EFFECT OF MULTIPLE CYCLES OF B-CELL DEPLETION THERAPY IN PATIENTS WITH RHEUMATOID ARTHRITIS ON SEROLOGICAL EVIDENCE OF PLASMABLAST ACTIVATION, SERUM BAFF LEVELS AND AUTOANTIBODY SPECIFICITY
Annals of the Rheumatic Diseases(2014)
摘要
Background and Objectives Rituximab induces clinical remission in a majority of seropositive patients with Rheumatoid arthritis (RA), however, all patients eventually relapse. Although B cell return precedes clinical relapse absolute B cell numbers are not predictive of relapse. The aim of this study was to determine whether there were any consistent dynamic changes in combinations of serological parameters following up to 3 cycles of B cell depletion therapy based on rituximab (RTX). Materials and Methods We included 23 RA patients (all clinical responders in each cycle) over 1, 21 over 2, and 15 over 3 cycles of RTX followed for up to 108 months and analysed in relation to B cell kinetics at 4 key points within each cycle of therapy. Serum analytes including Rheumatoid factors (RhF) and anti-citrullinated protein/peptide antibodies (ACPA), BAFF, serum free light chains (SFLC), soluble CD23 (sCD23 - cleaved from naive B cells coincident with CD27 expression), antibodies to tetanus toxoid (TT) and pneumococcal capsular polysaccharide (PCP) were measured by ELISA at 4 key points in each cycle: Baseline (pre-RTX in each cycle); when B-cell depleted (CD19 + B-cells + B-cells ≥5/ml); and at clinical relapse (ΔDAS28>1.2). Results Comparing levels of analytes at relapse after 3 cycles with baseline values before 1 st Cycle, BAFF levels were higher, anti-microbial remained relatively unchanged and IgM-RhF and IgM-CCP and IgG-CCP autoantibodies had decreased (p 5 months after B-cell return, significant rises in IgM-RhF, lSFLC and sCD23, and falls in BAFF, occurred between B cell return until clinical relapse. Conclusions Dynamic changes in the serum analytes IgM-RhF, λSFLC, sCD23 and BAFF were consistent over 3 cycles of rituximab and closely associated with clinical response/relapse. This suggests that the clinical response to RTX involves interuption of the genesis of short-lived immunoglobulin-secreting cells. Resumption of this process at relapse involved maturation of B-cell clones associated with sCD23 cleavage and of immunoglobulin-secreting cells accompanied by lSFLC release and IgM-RhF specificity. In patients with the longer periods of remission after B cell return the ‘delay’ in re-starting the inflammatory process may be due to a slower rate of selection and/or maturation of autoreactive B cell clones, despite raised serum BAFF.
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关键词
rheumatoid arthritis,serum baff levels,plasmablast activation,b-cell
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