Optimizing Lupus Nephritis Management

Click here to view video highlights from this interview.

AJMC^®: What strategies have you found effective for increasing the screening and early diagnosis of lupus nephritis in patients with either diagnosed or suspected systemic lupus erythematosus (SLE)?

KOCHAR: The strategy that I have used in my clinical practice really comes down to timely and regular follow-ups. The key is to get these patients referred to our clinics in a timely manner, [to] avoid delays, and then, once we do see them in clinic, [to] make sure we get their routine [laboratory testing] done. Most of these…are essentially a blood test and a urine test. That’s how we can pick up if they’re having any kidney involvement or lupus nephritis. The key really is to get these patients to the right specialist in a timely manner and then to start treatment early on.

AJMC: How can nephrologists contribute to increasing awareness and screening for lupus nephritis, especially considering its potentially asymptomatic presentation?

KOCHAR: Lupus nephritis is a common complication of SLE, and almost 50% of the SLE patients at some point can develop kidney involvement that we call lupus nephritis. At times, it can be asymptomatic and silent. Nonetheless, it’s an aggressive form [that] can be quite serious if it’s not diagnosed on time. The key is, again, to make sure that patients are aware that lupus nephritis can be asymptomatic. The diagnosis sometimes has to be made [based on results from] blood work and urine tests. They need routine work-up, and they need timely referrals. Again, they need to show up to their appointments, make sure they get their [laboratory testing] done, because they may not have symptoms of lupus nephritis. Some of the symptoms that we do educate the patients about are to look out for any foamy or frothy urine, swelling in the legs, worsening hypertension. But not all patients develop these symptoms, so they really need to show up to their appointments and make sure they get their routine [laboratory testing] done [on] a regular basis.

AJMC: How do the presentation, disease course, and management considerations of lupus nephritis differ from those of other progressive kidney diseases?

KOCHAR: Lupus nephritis can present differently in some patients. There may not be any symptoms, and the only way we [identify] lupus nephritis is [based on the results of] urine tests and on blood work. Most of our referrals are from our rheumatology colleagues. As soon as they see any protein in the urine, they will refer patients to the nephrologists. But in cases where it’s silent, it can be quite tricky to diagnose these patients, and that’s why if we don’t diagnose these patients on time, they can have progressive disease and eventually go on to requiring dialysis because of kidney failure or [need for] a kidney transplant. Compared [with patients with] other progressive diseases [who] may have some more obvious symptomatology, [those] with lupus nephritis sometimes…may not have any signs or symptoms, and [the disease] can present more aggressively. That’s why we really need to screen these patients early on and do their regular urine analysis. In our patients [with lupus], we like to check their urine every 3 months so that if we start seeing any protein being spilled or any blood in the urine, we start work-up right away for lupus nephritis.

AJMC: What measures do you take to monitor kidney function and proteinuria levels in patients with lupus nephritis over the long term?

KOCHAR: Once these patients get referred to us, the initial testing that we do includes a urine test and a blood test. On the urine test, we are looking for 2 things. We’re looking for any protein being spilled in the urine or any blood in the urine. If there’s spilling protein, that’s called proteinuria. If there’s blood in the urine, that’s called hematuria. The second thing we do is a blood test. We are looking for the level of kidney function, and we do routine testing, which includes a serum creatinine [test]. Based on the serum creatinine [level], we can estimate the level of kidney function in percentage, which is called [the] eGFR [estimated glomerular filtration rate]. That’s what the patients see on the report. Those are the 2 initial screening tests—a urine test and a blood test. Once we get the results, and if there’s a suspicion of lupus nephritis, then we go on to what we call a kidney biopsy that’s done to help confirm the diagnosis. The majority of the patients at some point will require a kidney biopsy. But again, that’s done after the initial screening is positive.

AJMC: What is the significance of rapidly achieving complete clinical response, including achieving specific urine protein-to-creatinine ratio targets, in the management of lupus nephritis?

KOCHAR: It is extremely important to get these patients into remission as soon as we can. Our more recent guidelines, our EULAR/ERA-EDTA (European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association) guidelines and our KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, have all modified their goals.^1,2 We are much more aggressive in lowering the proteinuria in these patients. Our goal is to really get these patients into what we call complete remission. Complete remission is defined by a level of protein in the urine that’s less than 0.5 g/d. We really need to get these patients into remission as early as we can and with the lowest dose of steroids, if possible. Again, if we get these patients into complete remission, it does improve kidney survival. That has been shown in trials, so it does lead to kidney preservation. That’s really our goal for these young patients—to get these patients into remission earlier so that we can preserve the kidney function.

AJMC: In your practice, how do you approach treating lupus nephritis while also considering the broader context of SLE management?

KOCHAR: We work very closely with our rheumatology colleagues. I think that’s really the key—to co-manage these patients with the rheumatologists. As I mentioned earlier, most of our referrals are from rheumatologists. They are the ones who will pick up early signs of kidney involvement, because they check [the results of] urine tests [from] their patients [with SLE] every 3 months. If they start seeing any protein being spilled in the urine, that’s when they refer these patients to nephrologists. The key is to really get these patients into our clinic earlier. Sometimes what we see is [that] patients are referred, but there can be a wait of 3 to 6 months. That’s really problematic, because by the time [that] they get seen, they may have progressive kidney damage. The way we work in our practice is as soon as the referral is made by the rheumatologists, I make sure [that] I get these patients in my clinic within 2 to 3 weeks. I think that’s really the key—early referral, and then getting them seen in the clinic as early as possible so [that] once we diagnose, we can start management and aggressively lower their proteinuria.

AJMC: What is the relevance of factors like patient comorbidities, kidney function, and disease activity in tailoring lupus nephritis treatment plans?

KOCHAR: We have a lot of newer options now for treating lupus nephritis, which is great for our patients [with SLE], because here recently we have 2 new FDA-approved drugs for use in lupus nephritis. These are very effective drugs, and these drugs are also steroid sparing. They help us to lower the steroid dose earlier and also help us use lower doses of steroids from the get-go. Some patients, based on their comorbid conditions, based on their kidney function, do require dose modifications, and that’s done based on their eGFR. Some patients may have issues with hyperkalemia or some other electrolyte abnormalities, [for which] we may have to adjust the dosages accordingly. We look at the overall patient and pick the right combination based on the comorbid conditions and their kidney function and also the severity of lupus or severity of kidney involvement. We have quite a few options now, and then based on the severity, based on the comorbid conditions, based on the kidney function, we can tailor therapy for these patients.

AJMC: What considerations guide your choice between calcineurin inhibitors and other therapeutic options for lupus nephritis?

KOCHAR: How do we choose the right drug for our lupus nephritis patients? It really does come down to the level of proteinuria and how aggressive…the clinical presentation is and what features we see on the kidney biopsy. In the past, the standard therapy has been using mycophenolate mofetil and steroids. But as I mentioned, now we do have 2 new FDA-approved drugs. One of them is voclosporin, and the other one is belimumab. These newer agents really help us be a bit more aggressive from the get-go so that we can use lower doses of steroids during induction.

What I do in my practice is [that] I go by the level of proteinuria. If there is significant proteinuria, my choice for my patients, based on evidence and based on our recent trials, is to go with voclosporin. We know that’s a CNI (calcineurin inhibitor), and it’s very effective in lowering proteinuria in these patients. In fact, the majority of my patients have gone into some sort of remission as early as 3 to 6 months. That’s really the key to get that level of protein down to less than 0.5 g/d as early as we can so we can improve kidney survival, because [the results of] studies have shown that the longer these patients remain proteinuric, the worse [their] kidney survival. So that’s been my preference in my practice and based on the data that we have seen recently. We have [results from] the AURORA 1 trial [NCT03021499] for voclosporin, and now we also have extension data from AURORA 2 trial [NCT03597464].^3,4 We have data for up onto 3 years with the use of this novel CNI…voclosporin, which have shown that it is safe to use this new medicine up until 3 years. So I’m quite comfortable using this CNI for my young patients. In fact, I have…20 to 22 patients now on voclosporin.

The other new FDA-approved drug is belimumab, which is a B-cell therapy. Again, that’s been approved for SLE for several years now, but [its use was] just recently approved for lupus nephritis.⁵ Again, that’s an effective drug. For our patients [who] have significant kidney involvement and significant proteinuria, it’s not as effective as voclosporin. When I see proteinuria [of] more than 1 [g/d] or so, my personal preference is to use voclosporin. And that’s in conjunction with low-dose steroids and with mycophenolate mofetil. We use triple therapy, or what we call a multitargeted approach.

AJMC: What is your perspective on the differences between the efficacy and safety profiles of belimumab and voclosporin in the treatment of lupus nephritis?

KOCHAR: Let’s talk about the 2 new FDA-approved drugs here. As I mentioned briefly earlier, we have voclosporin, which is a novel CNI, and then we have belimumab, which is a B-cell therapy. Let’s first talk about voclosporin. It’s a novel CNI, which makes it more potent, and the advantage with voclosporin for our patients is [that] it does not require drug level monitoring. That has been quite helpful for our patients to improve their compliance, because we don’t have to bring them back for multiple [laboratory testing] visits to get their levels checked. That really does help our patients, because already they’re going through so much. They have to take all these medications, [and then come in] for their follow-up visits…if you don’t have to bring them back for drug level monitoring, that’s been quite helpful.

The other advantage with using voclosporin in conjunction with our standard therapy is that we can lower the dose of steroids. In practice, when we are using voclosporin, we use mycophenolate mofetil, which is [given as 2 g/d] along with a lower dose of prednisone. We are not using higher doses like we used to in the past, which was 1 mg/kg per day. Now, with the addition of voclosporin, you can just start them on a much lower dose, which is either 20 or 25 mg/d to begin with. That’s weight based—if [they weigh] more than 45 kg, we use 25 [mg/d]. The taper is also quite aggressive—we start them at about 25 [mg/d] and then, every week, we go down by 5 [mg/d] so that the majority of these patients by week 16 or by 4 months are down to about 2.5 or 5 [mg/d] of prednisone. That’s a significantly lower dose of prednisone than we’ve used in the past, and patients are really happy that we don’t need to use those high doses of steroids for prolonged periods of time. It really helps with compliance—there are [fewer adverse] effects and less long-term organ damage. In our practice, we have mostly Hispanic patients and African American patients. We know that these patients have more aggressive disease, so voclosporin [given] in combination with low dose steroids and mycophenolate mofetil has been very effective for these patients. As I mentioned, I have close to about 20 to 25 patients on this drug, on this therapy now, on the combination therapy.

The other FDA-approved drug is belimumab, which is a B-cell therapy. And belimumab has been approved for SLE for several years now, but [it] just recently [was] approved for lupus nephritis. But do keep in mind, that’s in conjunction or in combination with your other standard therapy, so that’s in combination with either mycophenolate mofetil or cyclophosphamide and steroids. It’s not used by itself. I do have a few patients on belimumab; [treatment with this drug] was mainly started by [our] rheumatology [colleagues], and then [the patients] were referred for the management of lupus nephritis. In a couple of patients, we just kept them on belimumab, because they had lower levels of proteinuria, less than 1 [g/d]. But in the other patients [who] were referred to me, they were still spilling 2 or 3 [g/d] of protein in the urine. We know that looking at the data and the evidence, that belimumab may not be as effective when you have more significant proteinuria. In those patients, I did go ahead and add voclospori] to their management. That really helped to get these patients into remission.

It really comes down to the level of proteinuria. If there is significant proteinuria—and my cutoff is as low as even 1 [g/d]—I tend to lean towards using voclosporin for these patients in combination with mycophenolate mofetil and low-dose steroids. But if they have more systemic manifestations and lower degree of proteinuria, then we could use belimumab with standard therapy.

AJMC: What insights have you gained regarding coordinating care and having effective communication with rheumatologists and other specialists to provide comprehensive, long-term lupus nephritis management?

KOCHAR: I really feel that for all, or for at least [the] majority, of the patients [with lupus], the rheumatologists and nephrologists should have good communication. As I was discussing earlier, most of our referrals to the nephrology clinic…come from rheumatologists. They are the ones who are seeing these SLE patients in their clinic on a regular basis, and every 3 months, they do a urinalysis. On the urinalysis, they are looking for any evidence of lupus nephritis, and they’re looking for either proteinuria or for hematuria. Most of our referrals come from [our] rheumatology [colleagues], and in our practice, we are quite proactive. As soon as they see any signs of proteinuria in the urine, they will refer the patients to my clinic. A lot of times, they will just directly give me a call, because we know [that] in these patients a timely referral and timely management really makes a difference. Sometimes they’ll just call me to make sure the patient gets seen. I think that’s what we really need for these patients—once a referral is made, ideally, we should get these patients in our clinic within a month. As I mentioned, at least in my clinic, I try to get them in as early as 2 weeks. That communication between rheumatology and nephrology [colleagues], I think, is really the key, which could be a challenge in some of the practices.

I understand [that there are] some community hospitals or certain areas [in which] they may not have enough nephrologists or rheumatologists. That could be a challenge. But luckily, where I practice, it’s an academic hospital, and since it’s a dedicated lupus nephritis clinic, I do make sure that these patients get in within 2 weeks. We do educate our patients also to make sure [that] once a referral is made, you do follow up on that. Compliance is the thing—make sure you show up for your appointments, be your own advocate and ask questions, make sure you know you get all the testing done that’s required. Again, that’s really the key: early referral, good communication between the specialists. And then once they are seen, get these patients diagnosed early on so we can start treatment as early as possible.

AJMC: What challenges or barriers do patients face when accessing lupus nephritis treatment, and what resources are available to support patient education and access?

KOCHAR: This is a serious condition, and, sometimes, patients do not realize how severe the kidney involvement is, because, as I mentioned earlier, it could be silent. Quite a few of these patients are quite young when they are diagnosed, so it can be quite overwhelming to have this diagnosis of lupus nephritis or kidney involvement in lupus nephritis. Sometimes these patients are in denial, and they will not show up for the clinic appointments. I think education is the key, and we really need to sit down and spend time with these young patients to make sure they understand what’s going on with [their] kidneys, what could happen if they do not show up for the appointments or if they do not get routine [laboratory testing] done. They also need to understand what the symptoms could be when they have kidney involvement. It does require a lot of education, and I’ve seen [that] the first few visits can be a bit more challenging. But once they realize that, yes, what we are doing is in their best interest, I think that’s when [we] gain their confidence, and it really helps to effectively manage these patients. We also encourage these patients to bring a friend or a family member, because the information we provide to them sometimes can be overwhelming and a lot to process. If they can bring a family member or a friend to these appointments, it’s quite helpful to have that support.

We also tell our patients to maintain a diary or, just before each visit, [to] write down their questions, because we all forget questions when we are in the clinic. [They should] make sure [that] they write the questions, make sure [that they] ask whatever they need to ask so that they have a clear plan about their management. We also educate them to make sure [that] they keep track of how much protein they’re spilling in the urine and what their kidney function is. [During] each visit, it really helps if they understand how the kidneys are progressing. It helps them to understand how long the therapy will be, what to expect as we go along with their management. The treatment for these patients, it’s not like a few days or a few weeks—it can take years. The first 6 months is when we are more aggressive with the management, which is the induction therapy, [when] we use higher doses of these immunosuppressive agents. Again, the patients need to understand that, yes, the first 6 months will be tough [when we use] higher doses of these medications, but once we get the disease under control, then we can move on to the lower doses, what we call [the] maintenance phase. The key really is, again, to make sure that patients understand what’s going on with their kidneys, show up for their appointments, be compliant, and then ask questions so that they can be their own advocates.

AJMC: What emerging therapies or treatment approaches hold promise for improving outcomes of lupus nephritis in the future?

KOCHAR: In the lupus world, in lupus nephritis specifically, there [have] been a lot of ongoing research and multiple ongoing trials at this point, which is quite exciting for us nephrologists….Up until just a few years ago, we didn’t have too many options to treat lupus nephritis. But now we already have 2 new FDA-approved drugs that we discussed earlier. We have voclosporin, which is a novel CNI, and then we also have belimumab, a B-cell therapy. So we have 2 new FDA-approved drugs already, and we have multiple other trials ongoing as we speak. We are really hoping [that] in the next couple of years, we may have another couple of newer FDA-approved drugs. I’ll mention a couple of them. One of them is obinutuzumab, which is a B-cell therapy. It’s [an] anti-CD20 [monoclonal antibody] that has shown quite promising results in the phase 2 trial (NOBILITY [NCT02550652]), and the phase 3 trial (REGENCY [NCT04221477]) is currently ongoing.^6,7 It should be completed soon, and we should have the results, I’m hoping, by next year. Obinutuzumab is a drug that I [believe] could be quite helpful for our patients [with lupus nephritis], because it’s an infusion like rituximab, so it only requires 2 doses at the beginning, on day 1 and day 14. It’s a 1-g infusion just like rituximab, and then we repeat the same at 6 months. I think from the standpoint of compliance, it would be great just to have those 4 infusions. So that’s 1 drug to look out for, and I’m hoping there will be some data by next year on obinutuzumab.

The other drug I want to mention is anifrolumab. That’s an interferon inhibitor, which is already approved for use in SLE, and our rheumatologists are already using that for SLE and systemic manifestations. It’s not yet approved for lupus nephritis. But the phase 2 [TULIP] trial [NCT03262935] was recently completed…and the phase 3 trial [NCT02446899] is now ongoing.^8,9 We really hope that in the near future we should get results from this phase 3 trial and some encouraging data for the use of anifrolumab in our patients [with lupus nephritis].

Those are the main trials, the main 2 drugs [that] I wanted to mention. But then again, there are multiple complement inhibitors being looked at. And then also other B-cell therapies and what we call BAFF inhibitors or anti-BAFF therapies that are being looked at. I…am part of a phase 3 trial looking at 1 of these B-cell therapies. We hope that they get some more options to treat lupus nephritis in the future, but, as I said, it looks quite promising.

AJMC: Please provide any closing thoughts on disease management considerations for lupus nephritis that you find noteworthy.

KOCHAR: Again, lupus nephritis is a condition that affects our young patients and [members of minority groups] in a more aggressive form. The key is really to get these patients referred early on, to see them in a timely manner, to diagnose these patients effectively as early as possible and then to start therapy without any delays, because sometimes we see that there can be delays in getting blood work done or there can be delays in getting a kidney biopsy done or the patients don’t show up to clinic. What we can do as nephrologists, rheumatologists, and other physicians taking care of these patients is just to be persistent—to make sure we make the patients understand that if we do not get this under control, they could essentially have permanent damage and go on to dialysis. I think when they hear the word dialysis, that’s when they realize that yes, this is serious, and they need to do something about this so that they can prevent long-term kidney damage.

References

1. Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020;79(6):713-723. doi:10.1136/annrheumdis-2020-216924
2. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2023 Clinical Practice Guideline for the Management of Glomerular Diseases. Public review draft. KDIGO. March 2023. https://kdigo.org/wp-content/uploads/2023/03/KDIGO-2023-Lupus-Nephritis-Guideline_Public-Review_9-Mar-2023.pdf
3. 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
4. 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. Published online July 19, 2023. doi:10.1002/art.42657
5. New drug therapy approvals 2020. FDA. January 8, 2021. Accessed September 13, 2023. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2020
6. Furie RA, Aroca G, Cascino MD, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2022;81(1):100-107. doi:10.1136/annrheumdis-2021-220920
7. A study to evaluate the efficacy and safety of obinutuzumab in patients with ISN/RPS 2003 class III or IV lupus nephritis (REGENCY). ClinicalTrials.gov. Updated September 26, 2023. Accessed October 19, 2023. https://clinicaltrials.gov/study/NCT04221477
8. 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
9. Efficacy and safety of anifrolumab compared to placebo in adult subjects with active systemic lupus erythematosus. ClinicalTrials.gov. Updated January 10, 2023. Accessed October 18, 2023. https://clinicaltrials.gov/study/NCT02446899

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