Anti-CD20Monoclonal Antibody in Rheumatoid Arthritis and Systemic Lupus Erythematosus

  • F. Goldblatt
  • D. A. Isenberg
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 181)

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are both chronic autoimmune rheumatic diseases. In the last few years, evolution in the understanding of RA and SLE pathogenesis and underlying molecular mechanisms has resulted in development and availability of novel therapies. In particular, the recent acknowledgement of a more significant role for B cells in the pathogenesis of RA, in contrast to the view that it was predominantly a T cell disorder, provided rationale for trials of B cell depletion therapy with the chimeric anti-CD20 monoclonal antibody rituximab. The efficacy and favourable safety profile of rituximab have resulted in the recent approval by the European Medicines Agency for its usage in patients with RA unresponsive to conventional therapies. The salient features from the pivotal open and randomised controlled trials are reviewed in this chapter. Given the recognition of B cell dysfunction as central to SLE pathogenesis, the use of anti-CD20 antibody therapy for this patient group has also been established. Results of the open trials have been encouraging, particularly in patients not responding to usual therapies, and a randomised controlled trial is underway.


Rheumatoid Arthritis Systemic Lupus Erythematosus Lupus Nephritis Cell Depletion British Isle Lupus Assessment Group 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Albert DA, Khan SR, Stansberry JS, Tsai D, Kamoun M et al. 2003 A phase I trial of rituximab (anti-CD20) for treatment of systemic lupus. Arthritis Rheum 48:S3659Google Scholar
  2. Anolik JH 2002 B lymphocyte depletion in the treatment of systemic lupus erythematosus. Arthritis Rheum 46:S717Google Scholar
  3. Anolik JH, Campbell D, Felgar R et al. 2003 The relationship of FcgammaRIIIA genotype to degree of B cell depletion by rituximab in the treatment for systemic lupus erythematosus. Arthritis Rheum 48:455-459CrossRefPubMedGoogle Scholar
  4. Anolik JH, Barnard J, Cappione A, Pugh-Bernard AE, Felgar RE, Looney RJ, Sanz I 2004 Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum 50:3580-3590CrossRefPubMedGoogle Scholar
  5. Buyon JP, Clancy RM 2003 Neonatal lupus: Review of proposed pathogenesis and clinical data from the US-based research registry for neonatal lupus. Autoimmunity 36:41-50CrossRefPubMedGoogle Scholar
  6. Cambridge G, Leandro MJ, Edwards JCW, Ehrenstein MR, Salden M, Bodman-Smith M, Webster ADB 2003 Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 48:2146-2154CrossRefPubMedGoogle Scholar
  7. Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ 1999 A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med 189:1639-1648CrossRefPubMedGoogle Scholar
  8. Chan OT, Madaio MP, Shlomchik MJ 1999 The central and multiple roles of B cells in lupus pathogenesis. Immunol Rev 169:107-121CrossRefPubMedGoogle Scholar
  9. Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, Keystone EC, Loveless JE, Burmester GR, Cravets MW, Hessey EW, Shaw T, Totoritis MC 2006 Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54:2793-2806CrossRefPubMedGoogle Scholar
  10. Davas EM, Tsirogianni A, Kappou I, Karamitsos D, Economidou I, Dantis PC 1999 Serum IL-6, TNFalpha, p55 srTNFalpha, p75srTNFalpha, srIL-2alpha levels and disease activity in systemic lupus erythematosus. Clin Rheumatol 18:17-22CrossRefPubMedGoogle Scholar
  11. De Vita S, Zaja F, Sacco S et al. 2002 Efficacy of selelctive B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenic role of B cells. Arthritis Rheum 46:2029-2033CrossRefPubMedGoogle Scholar
  12. Dorner T, Kaufmann J, Wegener WA, Teoh N, Goldenberg DM, Burmester GR 2006 Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus. Arthritis Res Ther 8:R76CrossRefGoogle Scholar
  13. Edwards JCW, Cambridge G, Abrahams VM 1999 Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology 97:1868-1896CrossRefGoogle Scholar
  14. Edwards JCW, Cambridge G 2001 Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology 40:205-211CrossRefPubMedGoogle Scholar
  15. Edwards JCW, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T 2004 Efficacy of B-Cell-targeted therapy with rituximab in patients with rheumatoid arthritis. NEJM 350:2572-2581CrossRefPubMedGoogle Scholar
  16. Edwards JCW, Leandro MJ, Cambridge G 2005 Repeated B lymphocyte depletion therapy in rheumatoid arthritis. Arthritis Rheum 52:S13SGoogle Scholar
  17. Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh AM, Racewicz AJ, van Vollenhoven RF, Li NF, Agarwal S, Hessey EW, Shaw TM 2006 The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment. Arthritis Rheum 54:1390-1400CrossRefPubMedGoogle Scholar
  18. Emilie D, Mariette X 2001 Interleukin 10: A new therapeutic target in systemic lupus erythematosus? Joint Bone Spine 68:4-5CrossRefPubMedGoogle Scholar
  19. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Lightfoot RJ, Paulus H, Strand V et al. 1995 Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 38:727-735CrossRefPubMedGoogle Scholar
  20. Furie R 2003 Safety, pharmacokinetic and pharmacodynamic results of a phase I single and double dose-escalation study of LymphoStat-B (human monoclonal antibody to BLYs) in SLE patients. Arthritis Rheum 48:S377Google Scholar
  21. Hagelberg S, Lee Y, Bargman J et al. 2002 Longterm followup of childhood lupus nephritis. J Rheumatol 29:2635-2642PubMedGoogle Scholar
  22. Hay EM, Bacon PA, Gordon C et al. 1993 The BILAG index: A reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. Q J Med 86:447-458PubMedGoogle Scholar
  23. Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR 1998 Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41:1241-1250CrossRefPubMedGoogle Scholar
  24. Houssiau FA, Lefebvre C, Van den Berghe M, Lambert M, Devogelaer JP, Renauld JC 1995 Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activity. Lupus 4:393-395CrossRefPubMedGoogle Scholar
  25. Keystone EC 2005 B cells in rheumatoid arthritis: From hypothesis to the clinic. Rheumatology 44:ii8-ii12CrossRefPubMedGoogle Scholar
  26. Kneitz C, Wilhelm M, Tony HP 2004 Improvement of refractory rheumatoid arthritis after depletion of B cells. Scand J Rheumatol 33:82-86CrossRefPubMedGoogle Scholar
  27. Leandro MJ, Edwards JCW, Cambridge G 2002a Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocte depletion. Ann Rheum Dis 61:883-888CrossRefGoogle Scholar
  28. Leandro MJ, Edwards JCW, Cambridge G, Ehrenstein MR, Isenberg DA 2002b An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 46:2673-2677CrossRefGoogle Scholar
  29. Leandro MJ, Ehrenstein MR, Edwards JC, Manson J, Cambridge G, Isenberg DA 2003 Treatment of refractory lupus nephritis with B lymphocyte depletion. Arthritis Rheum 48:S924Google Scholar
  30. Leandro MJ, Cambridge G, Edwards JCW, Ehrenstein MR, Isenberg DA 2005 B-cell depletion in the treatment of patients with systemic lupus erythematosus: A longitudinal analysis of 24 patients. Rheumatology 44:1542-1545CrossRefPubMedGoogle Scholar
  31. Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JCW 2006 Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 54:613-620CrossRefPubMedGoogle Scholar
  32. Liu TF, Jones BM 1998 Impaired production of IL-12 in systemic lupus erythematosus. I. Excessive production of IL-10 suppresses production of IL-12 by monocytes. Cytokine 10:140-147CrossRefPubMedGoogle Scholar
  33. Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ, Sloand JA, Rosenblatt J, Sanz I 2004 B cell depletion as a novel treatment for systemic lupus erythematosus. Arthritis Rheum 50:2580-2589CrossRefPubMedGoogle Scholar
  34. Maloney DG, Smith B, Rose A 2002 Rituximab: Mechanism of action and resistance. Semin Oncol 29:2-9CrossRefPubMedGoogle Scholar
  35. Mannik M, Nardella FA 1985 IgG rheumatoid factors and self-association of these antibodies. Clin Rheum Dis 11:551-572PubMedGoogle Scholar
  36. McKay J, Chwalinska-Sadowska H, Boling E et al. 2005 Belimumab (BmAb), a fully human monoclonal antibody to B-lymphocyte stimulator (BLys), combined with standard of care reduces the signs and symptoms of rheumatoid arthritis in a heterogenous subject population. Arthritis Rheum 52:S710CrossRefGoogle Scholar
  37. Min DJ, Cho ML, Cho CS et al. 2001 Decreased production of interleukin-12 and interferongamma is associated with renal involvement in systemic lupus erythematosus. Scand J Rheumatol 30:159-163CrossRefPubMedGoogle Scholar
  38. Ng KP, Leandro MJ, Edwards JCW, Ehrenstein MR, Cambridge G, Isenberg DA 2006 Repeated B cell depletion in treatment of refractory systemic lupus erythematosus. Ann Rheum Dis 65:942-945CrossRefPubMedGoogle Scholar
  39. Panayi GS 2005 B cells: A fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology 44:ii3-ii7CrossRefPubMedGoogle Scholar
  40. Press OW, Appelbaum F, Ledbetter JA et al. 1987 Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas. Blood 69:584-591PubMedGoogle Scholar
  41. Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL 1995 Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38:44-48CrossRefPubMedGoogle Scholar
  42. Rahman A, Giles I, Haley J, Isenberg D 2002 Systematic analysis of sequences of anti-DNA antibodies - relevance to theories of origin and pathogenicity. Lupus 11:807-823CrossRefPubMedGoogle Scholar
  43. Sfikakis PP, Boletis JN, Lionaki S, Vigklis V, Fragiadaki KG, Iniotaki A et al. 2005 Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40ligans: An open label trial. Arthritis Rheum 52: 501-513CrossRefPubMedGoogle Scholar
  44. Specks U, Fervenza FC, McDonald TJ, Hogan MC 2001 Response of Wegener’s granulomatosis to anti-CD20 chimeric monoclonal antibody therapy. Arthritis Rheum 44:2836-2840CrossRefPubMedGoogle Scholar
  45. Stasi R, Pagano A, Stipa E, Amadori S 2001 Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopaenic purpura. Blood 98:952-957CrossRefPubMedGoogle Scholar
  46. Tahir H, Rohrer J, Bhatia A, Wegener WA, Isenberg DA 2005 Humanized anti-CD20 monoclonal antibody in the treatment of severe resistant systemic lupus erythematosusin a patient with antibodies against rituximab. Rheumatology 44:561-562CrossRefPubMedGoogle Scholar
  47. Takemura S, Klimiuk PA, Braun A, Goronzy JJ, Weyand CM 2001 T cell activation in rheumatoid synovium is B cell dependent. J Immunol 167:4710-4718PubMedGoogle Scholar
  48. Taylor PR, Carugati A, Fadok VA, Cook HT, Andrews M, Carroll MC, Savill JS, Henson PM, Botto M, Walport MJ 2000 A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 192:359-366CrossRefPubMedGoogle Scholar
  49. Tokano Y, Morimoto S, Kaneko H et al. 1999 Levels of IL-12 in the sera of patients with systemic lupus erythematosus (SLE) - relation to Th1- and Th2-derived cytokines. Clin Exp Immunol 16:169-173CrossRefGoogle Scholar
  50. Tokunaga M, Fujii K, Saito K, Nakayamada S, Tsujimura S, Nawata M et al. 2005 Downregulation of CD40 and CD80 on B cells in patients with life-threatening systemic lupus erythematosus after successful treatment with rituximab. Rheumatology 44:176-182CrossRefPubMedGoogle Scholar
  51. Vigna-Perez M, Hernandez-Castro B, Paredes-Saharopulos O, Portales-Perez D, Baranda L, Abud-Mendoza C, Gonzalez-Amaro R 2006 Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: A pilot study. Arthritis Res Ther 8:R83CrossRefPubMedGoogle Scholar
  52. Weng WK, Levy R 2003 Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Onc 21:3940-3947CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • F. Goldblatt
    • 1
  • D. A. Isenberg
    • 1
  1. 1.Centre for Rheumatology, Department of MedicineUniversity College London HospitalLondonUK

Personalised recommendations