TY - JOUR
T1 - Rituximab combination therapy in relapsing multiple sclerosis
AU - Cross, Anne H.
AU - Klein, Robyn S.
AU - Piccio, Laura
N1 - Funding Information:
The phase II clinical trial was funded by RG 3292 from the National MS Society (NMSS), USA and grants K24RR017100, PO1NS059560-01 and 5UL1 RR024992 from the NIH. Genentech, Inc. and Biogen-Idec provided rituximab for the study, and $3000/subject support. Dr Klein was supported by RG80186 and RG80588 from the NMSS. Dr Piccio is a Harry Weaver Neuroscience Scholar funded by the National MS Society (NMSS) (JF 2144A2/1). Dr Cross was supported by the Manny and Rosalyn Rosenthal–Dr John L. Trotter MS Center Chair in Neuroimmunology and the Barnes-Jewish Hospital Foundation.
PY - 2012/11
Y1 - 2012/11
N2 - In multiple sclerosis (MS), the presence of B cells, plasma cells and excess immunoglobulins in central nervous system lesions and in the cerebrospinal fluid implicate the humoral immune system in disease pathogenesis. However, until the advent of specific B-cell-depleting therapies, the critical role of B cells and their products in MS was unproven. Rituximab, a monoclonal antibody that depletes B cells by targeting the CD20 molecule, has been shown to effectively reduce disease activity in patients with relapsing MS as a single agent. Our investigator-initiated phase II study is the only published clinical trial in which rituximab was used as an add-on therapy in patients with relapsing MS who had an inadequate response to standard injectable disease-modifying therapies (DMTs). The primary endpoint, magnetic resonance imaging (MRI) gadolinium-enhanced (GdE) lesion number before versus after rituximab, showed significant benefit of rituximab (74% of post-treatment MRI scans being free of GdE lesions compared with 26% free of GdE lesions at baseline; p < 0.0001). No differences were noted comparing patients on different DMTs. Several secondary clinical endpoints, safety and laboratory measurements (including B- and T-cell numbers in the blood and cerebrospinal fluid (CSF), serum and CSF chemokine levels, antibodies to myelin proteins) were assessed. Surprisingly, the decline in B-cell number was accompanied by a significant reduction in the number of T cells in both the peripheral blood and CSF. Rituximab therapy was associated with a significant decline of two lymphoid chemokines, CXCL13 and CCL19. No significant changes were observed in serum antibody levels against myelin proteins [myelin basic protein (MBP) and myelin/oligodendrocyte glycoprotein (MOG)] after treatment. These results suggest that B cells play a role in MS independent from antibody production and possibly related to their role in antigen presentation to T cells or to their chemokine/cytokine production.
AB - In multiple sclerosis (MS), the presence of B cells, plasma cells and excess immunoglobulins in central nervous system lesions and in the cerebrospinal fluid implicate the humoral immune system in disease pathogenesis. However, until the advent of specific B-cell-depleting therapies, the critical role of B cells and their products in MS was unproven. Rituximab, a monoclonal antibody that depletes B cells by targeting the CD20 molecule, has been shown to effectively reduce disease activity in patients with relapsing MS as a single agent. Our investigator-initiated phase II study is the only published clinical trial in which rituximab was used as an add-on therapy in patients with relapsing MS who had an inadequate response to standard injectable disease-modifying therapies (DMTs). The primary endpoint, magnetic resonance imaging (MRI) gadolinium-enhanced (GdE) lesion number before versus after rituximab, showed significant benefit of rituximab (74% of post-treatment MRI scans being free of GdE lesions compared with 26% free of GdE lesions at baseline; p < 0.0001). No differences were noted comparing patients on different DMTs. Several secondary clinical endpoints, safety and laboratory measurements (including B- and T-cell numbers in the blood and cerebrospinal fluid (CSF), serum and CSF chemokine levels, antibodies to myelin proteins) were assessed. Surprisingly, the decline in B-cell number was accompanied by a significant reduction in the number of T cells in both the peripheral blood and CSF. Rituximab therapy was associated with a significant decline of two lymphoid chemokines, CXCL13 and CCL19. No significant changes were observed in serum antibody levels against myelin proteins [myelin basic protein (MBP) and myelin/oligodendrocyte glycoprotein (MOG)] after treatment. These results suggest that B cells play a role in MS independent from antibody production and possibly related to their role in antigen presentation to T cells or to their chemokine/cytokine production.
KW - B cells
KW - CXCL13
KW - T cells
KW - chemokines
KW - gadolinium-enhanced magnetic resonance imaging
KW - multiple sclerosis
KW - rituximab
UR - http://www.scopus.com/inward/record.url?scp=84868246228&partnerID=8YFLogxK
U2 - 10.1177/1756285612461165
DO - 10.1177/1756285612461165
M3 - Article
C2 - 23139702
AN - SCOPUS:84868246228
SN - 1756-2856
VL - 5
SP - 311
EP - 319
JO - Therapeutic Advances in Neurological Disorders
JF - Therapeutic Advances in Neurological Disorders
IS - 6
ER -