1820 Reference Putzki et al. [8] Oturia et al. [9] Sangalli et al. [10] Outteryck et al. [12] Prosperini et al. [11] Putzki et al. [16] Piehl et al. [17] Ferna´ndez et al. [18] Horga et al. [19] Ferna´ndez et al.f AFFIRM/Polman et al. [4] ARR at 1 year 0.2 0.68 0.26 0.59 0.22 0.27 – 0.13 0.24 0.25 0.26 (natalizumab) 0.81 (placebo) 91 73 88 73 90a 87 – 86 89 88 83 54 Table 5 Comparison of efﬁcacy in observational studies and the AFFIRM trial Decrease in ARR at 1 year with respect to previous year (%)e Patients relapse free after 1 year (%) Change in mean EDSS after 1 year 80.4 63 84 (78% at 2 years) 60 85a 78b – – 80.3 80 77 (natalizumab) 56 (placebo) 0.4 – – 0.5 0.2c 0.2 0.48d 0.05 0.2 0.5e – J Neurol (2012) 259:1814–1823 Patients with EDSS progression (C1.p point increase) at 1 year (%) 10 9 – – – 7 – – 9.2 6 13 (natalizumab) 21 (placebo) ARR annualized relapse rate, EDSS Expanded Disability Status Scale a Calculated for entire follow-up period (up to 29 months) b Calculated for entire follow-up period (median 17.2 months) c At 15 months follow-up d For the 363 patients who completed 24 months of treatment e Change in median f This study Table 6 Comparison of safety outcomes and the AFFIRM trial Reference a Only reported if leading to discontinuation b Persistent and leading to discontinuation c Only patients with suspected antibodies were tested for neutralizing antibodies. Nevertheless the percentage is calculated with respect to the total population on the assumption that antibodies were only tested in the event of clinical suspicion d This study Putzki et al. [8] Oturia et al. [9] Sangalli et al. [10] Outteryck et al. [12] Prosperini et al. [11] 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] Discontinuations 8 (8.2%) 27 (12%) 34 (12%) 35 (9.1%) 31 (16.3%) 10 (12%) 116 (10.4%) 13 (16.8%) 16 (14.4%) 176 (14%) 3.8% (natalizumab) 4.8% (placebo) Hypersensitivity reactions 2 (2.1%)a 9 (3.8%) 18 (6.3%) 15 (3.9%) 4 (2.1%)a 2 (2.4%)a – 1 (1.3%) 5 (4.5%) 46 (3.6%) 9% (natalizumab) 4% (placebo) Neutralizing antibodies 4 (4.1%)b 7 (2.9%) 19 (6.6%) 5 (1.3%)b 19 (10%)c 6 (7.1%)b 39 (3.9%) 9 (11.7%) – 34 (3.1%)c 57 (9%) – therapies. As of March 2011, 102 cases of PML had been conﬁrmed, in more than 78,800 patients exposed, corre- sponding to incidence of approximately 0.1% [21]. According to several studies [22, 23], the risk of PML increases with prior immunosuppressant exposure and treatment duration. Both cases of PML reported in our study occurred after approximately 1 year of treatment, and both patients had high EDSS scores. One patient had undergone hemato- poietic stem cell transplantation. Given its high toxicity, such an intervention has only been considered in patients with refractory disease [24]. Although PML has occa- sionally been reported as a complication of hematopoietic stem cell transplantation, it is generally considered rare in this type of intervention [25]. Therefore, it is possible that prior hematopoietic stem cell transplantation increases the risk of PML of natalizumab treatment. In the case of the second patient, no risk factors of note were identiﬁed and the patient had not received immunosuppressants. An algorithm for risk stratiﬁcation has recently been proposed, 123