J Neurol (2012) 259:1814–1823 Table 4 Comparison of patients enrolled in observational studies and the AFFIRM trial Reference Country/no. centers No. patients Duration of treatment Putzki et al. [8] Oturia et al. [9] Germany and Switzerland/5 Denmark/2 Sangalli et al. [10] Italy/3 Outteryck et al. [12] Prosperini et al. [11] Mancardi et al. [15] Putzki et al. [16] Piehl et al. [17] Ferna´ndez et al. [18] Horga et al. [19] Ferna´ndez et al.d AFFIRM/Polman et al. [4] France/not statedb Italy/1 Italy/164 Switzerland/3 Sweden/36 Spain/1 Spain Spain/86 Multinational/99 97 (six previously untreated) C12 months 234 (175 after switching from DMT, 45 switching from mitoxantrone, 14 treatment na¨ıve) 285 (233 after switching treatment, 52 treatment na¨ıve) 384 (5.6% treatment na¨ıve; efﬁcacy data for 127) 190 (efﬁcacy data for 169) 2,971 85 (after failure of DMT) 1,115 77 112 1,415 627 (natalizumab) 315 (placebo) Median 11.3 months (range 3–21.5 months) Up to 2 years C12 months Median 15 (range 1–29 months) – Median 17.2 (range 12–31.4 months) Mean 22 months Mean 14.7 months Mean 15.8 months Median 16 (range 1–50) 2 years ARR annualized relapse rate, DMT disease-modifying therapy, EDSS Expanded Disability Status Scale a Median b Data reported for two regions c For the 363 patients who completed 24 months of treatment d This study Mean ARR in year prior to treatment 2.3 2.53 2.13 2.19 2.0 – 2.0 – 0.96 2.25 2.23 1.53 (natalizumab) 1.50 (placebo) 1819 Mean baseline EDSS 3.4 4.0a Not reported 3.53 3.4a – 3.1 3.86c 3.18 4.0 3.23 2.53 observed in terms of reducing ARR and EDSS (Table 5). In all cases, the ARR is reduced to 0.2–0.3. An important outcome measure of treatment is whether patients are dis- ease free. Deﬁnitions vary, but in our study, we considered patients who had stable EDSS (increase \1.0), no relapses, and no Gd-enhancing or new T2-hyperintense lesions on MRI at 1 year. According to our deﬁnition, 63% of the patients were disease free at 1 year. This is similar to the 68% reported in the study by Prosperini et al. [11] using a similar deﬁnition. Our data are also in agreement with the ﬁndings to date of the Tysabri Observational Program (TOP), which has enrolled more than 3,000 patients treated with natalizumab in a clinical practice setting [18]. As of June 2010, 2,150 patients had been enrolled (58% with EDSS C3.5 com- pared with 46% in our study). The mean ARR before starting natalizumab was 1.98. After natalizumab treat- ment, the ARR had decreased to 0.26. A similar picture also emerges from the STRATA study, which enrolled patients who had participated in clinical trials for a further 48 weeks of treatment [19]. Thus the ARR remained low (0.18), even after median total number of natalizumab infusions of 37. The discontinuation rate in our study was 14%, which is slightly higher than most of the other observational studies (Table 6). This might be partly explained by the longer duration of follow-up than in most other studies. There was one discontinuation due to PML and one due to probable PML. Given that the case of suspected PML was later conﬁrmed, the incidence of PML in our study was 0.15%. This is somewhat higher than in an Italian observational study of the safety data which reported a rate of 0.03% [13] but lower than the 0.27% reported by a surveillance study in Sweden [15]. In a review of data from clinical trials, Yousry et al. [20] concluded that the risk of PML was approximately 0.1%. This ﬁgure, however, included two cases from the SEN- TINEL clinical trial in which natalizumab was given in combination with interferon beta 1a, and the approved label forbids concomitant treatment with other disease-modifying 123