Joanne Topping1, Ruth Dobson2, Sergey Lapin3, Alexey Maslyanskiy4, Harald Kropshofer5, David Leppert5, Gavin Giovannoni1, Evgeniy Evdoshenko6. 1. Blizard Institute, Queen Mary University, 4 Newark Street, London E1 2AT, England. 2. Blizard Institute, Queen Mary University, 4 Newark Street, London E1 2AT, England. Electronic address: ruth.dobson@qmul.ac.uk. 3. First Pavlov State Medical University, Center for Molecular Medicine, Laboratory of Autoimmune Diagnostics, 6/8 Leo Tolstoy St, 197022 Saint Petersburg, Russia. 4. Federal Almazov Medical Research Centre, Saint Petersburg, Russia. 5. F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Grenzacherstrasse, Basel, Switzerland. 6. MS Center (City Clinical Hospital 31), Saint Petersburg, Russia.
Abstract
OBJECTIVES: Clinical trials of IV-rituximab have proved successful. It is unclear whether intrathecal (IT)-rituximab is more efficacious at lower doses. We examine its effects on B-cell biomarkers. METHODS: MS patients received IT-rituximab at 3 time-points. CSF and serum samples were obtained at up to 5 time-points (days 0, 7, 14, 56 and 112). Serum and CSF BAFF and CXCL13, and CSF kappa and lambda free light chains (FLC) were measured. Flow cytometry was performed, examining effects on lymphocytes, CD3-19+ and CD3-20+ cells. RESULTS: CSF BAFF fell following rituximab (p=0.0091 absolute values, p=0.0284 change from baseline) whilst serum BAFF increased across time-points 1-4 (p=0.0005 absolute values, p=0.0017 change from baseline). There were significant reductions in CD20+ and CD19+ cells in blood from baseline (p<0.0001) but not in CSF. CSF kappa FLC levels significantly increased (p=0.0480). CONCLUSIONS: BAFF levels fall in CSF but increase in serum following IT-rituximab. Rituximab appears to act peripherally with dramatic decreases in peripheral CD20+ and CD19+ cells. It is likely that CSF B-cell counts were too low to enable differences to be seen. The rapid reduction in B-cells suggests rituximab has immediate effects. The profound depletion of B-cells, despite low doses of rituximab, underlines rituximab's efficacy.
OBJECTIVES: Clinical trials of IV-rituximab have proved successful. It is unclear whether intrathecal (IT)-rituximab is more efficacious at lower doses. We examine its effects on B-cell biomarkers. METHODS: MS patients received IT-rituximab at 3 time-points. CSF and serum samples were obtained at up to 5 time-points (days 0, 7, 14, 56 and 112). Serum and CSF BAFF and CXCL13, and CSF kappa and lambda free light chains (FLC) were measured. Flow cytometry was performed, examining effects on lymphocytes, CD3-19+ and CD3-20+ cells. RESULTS: CSF BAFF fell following rituximab (p=0.0091 absolute values, p=0.0284 change from baseline) whilst serum BAFF increased across time-points 1-4 (p=0.0005 absolute values, p=0.0017 change from baseline). There were significant reductions in CD20+ and CD19+ cells in blood from baseline (p<0.0001) but not in CSF. CSF kappa FLC levels significantly increased (p=0.0480). CONCLUSIONS:BAFF levels fall in CSF but increase in serum following IT-rituximab. Rituximab appears to act peripherally with dramatic decreases in peripheral CD20+ and CD19+ cells. It is likely that CSF B-cell counts were too low to enable differences to be seen. The rapid reduction in B-cells suggests rituximab has immediate effects. The profound depletion of B-cells, despite low doses of rituximab, underlines rituximab's efficacy.
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