Background.
The production of neutralizing antibodies (NAB) may be associated with a reduction in clinical effectiveness of interferon beta 1b (IFN beta-1b). However, there are some NAB-positive patients who continue to do well, so the relationship between the clinical state and the NAB state is not constant. Approximately 90% of NAB-positive patients become so between six and 18 months of therapy. In the IFN beta-1b clinical trial, the data indicate that the relapse rate in NAB-positive patients after 18 months of high dose IFN beta-1b reverted to a level similar to placebo treated patients. NAB-negative patients on high dose IFN beta-1b continued to show progress, with a relapse rate of one half of both the NAB-positive patients and the placebo patients.
In order to help in clinical decision-making, a test for the detection of neutralizing antibodies is available for physicians who wish to evaluate their patients for the presence of NAB. It is important to use a valid test with a biological end-point as non-neutralizing antibodies to interferons also occur in both the general population and in patients treated with the drug. Also, neutralizing antibodies are a response to the antiviral effects of the interferon, and may not represent the immunological effects. Currently, only neutralizing antibodies are associated with a reduction of some of the clinical benefits and the side effects of IFN beta-1b. The mechanism of the effects of NAB is unknown. No specific or new pathology has been associated with the occurrence of non-neutralizing or neutralizing antibodies.
The following guidelines should facilitate decisions about neutralizing antibody testing. The test currently available (MxA) correlates well with the original NAB tests used in the IFN beta-1b clinical trial. The MxA assay relies upon the response of a gene called the myxovirus resistance gene A to interferon beta 1b in tissue culture. Detailed information on the MxA assay is included with the testing information package. When patients are doing poorly and two consecutive blood samples at least three months apart have appropriately positive titers, the patient should be considered NAB positive. The possibility of stopping the drug should be discussed with the patient.
There is no evidence that a patient's condition is worsened by NAB. However, the long term impact of any of these antibodies is not understood. Also, a significant number of patients who are found to be NAB positive will revert to a negative state at some point.
The understanding of the clinical effect of NAB is an evolving one; these guidelines will be revised as more data become available.
Guidelines
1. Requirements for NAB Testing.
Each patient to be considered for NAB testing must have been on IFN beta-1b continuously for at least one year, and in the physician's opinion must be doing poorly. If a positive titer is obtained, the patient should be retested within 3 months. Patients who are doing well need not be tested.
2. Interpretation of Results.
After two consecutive appropriate titers at least three months apart, an NAB-positive result is determined.
3. Clinical Criteria to Consider for Stopping the IFN beta-1b.
Treatment Failure (patients doing poorly).
a. Steady documented progression of disability for 6 months or more.
b. Three or more disabling exacerbations per year requiring steroids or hospitalization or both.
If treatment failure occurs and the patient is found to be NAB positive, consider stopping IFN beta-1b. It is helpful to know the NAB status of the patient over a longer period of time to make the final decision regarding stopping the drug.
Patients known to be NAB negative need not be tested beyond two years of therapy as very few patients become positive after 18 months.
Patients who are NAB negative should be kept on the drug unless there is overwhelming evidence for treatment failure. IFN beta-1b is a partially effective preventive treatment. Even though patients may seem to be doing poorly, they could have been much worse untreated.
For information on the availability and technical aspects of the MxA assay in the USA, please phone Berlex Laboratories Professional Services Department at 1-800-888-4112 (USA only), 8:00 AM to 5:00 PM Pacific Time.
- Copyright 1996 by Advanstar Communications Inc.
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