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B lymphocytes and lupus nephritis: New insights into pathogenesis and targeted therapies
http://www.kidney-international.org
mini review
& 2008 International Society of Nephrology
B lymphocytes and lupus nephritis: New insights into pathogenesis and targeted therapies P Bhat1 and J Radhakrishnan1 1
Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA
Lupus nephritis (LN) in systemic lupus erythematosus (SLE) remains a major cause of morbidity and end-stage renal disease. While therapies such as corticosteroids, cyclophosphamide, and mycophenolate mofetil have improved outcomes, a significant proportion of patients have refractory disease or are unable to tolerate these agents. Limitations in existing therapies, along with advances in our understanding of the immunopathogenesis of SLE, have resulted in the development of new immunosuppressive and immunomodulatory treatments for SLE/LN. Dysfunction of the B lymphocyte—an important component of adaptive immunity—is thought to be important in the pathogenesis of SLE/LN. The goal of this study is to review our current understanding of the role of B cells in the pathogenesis of SLE, and to discuss new and emerging therapies that selectively target B cells in patients with SLE/LN. Novel strategies discussed include B-cell depletion by the monoclonal antibodies to B-cell markers, rituximab and epratuzumab; ‘pharmapheresis’ of pathogenic antibodies to dsDNA, by abetimus; blockade of T-cell costimulation of B cells by abatacept, belatacept, BG9588, and IDEC-131; and blockade of B-cell stimulation by belimumab. Preliminary results are promising, but in the absence of large controlled trials, caution must be exercised prior to the widespread use and acceptance of these treatments. Kidney International (2008) 73, 261–268; doi:10.1038/sj.ki.5002663; published online 14 November 2007 KEYWORDS: lupus nephritis; B-lymphocytes; therapies; immune response; monoclonal antibodies; rituximab
Renal involvement in systemic lupus erythematosus (SLE) remains a major cause of end-stage renal disease and is associated with a greater than four-fold increase in mortality in recent series.1 While clinical outcomes for proliferative lupus nephritis (LN) have improved since the 1990s with widespread adoption of the National Institutes of Health treatment strategy using intravenous cyclophosphamide and corticosteroids,2–4 up to 25% of patients fail to respond to this treatment.2,3,5 Furthermore, these therapies are limited by the high incidence of serious side effects including premature gonadal failure5,6 and malignancy.7 In recent years, many new immunosuppressive therapies have been evaluated for LN and many more are under consideration. Mycophenolate mofetil, a selective, reversible, noncompetitive inhibitor of purine synthesis that restricts lymphocyte and leukocyte proliferation, has been accepted as an alternative therapy to cyclophosphamide. While mycophenolate offers a superior side effect profile, with fewer serious infections and hospitalizations, the majority of patients did not achieve full remission in the largest controlled trial to date.8 Limitations in existing therapies, as well as rapid advances in our understanding of the immunopathogenesis of SLE over the past two decades, have stimulated intense interest in developing new immunosuppressive and immunomodulatory treatments for SLE and LN. B lymphocytes are intimately involved in the pathogenesis of SLE/LN.9–13 We aim to review our current understanding of the role of B cells in the pathogenesis of SLE, and to discuss new and emerging therapies that selectively target B cells in patients with SLE/ LN (summarized in Figure 1 and Table 1). ROLE OF B CELLS IN PATHOGENESIS OF SLE
Correspondence: J Radhakrishnan, PH-4124, Columbia Presbyterian Medical Center, 622 West 168th Street, New York, New York 10032, USA. E-mail: [email protected] Received 31 May 2007; revised 16 August 2007; accepted 21 August 2007; published online 14 November 2007 Kidney International (2008) 73, 261–268
B lymphocytes are components of the adaptive immune system. They arise from hematopoietic stem cells throughout life and express a diverse repertoire of immunoglobulins against a wide array of pathogens, and function as antigen presenting cells (APCs) to T lymphocytes. During development, the antigenic specificity of a B cell is determined through the process of gene rearrangement, resulting in antigen-specific cell-surface receptors. Some of these receptors may display specificity for ‘self ’-antigens. B-cell tolerance occurs through the processes of ‘passive tolerance,’ when the replication of autoreactive immature B cells in the bone marrow or in the peripheral lymphoid tissue is controlled 261
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1
Table 1 | New and evolving therapies for lupus nephritis
2
New and evolving therapies for lupus nephritis
3 5
B-lymphocyte
B-cell depletion Rituximab Epratuzumab T-lymphocyte
Pharmapheresis of antibodies to dsDNA Abetimus
BlyS/ BAFF
6
Blockade of T-cell costimulation Abatacept, Belatacept BG9588, IDEC-131
Figure 1 | B-lymphocyte-specific therapeutic targets in SLE. B-lymphocyte depletion (1) rituximab, (2) epratuzumab; reduction of dsDNA titers, (3) LJP 394/abetimus; blockade of T-cell costimulation (4) CTLA4-Ig (abatacept and belatacept), (5) IDEC131 and BG9588; blockade of B-cell stimulation, (6) belimumab.
Blockade of B-cell stimulation Belimumab
due to anergy or apoptosis, and ‘active tolerance’ mediated by CD4 þ regulatory T cells, which suppress activation of the immune system and prevent pathological self-reactivity.14,15 B-cell activation, on the other hand, is triggered by antigen, requires a second signal from a cognate CD4 þ T cell that has the same specificity, and is facilitated by secretion of cytokines such as interferon-g and interleukin-4.16 These events drive the naı¨ve B cell to progress through the cell cycle, promoting clonal expansion of the B cell. When stimulated by an antigen some B cells are converted into the immunoglobulin-secreting plasma cells that characterize the humoral immune response. Other activated B cells migrate into B-cell follicles where they coalesce into germinal centers, undergo intense proliferation (the germinal center reaction), and differentiate into either plasma cells or memory B cells in the presence of appropriate costimulation by CD40 or B7.13 Through these processes, immune complexes are formed and antigen is removed via recognition of immune complexes by cells bearing the Fc-receptor (FcR), and activation of the complement pathway occurs with concomitant recruitment of effector leukocytes, resulting in inflammation. On the other hand, when acting as APCs, B lymphocytes present internalized and processed antigen to T cells via major histocompatibility complex Class II in the setting of appropriate costimulation, leading to a cascade of events that result in activation of cognate T cells, release of stimulatory cytokines, and recruitment of more B cells.13,17 Autoimmune disease occurs when the adaptive immune response is mounted against ‘self ’-antigens, which cannot be removed by effector mechanisms. The immune response is sustained and chronic inflammation results. Effector responses in autoimmune tissue injury are mediated by T cells or antibodies, which cause complement activation via engagement of complement and FcR. Early models of autoimmunity postulated the autoantibody as the key component of disease pathogenesis. Evidence to support this view included maternal transfer of autoantibodies in neonatal lupus syndromes and animal models of passive transfer of disease through autoantibody inoculation.
Indirect evidence was offered in the observation that SLE disease activity correlates with titers of anti-dsDNA and that immune complexes are found in tissues affected by disease, such as the glomeruli. However, evidence for an antibodyindependent role for B cells is suggested by animal models, that is, an MRL lpr/lpr lupus prone mouse with nonsecretory plasma cells developed evidence of autoimmune disease,18 yet B-cell-deficient MRL lpr/lpr mice did not.19 B cells producing autoantibodies in SLE have undergone extensive clonal expansion, suggesting that the antibodies are produced in response to chronic stimulation of B cells by antigen and costimulatory autoreactive CD4 þ T cells—therefore suggesting an important role for the autoreactive T cell in addition to B lymphocytes. Another B-cell-related functions likely to be important in the pathogenesis of SLE is cytokine release, particularly proinflammatory interleukin-10, tumor necrosis factor (TNF)-a, and interleukin-6, all of which are produced in high levels in SLE, and BlyS/BAFF (Blymphocyte stimulator/B-cell activating factor; a TNF-family cytokine that promotes B-cell maturation and survival and plasma cell differentiation).20 The role of the B lymphocyte as an APC is also likely to be essential in the development of autoimmunity. In experimental models of autoimmune arthritis, the APC function of B cells was essential for the development of disease, while the antibody-secreting function was not.18,21 Ultimately, activated B cells can aggregate into ectopic lymph node-like structures containing plasmablasts, memory B cells, and plasma cells are observed in sites with chronic inflammation. This local generation of B cells can exacerbate disease through localized autoantibody generation, and stimulation of proinflammatory cytokines and effector leukocytes.
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CLINICAL STUDIES OF B-CELL THERAPIES IN SLE/LN B-cell depletion with anti-CD20 monoclonal antibody (rituximab)
Given substantial evidence for the role of B cells in the pathogenesis of SLE and the recent development of monoclonal antibodies to B-lymphocyte-specific targets, B-cell Kidney International (2008) 73, 261–268
P Bhat and J Radhakrishnan: B lymphocytes and lupus nephritis
depletion is an intuitive and attractive approach to SLE treatment. These drugs were initially developed for treatment of B-cell malignancies; however, there is now considerable clinical experience with these agents in autoimmune disease. Rituximab is a chimeric antibody directed against the CD20 antigen on the surface of pre-B cells and mature B lymphocytes. CD20 is a tetraspan cell surface molecule of 33–37 kDa molecular weight which may function as a calcium channel.22 Stem cells, pro-B cells, and plasma cells do not bear CD20 molecules and are unaffected by the immediate effects of therapy. Rituximab leads to profound depletion of B-cell subsets both in vitro and in vivo.23 In vitro B-cell depletion by rituximab occurs through antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity, or apoptosis.13 In humans, the degree of B-cell depletion by rituximab varies with polymorphisms of the FcR(gamma)IIIA allele, suggesting that antibody-dependent cell cytotoxicity is an important mechanism of B-cell depletion in vivo.24,25 Of interest, CD20 null mice have no obvious phenotype, and have normal B-cell responses;26 thus the function of CD20 remains unclear. Rituximab was first used successfully in the treatment of B-cell malignancies.23,27,28 The most commonly used dosing regimen, 375 mg m2 intravenous infusion given weekly for a total of 4 weeks, is based on dosing in clinical trials in nonHodgkin’s lymphoma;29 however, an alternative regimen— 1000 mg given twice in a 2-week interval—has been used with success in rheumatoid arthritis.30 T1/2 is about 20 days, with drug levels measurable for as long as 6 months after treatment and B-cell depletion, sometimes lasting longer than 1 year.23,31 In oncologic protocols, patients have been redosed with rituximab on the basis of clinical recurrence; experience in dosing and dose intervals in autoimmune diseases is limited. Clinically, administration of rituximab is generally followed by depletion of B lymphocytes to levels less than 5 ml1—an effect generally seen within days. Other blood elements are unaffected, including neutrophils and T lymphocytes. There is no significant early effect on serum immunoglobulin levels,23 which may account for the relative protection from infectious complications and suggests that the mechanism of therapeutic effect of rituximab in autoimmune disease is independent of decreases in autoantibody production.32 Evidence for the efficacy of rituximab in SLE has been mixed. The initial report of successful management of SLE with rituximab was in an 18-year-old female patient with SLE-associated autoimmune hemolytic anemia resistant to corticosteroids, cyclosporine A, and intravenous immunoglobulin. After treatment with two doses of rituximab (375 mg m2), she remained disease-free for 7 months.33 To date, more than 100 patients have been treated with rituximab, either alone or in combination with steroids and cyclosphosphamide, in multiple subsequent small open-label trials. Patient populations have been heterogeneous. All trials have investigated the use of rituximab as an induction agent, rather than for maintenance therapy. Some patients have Kidney International (2008) 73, 261–268
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shown improvement in disease activity in response to rituximab, with improved disease activity scores, urinary protein excretion, and anti-dsDNA titers. Occurrence of adverse events has been minimal. Many other patients, however, have failed to respond or have responded only partially (Table 2).24,34–42 There can be significant variability in the degree of B-cell depletion; factors affecting degree of response to rituximab include tumor burden (in lymphoma patients), amount of available circulating CD20, human antichimeric antibodies (HACA), proteinuria, and genetic polymorphisms of FcR(gamma)IIIA leading to a phenotype with low affinity to rituximab.24,34,43 Mechanisms other than B-cell depletion may be important in the therapeutic effect of rituximab, including downregulation of costimulatory T cells and shifts in B-cell population subsets.39,40 A multicenter randomized placebo-controlled trial of rituximab in addition to MMF in proliferative LN is currently underway (ClinicalTrials. gov Identifier: NCT00282347). Use of rituximab in autoimmune disease is associated with an increase in the incidence of HACA. The development of HACA, rare in the early lymphoma trials, has occurred frequently in autoimmune diseases. In the University of Rochester trial more than one-third of SLE patients developed high titers of HACA, ranging from 600 to 9900 ng ml1 in 6/18 patients, while five others had titers that were low but detectable. It is not yet clear whether development of HACA limits the efficacy of B-cell depletion34 or whether HACA are associated with adverse events. No major infectious complications have been reported to date in adult patients with SLE treated with rituximab. However, a recent Food and Drug Administration advisory warns of two cases of progressive multifocal leukoencephalopathy in patients with SLE nephritis treated with rituximab. Of note, no patients with rheumatoid arthritis who received treatment with rituximab developed progressive multifocal leukoencephalopathy (though it has been reported in lymphoma).44 Furthermore, there has been a high incidence of adverse events related to rituximab therapy in a pediatric SLE population, including three patients with infection requiring hospitalization.45 Infusion reactions are common, particularly during the first treatment, and can be minimized with use of acetaminophen, anti-histamines, and corticosteroids before infusion. B-cell depletion with anti-CD 22 monoclonal antibody (epratuzumab)
CD22, another B-cell surface restricted marker, is a 135 kDa glycoprotein member of a class of adhesion molecules that regulate B-cell activation and interact with T cells.46 CD22 has seven extracellular domains, and is rapidly internalized when bound to its natural ligand (a co-stimulatory signal for B cells). This marker is expressed in the cytoplasm of pro-B and pre-B cells, and on the surface of mature B cells. Like CD20, CD22 is not expressed on plasma cells. Unlike CD20, the CD22 molecule can deliver intracellular signals, either constitutively or after interaction with its ligand. 263
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Table 2 | Trials of rituximab in patients with SLE and LN Trial Sfikakis et al., Greece34 Leandro et al., at University College in London30,31
Looney et al. at University of Rochester29
Vigna-Perez et al., Mexico32
Smith et al., Cambridge, UK37
Willems et al., France40
n (Classes III, IV,V); previous treatment 10 (4, 6, 0) All refractory to CS, 5/10 refractory to CY 24 (0, 16, 1) All refractory to CS and CY
18 (3.3.0; 1 unspecified) No previous CY. Most received CS (varying doses) 22 (2, 18, 2) All previously treated with CS, 11/22 previously treated with CY 6/11 with renal involvement, unspecified class Most refractory to CY 11 (0, 6, 2); 7/8 previously treated with CY
Treatment regimen
Main outcomes
4 weekly infusions of 375 mg m2+oral prednisolone (0.5 mg kg1 day1 for 10 weeks 500 mg 2 doses followed by 750 mg 2 doses; OR 1000 mg 2 doses total in combination with CY (two doses of 750 mg each) and high-dose steroids Dose escalation study (100, 375, and 375 mg m2 4 doses) with rituximab added to ongoing therapies
4 CR, 4 PR at 12 months followup Significant reductions in BILAG scores and anti-dsDNA titers; nonsignificant decreases in proteinuria at 6 months followup. One patient developed HACA Those who depleted B cells (11/ 17) had decreases in SLAM and dsDNA titers 6/18 developed high titer HACA
500–1000 mg rituximab given on days 1 and 15
Most patients had a reduction in proteinuria
4 weekly infusions 375 mg m2 with one dose of CY (500 mg)
Proteinuria declined from mean 4.6 g/24 h to 0.45 g/24 h at 12 month follow-up 3 patients developed HACA Mean age 13.9 years 6/8 had CR 450% had serious adverse events (cytopenias 6/11, septicemia 2/11, febrile neutropenia in 1/11)
2–12 doses 350–450 mg m2
CR, complete remission; CS, corticosteroids; CY, cyclophosphamide; HACA, human anti-chimeric antibodies; PR, partial remission; SLAM, systemic lupus activity measure.
Furthermore, CD22 modifies signaling through CD19/21 and CD45.47 CD22-deficient mice show an increase in calcium signaling in response to B-cell receptor ligation and have reduced numbers of mature B cells peripherally and in the bone marrow (suggesting a role in B-cell development). Furthermore, B-cell life span is reduced, apoptosis enhanced, and there is a predisposition to autoimmune disease.48 Thus CD22 is an attractive target for therapy in autoimmune disease not only because its expression is restricted to the surface of mature B cells, but also for its potential function in the pathogenesis of autoimmunity.47–49 Epratuzumab is a recombinant humanized monoclonal immunoglobulin G (IgG) antibody to the CD22 antigen on B cells. It has been shown to mediate antibody-dependent cellular cytotoxicity in vitro and, but unlike rituximab, mediates only partial B-cell depletion—a 35–40% reduction in circulating B lymphocytes is seen in patients with SLE.50 It is thought that epratuzumab modifies the function of B lymphocytes without killing them, but the precise mechanisms of action remain unclear.49 Phase I/II clinical trials of epratuzumab in patients with non-Hodgkin lymphoma have demonstrated safety, with adverse events largely limited to infusion-related reactions, and objective response in terms of decreased tumor burden, and reduction of circulating B cells.51 Epratuzumab has also been used with success in combination with rituximab in refractory lymphoma.52 An 264
initial open-label nonrandomized single-center study of 14 Caucasian SLE patients has demonstrated safety and efficacy. There were no patients with severe renal disease; four patients had mild/stable proteinuria. On average, there was a sustained 35% decrease in B-cell levels over 32 weeks of follow-up. Development of anti-humanized antibodies was not observed.50 A multicenter randomized placebo-controlled clinical trial in SLE is underway (ClinicalTrials.gov Identifier: NCT00383513). Pharmapheresis of anti dsDNA antibodies with abetimus
A novel strategy in the treatment of SLE is inhibition of the survival and activation of autoreactive B cells—the so-called induction of tolerance. As reviewed above, two distinct signals are necessary for the activation of T cells. The first signal is binding of antigen to the B-cell receptor; the second involves the interaction of receptor–ligand pairs on APCs (including B cells) and cognate T cells. In the absence of this second co-stimulatory signal, the B cell with affinity to the specific antigen undergoes apoptopsis or becomes anergic. A targeted strategy is to create a state of inactivation—anergy or apoptosis—in B cells with receptors that express affinity to dsDNA, thereby reducing titers of anti-dsDNA. Abetimus (LJP 394, riquent) consists of four dsDNA epitopes conjugated to a nonimmunogenic polyethylene glycol platform. It acts by cross-linking anti-dsDNA surface Kidney International (2008) 73, 261–268
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immunoglobulin receptor on B cells and triggering signal tranduction pathways that lead to B-cell anergy or apoptosis and reduced titers of anti-dsDNA titers in animal models of SLE.53,54 The safety and efficacy of abetimus has been evaluated in 13 controlled and uncontrolled trials, enrolling a total of over 800 patients (reviewed in Cardiel55) with no notable adverse events. A placebo-controlled trial of this agent has shown significant reductions in anti-dsDNA titers.56,57 In a 76 week double-blind, placebo-controlled trial of abetimus in 230 patients with LN (including patients with Classes III, IV, and V LN), anti-dsDNA titers were reduced and C3 levels increased; however time to renal flare and number of renal flares—while lower—were not significantly different from the placebo group. Subgroup analysis revealed that patients with high-affinity anti-dsDNA antibodies had a significantly improved treatment response, with 8% of the abetimus treatment group flaring in comparison to 22% of the placebo group.58 However, in the larger Phase III trial, which specifically enrolled patients with high-affinity antibodies, the benefit was much less impressive, with 12% of LJP 394-treated patients flaring, in comparison with 16% of placebo-treated patients.59 Abetimus is currently being reevaluated in LN patients in a multinational trial (ClinicalTrials.gov Identifier: NCT00089804). Inhibiting costimulatory molecule CD28:B7 interaction with abatacept and belatacept
Tolerance can also be induced by blockade of targets of costimulatory interactions between T cells and B cells. The CD28:B7 costimulatory interaction was the first to be elucidated,60 and is the most important antigen-independent signal driving T-cell activation. CD28 is a glycoprotein expressed on T cells; its’ cognate ligands on APCs are B71(CD80) and B7-2(CD86). Stimulation of this pathway occurs when naı¨ve T cells encounter an APC with the appropriate major histocompatibility complex Class II bound antigen, and results in T-lymphocyte proliferation and differentiation. Cytotoxic T-lymphocyte antigen (CTLA4) is expressed only on activated T cells and also interacts with B7. However, this interaction leads to inhibition of T-cell activation, constituting a negative feedback mechanism. A fusion protein consisting of cytotoxic T-lymphocyte antigen (CTLA4) combined with immunoglobulin (CTLA4Ig, abatacept) binds B7 with a higher affinity than CD28, thereby inhibiting the costimulatory pathway. Evidence for the importance of this pathway in autoimmune disease is suggested by the finding that (NZBxNZW)F1 lupus prone mice treated with CTLA4-Ig fusion protein had significantly suppressed anti-dsDNA titers, decreased incidence of proteinuria, and improved survival while maintaining B-lymphocyte numbers.61 In other studies using (NZBxNZW)F1 mice, animals simultaneously treated with CTLA4-Ig and antimouse CD15462 (another T-cell costimulatory ligand) or cyclophosphamide63 had slower disease progression and improved survival compared with mice not treated with Kidney International (2008) 73, 261–268
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CTLA4-Ig. Two formulations of CTLA4-Ig have been used in humans, abatacept, and belatacept. Abatacept has been used with success in the treatment of psoriasis and rheumatoid arthritis,64,65 and belatacept was found to be as efficacious as cyclosporine in the prevention of acute allograft rejection in a Phase II clinical trial.66 Based on these experiences, an open-label pilot trial of CTLA4-IgG4m in combination with cyclophosphamide in patients with SLE nephritis is underway.67,68 Inhibiting costimulatory molecule CD40:CD40 ligand (CD 154) interaction with BG9588 and IDEC 131
The interaction between CD40 on B-cells and T-cell CD40L (or CD154) is another important costimulatory signal for lymphocyte proliferations and activation.69 CD40 is a 48 kDa transmembrane glycoprotein found on the surface of B lymphocytes and is a member of the TNF-receptor family. CD154 is a 39 kDa transmembrane protein that is a member of the TNF superfamily found on activated T- and B lymphocytes. This interaction provides growth signals to B cells and influences cell-mediated immunity. CD40 signaling in the presence of appropriate cytokines results in B-cell proliferation and differentiation into immunoglobulinsecreting cells. CD154:CD40 interactions are typical of germinal center reactions, where cells show markers characteristic of activation, proliferation, and secretion.70 Blockade of this interaction ameliorates nephritis in lupus-prone (NZBxNZW)F1 mice.62,71 Evidence for the importance of this pathway in human SLE is suggested by the finding that remission of proliferative LN following B-cell depletion therapy is preceded by downregulation of the T-cell costimulatory molecule CD40L.39 IDEC-131 and BG9588 are humanized monoclonal antibodies to CD154/CD40L. Of interest, patients with Class IV proliferative LN, who were treated with BG9588, showed a shift in peripheral B-cells markers away from a pattern typical of intensive germinal center activity, suggesting that germinal center activity is an important feature of the propensity to produce autoantibodies and disease.70 In a small open-label study to establish safety and efficacy, 28 patients with active proliferative LN (mean 3.26 g day1 urinary protein excretion, creatinine clearance 114 ml per min per 1.73 m2) were treated with BG9588 at doses of 20 mg kg1 at biweekly intervals for the first three doses and at monthly intervals for four additional doses. There was improvement in titers of anti-dsDNA titers and approximately 50% reduction in proteinuria in response to treatment; however, the trial was terminated early because of the incidence of thromboembolic events in patients receiving the study drug—namely, two nonfatal myocardial infarctions,72 perhaps as a result of CD154 expression on activated platelets.73 Although IDEC-131 was found to be safe in a Phase I clinical trial,74 a Phase II, double-blind, placebo-controlled, multicenter study enrolling 85 patients with mild-to-moderate active SLE with a follow-up of 20 weeks demonstrated no improvement in outcomes over placebo (or increase in thromboembolic incidents).69 265
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Blockade of B-cell stimulatory cytokine BLyS by belimumab
An alternative approach to targeting B cells is to block cytokines that are required for B-cell function. A multitude of cytokines are overexpressed in autoimmune disease, and the development of cytokine depleting agents has naturally led to the exploration of their use in SLE.75,76 BLyS, also known as BAFF, is a 285 amino-acid member of the TNF ligand superfamily.77 It binds to three different receptors—BCMA, BAFFR, and TACI. It is essential for B-cell survival and development. Mice genetically deficient in BlyS/BAFF show reductions in mature B cells and immunoglobulin levels.78 Overexpression of BlyS/BAFF in transgenic mice, conversely, leads to B-cell expansion, hypergammaglobulinemia, and autoimmunity.79,80 Elevated BlyS levels have been documented in lupus-prone mice and in human SLE.81,82 Belimumab (LymphoStat-B) is a fully humanized monoclonal antibody against BlyS/BAFF, which can cause depletion of circulating B cells. Preliminary results from a Phase II clinical trial enrolling 449 SLE patients with moderate disease activity show improvements in disease activity and quality of life scores.83 Controlled clinical trials in SLE nephritis are warranted. TACI-Ig—an alternative method for blockade of BlyS—is also under development as a treatment for SLE.84
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B-cell-targeted therapies offer the possibility of treatments for SLE/LN that are effective and have improved toxicity profiles. Goals for new therapies of LN are: (1) prevention of relapse, (2) improved side effect profile, (3) treatment of refractory disease, and (4) prevention of the development of chronic interstitial fibrosis and progressive renal failure or end-stage renal disease. Despite the considerable promise shown by newer therapies, it is important to note that only three drugs are approved by the United States Food and Drug Administration for treatment of SLE—corticosteroids, hydroxychloroquine, and low-dose aspirin—and no new therapies have been approved in nearly 40 years.85 While clinical trials of several novel drugs are underway, clinicians and regulatory bodies must pay close attention to unusual adverse events, such as progressive multifocal leukoencephalopathy in SLE patients treated with rituximab, and life threatening complications with anti-CD28 monoclonal antibodies in healthy volunteers.86 On the other hand, LN is associated with considerable morbidity, and efficacious new treatments must be made available to patients as expeditiously as is reasonable. Treatment plans need to be individualized for each patient. Furthermore, the exact role of these agents in the ever-expanding arsenal of medications needs to be better defined; that is, are these medications appropriate for induction and maintenance treatments? Should they be used as first line therapies or should they be reserved for refractory disease? Further carefully conducted clinical trials are needed.
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Berinstein NL, Grillo-Lopez AJ, White CA et al. Association of serum rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 1998; 9: 995–1001. Edwards JC, Szczepanski L, Szechinski J et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004; 350: 2572–2581. Tobinai K, Kobayashi Y, Narabayashi M et al. Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma. The IDEC-C2B8 Study Group. Ann Oncol 1998; 9: 527–534. Cambridge G, Leandro MJ, Edwards JC et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 2003; 48: 2146–2154. Perrotta S, Locatelli F, La Manna A et al. Anti-CD20 monoclonal antibody (rituximab) for life-threatening autoimmune haemolytic anaemia in a patient with systemic lupus erythematosus. Br J Haematol 2002; 116: 465–467. Looney RJ, Anolik JH, Campbell D 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: 2580–2589. Leandro MJ, Cambridge G, Edwards JC et al. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford) 2005; 44: 1542–1545. Leandro MJ, Edwards JC, Cambridge G et al. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002; 46: 2673–2677. Vigna-Perez M, Hernandez-Castro B, Paredes-Saharopulos O et al. Clinical and immunological effects of rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther 2006; 8: R83. Cambridge G, Leandro MJ, Teodorescu M et al. B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum 2006; 54: 3612–3622. Sfikakis PP, Boletis JN, Lionaki S et al. Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by downregulation of the T cell costimulatory molecule CD40 ligand: an openlabel trial. Arthritis Rheum 2005; 52: 501–513. Anolik JH, Barnard J, Cappione A et al. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 2004; 50: 3580–3590. Marks SD, Patey S, Brogan PA et al. B lymphocyte depletion therapy in children with refractory systemic lupus erythematosus. Arthritis Rheum 2005; 52: 3168–3174. Smith KG, Jones RB, Burns SM et al. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment. Arthritis Rheum 2006; 54: 2970–2982. Cartron G, Dacheux L, Salles G et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002; 99: 754–758. FDA. Information for healthcare professionals: Rituximab (marketed as Rituxan). http://www.fda.gov/cder/drug/infopage/rituximab/default.htm, accessed on 20 December 2006. Willems M, Haddad E, Niaudet P et al. Rituximab therapy for childhoodonset systemic lupus erythematosus. J Pediatr 2006; 148: 623–627. Dorner T. Crossroads of B cell activation in autoimmunity: rationale of targeting B cells. J Rheumatol Suppl 2006; 77: 3–11. Goldenberg DM. Epratuzumab in the therapy of oncological and immunological diseases. Expert Rev Anticancer Ther 2006; 6: 1341–1353. O’Keefe TL, Williams GT, Batista FD et al. Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies. J Exp Med 1999; 189: 1307–1313. Eisenberg R. Targeting B cells in systemic lupus erythematosus: not just de´ja`vu all over again. Arthritis Res Ther 2006; 8: 108. Dorner T, Kaufmann J, Wegener WA et al. Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther 2006; 8: R74. Leonard JP, Coleman M, Ketas JC et al. Epratuzumab, a humanized anti-CD22 antibody, in aggressive non-Hodgkin’s lymphoma: phase I/II clinical trial results. Clin Cancer Res 2004; 10: 5327–5334. Leonard JP, Coleman M, Ketas J et al. Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkin’s lymphoma. J Clin Oncol 2005; 23: 5044–5051. Abetimus. Abetimus sodium, LJP 394. BioDrugs 2003; 17: 212–215.
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Jones DS, Barstad PA, Feild MJ et al. Immunospecific reduction of antioligonucleotide antibody-forming cells with a tetrakisoligonucleotide conjugate (LJP 394), a therapeutic candidate for the treatment of lupus nephritis. J Med Chem 1995; 38: 2138–2144. Cardiel MH. Abetimus sodium: a new therapy for delaying the time to, and reducing the incidence of, renal flare and/or major systemic lupus erythematosus flares in patients with systemic lupus erythematosus who have a history of renal disease. Expert Opin Investig Drugs 2005; 14: 77–88. Weisman MH, Bluestein HG, Berner CM et al. Reduction in circulating dsDNA antibody titer after administration of LJP 394. J Rheumatol 1997; 24: 314–318. Furie RA, Cash JM, Cronin ME et al. Treatment of systemic lupus erythematosus with LJP 394. J Rheumatol 2001; 28: 257–265. Strand V, Aranow C, Cardiel MH et al. Improvement in health-related quality of life in systemic lupus erythematosus patients enrolled in a randomized clinical trial comparing LJP 394 treatment with placebo. Lupus 2003; 12: 677–686. Alarcon-Segovia D, Tumlin JA, Furie RA et al. LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: results from a randomized, double-blind, placebo-controlled study. Arthritis Rheum 2003; 48: 442–454. Harding FA, McArthur JG, Gross JA et al. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992; 356: 607–609. Finck BK, Linsley PS, Wofsy D. Treatment of murine lupus with CTLA4Ig. Science 1994; 265: 1225–1227. Daikh DI, Finck BK, Linsley PS et al. Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways. J Immunol 1997; 159: 3104–3108. Cunnane G, Chan OT, Cassafer G et al. Prevention of renal damage in murine lupus nephritis by CTLA-4Ig and cyclophosphamide. Arthritis Rheum 2004; 50: 1539–1548. Abrams JR, Lebwohl MG, Guzzo CA et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest 1999; 103: 1243–1252. Kremer JM, Westhovens R, Leon M et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003; 349: 1907–1915. Vincenti F, Larsen C, Durrbach A et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353: 770–781. Davidson A, Diamond B, Wofsy D et al. Block and tackle: CTLA4Ig takes on lupus. Lupus 2005; 14: 197–203. Diamond B, Bluestone J, Wofsy D. The immune tolerance network and rheumatic disease: immune tolerance comes to the clinic. Arthritis Rheum 2001; 44: 1730–1735. Kalunian KC, Davis Jr JC, Merrill JT et al. Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46: 3251–3258. Grammer AC, Slota R, Fischer R et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154–CD40 interactions. J Clin Invest 2003; 112: 1506–1520. Wang X, Huang W, Schiffer LE et al. Effects of anti-CD154 treatment on B cells in murine systemic lupus erythematosus. Arthritis Rheum 2003; 48: 495–506. Boumpas DT, Furie R, Manzi S et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 2003; 48: 719–727. Buchner K, Henn V, Grafe M et al. CD40 ligand is selectively expressed on CD4+ T cells and platelets: implications for CD40-CD40L signalling in atherosclerosis. J Pathol 2003; 201: 288–295. Davis Jr JC, Totoritis MC, Rosenberg J et al. Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol 2001; 28: 95–101. Smolen JS, Steiner G, Aringer M. Anti-cytokine therapy in systemic lupus erythematosus. Lupus 2005; 14: 189–191. Anolik JH, Aringer M. New treatments for SLE: cell-depleting and anti-cytokine therapies. Best Pract Res Clin Rheumatol 2005; 19: 859–878. Stohl W. SLE—systemic lupus erythematosus: a BLySful, yet BAFFling, disorder. Arthritis Res Ther 2003; 5: 136–138. Schiemann B, Gommerman JL, Vora K et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001; 293: 2111–2114.
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belimumab (fully human monoclonal antibody to B-lymphocyte stimulator [BLYS]) improves or stabilizes SLE activity. Ann Rheum Dis 2006; 65: 63. Ramanujam M, Wang X, Huang W et al. Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus. J Immunol 2004; 173: 3524–3534. Wallace DJ. What’s new in the management of lupus since 2000? J Clin Rheumatol 2006; 12: 307–313. Suntharalingam G, Perry MR, Ward S et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006; 355: 1018–1028.
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& 2008 International Society of Nephrology
B lymphocytes and lupus nephritis: New insights into pathogenesis and targeted therapies P Bhat1 and J Radhakrishnan1 1
Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA
Lupus nephritis (LN) in systemic lupus erythematosus (SLE) remains a major cause of morbidity and end-stage renal disease. While therapies such as corticosteroids, cyclophosphamide, and mycophenolate mofetil have improved outcomes, a significant proportion of patients have refractory disease or are unable to tolerate these agents. Limitations in existing therapies, along with advances in our understanding of the immunopathogenesis of SLE, have resulted in the development of new immunosuppressive and immunomodulatory treatments for SLE/LN. Dysfunction of the B lymphocyte—an important component of adaptive immunity—is thought to be important in the pathogenesis of SLE/LN. The goal of this study is to review our current understanding of the role of B cells in the pathogenesis of SLE, and to discuss new and emerging therapies that selectively target B cells in patients with SLE/LN. Novel strategies discussed include B-cell depletion by the monoclonal antibodies to B-cell markers, rituximab and epratuzumab; ‘pharmapheresis’ of pathogenic antibodies to dsDNA, by abetimus; blockade of T-cell costimulation of B cells by abatacept, belatacept, BG9588, and IDEC-131; and blockade of B-cell stimulation by belimumab. Preliminary results are promising, but in the absence of large controlled trials, caution must be exercised prior to the widespread use and acceptance of these treatments. Kidney International (2008) 73, 261–268; doi:10.1038/sj.ki.5002663; published online 14 November 2007 KEYWORDS: lupus nephritis; B-lymphocytes; therapies; immune response; monoclonal antibodies; rituximab
Renal involvement in systemic lupus erythematosus (SLE) remains a major cause of end-stage renal disease and is associated with a greater than four-fold increase in mortality in recent series.1 While clinical outcomes for proliferative lupus nephritis (LN) have improved since the 1990s with widespread adoption of the National Institutes of Health treatment strategy using intravenous cyclophosphamide and corticosteroids,2–4 up to 25% of patients fail to respond to this treatment.2,3,5 Furthermore, these therapies are limited by the high incidence of serious side effects including premature gonadal failure5,6 and malignancy.7 In recent years, many new immunosuppressive therapies have been evaluated for LN and many more are under consideration. Mycophenolate mofetil, a selective, reversible, noncompetitive inhibitor of purine synthesis that restricts lymphocyte and leukocyte proliferation, has been accepted as an alternative therapy to cyclophosphamide. While mycophenolate offers a superior side effect profile, with fewer serious infections and hospitalizations, the majority of patients did not achieve full remission in the largest controlled trial to date.8 Limitations in existing therapies, as well as rapid advances in our understanding of the immunopathogenesis of SLE over the past two decades, have stimulated intense interest in developing new immunosuppressive and immunomodulatory treatments for SLE and LN. B lymphocytes are intimately involved in the pathogenesis of SLE/LN.9–13 We aim to review our current understanding of the role of B cells in the pathogenesis of SLE, and to discuss new and emerging therapies that selectively target B cells in patients with SLE/ LN (summarized in Figure 1 and Table 1). ROLE OF B CELLS IN PATHOGENESIS OF SLE
Correspondence: J Radhakrishnan, PH-4124, Columbia Presbyterian Medical Center, 622 West 168th Street, New York, New York 10032, USA. E-mail: [email protected] Received 31 May 2007; revised 16 August 2007; accepted 21 August 2007; published online 14 November 2007 Kidney International (2008) 73, 261–268
B lymphocytes are components of the adaptive immune system. They arise from hematopoietic stem cells throughout life and express a diverse repertoire of immunoglobulins against a wide array of pathogens, and function as antigen presenting cells (APCs) to T lymphocytes. During development, the antigenic specificity of a B cell is determined through the process of gene rearrangement, resulting in antigen-specific cell-surface receptors. Some of these receptors may display specificity for ‘self ’-antigens. B-cell tolerance occurs through the processes of ‘passive tolerance,’ when the replication of autoreactive immature B cells in the bone marrow or in the peripheral lymphoid tissue is controlled 261
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1
Table 1 | New and evolving therapies for lupus nephritis
2
New and evolving therapies for lupus nephritis
3 5
B-lymphocyte
B-cell depletion Rituximab Epratuzumab T-lymphocyte
Pharmapheresis of antibodies to dsDNA Abetimus
BlyS/ BAFF
6
Blockade of T-cell costimulation Abatacept, Belatacept BG9588, IDEC-131
Figure 1 | B-lymphocyte-specific therapeutic targets in SLE. B-lymphocyte depletion (1) rituximab, (2) epratuzumab; reduction of dsDNA titers, (3) LJP 394/abetimus; blockade of T-cell costimulation (4) CTLA4-Ig (abatacept and belatacept), (5) IDEC131 and BG9588; blockade of B-cell stimulation, (6) belimumab.
Blockade of B-cell stimulation Belimumab
due to anergy or apoptosis, and ‘active tolerance’ mediated by CD4 þ regulatory T cells, which suppress activation of the immune system and prevent pathological self-reactivity.14,15 B-cell activation, on the other hand, is triggered by antigen, requires a second signal from a cognate CD4 þ T cell that has the same specificity, and is facilitated by secretion of cytokines such as interferon-g and interleukin-4.16 These events drive the naı¨ve B cell to progress through the cell cycle, promoting clonal expansion of the B cell. When stimulated by an antigen some B cells are converted into the immunoglobulin-secreting plasma cells that characterize the humoral immune response. Other activated B cells migrate into B-cell follicles where they coalesce into germinal centers, undergo intense proliferation (the germinal center reaction), and differentiate into either plasma cells or memory B cells in the presence of appropriate costimulation by CD40 or B7.13 Through these processes, immune complexes are formed and antigen is removed via recognition of immune complexes by cells bearing the Fc-receptor (FcR), and activation of the complement pathway occurs with concomitant recruitment of effector leukocytes, resulting in inflammation. On the other hand, when acting as APCs, B lymphocytes present internalized and processed antigen to T cells via major histocompatibility complex Class II in the setting of appropriate costimulation, leading to a cascade of events that result in activation of cognate T cells, release of stimulatory cytokines, and recruitment of more B cells.13,17 Autoimmune disease occurs when the adaptive immune response is mounted against ‘self ’-antigens, which cannot be removed by effector mechanisms. The immune response is sustained and chronic inflammation results. Effector responses in autoimmune tissue injury are mediated by T cells or antibodies, which cause complement activation via engagement of complement and FcR. Early models of autoimmunity postulated the autoantibody as the key component of disease pathogenesis. Evidence to support this view included maternal transfer of autoantibodies in neonatal lupus syndromes and animal models of passive transfer of disease through autoantibody inoculation.
Indirect evidence was offered in the observation that SLE disease activity correlates with titers of anti-dsDNA and that immune complexes are found in tissues affected by disease, such as the glomeruli. However, evidence for an antibodyindependent role for B cells is suggested by animal models, that is, an MRL lpr/lpr lupus prone mouse with nonsecretory plasma cells developed evidence of autoimmune disease,18 yet B-cell-deficient MRL lpr/lpr mice did not.19 B cells producing autoantibodies in SLE have undergone extensive clonal expansion, suggesting that the antibodies are produced in response to chronic stimulation of B cells by antigen and costimulatory autoreactive CD4 þ T cells—therefore suggesting an important role for the autoreactive T cell in addition to B lymphocytes. Another B-cell-related functions likely to be important in the pathogenesis of SLE is cytokine release, particularly proinflammatory interleukin-10, tumor necrosis factor (TNF)-a, and interleukin-6, all of which are produced in high levels in SLE, and BlyS/BAFF (Blymphocyte stimulator/B-cell activating factor; a TNF-family cytokine that promotes B-cell maturation and survival and plasma cell differentiation).20 The role of the B lymphocyte as an APC is also likely to be essential in the development of autoimmunity. In experimental models of autoimmune arthritis, the APC function of B cells was essential for the development of disease, while the antibody-secreting function was not.18,21 Ultimately, activated B cells can aggregate into ectopic lymph node-like structures containing plasmablasts, memory B cells, and plasma cells are observed in sites with chronic inflammation. This local generation of B cells can exacerbate disease through localized autoantibody generation, and stimulation of proinflammatory cytokines and effector leukocytes.
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CLINICAL STUDIES OF B-CELL THERAPIES IN SLE/LN B-cell depletion with anti-CD20 monoclonal antibody (rituximab)
Given substantial evidence for the role of B cells in the pathogenesis of SLE and the recent development of monoclonal antibodies to B-lymphocyte-specific targets, B-cell Kidney International (2008) 73, 261–268
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depletion is an intuitive and attractive approach to SLE treatment. These drugs were initially developed for treatment of B-cell malignancies; however, there is now considerable clinical experience with these agents in autoimmune disease. Rituximab is a chimeric antibody directed against the CD20 antigen on the surface of pre-B cells and mature B lymphocytes. CD20 is a tetraspan cell surface molecule of 33–37 kDa molecular weight which may function as a calcium channel.22 Stem cells, pro-B cells, and plasma cells do not bear CD20 molecules and are unaffected by the immediate effects of therapy. Rituximab leads to profound depletion of B-cell subsets both in vitro and in vivo.23 In vitro B-cell depletion by rituximab occurs through antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity, or apoptosis.13 In humans, the degree of B-cell depletion by rituximab varies with polymorphisms of the FcR(gamma)IIIA allele, suggesting that antibody-dependent cell cytotoxicity is an important mechanism of B-cell depletion in vivo.24,25 Of interest, CD20 null mice have no obvious phenotype, and have normal B-cell responses;26 thus the function of CD20 remains unclear. Rituximab was first used successfully in the treatment of B-cell malignancies.23,27,28 The most commonly used dosing regimen, 375 mg m2 intravenous infusion given weekly for a total of 4 weeks, is based on dosing in clinical trials in nonHodgkin’s lymphoma;29 however, an alternative regimen— 1000 mg given twice in a 2-week interval—has been used with success in rheumatoid arthritis.30 T1/2 is about 20 days, with drug levels measurable for as long as 6 months after treatment and B-cell depletion, sometimes lasting longer than 1 year.23,31 In oncologic protocols, patients have been redosed with rituximab on the basis of clinical recurrence; experience in dosing and dose intervals in autoimmune diseases is limited. Clinically, administration of rituximab is generally followed by depletion of B lymphocytes to levels less than 5 ml1—an effect generally seen within days. Other blood elements are unaffected, including neutrophils and T lymphocytes. There is no significant early effect on serum immunoglobulin levels,23 which may account for the relative protection from infectious complications and suggests that the mechanism of therapeutic effect of rituximab in autoimmune disease is independent of decreases in autoantibody production.32 Evidence for the efficacy of rituximab in SLE has been mixed. The initial report of successful management of SLE with rituximab was in an 18-year-old female patient with SLE-associated autoimmune hemolytic anemia resistant to corticosteroids, cyclosporine A, and intravenous immunoglobulin. After treatment with two doses of rituximab (375 mg m2), she remained disease-free for 7 months.33 To date, more than 100 patients have been treated with rituximab, either alone or in combination with steroids and cyclosphosphamide, in multiple subsequent small open-label trials. Patient populations have been heterogeneous. All trials have investigated the use of rituximab as an induction agent, rather than for maintenance therapy. Some patients have Kidney International (2008) 73, 261–268
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shown improvement in disease activity in response to rituximab, with improved disease activity scores, urinary protein excretion, and anti-dsDNA titers. Occurrence of adverse events has been minimal. Many other patients, however, have failed to respond or have responded only partially (Table 2).24,34–42 There can be significant variability in the degree of B-cell depletion; factors affecting degree of response to rituximab include tumor burden (in lymphoma patients), amount of available circulating CD20, human antichimeric antibodies (HACA), proteinuria, and genetic polymorphisms of FcR(gamma)IIIA leading to a phenotype with low affinity to rituximab.24,34,43 Mechanisms other than B-cell depletion may be important in the therapeutic effect of rituximab, including downregulation of costimulatory T cells and shifts in B-cell population subsets.39,40 A multicenter randomized placebo-controlled trial of rituximab in addition to MMF in proliferative LN is currently underway (ClinicalTrials. gov Identifier: NCT00282347). Use of rituximab in autoimmune disease is associated with an increase in the incidence of HACA. The development of HACA, rare in the early lymphoma trials, has occurred frequently in autoimmune diseases. In the University of Rochester trial more than one-third of SLE patients developed high titers of HACA, ranging from 600 to 9900 ng ml1 in 6/18 patients, while five others had titers that were low but detectable. It is not yet clear whether development of HACA limits the efficacy of B-cell depletion34 or whether HACA are associated with adverse events. No major infectious complications have been reported to date in adult patients with SLE treated with rituximab. However, a recent Food and Drug Administration advisory warns of two cases of progressive multifocal leukoencephalopathy in patients with SLE nephritis treated with rituximab. Of note, no patients with rheumatoid arthritis who received treatment with rituximab developed progressive multifocal leukoencephalopathy (though it has been reported in lymphoma).44 Furthermore, there has been a high incidence of adverse events related to rituximab therapy in a pediatric SLE population, including three patients with infection requiring hospitalization.45 Infusion reactions are common, particularly during the first treatment, and can be minimized with use of acetaminophen, anti-histamines, and corticosteroids before infusion. B-cell depletion with anti-CD 22 monoclonal antibody (epratuzumab)
CD22, another B-cell surface restricted marker, is a 135 kDa glycoprotein member of a class of adhesion molecules that regulate B-cell activation and interact with T cells.46 CD22 has seven extracellular domains, and is rapidly internalized when bound to its natural ligand (a co-stimulatory signal for B cells). This marker is expressed in the cytoplasm of pro-B and pre-B cells, and on the surface of mature B cells. Like CD20, CD22 is not expressed on plasma cells. Unlike CD20, the CD22 molecule can deliver intracellular signals, either constitutively or after interaction with its ligand. 263
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Table 2 | Trials of rituximab in patients with SLE and LN Trial Sfikakis et al., Greece34 Leandro et al., at University College in London30,31
Looney et al. at University of Rochester29
Vigna-Perez et al., Mexico32
Smith et al., Cambridge, UK37
Willems et al., France40
n (Classes III, IV,V); previous treatment 10 (4, 6, 0) All refractory to CS, 5/10 refractory to CY 24 (0, 16, 1) All refractory to CS and CY
18 (3.3.0; 1 unspecified) No previous CY. Most received CS (varying doses) 22 (2, 18, 2) All previously treated with CS, 11/22 previously treated with CY 6/11 with renal involvement, unspecified class Most refractory to CY 11 (0, 6, 2); 7/8 previously treated with CY
Treatment regimen
Main outcomes
4 weekly infusions of 375 mg m2+oral prednisolone (0.5 mg kg1 day1 for 10 weeks 500 mg 2 doses followed by 750 mg 2 doses; OR 1000 mg 2 doses total in combination with CY (two doses of 750 mg each) and high-dose steroids Dose escalation study (100, 375, and 375 mg m2 4 doses) with rituximab added to ongoing therapies
4 CR, 4 PR at 12 months followup Significant reductions in BILAG scores and anti-dsDNA titers; nonsignificant decreases in proteinuria at 6 months followup. One patient developed HACA Those who depleted B cells (11/ 17) had decreases in SLAM and dsDNA titers 6/18 developed high titer HACA
500–1000 mg rituximab given on days 1 and 15
Most patients had a reduction in proteinuria
4 weekly infusions 375 mg m2 with one dose of CY (500 mg)
Proteinuria declined from mean 4.6 g/24 h to 0.45 g/24 h at 12 month follow-up 3 patients developed HACA Mean age 13.9 years 6/8 had CR 450% had serious adverse events (cytopenias 6/11, septicemia 2/11, febrile neutropenia in 1/11)
2–12 doses 350–450 mg m2
CR, complete remission; CS, corticosteroids; CY, cyclophosphamide; HACA, human anti-chimeric antibodies; PR, partial remission; SLAM, systemic lupus activity measure.
Furthermore, CD22 modifies signaling through CD19/21 and CD45.47 CD22-deficient mice show an increase in calcium signaling in response to B-cell receptor ligation and have reduced numbers of mature B cells peripherally and in the bone marrow (suggesting a role in B-cell development). Furthermore, B-cell life span is reduced, apoptosis enhanced, and there is a predisposition to autoimmune disease.48 Thus CD22 is an attractive target for therapy in autoimmune disease not only because its expression is restricted to the surface of mature B cells, but also for its potential function in the pathogenesis of autoimmunity.47–49 Epratuzumab is a recombinant humanized monoclonal immunoglobulin G (IgG) antibody to the CD22 antigen on B cells. It has been shown to mediate antibody-dependent cellular cytotoxicity in vitro and, but unlike rituximab, mediates only partial B-cell depletion—a 35–40% reduction in circulating B lymphocytes is seen in patients with SLE.50 It is thought that epratuzumab modifies the function of B lymphocytes without killing them, but the precise mechanisms of action remain unclear.49 Phase I/II clinical trials of epratuzumab in patients with non-Hodgkin lymphoma have demonstrated safety, with adverse events largely limited to infusion-related reactions, and objective response in terms of decreased tumor burden, and reduction of circulating B cells.51 Epratuzumab has also been used with success in combination with rituximab in refractory lymphoma.52 An 264
initial open-label nonrandomized single-center study of 14 Caucasian SLE patients has demonstrated safety and efficacy. There were no patients with severe renal disease; four patients had mild/stable proteinuria. On average, there was a sustained 35% decrease in B-cell levels over 32 weeks of follow-up. Development of anti-humanized antibodies was not observed.50 A multicenter randomized placebo-controlled clinical trial in SLE is underway (ClinicalTrials.gov Identifier: NCT00383513). Pharmapheresis of anti dsDNA antibodies with abetimus
A novel strategy in the treatment of SLE is inhibition of the survival and activation of autoreactive B cells—the so-called induction of tolerance. As reviewed above, two distinct signals are necessary for the activation of T cells. The first signal is binding of antigen to the B-cell receptor; the second involves the interaction of receptor–ligand pairs on APCs (including B cells) and cognate T cells. In the absence of this second co-stimulatory signal, the B cell with affinity to the specific antigen undergoes apoptopsis or becomes anergic. A targeted strategy is to create a state of inactivation—anergy or apoptosis—in B cells with receptors that express affinity to dsDNA, thereby reducing titers of anti-dsDNA. Abetimus (LJP 394, riquent) consists of four dsDNA epitopes conjugated to a nonimmunogenic polyethylene glycol platform. It acts by cross-linking anti-dsDNA surface Kidney International (2008) 73, 261–268
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immunoglobulin receptor on B cells and triggering signal tranduction pathways that lead to B-cell anergy or apoptosis and reduced titers of anti-dsDNA titers in animal models of SLE.53,54 The safety and efficacy of abetimus has been evaluated in 13 controlled and uncontrolled trials, enrolling a total of over 800 patients (reviewed in Cardiel55) with no notable adverse events. A placebo-controlled trial of this agent has shown significant reductions in anti-dsDNA titers.56,57 In a 76 week double-blind, placebo-controlled trial of abetimus in 230 patients with LN (including patients with Classes III, IV, and V LN), anti-dsDNA titers were reduced and C3 levels increased; however time to renal flare and number of renal flares—while lower—were not significantly different from the placebo group. Subgroup analysis revealed that patients with high-affinity anti-dsDNA antibodies had a significantly improved treatment response, with 8% of the abetimus treatment group flaring in comparison to 22% of the placebo group.58 However, in the larger Phase III trial, which specifically enrolled patients with high-affinity antibodies, the benefit was much less impressive, with 12% of LJP 394-treated patients flaring, in comparison with 16% of placebo-treated patients.59 Abetimus is currently being reevaluated in LN patients in a multinational trial (ClinicalTrials.gov Identifier: NCT00089804). Inhibiting costimulatory molecule CD28:B7 interaction with abatacept and belatacept
Tolerance can also be induced by blockade of targets of costimulatory interactions between T cells and B cells. The CD28:B7 costimulatory interaction was the first to be elucidated,60 and is the most important antigen-independent signal driving T-cell activation. CD28 is a glycoprotein expressed on T cells; its’ cognate ligands on APCs are B71(CD80) and B7-2(CD86). Stimulation of this pathway occurs when naı¨ve T cells encounter an APC with the appropriate major histocompatibility complex Class II bound antigen, and results in T-lymphocyte proliferation and differentiation. Cytotoxic T-lymphocyte antigen (CTLA4) is expressed only on activated T cells and also interacts with B7. However, this interaction leads to inhibition of T-cell activation, constituting a negative feedback mechanism. A fusion protein consisting of cytotoxic T-lymphocyte antigen (CTLA4) combined with immunoglobulin (CTLA4Ig, abatacept) binds B7 with a higher affinity than CD28, thereby inhibiting the costimulatory pathway. Evidence for the importance of this pathway in autoimmune disease is suggested by the finding that (NZBxNZW)F1 lupus prone mice treated with CTLA4-Ig fusion protein had significantly suppressed anti-dsDNA titers, decreased incidence of proteinuria, and improved survival while maintaining B-lymphocyte numbers.61 In other studies using (NZBxNZW)F1 mice, animals simultaneously treated with CTLA4-Ig and antimouse CD15462 (another T-cell costimulatory ligand) or cyclophosphamide63 had slower disease progression and improved survival compared with mice not treated with Kidney International (2008) 73, 261–268
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CTLA4-Ig. Two formulations of CTLA4-Ig have been used in humans, abatacept, and belatacept. Abatacept has been used with success in the treatment of psoriasis and rheumatoid arthritis,64,65 and belatacept was found to be as efficacious as cyclosporine in the prevention of acute allograft rejection in a Phase II clinical trial.66 Based on these experiences, an open-label pilot trial of CTLA4-IgG4m in combination with cyclophosphamide in patients with SLE nephritis is underway.67,68 Inhibiting costimulatory molecule CD40:CD40 ligand (CD 154) interaction with BG9588 and IDEC 131
The interaction between CD40 on B-cells and T-cell CD40L (or CD154) is another important costimulatory signal for lymphocyte proliferations and activation.69 CD40 is a 48 kDa transmembrane glycoprotein found on the surface of B lymphocytes and is a member of the TNF-receptor family. CD154 is a 39 kDa transmembrane protein that is a member of the TNF superfamily found on activated T- and B lymphocytes. This interaction provides growth signals to B cells and influences cell-mediated immunity. CD40 signaling in the presence of appropriate cytokines results in B-cell proliferation and differentiation into immunoglobulinsecreting cells. CD154:CD40 interactions are typical of germinal center reactions, where cells show markers characteristic of activation, proliferation, and secretion.70 Blockade of this interaction ameliorates nephritis in lupus-prone (NZBxNZW)F1 mice.62,71 Evidence for the importance of this pathway in human SLE is suggested by the finding that remission of proliferative LN following B-cell depletion therapy is preceded by downregulation of the T-cell costimulatory molecule CD40L.39 IDEC-131 and BG9588 are humanized monoclonal antibodies to CD154/CD40L. Of interest, patients with Class IV proliferative LN, who were treated with BG9588, showed a shift in peripheral B-cells markers away from a pattern typical of intensive germinal center activity, suggesting that germinal center activity is an important feature of the propensity to produce autoantibodies and disease.70 In a small open-label study to establish safety and efficacy, 28 patients with active proliferative LN (mean 3.26 g day1 urinary protein excretion, creatinine clearance 114 ml per min per 1.73 m2) were treated with BG9588 at doses of 20 mg kg1 at biweekly intervals for the first three doses and at monthly intervals for four additional doses. There was improvement in titers of anti-dsDNA titers and approximately 50% reduction in proteinuria in response to treatment; however, the trial was terminated early because of the incidence of thromboembolic events in patients receiving the study drug—namely, two nonfatal myocardial infarctions,72 perhaps as a result of CD154 expression on activated platelets.73 Although IDEC-131 was found to be safe in a Phase I clinical trial,74 a Phase II, double-blind, placebo-controlled, multicenter study enrolling 85 patients with mild-to-moderate active SLE with a follow-up of 20 weeks demonstrated no improvement in outcomes over placebo (or increase in thromboembolic incidents).69 265
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Blockade of B-cell stimulatory cytokine BLyS by belimumab
An alternative approach to targeting B cells is to block cytokines that are required for B-cell function. A multitude of cytokines are overexpressed in autoimmune disease, and the development of cytokine depleting agents has naturally led to the exploration of their use in SLE.75,76 BLyS, also known as BAFF, is a 285 amino-acid member of the TNF ligand superfamily.77 It binds to three different receptors—BCMA, BAFFR, and TACI. It is essential for B-cell survival and development. Mice genetically deficient in BlyS/BAFF show reductions in mature B cells and immunoglobulin levels.78 Overexpression of BlyS/BAFF in transgenic mice, conversely, leads to B-cell expansion, hypergammaglobulinemia, and autoimmunity.79,80 Elevated BlyS levels have been documented in lupus-prone mice and in human SLE.81,82 Belimumab (LymphoStat-B) is a fully humanized monoclonal antibody against BlyS/BAFF, which can cause depletion of circulating B cells. Preliminary results from a Phase II clinical trial enrolling 449 SLE patients with moderate disease activity show improvements in disease activity and quality of life scores.83 Controlled clinical trials in SLE nephritis are warranted. TACI-Ig—an alternative method for blockade of BlyS—is also under development as a treatment for SLE.84
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B-cell-targeted therapies offer the possibility of treatments for SLE/LN that are effective and have improved toxicity profiles. Goals for new therapies of LN are: (1) prevention of relapse, (2) improved side effect profile, (3) treatment of refractory disease, and (4) prevention of the development of chronic interstitial fibrosis and progressive renal failure or end-stage renal disease. Despite the considerable promise shown by newer therapies, it is important to note that only three drugs are approved by the United States Food and Drug Administration for treatment of SLE—corticosteroids, hydroxychloroquine, and low-dose aspirin—and no new therapies have been approved in nearly 40 years.85 While clinical trials of several novel drugs are underway, clinicians and regulatory bodies must pay close attention to unusual adverse events, such as progressive multifocal leukoencephalopathy in SLE patients treated with rituximab, and life threatening complications with anti-CD28 monoclonal antibodies in healthy volunteers.86 On the other hand, LN is associated with considerable morbidity, and efficacious new treatments must be made available to patients as expeditiously as is reasonable. Treatment plans need to be individualized for each patient. Furthermore, the exact role of these agents in the ever-expanding arsenal of medications needs to be better defined; that is, are these medications appropriate for induction and maintenance treatments? Should they be used as first line therapies or should they be reserved for refractory disease? Further carefully conducted clinical trials are needed.
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