September 05, 2025
11 min read
Key takeaways:
- New advancements in lupus nephritis treatment are forcing both nephrologists and rheumatologists to keep pace with information.
- Various modalities of B-cell depletion may be a big part of lupus treatment moving forward.
A robust therapeutic pipeline and advancing research in revolutionary approaches like chimeric antigen receptor T-cell therapy have injected new hope into the lupus nephritis space.
Meanwhile, collaboration between nephrologists and rheumatologists — in advancing, digesting and acting on these advances — is at an all-time high. However, treatment challenges and unmet needs remain.
In 2024, the American College of Rheumatology published guidelines for lupus nephritis, following similar documents from the European Alliance of Associations for Rheumatology and the nephrology-focused nonprofit Kidney Disease: Improving Global Outcomes (KDIGO).
“It is important for the Healio readership to understand that these guidelines are being established by rheumatologists and nephrologists working together,” Brad H. Rovin, MD, director of nephrology and medical director of the Wexner Medical Center for Clinical Research Management, Lee A. Hebert professor of nephrology at Ohio State University, and co-author of the ACR lupus nephritis guidelines, told Healio. “The best care will be provided when both subspecialties are involved.”
These guidelines emerged in the wake of high-profile FDA approvals, including those for the B-cell targeting therapy belimumab (Benlysta, GlaxoSmithKline) in 2020 and the calcineurin inhibitor voclosporin (Lupkynis, Aurinia) in 2021. Although the B-cell depleting therapy rituximab (Rituxan, Genentech) failed to meet expectations, an FDA approval for a similar agent, obinutuzumab (Gazyva, Genentech), is expected soon.
“It is a very exciting time for lupus nephritis,” Shivani Garg,MD, PhD, of the University of Wisconsin School of Medicine and Public Health, said in an interview. “New drugs give us options for controlling the disease or putting it in remission.”
However, despite the enthusiasm, the stubborn reality is that the distribution of these benefits, particularly remission, has not been equal among patients, according to Fahmeedah Kamal, MD, clinical associate professor of nephrology at Stanford University.
“In some of our most successful trials, like the AURORA and BLISS, we still saw less than 50% complete response rates,” Kamal told Healio.
Rheumatologists agree there is ample room for improvement.
“We still do not have medications that clearly make a big difference,” Dafna D. Gladman MD, FRCPC, founder and co-director of the Gladman-Krembil Psoriatic Arthritis Research Program, co-director of the Lupus Program at Toronto Western Hospital, and professor emeritus at the University of Toronto, said in an interview. “The medications we have work to a certain extent but do not produce remission. We need something much more effective. We also need proper assessment tools that are widely accepted and available.”
Improved biomarkers — and communication — will help, experts said, as will understanding the current pipeline and treatment landscape for lupus.
‘We all treat patients a little differently’
According to Garg, who is also among the authors of the 2024 ACR lupus nephritis guidelines, the preferred first-line regimen now emphasizes early initiation of quadruple therapy, which typically includes intravenous glucocorticoids or high dose steroids initially with a quick taper, hydroxychloroquine, mycophenolate mofetil or mycophenolic acid, and either belimumab, voclosporin or tacrolimus.
“This approach aims to balance efficacy with reduced toxicity, particularly by minimizing glucocorticoid exposure,” she said.
Cyclophosphamide can also play a role in this early regimen, Garg added.
“This medication can be useful in very severe lupus nephritis with rapidly progressive glomerulonephritis and kidney function decline, as well as multi-system involvement,” she said. “In such scenarios, cyclophosphamide could be considered as an initial therapy before trying the combination.”
The specific sequence of the quadruple therapy approach is “not rigid,” but should be tailored based on several factors, according to Garg.
“These factors include adherence to oral therapy, side effects, severity and extent of extra-renal manifestations of lupus,” she said. “Additionally, clinicians should try to limit or reduce steroids whenever possible.”
Monitoring patients closely for proteinuria and other markers of a drug’s performance is critical, according to Kamal.
“The clinical course does not always match what we expect with proteinuria, serologies and flare,” Kamal added.
Clinicians should also recognize important distinctions between patients with class III or IV lupus nephritis and those with pure class V disease, she added.
“Pure class V lupus nephritis is not as inflammatory, and those patients with lower proteinuria may not reach end-stage kidney disease,” Kamal said.
As such, class V disease may be managed differently than class III or IV lupus nephritis.
“For some of these patients, we may not use steroids,” Kamal said. “Overall, there are less data on this, and the guidelines are variable. We all treat these patients a little differently.”
Clinicians should not be the only ones informing these decisions, according to Garg. Shared decision making with patients remains key to any treatment regimen.
“Treatment needs to be aligned with the disease presentation and patient preferences,” she said, referencing the ACR guideline development process. “Our patient panel members supported the use of shared decision-making approaches in all phases of their lupus nephritis treatment journey, and they value a strong partnership with their lupus care team.”
Part of shared decision-making process may include use of off-label therapies when appropriate, according to experts. A close watch on the lupus nephritis pipeline may help inform those choices.
A flowing pipeline
Although most experts acknowledge that rituximab did not perform as expected in lupus nephritis, the data nonetheless suggested an encouraging signal for B-cell depletion that led to trials of obinutuzumab. In that time, obinutuzumab has revealed itself to be a “much more potent” medication, according to Rovin.
In a study published in February in the New England Journal of Medicine, Furie and colleagues assessed obinutuzumab in patients with lupus nephritis at 1,000 mg on day 1, as well as at weeks 2, 24, 26, and 52, with or without a dose at week 50, or placebo. Results showed that 46.1% of patients in the obinutuzumab group achieved a complete renal response, compared with 33.1% of those in the placebo group (adjusted difference, 13.4 percentage points; P = .02).
“We get very excellent B-cell depletion with obinutuzumab,” said Rovin, who was one of the authors of the study. “It is at the top of the pipeline list and will hopefully soon be approved by regulatory agencies.”
According to Rovin, the importance of adding another agent to the lupus nephritis armamentarium cannot be overstated.
“We will be using B-cell depletion routinely as part of a multi-targeted approach,” he said. “What is remarkable to me as a clinician is that we can add B-cell depleting drugs to the rest of our regimen and patients do well. It is exciting to be able to add this to our toolkit.”
Still, more information is needed to understand exactly how expand that toolkit, according to Garg.
“The role of obinutuzumab is evolving,” she said. “Ongoing research is exploring its use in combination regimens and personalized approaches.”
Ongoing research is also investigating other drug classes in lupus nephritis.
In the phase 2 extension of the Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-LN trial, Jayne and colleagues assessed the safety and efficacy of the interferon antagonist anifrolumab (Saphnelo, AstraZeneca) in active lupus nephritis. The results, which were published in 2023 in Lupus Science and Medicine, demonstrated overall safety, with fewer than 10% of patients in each anifrolumab dosing group experiencing serious adverse events, and just two discontinuations among patients on active therapy.
Another drug in the pipeline is telitacicept (Tai’ai; Yantai Rongchang Pharmaceuticals, RemeGen), a recombinant fusion protein consisting of the extracellular domain of the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) receptor plus the fragment crystallizable region (Fc) domain of human immunoglobulin G (IgG).
“The extracellular domain of the TACI receptor binds and suppresses B-lymphocyte stimulator (BLyS) and proliferation-inducing ligand (APRIL) signaling, while the Fc domain of human IgG increases the stability of telitacicept,” Gladman said.
A key data set for telitacicept was published in 2024 by Wu and colleagues in the Annals of the Rheumatic Diseases.
“This molecule proved effective in the phase 2 trial in lupus with a delta of 34% between the drug treated and placebo treated patients,” Gladman said. “There is a current ongoing study in lupus nephritis.”
As the lupus nephritis community awaits these results, all eyes remain on another emerging, and potentially revolutionary, treatment — cell therapy.
‘Not seeing perfect responses’
According to Rovin, cell therapies are “top of mind” for many nephrologists and rheumatologists alike.
“It is a radical departure from how we have treated patients before,” he said.
However, Kamal noted that there remains “a long ways to go” to fully understand the realities of CAR T-cell therapies in lupus nephritis.
She added that, despite promising data, the clinical trial process has not been entirely smooth regarding these treatments.
“We are enrolling a trial of CAR T cells in lupus nephritis right now at Stanford, but we are having difficulties,” she said.
For example, the complications of the procedure compared with standard oral or IV therapies can be daunting for some patients.
“There is a rigorous conditioning regimen that goes with this procedure,” Rovin said.
There are also logistical challenges with hospital admission, Kamal added.
Despite these hurdles, it seems likely that investigation into cell therapies will advance in lupus nephritis.
The first blockbuster studies on CAR T-cell therapy in lupus from a group led by Georg Schett, MD, in Germany made headline news across health care specialties and into mainstream media outlets.
However, subsequent results have been less dramatic.
“Of course, we saw remarkable results in lupus patients at the beginning, but as this is rolled out to patients who are sicker and sicker, we are not seeing the perfect responses that were initially published,” Rovin said.
The procedure is likely to evolve as more data become available, he added.
“The current procedure involves taking the patient’s own T cells, manipulating them with a virus, and programming them to attack B cells,” Rovin said. “What is coming down the pike is creating allogeneic CAR T cells from a healthy source and not necessarily from the lupus nephritis patient.”
The endgame of this process would be to create a “huge repertoire” of cells that a physician can essentially pull off the shelf and put into the patient, according to Rovin.
“It will be possible to give them to anyone, and they would be almost invisible to the patient’s immune system,” he said.
Such a procedure would improve both clinical factors and logistics.
“There is potential to deliver this as an outpatient therapy,” Rovin said. “It would cut down on the conditioning and be safer and standardized for everyone.”
The future of B-cell strategies in lupus may not stop there.
In a 2024 abstract published in Lupus Science & Medicine, Furie described a new procedure being tested across the spectrum of autoimmune disease.
“A rather unique design is the bispecific antibody, which includes two targets in its construct,” he wrote.
One target is CD3, while the other is CD19 or CD20 on a B cell.
“Ligation of CD3 activates a T cell, and this activated T cell is then ‘introduced’ to the targeted B cell,” Furie wrote.
When the introduction is made, the B cell is killed.
Some experts believe this bispecific T-cell engagers (BiTEs) procedure may be a more effective way of targeting B cells in lupus nephritis.
“These new procedures result from our increased understanding of how important B cells are in lupus nephritis,” Rovin said. “The pipeline is very exciting.”
However, Rovin stressed that not all patients may have B-cell dominant disease that would benefit from cellular therapy.
“We need to make sure we are not ignoring other types of disease,” he said.
Timing is also a critical factor.
“You need to know when you have caught a patient in their disease, and when they are in a position for one of these approaches to be successful,” Rovin said.
Meanwhile, as lupus nephritis caregivers await the next wave of cell therapy trial data, they still have to contend with several unmet needs.
‘We are missing something’
Each of the experts who spoke to Healio suggested that improved biomarkers before, during and after treatment are the most substantial holes currently plaguing lupus nephritis care.
“I would love to know how a patient is going to respond to a medication before I give it to them,” Rovin said. “When I am treating a patient, I want to know how they are responding to the drug without doing kidney biopsies.”
It is easy enough to measure proteinuria and serum creatinine, but the information to be gleaned from these tests is limited, he added.
“If I am treating a patient with mycophenolate and a biologic and trying to get rid of steroids, I would like to be able to look at a biomarker and know if the patient is getting better,” Rovin said. “If it is not working, I want to be able to change in real time.”
According to Gladman, it is important to look beyond outcomes like proteinuria for signaling treatment response.
“We need to pay attention to GFR,” she said. “Overall kidney survival and mortality are also important outcomes in the long run, but they are often not be studied in clinical trials, which are relatively short.”
To that point, longer-term outcomes should become part of standard clinical trial data, according to Kamal.
“We need to know better what happens when we extend therapy beyond 3 years,” she said. “Guidelines are now saying that we can extend for up to 5 years of therapy.”
For Garg, personalization of care and precision medicine represent the primary unmet needs in lupus nephritis.
“There is so much heterogeneity in lupus nephritis treatment response,” she said. “Even MMF plus obinutuzumab had only a 47% complete renal response rate in the REGENCY trial. This clearly highlights that we are missing something.”
Patient-centric approaches and shared decision-making could be part of a personalized medicine regimen, according to Garg.
“It is also important to understand the differences in drug metabolism and drug absorption as drivers of heterogeneity in treatment, and address them with more precise treatment regimens and dosing,” she said.
Downstream complications are yet another area of interest for Garg.
“As our lupus nephritis patients are living longer, comorbidities such as chronic kidney disease or cardiovascular disease need more careful monitoring and prevention to improve overall quality of life,” she said.
According to Gladman, cross-specialty communication between rheumatology and nephrology is essential to meeting this important patient need.
‘Seeing the whole picture’
When collaborating between specialties in lupus nephritis, pre-treatment decisions can be just as important as treatment decisions, and understanding the knowledge base of the other specialty is critical to working together, according to Gladman.
Nephrologists and rheumatologists must recognize the lens through which their counterparts are viewing patients.
According to those who spoke to Healio, the two specialties are largely in agreement on fundamental principles like steroid sparing. However, there can be subtle differences in treatment selection and preferences.
“Rheumatologists understand that hydroxychloroquine is the foundational therapy for lupus overall, and that extends to lupus nephritis,” Garg said.
Additionally, rheumatologists may be more comfortable selecting belimumab over voclosporin because of their long-standing experience with the former in non-renal manifestations of lupus, according to Kamal.
“Nephrologists, on the other hand, may prefer calcineurin inhibitors such as voclosporin,” she said. “We use those drugs in other conditions and we see their benefits.”
Kamal added that the chronicity of many rheumatic and autoimmune diseases may inform how rheumatologists approach treatment decisions.
“They are accustomed to patients taking medications for a long time and the associated issues with treatment adherence,” she said. “Patients often talk to them about whether they prefer an oral, subcutaneous or IV formulation.”
For example, the voclosporin regimen is three capsules twice a day, according to Kamal. “Rheumatologists understand that patients may want to avoid this pill burden,” she said.
Nephrologists, meanwhile, may be more comfortable with cytotoxic agents due to experience in the transplant field, according to Rovin.
He added that although conventional wisdom states that rheumatologists have longer and more comprehensive experiences with biologic therapies than nephrologists, this dynamic may be changing.
“Our understanding of these drugs is improving,” he said. “It is expanding for kidney diseases almost as rapidly as it is expanding in rheumatology.”
However, no matter which specialty demonstrates greater experience with these medications, the bottom line remains: When collaboration occurs, patients benefit.
“Most of the nephrologists I work with have the same opinion that I do,” Gladman said. “We work together and make therapeutic decisions about our mutual patients together. We do not want patients to be caught between different opinions from different specialists.”
References:
Furie RA. Lupus Sci & Med. 2024; Volume 11, Issue Suppl 3.
Furie RA, et al. N Engl J Med. 2025;doi:10.1056/NEJMoa2410965.
Jayne D, et al. Lupus Sci Med. 2023;doi:10.1136/lupus-2023-000910.
Wu D, et al. Ann Rheum Dis. 2024;doi:10.1136/ard-2023-224854.
Zhu H, et al. Exper Ther Med. 2024;doi:10.3892/etm.2024.12660.
For more information:
Shivani Garg, MD, PhD, can be reached at sgarg@medicine.wisc.edu.
Dafna Gladman, MD, can be reached at dafna.gladman@utoronto.ca.
Fahmeedah Kamal, MD, can be reached at fkamal@stanford.edu.
Brad H. Rovin, MD, can be reached at brad.rovin@osumc.edu.
Sources/Disclosures
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Disclosures:
Garg reports no relevant financial disclosures. Gladman reports consulting fees from AstraZeneca, Bristol Myers Squibb and GlaxoSmithKline unrelated to this work. Kamal reports participation in advisory boards for Apellis and Travere Therapeutics unrelated to this work. Rovin reports consulting on the scientific/medical advisory boards for Alexion, Artiva, AstraZeneca, Aurinia, Biogen, Bristol Myers Squibb, Century, Genentech/Roche, Incyte and Novartis.
