PRESENTED BY
GABRIELLA MORONI

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Gabriella Moroni

Lupus nephritis (LN) is among the most serious manifestations of systemic lupus erythematosus (SLE). Despite the advances in management and outcomes, it still represents a major challenge for nephrologists. The paramount treatment goal in LN patients is the long-term preservation of renal function through the rapid achievement of therapeutic response, efficient treatment of refractory forms, minimizing the rate of relapses and reduction, or even elimination of corticosteroids. To achieve these goals short-term predictive endpoints are also important in clinical practice, as they help clinicians adjust the treatment plan (1).

According to the European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations, renal function and proteinuria are the main indicator of patients’ response to therapy. Complete remission is defined by proteinuria <0.5g/24h and (near) normal estimated glomerular filtration rate (eGFR), partial remission by ≥50% proteinuria reduction to subnephrotic levels and (near) normal eGFR; and no response include all the other cases (1). The current therapeutic regimens provide complete remission in nearly two-thirds of LN patients after 12 months of therapy. However, about one-fifth of patients never accomplish it, which puts them at a higher risk of further progression of renal function decline (1). Thus, more efficient treatment strategies are needed to ensure the achievement of complete or at least partial response.

The multitarget therapy for LN and novel therapeutic options
Cyclophosphamide combined with high-dose corticosteroids has been the standard first-line treatment for severe LN since the late eighties of the last century. However, in the last decades, several newer treatment strategies, which included mycophenolate mofetil and calcineurin inhibitors, alone and in combination, have been designed to improve remission rates and reduce toxicity. The multitarget therapy, that consists of tacrolimus, 4 mg/day, and mycophenolate mofetil, 1.0 g/day, has exhibited higher efficacy compared with intravenous cyclophosphamide in achieving response as both in induction and in maintenance treatment in randomized, open-label, multi-center 24-weeks and 18-months studies on biopsy-proven LN in Asian populations. Both groups also received 3 days of pulse methylprednisolone followed by a tapering course of oral prednisone therapy (2, 3). More recently, a new calcineurin inhibitor, voclosporin, has been investigated in a phase II randomized, controlled double-blind study compared to placebo on a background of mycophenolate-mofetil and corticosteroids in patients with active LN (4). At six months, the rate of complete response, the time to response and reduction of proteinuria were significantly better in voclosporin than in placebo group. However, even though preclinical observations suggested this drug was more potent and significantly less toxic than immunosuppressants in its class, in this study it exhibited more serious adverse events than placebo at either prescribed dosage. Thus, based on the currently available data, the most effective treatment to induce remission in severe forms of LN is a combination of mycophenolate-mofetil with a calcineurin inhibitor, followed by calcineurin inhibitors or mycophenolate mofetil alone, respectively (5). Cyclosporin also demonstrated excellent efficacy in decreasing proteinuria and preventing the LN flares compared to azathioprine (6).

Nearly a decade ago another promising drug has been introduced, a human monoclonal antibody that inhibits B-cell activating factor – belimumab. It improved renal parameters in patients with baseline renal involvement, but its benefits on clinical outcomes have only recently been investigated in the largest LN study to date – the BLISS-LN trial. The study randomized 448 patients with biopsy-proven LN (class III, IV, and/or V) to either monthly belimumab 10 mg/kg intravenously or placebo, plus standard therapy. At week 104 significantly more belimumab patients achieved primary efficacy renal response defined as urine protein/creatinine ratio ≤0.7; eGFR within 20% of the pre-flare value or ≥60 ml/min/1.73m2; and no rescue therapy. Furthermore, more belimumab than placebo-treated patients achieved a complete renal response, defined as urine protein/creatinine ratio <0.5; eGFR within 10% of the pre-flare value or ≥90 ml/min/1.73m2 and no rescue therapy (7). Thus, belimumab seems to significantly improve LN renal response compared to standard therapy alone, with a favorable safety profile as presented in Figure 1.

Figure 1. Results from the BLISS-LN trial on the efficacy and safety of belimumab in the treatment of LN (7, 8)

Treatment options for refractory LN
Refractory LN is broadly defined as a failure to attain clinical remission with the standard treatment regimen based on unspecific immunosuppressants. It is associated with an increased risk of relapses, progression to end-stage renal disease, and mortality. The poor prognosis of this form of the disease requires aggressive treatment, regular reevaluations of patient response, and a flexible approach to therapeutic regimens. One possible option for these patients may be B-cell ablation with the chimeric anti-CD20 antibody rituximab, which appears to effectively induce remission when standard LN therapies fail (9, 10). Adverse events of rituximab treatment include infections and infusion reactions, but they are usually not serious (10).

Another important issue with refractory LN is its long-term prognosis, which is still elusive as there are scarce reports on the outcome for patients followed for 5 years or more, and in most cases the number of patients was small. Based on the currently available data, it seems that favorable factors for the good long-term outcome are the achievement of complete renal remission, the absence of nephritic flares, and their complete reversibility after therapy (11).

How to reduce corticosteroids without increasing the frequency of relapses?
It is undeniable fact that the outcome of LN has changed dramatically since the introduction of corticosteroid therapy, which efficaciously reduced mortality from this condition. However, event though corticosteroids remain the cornerstone in the treatment of LN, their administration is linked to many and severe side effects leading to organ damage. It seems that after adjustment for other variables, corticosteroid therapy, along with age, ethnicity, and hypertension, is an important predictor of organ deterioration (12, 13). And even though it may affect different systems, renal damage is the most important predictor of mortality within the damage index (14). These observations called for considerations of possible therapeutic alternatives to corticosteroids which would be equally efficient, but cause fewer side effects. The aforementioned belimumab again seems to respond to both challenges. In the longest study which assessed its effects, based on up to 13 years observation in patients included in clinical trials that allowed the registration belimumab for lupus therapy, this drug was well tolerated with no new safety concerns and provided good long-term disease control even with a progressive reduced dosage of corticosteroids (15). Results in real-life setting confirmed that in patients with active SLE and low damage at baseline, treatment with belimumab early in the disease lead to favorable outcomes in terms of a higher rate of remission and a lower rate of flares (16). A posthoc analysis of over 200 patients with LN included in the studies that allowed the registration of belimumab for lupus treatment, also showed that patients who received belimumab experienced fewer flares and needed lower corticosteroid doses compared to the placebo group (17). Even more so, a very recent study suggested that belimumab in some cases of LN may even allow the withdrawal of corticosteroids without any major adverse events (18).

References

1. 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.

2. Liu Z, Zhang H, Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med. 2015;162(1):18-26.

3. Zhang H, Liu Z, Zhou M, et al. Multitarget Therapy for Maintenance Treatment of Lupus Nephritis. J Am Soc Nephrol. 2017;28(12):3671-3678.

4. Rovin BH, Solomons N, Pendergraft WF 3rd, 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.

5. Tunnicliffe DJ, Palmer SC, Henderson L, et al. Immunosuppressive treatment for proliferative lupus nephritis. Cochrane Database Syst Rev. 2018;6(6):CD002922.

6. Moroni G, Doria A, Mosca M, et al. A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years. Clin J Am Soc Nephrol. 2006;1(5):925-932.

7. Efficacy and Safety of Belimumab in Patients With Active Lupus Nephritis (BLISS-LN). ClinicalTrials.gov:NCT01639339.

8. Moroni G. Should I change my daily practice in the treatment of lupus nephritis with new drugs for SLE? Presented at the 57th European Renal Association – European Dialysis Transplantation Congress (fully virtual), June 7, 2020. Available at Virtual Meeting

9. Weidenbusch M, Römmele C, Schröttle A, Anders HJ. Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis. Nephrol Dial Transplant. 2013;28(1):106-111.

10. Iaccarino L, Bartoloni E, Carli L, et al. Efficacy and safety of off-label use of rituximab in refractory lupus: data from the Italian Multicentre Registry. Clin Exp Rheumatol. 2015;33(4):449-456.

11. Moroni G, Quaglini S, Gallelli B, Banfi G, Messa P, Ponticelli C. The long-term outcome of 93 patients with proliferative lupus nephritis. Nephrol Dial Transplant. 2007;22(9):2531-2539.

12. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677-2686.

13. Bruce IN, O’Keeffe AG, Farewell V, et al. Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort. Ann Rheum Dis. 2015;74(9):1706-1713.

14. Danila MI, Pons-Estel GJ, Zhang J, Vilá LM, Reveille JD, Alarcón GS. Renal damage is the most important predictor of mortality within the damage index: data from LUMINA LXIV, a multiethnic US cohort. Rheumatology (Oxford). 2009;48(5):542-545.

15. 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. 2019;71(7):1125-1134.

16. Gatto M, Saccon F, Zen M, et al. Early Disease and Low Baseline Damage as Predictors of Response to Belimumab in Patients With Systemic Lupus Erythematosus in a Real-Life Setting [published online ahead of print, 2020 Apr 10]. Arthritis Rheumatol. 2020;10.1002/art.41253.

17. M A Dooley 1, F Houssiau, C Aranow, D P D’Cruz, A Askanase, D A Roth, Z J Zhong, S Cooper, W W Freimuth, E M Ginzler, BLISS-52 and -76 Study Groups. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE Lupus 2013;22(1):63-72  doi: 10.1177/0961203312465781.

18. Binda V, Trezzi B, Del Papa N, et al. Belimumab may decrease flare rate and allow glucocorticoid withdrawal in lupus nephritis (including dialysis and transplanted patient) [published online ahead of print, 2020 Jan 30]. J Nephrol. 2020;10.1007/s40620-020-00706-3.

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