Lupus nephritis (LN) is a frequent and severe manifestation of systemic lupus erythematosus (SLE) that substantially affects renal outcomes and long-term survival. Notably, this disease remains a leading cause of SLE-related mortality. Glucocorticoids, hydroxychloroquine, immunosuppressive agents, and calcineurin inhibitors (CNIs) represent the standard therapy. As a next-generation CNI, the use of voclosporin represents a therapeutic advance for LN. This can be attributed to its optimized pharmacologic properties and dual mechanism of action, which involves potent inhibition of T-cell activation and direct stabilization of podocytes. In pivotal phase III trials, the addition of voclosporin to a background of mycophenolate mofetil and low-dose glucocorticoids significantly increased complete renal remission rates and produced a rapid, durable reduction in proteinuria. These findings support a “low steroid” treatment approach. Compared with conventional CNIs, voclosporin has more consistent pharmacokinetics, favorable metabolic safety, and lacks clinically meaningful drug–drug interactions with mycophenolate mofetil. Voclosporin is also cost effective, as suggested by economic evaluations conducted from multiple national health-system perspectives. The available evidence collectively indicates that voclosporin, through its efficacy, safety, and economic value, enables a more precise, efficient, and comparatively cost-effective treatment paradigm for LN.
| [1] |
Tanaka Y. State-of-the-art treatment of systemic lupus erythematosus. Int J Rheum Dis., 2020, 23(4): 465-471.
|
| [2] |
Basta F, Fasola F, Triantafyllias K, et al.. Systemic lupus erythematosus (SLE) therapy: the old and the new. Rheumatol Ther., 2020, 7(3): 433-446.
|
| [3] |
Smith PP, Gordon C. Systemic lupus erythematosus: clinical presentations. Autoimmun Rev., 2010, 10(1): 43-45.
|
| [4] |
Davidson A. What is damaging the kidney in lupus nephritis. Nat Rev Rheumatol., 2016, 12(3): 143-153.
|
| [5] |
Pons-Estel GJ, Serrano R, Plasín MA, et al.. Epidemiology and management of refractory lupus nephritis. Autoimmun Rev., 2011, 10(11): 655-663.
|
| [6] |
Hu YC, Tsai IJ, Hsu HY, et al.. Identification of monoclonal antibodies against human renal glomerular endothelial cells in lupus nephritis that induce endothelial interferon-alpha production. Arthritis Res Ther., 2021, 23(1): 171.
|
| [7] |
Yap DY, Lai KN. Pathogenesis of renal disease in systemic lupus erythematosus—the role of autoantibodies and lymphocytes subset abnormalities. Int J Mol Sci., 2015, 16(4): 7917-7931.
|
| [8] |
Yung S, Chan TM. Anti-dsDNA antibodies and resident renal cells—Their putative roles in pathogenesis of renal lesions in lupus nephritis. Clin Immunol., 2017, 185: 40-50.
|
| [9] |
Bagavant H, Fu SM. Pathogenesis of kidney disease in systemic lupus erythematosus. Curr Opin Rheumatol., 2009, 21(5): 489-494.
|
| [10] |
Cui W, Tian Y, Huang G, et al.. Clinical research progress of novel biologics for the treatment of lupus nephritis. Clin Exp Med., 2023, 23(8): 4153-4162.
|
| [11] |
Mahajan A, Amelio J, Gairy K, et al.. Systemic lupus erythematosus, lupus nephritis and end-stage renal disease: a pragmatic review mapping disease severity and progression. Lupus., 2020, 29(9): 1011-1020.
|
| [12] |
Hanly JG, O’Keeffe AG, Su L, et al.. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology (Oxford)., 2016, 55(2): 252-262.
|
| [13] |
Kidney Disease: Improving Global Outcomes Lupus Nephritis Work Group. KDIGO 2024 clinical practice guideline for the management of LUPUS NEPHRITIS. Kidney Int. 2024;105(1S):S1–S69.
|
| [14] |
Fanouriakis A, Kostopoulou M, Cheema K, et al.. sat0173 a systematic literature review informing the 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: 1028.
|
| [15] |
Fanouriakis A, Kostopoulou M, Andersen J, et al.. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis., 2024, 83(1): 15-29.
|
| [16] |
Almaani S, Meara A, Rovin BH. Update on lupus nephritis. Clin J Am Soc Nephrol., 2017, 12(5): 825-835.
|
| [17] |
Rovin BH, Furie R, Latinis K, et al.. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The lupus nephritis assessment with rituximab study. Arthritis Rheum., 2012, 64(4): 1215-1226.
|
| [18] |
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.
|
| [19] |
Wofsy D, Hillson JL, Diamond B. Comparison of alternative primary outcome measures for use in lupus nephritis clinical trials. Arthritis Rheum., 2013, 65(6): 1586-1591.
|
| [20] |
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., 2024, 76(1): 59-67.
|
| [21] |
Chen YE, Korbet SM, Katz RS, et al.. Value of a complete or partial remission in severe lupus nephritis. Clin J Am Soc Nephrol., 2008, 3(1): 46-53.
|
| [22] |
Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol., 1997, 15: 707-747.
|
| [23] |
Ponticelli C, Podestà MA. Calcineurin inhibitors in lupus nephritis. J Nephrol., 2021, 34(2): 399-402.
|
| [24] |
Kyttaris VC, Wang Y, Juang YT, et al.. Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus. J Immunol., 2007, 178(3): 1960-1966.
|
| [25] |
van Gelder T, Lerma E, Engelke K, et al.. Voclosporin: a novel calcineurin inhibitor for the treatment of lupus nephritis. Expert Rev Clin Pharmacol., 2022, 15(5): 515-529.
|
| [26] |
Blaine J, Dylewski J. Regulation of the actin cytoskeleton in podocytes. Cells., 2020, 9(7): 1700.
|
| [27] |
Ning L, Suleiman HY, Miner JH. Synaptopodin is dispensable for normal podocyte homeostasis but is protective in the context of acute podocyte injury. J Am Soc Nephrol., 2020, 31(12): 2815-2832.
|
| [28] |
Descazeaud V, Mestre E, Marquet P, et al.. Calcineurin regulation of cytoskeleton organization: a new paradigm to analyse the effects of calcineurin inhibitors on the kidney. J Cell Mol Med., 2012, 16(2): 218-227.
|
| [29] |
Faul C, Donnelly M, Merscher-Gomez S, et al.. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med., 2008, 14(9): 931-938.
|
| [30] |
Liao R, Liu Q, Zheng Z, et al.. Tacrolimus protects podocytes from injury in lupus nephritis partly by stabilizing the cytoskeleton and inhibiting podocyte apoptosis. PLoS One., 2015, 10(7. ArticleID: e0132724
|
| [31] |
Kuglstatter A, Mueller F, Kusznir E, et al.. Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr., 2011, 67(Pt 2): 119-123.
|
| [32] |
Bîrsan T, Dambrin C, Freitag DG, et al.. The novel calcineurin inhibitor ISA247: a more potent immunosuppressant than cyclosporine in vitro. Transpl Int., 2005, 17(12): 767-771.
|
| [33] |
Busque S, Cantarovich M, Mulgaonkar S, et al.. The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation. Am J Transplant., 2011, 11(12): 2675-2684.
|
| [34] |
Abdel-Kahaar E, Keller F. Clinical pharmacokinetics and pharmacodynamics of voclosporin. Clin Pharmacokinet., 2023, 62(5): 693-703.
|
| [35] |
Heo YA. Voclosporin: first approval. Drugs., 2021, 81(5): 605-610.
|
| [36] |
Ekmekçioğlu O, Turkan S, Yıldız Ş, et al.. Comparison of tacrolimus with a cyclosporine microemulsion for immunosuppressive therapy in kidney transplantation. Urol Res Pract., 2013, 39(1): 16-21.
|
| [37] |
Li Y, Palmisano M, Sun D, et al.. Pharmacokinetic disposition difference between cyclosporine and voclosporin drives their distinct efficacy and safety profiles in clinical studies. Clin Pharmacol Adv Appl., 2020, 12: 83-96
|
| [38] |
van Gelder T, Huizinga RB, Lisk L, et al.. Voclosporin: a novel calcineurin inhibitor with no impact on mycophenolic acid levels in patients with SLE. Nephrol Dial Transplant., 2022, 37(5): 917-922.
|
| [39] |
Dall’Era M, Kalunian K, Solomons N, et al. Comparison of a voclosporin-based triple immunosuppressive therapy to high-dose glucocorticoid-based immunosuppressive therapy: a propensity analysis of the AURA-LV and AURORA 1 studies and ALMS. Lupus Sci Med. 2024;11(2):e001319.
|
| [40] |
Ledingham D, Plant M, Mustafa F, et al.. Preserving fertility: using cyclophosphamide and other cytotoxics in young people. Pract Neurol., 2020, 20(2): 148-153.
|
| [41] |
Edimiris P, Krüssel JS. Fertility preservation options before gonadotoxic antirheumatic treatment: a review. Z Rheumatol., 2021, 80(8): 726-732.
|
| [42] |
Ogino MH, Tadi P. Cyclophosphamide. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023.
|
| [43] |
Mayo PR, Huizinga RB, Ling SY, et al.. Voclosporin food effect and single oral ascending dose pharmacokinetic and pharmacodynamic studies in healthy human subjects. J Clin Pharmacol., 2013, 53(8): 819-826.
|
| [44] |
LUPKYNIS (voclosporin) capsules, for oral use [Internet]. 2025 [cited 2025 Nov 10]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/213716s008lbl.pdf
|
| [45] |
Ling SY, Huizinga RB, Mayo PR, et al.. Pharmacokinetics of voclosporin in renal impairment and hepatic impairment. J Clin Pharmacol., 2013, 53(12): 1303-1312.
|
| [46] |
Ling SY, Huizinga RB, Mayo PR, et al.. Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin. Br J Clin Pharmacol., 2014, 77(6): 1039-1050.
|
| [47] |
Broen JCA, van Laar JM. Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology. Nat Rev Rheumatol., 2020, 16(3): 167-178.
|
| [48] |
Mejía-Vilet JM, Ayoub I. The use of glucocorticoids in lupus nephritis: new pathways for an old drug. Front Med., 2021, 8. ArticleID: 622225
|
| [49] |
Gregoor PJ, de Sévaux RG, Hené RJ, et al.. Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients. Transplantation., 1999, 68(10): 1603-1606.
|
| [50] |
Hesselink DA, van Hest RM, Mathot RA, et al.. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant., 2005, 5(5): 987-994.
|
| [51] |
Rovin BH, Solomons N, Pendergraft 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.
|
| [52] |
Al Sawah S, Zhang X, Zhu B, et al.. Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus—the Hopkins Lupus Cohort. Lupus Sci Med., 2015, 2(1. ArticleID: e000066
|
| [53] |
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100(4s):S1–S276.
|
| [54] |
Rovin BH, Onno Teng YK, 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.
|
| [55] |
Dall’Era M, Cisternas MG, Smilek DE, et al. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the euro-lupus nephritis cohort. Arthritis Rheumatol. 2015;67(5):1305–1313.
|
| [56] |
Houssiau FA, Vasconcelos C, D’Cruz D, et al.. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: Lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial. Arthritis Rheum., 2004, 50(12): 3934-3940.
|
| [57] |
Moroni G, Gatto M, Tamborini F, et al.. Lack of EULAR/ERA-EDTA response at 1 year predicts poor long-term renal outcome in patients with lupus nephritis. Ann Rheum Dis., 2020, 79(8): 1077-1083.
|
| [58] |
Davidson JE, Fu Q, Ji B, et al.. Renal remission status and longterm renal survival in patients with lupus nephritis: a retrospective cohort analysis. J Rheumatol., 2018, 45(5): 671-677.
|
| [59] |
Rovin BH, Cassol C, Parikh SV, et al.. Effect of long-term voclosporin treatment on renal histology in patients with active lupus nephritis with repeat renal biopsies. Arthritis Rheumatol., 2025, 77(10): 1387-1393.
|
| [60] |
Palmer BF, Tumlin JA, Radhakrishnan J, et al.. The kidney injury biomarker profile of patients with lupus nephritis remains unchanged with the second-generation calcineurin inhibitor voclosporin. Front Nephrol., 2025, 5: 1540471.
|
| [61] |
Dong Y, Shi J, Wang S, et al.. The efficacy of immunosuppressive drugs induction therapy for lupus nephritis: a systematic review and network meta-analysis. Ren Fail., 2023, 45(2): 2290365.
|
| [62] |
Racca F, Greco JM, Tatakis DN. Voclosporin-induced gingival enlargement: a case report. Clin Adv Periodontics. 2025;1–6.
|
| [63] |
Chong MCZ, Wu HHL, Ponnusamy A. Gum hyperplasia in a patient with lupus nephritis. Kidney360.2025;6(7):1248–1249.
|
| [64] |
Hahn BH, McMahon MA, Wilkinson A, et al.. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res., 2012, 64(6): 797-808.
|
| [65] |
Anders HJ, Federico R, Randhawa S, et al.. 1110 Voclosporin is effective in achieving proteinuria treatment targets in lupus nephritis defined by EULAR/ERA recommendations. Lupus Sci Med., 2022, 9(Suppl 3): A75.2-A76
|
| [66] |
Kale A, Shelke V, Lei Y, et al.. Voclosporin: unique chemistry, pharmacology and toxicity profile, and possible options for implementation into the management of lupus nephritis. Cells., 2023, 12(20): 2440.
|
| [67] |
Baum R, Geetha D, Fatola A, et al.. Treatment using both voclosporin and belimumab in four patients with lupus nephritis. Cureus., 2023, 15(5): e38848
|
| [68] |
Ebrahimi N, Ghozloujeh ZG, Momand D, et al.. Successful treatment of lupus nephritis with belimumab and voclosporin: a rare case. Am J Kidney Dis., 2023, 83(4): S16
|
| [69] |
Dykema AG, Vodusek Z, Karagenova R, et al.. Combination therapy with voclosporin and anifrolumab in two patients with lupus nephritis and discoid lupus erythematosus. Cureus., 2025, 17(5): e83337
|
| [70] |
Rovin BH, Furie R, Onno Teng YK, et al.. A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis. Kidney Int., 2022, 101(2): 403-413.
|
| [71] |
Tang W, Tummala R, Almquist J, et al.. Clinical pharmacokinetics, pharmacodynamics, and immunogenicity of anifrolumab. Clin Pharmacokinet., 2023, 62(5): 655-671.
|
| [72] |
Dall’Era M, Kalunian K, Eaddy M, et al. Real-world treatment utilization and economic implications of lupus nephritis disease activity in the United States. J Manag Care Specialty Pharm. 2023;29(1):36–45.
|
| [73] |
Mandrik O, Fotheringham J, Ren S, et al.. The cost-effectiveness of belimumab and voclosporin for patients with lupus nephritis in the United States. Clin J Am Soc Nephrol., 2022, 17(3): 385-394.
|
| [74] |
Kennedy L, Lee E, Flauto R, et al.. Evaluating the cost-effectiveness of voclosporin for the treatment of lupus nephritis in the United States. J Manag Care Spec Pharm., 2024, 30(8): 773-781
|
| [75] |
Gittfried A, Farrington E, Anell B, et al.. EE272 cost-effectiveness of voclosporin in combination with mycophenolate mofetil for active lupus nephritis in Sweden. Value Health., 2023, 26(12): S103-S104.
|
| [76] |
Duran NP, Salinas-Ortega L, de la Cuadra-Grande A, et al. #1672 Cost-effectiveness analysis of voclosporin vs mycophenolate or belimumab in the treatment of patients with lupus nephritis from the Spanish National Healthcare System perspective. Nephrol Dial Transplant. 2025;40(Supplement_3):gfaf116.1307.
|
RIGHTS & PERMISSIONS
The Author(s), under exclusive licence to the Huazhong University of Science and Technology
PDF
