Current Rheumatology Reports

, Volume 5, Issue 5, pp 350–356

B cell depletion therapy in systemic lupus erythematosus

  • Jennifer Anolik
  • Iñaki Sanz
  • R. John Looney
Article

Abstract

There is a growing body of experimental evidence that B lymphocytes play a central role in the pathogenesis of systemic lupus erythematosus (SLE). B cells are, by definition, the precursors of antibody-secreting cells, and thus are the source of pathogenic autoantibodies. However, recent data indicate that B cells are not merely the passive producers of immunoglobulins, but also play a central role in autoimmunity via nonconventional mechanisms, including autoantigen presentation and modulation of other immune cells. Thus, B lymphocyte depletion has recently emerged as a promising therapeutic approach to the treatment of autoimmune diseases, including SLE. Rituximab is a chimeric mouse-human monoclonal antibody against the B cell-specific antigen CD20, which selectively and profoundly depletes B lymphocytes and has been widely used to treat B cell lymphomas. Recent open-label studies indicate that rituximab is safe and may be efficacious in the treatment of SLE, and continued study with randomized clinical trials is justified.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Godfrey T, Khamashta M, Hughes G: Therapeutic advances in systemic lupus erythematosus. Curr Opin Rheumatol 1998, 10:435–441.PubMedCrossRefGoogle Scholar
  2. 2.
    Weisman M, Blustein H, Berner C: Reduction in circulating dsDNA antibody titer after adminstration of LJP 394. J Rheumatol 1997, 24:314–318.PubMedGoogle Scholar
  3. 3.
    Davis J, Tortoritis M, Rosenberg J: 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.PubMedGoogle Scholar
  4. 4.
    Shlomchik M, Craft JE, Mamula MJ: From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 2001, 1:147–153. A thorough review of abnormalities in the T and B cell compartments in lupus-prone mice is provided in the context of a model to explain the development and maintenance of autoimmunity in SLE. Emphasis is placed on self-reinforcing interactions of T and B cells that lead to the loss of self-tolerance to nuclear autoantigens. The hypothesis is put forth that simultaneous T and B cell directed therapies of SLE should be synergistic.PubMedCrossRefGoogle Scholar
  5. 5.
    Lipsky PE: Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol 2001, 2:764–766. An excellent review of B cell abnormalities in SLE, with a discussion of the multiple roles B cells play in the normal immune response and potential derangements in autoimmunity.PubMedCrossRefGoogle Scholar
  6. 6.
    Mohan C: Murine lupus genetics: lessons learned. Curr Opin Rheumatol 2001, 13:352–360.PubMedCrossRefGoogle Scholar
  7. 7.
    Izui S, McConahey P, Dixon F: Increased spontaneous polyclonal activation of B lymphocytes in mice with spontaneous autoimmune disease. J Immunol 1978, 121:2213.PubMedGoogle Scholar
  8. 8.
    Wofsky D, Ledbetter J, Hendler P, Seaman W: Treatment of murine lupus with monoclonal anti-T cell antibody. J Immunol 1985, 134:852–857.Google Scholar
  9. 9.
    Cerny A, Starobinski M, Hugin A, et al.: Treatment with high does of anti-IgM prevents, but with lower doses accelerates autoimmune disease in (NSWxBXSB)F1 hybrid mice. J Immunol 1987, 138:4222–4228.PubMedGoogle Scholar
  10. 10.
    Peng S, Madaio MP, Hughes DP, et al.: Murine lupus in the absence of T cells. J Immunol 1996, 156:4041–4049.PubMedGoogle Scholar
  11. 11.
    Shlomchik MJ, Madaio MP, Ni D, et al.: The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med 1994, 180:1295–1306.PubMedCrossRefGoogle Scholar
  12. 12.
    Chan OT, Hannum LG, Haberman AM, 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, 189:1639–1648. The authors use a novel approach to study the role of B cells in systemic autoimmunity by generating MRL/lpr lupus-prone mice that express a mutant transgene encoding surface IG that cannot be secreted. These mice have no circulating Ig, yet develop nephritis, indicating that B cells can play a pathogenic role in lupus independent of serum autoantibody—perhaps through antigen-presentation.PubMedCrossRefGoogle Scholar
  13. 13.
    Sobel E, Mohan C, Morel L, et al.: Genetic dissection of SLE pathogenesis: adoptive transfer of Sle1 mediates the loss of tolerance by bone marrow-derived B cells. J Immunol 1999, 162:2415–2421.PubMedGoogle Scholar
  14. 14.
    Mamula MJ, Fatenejad S, Craft J: B cells process and present lupus autoantigens that initiate autoimmune T cell responses. J Immunol 1994, 152:1453–1461.PubMedGoogle Scholar
  15. 15.
    Moulin V, Andris F, Thielemans K, et al.: B lymphocytes regulate dendritic cell (DC) function in vivo: increased interleukin 12 production by DCs from B cell deficient mice results in T helper cell type 1 deviation. J Exp Med 2000, 192:475–482.PubMedCrossRefGoogle Scholar
  16. 16.
    Linton PJ, Harbertson J, Bradley LM: A critical role for B cells in the development of memory CD4 cells. J Immunol 2000, 165:5558–5565.PubMedGoogle Scholar
  17. 17.
    Chan OT, Shlomchik MJ: Cutting edge: B cells promote CD8+ T cell activation in MRL-Fas(lpr) mice independently of MHC class I antigen presentation. J Immunol 2000, 164:1658–1662.PubMedGoogle Scholar
  18. 18.
    Klinman DM, Shirai A, Ishigatsubo Y, et al.: Quantitation of IgM- and IgG-secreting B cells in the peripheral blood of patients with systemic lupus erythematosus. Arthritis Rheum 1991, 34:1404–1410.PubMedCrossRefGoogle Scholar
  19. 19.
    Suzuki N, Sakane T: Induction of excessive B cell proliferation and differentiation by an in vitro stimulus in culture in human systemic lupus erythematosus. J Clin Invest 1989, 83:937–944.PubMedGoogle Scholar
  20. 20.
    Folzenlogen D, Hofer MF, Leung DY, et al.: Analysis of CD80 and CD86 expression on peripheral blood B lymphocytes reveals increased expression of CD86 in lupus patients. Clin Immunol Immunopathol 1997, 83:199–204.PubMedCrossRefGoogle Scholar
  21. 21.
    Liossis SN, Kovacs B, Dennis G, et al.: B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events. J Clin Invest 1996, 98:2549–2557. This report is the first to demonstrate a lupus-specific abnormality in B cell signal transduction in humans, with augmented calcium responses and protein tyrosine phosphorylation in response to B cell receptor crosslinking. This abnormality may underlie the B cell hyperactivity of lupus and be a defining pathogenic event in systemic autoimmunity.PubMedGoogle Scholar
  22. 22.
    Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK: Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 1996, 97:2063–2073.PubMedCrossRefGoogle Scholar
  23. 23.
    Higuchi T, Aiba Y, Nomura T, et al.: Cutting edge: ectopic expression of CD40L on B cells induces lupus-like autoimmune disease. J Immunol 2002, 168:9–12.PubMedGoogle Scholar
  24. 24.
    Daikh D, Finck B, Linsley P, 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.PubMedGoogle Scholar
  25. 25.
    Huang W, Sinha J, Newman J, et al.: The effect of anti-CD40 ligand antibody on B cells in human systemic lupus erythematosus. Arthritis Rheum 2002, 46:1554–1562.PubMedCrossRefGoogle Scholar
  26. 26.
    Arce E, Jackson DG, Gill MA, et al.: Increased frequency of pre-germinal center b cells and plasma cell precursors in the blood of children with systemic lupus erythematosus. J Immunol 2001, 167:2361–2369.PubMedGoogle Scholar
  27. 27.
    Odendahl M, Jacobi A, Hansen A, et al.: Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 2000, 165:5970–5979. In this study, it was found that patients with SLE have a marked peripheral naíve B cell lymphopenia and expansion of CD27 high plasmablasts. The latter CD20-negative population decreased with immunosuppressive therapy. These abnormalities in peripheral B cell homeostasis may variably reflect B cell activation, a disturbance in B cell trafficking, or cytokine dysregulation in SLE, but highlight the importance of B cells to the disease process.PubMedGoogle Scholar
  28. 28.
    Cappione A, Anolik J, Pugh-Bernard A, et al.: Defects in peripheral B cell tolerance in human SLE. Arthritis Rheum 2002, 46:S284.Google Scholar
  29. 29.
    Llorente L, Zou Y, Levy Y, et al.: Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 1995, 181:839–0.PubMedCrossRefGoogle Scholar
  30. 30.
    Bennett L, Palucka A, Arce E, et al.: Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 2003, 197:711–723.PubMedCrossRefGoogle Scholar
  31. 31.
    Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J:Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science 2001, 294:1540–1543. This study demonstrates that serum from pediatric patients with SLE can induce the maturation of monocytes into highly active antigenpresenting dendritic cells in an IFNá-dependent fashion (produced by plasmacytoid dendritic cells and other peripheral blood mononuclear cells). The authors postulate that unabated induction of dendritic cells by IFNá may drive the autoimmune process in SLE through presentation of autoantigens to T and B cells. Although the primary defect(s) in SLE needs further elucidation, this landmark study introduces another level of complexity to B cell regulation in autoimmunity.PubMedCrossRefGoogle Scholar
  32. 32.
    Reff ME, Carner K, Chambers KS, et al.: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994, 83:435–445.PubMedGoogle Scholar
  33. 33.
    Tedder TF, Engel P: CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today 1994, 15:450–454.PubMedCrossRefGoogle Scholar
  34. 34.
    Grillo-Lopez A, White C, Varns C, et al.: Overview of the clinical development of rituximab: first monoclonal antibody approved for the treatment of lymphoma. Semin Oncol 1999, 26:66–73.PubMedGoogle Scholar
  35. 35.
    McLaughlin P, Grillo-Lopez A, Link B: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998, 16:2825–2833.PubMedGoogle Scholar
  36. 36.
    Grillo-Lopez A: Rituximab: an insider’s historical perspective. Semin Oncol 2000, 27:9–16. An excellent review of the development of rituximab in the treatment of lymphoma and discussion of continued controversies in the field that have relevance for the use of this monoclonal antibody in autoimmune disease.PubMedGoogle Scholar
  37. 37.
    Clynes R, Towers T, Presta LG, Ravetch J: Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 2000, 6:443–446.PubMedCrossRefGoogle Scholar
  38. 38.
    Cartron G, Dacheux L, Salles G, et al.: Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgRIIIa. Blood 2002, 99:754–758.PubMedCrossRefGoogle Scholar
  39. 39.
    Kneitz C, Wilhelm M, Tony H: Effective B cell depletion with rituximab in the treatment of autoimmune diseases. Immunobiology 2002, 206:519–527.PubMedCrossRefGoogle Scholar
  40. 40.
    Gonzales-Stawinski G, Yu P, Love S, et al.: Hapten induced primary and memory humoral responses are inhibited by the infusion of anti-CD20 monoclonal antibody. Clin Immunol 2001, 98:175–179.CrossRefGoogle Scholar
  41. 41.
    van derKolk L, Baars J, Prins M, van Oers M: Rituximab treatment results in impaired secondary humoral immune responsiveness. Blood 2002, 100:2257–2259. One of the only reports on the effects of rituximab treatment on immune responses in lymphoma patients provides a rationale for the treatment of antibody-mediated autoimmune diseases.PubMedGoogle Scholar
  42. 42.
    Anolik JH, Campbell D, Ritchlin C, et al.: B lymphocyte depletion as a novel treatment for systemic lupus (SLE): phase I/II trial of rituximab in SLE. Arthritis Rheum 2001, 44:S387.Google Scholar
  43. 43.
    Anolik JH, Campbell D, Felgar R, et al.: The relationship of FcgRIIIa genotype to degree of B cell depletion by rituximab in the treatment of SLE. Arthritis Rheum 2003, 48:455–459. As part of a phase I/II dose-escalation trial of rituximab in the treatment of 18 patients with SLE, the authors demonstrate that B cell depletion is variable and dependent on serum rituximab levels and Fcγ RIIIa genotype. This is the first report in humans demonstrating a correlation between FcR genotype and B cell depletion in vivo and suggests the importance of ADCC or apoptosis induction via Fcγ RIIIa expressing effector cells in the mechanism of B cell depletion by rituximab.PubMedCrossRefGoogle Scholar
  44. 44.
    Anolik JH, Campbell D, Felgar R, et al.: B lymphocyte depletion in the treatment of systemic lupus: phase I/II trial of rituximab in SLE. Arthritis Rheum 2002, 46:S289.Google Scholar
  45. 45.
    Leandro M, Edwards J, Cambridge G, et al.: An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 2002, 46:2673–2677. A preliminary open study of rituximab (500 mg) in combination with intravenous cytoxan (750 mg) and high-dose daily oral steroids in six patients with active refractory SLE demonstrates safety and possible efficacy.PubMedCrossRefGoogle Scholar
  46. 46.
    Edwards J, Szczepanski L, Szechinski J, et al.: Efficacy and safety of rituximab, a B cell targeted chimeric monoclonal antibody: a randomized, placebo-controlled trial in patients with rheumatoid arthritis. Arthritis Rheum 2002, 46:S197. The only randomized, placebo-controlled trial of rituximab in autoimmune disease demonstrates significant efficacy in the treatment of rheumatoid arthritis at 6 months with rituximab alone or in combination with methotrexate or cytoxan. Although all groups received high-dose daily oral steroids, the addition of a short induction regimen with rituximab produced substantial clinical benefit compared with methrotrexate and steroids (P=0.059, 0.004, and 0.002 for ACR50 response with rituximab, rituximab/cytoxan, and rituximab/methotrexate, respectively, compared with methtrexate).CrossRefGoogle Scholar
  47. 47.
    Leandro M, Edwards J, Cambridge G: Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis 2002, 61:883–888.PubMedCrossRefGoogle Scholar
  48. 48.
    Stasi R, Pagano A, Stipa E, Amadori S: Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001, 98:952–957.PubMedCrossRefGoogle Scholar
  49. 49.
    Takada K, Bookbinder S, Furie R, et al.: A pilot study of rituximab therapy for refractory dermatomyositis. Arthritis Rheum 2002, 49:S489.Google Scholar
  50. 50.
    Quartier P, Brethon B, Philippet P, et al.: Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet 2001, 358:1511–1513.PubMedCrossRefGoogle Scholar
  51. 51.
    Levine T, Pestronk A: IgM antibody related polyneuropathies: B cell depletion chemotherapy using rituximab. Neurology 1999, 52:1701–1704.PubMedGoogle Scholar
  52. 52.
    Arzoo K, Sadeghi S, Liebman H: Treatment of refractory antibody mediated autoimmune disorders with an anti- CD20 monoclonal antibody (rituximab). Ann Rheum Dis 2002, 61:922–924.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2003

Authors and Affiliations

  • Jennifer Anolik
    • 1
  • Iñaki Sanz
  • R. John Looney
  1. 1.Department of Medicine: Immunology and RheumatologyUniversity of Rochester School of MedicineRochesterUSA

Personalised recommendations