B lymphocytes and lupus nephritis: New insights into pathogenesis and targeted therapies
2007; Elsevier BV; Volume: 73; Issue: 3 Linguagem: Inglês
10.1038/sj.ki.5002663
ISSN1523-1755
AutoresPremila Bhat, Jai Radhakrishnan,
Tópico(s)Monoclonal and Polyclonal Antibodies Research
ResumoLupus 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. 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. 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.Bernatsky S. Boivin J.F. Joseph L. et al.Mortality in systemic lupus erythematosus.Arthritis Rheum. 2006; 54: 2550-2557Crossref PubMed Scopus (719) Google Scholar 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.Fiehn C. Hajjar Y. Mueller K. et al.Improved clinical outcome of lupus nephritis during the past decade: importance of early diagnosis and treatment.Ann Rheum Dis. 2003; 62: 435-439Crossref PubMed Scopus (130) Google Scholar, 3.Korbet S.M. Lewis E.J. Schwartz M.M. et al.Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group.Am J Kidney Dis. 2000; 35: 904-914Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 4.Uramoto K.M. Michet Jr, C.J. Thumboo J. et al.Trends in the incidence and mortality of systemic lupus erythematosus, 1950–1992.Arthritis Rheum. 1999; 42: 46-50Crossref PubMed Scopus (367) Google Scholar up to 25% of patients fail to respond to this treatment.2.Fiehn C. Hajjar Y. Mueller K. et al.Improved clinical outcome of lupus nephritis during the past decade: importance of early diagnosis and treatment.Ann Rheum Dis. 2003; 62: 435-439Crossref PubMed Scopus (130) Google Scholar, 3.Korbet S.M. Lewis E.J. Schwartz M.M. et al.Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group.Am J Kidney Dis. 2000; 35: 904-914Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 5.Illei G.G. Austin H.A. Crane M. et al.Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis.Ann Intern Med. 2001; 135: 248-257Crossref PubMed Scopus (399) Google Scholar Furthermore, these therapies are limited by the high incidence of serious side effects including premature gonadal failure5.Illei G.G. Austin H.A. Crane M. et al.Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis.Ann Intern Med. 2001; 135: 248-257Crossref PubMed Scopus (399) Google Scholar,6.Mok C.C. Lau C.S. Wong R.W. Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy.Arthritis Rheum. 1998; 41: 831-837Crossref PubMed Scopus (213) Google Scholar and malignancy.7.Travis L.B. Curtis R.E. Glimelius B. et al.Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma.J Natl Cancer Inst. 1995; 87: 524-530Crossref PubMed Scopus (275) Google Scholar 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.Ginzler E.M. Dooley M.A. Aranow C. et al.Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.N Engl J Med. 2005; 353: 2219-2228Crossref PubMed Scopus (829) Google Scholar 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.Waldman M. Madaio M.P. Pathogenic autoantibodies in lupus nephritis.Lupus. 2005; 14: 19-24Crossref PubMed Scopus (115) Google Scholar, 10.Waldman M. Appel G.B. Update on the treatment of lupus nephritis.Kidney Int. 2006; 70: 1403-1412Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 11.Jacobi A.M. Diamond B. Balancing diversity and tolerance: lessons from patients with systemic lupus erythematosus.J Exp Med. 2005; 202: 341-344Crossref PubMed Scopus (47) Google Scholar, 12.Lipsky P.E. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity.Nat Immunol. 2001; 2: 764-766Crossref PubMed Scopus (461) Google Scholar, 13.Browning J.L. B cells move to centre stage: novel opportunities for autoimmune disease treatment.Nat Rev Drug Discov. 2006; 5: 564-576Crossref PubMed Scopus (235) Google Scholar 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).Table 1New and evolving therapies for lupus nephritisNew and evolving therapies for lupus nephritisB-cell depletion Rituximab EpratuzumabPharmapheresis of antibodies to dsDNA AbetimusBlockade of T-cell costimulation Abatacept, Belatacept BG9588, IDEC-131Blockade of B-cell stimulation Belimumab Open table in a new tab 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 due to anergy or apoptosis, and 'active tolerance' mediated by CD4+ regulatory T cells, which suppress activation of the immune system and prevent pathological self-reactivity.14.Kronenberg M. Rudensky A. Regulation of immunity by self-reactive T cells.Nature. 2005; 435: 598-604Crossref PubMed Scopus (248) Google Scholar,15.Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.Annu Rev Immunol. 2004; 22: 531-562Crossref PubMed Scopus (2798) Google Scholar B-cell activation, on the other hand, is triggered by antigen, requires a second signal from a cognate CD4+ T cell that has the same specificity, and is facilitated by secretion of cytokines such as interferon-γ and interleukin-4.16.Lund F.E. Garvy B.A. Randall T.D. et al.Regulatory roles for cytokine-producing B cells in infection and autoimmune disease.Curr Dir Autoimmun. 2005; 8: 25-54Crossref PubMed Google Scholar These events drive the naïve 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.Browning J.L. B cells move to centre stage: novel opportunities for autoimmune disease treatment.Nat Rev Drug Discov. 2006; 5: 564-576Crossref PubMed Scopus (235) Google Scholar 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.Browning J.L. B cells move to centre stage: novel opportunities for autoimmune disease treatment.Nat Rev Drug Discov. 2006; 5: 564-576Crossref PubMed Scopus (235) Google Scholar,17.Shlomchik M.J. Craft J.E. Mamula M.J. From T to B and back again: positive feedback in systemic autoimmune disease.Nat Rev Immunol. 2001; 1: 147-153Crossref PubMed Scopus (448) Google Scholar 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 antibody-independent 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.Chan O.T. Hannum L.G. Haberman A.M. et al.A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus.J Exp Med. 1999; 189: 1639-1648Crossref PubMed Scopus (572) Google Scholar yet B-cell-deficient MRL lpr/lpr mice did not.19.Shlomchik M.J. Madaio M.P. Ni D. et al.The role of B cells in lpr/lpr-induced autoimmunity.J Exp Med. 1994; 180: 1295-1306Crossref PubMed Scopus (308) Google Scholar 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+ 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)-α, and interleukin-6, all of which are produced in high levels in SLE, and BlyS/BAFF (B-lymphocyte stimulator/B-cell activating factor; a TNF-family cytokine that promotes B-cell maturation and survival and plasma cell differentiation).20.Martin F. Chan A.C. B cell immunobiology in disease: evolving concepts from the clinic.Annu Rev Immunol. 2006; 24: 467-496Crossref PubMed Scopus (276) Google Scholar 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.Chan O.T. Hannum L.G. Haberman A.M. et al.A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus.J Exp Med. 1999; 189: 1639-1648Crossref PubMed Scopus (572) Google Scholar,21.O'Neill S.K. Shlomchik M.J. Glant T.T. et al.Antigen-specific B cells are required as APCs and autoantibody-producing cells for induction of severe autoimmune arthritis.J Immunol. 2005; 174: 3781-3788Crossref PubMed Scopus (149) Google Scholar 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. 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 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.Bubien J.K. Zhou L.J. Bell P.D. et al.Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes.J Cell Biol. 1993; 121: 1121-1132Crossref PubMed Scopus (274) Google Scholar 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.Plosker G.L. Figgitt D.P. Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.Drugs. 2003; 63: 803-843Crossref PubMed Scopus (379) Google ScholarIn vitro B-cell depletion by rituximab occurs through antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity, or apoptosis.13.Browning J.L. B cells move to centre stage: novel opportunities for autoimmune disease treatment.Nat Rev Drug Discov. 2006; 5: 564-576Crossref PubMed Scopus (235) Google Scholar 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.Anolik J.H. Campbell D. Felgar R.E. et al.The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus.Arthritis Rheum. 2003; 48: 455-459Crossref PubMed Scopus (388) Google Scholar,25.Dall'Ozzo S. Tartas S. Paintaud G. et al.Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration–effect relationship.Cancer Res. 2004; 64: 4664-4669Crossref PubMed Scopus (352) Google Scholar Of interest, CD20 null mice have no obvious phenotype, and have normal B-cell responses;26.O'Keefe T.L. Williams G.T. Davies S.L. et al.Mice carrying a CD20 gene disruption.Immunogenetics. 1998; 48: 125-132Crossref PubMed Scopus (106) Google Scholar thus the function of CD20 remains unclear. Rituximab was first used successfully in the treatment of B-cell malignancies.23.Plosker G.L. Figgitt D.P. Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.Drugs. 2003; 63: 803-843Crossref PubMed Scopus (379) Google Scholar, 27.Davis T.A. Grillo-Lopez A.J. White C.A. et al.Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment.J Clin Oncol. 2000; 18: 3135-3143Crossref PubMed Scopus (627) Google Scholar, 28.Huhn D. von Schilling C. Wilhelm M. et al.Rituximab therapy of patients with B-cell chronic lymphocytic leukemia.Blood. 2001; 98: 1326-1331Crossref PubMed Scopus (316) Google Scholar The most commonly used dosing regimen, 375 mg m−2 intravenous infusion given weekly for a total of 4 weeks, is based on dosing in clinical trials in non-Hodgkin's lymphoma;29.Berinstein N.L. Grillo-Lopez A.J. White C.A. 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: 995-1001Crossref PubMed Scopus (474) Google Scholar however, an alternative regimen—1000 mg given twice in a 2-week interval—has been used with success in rheumatoid arthritis.30.Edwards J.C. 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: 2572-2581Crossref PubMed Scopus (2059) Google ScholarT1/2 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.Plosker G.L. Figgitt D.P. Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.Drugs. 2003; 63: 803-843Crossref PubMed Scopus (379) Google Scholar,31.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: 527-534Crossref PubMed Scopus (142) Google Scholar In oncologic protocols, patients have been re-dosed 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 μl−1—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.Plosker G.L. Figgitt D.P. Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.Drugs. 2003; 63: 803-843Crossref PubMed Scopus (379) Google Scholar 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.Cambridge G. Leandro M.J. Edwards J.C. et al.Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis.Arthritis Rheum. 2003; 48: 2146-2154Crossref PubMed Scopus (389) Google Scholar 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 m−2), she remained disease-free for 7 months.33.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: 465-467Crossref PubMed Google Scholar 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 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.Anolik J.H. Campbell D. Felgar R.E. et al.The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus.Arthritis Rheum. 2003; 48: 455-459Crossref PubMed Scopus (388) Google Scholar, 34.Looney R.J. Anolik J.H. 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: 2580-2589Crossref PubMed Scopus (666) Google Scholar, 35.Leandro M.J. Cambridge G. Edwards J.C. et al.B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients.Rheumatology (Oxford). 2005; 44: 1542-1545Crossref PubMed Scopus (328) Google Scholar, 36.Leandro M.J. Edwards J.C. Cambridge G. et al.An open study of B lymphocyte depletion in systemic lupus erythematosus.Arthritis Rheum. 2002; 46: 2673-2677Crossref PubMed Scopus (521) Google Scholar, 37.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: R83Crossref PubMed Scopus (252) Google Scholar, 38.Cambridge G. Leandro M.J. Teodorescu M. et al.B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles.Arthritis Rheum. 2006; 54: 3612-3622Crossref PubMed Scopus (180) Google Scholar, 39.Sfikakis P.P. Boletis J.N. Lionaki S. et al.Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial.Arthritis Rheum. 2005; 52: 501-513Crossref PubMed Scopus (369) Google Scholar, 40.Anolik J.H. Barnard J. Cappione A. et al.Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus.Arthritis Rheum. 2004; 50: 3580-3590Crossref PubMed Scopus (373) Google Scholar, 41.Marks S.D. Patey S. Brogan P.A. et al.B lymphocyte depletion therapy in children with refractory systemic lupus erythematosus.Arthritis Rheum. 2005; 52: 3168-3174Crossref PubMed Scopus (140) Google Scholar, 42.Smith K.G. Jones R.B. Burns S.M. et al.Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: remission, relapse, and re-treatment.Arthritis Rheum. 2006; 54: 2970-2982Crossref PubMed Scopus (331) Google Scholar 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 anti-chimeric antibodies (HACA), proteinuria, and genetic polymorphisms of FcR(gamma)IIIA leading to a phenotype with low affinity to rituximab.24.Anolik J.H. Campbell D. Felgar R.E. et al.The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus.Arthritis Rheum. 2003; 48: 455-459Crossref PubMed Scopus (388) Google Scholar, 34.Looney R.J. Anolik J.H. 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: 2580-2589Crossref PubMed Scopus (666) Google Scholar, 43.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: 754-758Crossref PubMed Scopus (1588) Google Scholar 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.Sfikakis P.P. Boletis J.N. Lionaki S. et al.Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial.Arthritis Rheum. 2005; 52: 501-513Crossref PubMed Scopus (369) Google Scholar,40.Anolik J.H. Barnard J. Cappione A. et al.Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus.Arthritis Rheum. 2004; 50: 3580-3590Crossref PubMed Scopus (373) Google Scholar A multicenter randomized placebo-controlled trial of rituximab in addition to MMF in proliferative LN is currently underway (ClinicalTrials.gov Identifier: NCT00282347).Table 2Trials of rituximab in patients with SLE and LNTrialn (Classes III, IV,V); previous treatmentTreatment regimenMain outcomesSfikakis et al., Greece34.Looney R.J. Anolik J.H. 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: 2580-2589Crossref PubMed Scopus (666) Google Scholar10 (4, 6, 0) All refractory to CS, 5/10 refractory to CY4 weekly infusions of 375 mg m−2+oral prednisolone (0.5 mg kg−1 day−1 for 10 weeks4 CR, 4 PR at 12 months follow-upLeandro et al., at University College in London30.Edwards J.C. 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: 2572-2581Crossref PubMed Scopus (2059) Google Scholar,31.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: 527-534Crossref PubMed Scopus (142) Google Scholar24 (0, 16, 1) All refractory to CS and CY500 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 steroidsSignificant reductions in BILAG scores and anti-dsDNA titers; nonsignificant decreases in proteinuria at 6 months follow-up. One patient developed HACALooney et al. at University of Rochester29.Berinstein N.L. Grillo-Lopez A.J. White C.A. 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: 995-1001Crossref PubMed Scopus (474) Google Scholar18 (3.3.0; 1 unspecified) No previous CY. Most received CS (varying doses)Dose escalation study (100, 375, and 375 mg m−2 × 4 doses) with rituximab added to ongoing therapiesThose who depleted B cells (11/17) had decreases in SLAM and dsDNA titers 6/18 developed high titer HACAVigna-Perez et al., Mexico32.Cambridge G. Leandro M.J. Edwards J.C. et al.Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis.Arthritis Rheum. 2003; 48: 2146-2154Crossref PubMed Scopus (389) Google Scholar22 (2, 18, 2) All previously treated with CS, 11/22 previously treated with CY500–1000 mg rituximab given on days 1 and 15Most patients had a reduction in proteinuriaSmith et al., Cambridge, UK37.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: R83Crossref PubMed Scopus (252) Google Scholar6/11 with renal involvement, unspecified class Most refractory to CY4 weekly infusions 375 mg m−2 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 HACAWillems et al., France40.Anolik J.H. Barnard J. Cappione A. et al.Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus.Arthritis Rheum. 2004; 50: 3580-3590Crossref PubMed Scopus (373) Google Scholar11 (0, 6, 2); 7/8 previously
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