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Vitamin D, smoking, EBV and long-term cognitive performance among CIS patients: 11-year follow-up of BENEFIT
ECTRIMS Online Library. Cortese M. Oct 12, 2018; 232074
Marianna Cortese
Marianna Cortese
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Abstract: 321

Type: Scientific Session

Abstract Category: N/A

Background: Cognitive impairment is a disabling problem in multiple sclerosis (MS). Whether known MS risk factors, especially modifiable ones, predict long-term cognitive status in patients is unknown.
Objective: To evaluate whether vitamin D, smoking, and Epstein-Barr virus (EBV) predict long-term cognitive status in clinically isolated syndrome (CIS) patients.
Methods: We prospectively assessed serum 25-hydroxyvitamin D (25(OH)D) (vitamin D biomarker), cotinine (tobacco use biomarker), and EBV nuclear-antigen 1 (EBNA-1) immunoglobulin G levels at several times (baseline, months 6, 12, 24; vitamin D: also years 5, 11) among the 468 CIS patients participating in BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment). We followed 278 patients for 11 years to assess cognitive function by Paced Auditory Serial Addition Test (PASAT-3); further we measured serum neurofilament light chain (NfL), a marker of neuro-axonal injury. The estimates and 95% confidence intervals (CI) from linear and logistic regression models were adjusted for age, sex, initial treatment allocation, steroid treatment, multifocal symptoms, T2-lesions, and body mass index.
Results: Higher 25(OH)D levels predicted better, and smoking predicted worse long-term cognitive function. A 50nmol/l increment in mean vitamin D within the first 2 years was related to 65% lower odds of scoring worse on the PASAT (below median) at year 11 (OR=0.35; 95% CI: 0.14-0.89, p=0.027). Standardized PASAT scores (mean=0, SD=1) were lower in smokers (cotinine >25ng/ml in all measurements: ß=-0.26, 95% CI: -0.69, 0.17) and heavy smokers (cotinine >189ng/ml, median in smokers, in all measurements: ß=-0.81, 95% CI: -1.60, -0.02) than non-smokers (p-trend=0.036). EBNA-1 levels after clinical onset did not predict cognitive function (p-trend across quartiles= 0.73). Associations with NfL concentrations at year 11 corroborated the main findings. A 50nmol/l increase in mean 25(OH)D the first 2 years was associated with 20% lower NfL (95% CI: 0.64-0.99, p=0.05), and smokers had 29% higher NfL levels as non-smokers (95% CI: 1.08-1.54, p=0.006), while EBNA-1 was not associated with NfL.
Conclusions: Vitamin D elevation and smoking cessation after clinical onset might protect cognitive function and neuronal integrity long-term in CIS patients.
Disclosure: · M. Cortese has nothing to disclose.
· K. L. Munger has nothing to disclose.
· E. H. Martínez-Lapiscina has received speaking honoraria from Roche, Biogen, Sanofi & Novartis and travel reimbursement from Roche, Sanofi, Biogen for international and national meetings over the last 3 years. She is a member of the working group of IMSVISUAL and a researcher in OCTIMS study, an observational study for validating OCT as a marker for MS sponsored by Novartis. She has participated in advisory Boards for Roche, Sanofi. She has received grants from the Instituto de Salud Carlos III (CM13/00150; MV15/00012; JR16/0006; MV17/00021;PI17/01228; RD16/0015/0003);
Fundació Marató TV3 (20142030) and GMSI (2016) and unrestricted grants from Fundaciò Cellex Barcelona, Sanofi, Novartis.
· C. Barro has received travel support from Teva and Novartis. 

· G. Edan has received honoraria for lectures or consulting from Biogen Idec, Merck Serono, and Sano -Aventis, and received personal compensation for serving on the BENEFIT scientific advisory board and for speaking from Bayer AG. He has also received research support from Serono, (a grant to University Hospital to support a research program on MRI in MS) and from Teva (a grant to support a research program on anti-IBF neutralizing antibodies).
· M. S. Freedman has received compensation from Bayer HealthCare, Biogen Idec, EMD Canada, Genzyme, Merck Serono, Novartis, Sano -Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau.
· H.-P. Hartung has received honoraria for consulting and speaking at symposia from Bayer HealthCare, Biogen, Genzyme, GeNeuro, Merck, Novartis, Receptos Celgene, Roche, and Teva, with approval by the rector of Heinrich-Heine University.
· X. Montalbán has received speaking honoraria and travel expenses for scientific meetings and has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer, Biogen Idec, EMD, Genentech, Genzyme, Merck Serono, Neurotec, Novartis, Sano -Aventis, Teva Pharmaceuticals, and Almirall.
· L. Kappos' institution (University Hospital Basel) received in the last 3 years and used exclusively for research support at the Department: steering committee, advisory board and consultancy fees from Actelion, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, Excemed, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, sanofi-aventis, Santhera, Teva, Vianex and royalties for Neurostatus-UHB products. For educational activities the institution received payments and honoraria from Allergan, Almirall, Baxalta, Bayer, Biogen, CSL-Behring, Desitin, Excemed, Genzyme, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva. He has served in the last 24 months as international or local principal investigator for the following drug studies BOLD EXT., EXPAND (Siponimod, Novartis), DECIDE, DECIDE EXT. (Daclizumab HYP, Biogen), ENDORSE (DMF, Biogen), FINGORETT, FTY-UMBRELLA, INFORMS, INFORMS EXT LONGTERMS. (Fingolimod, Novartis), MOMENTUM (Amiselimod, Mitsubishi) OCRELIZUMAB PHASE II EXT., OPERA, ORATORIO and extensions (Ocrelizumab, Roche), REFLEXION (IFN β-1a, Merck), STRATA EXT, TOP (Natalizumab, Biogen), TERIFLUNOMIDE EXT, TERRIKIDS (Teriflunomide, Sanofi-Aventis) and ASCLEPIOS I/II (Ofatumumab, Novartis). The Research of the MS Center in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union. In the last 24 months the institution also received grants for patient services from Bayer, Merck and CSL-Behring. L. Kappos is a member in the Editorial Boards of the following journals: “Journal of Neurology", “Multiple Sclerosis Journal”, “Neurology and Clinical Neuroscience“, "Multiple Sclerosis and Related Disorders", “Clinical and Translational Neuroscience”. Honoraria and other payments for all these activities have been exclusively used for funding of research at the department.
· F. Foley has received compensation for consulting with Biogen Idec and Bayer HealthCare Pharmaceuticals.
· I.K. Penner has received honoraria for speaking at scientific meetings, serving at scientific advisory boards and consulting activities from Actelion, Bayer-Schering, Biogen Nordic, Merck Serono, Novartis, Roche, Teva, Sanofi-Aventis.
· B. Hemmer has served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Novartis, Bayer AG, and Genentech; he has served as DMSC member for AllergyCare and TCG Therapeutics; he or his institution have received speaker honoraria from Biogen Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, Desitin, and F. Hoffmann-La Roche Ltd; his institution has received research support from Chugai Pharmaceuticals and Hoffmann-La-Roche; holds part of two patents; one for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon β.
· E. Fox has received consulting fees, honoraria, travel, or research support from Abbvie, Acorda, Allergan, Bayer, Biogen, Celgene, Chugai, EMD Serono, Genentech Roche, Mallinckrodt, MedDay, Novartis, Sanofi Genzyme, Teva, and TG Therapeutics.
· S. Schippling has received research grants from Biogen, Bayer Healthcare, Novartis and Sanofi Genzyme, and consulting/speaker fees as well as travel support from Bayer Healthcare, Biogen, Merck Serono, Novartis, Teva, and Sanofi-Genzyme.
· E.-M. Wicklein is a salaried employee of Bayer AG.
· J. Kuhle's institution (University Hospital Basel) received and used exclusively for research support: consulting fees from Biogen, Novartis, Protagen AG, Roche, Teva; speaker fees from the Swiss MS Society, Biogen, Novartis, Roche, Genzyme; travel expenses from Merck Serono, Novartis, Roche; grants from ECTRIMS Research Fellowship Program, University of Basel, Swiss MS Society, Swiss National Research Foundation (320030_160221), Bayer AG, Biogen, Genzyme, Merck, Novartis, and Roche. 

· A. Ascherio has nothing to disclose.
Funding: This study has been supported in part by grants awarded to Dr. Ascherio from the National Institute of Neurological Disease and Stroke and the National Multiple Sclerosis Society. Blood samples for vitamin D and other assays and linkage to clinical data have been provided by Bayer HealthCare at no cost to the investigators.

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