Lupus nephritis (LN), the prototypic immune complex glomerulonephritis, occurs in 40% of systemic lupus erythematosus (SLE) patients with a higher incidence among African Americans, Hispanics and Asians . Lupus nephritis treatment is divided into induction and maintenance phases. The goal of induction treatment is to reduce glomerular inflammation in order to prevent long-term kidney damage, whereas the aim of maintenance therapy is to prevent additional flares and damage. Despite available therapies, which include glucocorticoids along with either cyclophosphamide (CYC) or mycophenolate mofetil (MMF) , approximately 22% of LN patients develop end stage renal disease . This highlights an unmet need for new therapeutics, as our current treatment regimens are only partially effective and are potentially toxic. In this editorial, we will focus on emerging therapeutics for International Society of Nephrology/ Renal Pathology Society class III and IV proliferative LN (summarized in Table 1).
B-cell targeted therapies
Three monoclonal antibodies (mAbs) targeting CD20 have been evaluated in LN: rituximab (RTX); obinutuzumab; and ocrelizumab. The LUNAR trial compared RTX to placebo on background steroids and MMF (NCT00282347). Although this study failed to meet the endpoint of a statistically superior renal response at one year, numerical superiority in the response rate, a significant reduction in proteinuria at 78 weeks, and no CYC rescues (compared with 10% in the placebo group) were observed in the rituximab arm. These provocative findings indicated a need to further examine the therapeutic role of B-cell depletion in LN.
The BELONG study, which compared ocrelizumab to placebo in proliferative LN, was terminated prematurely due to excessive serious or opportunistic infections in patients living in Asia (NCT00626197). From an analysis of an incomplete data set, it was apparent that there was no statistically significant differentiation between the ocrelizumab and placebo response rates.
The failure of these clinical trials could be attributed to trial design, insufficient B-cell depletion, or the return of excessive numbers of circulating autoreactive B cells stimulated by increased levels of B-cell activating factor (BAFF) following RTX treatment .
Obinutuzumab, which is currently approved for chronic lymphocytic leukemia, is also currently under study in patients with LN (NCT02550652).
Anti-B lymphocyte stimulator
Belimumab, a mAb targeting BAFF (also known as B lymphocyte stimulator [BLyS]), which is currently approved for extra-renal SLE, is under investigation in LN (BLISS-LN, NCT01639339). The observation of high BAFF levels after B-cell depletion led to the design of the CALIBRATE study, exploring the sequential administration of RTX followed by belimumab (NCT02260934) in LN. The week 48 results of this study failed to demonstrate additional benefit with belimumab; however, week 96 data are forthcoming .
The use of proteasome inhibitors to induce depletion of B cells and plasma cells, a source of pathogenic autoantibodies in patients with SLE, is also being pursued as a potential treatment for LN. The administration of bortezomib to patients with refractory LN was associated with reductions in proteinuria, plasma cells and type I interferon (IFN) activity at 6 months in a small study . The proteasome inhibitor KZR-616 is being studied in early trials; however, a trial of ixazomib, which is currently approved for multiple myeloma, was terminated due to insufficient enrollment.
T-cell targeted therapies
T-cell effector cells are other key participants in LN pathogenesis. These autoreactive cells exert their functions by induction of proinflammatory and immunomodulatory cytokines, upregulation of major histocompatibility complex class II molecules and recruitment of macrophages in both humans and murine models .
Abatacept, a fusion protein that inhibits the CD28-CD80/86 costimulatory signaling pathway, failed to improve responses compared to placebo on either background MMF (NCT00430677) or CYC (NCT00774852). Despite an enhanced trial design, a 400-patient phase III study again failed to demonstrate added benefit of abatacept .
Calcineurin inhibitors (CNIs), specifically tacrolimus, were studied in Asia. A randomized trial comparing MMF to tacrolimus as first line induction treatment yielded comparable responses between groups, but with an increased tendency to relapse at 5 years in the tacrolimus arm (NCT00371319). In a separate study, the combination of low dose MMF with tacrolimus was superior to pulse CYC at 6 months (NCT00876616). Although this regimen was superior to pulse CYC, limitations to its adoption include: the generalizability across different ethnic groups, the increased rate of adverse events, and limited evidence of efficacy beyond 6 months.
Recently, voclosporin has received attention due to its higher potency and better safety profile compared with other CNIs. The AURA-LV phase II trial (NCT02141672), which compared two dosing regimens of voclosporin to placebo on background steroids and MMF, generated a higher response rate with low dose voclosporin compared with placebo (49.4% vs 23.9% at 48 weeks). These encouraging results supported a phase III trial that is currently underway (NCT03021499).
CD40-CD40 ligand inhibition
CD40 ligand (CD40L) belongs to the tumor necrosis factor superfamily and is expressed on activated T cells. The interaction between CD40L and CD40 on B cells plays a key role in the regulation of humoral and cellular responses . Limited data from a prematurely terminated open-label trial of BG9588 in LN have been reported by Boumpas et al . In addition, trials of anti-CD40 mAbs (CFZ533 and BI655064) are currently underway.
Type I IFN plays a role in the pathogenesis of SLE both in humans and murine models . Promising results in a phase II extra-renal trial (NCT01438489) along with the observations of plasmacytoid dendritic cells and interferon production in the kidneys of patients with LN [12,13] supported a phase II trial of anifrolumab in LN (TULIP-LN1; NCT02547922).
LN is the most common organ-threatening complication of SLE. Despite available therapies, a need for safer and more efficacious therapies exists. A reduction in glucocorticoid exposure is also a priority and was incorporated into the Rituxilup  and voclosporin protocols . While the lupus community has witnessed unprecedented clinical trial activity, the achievement of positive results has been particularly challenging and humbling. However, there is little doubt that the future holds promise, and that there will be new therapies that improve outcomes for patients with LN.