Monday, 18 April 2016

Intrathecal Rituximab is rubbish for killing CNS B cells, but works a treat for baclofen

Topping J, Dobson R, Lapin S, Maslyanskiy A, Kropshofer H, Leppert D, Giovannoni G, Evdoshenko E. The effects of intrathecal rituximab on biomarkers in multiple sclerosis. Mult Scler Relat Disord. 2016;6:49-53

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.

We have heard that an American study of intrathecal rituximab was halted because it found that the antibody did not deplete CNS B cells and as ProfG mentioned the intrathecal route is at the base of the CSF drain and he knew that this approach did not work because he and some Russian Colleagues have done this already. That injected into the CSF comes straight out and into the blood and depletes B cells in the blood. But this was achieved with a low dose.However this does ot mean that rituximab does not inhibit relapsesbecause it can.


Stampacchia G, Mazzoleni S, Gerini A.Effects of severe spasticity treatment with intrathecal Baclofen in multiple sclerosis patients: Long term follow-up. NeuroRehabilitation. 2016 . [Epub ahead of print]

BACKGROUND:Intrathecal Baclofen is available to treat severe generalized spasticity in Multiple Sclerosis (MS) unresponsive to oral drug delivery.
OBJECTIVE: The aims of this study were to investigate the effects and the drug dosage of intrathecal Baclofen in a selected population of MS patients, affected by severe spasticity at long term follow-up.
METHODS:A prospective cohort study of 14 MS patients is presented. Spasticity and pain were periodically assessed and the Baclofen dosage was adjusted.
RESULTS: The initial Baclofen dosage was 136.2 ± 109.3 μg, then it was increased at 12 months to 228.6 ± 179.2 μg (p <  0.05). The subsequent dose adjustments did not result in significant changes up to 76 months. Spasticity on the lower limbs decreased significantly from pre-implantation assessment (median: 3.5, IQR: 3.0-4.0) to 12 months evaluation (median: 0.5, IQR: 0.0-2.0) (p <  0.001); no further decrease was observed after 24 months (median: 0.5, IQR: 0.0-1.5); when pain was present, it decreased. Some effects on cerebellar symptoms were observed. Botulinum toxin injections were used with intrathecal Baclofen therapy.
CONCLUSIONS: A reduced spasticity and pain was observed after the intrathecal Baclofen infusion for at least 76 months. To obtain these results a dosage adjustment was needed only in the first year after the implantation.

However, this study shows that intrathecal delivery can work, but in this case the drug is targeting the spinal cord to target over activity and not get the drug in he brain as  it would case side effects

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