Appearance and disappearance of neutralizing antibodies during interferon-beta therapy
Sorensen PS, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtzen K; Danish Multiple Sclerosis Study Group;
Commented by , 23 Oct 2005
Background
The importance of therapy-induced neutralizing antibodies (NABs) against interferon beta (IFNb) has recently been revealed. Several clinical studies show, that NABs reduce the effect of INFb on relapse rate and MRI disease activity measurements, in patients with multiple sclerosis (MS). Controversy still exists regarding the appearance and disappearance of NABs, which the current study focuses on.
Aim
To analyze the appearance and persistence of NABs in MS patients treated with different commercially available INF-beta preparations.
Methods
The authors studied a nationwide cohort of MS patients, all receiving treatment with INFb for at least 24 months. An antiviral neutralization bioassay was used to measure NABs blindly from six months up to 78 months.
The patients were classified into three groups: Persistently NAB-negative (no positive samples), definitely NAB-positive (at least two consecutive NAB-positive samples with neutralizing capacity of 20% or more) and patients with fluctuating positive and negative NAB samples.
Results (selected)
A total of 455 patients were included in a modified intention to treat analysis. The authors found 52.3% persistently NAB-negative patients, 40.9% definitely NAB-positive and 6.8% fluctuating.
There were significant differences between the three IFNb preparations, since more patients treated with INFb-1a (Avonex) 30 mg once weekly, remained NAB-negative compared with INFb-1b (Betaferon) 250 mg every other day (p<0.0001) or INFb-1a (Rebif) 22/44 mg three times a week (p<0.0001).
The cumulative risk of becoming definitely NAB-positive at a high level was 0.08 at 12 months (CI 0.05– 0.10) and 0.38 at 60 months (CI 0.30-0.40). Again, Avonex was significantly less immunogenic than Betaferon and Rebif.
Of 169 definitely NAB-positive patients 34% subsequently became definitely NAB-negative. There was a significant preponderance of patients receiving Betaferon compared with Rebif in this group (p=0.005; Avonex not included since there were only seven patients).
Dr Blinkenberg's comments
The study show that NABs develops in a considerable proportion of patients treated with INFb and that there are large differences between commercial preparations.
The study corroborates the notion that Avonex is much less immunogenic compared with the other INFb preparations. Previous head to head studies of INFb efficacy, have shown superiority of Rebif and Betaferon compared with Avonex (ref. 1, ref. 2), but the current study questions whether this advantage should be weighted, compared with the increased risk of risk of inducing NABs to all INFb preparations.
The study also show that clinically important NABs may not occur until after 12 to 18 months of therapy, and the effect of NABs in short clinical trials (including the two head to head trials) of INFb are most likely not reflected in the results.
Still, NABs may disappear in NAB positive patients and immune tolerance may be re-established, which was true for a higher proportion of patients treated with Betaferon compared with Rebif. These results are interesting but need to be confirmed before conclusions can be made in a clinical context.
The authors suggest that NAB measurements can be discontinued in patients who remain NAB negative for 24 months during INFb therapy, since they rarely become NAB positive.
Patients who are definitely NAB positive during 12 through 30 months, usually remain positive for years, although some may convert to negative status. Whether converted patients may benefit from continued INFb treatment is currently unknown.
References
1. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2000; 359; 1453-1460
2. Panitch H, Goodin DS, Francis G, Chang P, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 2002; 59; 1496-1506