MS patients on IFN-β therapy, predominantly of northern European heritage, were recruited in Germany by primary-care physicians and neurologists. The initial study group included 268 individuals with known anti-IFN-β1 status. The ratio of males to females in the first cohort was 0.53. A total of 34 patients received IFN-β1a intramuscular injection (i.m.) once weekly (Avonex), 118 patients IFN-β1b subcutaneous injection (s.c.) every second day (Betaferon), 26 patients 22 μg and 90 patients 44 μg IFN-β1a s.c. three times a week (Rebif). The validation group compassed 242 patients with a male-female ratio of 0.36. Avonex treatment was administered to 68 patients, and Rebif was given to 88 individuals and 86 patients received Betaferon. As expected, IFN-β1a i.m. (Avonex)-treated patients were underrepresented in the study as a result of the lower frequency of antibody development in this group compared to patients treated with the formulations for s.c. application. Mean age was 39.8 yr in the first and 39.0 yr in the second group ( Table 1). Average treatment duration was 57 months in the first and 52 months in the second group. The duration of the drug exposure did not differ significantly among treatment groups. All patients gave their written informed consent. The study was approved by the ethics committees of the Universities of Düsseldorf and Munich.
Table 1 Clinical Characteristics of the Initial Study and Validation Groups
Initial Study Group (n = 268) Validation Group (n = 242)
Anti-IFN-β-Positive Patients Anti-IFN-β-Positive Patients
Parameter All AB+ (n = 136) NAB+ (n = 85) BAB+ (n = 51) Anti-IFN-β-Negative Patients (n = 132) All AB+ (n = 77) NAB+ (n = 59) BAB+ (n = 18) Anti-IFN-β-Negative Patients (n = 132)
Age in years [mean (range)] 40 (17–69) 40 (19–64) 41 (17–69) 39 (16–66) 39 (21–75) 39 (21–60) 39 (21–75) 39 (16–67)
Gender (male/female) 48/88 27/58 21/30 45/87 23/54 19/40 4/14 40/124
Therapy duration in months [mean (range)] 55 (16–147) 53 (16–147) 57 (17–112) 59 (12–156) 47 (7–127) 47 (7–111) 46 (20–127) 55 (7–146)
IFN-β1a (i.m., Avonex)-treated (n) 6 5 1 28 4 2 2 64
IFN-β1b (s.c., Betaferon)-treated (n) 70 37 33 48 36 24 12 50
IFN-β1a (s.c., Rebif 22 μg)-treated (n) 10 6 4 16 9 9 0 15
IFN-β1a (s.c., Rebif 44 μg)-treated (n) 50 37 13 40 28 24 4 36
cELISA, antibody reactivity (%) [median (range)] 74 (26–119) 91 (35–119) 48 (26–97) 3 (−9–23.5) 83 (35–140) 85 (57–140) 76 (35–96) 2 (−17–24)
In vivo MXA assays, induction (%) [median (range)] 23 (−64–135) −4 (−64–50) 89 (41–135) 92.6 (−12–93) 23 (−45–128) 17 (−45–57) 79 (53–128) 95 (70–202)
Both groups comprised a total of 510 IFN-β-treated subjects. Mean treatment duration exceeds 45 months in both cohorts. Ranges are given in brackets. Whereas the mean age of both groups was between 39 and 41 yr, the sex ratio differed among both groups. Females were slightly overrepresented in the validation group. Note that the number of BABs-positive subjects is higher in the IFN-β1b (Betaferon)-treated group.