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Progress with the use of monoclonal antibodies for the treatment of systemic lupus erythematosus

In recent years, significant progress has been made in the use of monoclonal antibodies in the treatment of systemic lupus erythematosus (SLE). Advances in our understanding of the complexity of SLE immunopathogenesis have led to the testing of several biologic agents in clinical trials. Monoclonal therapies currently emerging or under development include B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anticytokine therapies. Issues remain, however, regarding clinical trial design and outcome measures in SLE which need to be addressed to optimize translation of these promising therapies into clinical practice. Keywords:  APRIL • BAFF • B-cell depletion • belimumab • IFN-α • lupus nephritis • systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease which may manifest as mild, moderate or severe disease involving all organ systems [1] . SLE has a female preponderance and is more prevalent in patients of African ancestry (African–American or African–Caribbean) and Asian ancestry compared with Caucasians [2] . Although advances in education, diagnostic tests and therapeutic interventions have resulted in an improvement in the overall prognosis from a 5-year survival of less than 50% in the 1950s to more than 90% in recent decades, the mortality of lupus patients is up to 4.6× greater than the general population [3–7] . A proportion of lupus patients may be refractory to conventional immunosuppressant drugs and therefore the introduction of novel therapeutic agents, such as monoclonal antibodies, has been a welcome addition to the treatment options for lupus patients. Over the last two decades, our knowledge of the immunopathogenesis of lupus has increased and this has facilitated the creation of biologic drugs that target specific cells and molecules associated with lupus. Lupus patients have a failure of immune self-tolerance with the generation of pathogenic auto-antibodies and the

10.2217/IMT.14.118 © 2015 Future Medicine Ltd

Natasha Jordan‡,1, Pamela MK Lutalo‡,1,2 & David P D’Cruz*,1 Louise Coote Lupus Unit St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK 2 Peter Gorer Department of Immunobiology, King’s College London School of Medicine, Guy’s Hospital, Great Maze Pond, London, SE1 9RT, UK *Author for correspondence: david.d’cruz@ ‡ Authors contributed equally 1

deposition of immune-complex deposits in organs, implicating B cells in the pathogenesis of SLE [8,9] . B-cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are cytokines involved in the promotion of B-cell survival and proliferation, therefore play an integral role in the development and progression of SLE [10] . Lupus patients have defective cell signaling, defective complement cascades and a failure to effectively clear apoptotic cell debris, all of which have been implicated in the pathogenesis of lupus [9] . Published clinical trials have had varying and mostly negative results, reflecting different molecular targets, study designs and patient populations. The challenge now is to ensure that current and future clinical trials are robust in design, patient recruitment and trial end points which can be translated into clinical practice. Here, we explore the progress to date with the use of novel therapeutic biologic strategies, namely, monoclonal antibodies, for the management of SLE. B-cell depletion therapy Rituximab (anti-CD20)

Rituximab, an anti-CD20 chimeric monoclonal antibody, targets B cells which bear

Immunotherapy (2015) 7(3), 255–270

part of

ISSN 1750-743X


Review  Jordan, Lutalo & D’Cruz the CD20 cell surface marker via direct apoptosis, complement-dependent cell toxicity and antibodydependent cell toxicity (ADCC) (Figure 1)  [11] . Rituximab was originally approved by the US FDA for the management of non-Hodgkin’s lymphoma in 1997. Rituximab was approved for the management of rheumatoid arthritis in 2006 and ANCA (anti-neutrophil cytoplasmic antibody) associated vasculitis, granulomatosis with polyangiitis and microscopic polyangiitis in 2011, based on positive data from international, multicenter, randomized controlled trials [12–15] . Rituximab is currently not licensed for the management of SLE, although in the UK, it is reimbursable by National Health Service England providing strict criteria are met. This reflects the fact that rituximab is widely prescribed off license in severe SLE, which has failed to respond to conventional immuno­suppressant drugs. Progress has been made in the use of rituximab in SLE since 2000 when it was first used in a small cohort of severe, refractory SLE patients in the UK. The clinical practice data from the first 50 SLE patients treated with 1 g iv. rituximab, 250 mg iv. methylprednisolone and 750 mg iv. cyclophosphamide on two occasions, 2 weeks apart, at University College Hospital, London demonstrated that B-cell depletion therapy with rituximab was clinically effective in this cohort of patients [16] . Numerous case reports, case series and nonrandomized observational studies of rituximab in SLE have provided further evidence of the effectiveness of rituximab in clinical practice with the achievement of 65–100% response rate as assessed by validated disease activity indices including the British Isles Assessment Group Index (BILAG) score and the SLE disease activity index (SLEDAI) [17–22] . The randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of rituximab in patients with severe SLE (EXPLORER) compared rituximab plus standard immunosuppressants to placebo plus standard immunosuppressants in non­renal SLE patients [23] . The randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of rituximab in subjects with ISN/RPS Class III or IV lupus nephritis (LUNAR) compared rituximab plus mycophenolate mofetil to mycophenolate mofetil alone for the management of severe proliferative lupus nephritis class III and class IV [24] . EXPLORER and LUNAR did not demonstrate superiority of rituximab over standard immunosuppressants and failed to meet the primary or secondary end points (Table 1) . A post-hoc analysis of the EXPLORER patients reported clinical efficacy in African–Americans and Hispanics treated with rituximab with a major clinical response reported in 20% and partial clinical response reported in 13.8% of patients compared with placebo-treated


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patients, 9.4% of whom had major clinical response and 6.3% of whom had partial clinical response (p = 0.041). Rituximab-treated patients had significant increases in C3 levels (p = 0.0029) and C4 levels (p = 0.0045), and a reduction in the anti-dsDNA antibody titers (p = 0.0006) at the end of the EXPLORER trial. A post-hoc analysis of the LUNAR patients did not demonstrate efficacy differences in different ethnic groups, however the rise in C3 levels and fall in antidsDNA titers was statistically significant (p = 0.03 and p = 0.007, respectively). Significant progress has been made in designing rituximab clinical trials aimed at providing data on the potential use of rituximab. RITUXILUP is a multi­ center, open-labeled, randomized proof of concept trial aimed at demonstrating whether or not rituximab in combination with mycophenolate mofetil without oral corticosteroids is effective in managing new lupus nephritis flares and whether or not this steroid-­sparing regimen is as efficacious and safer compared with the standard remission induction regimen of highdose oral corticosteroids and mycophenolate mofetil (NCT01773616). The idea for the RITUXILUP trial originated in the UK where a tertiary referral center had conducted a prospective, observational, singlecenter study of lupus nephritis patients treated with rituximab and mycophenolate mofetil but no oral corticosteroids, and had reported the clinical effectiveness and the benefits of this regimen [25] . The recruitment period for the RITUXILUP trial is open from 2014 to 2017. RING – Rituximab for Lupus Nephritis With Remission as a Goal, an investigator-initiated randomized international open-label, multicenter study aims to determine the clinical effectiveness of rituximab in achieving complete renal remission in lupus nephritis patients with persistent proteinuria (≥1 g/day) despite a minimum of 6 months of standard immunosuppressant therapy (NCT01673295). Adverse infusion reactions, allergic or anaphylactic reactions, severe or recurrent infections and progressive multifocal leuco-encephalopathy (PML) associated with severe immunosuppression have been reported in rituximab-treated patients [36,37] . National biologics registries such as the BILAG biologics registry in the UK, which prospectively collects data on SLE patients treated with biologics will be of immense value in ascertaining the real-world long-term efficacy, tolerability and safety profile of rituximab in the management of SLE. Epratuzumab (anti-CD22)

Epratuzumab an anti-CD22 monoclonal antibody has completed Phase II clinical trials and is in Phase III

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Progress with the use of monoclonal antibodies for the treatment of SLE 


Rituximab Ocrelizumab Anti-CD40 ligand

Epratuzumab CD20 CD22

CD40L CD40



B lymphocyte TACI




T lymphocyte




Belimumab Blisibimod Tabalumab

Sifalimumab Rontalizumab

IFN-α Autoantibodies Dendritic cell

Figure 1. Monoclonal antibodies in systemic lupus erythematosus.

clinical trials for the management of moderate-tosevere SLE [27] . Epratuzumab acts on transitional B cells and naive mature B cells which have the CD22 cell surface marker and cause moderate B-cell depletion via ADCC (Figure 1) [38] . The first open-label study of epratuzumab-treated patients (n = 14) was published in 2006 and reported ≥50% total BILAG score improvement in 77% at week 6, 71% at week 10, 38% at week 18 and 15% at week 32, at epratuzumab iv. 360 mg/m2 fortnightly for four doses [39] . EMBLEMTM a 12-week, multicenter, randomized, double-blind, placebo-controlled, Phase IIb study to assess the efficacy and safety of epratuzumab and determine a dose regimen in patients with moderateto-severe SLE recruited 227 patients who were randomized to placebo n = 38, epratuzumab 200 mg cumulative dose (100 mg alternate weeks) n = 39, epratuzumab 800 mg cumulative dose (400 mg alternate weeks) n = 38, epratuzumab 2400 mg cumulative dose (600 mg weekly) n = 37, epratuzumab 2400 mg cumulative dose (1200 mg alternate weeks) n = 37, epratuzumab 3600 mg cumulative dose (1800 mg alternate weeks) n = 38 (Table 1) [27] .

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Epratuzumab at a cumulative dose of 2400 mg was well tolerated and clinically effective with a significant reduction in disease activity as measured by a composite disease activity score, the BILAG-based Combined Lupus Assessment (BICLA) [27] . The greatest improvement in all organ domain BILAG-2004 scores compared with placebo was seen in the epratuzumab 600 mg weekly group [27] . Overall, there were no significant differences in infusion-related reactions and adverse events with each epratuzumab group and placebo [27] . Two randomized controlled trials to evaluate the efficacy of epratuzumab in severe SLE (at least one BILAG A score) and moderate SLE (BILAG B scores in at least two domains), RCT SL0003 and RCT SL 0004, respectively, were discontinued due to irregularities in the manufacture of epratuzumab. The pooled results from the intention-to-treat population in both trials were analyzed. Epratuzumab improved BILAG compared with placebo (64 and 20% of the patients, respectively), facilitated the lowering of oral corticosteroid doses in treatment responsive patients, resulted in greater improvement in the physicians global assessment (76% epratuzumab 360 mg/m2 fortnightly group, 80% epratuzumab 720 mg/m2 fort-


Review  Jordan, Lutalo & D’Cruz

Table 1. Monoclonal therapies targeting B cells in systemic lupus erythematosus. Drug name

Mechanism of action


Clinical trials

Key references 

Current status

Chimeric anti-CD20 Safe and well tolerated in monoclonal antibody Phase I/II trials

Sanz et al., 2010 [11] 

RITUXILUP trial: Phase III open-label trial of rituximab and mycophenolate mofetil with minimal oral corticosteroids pending



Encouraging results in initial open-label trials Failed to meet primary end points in LUNAR (nephritis) and EXPLORER (nonnephritis) Phase III studies

EXPLORER trial: Merrill et al., 2010 [23]





LUNAR trial: Rovin et al., 2012 [24]





Condon et al., 2013 [25]



Humanized anti-CD22 Safe and well tolerated in monoclonal antibody Phase I/II trials of moderate(nondepleting) to-severe SLE with associated improvements in disease activity

ALLEVIATE study: Wallace et al., 2013 [26] 

EMBODY trial: Phase III trial in moderate-tosevere SLE ongoing




EMBLEM study: Wallace et al., 2014 [27]



Humanized anti-CD20 The BELONG study of monoclonal antibody ocrelizumab in SLE was terminated due to a high incidence of severe opportunistic infections

Mysler et al., 2013 [28]

Ocrelizumab programme terminated


Humanized anti-BLyS BLISS-52 study: 867 BLISS-52 monoclonal antibody SLE patients, SELENAstudy: Navarra et al., SLEDAI score ≥6 positive 2011 [29] SRI clinical response at week 52: belimumab 1 mg/kg: 51%; belimumab 10 mg/kg: 58%; placebo: 44%

BLISS-LN: Phase III trial in lupus nephritis ongoing



BLISS-76 study: 819 BLISS-76 SLE patients, SELENAstudy: Furie et al., SLEDAI score ≥6 positive 2011 [30] SRI clinical response at week 52: belimumab 1 mg/kg: 41%; belimumab 10 mg/kg: 43%; placebo: 34%

EMBRACE: Phase III trial in SLE patient of black race




Van Vollenhoven et al., 2012 [31]

Trial of belimumab in combination with rituximab planned


Anti-BLyS antagonist fusion protein

Safe and well tolerated in Phase I/II studies

Furie et al., 2014 [32]

CHABLIS-SC2 CHABLISSC1: Phase III studies in SLE patients with and without nephritis ongoing

SLE: Systemic lupus erythematosus; SRI: SLE responder index.


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Progress with the use of monoclonal antibodies for the treatment of SLE 


Table 1. Monoclonal therapies targeting B cells in systemic lupus erythematosus (cont.). Drug name

Mechanism of action


Humanized anti-BAFF Safe and well tolerated in monoclonal antibody Phase I/II studies Phase III trials of subcutaneous tabalumab failed to meet the primary outcomes

Clinical trials

Key references 

Current status


Recombinant fusion protein to TACI-Ig

Phase II trial prematurely terminated with only six patients recruited due to significant reduction in total immunoglobulin levels and reports of serious infections

Dall’era et al., 2007 [33]

To be determined



APRIL-SLE trial No difference in flare rate/ time to first flare between atacicept 75 mg and placebo Enrollment in atacicept 150 mg arm discontinued prematurely due to two deaths

Ginzler et al., 2012 [34]





Isenberg et al., 2014 [35]


Tabalumab program discontinued

SLE: Systemic lupus erythematosus; SRI: SLE responder index.

nightly group compared with 60% placebo group) and greater improvement in the patient’s global assessment (70% epratuzumab treated patients compared with 53% placebo group) [40] . Two Phase III, randomized, double-blind, placebocontrolled, multicenter studies of the efficacy and safety of four 12-week treatment cycles (48 weeks total) of epratuzumab in SLE subjects with moderate-to-severe disease EMBODY TM1 and EMBODY TM2 are expected to be completed in 2014 with a target recruitment of 780 patients. The main aim is to evaluate the efficacy, safety, tolerability and immunogenicity of epratuzumab in patients with moderate and severe SLE (NCT01262365, NCT01261793). A Phase III, multicenter, open-label, extension study to assess the safety and tolerability of epratuzumab treatment in SLE subjects EMBODY TM4 started recruiting in July 2011 and is aiming to recruit 1400 patients with a completion date of February 2016 (NCT01408576). Ocrelizumab (anti-CD20)

Ocrelizumab is a humanized anti-CD20 monoclonal antibody which depletes B cells via ADCC and complement-dependent cell toxicity (Figure 1) . The study to evaluate ocrelizumab in patients with nephritis due to SLE (BELONG) was terminated in 2010 after an independent monitoring board recommended the suspension of clinical trials of ocrelizumab in rheumatoid arthritis and SLE due to a high incidence of reported

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severe opportunistic in patients enrolled in ocrelizumab studies, particularly in East Asia where there were some fatalities (Table 1) [28] . The BELONG study had recruited lupus nephritis class III and class IV patients (n = 381) to study the clinical efficacy and safety of ocrelizumab intravenously prescribed as 400 mg or 1000 mg ocrelizumab at baseline, 2 weeks later then every 4 months thereafter. In addition, all the lupus nephritis patients were treated concomitantly with either mycophenolate mofetil and high-dose oral corticosteroids or intravenous cyclophosphamide 500 mg fortnightly for a total of six doses (the EuroLupus cyclophosphamide regimen)  [28] . Although the study was not completed, efficacy data were analyzed for patients who had been treated for ≥32 weeks (n = 223) and safety data were analyzed in 378 patients. In summary, the placebotreated, 400 mg ocrelizumab-treated, 1000 mg ocrelizumab-treated and combined ocrelizumab-treated patients had an overall renal response rate of 54.7, 66.7, 67.1 and 66.9%, respectively, which was numerically but not statistically significantly different. Targeting B-cell survival factors Belimumab (anti-BAFF)

Belimumab is a humanized immunoglobulin G1λ monoclonal antibody which blocks soluble BAFF to BAFF-R, BCMA and the TACI receptor on B cells and thereby inhibits the B-cell survival role of BAFF (Figure 1) [41] .


Review  Jordan, Lutalo & D’Cruz An understanding of the role of BAFF in the immuno­ pathogenesis of autoimmune disease has led to the development of BAFF inhibitor monoclonal antibodies. BAFF is mainly expressed by activated neutrophils, dendritic cells, monocytes and T cells. BAFF has an important role in promoting the maturation and survival of B cells via signaling through the BAFF-R, BCMA and TACI receptors with high, intermediate and low affinity, respectively. The BAFF homolog APRIL (a proliferation-inducing ligand) binds with higher affinity to the TACI receptor than BAFF [42] . A strong interaction of BAFF to the BAFF-R promotes the survival and maturation of naive B cells. APRIL and BAFF dimerize to the BCMA receptor to promote plasma cell maturation and the interaction of BAFF, APRIL and TACI to the TACI-R facilitates immunoglobulin gene class switching in the germinal center [42] . The abundance of BAFF in SLE patients may account in part to the survival of low-affinity self-reactive B cells which mature into selfreactive auto-antibody secreting plasma cells which play a role in the immunopathogenesis of SLE. Therefore it is logical to conclude that BAFF inhibition is a therapeutic option in SLE. In 2011, belimumab (10 mg/kg) became the first drug in over 50 years to be licensed for the treatment of SLE by the FDA and the European Medicines Evaluation Agency. Belimumab is approved for use in autoantibody-positive SLE, with the exception of patients with active lupus nephritis or CNS disease. The Belimumab International SLE Study (BLISS-52) Phase III trial enrolled 865 SLE patients from Central and Eastern Europe, Latin America and Asia Pacific [29] . The Belimumab International SLE Study (BLISS76) enrolled 819 SLE patients from centers in North America and Western and Central Europe [30] . Both the BLISS-52 and BLISS-76 trials excluded SLE patients with active lupus nephritis or CNS involvement. The primary clinical efficacy outcome was improvement in the SLE responder index (SRI) at week 52. SRI clinical response is defined as ≥4 points reduction in SELENA-SLEDAI score; no new BILAG A organ domain score and no new >1 new B organ domain score; and 10) therefore the approval for belimumab with combination standard therapy is for auto-antibody positive moderate-to-severe SLE [31] . BLISS-LN is a Phase III, randomized, doubleblind, placebo-controlled study to evaluate the efficacy and safety of belimumab plus standard of care versus placebo plus standard of care in adult subjects with active lupus nephritis which will provide clinically relevant information about the use of belimumab in lupus nephritis (NCT01639339). A Phase III/IV multicenter, randomized, doubleblind, placebo-controlled, 52-week study to evaluate the efficacy and safety of belimumab in adult subjects of black race with systemic lupus erythematosus (SLE) is planned as a future study (NCT01632241). Lower clinical effectiveness in patients of African ancestry (n = 148) was reported in an exploratory analysis of belimumab in different ethnic groups in the BLISS-52 and BLISS-76 clinical trials thus necessitating a large clinical trial to answer the question about efficacy in patients of African ancestry. Reports of adverse events or serious adverse events in belimumab-treated patients are available from clinical practice publications and clinical trial data. Patients treated with belimumab are at risk of severe delayed acute hypersensitivity reactions and there was one fatality in 2012. The safety labeling of belimumab has been amended to reflect this risk and long-term observational data from clinical practice will be of great value in ascertaining the long-term safety of belimumab [43] . Patients treated with belimumab have an increased susceptibility to common infections such as bronchitis, pharyngitis, cystitis and viral gastroenteritis. The clinical trial data report serious infections in 6% belimumab with standard therapy treated patients compared with 5.2% placebo with standard therapy patients, however there have not been any specific opportunistic infections or patterns of infection associated with belimumab treatment [29] . The immunosuppression that results from combining belimumab with standard immunosuppressant therapy may result in the reactivation of viruses, including JC virus which is associated with the onset of progressive PML. To date there have been two cases reported in the medical literature of PML in belimumab-treated patients [44] .

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Progress with the use of monoclonal antibodies for the treatment of SLE 

Blisibimod (anti-BAFF)

Targeting T cells

Blisibimod is an anti-BAFF monoclonal antibody which decreases B-cell survival by binding to BAFF and inhibiting its binding to B-cell BAFF receptors (Figure 1). A Phase II clinical trial called PEARL-SC investigated the efficacy, safety and tolerability of blisibimod in active SLE patients (n = 547) with patients randomized to blisibimod 100 mg once a week, blisibimod 200 mg once a week or placebo in matching dosing regimens for 24 weeks. This patients recruited to this trial were followed in an open-label extension trial of long-term safety. Blisibimod was well tolerated and safe at all dose levels with no serious adverse events or higher infection rate compared with placebo. The clinical efficacy measure of SRI-5 (>5 point improvement in SELENA-SLEDAI from baseline was only statistically significantly higher in blisibimod 200 mg once a week compared with placebo at week 20 (p = 0.02). In 2012, CHABLIS-SC1 and CHABLISSC2, Phase III international multicenter, randomized, double-blind clinical trials to evaluate the efficacy, safety, tolerability and immunogenicity of blisibimod in patients with severe active SLE (SELENA-SLEDAI >10) despite high-dose corticosteroids was approved by the FDA (NCT01395745 and NCT01395746).

Abatacept (CTLA-4-Ig fusion protein)

Tabalumab (anti-BAFF)

Tabalumab (LY2127399) is a human IgG4 monoclonal antibody targeting membrane-bound and soluble BAFF (Figure 1) . Recently, subcutaneous tabalumab failed to meet the primary end points in two large pivotal trials [45] . Atacicept (TACI-Ig fusion protein)

Atacicept while not a monoclonal antibody but a soluble, fully humanized, recombinant fusion protein, it targets the BAFF/APRIL axis and thus we have included it in this review. It is a TACI receptor fusion protein which inhibits B-cell stimulating factors BAFF and APRIL (Figure 1)  [46] . A Phase I trial of atacicept in SLE showed dose-dependent reductions in immunoglobulin levels and in mature and total B cells [33] . The initial Phase II trial of combination atacicept and mycophenolate mofetil in lupus nephritis was terminated after recruitment of only 6 patients due to a high frequency of reported serious infections likely related to a marked reduction in total immunoglobulin levels (Table 1) [34] . Efficacy in lupus nephritis was not evaluated. Clinical trials in MS (multiple sclerosis) were also prematurely terminated due to increased inflammatory activity with more clinical relapses and increased new lesions on MRI as compared with placebo. Phase II trials are currently recruiting to evaluate long-term safety and tolerability of atacicept in patients with SLE (NCT02070978 and NCT01972568).

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Abatacept is not a monoclonal antibody but a fusion protein comprising CTLA-4 combined with the Fc portion of human IgG1 (CTLA-4-Ig) (Figure 1) . Immunological tolerance can be induced by blockade of the co-stimulatory interactions between T and B lymphocytes. CD28 is a T lymphocyte co-stimulatory ligand that interacts with the co-stimulatory receptors B7-1 (CD80) and B7-2 (CD86). CTLA4 on activated T cells interacts with B7 with higher affinity than CD28 resulting in a negative feedback loop that prevents T-cell activation [47–49] . In murine lupus nephritis models, the combination of CTLA-4-Ig and cyclophosphamide significantly reduces proteinuria, autoantibody titers and increases longevity [50–52] . A Phase II randomized controlled trial of abatacept in SLE patients failed to meet its primary end point of a reduction of the proportion of patients with a new BILAG A/B flares [53] . The study cohort was comprised primarily of SLE patients with musculoskeletal and dermatologic involvement and was not specifically designed to examine the role of abatacept in lupus nephritis. A Phase II/III trial of abatacept in proliferative lupus nephritis failed to meet its study end point which defined complete renal response as achieving a glomerular filtration rate within 10% of preflare/baseline value, urinary protein creatinine ratio less than 0.26 mg/mg and an inactive urinary sediment [53] . Following this, a subanalysis of the same study data was undertaken assessing abatacept response using different outcome measures. In this instance, complete renal response was defined as achieving a normal serum creatinine or ≤125% of baseline value, urinary protein creatinine ratio

Progress with the use of monoclonal antibodies for the treatment of systemic lupus erythematosus.

In recent years, significant progress has been made in the use of monoclonal antibodies in the treatment of systemic lupus erythematosus (SLE). Advanc...
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