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Steven P. Menez1,*

, Basset El Essawy2 and Mohamed G. Atta

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1Johns Hopkins Department of Medicine, Division of Nephrology, Baltimore, MD, USA; 2Department of Medicine, Al-Azhar University, Nephrology Unit, Cairo, Egypt

A R T I C L E H I S T O R Y

Received: August 26, 2017

Revised: November 03, 2017 Accepted: November 13, 2017

DOI: 10.2174/1574887112666171123113200

Abstract: Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disorder character-

ized by chronic inflammation, which can result in a multitude of systemic or organ-limited manifesta-

tions, including the skin, lungs, heart, and kidney. SLE nephritis is present in an average of 38% of pa-

tients at the time of diagnosis, and may occur as the initial presentation of disease with progression to

End-Stage Renal Disease (ESRD) in roughly 10-20% of patients.

Methods: A review of the current literature was undertaken to investigate the evolution of treatment of

SLE nephritis based on randomized trials and robust observational studies. We aimed to provide a

timeline of the development of current induction and maintenance therapy, as well as the development

of novel targeted therapies, all leading to current guidelines.

Results: Based on all available current data on standard of care therapies for SLE nephritis, there is at

best a complete remission rate of 50-60%, and roughly 13-25% of patients experience periods of re-

lapse during maintenance therapy for SLE nephritis. Therefore, the need for newer, targeted therapies

has been the focus of many current, ongoing clinical trials.

Conclusion: Standard induction and maintenance therapies at present are anti-proliferative and non-

specific, that is, interfering with the process of autoantigen presentation and activation of autoreactive

leukocytes. However, newer agents with specific T-cell, B-cell, or proteasome targets are currently be-

ing investigated.

Keywords: Chronic kidney disease, clinical trials, End-Stage Renal Disease (ESRD), immunosuppression, kidney biopsy, sys-temic lupus erythematosus.

1. INTRODUCTION

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder characterized by chronic inflammation, which can result in a multitude of systemic or organ-limited manifesta-tions, including the skin, lungs, heart, and kidney [1]. Lupus involvement in the kidney manifests in a number of different ways, including thrombotic microangiopathy and renal-limited vasculitis, though of greatest concern is SLE nephri-tis. Immune complex deposition in various parts of the glomerulus defines the several classes of SLE nephritis, based on the 2003 ISN/RPS classification scheme [2]. SLE nephritis is present in an average of 38% of patients at the time of diagnosis, and may occur as the initial presentation of disease [3]. In general, renal involvement occurs in 40-70% of SLE patients, with progression to End-Stage Renal Disease (ESRD) developing in roughly 10-20% of patients based on USRDS data and the Johns Hopkins lupus cohort, though renal disease in general was not a strong predictor of survival [4, 5]. In SLE nephritis, and in renal disease in gen-eral, management of disease is essential to minimizing

*Address correspondence to this author at the Johns Hopkins Department of

Medicine, Division of Nephrology, Baltimore, MD, USA; Tel: 410-955-

5268; Fax: 410-367-2258; E-mail: smenez1@jhmi.edu

glomerular damage and slowing or stopping the progression to ESRD [6].

It has been well described that SLE affects women pre-dominantly, but overall disease burden can vary greatly based on demographics [7]. Significant disparities exist re-garding the incidence and prevalence of SLE in various parts of the world, and within countries based on race. From the LUMINA (Lupus in minority populations: nature vs. nurture) cohort, for instance, Bastian and colleagues demonstrated that there is a significantly higher rate of SLE nephritis among Hispanics and African Americans with SLE in the USA, compared to Caucasians [8].

In a recent review, the overall incidence of ESRD in pa-tients diagnosed with SLE was shown to be 4.3% (95% CI: 2.8-5.8%), but among patients diagnosed with SLE nephritis, that incidence rose to 10.1% (95% CI: 6.6-13.6%) [3]. Fur-ther, patients with SLE nephritis were found to have a higher risk of death overall, with a hazard ratio (HR) of 2.98 (95% CI: 1.48-5.99; P=0.002). Further, the rates of progression to ESRD and mortality have not changed appreciably in recent years [9, 10]. Specifically, from 1995 to 2005, Costenbader and colleagues found a shift in the socio-demographics and clinical characteristics of patients who develop ESRD from SLE nephritis over time (such as higher BMI, and greater

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106 Reviews on Recent Clinical Trials, 2018, Vol. 13, No. 2 Menez et al.

incidence of diabetes mellitus and hypertension at time of diagnosis). However, there were no significant improve-ments in progression to ESRD or to survival after ESRD diagnosis. Indeed, Croca and colleagues found that mortality rates by decade from 1975-2005 have declined significantly, from 17.2 % to 4.7%, with a longer time interval from ESRD diagnosis to death. However, over the 10 years from 1996 to 2005, these rates have not changed appreciably, leading to the conclusion that standard therapies up to that point have reached their maximal benefit. Efforts to develop and im-plement new therapies will be explored in this review.

2. PATHOPHYSIOLOGY

Anders and Rovin recently outlined major pathophysi-ological mechanisms through which SLE nephritis develops [11]. The first cornerstone of action they describe is the autovaccination against nuclear antigens. Checkpoint mechanisms within the body work to ensure self-tolerance, and like other autoimmune disorders, in SLE there is a loss of this self-tolerance against various self-antigens. After this loss of immune tolerance, there is an expansion of auto-reactive lymphocytes, often in the setting of one of the many potential triggers (including infection, at which time the authors note that patient will typically start to develop symp-toms of SLE, including fevers, fatigue, and arthralgias). Eventually, with persistent autoimmune activation of T and B-cells without treatment, organ damage can occur. Within the kidney itself, there can be immune deposition at various locations within the glomerulus, including within the mesan-gium (SLE nephritis classes I and II), sub-endothelial im-mune deposition (classes III and IV) and sub-epithelial im-mune deposition (class V).

Related to this phenomenon is the modification of auto-antigens, also with the consequence of increasing immuno-genicity. As described by Radic and Muller, self or auto-antigens are in a state of constant modification [12]. Post translational modifications to proteins ensure that this system remains in a constant flux, and errors in this system can lead to under or over-regulation of certain processes in this chain of events. This can have a myriad of effects, one of which is the erroneous identification of an endogenous cellular compo-nents as foreign, thus leading to increased immunogenicity.

Another pathway for increased immunogenicity in auto-immune disease involves the formation and activation of chromatin “traps” designed to combat infection [12-14]. Ac-tivated neutrophils combine various intracellular proteins and chromatin together, and externalize this aggregate to the cell surface, which can serve as Neutrophil Extracellular Traps (NETs) for bacteria, viruses, and fungi. Gupta and Kaplan propose several mechanisms by which this pathway can become altered in the setting of SLE specifically [14]. Patients with SLE possess low-density granulocytes, a subset of granulocytes that have an enhanced ability to produce NETs. The components in such NET’s tend to have more pro-inflammatory and autoimmune capacity, such as double-stranded DNA. Further, as with the defective apoptosis noted below, NETs in these patients may not be effectively cleared, leading to another pathway for complement activation.

Defective clearance of apoptotic waste has also been demonstrated to contribute to the pathophysiology of SLE

development [15]. Deficiencies in a number of genes inclu- deing TREX1 and ATG5 have been associated with the ac- cumulation of protein byproducts and chromatin. Persistence of apoptotic cells and subsequent buildup of cellular debris have been postulated to create and perpetuate a chronic in- flammatory response [16, 17]. Ultimately this may lead to the initiation of systemic autoimmunity, specifically if the apoptotic debris and subsequent inflammation occurs in germinal centers where complement activation and further autoimmunity can progress [16].

Another hallmark of SLE nephritis pathophysiology as outlined by Anders and Rovin is the presence of lupus autoantigens triggering immune responses, with clinical symptoms similar to that of viral infections. With loss of self-tolerance, endogenous nucleic acids may be targeted as exogenous antigens via Toll Like Receptors (TLR’s), inducing interferon-�-dependent auto-immune responses. Clinically, patients may experience arthralgias, myalgias, fevers, etc. similar to the response to viral infections, termed “pseudoan- tiviral immunity” [18]. This concept is based on the idea that under certain conditions in a specific host, nucleic acids trig- ger immune responses that are in place against viral infections.

Additionally, various groups have explored the role of the complement cascade in the pathogenesis of SLE nephritis [19-21]. The classical complement cascade is most strongly implicated in the development of SLE nephritis, as opposed to the alternative and lectin pathways. Specifically, deficien- cies in C1, of which one component is C1q, either through missense or nonsense mutations, lead to defective cleavage of C4 and C2, therefore leading to defective cleavage of C3 to C3a and C3b, ultimately leading to lack of formation of the C5b-C9 membrane attack complex. Overall these defi- ciencies lead to an increased risk of SLE.

However, it is the over-activation of complement and immune complex deposition that leads to many of the clini-cal consequences seen in SLE nephritis (Fig. 1). It has been established that complement levels, specifically C3 and C4 measured in the serum, are low in roughly 75% of patients with focal SLE nephritis, and up to 90% in patients with dif-fuse SLE nephritis [22]. Patients with SLE have been shown to have higher antibody titers against C1q, specifically the collagenous tail of C1q, and low levels of C1q have been associated with active disease. Numerous studies to date have demonstrated the association between C1q auto-antibodies and SLE nephritis, hypo-complementemia, and circulating immune complexes, which can deposit in glome-ruli [2, 20].

As self nucleic acids and viral antigens activate the same TLR’s, cytokines released in response to the presence of both can turn on immune activation, both innate and im- mune, leading to immune complex deposition and clinically can lead to similar pictures, as outline above [23]. Specifi- cally, Weidenbusch and colleagues argue that the innate im- mune system initiates the inflammatory cascade that leads to disease onset, and continues to perpetuate the adaptive im- mune responses that lead to ongoing activity.

Previous work has also shown that Type I interferons be- long to a class of antiviral cytokine family, specifically IFN- � and IFN-�, are associated with SLE [24]. Theofilopoulos and colleagues have shown that both IFN-� and IFN-�

Lupus Nephritis: Current Treatment Paradigm and Unmet Needs Reviews on Recent Clinical Trials, 2018, Vol. 13, No. 2 107

production are initiated early in the innate immune response and play major roles in downstream events, including influ-encing the expression and function of other cytokines such transforming growth factor � and IL-1 receptor antagonists, and TNF � receptors. Clinical manifestations of SLE nephri-tis commonly seen include proteinuria, often nephrotic range, as well as hematuria, hypertension, and a necessary decline in renal function.

3. CURRENT TREATMENTS IN SLE NEPHRITIS

3.1. Induction Therapy

In general in kidney disease management, the goal is to reduce inflammation to preserve kidney function as much as possible, as well as prevent overall mortality with a focus on cardiovascular mortality, as cardiovascular disease is the leading cause of death in patients with CKD [25]. Specifi-cally in SLE nephritis, Kidney Disease Improving Global Outcomes (KDIGO) released the current definitions regard-ing response to therapy in 2012 [26]. Complete response to treatment was defined as a return of serum creatinine (sCr) to previous baseline, as well as a decline in a spot urine pro-tein/creatinine (uPCR) to <500 mg/g. A partial response was defined as stabilization, up to 25% above or below sCr peak, or an improvement of sCr but not back to previous baseline. As well, there must be a �50% decrease in uPCR (with an absolute reduction to <3000 mg/g for patients with neph-rotic-range proteinuria. Deterioration was not explicitly de-fined, though the authors note that in general, a 25% increase in sCr was considered treatment failure.

Austin and colleagues showed in 1986 the survival bene-fit incurred with various treatments, including prednisone and cytotoxic drugs, from several randomized controlled trial

for SLE nephritis [27, 28]. With a mean follow-up of 85 months, oral azathioprine alone had a statistically significant benefit over prednisone monotherapy with respect to pro-gression to ESRD (P=0.09). Further, those patients on a combination of oral cyclophosphamide and oral azathioprine had better outcomes still. However, those on either oral or IV cyclophosphamide, in addition to low-dose maintenance prednisone, had a much lower rate of progression to ESRD compared to all other groups. Given high doses of cytotoxic therapy (up to 4 mg/kg per day of azathioprine, and up to 1 g per m

2 of body-surface area in the IV cyclophosphamide

group, every 3 months for up to 5 doses), there was some concern for a risk of higher mortality with the more cyto-toxic regimens. However, no significant differences in sur-vival were noted among any groups, in fact with a trend to-wards higher mortality amongst the prednisone-only group. The authors also point out that no reported deaths were re-lated to leukemia or lymphoid malignancy. Further studies investigated optimal cyclophosphamide dosing and treatment intervals [28-30].

With regard to the total number of treatments of cyclo-phosphamide to administer, there has been considerable con-cern regarding total cumulative dose needed to achieve sta-ble renal function, balanced against the medicine’s toxic side effect profile. One notable side effect among women on in-termittent pulse IV cyclophosphamide was identified as per-sistent amenorrhea [30]. Boumpas and colleagues conducted a retrospective study of 39 women treated with cyclophos-phamide for active SLE or neuropsychiatric lupus, from 0.5-1g/m

2 body surface area for a total of seven doses (short

course) vs. fifteen or more doses (long course). They found that sustained amenorrhea occurred in two out of the sixteen patients in the short arm (12%) compared to nine out of

Fig. (1). Pathogenesis of SLE nephritis.�

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108 Reviews on Recent Clinical Trials, 2018, Vol. 13, No. 2 Menez et al.

twenty-three patients in the long arm (39%) (P=0.07). This difference was most notable in patients over the age of 25. This effect was postulated to be dose and age-related due to cross-linking in DNA from cyclophosphamide is com-pounded with decreased estrogen levels, with subsequent up-regulation of Follicle-Stimulate Hormone (FSH) secretion, whereby more developing follicles are destroyed by cyclo-phosphamide.

Later studies investigated not just the total dose of cyclo-phosphamide to be administered, but the dose per treatment for induction, as well as the appropriate maintenance therapy [31, 32]. Houssiau and colleagues demonstrated no signifi-cant change in rates of death, progression to end-stage renal disease, or doubling of sCr in low-dose vs. high-dose cyclo-phosphamide groups. In this study, low-dose cyclophos-phamide was defined as 500 mg every two weeks for a total of six doses. In contrast, those in the high-dose group re-ceived six monthly pulses plus two quarterly doses (eight total) of 0.5 g/m

2 body surface area, with subsequent dose

increased by 250 mg as tolerated based on the white blood cell count nadir on day 14, but with total dose per admini-stration not to exceed 1500 mg. To note, all patients in this study received azathioprine 2 mg/k/day for maintenance, to start two weeks after last cyclophosphamide administration, and continued through month 30 (“Euro-lupus protocol”) [32]. Overall, remission was noted in 71% of the low-dose group and 54% of the high-dose group, which was found not to be statistically different, and both regimens led to similar rates of renal flares (27% in the low-dose group vs. 29% in the high-dose group). At ten-year follow-up, Houssiau and colleagues demonstrated sustained long-term results [31].

Chan and colleagues conducted a randomized clinical trial of 42 patients using mycophenolate mofetil vs. cyclophosphamide for induction therapy in SLE nephritis [33]. Patients in Group 1 received oral mycophenolate mofetil one gram twice daily, along with prednisolone 0.8 mg/kg/day, for induction, whereas those in Group 2 received oral cyclophosphamide 2.5 mg/kg/day with the same dose of prednisolone for induction. In Group 1, the MMF dose was halved at 6 months, then continued for an additional 6 months before transitioning to oral azathioprine (1 mg/kg per day). In Group 2, cyclophosphamide was stopped after six months and patients were switched to azathioprine at 1.5 mg/kg/day, then to 1 mg/kg/day at 12 months. At 12-month follow-up, there was no statistical difference between sCr, urinary protein excretion, or serum C3 levels between the two treatment groups. Further, the incidence of complete or partial remission, as well as the time to complete or partial remission, were also similar. Of note, in this study, complete remission in the MMF group was found to be 81%, and for the cyclophosphamide group at 76%, results which have not been replicated since. One benefit of use of MMF over cyclophosphamide use is the lack of bladder and ovarian toxicity as seen with cyclophosphamide previously [34].

Ginzler and colleagues in 2005 conducted a larger study of 140 patients, again comparing MMF with cyclophos-phamide for induction [35]. The MMF group received 500 mg twice daily, increased to 750 mg twice daily at two weeks, then advanced weekly to a maximum of 1000 mg three times daily, as tolerated with a goal white blood cell count > 3000/mm

3. In this study, cyclophosphamide was

given intravenously at monthly pulses per NIH protocol, with adjustment based also on white blood cell count (goal >2500/mm

3). Both groups received prednisone on the same

tapering schedule. With a follow-up period of 24 weeks, there was no statistically significant difference in the rate of first renal flare, progression to end-stage renal disease, or death among the two groups. In intention-to-treat analysis, there was complete remission in 16/71 MMF patients (22.5%) vs. 4/69 cyclophosphamide patients (5.8%), a differ-ence of 16.7% (P=0.005). Partial remission rates were simi-lar between both groups [35].

Later, Appel and colleagues conducted an international study comparing MMF and IV cyclophosphamide for induc-tion therapy [36]. 370 patients with proliferative and/or membranous SLE nephritis were randomized either to MMF with a goal dose of 3 grams/day, vs. IV cyclophosphamide with a median of six total doses, with dosage per infusion between 0.5-1 g/m

2. Over a 24-week induction period, there

was no significant difference in response to MMF vs. IV cyclophosphamide, defined as a total reduction in uPCR < 3 grams on a 24-hour collection, or a reduction of �50% in patients with baseline sub-nephrotic proteinuria. Again, in this trial as shown in others, the adverse event rate and death rate in both treatment arms were similar.

3.2. Maintenance Therapy

A number of groups have investigated the optimal agents and length of time for maintenance therapy in SLE nephritis [37-39]. Contreras and colleagues in 2004 investigated the use of quarterly IV cyclophosphamide boluses vs. oral azathioprine vs. oral MMF for a total follow-up period of one to three years [37]. Specifically, after induction with steroids and IV cyclophosphamide for a total of seven monthly doses, each group was placed on oral prednisone and randomized to one of the three regimens: quarterly IV cyclophosphamide infusions at 0.5-1g/m

2 every three months for up to 36

months, vs. 1-3 mg/kg/day of oral azathioprine, vs. 500-3000 mg of oral MMF per day, titrated to side effects and leuko-penia (lower limit of acceptable - 2000/mm

3). The primary

end-point of this study was defined as overall survival and progression to end-stage renal disease. Out of a total of 59 patients, 4/20 in the cyclophosphamide arm died during maintenance phase, all from sepsis. In contrast, 1/20 died in the MMF arm and 0/19 in the azathioprine arm. The authors found that overall, either azathioprine or MMF had a much higher probability of survival at 72 months compared to cy-clophosphamide maintenance. The difference in survival between the MMF arm and the azathioprine arm was not significant. Similarly, both MMF and azathioprine had a higher cumulative probability of event-free survival (defined as composite end point of death or chronic renal failure) compared to IV cyclophosphamide. Further, the risk of in-fection in the IV cyclophosphamide group was statistically significantly higher compared to either the MMF or azathio-prine group, particularly with respect to major infections defined as pneumonia, sepsis with bacteremia, or meningitis.

The ALMS group later conducted a head-to-head study comparing MMF vs. azathioprine for maintenance therapy in SLE nephritis [38]. The authors carried out a randomized double-blind, double-dummy phase III trial comparing MMF

Lupus Nephritis: Current Treatment Paradigm and Unmet Needs Reviews on Recent Clinical Trials, 2018, Vol. 13, No. 2 109

at 2g/day to azathioprine (AZA), 2 mg/kg/day for mainte-nance therapy, with follow-up time of 36 months. After in-duction therapy either with steroids/MMF or steroids/cyclo-phosphamide over 24 weeks, patients were monitored ini-tially every 4 weeks for the first two months, and then quar-terly, for response to treatment. Both the MMF group and the AZA groups had high rates of withdrawal, mostly for ad-verse events or SLE nephritis flares. In this study, MMF was found to be statistically significantly superior to AZA with respect to time to treatment failure (HR 0.44, 95% CI 0.25-0.77; P=0.003). Secondary end points included time to documented or suspected renal flare, time to ESRD, and time to sustained doubling of sCr.

As outlined by Parikh and Rovin in 2016, the current

standard of care with lupus nephritis induction therapy in-cludes steroids, either prednisone 1 mg/kg/day, to a max of

80 mg per day, over several weeks, vs. IV methylpredniso-

lone 0.25-1 g/day for 1-3 days, then to oral steroids [40]. Additionally, induction included either cyclophosphamide or

MMF, with the cyclophosphamide administered orally at 1-

1.5 mg/kg/day up to 150 mg/day for two to four months, vs. monthly infusions of 0.5-1 g/m2 for a total of 6 doses (NIH

protocol), vs. 500 mg IV every two weeks for a total of six

doses (Euro-Lupus protocol). MMF should be given to a goal dose of 2-3 grams/day for a total of six months. After

induction, standard maintenance therapy for SLE nephritis

consists of prednisone 5-10 mg daily, along with either MMF at one to two grams daily or azathioprine 1-2.5

mg/kg/day. A calcineurin inhibitor (tacrolimus or cy-

closporine A) can be considered as an alternative therapy, if neither MMF nor azathioprine are not tolerated [41]. In gen-

eral, MMF is favored over azathioprine, though azathioprine

may be favored in certain circumstances, such as pregnancy. The total time for maintenance therapy remains unclear, with

studies varying in time course from 12 months to 36 months

after induction [37-39].

Current KDIGO guidelines as of 2012 recommend a

switch to another agent for resistant severe proliferative SLE nephritis for induction [26]. Alternatives would be to add an

additional pulse of methylprednisolone one gram IV for

three daily doses, rituximab one gram IV for two doses 14 days apart, intravenous immunoglobulin (IVIg), or multiple

concurrent agents (that is, MMF plus cyclosporine plus ster-

oids). While membranous class V SLE nephritis has been included in many of the studies of induction and mainte-

nance therapy, KDIGO guidelines recommend a different

approach to pure class V SLE nephritis [26]. With sub-nephrotic range proteinuria and normal renal function in an

otherwise asymptomatic patient, RAS blockade with good

response does not warrant further treatment. For those with refractory sub-nephrotic proteinuria, or for those who do

have nephrotic range proteinuria prior to RAS blockade,

initiation of therapy with MMF two to three grams per day or azathioprine 1-2.5 mg/kg/day with oral steroids for six

months is warranted. With either a partial or complete re-

sponse, maintenance with MMF or azathioprine can be con-tinued indefinitely. If there is no response after RAS block-

ade and initial treatment, once can start induction therapy,

either with NIH or Euro-Lupus protocol, and proceed with maintenance afterwards.

4. NOVEL THERAPIES

Based on all available current data on standard of care therapies for SLE nephritis, there is at best a complete remis-sion rate of 50-60%, and roughly 13-25% of patients experi-ence periods of relapse during maintenance therapy for SLE nephritis [38, 39]. Therefore, the need for newer, targeted therapies has been the focus of many current, ongoing clini-cal trials. Standard induction and maintenance therapies at present are anti-proliferative and non-specific, that is, inter-fering with the process of autoantigen presentation and acti-vation of autoreactive leukocytes. However, newer agents with specific T-cell, B-cell, or proteasome targets are cur-rently being investigated [11, 42, 43].

Anti-cytokine therapy has evolved from the idea that cy-tokines actively producing inflammation, particularly in the kidney parenchyma, through various mediators such as TNF-�, IL-1, IL-6, and IFN-� may be appropriate targets [44]. La Cava and others have postulated that using anticytokine therapies to directly reduce the inflammatory cascade may help reduce end organ damage as well as reducing the need for high-dose immunosuppressive medications [45]. How-ever, trials of anti-cytokine therapy such as the TNF- block-ers infliximab and etanercept have not shown great promise.

4.1. B Cell Therapy

B cells have been long known to have a significant role in the pathogenesis of SLE. Abnormal B cell proliferation and autoantibody production are associated with immune dysregulation [46]. Dorner and colleagues report that while specific causes of diffuse B-cell over-activity remain unclear in SLE, murine models suggest that abnormalities in B-cell activation or clearance of cells targeted for apoptosis may be defining molecular pathways in human SLE. Evidence exists in both murine and human SLE of B-cell hyperactivity, with specific perturbations of B-cell maturation and differentia-tion. The authors describe a potential aberration in T-cell dependent activation of B cells in SLE. Initially, there is an-tigenic stimulation which activates B cells, which in SLE may be hyperactive at baseline. This can lead to somatic hyper-mutation, class-switch recombination, selection of specific auto-reactive clones, and an increase in apoptosis with a decrease in clearance of apoptotic material, all leading to the formation of auto-antibody secreting plasma cells as well as memory B cells. One implication the authors discuss is that auto-antigens do not necessarily induce auto-antibody production, but rather select for B cells induced to become auto-reactive by somatic hyper-mutation. Additionally, other B cells activated by T cell antigen presentation may propa-gate as antigen-presenting cells, releasing increasing amounts of inflammatory cytokines including interferon-�, IL-6, IL-10, and TNF- �.

Targeted therapies work to eliminate antigen-presenting cells as well as precursors for auto-antibody producing cells. Without antibody-antigen immune complex formation, there would theoretically be less down-stream inflammation. Mul-tiple agents targeting B-cell populations have been attempted in moderate to severe SLE, as well as specifically for SLE nephritis, including ocrelizumab, rituximab (anti-CD-20), and epratuzumab (anti-CD-22) [42, 44, 47-49]. The LUNAR

110 Reviews on Recent Clinical Trials, 2018, Vol. 13, No. 2 Menez et al.

Study investigated the use of rituximab, along with standard induction therapy with steroids and MMF, in patients with SLE nephritis. In this phase II trial with a primary end point of renal response at week 52, those randomized to rituximab received infusions of 1,000 mg at days 1, 15, 168, and 182. In this study, complete renal response was defined as normal sCr if abnormal at baseline, or a sCr �115% of baseline if normal at baseline. For complete renal response, there also had to be an inactive urinary sediment and uPCR �0.5. The authors describe a depletion in the CD19+ B cells in nearly all patients treated with rituximab, however the renal re-sponse rates were noted to be 45.8% in those treated with placebo, vs. 56.9% in those treated with rituximab (P=0.18). There were statistically significant improvements in patients’ complement levels, anti-dsDNA titers, and an overall reduc-tion in proteinuria. Based on these results, rituximab was not FDA approved for use in SLE nephritis, though as Gunnars-son notes, there have been case reports of success with SLE nephritis in subsequent years for patients with severe refrac-tory SLE nephritis, resistant to other therapies [50]. Aggre-gating results of a number of small observational studies, and recognizing the heterogeneous nature of all studies involved, Gunnarsson argues that there may be some benefit for the use of rituximab as induction therapy for refractory LN, or relapsing renal disease.

Even more specific targeted approaches to SLE nephritis focus on specific functions and pathways within B and T cell activation in the pathogenesis of SLE nephritis, beyond a global B cell targeted approach [43]. For example, targets include the inhibition of cytokine release via interferon, in-terference of transcription regulation in B cell formation, and the targeting of immune checkpoints [43]. One specific B-cell target of increasing interest is soluble B-cell activating factor (BAFF), also known as soluble B lymphocyte stimula-tor (BLyS). Recent work by Steri and colleagues have dem-onstrated the association of genetic mutations related to BAFF and the incidence of autoimmune conditions, includ-ing SLE [51]. The authors conducted a genome-wide asso-ciation study using case-control samples of patients with Multiple Sclerosis (MS) from Sardinia, Italy, with TNFSF13B locus-specific association for patients with SLE. The authors found that a variant in this gene, which encodes BAFF, was associated with MS as well as SLE. The causal variant was found to be an insertion-deletion, GCTGT�A, which ultimately led to a shorter transcript that was not sus-ceptible to microRNA inhibition, thus leading to an increase in BAFF. This leads an increase in the number of circulating B cells, increase in antibody production in general, and a decreased number of monocytes, ultimately leading to an up-regulation in humoral immunity.

Belimumab is a fully humanized monoclonal IgG1� that binds BLyS, inhibiting further down-stream effects, and was demonstrated in a Phase II study published by Wallace and colleagues in 2009 to lead to reduction in circulating CD20+ B [52]. Two phase III trials published in 2011 further eluci-dated its role and effectiveness in SLE treatment [53, 54]. Furie and colleagues randomized 819 patients either to pla-cebo, belimumab 1 mg/kg/infusion, or belimumab 10 mg/kg/ infusion. Patients received infusions on days 0, 14, 28, and every 4 weeks thereafter, for a total of 72 weeks of treat-ment. Primary end-point in this study was defined as SLE

Responder Index (SRI) response. The authors found that there were more SRI responders at 52 weeks in the high-dose belimumab group compared to placebo, with a P-value of 0.017, with a non-statistically significant difference compar-ing the low-dose belimumab dose to placebo (P=0.089). Overall, there was a trend towards a greater reduction in SLE flares in patients treated with eighter dose of belimumab, as well as decreased steroid use and sustained reduction in dis-ease activity, based on anti-dsDNA titers and stable im-provements in complement levels. Navarra and colleagues conducted as similar study in patients from multiple coun-tries in Latin America, Asia-Pacific, and Eastern Europe [53]. In this study patients were again randomized in a 1:1:1 fashion to placebo, high-dose belimumab, and low-dose be-limumab in the same concentrations as the Furie study, and with identical dose schedules. In a follow-up period of 48 weeks, this group showed a similar statistically significant improvement in SRI response and decrease in flares in the high-dose belimumab group, but also showed a benefit to the low-dose belimumab administration (1 mg/kg/dose) compared to placebo, with an odds ratio of 1.55 (95% CI: 1.10-2.19; P=0.0129).

Based on these trials, belimumab received FDA approval for use in SLE as the first targeted B-cell therapy for lupus treatment. In 2013, Dooley and colleagues performed a pooled post-hoc analysis on renal outcomes with belimumab use [55]. To note, patients with severe SLE nephritis were excluded from both trials listed above. Exclusion criteria in the trials included proteinuria >6g/24hours, as well as a base-line sCr >2.5 mg/dL, those on hemodialysis, or those receiv-ing high-dose prednisone 90 days prior to study initiation. As the authors note, the BLISS trials were designed to assess efficacy of belimumab in SLE in general, without a specific focus on renal outcomes or SLE nephritis. In this post-hoc analysis, outcomes were defined as a renal flare attributable to SLE, defined as having at least one of the following: an increase in proteinuria from baseline, a reproducible increase in sCr >20% from baseline (or absolute rise >0.3 mg/dL) along with proteinuria >1g or hematuria, or new reproduci-ble hematuria (or 2-grade increase in hematuria from base-line with dysmorphic RBC’s on UA, along with an increase in proteinuria and/or red cell casts on microscopy). Specifi-cally, proteinuria was defined as having an increase in 24-hour urine protein to >1,000 mg for those with a baseline <200, or to >2,000 mg if baseline as between 200 and 1,000 mg. If patients had a baseline 24-hour protein >1,000 mg, a flare was defines as having at least a doubling from baseline. The authors showed that in the BLISS trials, patients on ei-ther dose of belimumab showed renal improvement at week 52, and of patients with generally stable active renal disease, those receiving standard treatment plus high-dose belimu-mab had a higher rate of renal remissions compared to pla-cebo. There was also a non-statistically significant difference in the number of renal flares on high-dose belimumab com-pared to low-dose or placebo; 1.1% vs. 2.1% vs. 3.0% re-spectively. Overall, change in sCr among all three groups remained relatively stable throughout.

In a 2017 review of pooled data from 11 studies, with a total of 2,004 patients total, Sclascia and colleagues demon-strated improvement in renal specific outcomes with the use of belimumab [56]. Of the 2,004 patients in the pooled

Lupus Nephritis: Current Treatment Paradigm and Unmet Needs Reviews on Recent Clinical Trials, 2018, Vol. 13, No. 2 111

analysis, 326 had SLE nephritis at baseline, of which 234 received belimumab. The authors showed that of those 234 patients, 129 had had improvement in renal parameters in-cluding rates of renal flare, remission, and pooled renal out-comes based on SELENA-SLEDAI, SLEDAI-2K, BILAG, and SLAM indices. Additionally, for those patients with baseline proteinuria of >0.2 g/24hr, of which there were 687 in the review, those patients who received belimumab had a mean reduction in proteinuria of 38%. And in looking more specifically at those patients with proteinuria >1g/24hr, roughly 70% achieved renal remission. In this review, the authors identified 7 patients with active SLE nephritis by biopsy, with a therapeutic response of 100% with a median follow-up of 18 months. To note, patients in the BLISS trials were excluded if they had severe active SLE nephritis on biopsy.

In SLE nephritis specifically, other targeted therapies in various stages of investigation include proteasome inhibitors, such as bortezomib and delanzomib. In a murine model us-ing NZBxNZW F1 mice, who develop lupus-like disease with extensive and fatal nephritis as first described in 1960s, bortezomib was shown to inhibit antibody production and the development of lupus nephritis compared to those treated with placebo [57-59].

Bortezomib had been shown in 2015 to ameliorate clini-cal manifestations of refractory SLE in general, based on results from 12 patients [60]. In early 2017, Zhang and col-leagues described the use of bortezomib with glucocorticoids for the treatment of refractory SLE nephritis [61]. Five pa-tients were selected for this study, who had biopsy-proven SLE nephritis, with SLE Disease Activity Index (SLEDAI) all greater than 10 and with no response to at least one type of immunosuppressive regimen for a minimum of 6 months, or relapse during maintenance on standard therapy. In addi-tion to pulse steroids (500 mg IV methylprednisolone for

three days), Bortezomib was administered at 1.3 mg/m2 body

surface area on days 1, 4, 8, and 11 during each 21-day treat-ment cycle, for a total goal of four cycles; one patient stopped after three cycles due to development of herpes zos-ter, and another received fewer doses in cycles three and for due to transient fevers. Overall, four out of the five patients achieved a partial response, with SLEDAI scores decreasing from pre-treatment range of 12-16, down to 4-8. Delanzomib in a similar study was shown to reduce serum pro-inflammatory cytokines, and suppressed the development and progression of renal injury [62]. The authors also dem-onstrated a reduction in proteinuria in those mice treated with delanzomib compared to placebo.

4.2. T-cell Therapy

T-cell targeted therapies have also garnered significant interest in the treatment of SLE nephritis in recent years. Given the need for T-cell dependence for B-cell activation and propagation of autoimmune downstream effects, efforts have bene made to interrupt this T-cell-B-cell signaling and interaction. Abatacept, a fusion protein composed of CTLA4-IgG1 dimer, is currently approved for treatment of rheumatoid arthritis. With its selectivity to the CD28-CD80/86 signaling pathway, Furie and colleagues investi-gated its effects on SLE nephritis outcomes [63]. To note, a prior phase II study of abatacept in SLE in general showed a reduction in major SLE flares as well as quality-of-life measures [64]. Patients were recruited from centers world-wide and a total of 298 patients were randomized to low-dose abatacept, high-dose abatacept, or placebo with a total follow-up period of 52 weeks. Dosing for high-dose abata-cept was as follows: 30 mg/kg on days 1, 15, 29, and 57, then roughly 10 mg/kg/dose on days 85, 113, 141, 169, 197, 225, 253, 281, 309, and 337. Patients receiving low-dose abatacept received 10 mg/kg/infusion on all infusion days.

Table 1. New agents and newer combinations of agents for both induction and/or maintenance therapy in SLE nephritis, currently

under investigation.

Drug/Agent� Clinical Trial� Target� Enrollment Start� Target Completion� Target Enrollment�

Anifrolumab� NCT02547922� IFN �/�� November 2015� September 2019� 150�

Rituximab �

belimumab�NCT02260934� CD-20, BAFF� October 2014� June 2019� 40�

ACTH gel� NCT02226341� �� October 2014� July 2024� 20�

Mizoribine� NCT02256150� DNA synthesis� November 2014� March 2018� 250�

Anifrolumab� NCT02547922� IFN �� November 2015� September 2019� 150�

Ixazomib� NCT02176486� Proteasome� July 2014� February 2017� 40�

BI 655064� NCT02770170� CD40� May 2016� November 2018� 120�

Obinutuzumab� NCT02550652� CD20� November 2015� April 2019� 120�

Leflunomide vs. AZA� NCT01172002� DNA synthesis� March 2010� June 2018� 200�

OMS721� NCT02682407� MASP-2� February 2016� February 2017� 16�

Milatuzumab� NCT01845740� CD74� January 2015� May 2017� 30�

Blisibimod� NCT02514967� BAFF� June 2016� December 2018� 350�

112 Reviews on Recent Clinical Trials, 2018, Vol. 13, No. 2 Menez et al.

Overall, the primary end point of a complete renal response at week 52, defined as an eGFR (by MDRD) �90% of screening sCr, or �90% of the patient’s 6-month pre-flare value if elevated at time of screening. To have a complete response, patients were also required to have a uPCR <0.26g/g Cr, and an inactive urinary sediment, all reproduci-ble 4 weeks after testing. Overall the authors demonstrated that complete response was similar in all groups (placebo, low-dose, and high-dose abatacept) and the time to con-firmed complete response was similarly not significantly different among all groups. In sub-group analyses, there was an association noted between abatacept use (either low or high-dose) and reductions in uPCR in those with nephrotic-range proteinuria, as well as decreases in anti-dsDNA and complement levels.

Current studies that have completed recruitment for SLE nephritis therapy include tacrolimus versus cyclophos-phamide (NCT01207297), tacrolimus vs. placebo in refrac-tory SLE nephritis (NCT00429377), laquinimod vs. placebo for active SLE nephritis (NCT01085097), deoxyspergualin vs. placebo (NCT00709722), CNTO 136 vs. placebo (NCT 01273389). Table 1 details new agents and newer combina-tions of agents for both induction and/or maintenance ther-apy in SLE nephritis, currently under investigation.

CONCLUSION

SLE nephritis is a common complication among patient with lupus and carries a significant morbidity and mortality risk. Current treatment regimens include induction and main-tenance phases of treatment, with steroid use and various global anti-inflammatory agents. The success of these regi-mens, with varying dosing schedules and length of treatment, appear to have reached their maximal benefit. With a greater understanding of the pathophysiology of SLE nephritis, new therapies have emerged with more specific targets during both SLE disease initiation and progression. The efficacy of these targeted therapies have shown some promise, but the need for randomized controlled trial investigating efficacy in SLE nephritis, specifically, still exists. Ongoing trials aim to shed more light on this topic in the coming years, with the hope for greater efficacy and more life-sustaining outcomes.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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