J. C. W. Edwards

Anti-CD20 monoclonal antibody (rituximab) as an adjunct in the treatment of giant cell arteritis.

We describe a patient with polymyalgia rheumatica/giant cell arteritis (PMR/GCA) whose disease was refractory to a reduction in the dose of her glucocorticoid to an acceptable level. Our patient improved after B lymphocyte depletion but developed respiratory problems. To our knowledge this is the first description of such a case. An 82 year old woman presented with a 4 week history of symptoms consistent with GCA of the temporal arteries and PMR. Of significance in her past medical history she had significant chronic airflow limitation with an FEV1/FVC (forced expiratory volume in 1 second/forced vital capacity) of 0.7/1.2. Computed tomography of her chest identified a small area of bronchiectasis in the left lower lobe of her chest. Her erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) were, 109 mm/1st h (normal 1–20) and 230 mg/l (normal 0–5.0), respectively. Treatment was started with 50 mg of prednisolone. Three weeks later …

B-cell-activating factor receptor expression on naive and memory B cells: relationship with relapse in patients with rheumatoid arthritis following B-cell depletion therapy

Objectives To examine the expression of B-cell-activating factor receptor (BAFF-R) on naive CD27− and memory CD27+ B cells in normal individuals and patients with rheumatoid arthritis (RA) undergoing B-cell depletion therapy with rituximab. Patients and Methods BAFF-R expression on B-cell subsets was determined in normal controls (NC; n=11), active patients with RA pre-rituximab (pre-RX; n=15), relapsing patients either concordant for B-cell repopulation (C-R, n=13) or discordant, with relapse more than 3 months after repopulation (D-R, n=11) and patients in remission over 3 months postrepopulation (discordant non-relapsing (D-NR), n=5). Serum BAFF was measured by ELISA and analysed using Mann–Whitney. Results There was no significant difference between NC, pre-RX and D-NR patients in %BAFF-R-positive B cells or mean fluorescence intensity (MFI) in naive and memory B cells. Relapsing patients had significantly lower MFI and %BAFF-R-positive cells in both naive and memory compartments from NC and pre-RX (C-R and D-R; p<0.01). BAFF levels in pre-RX patients were within the normal range and did not correlate with BAFF-R expression in any patient group. D-NR patients had relatively lower proportions of pre and postswitch CD27+ B cells than pre-RX patients (D-NR vs pre-RX; p<0.05 for both) and also lower numbers of postswitch B cells than D-R patients (D-NR vs D-R, p<0.05). Conclusion BAFF-R expression was significantly reduced on both naive and memory B cells in patients at relapse, regardless of the relationship with B-cell repopulation or serum BAFF levels. Re-establishment of active disease was also associated with an increase in class-switch recombination. Factors responsible for lower levels of BAFF-R may relate to altered thresholds for autoreactive B-cell generation at relapse in patients with RA.

A1.41 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

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 naïve 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<5/ml); at B-cell return (CD19+ 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 1st Cycle, BAFF levels were higher, anti-microbial remained relatively unchanged and IgM-RhF and IgM-CCP and IgG-CCP autoantibodies had decreased (p<0.05). The most consistent changes between baseline to B cell depletion in each cycle, over all 3 cycles, were in lSFLC, sCD23 and IgM-RhF which fell and BAFF levels which rose (p<0.05). Incremental rises in sCD23 levels in Cycles 2 and 3 were associated with time to relapse. In patients with relapse >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.