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NAb-bed: Neutralizing Antibodies Block Benefits of ß-Interferon in MS

Certain treatment nonresponders should be tested for persistently elevated antibody levels.

The authors present prospective data on the effect of the neutralizing antibodies (NAbs) against interferon-ß (IFN-ß) in 78 people with relapsing-remitting multiple sclerosis (MS). Participants were treated for up to 3 years with one of the three approved preparations of IFN-ß: 20 patients received interferon ß-1b (Betaferon), 25 received subcutaneous interferon ß-1a (Rebif), and 33 received intramuscular interferon ß-1a (Avonex). The researchers measured antibody titers and recorded relapses every 3 months. Patients were divided into three groups based on their NAbs status: those persistently antibody-negative, those with the transient appearance of NAbs, and those with persistently elevated titers (i.e., on 2 tests). The researchers compared clinical outcomes in the first and third groups.

Betaferon induced persistent NAbs in 35% of recipients, Rebif in 20%, and Avonex in 3%. The presence of persistent NAbs was associated with a relatively poor clinical outcome according to all four clinical parameters tested (annual relapse rate, percentage of relapse-free patients, time between first and second relapse, and percentage with sustained disability). The differences reached statistical significance in all of the outcomes except the percentage of relapse-free patients. Poor outcomes persisted over time and, in some instances, these patients' conditions declined further over the 3-year study period.

Comment: These persuasive findings add to the mounting evidence that persistently elevated levels of neutralizing antibodies significantly reduce the effectiveness of IFN-ß in MS, in some instances to levels no better than placebo. Measurement of NAbs is costly, not necessarily covered by health insurance, and not readily available. Because NAbs may be transient, at least two positive values should be obtained before deciding that non-responsiveness to IFN-ß is due to the presence of NAbs. In addition, because MS is most likely a syndrome, with different pathogenic mechanisms, some patients may be nonresponsive to treatment for reasons other than the presence of NAbs. Not every nonresponder can be tested, so I test for NAbs in non-responding patients who are taking low-dose interferon ß-1a before changing them to a higher dose, and also in patients receiving high-dose IFN-ß who were doing well before substantive changes in their clinically- or MRI-evidenced disease activity. We badly need a simple, rapid, inexpensive assay for NAbs and a way to detect, a priori, patients who are genetically predisposed to mount an immune response to IFN-ß.

— Gary Birnbaum, MD

Dr. Birnbaum is Director, MS Treatment and Research Center, Minneapolis Clinic of Neurology, Golden Valley, MN, and Clinical Professor of Neurology, University of Minnesota School of Medicine, Minneapolis.

Published in Journal Watch Neurology September 10, 2004

Citation(s):

Malucchi S et al. Neutralizing antibodies reduce the efficacy of ßIFN during treatment of multiple sclerosis. Neurology 2004 Jun 8; 62:2031-7.

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