Contributions
Abstract: P1135
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Biomarkers
Background: The risk of developing MS increases with seroconversion and with increasing anti-Epstein Barr Nuclear Antigen 1 (EBNA1) antibody titres. Anti-EBNA1 titres have also been associated with greater subsequent focal inflammatory disease activity in adults with established MS. We recently reported that the thalamus is one of the most affected CNS structures in children with MS. Whether and how trajectories of thalamic growth may be related to anti-EBNA1 antibodies in MS is unknown.
Objectives: To examine whether anti-EBNA1 antibody titres are associated with the failure of thalamic growth in pediatric-onset MS.
Methods: We prospectively studied 60 children from the time of presentation with an incident acquired demyelinating syndrome (ADS) with serial co-registered brain MRI and serum sampling; 25 were subsequently (median follow-up 4.2 years) ascertained to have MS; the other 35 remained monophasic (monoADS). We used normative growth trajectory data (NIH Study of Normal Brain Development) as a frame-of-reference for expected brain growth. We measured anti-EBNA1 titres using ELISA, then used linear mixed effect modeling to study the association of anti-EBNA1 titres at presentation and growth trajectories of whole brain and brain-normalized thalamus. We used receiver operator characteristic (ROC) analysis and leave-one-out validation to predict growth at individual level.
Results: At the group level, increasing anti-EBNA1 titres predicted slower subsequent thalamic growth in children with MS (-6.97×10-04 z-score/year/anti-EBNA Unit, p< 0.0001) but not monoADS (p = 0.602), reflecting an MS-specific association (p = 7.0×10-4). The association between anti-EBNA1 titres and brain growth trajectory was not significant in either group. The anti-EBNA1 titre was a good predictor of failure of normal thalamic growth also at the level of individual children with MS, with an area under the ROC curve of up to 0.88. Anti-EBNA titers tended to be stable in individual children over time, such that their measurement at times that followed initial ADS presentation also predicted subsequent thalamic growth.
Conclusions: Our findings suggest that early anti-EBNA1 measurements may identify individual pediatric MS patients who will experience a more severe disease trajectory, and may benefit from more aggressive therapy. Whether these antibodies have pathogenic effects on trajectories or are merely markers of disease trajectories remains to be elucidated.
Disclosure: G. Fadda has nothing to disclose.
R.A. Brown has received personal compensation from NeuroRx Research for consulting services.
B. Aubert-Broche has nothing to declare
C. Yea has nothing to declare
J. O"Mahony has nothing to declare
R.A. Marrie receives funding from the Canadian Institutes of Health Research, Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, Rx & D Health Research Foundation, Research Manitoba and sanofi-aventis (clinical trial).
A. Yeh disclosures: Funding from NMSS, MS Foundation/MSSC, Mario Battaglia Foundation, Centre for Brain and Mental Health, OIRM, SickKids Foundation. Speaker´s honoraria Novartis.
D.L. Arnold reports personal fees for consulting from Acorda, Biogen, Hoffman LaRoche, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi-Aventis; grants from Biogen and Novartis; and an equity interest in NeuroRx Research.
D. L. Collins receives funding from the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada. DLC also receives consulting from NeuroRx Research and has equity interest in True Positive Medical Devices.
B. Banwell has served as an unpaid consultant to Biogen-Idec, Novartis, Teva Neuroscience, and Merck-Serono; as a remunerated central MRI reviewer for the present trial, and she is Chief Editor for MS and Related Disorders and funded by Canadian MS scientific research foundation (CMSRF), Canadian Multiple Sclerosis Society (CMSS), National Multiple Sclerosis Society (NMSS), and Canadian Institutes of Health Research (CIHR).
A. Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Biogen Idec, Diogenix, Genentech, Sanofi-Genzyme, GlaxoSmithKline, Novartis, Ono Pharma, Teva Neuroscience, Receptos Inc, Roche, and Merck/EMD Serono.
Abstract: P1135
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Biomarkers
Background: The risk of developing MS increases with seroconversion and with increasing anti-Epstein Barr Nuclear Antigen 1 (EBNA1) antibody titres. Anti-EBNA1 titres have also been associated with greater subsequent focal inflammatory disease activity in adults with established MS. We recently reported that the thalamus is one of the most affected CNS structures in children with MS. Whether and how trajectories of thalamic growth may be related to anti-EBNA1 antibodies in MS is unknown.
Objectives: To examine whether anti-EBNA1 antibody titres are associated with the failure of thalamic growth in pediatric-onset MS.
Methods: We prospectively studied 60 children from the time of presentation with an incident acquired demyelinating syndrome (ADS) with serial co-registered brain MRI and serum sampling; 25 were subsequently (median follow-up 4.2 years) ascertained to have MS; the other 35 remained monophasic (monoADS). We used normative growth trajectory data (NIH Study of Normal Brain Development) as a frame-of-reference for expected brain growth. We measured anti-EBNA1 titres using ELISA, then used linear mixed effect modeling to study the association of anti-EBNA1 titres at presentation and growth trajectories of whole brain and brain-normalized thalamus. We used receiver operator characteristic (ROC) analysis and leave-one-out validation to predict growth at individual level.
Results: At the group level, increasing anti-EBNA1 titres predicted slower subsequent thalamic growth in children with MS (-6.97×10-04 z-score/year/anti-EBNA Unit, p< 0.0001) but not monoADS (p = 0.602), reflecting an MS-specific association (p = 7.0×10-4). The association between anti-EBNA1 titres and brain growth trajectory was not significant in either group. The anti-EBNA1 titre was a good predictor of failure of normal thalamic growth also at the level of individual children with MS, with an area under the ROC curve of up to 0.88. Anti-EBNA titers tended to be stable in individual children over time, such that their measurement at times that followed initial ADS presentation also predicted subsequent thalamic growth.
Conclusions: Our findings suggest that early anti-EBNA1 measurements may identify individual pediatric MS patients who will experience a more severe disease trajectory, and may benefit from more aggressive therapy. Whether these antibodies have pathogenic effects on trajectories or are merely markers of disease trajectories remains to be elucidated.
Disclosure: G. Fadda has nothing to disclose.
R.A. Brown has received personal compensation from NeuroRx Research for consulting services.
B. Aubert-Broche has nothing to declare
C. Yea has nothing to declare
J. O"Mahony has nothing to declare
R.A. Marrie receives funding from the Canadian Institutes of Health Research, Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, Rx & D Health Research Foundation, Research Manitoba and sanofi-aventis (clinical trial).
A. Yeh disclosures: Funding from NMSS, MS Foundation/MSSC, Mario Battaglia Foundation, Centre for Brain and Mental Health, OIRM, SickKids Foundation. Speaker´s honoraria Novartis.
D.L. Arnold reports personal fees for consulting from Acorda, Biogen, Hoffman LaRoche, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi-Aventis; grants from Biogen and Novartis; and an equity interest in NeuroRx Research.
D. L. Collins receives funding from the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada. DLC also receives consulting from NeuroRx Research and has equity interest in True Positive Medical Devices.
B. Banwell has served as an unpaid consultant to Biogen-Idec, Novartis, Teva Neuroscience, and Merck-Serono; as a remunerated central MRI reviewer for the present trial, and she is Chief Editor for MS and Related Disorders and funded by Canadian MS scientific research foundation (CMSRF), Canadian Multiple Sclerosis Society (CMSS), National Multiple Sclerosis Society (NMSS), and Canadian Institutes of Health Research (CIHR).
A. Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Biogen Idec, Diogenix, Genentech, Sanofi-Genzyme, GlaxoSmithKline, Novartis, Ono Pharma, Teva Neuroscience, Receptos Inc, Roche, and Merck/EMD Serono.