a keto[genic] diet?” Patients want specific answers to it. I try, based on the evidence, to give them those specific answers rather than just vague doctor-sounding advice. Making sure you’re answering the patient’s questions, being as helpful as possible, especially in those first couple visits, I think is very important. And again, discussing other things [so] that we can address the low-hanging fruit—not smoking, maintaining a normal weight, things like that. And as I mentioned previously, making sure that they have a good social support network [that] can help advocate for themselves and help manage this chronic disease that is unlikely to just go into remission spontaneously.

AJMC: What are emerging therapies or novel treatment approaches that show promise in advancing the treatment and management of lupus nephritis?

WISE: There is an ongoing study looking at higher doses of anifrolumab, which is a biologic that is already approved for [the treatment of] systemic lupus.⁵ They’re looking at higher doses of this specifically for [use by patients with] lupus nephritis. Anifrolumab has good data just for treating systemic lupus, but patients with active lupus nephritis were not included in their original trials. This is something [for which] we’ll have data out soon for the treatment of lupus nephritis, as well. And then in terms of more novel approaches, there are some interesting but small studies looking at some dietary supplements. There’s an interesting one out of China looking at fish oil supplement in addition to cyclophosphamide. It was only a Chinese population, and they had a pretty low degree of proteinuria, but they supplemented patients who had lupus nephritis. The patients who received the fish oil supplement had higher rates of remission and [fewer adverse] effects than [did] the population [given] cyclophosphamide alone.⁶ All I’ll do with that data is encourage my patients to eat more fish while they’re getting treated for lupus nephritis and maybe add a fish oil supplement, as well. But that kind of goes in line with patients asking, “Well, what should I do? What should I eat or drink while I’m getting treatment for my lupus nephritis?” I’m looking forward to the anifrolumab data when [they come] out.

AJMC: Do you have any closing thoughts about the management of lupus nephritis that you’d like to share?

WISE: My big takeaway for the treatment of lupus nephritis is to screen for it frequently and to treat aggressively and early. The data for treating lupus nephritis show that we should not be watching these patients deteriorate slowly over time. Not that anyone really means to do that or wishes that on a patient, but the data show that if we can get to a low proteinuria level—and by low, the thought is somewhere between 0.5 to 0.8 [g/d]—at about the 1-year mark after the lupus nephritis diagnosis, that’s associated with the best long-term outcomes. When I work with trainees [residents or fellows], and they want to know of a magic number, what should we be looking at, I’ll tell them [to] look at the proteinuria after the lupus nephritis diagnosis. We want to get to this magic range of 0.5 to 0.8 [g/d] after the 1-year mark of diagnosis.

Try to be aggressive in your treatment plan. Don’t just throw on 1 agent and wish for the best. If you have to use dual agents right from the get-go, [you should realize that] the literature shows that dual agents likely work best; again, this involves mycophenolate with a calcineurin inhibitor or belimumab. And treat aggressively. So far, it does not look like we’re going to have increased rates of infections with using dual agents. And if anything, we’re going to have better rates of remission at the 1-year mark. Don’t be afraid to treat early, treat aggressively, and you’ll likely get better outcomes, including long-term kidney survival at the 1-year mark. Screen frequently and treat aggressively for lupus nephritis. 

References

1. Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383(12):1117-1128. doi:10.1056/NEJMoa2001180
2. 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
3. Liu T, Neuner R, Thompson A, et al. Clinical pharmacology considerations for the approval of belimumab for the treatment of adult patients with active lupus nephritis: a regulatory perspective. Lupus. 2022;31(4):424-432. doi:10.1177/09612033221079771
4. Rovin BH, Solomons N, Pendergraft WF 3rd, et al; AURA-LV Study Group. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int. 2019;95(1):219-231. doi:10.1016/j.kint.2018.08.025
5. Jayne D, Rovin B, Mysler E, et al. Anifrolumab in lupus nephritis: results from second-year extension of a randomised phase II trial. Lupus Sci Med. 2023;10(2):e000910. doi:10.1136/lupus-2023-000910
6. Zhang C, Ge C, Wang J, Sun D. Fish oil enhanced the efficacy of low-dose cyclophosphamide regimen for proliferative lupus nephritis: a randomized controlled double-blind trial. Food Nutr Res. Published online July 26, 2021. doi:10.29219/fnr.v65.7842

For other articles and videos in this AJMC(R) Perspectives publication, please visit "Navigating Lupus Nephritis Care: Insights for Managed Care Decision Makers"