1816 Variable Sex Female Male Mean ± SD age on diagnosis of MS, years Mean ± SD time since diagnosis of MS, years Mean ± SD age on starting natalizumab, years Clinical form of MS prior to starting natalizumab Relapsing–remitting Secondary progressive Prior MS treatments No Yes One prior treatment Two prior treatments [2 prior treatments Interferon beta 1a SC Interferon beta 1b SC Interferon beta 1a IM Glatiramer acetate Immunosuppressants Mitoxantrone Methotrexate Cyclophosphamide Azathioprine Other treatments EDSS score in year prior to treatment Annualized relapse rate in year prior to starting natalizumab No. of T1 Gd-enhancing lesions prior to natalizumab 0 lesions 1–5 lesions 6–9 lesions [9 lesions n = 1,364 944 (69.3%) 418 (30.7%) 29.6 ± 8.50 9.62 ± 5.65 39.2 ± 8.95 1,173 (86.8%) 178 (13.2%) 95 (7.0%) 1,268 (93%) 603 (44.2%) 431 (31.6%) 234 (17.1%) 655 (51.7%) 447 (35.3%) 364 (28.7%) 330 (26.0%) 113 (8.9%) 98 (7.7%) 7 (0.6%) 9 (0.7%) 4 (0.3%) 120 (9.5%) 3.0 (0.0–8.0) 2.0 (1–14) 530 (47.7%) 467 (42.0%) 49 (4.4%) 66 (5.9%) EDSS Expanded Disability Status Scale, IM intramuscular, MS mul- tiple sclerosis, SC subcutaneous received two or more prior treatments (up to a maximum of six). Overall, 113 (8.9%) had received prior immunosup- pressive therapy (mainly mitoxantrone). The reasons for switching to natalizumab were cited as lack of efﬁcacy in 75.2%, poor tolerability in 18.5%, and patient decision in 6.2% (more than one reason possible). The median number of natalizumab infusions received was 16.0 (range 1–50). In total, 287 (21.0%) had received natalizumab for more than 2 years. One patient, who had been enrolled in a clinical trial with natalizumab, had received natalizumab for more than 4 years (natalizumab has only been available in Spain since 2007). 123 Table 1 Demographic and baseline disease characteristics Safety data: discontinuation of treatment J Neurol (2012) 259:1814–1823 Overall, 176/1,249 patients (14.1%) discontinued treat- ment. Reasons for discontinuation were cited as lack of efﬁcacy [37/1,249 (3.0%)], tolerability [36/1,249 (2.9%)], and patient decision [36/1,249 (2.9%)]. Other reasons for discontinuation were pregnancy or desire to become pregnant [15/1,249 (1.2%)], neutralizing antibodies [34/ 1,082 (3.1%)], and hypersensitivity [46/1,284 (3.6%)] (more than one reason possible). Most discontinuations occurred in the ﬁrst year [103/176 (58.5%), of which 55 (31.3%) occurred within 6 months of starting natalizumab]. Discontinuations due to lack of efﬁcacy tended to occur between 6 and 12 months after starting treatment [19/37 (51.4%)], whereas discontinua- tions due to tolerability tended to occur in the ﬁrst 6 months [20/36 (55.6%)]. Of note was one discontinuation due to PML after 13 infusions and another due to suspected PML (later con- ﬁrmed) after 14 infusions. The patient with conﬁrmed PML had the secondary progressive form of the disease (EDSS of 5.5 on starting treatment) and had undergone bone marrow transplant prior to initiating treatment with natal- izumab. The patient with suspected PML had the relaps- ing–remitting form, but his EDSS score had increased from 4.5 in the year prior to treatment to 5.5 on initiating treatment. She did not have a history of treatment with immunosuppressants. Limited data are available on patients after discontinu- ation of natalizumab (n = 112). Of the 82 who were doc- umented to have received treatment, 78 had details available. The most common treatments after discontinua- tion of natalizumab were glatiramer acetate [16/78 (20.5%)] and mitoxantrone [13/78 (16.7)]. Reactivation of the dis- ease was reported in 47 out of 136 patients with data available (34.6%) during follow-up. Reactivation was in the form of relapses in 93%, MRI lesions in 31%, and increased EDSS in 50%, and almost half (47.6%) had more than one form of disease reactivation. The median time to disease reactivation was 3.5 months (range 1.0–24.0 months). Safety data: hypersensitivity reactions, neutralizing antibodies, and concomitant infections Hypersensitivity reactions were reported in 46 patients (3.6%), although as noted above, only ten of these patients actually withdrew due to such reactions. Thirty-four patients, that is, 2.5% of the entire population and 3.1% of the 1,082 with information on neutralizing antibodies, had positive status in an antibody test. We note, however, that patients were only tested in the event of suspicion of neutralizing antibodies and that this test had only been performed in approximately 20% of these patients.