• 1.

    Parikh SV, et al.. Update on lupus nephritis: Core curriculum 2020. Am J Kidney Dis 2020; 76:265281. doi: 10.1053/j.ajkd.2019.10.017

  • 2.

    Furie R, et al.. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med 2020; 383:11171128. doi: 0.1056/NEJMoa2001180

  • 3.

    Atisha-Fregoso Y, et al.. Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis. Arthritis Rheumatol [published online ahead of print August 4, 2020]. doi: 10.1002/art.41466; https://onlinelibrary.wiley.com/doi/10.1002/art.41466

    • Search Google Scholar
    • Export Citation
  • 4.

    Furie R, et al.. A phase II randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of obinutuzumab or placebo in combination with mycophenolate mofetil in patients with active class III or IV lupus nephritis (abstract). Arthritis Rheumatol 2019; 71 (Suppl 10):939. https://acrabstracts.org/abstract/a-phase-ii-randomized-double-blind-placebo-controlled-study-to-evaluate-the-efficacy-and-safety-of-obinutuzumab-or-placebo-in-combination-with-mycophenolate-mofetil-in-patients-with-active-class-iii/

    • Search Google Scholar
    • Export Citation
  • 5.

    Rovin BH, 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; 95:219231. doi: 10.1016/j.kint.2018.08.025

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Arriens C, et al.. AURORA phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis. Aurinia. June 5, 2020. https://d1io3yog0oux5.cloudfront.net/_b9287cb2b9b32ac3fbb5d08113841567/auriniapharma/db/246/1327/pdf/EULAR+2020+AURORA_Presentation+Deck+05Jun2020.pdf

    • Search Google Scholar
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  • 7.

    Aurinia. FDA Approves Aurinia Pharmaceuticals’ LUPKYNIS™ (voclosporin) for Adult Patients with Active Lupus Nephritis. January 22, 2021. https://ir.auriniapharma.com/press-releases/detail/210

    • Search Google Scholar
    • Export Citation
  • 8.

    MetroHealth Medical Center. Pentoxifylline in Lupus Nephritis (Pentoxifylline). ClinicalTrials.gov: NCT03859570. https://clinicaltrials.gov/ct2/show/NCT03859570

    • Search Google Scholar
    • Export Citation
  • 9.

    BeiGene. Zanubrutinib in Participants with Active Proliferative Lupus Nephritis. ClinicalTrials.gov: NCT04643470. https://clinicaltrials.gov/ct2/show/NCT04643470

    • Search Google Scholar
    • Export Citation
  • 10.

    Janssen Research & Development, LLC. A Study of Guselkumab in Participants with Active Lupus Nephritis (ORCHID-LN). ClinicalTrials.gov: NCT04376827. https://clinicaltrials.gov/ct2/show/NCT04376827

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2021 and Beyond—Lupus Nephritis

  • 1 Marco Bonilla, MD, is a nephrology fellow at Northwell Health, Great Neck, NY. Kenar D. Jhaveri, MD, FASN, is a professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, and is editor-in-chief of ASN Kidney News.
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Lupus nephritis is a serious end organ manifestation of systemic lupus erythematosus (SLE). Regardless of the remarkable advances in the knowledge and understanding of lupus nephritis pathophysiology, it remains a weighty source of morbidity and mortality, and 10% to 30% of affected patients progress to end-stage kidney disease within 10 years of being diagnosed with SLE (1).

Therapy for lupus nephritis has continued to evolve, from the use of cyclophosphamide, azathioprine, and steroids developed in the 1970s–1980s to the use of mycophenolate, tacrolimus, cyclosporine, and rituximab in the 2000s (Figure 1). Given the significant adverse effects of some of the current agents, novel therapies are in the pipeline. The determination of an ideal management has been extremely challenging. Here, we highlight several potential treatments for lupus nephritis that we may see in 2021 and beyond.

Figure 1.
Figure 1.

Timeline for lupus nephritis treatment options

Citation: Kidney News 13, 3

Belimumab

Belimumab is a humanized monoclonal antibody (mAb) against a B cell–activating factor that has been studied in two prospective clinical trials: Efficacy and Safety of Belimumab in Patients With Active Lupus Nephritis (BLISS-LN) (2) and Rituximab and Belimumab for Lupus Nephritis (CALIBRATE) (3) studies.

The BLISS-LN study (2) was a phase 3, multi-center, international, randomized, double-blind, placebo-controlled trial, comparing belimumab (dose of 10 mg/kg of body weight) with matching placebo, in addition to standard therapy. The study showed that patients in the belimumab group had a higher complete kidney response than the placebo group (30% vs. 20%, respectively), and kidney adverse events were lower in the belimumab group compared to placebo. This has led to US Food and Drug Administration (FDA) approval of this agent in use of lupus nephritis. What is interesting is that the primary endpoint of the trial was changed 5 years after the commencement of the trial. The original endpoints categorized responses as complete, partial, or no response, according to the level of proteinuria and estimated glomerular filtration rate (eGFR) from 24 h urine collections, and microscopic examination of urinary sediment, although favoring belimumab, was not significantly different between the belimumab and placebo groups. Limitations of the study include the following: only two induction agents were permitted, the induction agent was not randomly assigned, and low enrollment of patients of Black race. The current trial still leaves us with a few uncertainties but leads the groundwork for ongoing trials using this novel agent. Could belimumab decrease the progression to end-stage kidney disease and subsequent flares in patients with severe lupus nephritis? It is yet to be seen.

The CALIBRATE study (3) was a phase 2, multi-center, randomized, controlled, open-label trial of cyclophosphamide plus rituximab, followed by belimumab, in patients with active lupus nephritis. The study showed at week 48, a complete or partial kidney response in the belimumab group compared to the control group (52% vs. 41%, respectively), and patients in the belimumab group did not have an increased frequency of adverse events. In the final conclusion, the addition of belimumab to a treatment regimen with rituximab and cyclophosphamide was safe in patients with refractory lupus nephritis. This regimen diminished maturation of transitional-to-naive B cells during B cell reconstitution and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and cyclophosphamide in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with lupus nephritis.

Obinutuzumab

Based on their mechanisms of action, CD20 mAbs are grouped into two types. Type I mAbs deplete B cells by inducing complement-dependent cytotoxicity (CDC), such as rituximab, and are referred to as antibody-dependent cell-mediated cytotoxic (ADCC). Alternatively, type II mAbs deplete B cells by initiating a combination of programmed cell death (PCD) and ADCC. Obinutuzumab and tositumomab are examples of type II agents.

Obinutuzumab, a type II anti-CD20 mAb that has been shown to be superior to rituximab (type I) in depleting B cells, was tested in the NOBILITY study (4). This was a phase 2, randomized, double-blind, placebo-controlled, multi-center study. The trial included patients with active class III/IV lupus nephritis who received obinutuzumab vs. placebo, combined with mycophenolate mofetil and steroids. The primary endpoint was complete kidney response at 52 weeks. The study showed that obinutuzumab had higher complete kidney response vs. placebo; serious adverse events and serious infections were not increased in the obinutuzumab group. The novel agent was not associated with increases in rates of serious adverse events or serious infections. Forthcoming data through week 104 will permit further assessment of the longer-term safety and efficacy of obinutuzumab in proliferative lupus nephritis. We again await the fully published results of yet another potential treatment for lupus nephritis. However, we should note that obinutuzumab was not compared directly to rituximab.

Voclosporin

The efficacy and safety of this novel calcineurin inhibitor were tested by the Aurinia Urinary Protein Reduction Active-Lupus with Voclosporin (AURA-LV) study. This was a phase 2, multi-center, randomized, placebo-controlled trial. This study showed a higher complete remission rate in the low-dose group, as well as the high-dose group, when compared to placebo at 48 weeks but a higher frequency of adverse events in the voclosporin group, with a higher mortality rate in the low-dose group when compared to the placebo group (5). In the abstract format presented at the European League Against Rheumatism (EULAR) meetings in 2020, the efficacy seen in Aurinia Renal Response in Active Lupus with Voclosporin (AURORA) was again demonstrated, as voclosporin improved the kidney response by 18.3% at 1 year (40.8% vs. 22.5%) (6). Voclosporin is now FDA-approved as of late January 2021 for use for lupus nephritis (7). At the time of this writing, the peer-reviewed publication of the AURORA trial had not yet been published.

Although the above three drugs may show promise this year, several clinical trials are either completed or recruiting for trials in lupus nephritis with other novel agents. Pentoxifylline is an oral phosphodiesterase inhibitor introduced 45 years ago for treatment of vascular insufficiency. It has also recently been found to reduce proteinuria in patients with diabetic nephropathy. The mechanism of this intriguing finding is not certain but may, in part, involve inhibition of the production of tumor necrosis factor (TNF)-a, an inflammatory cytokine known to be present in urine and kidneys of patients with lupus nephritis. Currently, a multi-center, double-blind, placebo-controlled, randomized trial of pentoxifylline or placebo, in addition to standard of care for treatment of proteinuria in patients with lupus nephritis, is ongoing (8).

Borrowing from the onconephrology world, zanubrutinib (a Bruton’s tyrosine kinase inhibitor) is being studied in lupus nephritis as well. Currently, there is a phase 2, multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of zanubrutinib in patients with active proliferative lupus nephritis (9). Finally, guselkumab is a mAb that binds to human interleukin (IL)-23 with high affinity and blocks binding of extracellular IL-23 to the cell surface IL-23 receptor, inhibiting IL-23-specific intracellular signaling and subsequent activation and cytokine production. It is used in treatment of psoriatic arthritis, generalized pustular psoriasis, and erythrodermic psoriasis. There is an ongoing study (10) that will evaluate the safety and efficacy of guselkumab added to standard of care compared to placebo added to standard of care.

So as we enter 2021, the field of lupus nephritis is exploding with potential novel therapies on the horizon.

Figure by Kenar D. Jhaveri using biorender.com

The authors report no conflict of interest related to the article.

References

  • 1.

    Parikh SV, et al.. Update on lupus nephritis: Core curriculum 2020. Am J Kidney Dis 2020; 76:265281. doi: 10.1053/j.ajkd.2019.10.017

  • 2.

    Furie R, et al.. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med 2020; 383:11171128. doi: 0.1056/NEJMoa2001180

  • 3.

    Atisha-Fregoso Y, et al.. Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis. Arthritis Rheumatol [published online ahead of print August 4, 2020]. doi: 10.1002/art.41466; https://onlinelibrary.wiley.com/doi/10.1002/art.41466

    • Search Google Scholar
    • Export Citation
  • 4.

    Furie R, et al.. A phase II randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of obinutuzumab or placebo in combination with mycophenolate mofetil in patients with active class III or IV lupus nephritis (abstract). Arthritis Rheumatol 2019; 71 (Suppl 10):939. https://acrabstracts.org/abstract/a-phase-ii-randomized-double-blind-placebo-controlled-study-to-evaluate-the-efficacy-and-safety-of-obinutuzumab-or-placebo-in-combination-with-mycophenolate-mofetil-in-patients-with-active-class-iii/

    • Search Google Scholar
    • Export Citation
  • 5.

    Rovin BH, 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; 95:219231. doi: 10.1016/j.kint.2018.08.025

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Arriens C, et al.. AURORA phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis. Aurinia. June 5, 2020. https://d1io3yog0oux5.cloudfront.net/_b9287cb2b9b32ac3fbb5d08113841567/auriniapharma/db/246/1327/pdf/EULAR+2020+AURORA_Presentation+Deck+05Jun2020.pdf

    • Search Google Scholar
    • Export Citation
  • 7.

    Aurinia. FDA Approves Aurinia Pharmaceuticals’ LUPKYNIS™ (voclosporin) for Adult Patients with Active Lupus Nephritis. January 22, 2021. https://ir.auriniapharma.com/press-releases/detail/210

    • Search Google Scholar
    • Export Citation
  • 8.

    MetroHealth Medical Center. Pentoxifylline in Lupus Nephritis (Pentoxifylline). ClinicalTrials.gov: NCT03859570. https://clinicaltrials.gov/ct2/show/NCT03859570

    • Search Google Scholar
    • Export Citation
  • 9.

    BeiGene. Zanubrutinib in Participants with Active Proliferative Lupus Nephritis. ClinicalTrials.gov: NCT04643470. https://clinicaltrials.gov/ct2/show/NCT04643470

    • Search Google Scholar
    • Export Citation
  • 10.

    Janssen Research & Development, LLC. A Study of Guselkumab in Participants with Active Lupus Nephritis (ORCHID-LN). ClinicalTrials.gov: NCT04376827. https://clinicaltrials.gov/ct2/show/NCT04376827

    • Search Google Scholar
    • Export Citation
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