Tohoku J. Exp. Med., 2012 Oct, 228(2)

Neutralizing Antibodies Are Associated with a Reduction of Interferon-β Efficacy during the Treatment of Japanese Multiple Sclerosis Patients

DOUGLAS KAZUTOSHI SATO,¹ ICHIRO NAKASHIMA,¹ TOSHIYUKI FUKAZAWA,² YUKO SHIMIZU,³ YUJI TOMIZAWA,⁴ KAZUMASA YOKOYAMA,⁴ TATSURO MISU,⁵ PAUL I. CREEKE,⁶ RACHEL FARRELL,⁷ GAVIN GIOVANNONI,⁶ YASUTO ITOYAMA,⁸ KAZUO FUJIHARA⁵ and MASASHI AOKI¹

¹Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
²Sapporo Neurology Clinic, Sapporo, Japan
³Department of Neurology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
⁴Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
⁵Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan
⁶Queen Mary University of London, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK
⁷University College London, Institute of Neurology, London, UK
⁸National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system. Interferon-β (IFN-β) has been used as the first line therapy for MS treatment in Japan, but patients treated with IFN-β may develop antibodies, known as neutralizing antibodies (NAbs), which abrogate its therapeutic effects. Intramuscular IFN-β 1a and subcutaneous IFN-β 1b are currently available in Japan, but large-scale studies evaluating the prevalence and clinical implications of NAbs against these IFN-β preparations in MS patients have only been performed in Caucasian populations. NAbs positivity has been reported to be associated with HLA-DRB1 alleles, suggesting that the positivity might differ among populations with distinct genetic backgrounds. Clinical information and sera were collected from 229 consecutive MS patients treated with IFN-β in 4 centers in Japan. Sera were tested for NAbs using a luciferase reporter gene assay. In total, 5.2% of IFN-β-1a-treated patients (4/77) and 30.3% of IFN-β-1b-treated patients (46/152) were positive for Nabs. The frequency of NAbs was highest in patients treated for 13 to 24 months. Clinical relapse and contrast-enhancing lesions in the magnetic resonance imaging increased together with NAbs titers in this group. In conclusion, the prevalence of NAbs in Japanese MS patients is similar to that in Caucasian populations and is associated with an increase in disease activity. Therefore, routine NAbs testing is recommended also in Asian populations to ensure the early identification of patients who would benefit from a change in therapy.

keywords —— beta-interferon; immunomodulatory therapy; multiple sclerosis; neutralizing antibodies; serologic tests

© 2012 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2012, 228, 85-92

Correspondence: Douglas Kazutoshi Sato, M.D., Department of Neurology, Tohoku University Graduate School of Medicine, 1-1, Seiryomachi, Aobaku, Sendai, Miyagi 980-8574, Japan.

e-mail:douglas.sato@med.tohoku.ac.jp