title: No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT.
abstract: OBJECTIVE
  To evaluate whether Epstein-Barr virus (EBV) immunoglobulin G (IgG) antibody levels or tobacco use were associated with conversion to multiple sclerosis (MS) or MS progression/activity in patients presenting with clinically isolated syndrome (CIS).
  
  
  METHODS
  In this prospective, longitudinal study, we measured EBV IgG antibody and cotinine (biomarker of tobacco use) levels at up to 4 time points (baseline, months 6, 12, and 24) among 468 participants with CIS enrolled in the BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) clinical trial. Outcomes included time to conversion to clinically definite or McDonald MS, number of relapses, Expanded Disability Status Scale (EDSS) changes, brain and T2 lesion volume changes, and number of new active lesions over 5 years. Analyses were adjusted for age, sex, treatment allocation, baseline serum 25-hydroxyvitamin D level, number of T2 lesions, body mass index, EDSS, steroid treatment, and CIS onset type.
  
  
  RESULTS
  We found no associations between any EBV IgG antibody or cotinine levels with conversion from CIS to MS or MS progression as measured by EDSS or activity clinically or on MRI. The relative risk of conversion from CIS to clinically definite MS was 1.14 (95% confidence interval 0.76-1.72) for the highest vs the lowest quintile of EBNA-1 IgG levels, and 0.96 (95% confidence interval 0.71-1.31) for cotinine levels >25 ng/mL vs <10.
  
  
  CONCLUSIONS
  Neither increased levels of EBV IgG antibodies, including against EBNA-1, nor elevated cotinine levels indicative of tobacco use, were associated with an increased risk of CIS conversion to MS, or MS activity or progression over a 5-year follow-up.
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany. kgorham@hsph.harvard.edu.
authors.forename: Kassandra L
authors.initials: KL
authors.lastname: Munger
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Fitzgerald
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: David H
authors.initials: DH
authors.lastname: Miller
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalbán
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Gilles
authors.initials: G
authors.lastname: Edan
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Suarez
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Ernst-Wilhelm
authors.initials: EW
authors.lastname: Radue
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Sandbrink
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Pohl
authors.affiliation: From the Departments of Nutrition (K.L.M., K.C.F., A.A.) and Epidemiology (A.A.), Harvard T.H. Chan School of Public Health, Boston, MA; Ottawa Hospital Research Institute (M.S.F.), Canada; Heinrich-Heine Universität (H.-P.H., R.S.), Düsseldorf, Germany; UCL Institute of Neurology (D.H.M.), London, UK; Hospital Universitari Vall d'Hebron (X.M.), Barcelona, Spain; CHU-Hôpital Pontchaillou (G.E.), Rennes, France; VU University Medical Center (F.B.), Amsterdam, the Netherlands; Bayer HealthCare Pharmaceuticals (G.S.), Montville, NJ; Medical Image Analysis Center (E.-W.R.), and Neurology, Departments of Medicine, Clinical Research and Biomedicine (L.K., C.P.), University Hospital Basel, Switzerland; Bayer HealthCare (R.S.), Berlin; and Department of Neurology (C.P.), University Hospital of Bonn, Germany.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ascherio
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D003367:Cotinine / Q000097:blood; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D009103:Multiple Sclerosis / Q000097:blood* / Q000175:diagnosis* / Q000453:epidemiology; D011446:Prospective Studies; D064424:Tobacco Use / Q000097:blood* / Q000453:epidemiology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007074:Immunoglobulin G; D003367:Cotinine