top 10 developments in lupus nephritis

SYSTEMIC LUPUS ERYTHEMATOSUS (M PETRI, SECTION EDITOR)

Top 10 Developments in Lupus Nephritis

Teresa K. Chen & Derek M. Fine

# Springer Science+Business Media New York 2013

Abstract Lupus nephritis affects up to 60 % of patients withsystemic lupus erythematosus and is associated with worseclinical outcomes. Traditionally, it has been treated withhigh-dose immunosuppression consisting of cyclophospha-mide and prednisone; however, recent trials have demon-strated mycophenolate mofetil as a safe and effective alter-native for both induction and maintenance of disease. Otherprogress has been made in our understanding of the patho-genesis of lupus nephritis, outcomes in renal transplantation,and associations with genetic risk factors. This review high-lights key developments in our understanding of lupus ne-phritis over the past decade.

Keywords Lupus nephritis . Kidney . Proliferative lupusnephritis . Membranous lupus nephritis . Renaltransplantation .APOL1 . Induction therapy .Maintenancetherapy . Systemic lupus erythematosus . SLE .

Mycophenolate mofetil . Rituximab . Treatment .

Multitargeted therapy . Epidemiology

Introduction

Systemic lupus erythematosus (SLE) often presents with renalinvolvement, with up to 10–60 % of patients with lupusnephritis ultimately developing end-stage renal disease(ESRD) [1]. Moreover, lupus nephritis is associated withincreased morbidity and mortality [2•]. This review highlightsthe key recent advancements in lupus nephritis research that

have allowed rheumatologists and nephrologists to providebetter evidence-based care to the patient with lupus nephritis.

Successful Induction with Mycophenolate Mofetil Therapy

Intravenous cyclophosphamide has traditionally been con-sidered the standard of care when it comes to the treatment ofsevere lupus nephritis. Its use, however, is often limited byits many potential toxicities. These include the possibility ofpremature gonadal failure, hemorrhagic cystitis, malignancy,and increased risk for infection [3, 4]. As such, efforts havebeen made to identify other agents for induction therapy inlupus nephritis.

One of the most important developments has been the adventof mycophenolate mofetil as an induction agent in lupus nephri-tis [5, 6]. After successful use in solid-organ transplantation,mycophenolate mofetil generated interest as a potential therapyfor lupus nephritis. The use of mycophenolate mofetil in thetreatment of human glomerular disease was pioneered by Briggsand colleagues, the first to effectively treat 2 patients withproliferative lupus nephritis with this agent [7]. Dooley et al.subsequently reported their experiences with mycophenolatemofetil in a series of 13 lupus nephritis patients who failed torespond or refused cyclophosphamide therapy [8]. Finally, Chanet al. conducted a small, randomized controlled trial in 2000demonstrating that mycophenolate mofetil was as effective asoral cyclophosphamide for induction of remission in Chinesepatients with diffuse proliferative lupus nephritis [9].

Since then, two key studies have further explored the use ofmycophenolate mofetil as an alternative to intravenous cyclo-phosphamide as induction therapy [5, 6]. First, Ginzler et al.conducted a randomized controlled noninferiority trial of 140individuals with active lupus nephritis. All participants hadbiopsy proven World Health Organization class III (focalproliferative), IV (diffuse proliferative), or V (membranous)lupus nephritis with clinical and/or laboratory features tosupport active disease. They were randomized to receive daily

This article is part of the Topical Collection on Systemic LupusErythematosus

T. K. Chen (*) :D. M. FineDivision of Nephrology, The Johns Hopkins University Schoolof Medicine, 1830 E. Monument Street, Suite 416, Baltimore,MD 21205, USAe-mail: [email protected]

Curr Rheumatol Rep (2013) 15:358DOI 10.1007/s11926-013-0358-7

oral mycophenolate mofetil (target of 3,000 mg/day) or intra-venous monthly cyclophosphamide (0.5–1.0 g/m2 monthly)for 24 weeks [3–5]. Both groups also received prednisone at1 mg/kg/day. The primary outcome was complete remission,defined as an improvement in serum creatinine, proteinuria,and urine sediment to within 10 % of normal values. Thesecondary outcome was partial remission, defined as an im-provement in these same laboratory parameters by 50 %. At24 weeks, 22.5 % in the mycophenolate mofetil group and5.8 % in the cyclophosphamide group had achieved a com-plete remission (p=0.005). Partial remission rates were similarbetween the two groups (29.6 % for mycophenolate mofetilvs. 24.6 % for cyclophosphamide; p=0.51). Of note, therewere 2 deaths in the cyclophosphamide group and none in themycophenolate mofetil group.Moreover, individuals random-ized to cyclophosphamide were more likely to have severeinfections and lymphopenia, whereas those randomized tomycophenolate mofetil were more likely to have diarrhea.These findings provided support that mycophenolate mofetilwas not inferior to intravenous cyclophosphamide for induc-tion therapy in lupus nephritis, and perhaps even preferredgiven its better adverse event profile [5].

In a second study, the Aspreva Lupus Management StudyGroup (ALMS) investigated whether mycophenolate mofetilwas superior to intravenous cyclophosphamide for the in-duction of remission in lupus nephritis. In this larger multi-national randomized controlled superiority trial, 370 individ-uals with active lupus nephritis [International Society ofNephrology/Renal Pathology Society (ISN/RPS) Class III–V] were randomized to receive oral mycophenolate mofetil(target of 3,000 mg/day) or intravenous cyclophosphamide(0.5–1.0 g/m2 monthly) for 24 weeks. The participants in thisstudy also received concurrent prednisone therapy with amaximum starting dose of 60 mg/day that was tapered astolerated. The primary endpoint was response to treatment,defined as a stable or improving serum creatinine, accompa-nied by an improvement in proteinuria to <3 g/day if baselineproteinuria was ≥3 g/day or a ≥50 % decrease if baselineproteinuria was <3 g/day. At 24 weeks, there was no signif-icant difference in treatment response between the twogroups (56.2 % in mycophenolate mofetil group vs. 53.0 %in cyclophosphamide group; OR 1.2; 95 % CI 0.8–1.8;p=0.58). However, the treatment effect appeared to be modi-fied by race, with similar response rates between themycophenolate mofetil and cyclophosphamide groups amongAsians (p=0.24) and Caucasians (p=0.83) but not in the“other” group, which consisted of primarily African-Americans and mixed-race individuals (OR 2.4 favoringmycophenolate mofetil; 95%CI 1.1–5.4; p=0.033). Addition-al post hoc analyses in Hispanics also demonstrated a greaterresponse rate to mycophenolate mofetil compared to cyclo-phosphamide (OR 2.5; 95 % CI 1.2–5.1; p=0.011). Thus,while the ALMS study failed to show a difference between

the two treatment regimens in inducing remission, certain sub-groups, such as those of African-American or Hispanic de-scent, may respond more favorably to mycophenolate mofetilover cyclophosphamide. Additional studies are needed to ex-plore these associations further, with longer follow-up andlarger sample size. Until then, mycophenolate mofetil andcyclophosphamide should both be considered as first lineagents, in conjunction with corticosteroid therapy, for theinduction of remission in patients with active lupus nephritis[6, 10••, 11••].

Better Maintenance Therapy Options

Similarly, efforts have been made to identify the optimal main-tenance regimen for those individuals who do go into remission.In 2004, Contreras et al. reported the benefits of a sequentialapproach to treating proliferative lupus nephritis. They demon-strated that, among patients who had received intravenous cy-clophosphamide for induction therapy, mycophenolate mofetilor azathioprine was not only better tolerated but also moreeffective in maintaining remission compared to continued useof intravenous cyclophosphamide [12]. Since then, two majortrials have sought to determine whether mycophenolate mofetilor azathioprine should be the preferred agent for the mainte-nance of remission in proliferative lupus nephritis [13••, 14••].

In the MAINTAIN Nephritis Trial, 105 European individ-uals with proliferative lupus nephritis were randomized toreceive mycophenolate mofetil (target of 2,000 mg/day) orazathioprine (target of 2 mg/kg/day) following induction ther-apy consisting of intravenous cyclophosphamide (500 mg ev-ery 2 weeks×6 doses) and glucocorticoids. Mean follow-upwas 48 months and the primary outcome was time to renalflare, defined as the development of nephrotic syndrome, a ≥33% rise in serum creatinine, or increase in proteinuria withconcurrent microscopic hematuria. The authors reported nodifference between the two groups for this outcome (HR 0.75comparing mycophenolate mofetil to azathioprine; 95 % CI0.33–1.71; p=0.486). Adverse events were notable for 2deaths in the mycophenolate mofetil group while the azathio-prine group experienced more cytopenias. These findings sug-gest that mycophenolate mofetil and azathioprine are equallyeffective as maintenance therapy in lupus nephritis [13••].

In the second study, participants demonstrating a clinicalresponse to the induction phase of the ALMS trial were furtherrandomized at 24 weeks to receive either mycophenolatemofetil (target dose of 2,000 mg/day) or azathioprine (targetof 2 mg/kg/day) as maintenance therapy. The primary end-point for this second phase of the ALMS trial was time totreatment failure, defined as renal flare, need for rescue im-munosuppressive therapy, doubling of serum creatinine,ESRD, or death. After 3 years of follow-up, 16.4 % in themycophenolate mofetil group and 32.4 % in the azathioprinegroup had failed treatment (HR 0.44 favoring mycophenolate

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mofetil; 95 % CI 0.25–0.77; p=0.003). For the secondaryendpoint of time to renal flare, the mycophenolate mofetilgroup also proved to be superior (HR 0.50; 95 % CI 0.26–0.93; p=0.03). While the incidence of adverse events wassimilar between the two groups (p=0.68), a greater proportionof patients in the azathioprine group withdrew due to studydrug intolerance (39.6 % compared to 25.2 % in themycophenolate mofetil group; p=0.02). In short, the secondphase of the ALMS trial provided support that mycophenolatemofetil was superior to azathioprine for the maintenance ofrenal remission among patients with lupus nephritis [14••].

This discrepancy in findings is most likely related todifferences in study design. First, the study populations inthe two trials were markedly different. MAINTAIN wasprimarily a European study consisting of 79 % Caucasianswhereas ALMS was international, consisting of 43.6 % Cau-casians. Results from the induction phase of ALMS haveraised the question of whether response to mycophenolatemofetil is differential by race. Second, the induction thera-pies for the two studies also varied. In MAINTAIN, all of theparticipants received intravenous cyclophosphamide, where-as in ALMS, participants could receive intravenous cyclo-phosphamide or oral mycophenolate mofetil. It is possiblethat the mycophenolate group did better in the ALMS trialbecause those same individuals had also demonstrated re-sponse to the same agent during the induction phase of thetrial. Finally, theMAINTAIN trial did not require its participantsto be in remission prior to transitioning to maintenance therapywith mycophenolate mofetil or azathioprine. It is unclear wheth-er the renal flares observed during follow-up were due to failureof maintenance therapy or inability to achieve remission in thefirst place. As such, both mycophenolate mofetil and azathio-prine are likely reasonable options for the maintenance of re-mission in proliferative lupus nephritis, with the possibility ofmycophenolate mofetil being the preferred agent [11••, 13••,14••, 15]. Ultimately, other factors may drive this decision, suchas preference for azathioprine in the patient desiring pregnancyor avoidance of azathioprine in the patient with low TPMTactivity [16, 17].

Treatment of Membranous Lupus Nephritis

The role of immunosuppressive therapy in Class V(membranous) lupus nephritis is less clear. Accounting forapproximately 20 % of all biopsy-proven cases of lupus ne-phritis, membranous lupus nephropathy can also be associatedwith increased morbidity and mortality [18]. Austin et al.conducted a small, randomized controlled trial of 42 patientswith Class V lupus nephritis who were randomized to one ofthree treatment arms: prednisone with oral cyclosporine, pred-nisone with intravenous cyclophosphamide, or prednisonealone. They found that the cumulative probability of proteinuriaremission was higher among the groups that had received

combination therapy (83 % for cyclosporine/prednisone and60 % for cyclophosphamide/prednisone) compared to the pred-nisone only group (27%; p=0.002 and 0.04, respectively) [19].

Several small case series have also reported successful treat-ment of membranous lupus nephropathy with mycophenolatemofetil [20–22]. Subsequently, Radhakrishnan et al. pooleddata from 84 individuals with pure Class V lesions who hadparticipated in two large randomized controlled trials on induc-tion therapy for lupus nephritis (24 from the Ginzler et al. studyand 60 from the ALMS study). Among those who completed24 weeks of follow-up, 33 received mycophenolate mofetil and32 received intravenous cyclophosphamide. Again, all patientsreceived concurrent prednisone therapy. The weighted meandifference of percent change in proteinuria was similar betweenthe two treatment groups (−3.49 % comparing mycophenolatemofetil to cyclophosphamide; 95 % CI −26.88 to 19.90 %;p=0.77) as was percent change in serum creatinine (−2.55 %;95 % CI −18.49 to 13.38 %; p=0.75). In subgroup analyses ofpatients presenting with nephrotic-range proteinuria, the oddsof achieving partial remission was also comparable betweenthose receiving mycophenolate mofetil versus cyclophospha-mide (OR 1.19; 95 % CI 0.29–4.91; p=0.81). Thus, bothmycophenolate mofetil and intravenous cyclophosphamide ap-pear to be equally effective in inducing remission among pa-tients with Class V lupus nephritis, including those who presentwith nephrotic-range proteinuria [23•]. More studies are neededto better define the optimal induction and maintenance thera-pies in this subset of lupus nephritis patients; the potential roleof calcineurin inhibitors deserves particular attention [19]. Untilthen, an American College of Rheumatology Task Force rec-ommends that mycophenolate mofetil with prednisone be usedas first line induction therapy in those with Class V lupusnephritis [11••].

(Limited) Therapeutic Role of Rituximab in Lupus Nephritis

Rituximab, a monoclonal antibody directed against CD20+ Bcells, has been used for the treatment of several rheumatologicdisorders, including rheumatoid arthritis, granulomatosis withpolyangiitis, and microscopic polyangiitis [24–26]. The EX-PLORER (Exploratory Phase II/III SLE Evaluation of Ritux-imab) study failed to demonstrate benefit of rituximab overplacebo among patients with moderate to severe active SLEon background immunosuppressive therapy [27].

In LUNAR (the Lupus Nephritis Assessment with Ritux-imab Study), a double-blind placebo-controlled trial of 144patients with Class III or IV proliferative nephritis, partici-pants were randomized to rituximab (1,000 mg intravenous-ly on days 1, 15, 168, and 182) or placebo as add-on therapyto mycophenolate mofetil (target of 3,000 mg/day) and cor-ticosteroids. The primary outcome was renal response, de-fined as complete, partial, or no renal response, at 52 weeks.Although the rituximab group achieved greater decreases in

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anti-dsDNA and greater increases in C3 and C4, there was nodifference in renal response rate between the two groups(p=0.55). Pre-specified subgroup analyses by race illustrateda trend towards higher response rates among African-Americans who received rituximab compared to placebo,but this was not statistically significant (70 vs. 45 %, respec-tively; p=0.20). Reported adverse events were similar be-tween the two groups, though neutropenia and leukopeniawere more common with rituximab. There were two deaths,both in the rituximab group, attributed to other causes [28••].At present, there are insufficient data to support the use ofrituximab in the initial management of proliferative lupusnephritis [10••].

The Potential of Multitargeted Therapy

With complicated B- and T-cell interactions implicated in thepathogenesis of lupus, the strategy of targeting both cell types isappealing [29]. Bao et al. explored whether combination ther-apy with tacrolimus (targeting T-cells), mycophenolate mofetil(targeting predominantly B-cells), and corticosteroids was mo-re effective than intravenous cyclophosphamide for the induc-tion of remission in lupus nephritis. In this small trial fromChina, 40 patients with both Class IV and V lesions, on renalbiopsy, were randomized to receive either multitargeted therapy(tacrolimus with goal trough 5–7 ng/ml, mycophenolatemofetil with target dose of 1,000 mg/day, and prednisolone at0.6–0.8 mg/kg/day with subsequent taper) or intravenous cy-clophosphamide (0.5–1.0 g/m2 monthly) with prednisolone(same dose as multitargeted group). Both groups also receivedintravenous methylprednisolone therapy for the first 3 days.The primary outcome was complete remission, defined asimprovement or less than 15 % rise in serum creatinine, serumalbumin ≥3.5 g/dL, reduction in proteinuria to <0.4 g/day, andnormalization of urinary sediment. The secondary outcomewas partial remission, defined as improvement or less than15 % rise in serum creatinine, serum albumin ≥3.0 g/dL, andimprovement in proteinuria and hematuria by ≥50 %. At6 months, 50 % in the multitargeted therapy group and 5 %in the cyclophosphamide group had achieved complete re-mission (absolute treatment difference of 45%, 95%CI 21.1–68.9 %; p=0.001). The number of partial remissions did notdiffer significantly between the two groups (p=1.000). At9 months, the multitargeted therapy group still had morecomplete remissions than the cyclophosphamide group (65vs. 15 %, respectively, with absolute treatment difference of50 %; 95 % CI 23.9–76.1 %; p=0.001) with no difference inpartial remissions (p=0.507). No deaths were reported. Onepatient in the multitargeted therapy group withdrew from thestudy because of a >30 % rise in serum creatinine; however,repeat biopsy demonstrated that this was secondary to treat-ment failure rather than calcineurin inhibitor toxicity. Of note,

patients with a serum creatinine >3 mg/dL or creatinine clear-ance <30ml/min/1.73m2 were excluded from the study. Thus,there may be a role for the use of calcineurin inhibitors inconjunction with other currently available therapies for lupusnephritis. Additional studies are needed to determine theoptimal regimen and whether its effectiveness holds true inother populations [30].

Greater Understanding of Disease Epidemiology

Despite advancements in the management of lupus nephritis,unfortunately there have been no demonstrated improvementsin the outcomes of ESRD ormortality. Using data from the USRenal Data System (USRDS), a nationwide databaseencompassing 94 % of the United States population withESRD on renal replacement therapy (dialysis or renal trans-plant), Costenbader et al. reported that the incidence of ESRDdue to lupus nephritis did not changemuch from 1995 through2006. In total, there were 12,344 incident cases of ESRDattributed to lupus nephritis. However, standardized incidencerates for the development of ESRD secondary to lupus ne-phritis (per million population per year) did increase over timeamong individuals who were younger (age <39 years), ofAfrican or Native American descent, or residing in the South-ern United States. In multivariate analyses, rates of kidneytransplantation within 3 years of ESRD onset declined (HR0.87 comparing ESRD onset groups 2001–2003 vs. 1995–1997; 95 % CI 0.76–0.99; p for trend =0.03) whereas mortal-ity rates remained the same (p=0.44). Of note, the major trialson lupus nephritis treatment mentioned previously were notpublished until 2005 or later. As such, this study likely doesnot reflect changes in clinical practice that might have oc-curred as a direct result of those trials. Another cause forconcern is the increase in standardized incidence rates forESRD among African-Americans and Native Americans withSLE. Further investigations are warranted to better understandthe association between racial disparities and worse outcomesin lupus nephritis [2•].

Effective Renal Transplantation in Lupus Nephritis

Prior studies have estimated the risk of recurrent lupus nephri-tis in the transplanted kidney to range from 3.8 to 44 %[31–33]. More recently, Contreras et al. used data from theUnited Network for Organ Sharing (UNOS) to study therecurrence of lupus nephritis among kidney transplant recip-ients. Among 6,850 individuals who received a renal allograftbetween the years of 1987 and 2006, only 167 (2.4 %) devel-oped recurrent lupus nephritis, with 83 (50 %) of the 167 alsohaving rejection. Another 1,770 (25.8 %) recipients had re-jection without recurrence of lupus nephritis. In multivariateanalyses, individuals who were younger (OR 1.69 comparing


age <33 vs. ≥33 years; 95 % CI 1.23–2.31), female (OR 1.70;95 % CI 1.05–2.76), or black non-Hispanic (OR 1.88; 95 %CI 1.37–2.57) were at increased risk for recurrent nephritis.Both recurrent lupus nephritis (HR 4.09 compared to controlgroup without rejection; 95 % CI 3.41–4.92) and rejection(HR 3.97; 95 % CI 3.63–4.34) were independent risk factorsfor allograft loss. However, only 7 % of graft failures wereattributable to recurrent lupus nephritis whereas 43 % werefelt to be secondary to rejection. In summary, the risk forrecurrence of lupus nephritis in the renal allograft is low.Patients with lupus nephritis should be offered the option ofrenal transplantation when appropriate [34].

APOL1 Risk Alleles and Lupus Nephritis

The apolipoprotein L1 (APOL1) gene, located on chromo-some 22, has emerged as a major risk factor for kidneydisease development among African-Americans. It has beendemonstrated that two APOL risk alleles (G1 and G2) pro-vide protection against Trypanosoma brucei rhodesienseinfection, but at the cost of significantly increased suscepti-bility to developing focal segmental glomerulosclerosis (in-cluding HIV-associated disease) and hypertension-attributedend stage kidney disease in those who carry two risk alleles[35–37].

In 2012, Salvatore et al. described a series of 19 patientswith SLE or SLE-like disease who presented with massiveproteinuria and biopsy findings consistent with collapsingglomerulopathy [38]. Larsen et al. subsequently investigatedwhether African-Americans with SLE and two APOL1 high-risk alleles were at increased risk for developing collapsingglomerulopathy. A total of 546 renal biopsies were included,188 of which were from individuals with no APOL1 riskalleles, 264 from individuals with one risk allele, and 94 fromindividuals with two risk alleles. Twenty-six cases of collaps-ing glomerulopathy were identified. The authors found thatAfrican-Americans with SLE and two APOL1 risk alleleswere more likely to have non-necrotizing crescents (OR 1.6;95 % CI 1.2–2.3; p=0.008) and microcystic tubular dilatation(OR 2.2; 95 % CI 1.4–3.3; p=0.001) present on biopsy.Moreover, a greater percentage of patients with two riskalleles had evidence of collapsing glomerulopathy comparedto those with one or zero risk alleles (14 vs. 5 and 0.5 %,respectively; OR 5.4; 95 % CI 2.4–12.1; p<0.001). Thesefindings provide growing support for a possible role of theAPOL1 gene in the pathogenesis of certain pathologic lesionsseen in lupus patients. Since patients of African descent com-prise a significant proportion of those with SLE and lupusnephritis and APOL1 risk alleles are being realized as animportant contributor of kidney disease development in thisspecific population, further studies are expected to betterelucidate the underlying mechanisms at hand [39•].

A Need for Standardization of Outcome Measures

One of the foremost challenges in lupus nephritis research isthe lack of standardization in outcome measures among stud-ies. Sample endpoints have included complete remission,partial remission, total response, treatment failure, major clin-ical response, time to complete response, time to renal flare,and improvement in proteinuria and/or estimated glomerularfiltration rate (eGFR). The timing as to when these outcomesare assessed can range from weeks to years. Moreover, thedefinitions of these individual endpoints can vary from studyto study [5, 6, 13••, 14••, 28••, 40•]. As a result, the lupusresearch community has made a concerted effort to gainconsensus on outcome measures for lupus nephritis research,such that for more effective studies can be conducted [41].

Wofsy et al. attempted to determine the optimal outcomemeasures for studies in lupus nephritis [40•]. They hadpreviously demonstrated that the success or failure of a studycould depend on how the outcomes for that particular studywere defined [42]. Using data from a large randomizeddouble-blind trial comparing the addition of abatacept versusplacebo to a background of treatment with mycophenolatemofetil and steroids in lupus nephritis, they performed sev-eral analyses with the following outcomes: (1) completeresponse and partial response criteria as defined in the LU-NAR trial; (2) major clinical response, defined as either acomplete response or a reduction in proteinuria to <1 g/dayfor those with nephrotic-range proteinuria but also meetingall other criteria for complete response; (3) proteinuria im-provement by ≥75 %; (4) eGFR improvement by ≥25 %; (5)treatment failure, defined as persistence of nephrotic-rangeproteinuria, failure of proteinuria to improve by ≥25 %,reduction in eGFR by >25 %, inability to taper steroids to adose ≤10 mg/day, or study withdrawal due to worseningdisease or intolerance of study drug; and (6) time to completeremission. They found that the most robust primary out-comes providing a clear distinction between treatment andcontrol were complete response at 52 weeks, major clinicalresponse at 52 weeks, and time to complete response. Suchstudies highlight the importance of having standardized out-come measures, easing the interpretability and comparabilityof future studies [40•].

Possible Future Therapies for Lupus Nephritis

As our understanding of the pathogenesis of SLE has in-creased, the targeting of specific immune processes has uncov-ered a plethora of potential treatments. One such drug isbelimumab, a monoclonal antibody directed against B-lymphocyte stimulator (BLyS). BLyS is a cytokine necessaryfor the survival of B-lymphocytes that has been shown to beoverexpressed in patients with lupus [43–47]. The efficacy and


safety of belimumab in patients with SLE was evaluated by theBLISS-52 Study group in a multicenter randomized placebo-controlled phase 3 trial. Briefly, 867 individuals with activeSLE, as determined by a SELENA-SLEDAI score of ≥6, wererandomized to receive intravenous belimumab at 1 or 10mg/kg,or placebo for 48 weeks (every 2 weeks for 3 doses, then every4 weeks until week 48). Study outcomes were based on diseaseactivity scores at 52 weeks. Of note, patients with severe lupusnephritis were excluded from the study. Mean baseline protein-uria for the three treatment groups ranged from 0.5 to 0.6 g/day,with 7–9 % of patients having ≥2 g/day. The investigatorsreported that individuals randomized to the belimumab groupshad significantly higher rates of improvement in their diseaseactivity scores compared to placebo, and adverse event rateswere similar for all three groups [47]. A post-hoc analysis onrenal outcomes was conducted, pooling data from this studyand BLISS-76, another phase 3 trial assessing the safety andefficacy of belimumab in SLE [48, 49]. Although underpow-ered, there was some suggestion that the addition of belimumabto a background of mycophenolate mofetil therapy might beassociated with improved renal parameters [49]. Thus,belimumab appears to be a promising agent for the treatmentof SLE in the future; however, further studies are needed todetermine its efficacy in active lupus nephritis.

The use of biologic agents in the treatment of SLE prom-ises to be a topic of great interest in coming years. Hopefully,more effective agents will be discovered, with an increase intreatment options for this challenging disease.

Conclusions

Our understanding of the pathogenesis and management oflupus nephritis has grown tremendously over the past de-cade. Much of this stems from the pivotal trials described inthis review, with mycophenolate mofetil emerging as aneffective and possibly safer alternative to cyclophosphamidefor induction and maintenance of remission in lupus nephri-tis [5, 6, 13••, 14••]. Continued collaboration between basicscience and clinical researchers is needed to identify newtherapeutic targets while also enhancing the use of currentlyavailable treatments in lupus nephritis. We look forward towhat the future holds.

Compliance with Ethics Guidelines

Conflict of Interest Teresa K. Chen was the recipient of a researchmini-grant award (2012–2013) from the National Kidney Foundation ofMaryland.

Derek M. Fine has served as a consultant for USB Biosciences.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with animal subjects performed by any of theauthors.

With regard to the authors’ research cited in this paper, all pro-cedures were followed in accordance with the ethical standards of theresponsible committee on human experimentation and with the HelsinkiDeclaration of 1975, as revised in 2000 and 2008.

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