Novel therapeutic agents in clinical development for systemic lupus erythematosus

Abstract

Conventional immunosuppressive therapies have radically transformed patient survivalin systemic lupus erythematosus (SLE), but their use is associated with considerabletoxicity and a substantial proportion of patients remain refractory to treatment. Amore comprehensive understanding of the complexity of SLE immunopathogenesis hasevolved over the past decade and has led to the testing of several biologic agents inclinical trials. There is a clear need for new therapeutic agents that overcome theseissues, and biologic agents offer exciting prospects as future SLE therapies.

An array of promising new therapies are currently emerging or are under developmentincluding B-cell depletion therapies, agents targeting B-cell survival factors,blockade of T-cell co-stimulation and anti-cytokine therapies, such as monoclonalantibodies against interleukin-6 and interferon-α.

Introduction

Systemic lupus erythematosus (SLE) is a complex autoimmune rheumatic disease,characterized by unpredictable exacerbations and remissions. Clinical manifestations arevariable ranging from arthralgia, photosensitivity and the classic‘butterfly’ rash to internal organ involvement, most notably renal andcentral nervous system disease [1]. Theprevalence of SLE varies significantly in different ethnic groups. SLE is more commonlyseen in those of Afro-Caribbean and Asian origin than in Caucasian populations[2]. The overall prevalence of SLE in theUK is approximately 28 per 100,000 head of population, rising to approximately 200 per100,000 in Afro-Caribbean females [3].

Lupus nephritis remains a major cause of morbidity and mortality in SLE. There have beenmajor improvements in the risk of premature mortality in patients with lupus nephritis[4]. However, despite advances in theclinical management of lupus nephritis in recent decades with earlier diagnosis ofdisease and optimization of the currently available immunosuppressive regimens, anestimated 10% to 15% of patients progress to end-stage renal disease (ESRD)[5]. The rate of progression to ESRD andthe risk of premature mortality is likely to be even higher in patients ofAfro-Caribbean descent [6]. A significantproportion of lupus nephritis patients are refractory to conventional immunosuppressiveagents and the potential side effects of these therapies remain significant.

A retrospective review of lupus nephritis patients over a 30-year period (1975 to 2005)from a single center showed that five-year mortality decreased by 60% between the firstand second decades of the study but remained unchanged over the third decade with ratesof 17.2, 7.7 and 4.7%, respectively, after the diagnosis of renal disease [7]. The rate of progression to ESRD also reached aplateau in the third decade. These results suggest that the benefits of conventionalimmunosuppressive therapies have been maximized and if further advances in SLE outcomesare to be achieved, novel therapeutic targets must be developed [7].

Over the last two decades, there have been tremendous advances in the understanding ofthe immunopathology of this autoimmune disorder. A variety of novel therapeutic targetshave been identified and there have been many clinical trials in patients with SLE in anattempt to translate these new treatments into clinical practice. The results of thesestudies have been very mixed and there has been a steep learning curve for everyoneinvolved in designing and executing these trials. SLE is a particularly challengingdisease to study due to the broad spectrum of clinical manifestations and varyingpatterns of disease activity. Furthermore, disease specific outcome measures that weredeveloped for use in observational clinical studies were exposed as inadequate when usedin therapeutic clinical trials. This has led to the development of a composite outcomemeasure, the Systemic Lupus Erythematosus Responder Index (SRI), which has become theindustry standard for lupus trials [8]. Anothertheme that has emerged is the excessive use of corticosteroids. Not only are these amajor confounder in assessing disease response, it is now recognized that high dosecorticosteroids have significant deleterious effects that may contribute to thedevelopment of damage and, hence, long term morbidity and premature mortality[9]. Here we describe novel therapeuticstrategies under development for the treatment of SLE, which are summarized inTable  1.

Table 1 Summary of potential novel therapeutic options and biologics for SLE

B-cell depletion therapy

Given that autoantibody production is the hallmark of SLE, it is not surprising thatB cell depletion therapy is a promising therapeutic option in the management of SLE.The main drug in current clinical practice is rituximab, with other drugs indevelopment including epratuzumab. B cells, including the populations that interactwith T cells, play an integral part in the autoimmune pathogenesis of SLE, and it isthought that after B cell depletion, disease activity may be modified and durabledisease remission achieved, minimizing the use of other immunosuppressive agents andcorticosteroids.

Rituximab (anti-CD20)

Rituximab is a chimeric anti-CD20 monoclonal antibody that has been used off-licensein the management of severe refractory SLE since 2002. The mechanism of action ofrituximab involves antibody-dependent cell toxicity (ADCC), complement-dependent celltoxicity (CDC) and direct apoptosis of CD20⁺ B lymphocytes which resultsin complete B cell depletion [10]. Plasmacells are unaffected by rituximab as they lack the CD20 surface marker.

A recent review of the efficacy of rituximab in the management of SLE patients withbiopsy-proven severe lupus nephritis from pooled data in European cohorts (n = 164)reported the clinical efficacy of rituximab in clinical practice [11]. This open-label data, showing that approximatelytwo-thirds of patients previously unresponsive to conventional therapies had clinicalbenefit, is in contrast to the two randomized controlled clinical trials (RCTs) ofrituximab, which did not meet the primary and secondary endpoints set out during thetrial design.

The Study to Evaluate the Efficacy and Safety of Rituximab in Patients With SevereSystemic Lupus Erythematosus (EXPLORER) included patients with moderate to severe SLEbut excluded lupus nephritis patients (n = 257) [12]. The EXPLORER RCT compared rituximab plus standardimmunosuppressive drugs including mycophenolate mofetil (MMF) (n = 169) to placeboplus standard immunosuppressive therapy, with all patients receiving 10 weeks of highdose corticosteroids. Published data report the failure of the EXPLORER trial to showsuperiority of rituximab or statistically significant differences in clinicalactivity when the two treatment arms were compared [12]. Closer examination of the data shows that rituximab achievedeffective B cell depletion and, in those patients with positive anti-dsDNA antibodiesand low complement levels, significant improvements were seen in these parameters inthe rituximab treated patients compared to the placebo group.

The Study to Evaluate the Efficacy and Safety of Rituximab in Subjects with ISN/RPSClass III or IV Lupus Nephritis (LUNAR) trial compared rituximab plus MMF to MMFalone for the management of severe proliferative lupus nephritis class III and classIV. The published results did not show superiority of the rituximab combinationtherapy [13]. As with the EXPLORER study,rituximab therapy achieved B cell depletion as well as improvements in the levels ofanti-dsDNA antibodies and complement levels compared to the placebo treated patients.Thus, in both these studies, a biological effect was seen in the rituximab arms thatdid not translate into a clinical benefit over and above standard therapies.

There are many possible explanations for the failure of the EXPLORER and LUNAR trialssuch as the relatively short trial duration and high doses of concomitantcorticosteroids. Rituximab continues to be used off-label in a select group ofpatients with severe refractory SLE. This off-license use of rituximab takes intoaccount the potential benefits reported from clinical practice and the possiblecomplications of biologic therapy, such as severe or recurrent infections, adversedrug reactions and the few case reports of progressive multi-focalleuco-encephalopathy (PML) [14, 15].

An additional benefit of rituximab induction therapy followed by MMF maintenancetherapy for the management of severe proliferative lupus nephritis class III andclass IV, is the ability to reduce and eventually withdraw corticosteroid therapy inpatients who respond to treatment [16].

A new treatment strategy termed the Rituxilup regimen has been pioneered in a centerin the United Kingdom. The Rituxilup regimen avoids the use of concomitant oralcorticosteroid therapy after rituximab induction therapy, thereby minimizing theduration of corticosteroid exposure and steroid side-effects [17]. A proposed randomized controlled trial will be of greatclinical relevance in ascertaining the clinical effectiveness, benefits andconsequences of this steroid-sparing regimen.

RING – Rituximab for Lupus Nephritis With Remission as a Goal, aninvestigator-initiated randomized international open multicenter study, aims todetermine the clinical effectiveness of rituximab in achieving complete renalremission in lupus nephritis patients with persistent proteinuria (≥1grams/day) despite a minimum of six months of standard immunosuppressive therapy(http://www.clinicaltrials.gov). This study is still at the developmentstage.

Epratuzumab (anti-CD22)

Epratuzumab is an anti-CD22 monoclonal antibody that is currently under investigationfor the management of moderate to severe SLE and shows great promise.

CD22 is a B cell specific trans-membrane sialo-glycoprotein which is present on thecell surface of mature naive B cells and transitional B cells but not present onmemory B cells or plasma cells [18]. CD22 isa lectin-like adhesion receptor which has an important role to play in the regulationof B cell function and also forms part of the B cell activation complex[18]. As an anti-CD22 monoclonalantibody, epratuzumab can cause moderate depletion of B cells via ADCC; however,unlike rituximab, epratuzumab does not exhibit CDC or direct apoptosis of B cells[18]. Epratuzumab predominantly targetsCD27^- B cells such as naive mature and transitional B cells and it isestimated that the reduction in peripheral B cell counts in SLE patients approximates40% post-epratuzumab therapy [19].

EMBLEM™ is a 12-week, multi-center, randomized, double-blind,placebo-controlled, phase IIb study to assess the efficacy and safety of epratuzumaband determine a dose regimen in patients with moderate to severe SLE. A total of 227patients were recruited and randomized to placebo n = 38, epratuzumab 200 mgcumulative dose (100 mg alternate weeks) n = 39, epratuzumab 800 mg cumulative dose(400 mg alternate weeks) n = 38, epratuzumab 2,400 mg cumulative dose (600 mg weekly)n = 37, epratuzumab 2,400 mg cumulative dose (1,200 mg alternate weeks) n = 37,epratuzumab 3,600 mg cumulative dose (1,800 mg alternate weeks) n = 38.

Epratuzumab at a cumulative dose of 2,400 mg was clinically effective anddemonstrated a significant reduction in disease activity as measured by a compositedisease activity score. Epratuzumab 600 mg weekly was associated with the greatestimprovement in British Isles Lupus Assessment Group (BILAG)-2004 scores (from A/B toC/D) than placebo in all organ domains included in the study. Overall epratuzumab waswell tolerated [18].

Two randomized controlled trials evaluating the efficacy of epratuzumab in severe SLEas determined by the presence of BILAG A (RCT SL0003) and/or moderate patients withBILAG B in at least two systems (RCT SL0004) were discontinued due to irregularitiesin the manufacture of epratuzumab. The results of patients recruited in these trialswere pooled and indicate the potential benefit of epratuzumab in facilitating areduction in prescribed corticosteroid dose [18].

Two Phase III, randomized, double-blind, placebo-controlled, multicenter studies ofthe efficacy and safety of four 12-week treatment cycles (48 weeks total) ofepratuzumab in SLE subjects with moderate to severe disease EMBODY™1 &EMBODY™2 have an expected completion date of February 2014 with a recruitmentof 780 patients. The main aim is to evaluate the efficacy, safety, tolerability andimmunogenicity of epratuzumab in patients with moderate and severe SLE (NCT01262365,NCT01261793, http://www.clinicaltrials.gov). A phase III, multicenter,open-label, extension study to assess the safety and tolerability of epratuzumabtreatment in SLE subjects EMBODY™4 started recruiting in July 2011 and isaiming to recruit 1,400 patients with a completion date of February 2016(NCT01408576, http://www.clinicaltrials.gov).

Ocrelizumab (anti-CD20)

Ocrelizumab is a humanized anti-CD20 monoclonal antibody. In 2010 an independentmonitoring board recommended the suspension of clinical trials of ocrelizumab inrheumatoid arthritis and SLE due to a high frequency of reported severe andopportunistic infections in the patients enrolled in the trials. Therefore, the Studyto Evaluate Ocrelizumab in Patients With Nephritis Due to Systemic LupusErythematosus (BELONG) trial was suspended [20].

The BELONG study had recruited 381 lupus nephritis class III and class IV patients tostudy the clinical efficacy and safety of ocrelizumab 400 mg or ocrelizumab 1,000 mgadministered at baseline, a fortnight later, then every four months thereafter. Alllupus nephritis patients enrolled in the study were treated with either intravenouscyclophosphamide using the EuroLupus regimen or MMF and high-dose corticosteroidsconcomitantly. Week 42 data from 221 patients who had enrolled at least 32 weeksprior to study termination have been reported in abstract form and, althoughocrelizumab is clinically effective in reducing lupus nephritis disease activity, thedata have not demonstrated superiority to standard immunosuppression [20].

Targeting B-cell survival factors

Belimumab (anti-BLys)

Belimumab is a human immunoglobulin G1λ monoclonal antibody which blocks thebinding of the soluble form of the cytokine B-lymphocyte stimulator (B-Lys), alsoknown as B cell activating factor (BAFF), to the transmembrane activator/calciummodulator/cyclophilin ligand interactor (TACI) receptor, B-cell maturation (BCMA)receptor and BAFF receptor 3 (BR3) on B cells and thus interrupts the B cellsurvival role of B-Lys [21].

BAFF/BLys is expressed by several cells including dendritic cells, monocytes,activated neutrophils and T cells. It is vital in facilitating the maturation andsurvival of B cells via signaling through the BAFF-R, BCMA and TACI receptors withhigh, intermediate and low affinity respectively. APRIL, a BAFF homologueproliferation-inducing ligand binds with higher affinity to the TACI receptor thanBAFF [22]. Dimerization of BAFF and APRILto the BCMA receptor is required to support the maturation of plasma cells[22]. A strong interaction of BAFFto the BAFF-R propagates the maturation and survival of naive B cells and theinteraction of BAFF/BLys, APRIL and TACI to the TACI-R facilitates immunoglobulin(Ig) gene class switching in the germinal center [22].

In the presence of an excess amount of BAFF/BLys, low-affinity self-reactive Bcells may survive and mature into self-reactive auto-antibody secreting plasmacells implicated in autoimmune disease pathogenesis. As a result, it has beendeduced that the inhibition of BAFF/BLys by belimumab has therapeutic implicationsin SLE.

In March 2011 the United States Food and Drug Administration (FDA) and theEuropean Medicines Evaluation Agency (EMEA) licensed belimumab as the first newdrug in over 50 years for SLE. Belimumab was licensed as a biologic agent to beprescribed with standard therapy for autoantibody-positive adult SLE patientsexcluding those with active lupus nephritis and central nervous systemmanifestations of SLE.

Belimumab is administered on a weight-based dosing schedule of belimumab 10 mg/kgas an hour long intravenous infusion fortnightly for three infusions then monthlythereafter.

A phase III randomized placebo-controlled trial Belimumab International SLE Study(BLISS-52) conducted between May 2007 and July 2009 included 865 SLE patientsenrolled in Central and Eastern Europe, Latin America, and Asia Pacific[19]. A phase III randomizedplacebo-controlled trial Belimumab International SLE Study (BLISS-76) wasconducted between February 2007 and February 2010 enrolling 819 patients in NorthAmerica and Western and Central Europe [23]. These studies used the composite SRI outcome measurewhich requires improvement in the SELENA-SLEDAI but no worsening in the BILAG andPhysician Global Assessment scores.

The trial outcome at 52 weeks in BLISS-52 reported positive clinical response in44% of those treated with placebo with standard therapy, 51% of those treated withbelimumab 1 mg/kg with standard therapy and 58% of those treated with belimumab 10mg/kg with standard therapy (P = 0.013 and P = 0.0006,respectively) [23].

The trial outcome at 52 weeks in BLISS-76 reported positive clinical response in34% of those treated with placebo with standard therapy, 41% of those treated withbelimumab 1 mg/kg with standard therapy and 43% of those treated with belimumab 10mg/kg with standard therapy (P = 0.10 and P = 0.021,respectively) [23]. However, at 76 weeks,there was no significant difference in responder rates between the belimumab andplacebo groups.

The BLISS-52 and BLISS-76 clinical trials both excluded patients with active lupusnephritis. BLISS-LN is a phase III, randomized, double-blind, placebo-controlledstudy to evaluate the efficacy and safety of belimumab plus standard of careversus placebo plus standard of care in adult subjects with active lupus nephritiswhich will provide clinically relevant information about the use of belimumab inlupus nephritis NCT01639339 (http://www.clinicaltrials.gov).

An exploratory analysis of belimumab use in patients of black ethnicity in theBLISS-52 and BLISS-76 trials (n = 148) reported lower clinical effectiveness inthis group as compared to other ethnic groups.

A phase III/IV multi-center, randomized, double-blind, placebo-controlled, 52-weekstudy to evaluate the efficacy and safety of belimumab in adult subjects of blackrace with SLE is planned as a future study NCT01632241(http://www.clinicaltrials.gov).

Belimumab may be more effective in specific sub-groups of lupus patients.Published data indicate that belimumab is significantly more efficacious in SLEpatients who are ds-DNA positive, hypocomplementemic or have high disease activityas measured by SELENA-SLEDAI score >10 [24].

In 2012, fatal anaphylaxis was reported in a patient treated with belimumab and itis now known that there is a risk of a delayed acute hypersensitivity reaction tobelimumab, especially in patients with multiple drug allergies. Long-termobservational data will provide further safety and tolerability data on belimumab.At present the FDA Center for Drug Evaluation and Research has reviewed the safetylabeling for belimumab(http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm299628).

The increased susceptibility to infection after belimumab treatment may be as aconsequence of alterations in the signaling pathways involving BAFF/BLys and theTACI receptor. The TACI molecule has a complex role in host immunity involvingactivation of B cells and T cell independent immune regulation; however, this isyet to be completely understood [25]. Inlight of this, it has been postulated that the post-belimumab low BAFF/BLys levelsresult in a reduction in TACI signaling and hamper the host immune defensesagainst pathogens, such as polysaccharide encapsulated bacteria. Patients treatedwith belimumab have an increased susceptibility to infection, the commonest beingpharyngitis, bronchitis, cystitis and viral gastroenteritis [23]. In the clinical trials serious infectionshave been reported in 6% of belimumab-treated patients as compared to 5.2% inplacebo controls but there have been no reports to date of PML in belimumabtreated patients [26].

Although belimumab received regulatory approval from the US FDA and the EMEA, itsuse in some countries has been restricted until approval by national drugevaluation organizations. The German Institute for Quality and Efficiency inHealth Care (IQWiG) has recommended evaluation of belimumab for additional benefitover optimized immune-suppression rather than over standard therapy prior to fullapproval (http://www.iqwig.de).

In 2012 The National Institute for Health and Clinical Excellence (NICE) provideda draft national guidance on the use of belimumab for SLE in the United Kingdom.NICE did not recommend belimumab within its licensed indication as add-on therapyto standard immune-suppressive drugs in adult patients with active auto-antibodypositive SLE. In making this decision, NICE considered the clinical trialevidence, clinical specialist and patient opinions. NICE concluded that the use ofbelimumab was not sufficiently cost-effective to the National Health Service (NHS)in relation to its reported clinical effectiveness. A final decision will beexpected after the appeals process has been concluded(http://www.nice.org.uk).

Blisibimod (anti-B-Lys)

In 2010 a Phase II study called PEARL-SC commenced with the aim of investigating theefficacy, safety, and tolerability of blisibimod, a B lymphocyte stimulatoryantagonist, in patients with active SLE. In 2011 an open-label long-term safetyextension trial for patients with SLE who completed the protocol PEARL-SC wascommenced.

In 2012 approval was granted by the EMEA and FDA for phase III clinical trials ofblisibimod, CHABLIS-SC1 and CHABLIS-SC2. These international multicenter, randomized,double-blind trials aim to evaluate the efficacy, safety, tolerability andimmunogenicity of blisibimod in patients with severe active SLE (SELENA-SLEDAI >10)despite high-dose corticosteroids NCT01395745(http://www.clinicaltrials.gov).

Tabalumab (anti-B-Lys)

Tabalumab (LY2127399) is a human IgG4 monoclonal antibody targeting membrane-boundand soluble BAFF. A phase III, multicenter, randomized, double blind,placebo-controlled study to evaluate the efficacy and safety of subcutaneousLY2127399 in patients with SLE is expected to be completed in May 2015 (NCT01196091).Tabalumab is administered subcutaneously in addition to standard of care therapy foractive SLE (http://www.clinicaltrials.gov).

Atacicept (TACI-Ig fusion protein)

Atacicept is a TACI receptor fusion protein which inhibits BLys and APRIL in immatureB cells, mature B cells and plasma cells. It is currently under investigation as apotential new therapy for SLE and is in a phase II/III clinical trial for patientswith SLE excluding lupus nephritis [27]. Theinitial phase II trial of atacicept and MMF combination therapy for lupus nephritiswas stopped due to a high frequency of reported infections likely related to a markedreduction in total Ig levels [28]. Theprematurely terminated randomized, double-blind, placebo-controlled Phase II/III,52-week study, APRIL-LN, reported adverse events in the patients randomized toatacicept (n = 4). Patients developed significant IgG hypogammaglobulinemia below theprotocol-defined criteria for discontinuation (n = 3) and serious infectionsincluding, haemophilus influenza pneumonia, legionella pneumophilia pneumonia andbacillus bacteremia. Interestingly, atacicept trials in rheumatoid arthritis have notyielded this severity of adverse events [29].This implies that the immunopathogenesis of lupus nephritis may have influenced theresults of this atacicept trial.

Blockade of T-cell co-stimulation

Abatacept (CTLA-4-Ig fusion protein)

Blockade of the co-stimulatory interactions between T and B lymphocytes can induceimmunological tolerance. The most well characterized T lymphocyte co-stimulatoryligand is CD28, a glycoprotein which interacts with the co-stimulatory receptorsB7-1 (CD80) and B7-2 (CD86). CTLA4 (cytotoxic T-lymphocyte antigen) is expressedon activated T cells and interacts with B7 with higher affinity than CD28resulting in a negative feedback mechanism that inhibits T cell activation[30–32]. Abatacept is a fusion protein consisting of CTLA-4combined with the Fc portion of human IgG1 (CTLA-4-Ig). Combination therapy ofCTLA-4-Ig and cyclophosphamide significantly reduces proteinuria, autoantibodytitres and improves mortality in murine lupus nephritis [33–35].However, a randomized controlled trial of abatacept in 175 SLE patients failed tomeet its primary end-point of a reduction of the proportion of patients with a newSLE flare [36]. Approximately one-fifth ofthe patients included in this study were sero-negative for ANAs and anti-dsDNA.There were, however some improvements in quality of life measures by the SF-36physical component scores, fatigue and sleep problem scores in the abatacepttreated group. Patients in this study primarily had musculoskeletal anddermatologic features of SLE and the trial was not specifically designed toexamine the role of abatacept in lupus nephritis.

A 12-month Phase II/III double-blind placebo controlled trial in proliferativelupus nephritis failed to meet its primary end-point of time to complete renalresponse as defined as glomerular filtration rate within 10% ofpre-flare/screening value, urinary protein creatinine ratio <0.26 mg/mg andinactive urinary sediment [37]. Howeverwhen the same data were analyzed using different outcome measures, with completeresponse defined as serum creatinine either normal or ≤125% of baseline,urinary protein creatinine ratio <0.5 g/g, and prednisone dose ≤10 mg/dat study day 365, the study showed a positive outcome in favor of abatacept[38]. This highlights the importanceof choosing outcomes measures in clinical trials of lupus nephritis and thenecessity for standardization of outcomes across studies.

Anti-CD40 ligand

CD40 ligand (CD40L) is a transmembrane glycoprotein belonging to the tumor necrosisfactor (TNF) super family which binds with CD40 on the surface of B-cells andmacrophages. The interaction between CD40/CD40L plays a pivotal role in B-cell classswitching [39]. CD40L is over expressed inmurine lupus models and monoclonal antibodies against CD40L have successfully treatedmurine lupus nephritis [40]. There have beentwo clinical trials of humanized anti-CD40L monoclonal antibodies (IDEC-131 andBG9588) in SLE patients. Eighty-five SLE patients treated with IDEC-131 failed todemonstrate clinical improvement as compared to placebo at 20 weeks [41]. A trial of 28 lupus nephritis patients treatedwith BG9588 showed initial promise with reduced anti-dsDNA titres and increasingcomplement levels but was discontinued prematurely due to unexpected thrombo-embolicside effects [42]. Given the lack of efficacyand toxicity demonstrated in these studies, it is unlikely that anti-CD40L willprogress to larger clinical trials in SLE patients.

Cytokine therapies

Tocilizumab (anti-IL-6)

IL-6 is a pleiotropic cytokine with both pro-inflammatory and anti-inflammatoryproperties and has been implicated in the pathogenesis of lupus nephritis.Exogenous IL-6 increases autoantibody production and accelerates progression ofnephritis in both the NZB/NZW and BXSB lupus mouse models [43, 44]. Treatment of lupus prone micewith an IL-6 monoclonal antibody decreases anti-dsDNA titres and proteinuria andreduces mortality [45, 46]. In SLE patients, IL-6 levels have been shown to correlatewith clinical activity and anti-dsDNA antibody levels [47, 48]. Urinary excretion of IL-6 isincreased in proliferative lupus nephritis and is reduced followingcyclophosphamide therapy [49, 50].

Tocilizumab is a fully humanized monoclonal antibody against the IL-6 receptor andprevents binding of IL-6 to both membrane bound and soluble IL-6 receptor. A phaseI trial over a 12 week period has demonstrated the safety and tolerability oftocilizumab in SLE patients. While active urinary sediment and anti-dsDNA antibodytitres were reduced, proteinuria remained unchanged [51]. The short duration of the study renders it difficultto draw conclusions as to the longer term effects of tocilizumab in the treatmentof lupus nephritis. Randomized controlled trials of tocilizumab in SLE areawaited. Sirukumab (CNTO 136) a human monoclonal antibody that targets IL-6 iscurrently in a phase II study in lupus nephritis (NCT01273389)(http://www.clinicaltrials.gov).

Targeting interferon-α

Recent studies of SLE patients and data from murine models of lupus, suggest thatinappropriate activation of type I IFNs play an essential role in SLE pathogenesis.Microarray gene expression analysis has shown widespread activation of IFN-induciblegenes in SLE patients which correlates with disease activity [52, 53]. In addition, IFN pathwayactivation has been associated with lupus nephritis activity [54]. A scoring system based on expression of type IIFN-inducible mRNAs, which may divide SLE patients into two distinct subgroups hasbeen proposed to enable type I IFN-inducible genes to be used as biomarkers toidentify patients who might respond better to anti-type I IFN treatment[36]. Given the role of IFN-α inthe host defense against viral infection, close clinical monitoring is mandatory inthe development of any potential agents targeting this pathway.

Sifalimumab, a fully human anti-IFN-α monoclonal antibody, induced adose-dependent inhibition of type I IFN-induced mRNAs (type I IFN signature) in wholeblood in a phase I study. No increase in viral infections was noted and a generaltrend towards improvement in disease activity was seen [55]. Further studies examining the efficacy of sifalimumab inSLE are in recruitment (NCT01283139) (http://www.clinicaltrials.gov). APhase II clinical trial evaluating rontalizumab, a recombinant humanized monoclonalantibody to IFN-α for SLE is also ongoing (NCT00962832)(http://www.clinicaltrials.gov).

The efficacy and safety of rontalizumab, a recombinant humanized monoclonal antibodyto IFN-α was recently assessed in a randomized, double-blind, placebo-controlledphase II trial in adults with moderate to severe non-renal SLE. An abstract byKalunian K et al. entitled ‘Efficacy and Safety of Rontalizumab(Anti-Interferon Alpha) in SLE Subjects with Restricted Immunosuppressant Use:Results of a Randomized, Double Blind, Placebo-Controlled Phase 2 Study’ waspresented at the American College of Rheumatology Annual Scientific Conference inNovember 2012.

In the initial part of the study, SLE patients received either 750 mg intravenouslyof rontalizumab or placebo for four weeks. In the second part of the study, SLEpatients received either 300 mg subcutaneously of rontalizumab or placebo for twoweeks. Overall, response rates at 24 weeks as measured by BILAG and SRI were similarbetween rontalizumab and placebo. However, in patients taking >10 mg/kg of steroidsdaily, rontalizumab was more effective in reducing lupus disease activity thanplacebo. Patients were further analyzed as per their IFN gene expression signature,which showed that rontalizumab was more effective in those with a more elevated IFNsignature.

Complement therapies

Eculizumab (anti-C5)

The complement system plays an important role in the pathophysiology of SLEalthough individual complement components have distinct and varied functions inthe disease process. Early components of the complement cascade are critical inthe clearance of immune complexes and apoptotic material. Their absence incongenital C3 or C4 deficiency predisposes individuals to development of SLE.Activation of terminal complement components is associated with exacerbations ofdisease, particularly in lupus nephritis.

Monoclonal antibodies that specifically inhibit terminal complement activationwhile preserving early complement function have been developed. Eculizumab, amonoclonal antibody directed against the complement protein C5, inhibits thecleavage of C5 to C5a and C5b and thus blocks the formation of the terminalmembrane attack complex C5b-9 [56].Anti-C5 therapy delays onset of proteinuria, improves renal histology and survivalin murine lupus nephritis [57]. A phase Itrial of eculizumab in SLE demonstrated safety and tolerability, but no clearclinical improvements were seen by day 28 and 56 of the study [58]. To date there have been no further clinicaltrials to examine the potential efficacy of this therapy in SLE.

Targeting Fcγ receptor IIB

Fcγ receptors are a heterogeneous group of hematopoietic cell surfaceglycoproteins that recognize the Fc portion of specific Ig isotypes, facilitatingantibody-antigen interactions with effector cells and, thus, play a key role in theclearance of immune complexes [56]. Fcγreceptor IIB (FcγRIIB) is the sole inhibitory receptor in the Fcγ receptorfamily and competes with activatory Fcγ receptors expressed on immune cells forpathogenic immune complexes. FcγRIIB may also interfere with formation ofmemory/plasma cells that develop autoantibodies [56]. Treatment of lupus-prone NZB/NZW F1 mice with recombinantsoluble FcγRIIB significantly delayed onset of proteinuria, reducedhistopathological findings and improved survival [57]. Currently a soluble FcγRIIB (SM101) is undergoing phaseII trials in SLE and primary immune thrombocytopenia (ITP).

Laquinimod

Laquinimod is an oral quinoline-3-carboxamide small molecule which to date has beenmainly investigated in the context of relapsing-remitting multiple sclerosis (MS). InMS, laquinimod biases the CD4+ phenotype in favor of Th2/Th3 cytokine production andinhibits disease development and infiltration of inflammatory cells into the CNS[58, 59].Laquinimod also suppresses major histocompatibility class II antigen presentation anddown-regulates epitope spreading [60].Laquinimod is currently in phase II trials in lupus arthritis and lupus nephritis.(http://www.clinicaltrials.gov).

Janus kinase (JAK) and spleen tyrosine kinase (Syk) inhibitors

Tofacitinib (JAK inhibitor)

Tofacitinib is a Janus kinase (JAK) selective inhibitor which has been approved asthe first oral biologic for the management of rheumatoid arthritis. JAKs areessential for signal transduction of cytokines and contribute to inflammatoryresponses [59]. Targeting JAKs in SLEwould be a logical therapeutic option which can be studied further starting withtrials to determine the safety, pharmacodynamics and efficacy of these drugs inSLE.

Fostamatinib (Syk inhibitor)

Spleen tyrosine kinase (Syk) is implicated in the B cell immunopathogenesis of SLEand is a potential therapeutic target. Syk inhibitors have been shown to prevent theonset of skin and renal disease in lupus-prone mice. In addition, Syk inhibitorsreduce inflammatory arthritis. Fostamatinib is an oral Syk inhibitor being evaluatedfor the management of autoimmune rheumatic diseases [60].

Discussion

The management of SLE is likely to change significantly with the introduction of newbiological therapies and the discovery of other therapeutic targets. The exact role ofthese drugs will be determined after completion of the trials and with clinicalexperience. It is envisioned that the majority of the biological therapies willinitially be reserved for patients who have failed to respond satisfactorily to optimalconventional immunosuppressive drugs. The new biological drugs will need to be usedappropriately to target disease remission; reduction of the disease severity; frequencyof lupus flares and the subsequent high morbidity associated with lupus.

Conventional immunosuppressive therapies have radically transformed patient survival inSLE, but their use is associated with considerable toxicity and a substantial proportionof patients remain refractory to treatment. A more comprehensive understanding of thecomplexity of SLE immunopathogenesis has evolved over the past decade and has led to thetesting of several biologic agents in clinical trials. An array of promising newtherapies are yet to emerge or are under development. There is a clear need for newtherapeutic strategies that overcome these issues, and biologic agents offer excitingprospects as future SLE therapies. The role of new therapeutic agents to date haschiefly centered on SLE patients who have been refractory to conventional therapies.There are few clinical trials examining their role as first line induction ormaintenance therapy. Questions remain as to how these therapies can potentially becombined with existing proven treatments and indeed with one another to achieve maximumclinical benefit while minimizing toxicity. Although so far many biologics have beengenerally well tolerated, we must not be complacent regarding potential toxicity ofthese new agents, as we do not yet know the long-term effects of these medications onthe immune system. Rituximab is currently used off-license for the management of severerefractory SLE and is likely to continue to be used for this indication due to overallpositive clinical experience.

Based on the clinical trial and extension study data, belimumab has a modest level ofclinical effectiveness when used in combination with standard immunosuppressive drugs inautoantibody-positive SLE patients. The BILAG data at week 52 of the BLISS trialssuggested more favorable outcomes in the mucocutaneous, musculoskeletal domains. TheSELENA-SLEDAI cutaneous, musculoskeletal, immunologic, vascular and CNS componentssignificantly improved at week 52 in the BLISS trials. Physicians will, therefore, beinclined to closely monitor patients on belimumab and switch to alternate therapeuticregimens if the clinical response is inadequate after six months. SLE patients of blackethnicity are to be studied in greater numbers than in the original BLISS trials inorder to ascertain whether or not belimumab is beneficial in this group of patients. Asbelimumab use becomes more prevalent and the results of the on-going belimumab clinicaltrials are published, the group of SLE patients likely to benefit the most from thisdrug may be identified and this will guide future use of this medication.

The place for other therapeutic agents in development for the management of SLE, such asepratuzumab, blisibimod, tabalumab and atacicept, as induction or maintenance therapieswill be determined after robust reviews of the clinical trial data which are expectedupon completion of the studies. It is anticipated that only drugs which show long-termclinical effectiveness, benefit as steroid-sparing agents and satisfactory safetyprofiles in SLE will gain approval for clinical use.

Some novel biologic therapies have been associated with significant toxicity leading topremature discontinuation of clinical trials such as the association of anti-CD40L andthrombo-embolic events and the high frequency of reported severe and opportunisticinfections associated with ocrelizumab. Although some drugs have not progressed to phaseII or III clinical trials after phase I studies, research into cytokine therapies, drugstargeting FcγRIIB and small molecule targets is on-going and may yield importantresults for the future of SLE management.

Health economic studies will be essential in determining the future use of the newtherapeutic agents in SLE and may influence the international use of these drugs.

A number of key questions remain. How can these therapies be potentially combined withexisting proven treatments and indeed with one another to achieve maximum clinicalbenefit with minimal side-effects, such as increased risk of serious infection. As isclear to all physicians involved in the day to day management of SLE patients, this is aheterogeneous disease and there is not one therapeutic regimen suitable for all. With adeeper understanding of the pathophysiology of SLE particularly from a geneticperspective, the era of personalized therapy may represent the greatest advance that isyet to come in optimizing treatment of SLE.

Conclusions

Conventional immunosuppressive therapies have radically transformed patient survival inSLE, but their use is associated with considerable toxicity and a substantial proportionof patients remain refractory to treatment. A more comprehensive understanding of thecomplexity of SLE immunopathogenesis has evolved over the past decade and has led to thetesting of several biologic agents directed against new molecular targets in clinicaltrials. An array of promising new therapies is yet to emerge or is under development.There is a clear need for new therapeutic agents that overcome these issues, andbiologic agents offer exciting prospects as future SLE therapies. Several challengesstill remain in designing clinical trials in SLE. One of the main issues is thatconventional therapies have been optimized and are effective in the majority ofpatients. There is, therefore, quite a high bar for new therapies to demonstrate asignificant benefit over conventional approaches and progress is likely to beincremental rather than revolutionary.

The role of new therapeutic agents has chiefly centered on SLE patients who have beenrefractory to conventional therapies. There are few clinical trials examining their roleas first line induction or maintenance therapy. Questions remain around how thesetherapies can potentially be combined with existing proven treatments and indeed withone another to achieve maximum clinical benefit while minimizing toxicity. As is clearto all physicians involved in the day to day management of SLE patients, this is aheterogeneous disease and there is no single therapeutic regimen suitable for all. Witha deeper understanding of the pathophysiology of SLE particularly from a geneticperspective, the era of personalized therapy may represent the greatest advance that isyet to come in optimizing treatment of SLE.

Authors’ information

NJ joined the lupus team at St Thomas’ Hospital in 2009 and was subsequentlyawarded an Arthritis Research UK clinical research fellowship to undertake a PhDfocusing on lupus nephritis. Her research is based at the Centre for Molecular andCellular Biology of Inflammation at King’s College London and she continues towork as a clinician at the Louise Coote Lupus Unit primarily in the areas of lupusnephritis and vasculitis. PL joined the lupus team at St Thomas’ Hospital in 2010as a specialist registrar in Rheumatology and is currently a clinical research fellow atthe Peter Gorer Department of Immunobiology King’s College London and Lupus UnitSt Thomas’ Hospital studying the effects of B cell depletion therapy on lymphocytesubsets in lupus and vasculitis. DDC is clinical team lead for the Louise Coote LupusUnit and is Professor of Lupus Biology and Consultant Rheumatologist.