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Is the treatment effect of IFN- restored after the disappearance of neutralizing antibodies?

¹ Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
² Department of Neurology, Aalborg Hospital, Aalborg, Denmark; The Danish MS Treatment Register, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
³ National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
⁴ Institute for Inflammation Research, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; BioMonitor A/S, Copenhagen, Denmark

^* To whom correspondence should be addressed.

	Abstract

Objective

To establish whether multiple sclerosis (MS) patients, who have lost the therapeutic effect of interferon-beta (IFN-) owing to neutralizing antibodies (NAbs) and subsequently revert from a NAb-positive to a NAb-negative state under continued IFN--1b therapy, regain clinical effect after reversion.

Background

Several studies have shown that a significant proportion of patients treated with IFN- develop NAbs that hamper or abolish the therapeutic effect of IFN-. However, some patients, who become NAb-positive under treatment with IFN--1b, may revert to a NAb-negative state under continuous treatment.

Methods

We identified 40 patients from the Danish IFN protocol, who fulfilled the criteria: NAb-positive status for at least 12 months followed by reversion to NAb-negative state for at least 12 months. For comparison, we included 64 matching cases that had remained NAb-negative during an observation time of at least 36 months. The two groups were clinically and demographically alike. We measured NAb-neutralizing capacity using a clinically validated cytopathic effect assay. A blood sample with a neutralizing capacity of 20% or more was considered as NAb-positive. A patient was defined as NAb-positive after two consecutive blood tests separated by at least 6 months. Reversion to a NAb-negative state required at least two consecutive negative tests. To allow for the confounding effect of time we employed a mixed Poisson model.

Results

Patients who had been NAb-positive and reverted to a NAb-negative state regained treatment effect with the relapse rate as before the NAb-positive period adjusting for the effect of time, and the relapse rate was the same as in the permanently NAb-negative patients in corresponding time periods. The relapse rate ratio comparing the NAb-positive with the NAb-negative periods was 1.98 (95% confidence interval: 1.32–2.97).

Conclusion

Under NAb-positive periods, the clinical effect of IFN- was abolished. When NAbs disappeared spontaneously under continued treatment, patients regained the full effect of INF--1b therapy with no negative carry-over effect from the previous NAb-positive period.

Key Words: interferon-beta, interferon-beta antibodies, multiple sclerosis, neutralizing antibodies, therapy, treatment effect

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