The efficacy of novel B cell biologics as the future of SLE treatment: A review

AUTREV-01593; No of Pages 8 Autoimmunity Reviews xxx (2014) xxx–xxx

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Review

The efficacy of novel B cell biologics as the future of SLE treatment: A review Ameer Kamal ⁎ King's College London, The Rayne Institute, 4th Floor Lambeth Wing, St Thomas' Hospital, Westminster Bridge Road, SE1 7EH London, UK

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Article history: Received 6 May 2014 Accepted 28 May 2014 Available online xxxx Keywords: B cells Biologics Systemic lupus erythematosus

a b s t r a c t Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with wide ranging multisystemic effects. Current understanding centralises B cells in SLE pathogenesis with clinical features resulting from autoantibody formation, immune complex deposition, antigen presentation and cytokine activation. Existing standard of care therapies generates adverse side effects; secondary to corticosteroid use and untargeted immunosuppression. The inability to uphold remission and abolish the disease process, in addition to the increasing numbers of patients seen with refractory disease with these therapies, has provoked the development of novel B cell biologics targeting specific pathogenic pathways fundamental to the SLE disease process. Current evidence highlighting the efficacy of Rituximab, Ocrelizumab and Epratuzumab in inducing B cell depletion and achieving disease amelioration through specific B cell surface receptor antagonism is discussed. We review the efficacy of Atacicept, Briobacept and Belimumab in antagonising B lymphocyte stimulator (BLyS) and A proliferation inducing ligand (APRIL), two stimulatory cytokines crucial to B cell survival, growth and function. Two large multicentre randomised controlled trials, BLISS-52 and BLISS-76, have led to FDA approval of Belimumab. Following this breakthrough, other anti-BLyS therapies, Blisibimod and Tabalumab, are currently under Phase III evaluation. Similarly, murine models and Phase I/II trials have demonstrated significant efficacy of Rituximab, Epratuzumab, Briobacept and Atacicept as potential future therapies and we now eagerly await results from Phase III trials. Future research must compare the efficacy of different biologics amongst different patient subpopulations and SLE manifestations, in order to develop clinically and cost effective therapies. © 2014 Published by Elsevier B.V.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapeutics in SLE: current and future medications . . . . . . . . . . . . . . Targeting cell surface receptors: B cell inhibition/depletion . . . . . . . . . . . 4.1. Anti-CD20: Rituximab . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Anti-CD20: Ocrelizumab . . . . . . . . . . . . . . . . . . . . . . . 4.3. Anti-CD22: Epratuzumab . . . . . . . . . . . . . . . . . . . . . . 5. Targeting soluble mediators to inhibit B cell growth and function . . . . . . . . 5.1. B lymphocyte stimulator (BLyS) & A proliferation inducing ligand (APRIL) 5.2. Anti-BLyS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. Belimumab . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2. Blisibimod & Tabalumab . . . . . . . . . . . . . . . . . . . 5.3. TACI-Ig: Atacicept . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. BR3-Fc: Briobacept . . . . . . . . . . . . . . . . . . . . . . . . . 6. Cost effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Tel.: +44 207 188 3571; fax: +44 207 620 2658. E-mail address: [email protected].

http://dx.doi.org/10.1016/j.autrev.2014.08.020 1568-9972/© 2014 Published by Elsevier B.V.

Please cite this article as: Kamal A, The efficacy of novel B cell biologics as the future of SLE treatment: A review, Autoimmun Rev (2014), http:// dx.doi.org/10.1016/j.autrev.2014.08.020

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Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction SLE is a relapsing and remitting, chronic autoimmune inflammatory disease with wide ranging multi-systemic effects. Clinical features develop through autoantibody formation, immune complex deposition and cytokine activation. Symptoms vary from general malaise, fever, lethargy and depression to more severe musculoskeletal, cutaneous, pulmonary, renal, haematopoietic, cardiac and nervous system manifestations [1]. (See Figs. 1 and 2.) African–American (AA) women are the highest risk sub-population affected by SLE with 1 in 500 people affected [2]. 80% of patients are females of childbearing age, with males 9 times less likely to develop SLE [2,3]. Klinefelter's syndrome (47 XXY) patients, as well as SLE females on hormone replacement therapy have been shown to have an

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increased risk of relapsing lupus — together suggesting an aetiological role for oestrogen [4,5]. Hereditary factors (40% rate of concordance seen in monozygotic twins), environmental trigger factors (Epstein– Barr virus, UV light and drug interventions such as isoniazid, penicillamine and hydralazine) as well as genetic influences (approximately 200 different genetic loci coding for HLA variants and complement deficiencies have been described) also play a complex multifactorial role in the aetiology of SLE [6–9]. 2. Pathogenesis Following triggers such as EBV infection or UV radiation, inherent abnormalities in the innate and adaptive immune systems result in the collection of ineffectively cleared apoptotic nuclear fragments.

Fig. 1. Systemic lupus erythematosus pathogenesis. The B cell has three key roles: B–T cell antigen presentation, cytokine release and autoantibody formation, which together contribute to the clinical manifestations of lupus through direct inflammation, tissue damage and immune complex deposition. APRIL: A proliferation inducing ligand, BLyS: B lymphocyte stimulator, BAFF-R: BLyS receptor, TACI: transmembrane activator and calcium-modulator and cyclophilin ligand interactor, BCMA: B cell maturation antigen. BLyS targets all three receptors, whereas APRIL targets the latter two. INF α: Interferon alpha, TCR: T cell receptor, MHC II: Major histocompatibility complex class II.

Please cite this article as: Kamal A, The efficacy of novel B cell biologics as the future of SLE treatment: A review, Autoimmun Rev (2014), http:// dx.doi.org/10.1016/j.autrev.2014.08.020

A. Kamal / Autoimmunity Reviews xxx (2014) xxx–xxx

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Fig. 2. Impending targets for novel B cell biologics in lupus. Targeting B cells to prevent antigen presentation (T cell interaction), cytokine release and autoantibody formation is an appealing therapeutic strategy in order to specifically ameliorate the clinical manifestations of lupus. The green biologics are beyond the scope of this review whereas the efficacy of those in blue is discussed.

These include double and single stranded DNAs (dsDNA, ssDNA), RNA binding nuclear antigens (Ro, La and Smith antigens) and non-nuclear fragments, which are then processed by Antigen Presenting Cells (APCs) such as B cells or plasmacytoid dendritic cells (pDCs) [10]. Selfantigens are presented on the cell surface to auto-reactive T cells, which subsequently trigger auto-B cells into self-antibody production and propagate their APC function. APCs are thought to release cytokines such as Interferon α (IFN α), interleukins (IL-6 and IL-10), B lymphocyte stimulator (BLyS), TNF α and A proliferation inducing ligand (APRIL) which positively enhance auto-B cell and subsequent auto-T cell activation. A landmark murine study using a knockout gene mutation to prevent lupus mice developing B cells resulted in no evidence of autoantibody formation or clinical manifestations (nephritis or vasculitis), indicating the key role of aberrant B cell autoreactivity in SLE commencement and maintenance [11]. Additionally, these mice exhibited a significantly reduced number of activated T cells suggesting the importance of B–T cell interaction as a role of B cells in SLE [12]. Vlahakos et al. injected normal mice with autoantibodies to nuclear material from MRL-lpr/lpr and (NZB x SWR)F1 lupus mice and observed self antibodyantigen immune complex deposition in the renal glomeruli, increased cell turnover and proteinuria: lupus nephritis [13]. The results suggested that the formation of immune complexes resulted in inflammation, tissue damage and widespread clinical manifestations. Chan and colleagues subsequently engineered variant lupus mice that expressed surface immunoglobulins but were unable to secrete soluble antibodies. These mice demonstrated T cell activation and developed nephritis, despite the inability of their B cells to secrete antibodies. Thus, the combination of these studies showed that B cell intolerance plays a key role in

mediating an autoimmune response in SLE, in addition to and independent of auto-antibody secretion through direct involvement in nearby inflammation and acting as APCs for auto-T cells [14].

3. Therapeutics in SLE: current and future medications The existing standard of care for SLE depends primarily on disease severity and has been in place for over 60 years. NSAIDS (Aspirin, Ibuprofen and Diclofenac) and anti-malarials (hydroxychloroquine) are used in mild disease. Corticosteroids are vital in moderate–severe disease with additional immunosuppressives such as Mycophenolate mofetil (MMF), Azathioprine (AZT), Cyclophosphamide and Cyclosporine effective in severe cases of SLE [15]. The efficacy of current SLE medication has been questioned by treatment related adverse side effects secondary to corticosteroid use and untargeted immunosuppression, and by the increasing numbers of patients seen with refractory disease [16]. The inability to uphold remission and abolish the disease process in SLE has led to the development of novel B cell specific biologics in order to focus on specific SLE pathogenic pathways. Previous studies using tumour necrosis factor α inhibitors in rheumatoid arthritis patients have been successful and thus development of biologics to achieve a reduced side effect profile and higher efficacy in ameliorating the SLE disease process remains the next challenge [17]. Within this review, we focus on current research targeting the intricate pathways thought to be central to SLE pathogenesis, evaluating the efficacy of novel B cell biologics that target specific B cell surface receptors and cytokines.

Please cite this article as: Kamal A, The efficacy of novel B cell biologics as the future of SLE treatment: A review, Autoimmun Rev (2014), http:// dx.doi.org/10.1016/j.autrev.2014.08.020

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4. Targeting cell surface receptors: B cell inhibition/depletion 4.1. Anti-CD20: Rituximab CD20 is a surface antigen expressed throughout B cell maturation and is involved in B cell activation by aiding Ca2+ influx [19]. CD20 is not expressed on haematopoietic lymphoid stem cells or pre-B cells and is lost upon terminal differentiation into plasma B cells — thus antagonism would not prevent B cell regeneration [20]. Rituximab is an anti-CD20 human-murine monoclonal chimeric antibody that causes selective short-term depletion of matured B cells through three mechanisms: induction of apoptosis (programmed cell death, PCD), complement-dependent cytotoxicity (CDC) and antibodydependent cytotoxicity (ADCC) [10,21]. An open trial assessing the efficacy of Rituximab (1 g) in 22 female and 2 male patients with severe refractory SLE demonstrated clear efficacy of the treatment at a 6 month follow-up [22]. There was a significant decrease in anti-double stranded DNA (anti-ds DNA) antibody levels (p b 0.002) and improvements in serum C3 levels (p b 0.0005) — which are usually high and low in active lupus respectively. Additionally, the global BILAG (British Isles Lupus Assessment Group) disease index score attenuated from an average of 13.9 to 5.0 (p b 0.00001) at 6 months post treatment. Improvements were noted in all body systems including mucocutaneous, CNS, chest, renal, haematological and vasculitis, suggesting significant benefit of anti-CD20 therapy through reduced autoantibody formation. Lindholm et al. demonstrated the efficacy of Rituximab in SLE patients with refractory thrombocytopenia and nephritis, using the SLE Disease Activity Index (SLEDAI) [23]. There was a significant increase in platelet count in the thrombocytopenic patients 1-month posttreatment (p b 0.01) with 50% achieving normalised platelet counts within 6 months. Similarly, 47% of lupus nephritis patients experienced an increase in glomerular filtration rate by at least 25%. These clinical benefits were paralleled with a significant reduction in auto-ds DNA antibodies suggesting Rituximab is beneficial in refractory SLE patients. Looney et al. demonstrated the efficacy of Rituximab in addition to standard of care therapies in SLE patients [24]. In the majority of patients B cell depletion was achieved and the Systemic Lupus Activity Measure (SLAM) score was also significantly improved 1-year post follow-up. A histological section of a renal glomerulus attained by biopsy from one patient in the study demonstrated almost complete resolution of Class IV glomerulonephritis 1-year post-Rituximab therapy. Interestingly, the amelioration of disease was not correlated with a decrease in auto-anti-ds DNA antibodies, suggesting that the B cell mediated improvement in SLE disease severity was independent of auto-antibodies and more likely as a result of reduced B cell dependent auto-T cell activation, direct cytokine release and local tissue damage. A study using anti-mouse CD20 antibody in lupus (NZB x NZW)F1 mice revealed that early B cell depletion leads to a prolonged time before disease onset. Similarly, intervention in advanced SLE mice leads to a reduction in further progression of nephritis. The effects remained post-B cell regeneration and were associated with reduced activation of auto-T-cells in their lymphoreticular systems but no significant reduction in autoantibodies, suggesting an autoantibody independent mechanism of action [25]. Similarly, Ahuja et al. found using a transgenic SLE prone (MRL/lpr) mouse model that the depletion of B cells using anti-CD20 monoclonal antibody (mAb) resulted in a significant decrease in anti-ds DNA antibodies and subsequently improved nephritic disease [26]. The authors also deciphered that B cells were more resistant to reduction in autoimmune prone mice compared to control mice, suggesting that if attained, B cell depletion could benefit some SLE patients, however others may remain refractory to treatment. In agreement another study found 100% survival, negligible renal disease and normalised serological markers in SLE prone (BWF1) mice that were administered an anti-

CD20 antibody gene by an adenovirus immunisation technique compared to control mice (p b 0.05) [27]. A French study involving 136 SLE patients treated with Rituximab in addition to standard of care treatment demonstrated significant benefit of the drug in reducing disease severity as assessed by SLEDAI [28]. There was a significant improvement in haematological, renal, cutaneous & articular systems in 88%, 74%, 70% and 72% of patients respectively. Only 41% of patients relapsed after a mean 18.6 months (p = 0.04), with 91% of those responding to retreatment with Rituximab. Patients treated with Rituximab alone achieved a mean reduction in SLEDAI score of 6.6 compared to 8.5 in those received additional immunosuppressives (p = 0.26). Whilst not statistically significant, the patients receiving combined therapies had more clinically severe baseline disease, 13.9 (mean SLEDAI) compared to those receiving Rituximab alone, 8.7 (p = 0.003), and so the absolute benefit of combined therapy over Rituximab monotherapy remains unresolved. Interestingly, Turner-Stokes et al. demonstrated in a study of Rituximab efficacy in 76 refractory SLE patients that repeating doses of Rituximab infusion (1 g IV two separate doses) lead to 26% more patients achieving and maintaining remission after 1 year follow-up, as assessed by BILAG score and serological markers (anti-ds DNA antibody (p b 0.01) & C3 levels (p b 0.001)) [29]. One third of patients in the trial had not experienced a relapse in disease for a mean of 24.5 months, suggesting that repeated doses of Rituximab are beneficial for treating refractory SLE patients. In agreement, Roccatello et al. achieved long term remission in 8 severely affected SLE patients with systemic organ involvement through repeated Rituximab infusions (375 mg/m2 weekly for one month, followed by monthly for 2 further months) in combination with low dose standard therapies [30]. Constitutional symptoms were abolished and SLEDAI score was reduced by a mean 14.2 posttreatment for at least 1 year (p b 0.001). Serological markers of SLE activity were significantly improved (p b 0.01), suggesting significant benefit of anti-CD20 treatment with Rituximab in severe SLE. Whilst the results from murine models and open label studies have been promising, suggesting significant potential benefit for SLE patients, two recent double-blind randomised controlled trials have not been as successful. The landmark randomised double-blind placebo controlled EXPLORER (The Exploratory Phase II/III SLE Evaluation of Rituximab) trial assessed the efficacy of B cell depletion by Rituximab (1 g) in 257 patients with moderate–severe SLE and extra-renal manifestations over a 1-year period [31]. Patients were permitted to continue immunosuppressive therapies and were commenced on a tapering dose of prednisolone to limit active disease. SLE activity and severity were assessed by BILAG score indices. Anti-CD20 therapy significantly ameliorated serological markers, in terms of reduced autoantibodies (p b 0.06), improved complement levels (p = 0.0045, p = 0.0029) and B cell depletion. However this was not translated into an improvement in clinical manifestations as no significant difference was observed between placebo (28.4%) and treatment (29.6%) arms in achieving a clinical response (p = 0.975). These results therefore suggest that anti-CD20 monoclonal antibodies such as Rituximab may not be an effective therapy for moderate–severe refractory SLE. It should be noted however, that the follow-up of patients was short (1 year) and the end points within the study were very specific, thus any mild and temporary disease flare would constitute a failure of treatment. Interestingly, post hoc reanalysis of the EXPLORER trial results revealed that Rituximab significantly reduced the mean yearly severe rates of SLE flares by 39% (p = 0.038). Additionally, Rituximab resulted in minimal disease activity and no further severe flares in 14.5% more patients compared to placebo (p = 0.027) — suggesting that in severe lupus, Rituximab may actually be highly beneficial [32]. Furthermore, the EXPLORER trial neglected patients with common and severe renal manifestations in which several previous studies have shown Rituximab to be efficacious [22,23,25–27]. The trial permitted standard of care therapies and it could therefore be argued that the true effect of Rituximab may have been masked as a result of the poly-

Please cite this article as: Kamal A, The efficacy of novel B cell biologics as the future of SLE treatment: A review, Autoimmun Rev (2014), http:// dx.doi.org/10.1016/j.autrev.2014.08.020

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pharmacy the patients were subjected to. In agreement with this, the authors demonstrated a reduction in BILAG scores in both placebo and treatment arms within the first month of the trial due to the addition of prednisolone, which was subsequently maintained through background immunosuppression. This same benefit is seen in both the placebo and treatment groups suggesting Rituximab was not responsible for this sustained amelioration. Therefore a future trial should consider removing maintained immunosuppression permitting a true analysis of Rituximab compared to placebo in terms of BILAG score reduction, as any added benefit remains unclear [28,31]. Interestingly, Rituximab significantly increased the proportion of African–American/Hispanic patients clinically responding to treatment by 18.1% compared to placebo (p = 0.0408), suggesting that it may actually be beneficial for certain subsets of patients. Similarly, the Lupus Nephritis Assessment With Rituximab (LUNAR) double blind randomised controlled trial, evaluated the efficacy of Rituximab (1 g) compared to placebo in combination with standard of care therapy (MMF) in 144 patients with severe SLE nephritis [33]. Despite Rituximab successfully depleting B cells in 99% of patients and ameliorating serological markers of active lupus there was no significant difference in overall renal response rates or clinical efficacy at 1 year between placebo (45.8%) and treatment arms (56.9%) of the trial (p = 0.18). Thus, the efficacy of Rituximab as a novel therapy for SLE remains controversial and it tends to be used “off label” whilst awaiting approval upon successful trials. Whilst some smaller, open and retrospective studies in both human and murine models have demonstrated significant benefit of the drug, the main two double blind randomised trials, EXPLORER and LUNAR both suggest that more caution is required. These trials however have been criticised for their short follow-up (52 weeks), the combined use of standard therapies masking the true effect of Rituximab alone, and very sensitive end points [21]. It is not entirely clear whether a combination with immunosuppressive agents or Rituximab monotherapy confers the highest efficacy for severely affected lupus patients [28,31–33]. The most common side effects associated with Rituximab include mild infusion reactions (35%); neutropenia and infections (10%), and there have been two cases of progressive multifocal leukoencephalopathy recorded, so caution is required particularly in SLE patients with neuropsychiatric involvement [34]. 4.2. Anti-CD20: Ocrelizumab Another anti-CD20 monoclonal antibody is Ocrelizumab, which has been studied in two doses (400 mg and 1 g) in a large double blind randomised controlled trial (BELONG study) in 381 patients with severe lupus nephritis. The trial was arrested early due to the development of serious opportunistic infections in the treatment arm of the trial, which included a requirement for intravenous antibiotics. However at 42 weeks, 12% more patients had clinically responded to treatment compared to placebo suggesting some potential of ocrelizumab in SLE [18,35,36]. It has not been studied further. 4.3. Anti-CD22: Epratuzumab The glycoprotein co-receptor CD22 is vital for B cell survival and development through an interaction with signalling molecules and the B cell receptor complex. It is present on mature B cells and like CD20 is lost upon plasma B cell formation, making it an attractive therapeutic target [21,36]. Epratuzumab, a monoclonal antibody to the CD22 receptor, acts as a B cell immunomodulator as opposed to Rituximab (anti-CD20 mAb), which causes B cell depletion [17]. Epratuzumab causes up to a 45% reduction in the number of auto-B cells through antibody dependent cellular cytotoxic mechanisms, including internalisation of the CD22 receptor and subsequent down regulation of B receptor signalling, with a preference for naïve and transitional B cells [37].

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Dörner et al. were the first to clinically evaluate the efficacy of Epratuzumab in 14 moderately affected SLE patients [38]. Using four repeated infusions of 360 mg/m2 Epratuzumab, in the absence of additional corticosteroid or immunosuppressive therapies, the authors observed an attenuation of at least 50% in BILAG scores in 100% of the patients posttreatment and subsequent clinical improvement in almost all body systems. Over 90% of patients sustained lowered BILAG scores at least 4.5 months posttreatment and 3 of the patients had a complete resolution of disease. There were no serious side effects and thus the study suggests that Epratuzumab could have significant benefit for SLE patients. ALLEVIATE 1 and ALLEVIATE 2 were two randomised double blind controlled trials assessing the efficacy of Epratuzumab in addition to standard of care therapies, in severe SLE patients assessed by BILAG scores [39]. There was a significantly greater reduction in BILAG scores 48 weeks posttreatment with increasing doses of treatment (5.4 with placebo, 6.9 with 360 g/m2 and 9.0 with 720 mg/m2 ), which correlated with 19%, 35% and 72% B cell depletion with placebo, 360 g/m2 and 720 mg/m2 Epratuzumab respectively. The treatment also permitted a reduction in steroid usage, suggesting significant clinical benefit. Unfortunately, due to an altercation in therapy supply the study was abandoned prematurely. A continuation study noted that patients in the treatment arm maintained amelioration of the disease as well as significantly improved health related quality of life scores over approximately four years [16,40]. Thus these encouraging results have led to the development of the EMBODY 1 trial, a Phase III, large double blind randomised placebo controlled trial, further evaluating the long term efficacy of Epratuzumab from which we eagerly await the results [41].

5. Targeting soluble mediators to inhibit B cell growth and function 5.1. B lymphocyte stimulator (BLyS) & A proliferation inducing ligand (APRIL) Two of the key B cell stimulatory cytokines include components of the TNF ligand superfamily, member 13 or APRIL and member 13b or BLyS (B cell activating factor, BAFF) [18]. Several studies have deduced the vital role of BLyS in B cell survival, proliferation and antibody secretion, through actions upon three main receptors: the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), the BLyS receptor (BAFF-R) and the B cell maturation antigen (BCMA). APRIL, a homologous cytokine to BLyS, binds to TACI and BCMA receptors but not the BAFF-R, which is only expressed in immature B cells unlike the others, which are expressed at full maturation into plasma B cells [10]. Interestingly, the concentration of these cytokines, APRIL and BLyS both positively correlate with disease severity and serological markers such as anti-ds DNA antibody levels, suggesting that they play a significant role in the pathogenesis of SLE [42]. Murine studies have shown that transgenic lupus-prone mice engineered to overexpress BLyS cytokines go on to develop severe SLE [10]. This is evidenced by increased concentrations of anti-ds DNA autoantibodies and immune complex deposition, and also occurs in BLyS transgenic mice depleted of T cells [43]. Similarly, knockout-BLyS SLE mice (NZM.Baff (−/−)) have reduced mortality and approximately 80% reduced disease severity at 1 year (p b 0.001) [44]. Interestingly, BLyS and APRIL double knockouts in SLE mice do not confer added serological advantage in lupus nephritis to BLyS knockout mice alone [45]. However compared to control, neither group developed clinical manifestations of SLE, further evidenced by histological analysis in the knockout groups which showed no leukocytes, atrophic lesions or glomerular hypercellularity compared to wild type mice. These results suggest a potential therapeutic target for SLE patients with BLyS and/or APRIL antagonists.

Please cite this article as: Kamal A, The efficacy of novel B cell biologics as the future of SLE treatment: A review, Autoimmun Rev (2014), http:// dx.doi.org/10.1016/j.autrev.2014.08.020

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5.2. Anti-BLyS 5.2.1. Belimumab Belimumab is a monoclonal antibody that antagonises BLyS which is overexpressed in lupus, thus inhibiting B cell survival and differentiation, which should therefore ameliorate SLE pathogenesis by promoting selective auto-B cell apoptosis [46]. Two pioneering multicenter, randomised placebo controlled double blind studies, BLISS-52 and BLISS-76, investigated the efficacy of Belimumab at both a low dose, 1 mg/kg and high dose, 10 mg/kg compared to placebo with standard of care therapies in the treatment of active lupus [47,48]. BLISS-52 was a 52-week trial of 867 patients based in Eastern Europe, Asia-Pacific and Latin America, whereas BLISS-76 was a 76-week trial of 819 patients based in North America and Europe — with a common primary end point of amelioration in the patient SLE responder index (SRI) [36]. The BLISS-52 group demonstrated at 1 year posttreatment that the SRI rates were 58% (p = 0.0006), 51% (p = 0.0129) and 44% in the Belimumab 10 mg/kg, 1 mg/kg and placebo groups respectively, suggesting significant disease improvement with an increased dose of Belimumab [48]. Similarly, 58% (p = 0.0024) of patients in the high dose Belimumab had a decrease in their SLEDAI score of at least 4 points throughout the year, compared to 53% (p = 0.0189) of the low dose Belimumab group and only 46% of the placebo arm. Physician Global Assessment score at 1 year was significantly improved in 49%, 59% (p = 0.0147) and 64% (p = 0.0002) of placebo, low dose and high dose treatment patients respectively. 81% of patients on high dose Belimumab had no new severe flare ups compared to only 73% of the placebo group (p = 0.0181) and there was no significant difference between frequency of serious side effects between intervention and placebo with serious infections reported in 4% of high dose Belimumab patients compared to 6% of the placebo arm. Additionally, a reduction in steroid dose of at least 50% at 1-year posttreatment was observed in 28% (p = 0.0122), 23% (p = 0.1635) and 18% of high dose, low dose treatment and placebo arms respectively suggesting a potential concurrent reduction in corticosteroid requirement with increased dose of Belimumab. This is ultimately beneficial for the patient through reduced immunosuppressive associated side effects. The clinical improvement in disease severity and health related quality of life associated with increasing doses of Belimumab was also evidenced through amelioration in serological markers. Collectively, these results strongly highlight the efficacy and tolerability of Belimumab as a novel biologic for the treatment of SLE. It would be useful to investigate in future trials the efficacy of Belimumab in specific patient sub-populations, for example, paediatric patients and those with CNS manifestations of lupus as these patients were not included in the trial. We eagerly await the results from the 52 week (PLUTO) randomised placebo controlled trial evaluating the efficacy of IV monthly 10 mg/kg Belimumab in combination with standard therapies for active lupus patients aged 5 to 17 [49]. Additionally, comparing Belimumab to current therapies would also be useful to determine how best to prescribe the treatment (induction or maintenance) and in order to determine which patients are the most likely to benefit. The BLISS-76 group attained similar results to the BLISS-52 group showing that Belimumab, in a dose dependent manner, significantly reduced active disease, relapse rates, time to onset of relapse and requirement of steroids compared to placebo [47]. At 52 weeks, the SRI rate was almost 10% higher in high dose (10 mg/kg) Belimumab (43.2%) compared to placebo (33.5%) (p = 0.017). At 76 weeks, the authors demonstrated an SRI rate of 39.1% in the low dose (1 mg/kg) Belimumab arm compared to 32.4% in the placebo arm of the trial. Similarly, at 76 weeks, there was a mean 37% decrease in disease activity in patients on high dose Belimumab compared to only a 27.8% decrease with those in the Placebo arm (p b 0.05). Moreover, Belimumab significantly reduced the risk of severe relapses over the trial period compared to placebo, with 26.5% of the placebo arm reporting a severe

flare compared to only 18.5% in the low dose treatment arm (p = 0.023). Serologically, anti-BLyS therapeutic intervention led to significant dose dependent amelioration in complement C4 levels and reduction in anti-ds DNA antibodies in these SLE patients, which was maintained throughout the whole 76 weeks. Thus, the results from these two major studies strongly support the use of Belimumab as a novel biologic in the treatment of SLE and the FDA approved this drug in 2011. Interestingly an ongoing seven-year follow-up of lupus patients assessing the tolerability and efficacy of Belimumab in addition to standard of care therapies has shown that there was a maintained significant reduction in corticosteroid use and low rates of adverse effects [50]. At 7 years post-Belimumab treatment, the authors observed up to a 70% decline from baseline in autoantibodies to dsDNA as well as an annual frequency of severe flares declining to as low as 2–9% (which was similar to 5 years posttreatment). Interestingly, the Physician's Global Assessment (PGA) scores of lupus severity were all maintained between 40 and 50% lower than baseline up to 7 years posttreatment. Collectively, these results suggest that anti-BLyS treatment with Belimumab maintains significant clinical benefits and is well tolerated in the long term. Despite the perceived long-term benefits with Belimumab treatment, a 100% response rate was not achieved; with approximately 65% of patients responding 7 years posttreatment. However this may be explained by the fact that permanent BLyS elevation is only seen in approximately half of lupus patients [51]. 5.2.2. Blisibimod & Tabalumab On the basis of success and FDA approval of Belimumab two further anti-BLyS agents, Blisibimod and Tabalumab, are currently being assessed in Phase III randomised placebo controlled trials to decipher their efficacy in lupus [52,53]. Blisibimod is a human peptibody immunoglobulin synthetically produced to selectively target BLyS, and has recently been evaluated in a Phase II Clinical trial (PEARL-SC) [54,55]. The authors showed that high dose Blisibimod (200 mg once weekly) produced significantly higher responder rates compared to placebo in patients with ≥ 7 (25%) or ≥8 (25%) point reduction in SLEDAI (p = 0.003, p = 0.001 respectively). Similarly, patients with baseline severe SLE (SLEDAI ≥ 10 and under corticosteroid treatment) demonstrated even greater benefit, with 41.7% responder rate achieving either ≥ 7 or ≥ 8 SLEDAI point decrease in the high dose Blisibimod group compared to placebo (p = 0.002, p b 0.001 respectively). These results were associated with a significant decrease in anti-ds DNA (p b 0.001) and increase in C3 (p b 0.01) and C4 (p b 0.001) in the Blisibimod arm compared to placebo — sustained after 6 months. On the basis of this trial, the efficacy and tolerability of Blisibimod (subcutaneous injection weekly for 1 year) compared to placebo is being assessed in addition to standard of care therapies in patients with highly active and refractory SLE, for which we eagerly anticipate the results [52]. Tabalumab (LY2127399) is a monoclonal antibody that antagonises BLyS in both membrane and soluble forms (unlike Belimumab, which is thought to target soluble BLyS only). Like Blisibimod, it is currently being assessed in a Phase III randomised placebo controlled trial to decipher its efficacy in addition to standard therapies for patients with active SLE [53]. Following a 240 mg loading dose, the efficacy of high dose (120 mg subcutaneous injection every fortnight for 1 year), low dose (alternating placebo and Tabalumab 120 mg subcutaneous injection every fortnight for 1 year) and placebo is being assessed. 5.3. TACI-Ig: Atacicept Atacicept is a recombinant fusion protein containing both human IgG and the extracellular section of the B cell surface receptor TACI [18,36]. Thus, it is able to inhibit activation of the TACI receptor by both APRIL and BLyS.

Please cite this article as: Kamal A, The efficacy of novel B cell biologics as the future of SLE treatment: A review, Autoimmun Rev (2014), http:// dx.doi.org/10.1016/j.autrev.2014.08.020

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A landmark study by Gross et al. in a murine lupus model (NZBWF1 mice) identified that low (20 μg) and high (100 μg) TACI-Ig infusions in SLE mice resulted in a significant attenuation in proteinuria in a dose dependent manner compared to control protein infusions (p b 0.01) [56]. Similarly, Atacicept resulted in significantly lowered mortality rates with 100% survival amongst mice in the high dose treatment arm 3 months posttreatment, compared to only 47% survival in the control arm. Dall'Era et al. demonstrated in a Phase I, randomised placebo controlled double blind trial that Atacicept caused a 45–60% attenuation in mature B cells as well as significant dose dependent decreases in autoantibody levels, compared to placebo [57]. There were no significant differences in levels of adverse events between intervention or placebo arms of the trial. The results from murine studies and this Phase I trial warrant further research and we now eagerly await the results from a Phase II/III study (APRIL-SLE) which is investigating the efficacy of TACI-Ig compared to placebo in ameliorating disease severity in SLE [18,46,58]. 5.4. BR3-Fc: Briobacept Briobacept is a protein containing both IgG and the ligand binding section of the BAFF-R, acting to inhibit BLyS and thus encourage B cell apoptosis [36]. Kayagaki et al. demonstrated in SLE (NZBWF1) mice that three weekly, 100 μg Briobacept infusions for five weeks was therapeutically effective by inhibiting dsDNA autoantibody formation [59]. Mice treated with Briobacept had 100% survival around 6 months posttreatment compared to 40% survival amongst the control mice and Briobacept significantly ameliorated nephritis with no mice suffering from severe proteinuria at 40 weeks. Thus promising results from murine trials warrant investigation of Briobacept efficacy in randomised human SLE studies [17].

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CD40–CD40L and IL-6/IFNα respectively in addition to other TNF family members, are beyond the scope of this review but covered excellently elsewhere [17,21,34,59]. Targeting lupus anti-ds DNA antibodies may also provide another more specific therapeutic option for future SLE patients [61]. Whilst double BLyS and APRIL knockouts do not seem to confer significant added benefit to lupus mice [45], future research should investigate if there is an added benefit in combining biologics acting on different parts of the pathway to treat SLE. Similarly, whilst the stimulatory cytokines BLyS and APRIL have been targeted themselves, targeting their receptors (TACI, BCMA, BAFF-R) can also provide another therapeutic hypothesis for future investigation. Furthermore, patients may have slightly different underlying pathophysiology, rendering interventions ineffective in some patients but effective in others. Comparing the efficacy of various biologics in different patient subpopulations as well as in different SLE manifestations would help determine which biologics are most suited for certain types of patients and clinical manifestations. This would result in both clinically and cost effective novel biologics for SLE. Take Home Messages • Standard of care therapies produces adverse side effects through untargeted actions. • B cell biologics are an attractive therapeutic option specific to SLE pathogenesis. • Early phase trials have been successful and Belimumab has been FDA approved. • Other B cell depletion and anti-cytokine treatments are under Phase III assessment. • Different subpopulations and manifestations may respond differently to treatment.

6. Cost effectiveness Conflict of Interest The cost burden of SLE morbidity was recently assessed in the UK amongst 86 lupus patients with a mean SLEDAI score of 7.7 [60]. The mean total cost for severe and non-severe lupus patients was £4652 and £2105 per year respectively (p b 0.001). For both groups, immunosuppressive therapies accounted for the majority of the cost, £1187 (25.5%) and £523 (24.8%) (p = 0.003), whereas biological therapies cost £532 (11.4%) and £109 (5.2%) for severe and non-severe groups respectively (p = 0.007). These results therefore suggest that attaining effective biological therapies would be not only clinically effective but also cost effective for patients, particularly those with more severe refractory forms of the disease. 7. Conclusion Recent advances in SLE research have begun to deduce the intricate pathogenesis underlying this autoimmune condition highlighting the critical role of auto-B cells in autoantibody formation, antigen presentation and T cell interaction. Standard of care therapy drawbacks has initiated the quest for SLE disease pathway specific biologics to ameliorate the condition with minimal side effects. In 2011 the FDA signified a new direction for SLE by approving Belimumab as the first novel therapy for over 50 years. Murine models and early phase studies of Rituximab (anti-CD20), Epratuzumab (antiCD22) and Briobacept, Blisibimod (Anti-BLyS), Atacicept (Anti-BLyS/ APRIL) targeting B cell surface receptors and soluble mediators respectively, have shown significant efficacy as future SLE therapies. Multicenter randomised controlled trials with long-term follow-ups are now required as the approval of other biologics in addition to Belimumab looks to be on the horizon. The efficacy of other novel therapies targeting B cell–T cell interactions and other dendritic/ T cell mediated cytokines such as anti-

There are no conflicts of interest to declare and no funding or grants have been received for this research. Acknowledgements None. References [1] Chugh PK, Kalra BS. Belimumab: targeted therapy for lupus. Int J Rheum Dis 2013; 16(1):4–13. [2] Frieri M. Mechanisms of disease for the clinician: systemic lupus erythematosus. Ann Allergy Asthma Immunol 2013;110(4):228–32. [3] Gatto M, Zen M, Ghirardello A, Bettio S, Bassi N, Iaccarino L, et al. Emerging and critical issues in the pathogenesis of lupus. Autoimmun Rev 2013;12(4):523–36. [4] Holroyd CR, Edwards CJ. The effects of hormone replacement therapy on autoimmune disease: rheumatoid arthritis and systemic lupus erythematosus. Climacteric 2009;12(5):378–86. [5] Dillon S, Aggarwal R, Harding JW, Li LJ, Weissman MH, Li S, et al. Klinefelter's syndrome (47, XXY) among men with systemic lupus erythematosus. Acta Paediatr 2011;100(6):819–23. [6] James JA, Harley JB, Scofield RH. Review Epstein–Barr virus and systemic lupus erythematosus. Curr Opin Rheumatol 2006;18(5):462–7. [7] Sestak AL. Genetics of systemic lupus erythematosus. Future Rheumatol 2008;3(1): 51–7. [8] Sestak AL, Fürnrohr BG, Harley JB, Merrill JT, Namjou B. The genetics of systemic lupus erythematosus and implications for targeted therapy. Ann Rheum Dis 2011; 70(Suppl. 1):i37–43. [9] Kulkarni OP, Anders HJ. Lupus nephritis. How latest insights into its pathogenesis promote novel therapies. Curr Opin Rheumatol 2012;24(5):457–65. [10] Chan VS, Tsang HH, Tam RC, Lu L, Lau CS. B-cell-targeted therapies in systemic lupus erythematosus. Cell Mol Immunol 2013;10(2):133–42. [11] Shlomchik MJ, Madaio MP, Ni D, Trounstein M, Huszar D. The role of B cells in lpr/ lpr-induced autoimmunity. J Exp Med 1994;180:1295–306. [12] Chan O, Shlomchik MJ. A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice. J Immunol 1998;160:51–9.

Please cite this article as: Kamal A, The efficacy of novel B cell biologics as the future of SLE treatment: A review, Autoimmun Rev (2014), http:// dx.doi.org/10.1016/j.autrev.2014.08.020

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[13] Vlahakos D, Foster MH, Ucci AA, Barrett KJ, Datta SK, Madaio MP. Murine monoclonal anti-DNA antibodies penetrate cells, bind to nuclei, and induce glomerular proliferation and proteinuria in vivo. J Am Soc Nephrol 1992;2:1345–54. [14] Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med 1999;189:1639–48. [15] Francis L, Perl A. Pharmacotherapy of systemic lupus erythematosus. Expert Opin Pharmacother 2009;10:1481–94. [16] Touma Z, Urowitz MB, Gladman DD. Systemic lupus erythematosus: an update on current pharmacotherapy and future directions. Expert Opin Biol Ther 2013;13(5): 723–37. [17] Mok MY. The immunological basis of B-cell therapy in systemic lupus erythematosus. Int J Rheum Dis 2010;13(1):3–11. [18] Gregersen JW, Jayne DR. B-cell depletion in the treatment of lupus nephritis. Nat Rev Nephrol 2012;8(9):505–14. [19] Bubien JK, Zhou LJ, Bell PD, Frizzell RA, Tedder TF. Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. J Cell Biol 1993;121(5):1121–32. [20] Gopal A, Press OW. Clinical applications of anti-CD20 antibodies. J Lab Clin Med 1999;134:445–50. [21] Bezalel S, Asher I, Elbirt D, Sthoeger ZM. Novel biological treatments for systemic lupus erythematosus: current and future modalities. Isr Med Assoc J 2012;14(8): 508–14. [22] Leandro MJ, Cambridge G, Edwards JC, Ehrenstein MR, Isenberg DA. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford) 2005;44(12):1542–5. [23] Lindholm C, Börjesson-Asp K, Zendjanchi K, Sundqvist AC, Tarkowski A, Bokarewa M. Long term clinical and immunological effects of anti-CD20 treatment in patients with refractory systemic lupus erythematosus. J Rheumatol 2008;35(5):826–33. [24] Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ, et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum 2004;50(8):2580–9. [25] Bekar KW, Owen T, Dunn R, Ichikawa T, Wang W, Wang R, et al. Prolonged effects of short-term anti-CD20 B cell depletion therapy in murine systemic lupus erythematosus. Arthritis Rheum 2010;62(8):2443–57. [26] Ahuja A, Shupe J, Dunn R, Kashgarian M, Kehry MR, Shlomchik MJ. Depletion of B cells in murine lupus: efficacy and resistance. J Immunol 2007;179(5):3351–61. [27] Wang C, Wang M, Liu Y, Zeng P. Administration of adenovirus encoding anti-CD20 antibody gene induces B-cell deletion and alleviates lupus in the BWF1 mouse model. Int Immunopharmacol 2011;11(6):693–7. [28] Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, et al. Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 2010;62(8): 2458–66. [29] Turner-Stokes T, Lu TY, Ehrenstein MR, Giles I, Rahman A, Isenberg DA. The efficacy of repeated treatment with B-cell depletion therapy in systemic lupus erythematosus: an evaluation. Rheumatology (Oxford) 2011;50(8):1401–8. [30] Roccatello D, Sciascia S, Rossi D, Alpa M, Naretto C, Baldovino S, et al. Intensive shortterm treatment with rituximab, cyclophosphamide and methylprednisolone pulses induces remission in severe cases of SLE with nephritis and avoids further immunosuppressive maintenance therapy. Nephrol Dial Transplant 2011;26(12):3987–92. [31] Merrill J, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62(1):222–33. [32] Merrill J, Buyon J, Furie R, Latinis K, Gordon C, Hsieh HJ, et al. Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER). Lupus 2011; 20(7):709–16. [33] Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012;64(4): 1215–26. [34] Murdaca G, Colombo BM, Puppo F. Emerging biological drugs: a new therapeutic approach for systemic lupus erythematosus. An update upon efficacy and adverse events. Autoimmun Rev 2011;11(1):56–60. [35] Mysler EF, Spindler AJ, Guzman R, Bijl M, Jayne D, Furie RA, et al. Efficacy and safety of ocrelizumab, a humanized antiCD20 antibody, in patients with active proliferative lupus nephritis (LN): results from the Randomized, Double-Blind Phase III BELONG Study. Arthritis Rheum 2010;62(Suppl.10):1455. [36] La Cava A. Targeting B cells with biologics in systemic lupus erythematosus. Expert Opin Biol Ther 2010;10(11):1555–61. [37] Jacobi AM, Goldenberg DM, Hiepe F, Radbruch A, Burmester GR, Dörner T. Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls. Ann Rheum Dis 2008;67(4):450–7. [38] Dörner T, Kaufmann J, Wegener WA, Teoh N, Goldenberg DM, Burmester GR. Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther 2006;8(3):R74. [39] Traczewski P, Rudnicka L. Treatment of systemic lupus erythematosus with epratuzumab. Br J Clin Pharmacol 2011;71(2):175–82. [40] Strand V, Petri M, Kalunian K, Gordon C, Wallace DJ, Hobbs K, et al. Epratuzumab for patients with moderate to severe flaring SLE: health-related quality of life outcomes

[41]

[42]

[43] [44]

[45] [46] [47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55] [56]

[57]

[58]

[59]

[60]

[61]

and corticosteroid use in the randomized controlled ALLEVIATE trials and extension study SL0006. Rheumatology (Oxford) 2014;53(3):502–11. ClinicalTrials.gov. Identifier NCT01262365, a phase 3, randomized, double-blind, placebo-controlled, multicenter study of the efficacy and safety of four 12-week treatment cycles (48 weeks total) of epratuzumab in systemic lupus erythematosus subjects with moderate to severe disease (EMBODY 1); 14th Dec 2010 — [cited 30th March 2014]; [about 6 screens]. [Internet] Bethesda (MD): National Library of Medicine (US); Feb 29 2000 [Available from: http://clinicaltrials.gov/ct2/show/ NCT01262365]. Chu VT, Enghard P, Schürer S, Steinhauser G, Rudolph B, Riemekasten G, et al. Systemic activation of the immune system induces aberrant BAFF and APRIL expression in B cells in patients with systemic lupus erythematosus. Arthritis Rheum 2009; 60(7):2083–93. Groom JR, Fletcher CA, Walters SN, et al. BAFF and MyD88 signals promote a lupuslike disease independent of T cells. J Exp Med 2007;204(8):1959–71. Jacob CO, Pricop L, Putterman C, et al. Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand mixed 2328 mice deficient in BAFF. J Immunol 2006;177(4):2671–80. Jacob CO, Guo S, Jacob N, et al. Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice. Arthritis Rheum 2012;64(5):1610–9. Sanz I, Lee FE. B cells as therapeutic targets in SLE. Nat Rev Rheumatol 2010;6(6): 326–37. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63(12):3918–30. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377(9767):721–31. ClinicalTrials.gov. Identifier NCT01649765, a multi-center, randomized, placebocontrolled trial to evaluate the safety, efficacy, and pharmacokinetics of belimumab, a human monoclonal anti-BLyS antibody, plus standard therapy in pediatric patients with systemic lupus erythematosus (PLUTO); 23rd July 2012 — [cited 8th April 2014]; [about 6 screens]. [Internet] Bethesda (MD): National Library of Medicine (US); Feb 29 2000 [Available from: http://clinicaltrials.gov/ct2/show/ NCT01649765]. Ginzler EM, Wallace DJ, Merrill JT, et al. Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol 2014;41(2):300–9. Stohl W1, Metyas S, Tan SM, Cheema GS, Oamar B, Xu D, et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum 2003;48:3475–86. ClinicalTrials.gov. Identifier NCT01395745, a randomised, double-blind, placebocontrolled phase 3 study to evaluate the efficacy and safety of blisibimod administration in subjects with systemic lupus erythematosus (CHABLIS-SC1); 14th July 2011 — [cited 8th April 2014]; [about 6 screens]. [Internet] Bethesda (MD): National Library of Medicine (US); Feb 29 2000 [Available from: http://clinicaltrials.gov/ct2/ show/NCT01395745]. ClinicalTrials.gov. Identifier NCT01196091, a phase 3, multicenter, randomized, double blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous LY2127399 in patients with systemic lupus erythematosus (SLE); 3rd September 2010 — [cited 8th April 2014]; [about 6 screens]. [Internet] Bethesda (MD): National Library of Medicine (US); Feb 29 2000 [Available from: http:// clinicaltrials.gov/ct2/show/NCT01196091]. Furie RA, Leon G, Thomas M, Petri MA, Chu AD, Hislop C, et al. A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis Apr 19 2014. http://dx.doi.org/10.1136/ annrheumdis-2013-205144 [Epub ahead of print]. Croft M, Benedict CA, Ware CF. Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 2013;12(2):147–68. Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 2000;404(6781):995–9. Dall'Era M, Chakravarty E, Wallace D, Genovese M, Weisman M, Kavanaugh A, et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum 2007; 56(12):4142–50. Sousa E, Isenberg D. Treating lupus: from serendipity to sense, the rise of the new biologicals and other emerging therapies. Best Pract Res Clin Rheumatol 2009; 23(4):563–74. Kayagaki N, Yan M, Seshasayee D, Wang H, Lee W, French DM, et al. BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2. Immunity 2002;17(4):515–24. Khamashta MA, Bruce IN, Gordon C, Isenberg DA, Ateka-Barrutia O, Gayed M, et al. The cost of care of systemic lupus erythematosus (SLE) in the UK: annual direct costs for adult SLE patients with active autoantibody-positive disease. Lupus 2014; 23(3):273–83. Bosch X, Ramos-Casals M, Khamashta MA. The DWEYS peptide in systemic lupus erythematosus. Trends Mol Med 2012;18(4):215–23.

Please cite this article as: Kamal A, The efficacy of novel B cell biologics as the future of SLE treatment: A review, Autoimmun Rev (2014), http:// dx.doi.org/10.1016/j.autrev.2014.08.020