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J Neurol (2004) 251 [Suppl 2] : II/1II/3

DOI 10.1007/s00415-004-1201-x

Hans-Peter Hartung
Huub Schellekens
Frederick E. Munschauer III


Neutralizing antibodies to interferon beta

in patients with multiple sclerosis: scientific
background and clinical implications

Interferon beta (IFN) and glatiramer acetate are the

standard of care for the treatment of patients with relapsing MS. Three different IFN formulations are available for the treatment of MS: IFN-1b (Betaseron,
Berlex Laboratories, Montville, N. J., USA; Betaferon,
Schering, Berlin, Germany), IFN-1a-Avonex (Biogen,
Inc., Cambridge, Mass., USA), and IFN-1a-Rebif
(Serono, Inc., Rockland, Mass., USA). However, one of
the challenges associated with use of all protein therapeutics, including the use of IFN treatment in patients
with MS, is the development of neutralizing antibodies
Clear evidence exists in the MS literature of the differences in immunogenicity among IFN products, with
studies showing that 28 % to 47 % of patients develop
NAbs to IFN-1b [2, 8, 19], 12 % to 28 % develop NAbs to
IFN-1a-Rebif [2, 1416, 18], and 2 % to 6 % develop
NAbs to IFN-1a-Avonex [3, 7, 10, 14, 20]. Hence, IFN1b therapy is more immunogenic than IFN-1a therapy,
Hans-Peter Hartung, MD
Heinrich-Heine University
Department of Neurology
Dsseldorf, Germany
Huub Schellekens, MD
Central Laboratory Animal Institute and Department
of Innovation Studies
Utrecht University
Utrecht, The Netherlands
Frederick E. Munschauer III, MD
The Jacobs Neurological Institute
Buffalo General Hospital
Buffalo, New York, USA

JON 1201

Professor Hans-Peter Hartung, MD ()

Department of Neurology
Heinrich-Heine University
Moorenstrasse 5
40225 Dsseldorf, Germany
Tel.: +49-211-81-17880
Fax: +49-211-81-1869
E-Mail: hans-peter.hartung@uni-duesseldorf.de

and IFN-1a-Rebif treatment is more immunogenic

than IFN-1a-Avonex treatment. Factors that likely contribute to differences in immunogenicity among these
formulations include differences in chemical structure,
route of administration, dose, and frequency of administration [3, 11, 12, 19].
The clinical significance of NAbs to IFN has been a
controversial issue within the medical community. This
controversy likely stems from a general lack of consensus regarding how and when NAbs should be measured,
who should be tested for NAbs, and which titer levels
should be considered clinically relevant. However,
recognition is increasing that NAbs reduce the therapeutic efficacy of IFN; data from phase III studies [4, 9]
and extensions of large phase III clinical trials [16] have
shown diminished clinical efficacy of IFNs in patients
who have a positive result on NAb testing compared
with those who have a negative result. This phenomenon
is not unique to IFN in patients with MS; antibodies to
other protein-based therapies have been shown to have
adverse effects on clinical outcomes [21]. For example,
antibodies to factor VIII result in neutralization of its
clotting effects in hemophilia [13] and antibodies to
IFN-alpha are associated with a loss of efficacy in patients with hepatitis or cancer [1, 5, 6, 17, 22]. Therefore,
it is important for neurologists to consider the potential
for the development of NAbs to effectively manage patients with MS on IFN therapy.
This supplement is based on the proceedings of an
international consensus conference, which was held on
August 30, 2002, in Paris, France. At this conference,
neurologists and other experts from 11 countries who
specialize in the treatment of MS explored issues related
to the development of NAbs to IFNs. The goals of this
meeting were to [1] review the state of the art for NAb
testing, [2] reach a consensus on the clinical relevance of
NAbs to IFNs in patients with MS, and [3] establish a
framework for the development of patient management
guidelines. Topics that are addressed in the supplement


include the following: the mechanism of action of IFN

in the treatment of MS; immunogenicity of other protein therapeutics; incidence and significance of NAbs
reported during clinical studies of IFN in MS; and
types of assays used to measure NAbs to IFN.
This supplement concludes with recommendations
for monitoring NAbs and provides neurologists with options for managing patients who develop NAbs. It is
hoped that the information provided herein will ultimately reduce the risk of development of NAbs during
IFN therapy, maximize clinical outcomes, and optimize
the choice of therapy in this patient population.
Acknowledgments The participation of the following individuals
in the consensus conference is gratefully acknowledged: Antonio

Bertolotto, MD, Centro Riferimento Regionale Sclerosi Multipla, Orbassano, Italy; Nicole Casadevall, MD, Hopital Hotel Dieu, Paris,
France; Juha-Pekka Erlinna, MD, Finnish Special Neurology Center,
Turku, Finland; Professor Hans-Peter Hartung, Heinrich-Heine University, Dsseldorf, Germany; Professor Thibault Moreau, Hopital
General, Dijon, France; Professor Alfons Billiau, Rega Institute University of Leuven, Leuven, Belgium; Professor Florian Deisenhammer,
University of Innsbruck, Innsbruck, Austria; Paolo Gallo, MD, Clinica
Neurologica Prima, Padova, Italy; Professor Reinhard Hohlfeld, MaxPlanck-Institute for Neurobiology, Martinsried, Germany; Frederick
Munschauer, MD, The Jacobs Neurological Institute, Buffalo General
Hospital, Buffalo, New York, USA; Professor George Rice, Multiple
Sclerosis Clinic, London, Ontario, Canada; Pierrette Seeldrayers, MD,
CHU Charleroi, Charleroi, Belgium; Timothy Vartanian, MD, PhD,
Harvard Institute of Medicine, Boston, Mass., USA; Huub Schellekens,
MD, Utrecht University, Utrecht, The Netherlands; Professor Per
Slberg Srensen, Rigshospitalet, Copenhagen, Denmark.

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