Contributions
Abstract: P469
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Progressive MS
Background: The understanding of the pathogenesis of progressive multiple sclerosis (MS) is challenged by the lack of biomarkers reflecting the complex pathology. Cerebrospinal fluid (CSF) biomarker studies have demonstrated high sensitivity for intrathecal inflammation by soluble CD27 (sCD27, a marker of T cell inflammation) and markers of B cells (sCD21) and microglia/macrophage inflammation (sCD14 and sCD163). We investigated the effects of treatment with natalizumab (NTZ) and methylprednisolone (MP) on these soluble biomarkers and other candidate CSF biomarkers of inflammation in progressive MS.
Methods: Baseline and week 60 follow-up CSF samples from progressive MS patients from two open-label trials of NTZ or MP treatment were included. CSF concentrations of soluble surface markers, a panel of chemokines and cytokines, and neurofilament light chain (NFL, a marker of axonal damage) and myelin basic protein (MBP, a marker of demyelination) were analysed by electrochemiluminescent assay and ELISA assays.
Results: NTZ treatment significantly reduced CSF concentrations of sCD21, sCD27, IL10, IL12p40, TNF-alpha and CXCL10, while IL5 and IL7 concentrations increased. MP treatment significantly reduced sCD21, sCD27 and IL12p40 and increased sCD163, IL5, IL7, IL15 and CCL2 concentrations. For both treatments, CSF sCD27 and sCD21 showed the most significant decreases and superior signal-to-noise ratios for change after treatment, but remained above reference levels for healthy donors. Correlation analysis of baseline concentrations (N=52) of CSF markers of inflammation and axonal damage (NFL) demonstrated significant positive correlations between NFL and sCD14, sCD21, sCD27, sCD163, CHI3L1, IL8, IL10, TNF-a, VEGF, CCL11, CCL22 and CXCL10, while MBP concentrations correlated with sCD14 and sCD163. Correlation analyses of CSF concentrations after 60 weeks of NTZ (N=17) or MP (N=23) treatment showed sCD27 to be the only marker of intrathecal inflammation consistently correlating with NFL.
Conclusions: Treatment of progressive MS with NTZ or MP results in significant decreases of CSF markers of intrathecal inflammation which correlate with axonal damage, but still substantial residual T- and B-cell inflammation remains after treatment. CSF biomarkers of T- and B-cell inflammation, sCD27 and sCD21, demonstrated consistent responsiveness and low signal-to-noise ratios during both treatments, supporting their potential use in future progressive MS clinical trials.
Disclosure:
JRC has received speaker honoraria from Novartis and TEVA, consultant honoraria from Biogen Idec and TEVA, and has had travel expenses reimbursed by Biogen Idec.
MK declares no conflict of interest.
MRvE declares no conflict of interest.
RR has had travel expenses reimbursed by BiogenIdec and Genzyme.
LB has received support for conference participation from Genzyme and Novartis and has received research grants from the Danish Multiple Sclerosis Society.
BB is a co-inventor on several NIH patents related to daclizumab and as such has received patent royalty payments from NIH.
FS has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, EMD Serono, Genzyme, Lundbeck, Merck Serono, Novartis and Teva.
Abstract: P469
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Progressive MS
Background: The understanding of the pathogenesis of progressive multiple sclerosis (MS) is challenged by the lack of biomarkers reflecting the complex pathology. Cerebrospinal fluid (CSF) biomarker studies have demonstrated high sensitivity for intrathecal inflammation by soluble CD27 (sCD27, a marker of T cell inflammation) and markers of B cells (sCD21) and microglia/macrophage inflammation (sCD14 and sCD163). We investigated the effects of treatment with natalizumab (NTZ) and methylprednisolone (MP) on these soluble biomarkers and other candidate CSF biomarkers of inflammation in progressive MS.
Methods: Baseline and week 60 follow-up CSF samples from progressive MS patients from two open-label trials of NTZ or MP treatment were included. CSF concentrations of soluble surface markers, a panel of chemokines and cytokines, and neurofilament light chain (NFL, a marker of axonal damage) and myelin basic protein (MBP, a marker of demyelination) were analysed by electrochemiluminescent assay and ELISA assays.
Results: NTZ treatment significantly reduced CSF concentrations of sCD21, sCD27, IL10, IL12p40, TNF-alpha and CXCL10, while IL5 and IL7 concentrations increased. MP treatment significantly reduced sCD21, sCD27 and IL12p40 and increased sCD163, IL5, IL7, IL15 and CCL2 concentrations. For both treatments, CSF sCD27 and sCD21 showed the most significant decreases and superior signal-to-noise ratios for change after treatment, but remained above reference levels for healthy donors. Correlation analysis of baseline concentrations (N=52) of CSF markers of inflammation and axonal damage (NFL) demonstrated significant positive correlations between NFL and sCD14, sCD21, sCD27, sCD163, CHI3L1, IL8, IL10, TNF-a, VEGF, CCL11, CCL22 and CXCL10, while MBP concentrations correlated with sCD14 and sCD163. Correlation analyses of CSF concentrations after 60 weeks of NTZ (N=17) or MP (N=23) treatment showed sCD27 to be the only marker of intrathecal inflammation consistently correlating with NFL.
Conclusions: Treatment of progressive MS with NTZ or MP results in significant decreases of CSF markers of intrathecal inflammation which correlate with axonal damage, but still substantial residual T- and B-cell inflammation remains after treatment. CSF biomarkers of T- and B-cell inflammation, sCD27 and sCD21, demonstrated consistent responsiveness and low signal-to-noise ratios during both treatments, supporting their potential use in future progressive MS clinical trials.
Disclosure:
JRC has received speaker honoraria from Novartis and TEVA, consultant honoraria from Biogen Idec and TEVA, and has had travel expenses reimbursed by Biogen Idec.
MK declares no conflict of interest.
MRvE declares no conflict of interest.
RR has had travel expenses reimbursed by BiogenIdec and Genzyme.
LB has received support for conference participation from Genzyme and Novartis and has received research grants from the Danish Multiple Sclerosis Society.
BB is a co-inventor on several NIH patents related to daclizumab and as such has received patent royalty payments from NIH.
FS has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, EMD Serono, Genzyme, Lundbeck, Merck Serono, Novartis and Teva.