| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
From the Departments of Neurology and Research (Dr. Kappos) and Neuroradiology (Dr. Radue), University Hospital Basel, Switzerland; Service de Neurologie (Dr. Clanet), CHU-H
pital Purpan, Toulouse, France; Department of Neurology (Dr. Hartung), Heinrich-Heine-Universität, Düsseldorf, and Neurology Clinic (Dr. Hohlfeld), Munich, Germany; Department of Neurology (Dr. Sandberg-Wollheim), University Hospital, Lund, Sweden; and Biogen Idec, Inc. (Drs. Xu, Bennett, Sandrock, and Goelz), Cambridge, MA.
Address correspondence and reprint requests to Dr. L. Kappos, Department of Neurology, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland; e-mail: lkappos{at}uhbs.ch
Objective: To determine the incidence and clinical significance of neutralizing antibody (NAb) formation in patients with relapsing multiple sclerosis (MS) who participated in the European Interferon Beta-1a IM Dose-Comparison Study.
Methods.: Patients were randomized to treatment with interferon ß-1a (IFNß-1a) 30 µg or 60 µg IM once weekly for up to 4 years. Serum samples obtained at baseline and every 3 months thereafter were screened for the presence of IFN binding antibodies by ELISA. Patients whose results were seropositive on ELISA were screened for the presence of NAbs using an antiviral cytopathic effect assay. Patients were considered to be positive for NAbs (NAb+) if the baseline NAb titer was 0 and two or more consecutive postbaseline titers were 
20. Patients were considered to be negative for NAbs (NAb–) if the baseline NAb titer was 0 and all postbaseline NAb titers were <5.
Results: The proportion of patients who became NAb+ was lower in patients who received 30 µg of IFNß-1a than in those who received 60 µg (7/400 [1.8%] vs 19/395 [4.8%]; p = 0.02). The mean time to NAb+ status was 14.5 ± 6.2 months. Compared with patients who remained NAb–, NAb+ patients showed the following: higher relapse rates from months 12 to 48 (p = 0.04), higher rate of mean change (worsening) in Expanded Disability Status Scale score from baseline to month 48 (p = 0.01), greater number of T1 gadolinium-enhanced lesions at months 24 and 36 (p = 0.02 and 0.03), and greater accrual of new or enlarging T2 lesions from month 12 to months 24 and 36 (p = 0.05 and 0.09)
Conclusions: Neutralizing antibodies (NAbs) to interferon ß-1a (IFNß-1a), as observed with other IFNßs used in the treatment of multiple sclerosis, reduce the therapeutic benefits measured by relapses and MRI activity. Data from this study also suggest NAbs to IFNß-1a reduce treatment benefits as measured by change in Expanded Disability Status Scale score.
Editorial, see page 6
Supported by Biogen Idec, Inc. L. Kappos is supported by the Swiss Multiple Sclerosis Society.
L. Kappos, M. Clanet, E.W. Radue, H.P. Hartung, and R. Hohlfeld have received research support, remuneration for consulting, participation in clinical trials, and advisory board and steering committee membership, as well as speaker honoraria from companies involved in the development and marketing of drugs for treatment of multiple sclerosis, including Biogen Idec, Inc. All payments to L. Kappos were exclusively used for research projects at the Department of Neurology. J. Xu, D. Bennett, A. Sandrock, and S. Goelz are employees of and own stock in Biogen Idec Inc.
Received December 3, 2004. Accepted in final form May 10, 2005.
Related Articles
Neurology 2005 65: 2-3.
Neurology 2005 65: 33-39.
Neurology 2005 65: 48-55.
Neurology 2005 65: 6-8.
This article has been cited by other articles:
|
|
 |
|
  N Koch-Henriksen, P. Sorensen, K Bendtzen, and E. Flachs The clinical effect of neutralizing antibodies against interferon-beta is independent of the type of interferon-beta used for patients with relapsing-remitting multiple sclerosis Multiple Sclerosis, May 1, 2009; 15(5): 601 - 605. [Abstract] [PDF]
|
|
|
|
|
|
M Ravnborg, K Bendtzen, O Christensen, P. Jensen, D Hesse, M. Tovey, and P. Sorensen Treatment with azathioprine and cyclic methylprednisolone has little or no effect on bioactivity in anti-interferon beta antibody-positive patients with multiple sclerosis Multiple Sclerosis, March 1, 2009; 15(3): 323 - 328. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Gilli, P. Valentino, M. Caldano, L. Granieri, M. Capobianco, S. Malucchi, A. Sala, F. Marnetto, and A. Bertolotto Expression and regulation of IFN{alpha}/{beta} receptor in IFN{beta}-treated patients with multiple sclerosis Neurology, December 9, 2008; 71(24): 1940 - 1947. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Soelberg Sorensen Review: Neutralizing antibodies against interferon-beta Therapeutic Advances in Neurological Disorders, September 1, 2008; 1(2): 125 - 141. [Abstract] [PDF]
|
|
|
|
|
|
P. Sorensen, N Koch-Henriksen, E. Flachs, and K Bendtzen Is the treatment effect of IFN-{beta} restored after the disappearance of neutralizing antibodies? Multiple Sclerosis, July 1, 2008; 14(6): 837 - 842. [Abstract] [PDF]
|
|
|
|
 |
|
 J. Killestein and H.-P. Hartung Interferon {beta} in multiple sclerosis: predicting response at an early stage J. Neurol. Neurosurg. Psychiatry, June 1, 2008; 79(6): 616 - 617. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Krumbholz, H. Faber, F. Steinmeyer, L.-A. Hoffmann, T. Kumpfel, H. Pellkofer, T. Derfuss, C. Ionescu, M. Starck, C. Hafner, et al. Interferon-{beta} increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity Brain, June 1, 2008; 131(6): 1455 - 1463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Farrell, R. Kapoor, S. Leary, P. Rudge, A. Thompson, D. Miller, and G. Giovannoni Neutralizing anti-interferon beta antibodies are associated with reduced side effects and delayed impact on efficacy of Interferon-beta Multiple Sclerosis, March 1, 2008; 14(2): 212 - 218. [Abstract] [PDF]
|
|
|
|
|
|
A Sominanda, J Hillert, and A Fogdell-Hahn In vivo bioactivity of interferon-beta in multiple sclerosis patients with neutralising antibodies is titre-dependent J. Neurol. Neurosurg. Psychiatry, January 1, 2008; 79(1): 57 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Sorensen, A. Bertolotto, and D. S. Goodin Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: An evidence report: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Neurology, October 9, 2007; 69(15): 1552 - 1553. [Full Text] [PDF]
|
|
|
|
|
|
P. A. Calabresi, G. Giovannoni, C. Confavreux, S. L. Galetta, E. Havrdova, M. Hutchinson, L. Kappos, D. H. Miller, P. W. O'Connor, J. T. Phillips, et al. The incidence and significance of anti-natalizumab antibodies: Results from AFFIRM and SENTINEL Neurology, October 2, 2007; 69(14): 1391 - 1403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Garg, B. Weinstock-Guttman, K. Bhasi, J. Locke, and M. Ramanathan An association between autoreactive antibodies and anti-interferon-{beta} antibodies in multiple sclerosis Multiple Sclerosis, August 1, 2007; 13(7): 895 - 899. [Abstract] [PDF]
|
|
|
|
|
|
P. Sorensen, N. Koch-Henriksen, and K. Bendtzen Are ex vivo neutralising antibodies against IFN-{beta} always detrimental to therapeutic efficacy in multiple sclerosis? Multiple Sclerosis, June 1, 2007; 13(5): 616 - 621. [Abstract] [PDF]
|
|
|
|
|
|
R. A Farrell and G. Giovannoni Measuring and management of Anti-Interferon Beta Antibodies in subjects with Multiple Sclerosis Multiple Sclerosis, June 1, 2007; 13(5): 567 - 577. [Abstract] [PDF]
|
|
|
|
|
|
R. Zivadinov, L. Locatelli, D. Cookfair, B. Srinivasaraghavan, A. Bertolotto, M. Ukmar, A. Bratina, C. Maggiore, A. Bosco, A. Grop, et al. I nterferon beta-1a slows progression of brain atrophy in relapsing-remitting multiple sclerosis predominantly by reducing gray matter atrophy Multiple Sclerosis, May 1, 2007; 13(4): 490 - 501. [Abstract] [PDF]
|
|
|
|
|
|
S. E. Goelz and L. Walt Development of neutralizing antibodies to intramuscular interferon beta-1a (Avonex (R)) Multiple Sclerosis, May 1, 2007; 13(1_suppl): 14 - 20. [Abstract] [PDF]
|
|
|
|
|
|
F. Blanchette Clinical significance of glatiramer acetate antibodies Multiple Sclerosis, May 1, 2007; 13(1_suppl): 28 - 35. [Abstract] [PDF]
|
|
|
|
|
|
J. Oger and E. Gibbs Binding antibodies: Vancouver's perspective Multiple Sclerosis, May 1, 2007; 13(1_suppl): 36 - 43. [Abstract] [PDF]
|
|
|
|
|
|
A.T. Reder Neutralizing antibodies in multiple sclerosis: a complex impact on interferon responses, magnetic resonance imaging findings and clinical outcomes Multiple Sclerosis, May 1, 2007; 13(1_suppl): 53 - 62. [Abstract] [PDF]
|
|
|
|
|
|
D. S. Goodin, E. M. Frohman, B. Hurwitz, P. W. O'Connor, J. J. Oger, A. T. Reder, and J. C. Stevens Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: An evidence report: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Neurology, March 27, 2007; 68(13): 977 - 984. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Sominanda, U Rot, M Suoniemi, F Deisenhammer, J Hillert, and A Fogdell-Hahn Interferon beta preparations for the treatment of multiple sclerosis patients differ in neutralizing antibody seroprevalence and immunogenicity Multiple Sclerosis, March 1, 2007; 13(2): 208 - 214. [Abstract] [PDF]
|
|
|
|
|
|
C Gneiss, P Tripp, F Reichartseder, R Egg, R Ehling, A Lutterotti, M Khalil, B Kuenz, I Mayringer, M Reindl, et al. Differing immunogenic potentials of interferon beta preparations in multiple sclerosis patients Multiple Sclerosis, November 1, 2006; 12(6): 731 - 737. [Abstract] [PDF]
|
|
|
|
|
|
F Gilli, F Hoffmann, A Sala, F Marnetto, M Caldano, P Valentino, L Kappos, A Bertolotto, and R L. Lindberg Qualitative and quantitative analysis of antibody response against IFN{beta} in patients with multiple sclerosis Multiple Sclerosis, November 1, 2006; 12(6): 738 - 746. [Abstract] [PDF]
|
|
|
|
 |
|
 T J Murray Diagnosis and treatment of multiple sclerosis. BMJ, March 4, 2006; 332(7540): 525 - 527. [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Frohman, O. Stuve, E. Havrdova, J. Corboy, A. Achiron, R. Zivadinov, P. S. Sorensen, J. T. Phillips, B. Weinshenker, K. Hawker, et al. Therapeutic Considerations for Disease Progression in Multiple Sclerosis: Evidence, Experience, and Future Expectations Arch Neurol, October 1, 2005; 62(10): 1519 - 1530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Giovannoni and A. Goodman Neutralizing anti-IFN-{beta} antibodies: How much more evidence do we need to use them in practice? Neurology, July 12, 2005; 65(1): 6 - 8. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
