title: Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity.
abstract: BACKGROUND
  B-cell depletion has become a common treatment strategy in anti-TNF-refractory rheumatoid arthritis (RA). Although the exact mechanism of how B-cell depletion leads to clinical amelioration in RA remains to be elucidated, repetitive treatment with B-cell-depleting agents leading to long-term B-cell depletion has been reported to be beneficial. The latter has led to the hypothesis that the beneficial effects of B-cell depletion might act through their influence on pathogenic autoreactive plasma cells.
  
  
  METHODS
  In this study, we investigated the effects of a fixed retreatment regimen with anti-CD20 mAbs on the humoral (auto)immune system in a cohort of therapy-refractory RA patients.
  
  
  RESULTS
  Fixed retreatment led to long-term B-cell depletion in peripheral blood, bone marrow and, to a lesser extent, synovium. Also, pathologic autoantibody secretion (that is, anticitrullinated peptide antibodies (ACPAs)) was more profoundly affected by long-term depletion than by physiological protective antibody secretion (that is, against measles, mumps and rubella). This was further illustrated by a significantly shorter estimated life span of ACPA-IgG secretion compared to total IgG secretion as well as protective antibody secretion.
  
  
  CONCLUSIONS
  By studying plasma cell function during an extensive 2-year period of B-cell depletion, autoantibody secretion was significantly shorter-lived than physiologically protective antibody secretion. This suggests that the longevity of autoreactive plasma cells is different from protective long-lived plasma cells and might indicate a therapeutic window for therapies that target plasma cells.
authors.affiliation: Department of Rheumatology, C1-R, Leiden University Medical Center, PO Box 9600, NL-2300 RC Leiden, The Netherlands. y.k.o.teng@lumc.nl
authors.forename: Y K Onno
authors.initials: YK
authors.lastname: Teng
authors.forename: Gillian
authors.initials: G
authors.lastname: Wheater
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: Hogan
authors.forename: Philip
authors.initials: P
authors.lastname: Stocks
authors.forename: E W Nivine
authors.initials: EW
authors.lastname: Levarht
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Jacob M
authors.initials: JM
authors.lastname: van Laar
mesh_terms: D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000096:biosynthesis / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000069283:Rituximab; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D000069283:Rituximab