Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis
Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K, Kristensen O, et al;
Commented by , 21 Nov 2003
Background
Interferon beta (INF-beta) has well documented effect on frequency and severity of relapses, as well as disease progression in MS. However, 7 to 42% of treated patients develop neutralising antibodies against INF-beta (NAB) questioning the effect of treatment. Some of these patients are not persistent positive, which means that they revert to NAB negative (NAB-) status, although INF-beta treatment is ongoing.
The clinical significance of NAB is still not clarified, and recent guidelines still recommend, that treatment change is to be based on clinical symptoms and not NAB status (Wolinsky et al., Lancet Neurology 2003;2:528). In the current study the authors challenge this viewpoint in an extensive prospective study.
Aim
To assess the clinical effect of neutralising antibodies.
Methods
Neutralising antibodies was measured every 12 months, for up to 60 months, in all patients who started INF-beta in Denmark between 1996 and 1999. Results were recorded in a national multiple sclerosis database. Clinical data (e.g. EDSS score and relapse rate) was also contained in the database.
Samples were assessed from 541 patients who were treated with Betaferon, Rebif or Avonex in recommended dose. Patients who changed or discontinued treatment left the study. An antiviral neutralisation bioassay, with high, medium and low sensitivity, was used to analyse the blinded samples. Different neutralising capacities were used as cut off value for definition of a neutralising antibody-positive result.
Results
Relapse rates were significantly higher during antibody-positive (NAB+; defined as 20% neutralising capacity as cut off in a medium sensitivity assay) periods compared with NAB- periods (0,64-0,70 vs. 0,43-0,46; p<0,03). Odds ratios were in the range of 1,51-1,58 (p<0,03) for these data. Time to first relapse was increased by 244 days in NAB- patients at 12 months (log rank test 6,38, p=0,009).
Results depended considerably on sensitivity of assay, especially between high and medium sensitivity (see original paper for details). The presence of NAB did not affect disease progression measured with EDSS.
Discussion
The paper provides valuable information on a complex clinical issue. The authors demonstrate a considerable negative effect of NAB+ on clinical measurements. The effect was not seen in measurements of disability, and long term studies are needed in order to clarify this. MRI data was not presented in the paper, and these results are awaited for further evaluation.
An issue that the authors do not touch upon in the discussion is the group of patients converting from NAB+ to NAB- (17% between 12-24 months). Do these patients convert to a low relapse rate? What is the consequence of removing non-persistent NAB patients from the analysis?
A number of questions are still unanswered, and time will probably tell us more, since the study is still going on. Firm conclusions cannot be made regarding discontinuation of treatment in NAB+ patients, although the bulk of evidence suggesting reduced biological and therapeutic effect is increasing.
Decisions regarding treatment change should still be based on clinical grounds, although the study encourages the use of routine NAB measurements, in the clinical evaluation of the INF-treated MS patient.