title: ZAP-70+ B cell subset influences response to B cell depletion therapy and early repopulation in rheumatoid arthritis.
abstract: OBJECTIVE
  To define the role of ZAP-70+ B cells (CD19+/ZAP-70+) as a biomarker of response to B cell depletion therapy (BCDT), their relationship with clinical outcome, and their behavior during repopulation of peripheral blood in patients with rheumatoid arthritis (RA).
  
  
  METHODS
  Thirty-one patients with RA underwent BCDT and were followed for 12 months. Disease activity was assessed with the European League Against Rheumatism (EULAR) criteria. Cytofluorimetric analysis of peripheral blood B cell subsets at baseline and at 6- and 12-month intervals after BCDT was performed using surface markers (CD45, CD3, CD56, CD19, IgD, CD38, CD27) and intracellular ZAP-70.
  
  
  RESULTS
  A moderate/good EULAR response was achieved in 66.6% of the RA cohort. The baseline percentage of CD19+/ZAP-70+ cells was lower in good responder patients (1.8% ± 1.7%) compared to poor responders (5.6% ± 4.9%; p = 0.02). A decrease of plasmablasts (IgD-CD27+CD38+) and pre-switch memory (IgD+CD27+) B cells occurred after BCDT. Recovery of B cells in peripheral blood after the first course of BCDT was characterized by the reappearance of B cell subtypes that showed a naive, activated phenotype, coupled with a decrease in memory cells. B cells carrying intracytoplasmic ZAP-70 increased significantly from the baseline value of 4.4% ± 4.5% to 12.4% ± 9.2% (p = 0.001) at the 6-month and to 9.4% ± 6.4% (p = 0.002) at the 12-month followup.
  
  
  CONCLUSIONS
  Baseline percentage of CD19+/ZAP-70+ cells is associated with the clinical outcome after BCDT in patients with RA. Depletion of plasmablasts and pre-switch memory B cells and increase of CD19+/ZAP-70+ cells are features of the recovery of the B cell pool after BCDT.
authors.affiliation: Division of Rheumatology, Institute of Rheumatology and Affine Sciences (IRSA), School of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gremese
authors.forename: Barbara
authors.initials: B
authors.lastname: Tolusso
authors.forename: Anna Laura
authors.initials: AL
authors.lastname: Fedele
authors.forename: Silvia
authors.initials: S
authors.lastname: Canestri
authors.forename: Stefano
authors.initials: S
authors.lastname: Alivernini
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Ferraccioli
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006304:Health Status; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D007596:Joints / Q000503:physiopathology; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D051746:ZAP-70 Protein-Tyrosine Kinase