1818 new T2-hyperintense lesions on MRI. According to this deﬁnition, 63% were free of disease during the year of treatment with natalizumab. Of the 178 patients (13%) who had a secondary pro- gressive (SP) form of the disease, 102 received treatment with natalizumab for at least 12 months. For these patients, the median ARR of 1.0 (mean 1.27, 95% CI 1.07–1.48) the year prior to the treatment decreased to 0 (mean 0.13, 95% CI 0.05–0.21) after 1 year of treatment. The median EDSS score at baseline for these patients was 6.0 (mean 5.54, 95% CI 5.33–5.74), and at 12 months showed little varia- tion (median 6, mean 5.32, 95% CI 5.06–5.58). Thirty-three percent of the SP patients showed an improvement in EDSS and only 15% showed worsening between baseline and 1 year after treatment; the rest (53%) remained stable. In total, 73% of the SP patients were free of disease (according to the above deﬁnition) during the year of treatment with natalizumab. Discussion Although randomized clinical trials provide the highest level of evidence for the efﬁcacy of a given drug, their restrictive inclusion criteria and necessarily rigid protocols may compromise their relevance for clinical practice. Moreover, certain safety signals may only become apparent when the drug has been administered to large numbers of patients and so may not be detected in clinical trials during drug development. It is therefore important to conduct observational studies with a view to providing data from real clinical practice. In the case of natalizumab, the need for ‘‘real-life’’ data is particularly pertinent given that the ﬁnal approved indications limit use of the drug to patients who have failed front-line therapies and those with highly active disease. In the present study, we retrospectively collected data from a large sample of natalizumab-treated patients, accounting for approximately 85% of patients treated with this drug in Spain. As expected, ARRs in the year prior to treatment and baseline EDSS were higher in our study than those reported in the pivotal AFFIRM trial [6]. Nevertheless, despite a higher pretreatment ARR, the ARR in our study in the year after treatment was similar to that seen in the AFFIRM trial. Of note is that the decrease in the number of relapses is observed regardless of baseline EDSS, even in patients with baseline EDSS [6.0 (the AFFIRM trial did not include any patients with baseline EDSS [6.0). Also of note was a signiﬁcant decrease in EDSS for patients who completed 12 months of treatment (from median EDSS 3.5 to 3.0 and from mean EDSS 3.77 to 3.38). A number of points need to be addressed when inter- preting the results of an observational study; for example, 123 J Neurol (2012) 259:1814–1823 patients who are included may be those who the treating physicians consider will do well on treatment. In addition, patients who do not complete 12 months of treatment with natalizumab may be more likely to have poor outcomes if they stay on therapy, and these patients are often not considered in the ﬁnal efﬁcacy analysis of observational studies. In our study, 37 patients withdrew due to lack of efﬁcacy (among other possible reasons). Even if all patients who discontinued treatment (14% of total sample analyzed) were considered as efﬁcacy failures, rough calculations based on a sample that either completed 12 months of treatment or discontinued treatment suggest that the treat- ment effect would still be considerable (approximately 70% free of relapses, which is closer to the 77% observed in the active treatment arm of the AFFIRM trial). Another possible confounder in the interpretation of observational studies with no control arm is that the treatment effect may be partly explained by regression to the mean. Thus, patients are likely to start natalizumab treatment during moments of high disease activity and this activity would subside to a certain extent anyway, regardless of treatment. In addition, we should also bear in mind the tendency for fewer exacerbations as MS pro- gresses, although the period of observation here was probably too short to have a major impact on the results. In our study, the decrease in ARR observed was 87.6% when calculated relative to the previous year for all patients and 75.6% when calculated for patients on treatment for 1 year. These values are very similar to the relative decrease in ARR at 1 year observed between the active treatment and placebo arm of the AFFIRM trial (68%), so that the effect of regression to the mean was probably small in our study. Particularly interesting are the results obtained in patients already in the SP phase of the disease. The retrospective nature of data collection may also introduce a bias into the study results. Given these caveats in the interpretation of observational studies, it is reassur- ing that other observational studies performed in similar patient populations in Germany, Switzerland, Denmark, Italy, France, Sweden, and Spain show similar results [8– 17]. Table 4 summarizes the baseline characteristics of the principal European observational studies. As in our study, patients appear to have more severe disease than those patients enrolled in the AFFIRM trial, reﬂecting the approved indications for natalizumab. Patients in the Danish study by Oturai et al. [9], however, appeared to have a higher ARR in the year prior to treatment and a higher baseline EDSS than the rest. This perhaps suggests that, in Danish clinical practice, natalizumab is reserved for patients with more active or severe disease. It is encour- aging to see that, despite different methodologies and presumably some variation in clinical practice and treat- ment protocols in the different countries, good efﬁcacy is