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Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response

R M Thurlings¹, K Vos², C A Wijbrandts¹, A H Zwinderman³, D M Gerlag¹, P P Tak¹

¹ Division of Clinical Immunology and Rheumatology, Academic Medical Centre/University of Amsterdam, The Netherlands
² Jan van Breemen Institute, Amsterdam, The Netherlands
³ Department of Medical Statistics, Clinical Epidemiology and Biostatistics, Academic Medical Centre/University of Amsterdam, The Netherlands

Professor P P Tak, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; p.p.tak{at}amc.uva.nl

Objective: To investigate the synovial tissue in patients with rheumatoid arthritis (RA) treated with rituximab and to identify possible predictors of clinical response.

Methods: A total of 24 patients with RA underwent synovial biopsy before, 4 and 16 weeks after initiation of rituximab treatment (without peri-infusional corticosteroids to prevent bias). Immunohistochemical analysis was performed and stained sections were analysed by digital image analysis. Linear regression analysis was used to identify predictors of clinical response.

Results: The 28-joint Disease Activity Score (DAS28) was unaltered at 4 weeks, but significantly reduced at 16 and 24 weeks. Serum levels of IgM-rheumatoid factor (RF) decreased significantly at 24 weeks and anti-citrullinated peptide antibody (ACPA) levels at 36 weeks. Peripheral blood B cells were depleted at 4 weeks and started to return at 24 weeks. Synovial B cells were significantly decreased at 4 weeks, but were not completely depleted in all patients; there was a further reduction at 16 weeks in some patients. We found a significant decrease in macrophages at 4 weeks, which was more pronounced at 16 weeks. At that timepoint, T cells were also significantly decreased. The reduction of plasma cells predicted clinical improvement at 24 weeks.

Conclusions: The results support the view that B cells orchestrate local cellular infiltration. The kinetics of the serological as well as the tissue response in clinical responders are consistent with the notion that rituximab exerts its effects in part by an indirect effect on plasma cells associated with autoantibody production, which could help explain the delayed response after rituximab treatment.

Trial registration number: ISRCTN05568900 [controlled-trials.com] .

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