ACR 2021 Debate: Enhancing Standard Lupus Nephritis Therapy With Belimumab or Voclosporin

At this year’s ACR Convergence Great Debate, Michelle Petri, MD, MPH, and Brad Rovin, MD, discuss their preferred choice of add-on drug – belimumab or voclosporin – to standard lupus nephritis therapy.

Lupus nephritis (LN) is known to affect approximately 40% of patients with systemic lupus erythematous (SLE),1 with kidney disease being one of the most serious manifestations of SLE, affecting quality of life as well as prognosis and survival rates.2

The US Food and Drug Administration (FDA) recently approved 2 new treatments – parental B-lymphocyte inhibitor belimumab and oral calcineurin inhibitor voclosporin –for active LN in patients receiving standard-of-care treatment (ie, mycophenolate mofetil [MMF], cyclophosphamide, and glucocorticoids).

In light of the varying perspectives on the use of these drugs as add-on LN therapies, the topic discussed at the American College of Rheumatology (ACR) 2021 Convergence Great Debate was Enhancing Lupus Nephritis Therapy: Is Your Next Step Belimumab or Voclosporin?

In a session moderated by Namrata Singh, MD, MSc, Michelle Petri, MD, MPH, of the Johns Hopkins University School of Medicine, Baltimore, Maryland, advocated for the use of add-on belimumab for LN management, while Brad H. Rovin, MD, Lee A. Hebert professor of nephrology and division director of nephrology at The Ohio State University Wexner Medical Center, spoke in support of voclosporin as an add-on therapy to standard-of-care treatment.

Belimumab vs Voclosporin in Active LN

Dr Petri referenced the BLISS-LN trial (Efficacy and Safety of Belimumab in Patients With Active Lupus Nephritis; Identifier: NCT01639339) to present the safety and efficacy of belimumab in active LN.

Dr Rovin referred to the AURA-LV trial (Aurinia Urinary Protein Reduction Active – Lupus With Voclosporin; Clinical Identifier: NCT02141672) and the AURORA trial (Aurinia Renal Response in Active Lupus With Voclosporin; Identifier: NCT03021499) to highlight data on voclosporin treatment in LN.

Both drugs were comparatively discussed in terms of measurements of efficacy and safety.


  • Renal Response

Dr Petri began her presentation with the fact that there is a large unmet need in lupus nephritis treatment options and that the risk for kidney failure is 20% among patients with kidney disease diagnosed within 1 year of SLE onset.3

Based on findings from the BLISS-LN trial, significantly more study participants with LN in the belimumab vs placebo group achieved the primary efficacy renal response (43% vs 32%, respectively; P =.03) and complete renal response (30% vs 20%, respectively, P =.02).4

Dr Rovin pointed out data from the AURA-LV and AURORA trials, which showed that compared with MMF alone, voclosporin plus MMF was significantly more effective at inducing a complete renal response. He added that patients who received treatment with voclosporin plus MMF required significantly less glucocorticoids.5

In a subgroup analyses of the AURORA trial, voclosporin plus MMF was found to be effective among patients of diverse racial and ethnic backgrounds.6

While comparing the efficacy of belimumab vs voclosporin for LN, Dr Petri acknowledged the difference in study designs of the clinical trials. However, overall, belimumab was found to be favorable compared with voclosporin among all subsets of patients except those with class 5 LN.4,6

  • Time to Renal Flare

Using data from the BLISS-LN trial, Dr Petri showed that increased time to a renal-related event or death was improved with belimumab treatment vs placebo.4 In addition, research presented at the American Society of Nephrology (ASN) Kidney Week Annual Meeting in 2020 indicated that time to first renal flare was in also in favor of belimumab vs placebo.7

On the other hand, Dr Petri pointed out that treatment with belimumab vs placebo in terms of time to first renal flare failed to reach statistical significance among Black patients; however, with voclosporin, statistical significance was achieved in this patient population.4,6

  • Proteinuria Reduction

In his argument, Dr Rovin highlighted the role of voclosporin vs placebo in reducing proteinuria. Providing further insight into the rapid response with voclosporin plus MMF, Dr Rovin explained the effect of calcineurin activation on glomerular podocytes, which are kidney-protective.6

Dr Rovin mentioned research published by Pirson and colleagues that found that patients who achieved late remission were more likely to develop chronic kidney disease (CKD)8 and that remission was achievable with voclosporin.9

  • Extra-Renal Lupus

Both Dr Petri and Dr Rovin spoke about the risk for extra-renal lupus in patients with LN.

Dr Petri pointed to several studies10,11 that have shown the beneficial effect of belimumab in non-renal lupus. Dr Rovin highlighted a study published in the Lancet with the efficacy of voclosporin with regard to serologic and extra-renal manifestations of LN.6


The safety of belimumab vs voclosporin was examined in detail. Dr Petri pointed out the issue of acute and chronic nephrotoxicity with calcineurin inhibitors, including voclosporin12; however, Dr Rovin noted the reversible effects of calcineurin inhibitor-related hemodynamic changes.

Dr Petri went on to provide data about estimated glomerular filtration rate (eGFR) protection with belimumab as early as 3 to 4 months after treatment, which was maintained at the 2-year follow-up.4 She cited the voclosporin package insert, in which the drug was not deemed safe for patients with a baseline eGFR within 45 mL/min/1.73 m2 unless the benefit exceeded the risk, as these patients may be at increased risk for acute and/or chronic nephrotoxicity.13

Dr Petri noted the increased risk for infections with voclosporin vs placebo and compared with belimumab that did not show any serious or fatal infections vs placebo.14

Calcineurin inhibitors were also found to be increase cardiovascular risk factors, including hypertension, diabetes, and hyperlipidemia, and risk for malignancy.13 Other adverse events discussed were neurologic toxicity, osteoporosis, drug-drug interactions, and deaths all of which were in favor of belimumab compared with voclosporin.

Dr Rovin pooled adverse events, including serious adverse events, infections, and death, to show that the combination of voclosporin plus MMF vs placebo was safe in LN.15

An important finding regarding the use of belimumab and voclosporin in pregnancy was that while there are inconclusive data regarding belimumab, voclosporin is currently contraindicated in pregnancy due to its alcohol content.13 Toward the end of the session, Dr Petri noted that treatment of LN during pregnancy must be personalized and that she currently recommends tacrolimus plus azathioprine in pregnant persons with LN.

The Battle of Belimumab vs Voclosporin in LN

In the rebuttal, when asked about belimumab vs voclosporin, Dr Petri said, “We don’t want rheumatologists to use belimumab and nephrologists to use voclosporin,” to which Dr Rovin agreed. But Dr Petri also noted that belimumab was considered efficacious and safe because it was being used for more than 10 years. Voclosporin, on the other hand, should be reconsidered for long-term use due to its potential adverse effects, Dr Rovin cautioned.

A question put forward by one of the attendees was why choose 1 drug over the other and not use them together instead. Dr Rovin said that although further trials need to be conducted in this area, researchers must think ahead about developing unique combinations of drugs.

Both Dr Petri and Dr Rovin noted the importance of biomarker research in LN.

Final Results

The poll results showed that approximately 70% of attendees would chose belimumab compared with voclosporin as an add-on to standard therapy in LN.

Disclosures: Michelle Petri, MD, and Brad Rovin, MD, declared affiliations with the pharmaceutical industry.


  1. Hoover PJ, Costenbader KH. Insights into the epidemiology and management of lupus nephritis from the U.S. rheumatologist’s perspective. Kidney Int. 2016;90(3):487-492. doi:10.1016/j.kint.2016.03.042
  2. Mok CC, Kwok RCL, Yip PSF. Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus. Arthritis Rheumatol. Published online June 10, 2013. doi:10.1002/art.38006
  3. Petri M, Barr E, Magder LS. Risk of renal failure within 10 or 20 years of systemic lupus erythematosus diagnosis. J Rheumatol. 2021;48(2):222-227. doi:10.3899/jrheum.191094
  4. Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383:1117-1128.
  5. Rubio J, Kyttaris V. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomized, multicenter, placebo-controlled, phase 3 trial. ACR Open Rheumatol. Published online August 31, 2021. doi:10.1002/acr2.11338
  6. 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
  7. Furie R, Rovin BH, Houssiau, et al. BLISS-LN: a randomised, double-blind, placebo-controlled phase 3 trial of intravenous belimumab in patients with active lupus nephritis [abstract]. Ann Rheum Dis. 2020;79:103. doi:10.1136/annrheumdis-2020-eular.3881
  8. Pirson V, Enfrein A, Houssiau FA, Tamirou F. Absence of renal remission portends poor long-term kidney outcome in lupus nephritis. Lupus. 2021;8:e000533. doi:10.1136/lupus-2021-000533
  9. Rovin BH, Solomons N, Pendergraft III WF, et al. 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
  10. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731. doi:10.1016/S0140-6736(10)61354-2
  11. Wallace DJ, Ginzler EM, Merrill JT, et al. Safety and efficacy of belimumab plus standard therapy for up to thirteen years in patients with systemic lupus erythematosus. Arthritis Rheumatol. Published online February 16, 2019. doi:10.1002/art.40861
  12. Nankivell BJ, Borrows RJ, Chir B, et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349:2326-2333. doi:10.1056/NEJMoa020009
  13. Lupkynis. Package insert. Aurinia Pharmaceuticals Inc; 2021.
  14. Ni R, Zheng J, Guo R. Effects of B Cell activating factors/B lymphocyte stimulator inhibitors added to standard of care on infection in patients with systemic lupus erythematosus: a systematic review and meta-analysis of randomized controlled trials. Presented at: ACR Convergence 2021; November 3-10, 2021. Abstract 1732.
  15. Rovin BH, Parikh SV, Huizinga RB, Solomons N. Randhawa S. Management of lupus nephritis (LN) with voclosporin: an update from a pooled analysis of 534 patients. Presented at: ASN Kidney Week; October 22, 2020. Abstract PO1917.