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Long-term effects of rituximab on B cell counts and autoantibody production in rheumatoid arthritis: use of high-sensitivity flow-cytometry for more sensitive assessment of B cell depletion
  1. Andrea Váncsa1,
  2. Zoltán Szabó1,
  3. Szilvia Szamosi1,
  4. Nóra Bodnár1,
  5. Lajos Gergely2,
  6. Gabriella Szűcs1,
  7. Sándor Szántó1,
  8. Zoltán Szekanecz1
  1. 1Department of Rheumatology, Institute of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen, Hungary
  2. 2Third Department of Medicine, Division of Haematology, Institute of Medicine, University of Debrecen Medical and Health Sciences Center, Debrecen, Hungary

Abstract

Objective Rituximab (RTX) treatment results in B cell depletion in rheumatoid arthritis (RA), however, clinical responses to RTX may differ. In this study, the authors wished to assess the efficacy and safety of long-term RTX therapy and study correlations between B cell depletion, clinical response and autoantibody production.

Patients and methods Seventy-seven patients with active RA (male:female ratio 12:65) received 1000 mg of rituximab in two infusions, 2 weeks apart. Patients were re-treated with these two infusions every 6 months following a fixed protocol regardless of the extent of clinical response. All patients received at least 5 cycles of RTX. The authors included RA patients exerting active disease (DAS28>5.1) despite treatment with conventional DMARDs and at least one antitumour necrosis factor α agent. The authors assessed DAS28, as well as IgM rheumatoid factor (RF) and anticyclic citrullinated peptide (CCP) antibody levels at baseline, after 15 days and then every 6 months for 24 months. Clinical response was recorded according to EULAR response criteria. Absolute CD19+ B lymphocyte counts were also determined in 50 patients using high-sensitivity flow-cytometry (hsFACS). The authors considered complete depletion if absolute B cell counts were <0.0001 G/l. The authors also recorded side-effects during and after treatment for up to 48 months.

Results Patients received an initial and at least 4 re-treatment cycles. After 6, 12, 18 and 24 months, 51.6%, 51.9%, 73.3% and 83.8% of patients showed good EULAR responses, respectively. Significant and sustained reduction in IgM RF and anti-CCP levels were observed as early as after 6 months and 12 months, respectively. CD19+ B cells were detected in the peripheral blood of all patients before treatment. The baseline mean absolute B cell number was 0.234 G/l. B cell numbers significantly dropped after the very first infusion by day 15 (0.104 G/l; p=0.007), which further decreased until 24 months (0.0013 g/l; p<0.001). One RTX infusion resulted in incomplete depletion in 76.7% of patients. Six, 12, 18 and 24 months after the very first infusion, 75.7%, 70.8%, 56.5% and 50.0% of patients, respectively, had detectable CD19+ B cells in their peripheral blood (≥0.0001 G/l). B cell numbers positively correlated with DAS28 (r=0.964; p<0.001), IgM RF (r=0.955; p<0.001) and anti-CCP levels (r=0.755; p<0.01). Reduction in DAS28 also correlated with lower IgM RF (r=0.979; p<0.001) and anti-CCP levels (r=0.903; p<0.001). No safety issues arose.

Conclusions In RA, clinical response to RTX is associated with the extent of B cell depletion, as well as with autoantibody production. hsFACS may be a useful method to more accurately assess incomplete B cell depletion and maybe, as in oncohematology, minimal residual disease.

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