BASIC AND TRANSLATIONAL RESEARCH

Residual inflammation after rituximab treatment is associated with sustained synovial plasma cell infiltration and enhanced B cell repopulation

Y K O Teng¹, E W N Levarht¹, Rene E M Toes¹, Tom W J Huizinga¹, Jacob M van Laar^1,2

¹ Department of Rheumatology, Leiden University Medical Center, The Netherlands
² Musculoskeletal Research Group, Institute of Cellular Medicine, School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

J M van Laar, Musculoskeletal Research Group, Institute of Cellular Medicine, School of Clinical Medical Sciences, Newcastle University, Fourth Floor, Catherine Cookson Building, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; j.m.van-laar{at}ncl.ac.uk

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 (DAS₄₄). 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 (DAS₄₄<2.4: LoA group) and those with persistent disease activity (DAS₄₄>2.4: HiA group) at any time after rituximab treatment. At baseline, the low activity (LoA) group had significantly lower DAS₄₄ 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). DAS₄₄ 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.

Conclusion: 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.

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