Interferon β-1b–neutralizing antibodies 5 years after clinically isolated syndrome

The objective of this is study is to determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon β-1b (IFNβ-1b).
In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study, patients were randomly assigned to 250 μg IFNβ-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNβ-1b for up to 5 years. NAb status was assessed every 6 months by the myxovirus protein A induction assay. A titer >20 NU/mL was considered NAb-positive, with low (≥20–100 NU/mL), medium (≥100–400 NU/mL), and high (≥400 NU/mL) titer categories. Here we examine early-treated patients, who received IFNβ-1b for up to 5 years.
NAbs were measured in 277 of 292 early-treated patients and detected at least once in 88 (31.8%) patients, with 53 (60.2%) reverting to NAb negativity by year 5. Time to CDMS, time to confirmed disability progression, and annualized relapse rate did not differ between NAb-positive and NAb-negative patients or between periods of NAb positivity vs NAb negativity within patients. Increases in newly active lesion number and T2 lesion volume and conversion to McDonald MS were associated with NAb positivity and were more pronounced with higher titers.

Table 1        Cross-sectional analyses for risk of CDMS, confirmed EDSS progression, and McDonald MS in NAb negative vs eventually NAb positive patients with 2 consecutively positive NAb measurements

Risk of event

HR (95% CI)
p Value
EDSS progression
HR (95% CI)
p Value
McDonald MS
HR (95% CI)
p Value
Positive (≥20 NU/mL) vs negative
0.77 (0.05–1.18)
p = 0.24
0.88 (0.50–1.54)
p = 0.28
1.54 (1.15–2.08)
p = 0.0044
Single model
Low titer (20–100 NU/mL) vs negative
0.73 (0.41–1.31)
p = 0.29
1.05 (0.51–2.15)
p = 0.99
1.41 (0.94–2.12)
p = 0.09
Medium titer (100–400 NU/mL) vs negative
0.91 (0.46–1.82)
p = 0.80
0.57 (0.18–1.83)
p = 0.34
1.71 (1.10–2.77)
p = 0.03
High titer (≥400 NU/mL) vs negative
0.71 (0.32–1.56)
p = 0.39
0.91 (0.05–1.18)
p = 0.85
1.62 (0.99–2.65)
p = 0.06
Abbreviations: CDMS = clinically definite multiple sclerosis; EDSS = expanded disability status scale; NAb = neutralizing antibody; HR = hazard ratio, CI = confidence interval.
*By Cox proportional hazards regression adjusted for age, gender, number of T2/gadolinium-enhancing lesions, mono-/multifocal presentation, and use of steroids at the time of a first clinical event suggestive of MS. Hazard ratios above 1.0 indicate increased risk.

In conclusion, although NAb positivity was associated with increased brain MRI activity, no discernible effects on clinical outcomes were found. This finding may reflect the greater power of MRI compared with clinical outcomes to detect the treatment effects of IFNβ-1b and may also result from temporal changes in NAb titers and biology.