title: Short- and long-term effects of anti-CD20 treatment on B cell ontogeny in bone marrow of patients with rheumatoid arthritis.
abstract: BACKGROUND
  In the present study we evaluated changes in the B cell phenotype in peripheral blood and bone marrow (BM) of patients with rheumatoid arthritis (RA) following anti-CD20 treatment using rituximab.
  
  
  METHODS
  Blood and BM samples were obtained from 37 patients with RA prior to rituximab treatment. Ten of these patients were resampled 1 month following rituximab, 14 patients after 3 months and the remaining 13 patients were included in the long-term follow up. B cell populations were characterized by CD27/IgD/CD38/CD24 expression.
  
  
  RESULTS
  One and three months following rituximab BM retained up to 30% of B cells while circulation was totally depleted of B cells. Analysis of the remaining BM B cells showed prevalence of immature and/or transitional B cells (CD38++CD24++) and CD27+IgD- memory cells, while IgD+ cells were completely depleted. A significant reduction of CD27+ cells in BM and in circulation was observed long after rituximab treatment (mean 22 months), while levels of naive B cells in BM and in circulation were increased. The levels of rheumatoid factor decline after rituximab treatment but returned to baseline levels at the time of retreatment.
  
  
  CONCLUSIONS
  Anti-CD20 treatment achieves a depletion of IgD+ B cells shortly after the treatment. At the long term follow up, a reduction of CD27+ B cells was observed in blood and BM. The prolonged inability to up-regulate CD27 may inhibit the renewal of memory B cells. This reduction of CD27+ B cells does not prevent autoantibody production suggesting that mechanisms regulating the formation of auto reactive clones are not disrupted by rituximab.
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Guldhedsgatan 10A, Gothenburg, Sweden. maria.rehnberg@rheuma.gu.se
authors.forename: Maria
authors.initials: M
authors.lastname: Rehnberg
authors.forename: Sylvie
authors.initials: S
authors.lastname: Amu
authors.forename: Andrej
authors.initials: A
authors.lastname: Tarkowski
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
authors.forename: Mikael
authors.initials: M
authors.lastname: Brisslert
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD / Q000096:biosynthesis; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007072:Immunoglobulin D / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D000069283:Rituximab; D013995:Time; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D018951:Antigens, CD20; D018501:Antirheumatic Agents; D007072:Immunoglobulin D; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D000069283:Rituximab
references.citation: Exp Hematol. 2005 Apr;33(4):480-6
references.pmid: 15781339
references.citation: J Immunol. 2004 Jun 15;172(12):7694-702
references.pmid: 15187152
references.citation: J Immunother. 2005 May-Jun;28(3):212-9
references.pmid: 15838377
references.citation: Arthritis Rheum. 2000 Dec;43(12):2619-33
references.pmid: 11145019
references.citation: Blood. 1994 Jan 15;83(2):435-45
references.pmid: 7506951
references.citation: Scand J Immunol. 2007 Oct;66(4):476-83
references.pmid: 17850593
references.citation: J Immunol. 2005 Apr 1;174(7):4389-99
references.pmid: 15778404
references.citation: J Exp Med. 1994 Jul 1;180(1):329-39
references.pmid: 8006591
references.citation: J Immunol. 2005 Jan 15;174(2):817-26
references.pmid: 15634903
references.citation: Clin Immunol. 2007 Feb;122(2):139-45
references.pmid: 17008130
references.citation: Arthritis Rheum. 1999 Sep;42(9):1854-60
references.pmid: 10513799
references.citation: Ann Rheum Dis. 2006 Sep;65(9):1255-7
references.pmid: 16540545
references.citation: J Immunol. 1984 Aug;133(2):684-91
references.pmid: 6429242
references.citation: J Immunol. 1983 Oct;131(4):1754-61
references.pmid: 6413577
references.citation: Semin Immunol. 2008 Feb;20(1):67-82
references.pmid: 18258454
references.citation: Hum Antibodies. 2004;13(3):55-62
references.pmid: 15598985
references.citation: Transpl Immunol. 2003 Oct-Nov;12(1):19-28
references.pmid: 14551029
references.citation: Arthritis Rheum. 2007 May;56(5):1464-77
references.pmid: 17469105
references.citation: Leukemia. 1999 Mar;13(3):419-27
references.pmid: 10086733
references.citation: Rheumatology (Oxford). 2007 Jan;46(1):29-36
references.pmid: 16735454
references.citation: J Clin Invest. 2007 Jun;117(6):1558-65
references.pmid: 17510706
references.citation: Annu Rev Immunol. 2006;24:467-96
references.pmid: 16551256
references.citation: Clin Immunol. 2008 Apr;127(1):14-25
references.pmid: 18191619
references.citation: Blood. 2005 Jun 1;105(11):4390-8
references.pmid: 15701725
references.citation: J Immunol. 2001 Oct 1;167(7):3610-8
references.pmid: 11564773
references.citation: Ann Rheum Dis. 2009 Sep;68(9):1447-52
references.pmid: 18782791
references.citation: Scand J Immunol. 2007 Feb;65(2):182-91
references.pmid: 17257224
references.citation: Arthritis Rheum. 2003 Aug;48(8):2146-54
references.pmid: 12905467
references.citation: Ann Rheum Dis. 2008 Mar;67(3):402-8
references.pmid: 17644541
references.citation: Arthritis Rheum. 1988 Mar;31(3):315-24
references.pmid: 3358796
references.citation: Arthritis Rheum. 2008 Jun;58(6):1566-75
references.pmid: 18512772
references.citation: N Engl J Med. 2004 Jun 17;350(25):2572-81
references.pmid: 15201414
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):109-21
references.pmid: 6361139
references.citation: J Exp Med. 2004 Jun 21;199(12):1659-69
references.pmid: 15210744
references.citation: J Rheumatol. 1999 Mar;26(3):705-11
references.pmid: 10090187
references.citation: Arthritis Rheum. 2007 Dec;56(12):3909-18
references.pmid: 18050222
references.citation: J Immunol. 2001 Oct 15;167(8):4710-8
references.pmid: 11591802
references.citation: Ann Rheum Dis. 2008 Jul;67(7):917-25
references.pmid: 17965121
references.citation: Arthritis Rheum. 2007 Mar;56(3):772-8
references.pmid: 17328049
references.citation: Blood. 2001 Oct 15;98(8):2498-507
references.pmid: 11588048
references.citation: Arthritis Rheum. 2006 Sep;54(9):2793-806
references.pmid: 16947627
references.citation: Arthritis Rheum. 2006 May;54(5):1390-400
references.pmid: 16649186
references.citation: Cytometry A. 2004 Sep;61(1):69-75
references.pmid: 15351991
references.citation: Scand J Immunol. 2007 Jul;66(1):77-86
references.pmid: 17587349
references.citation: Arthritis Rheum. 2006 Aug;54(8):2377-86
references.pmid: 16869000
references.citation: J Immunol. 1990 Jan 15;144(2):638-41
references.pmid: 2153173
references.citation: Nat Rev Immunol. 2004 Aug;4(8):648-55
references.pmid: 15286731