title: Residual inflammation after rituximab treatment is associated with sustained synovial plasma cell infiltration and enhanced B cell repopulation.
abstract: OBJECTIVE
  To investigate the clinical effects of rituximab treatment in relation to immunological effects of rituximab on tissue-derived B lineage cells and repopulation of circulating B cells.
  
  
  METHODS
  A total of 24 patients with rheumatoid arthritis (RA) were treated with 2x1000 mg rituximab and assessed clinically at 4, 12, 18 and 24 weeks using a 44-joint Disease Activity Score (DAS(44)). Synovial biopsies were analysed with immunohistochemistry at baseline and 12 weeks after treatment. Peripheral blood mononuclear cells were analysed by high sensitivity flow cytometry at all timepoints.
  
  
  RESULTS
  In this study, a cohort of patients was dichotomised according to those who achieved a low disease activity score (DAS(44)<2.4: LoA group) and those with persistent disease activity (DAS(44)>2.4: HiA group) at any time after rituximab treatment. At baseline, the low activity (LoA) group had significantly lower DAS(44) scores (median 3.33, range 2.84 to 4.23) than the high activity (HiA) group (median 3.73, range 3.03 to 5.23; p = 0.022) and significantly less histological inflammation in synovium (median 6.7, range 1 to 15 vs 16.6, range 4 to 22; p = 0.036). DAS(44) scores before and after rituximab treatment were associated with synovial infiltration of CD79a+ CD20- B cells, morphologically resembling plasma cells. Following treatment with rituximab, the LoA group had significantly reduced repopulation of circulating pre-switched IgD+ B cells (median 0.044%, range 0.002 to 0.66 vs 0.45%, range 0.07 to 9.47; p = 0.006) and post-switched CD27+ B cells (median 0.17%, range 0.04 to 0.39 vs 0.67, range 0.08 to 2.05; p = 0.005) compared to the HiA group.
  
  
  CONCLUSIONS
  The present study demonstrated that a low disease activity state following rituximab was associated with reduced infiltration of CD79a+ CD20- plasma cells in synovium and reduced B cell repopulation.
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, The Netherlands.
authors.forename: Y K O
authors.initials: YK
authors.lastname: Teng
authors.forename: E W N
authors.initials: EW
authors.lastname: Levarht
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Jacob M
authors.initials: JM
authors.lastname: van Laar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000032:analysis; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D051925:CD79 Antigens / Q000032:analysis; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D000069283:Rituximab; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000276:immunology* / Q000473:pathology; D017211:Treatment Failure
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D018501:Antirheumatic Agents; D051925:CD79 Antigens; D000069283:Rituximab