What happens when natalizumab therapy is stopped?

Natalizumab is an α-4 integrin antagonist used for the treatment of relapsing multiple sclerosis (MS). Concerns with the drug have a risen owing to a heightened risk of progressive multifocal leukoencephalopathy, which has caused some physicians to interrupt or stop treatment altogether. The article under review evaluates the safety of natalizumab treatment interruption, including the rate and magnitude of the return of MS disease activity toward baseline levels by clinical and MRI measures. The investigators found that by 4-7 months after natalizumab treatment interruption, MS disease activity began to reach baseline levels, which is consistent with the known elimination kinetics of natalizumab. The duration of prior natalizumab exposure or alternate MS treatments during interruption was demonstrated to not affect return of disease activity. Despite nearly similar disease activity after natalizumab treatment, patients with highly active disease prior to treatment had a return of disease activity that was greater in magnitude when compared with those with less active disease. Most significantly, the study did not show evidence of rebound following natalizumab cessation. We agree with these conclusions, but note that a subgroup of MS patients may demonstrate highly active disease after natalizumab cessation.     

Natalizumab dosage suspension: Are we helping or hurting?

The risk of developing progressive multifocal leukoencephalopathy increases with the duration of treatment with natalizumab. Planned dosage interruptions have been proposed as a means of decreasing cumulative risk. The clinical consequences of dosage interruption were evaluated in a single center cohort of natalizumab‐treated patients. Medical records were reviewed for 84 patients identified with multiple sclerosis who received 12 or more infusions of natalizumab at an academic multiple sclerosis center. Eighty‐one percent (68/84) underwent a dosage interruption, and 19% (16/84) had no interruption in natalizumab treatment. Of those with a treatment interruption, 27.9% (19/68) experienced a clinical relapse within 6 months of the suspension, whereas none of the patients with ongoing treatment experienced a flare during months 12 to 18 of treatment (p = 0.017, Fisher exact test). Survival analysis showed that Kaplan‐Meier curves comparing dosage interruption to ongoing treatment diverged (p = 0.025). Median time from treatment interruption to relapse onset was 3 months. No clinical predictors associated with an increased risk of developing flares during dosage interruption were identified. Among the 19 patients who had a flare, 7 had severe flares, with a mean number of 16 Gad+ lesions on brain magnetic resonance imaging (range, 6–40). Their median Expanded Disability Status Scale at natalizumab interruption was 3.0 and increased to 6.0 during the flare (p = 0.0008). Natalizumab dosage interruption is associated with clinical flares and return of radiographic inflammatory disease activity. Some of these flares can be clinically severe, with a high number of contrast‐enhanced lesions, suggesting a possible rebound of disease activity. Ann Neurol 2010;68:395–399     

Pulse monthly steroids during an elective interruption of natalizumab: a post-marketing study

Background and purpose: Temporary discontinuation of natalizumab is sometimes considered as the observed risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS). However, interruption of natalizumab may result in a re‐start of disease activity. Methods: In this prospective post‐marketing study, 23 patients with MS treated with natalizumab elected a trial of treatment interruption (90–150 days) because of safety concerns on the risk of developing PML. To reduce the risk of disease activity return, patients received monthly intravenous (i.v.) steroid pulses before natalizumab re‐start. Results: Despite the steroid coverage, seven patients (30.4%) had an active scan during the natalizumab interruption period; of these, four also had a concomitant clinical exacerbation. Conclusions: Our findings suggest that i.v. steroids are not currently recommendable as drug coverage during a scheduled treatment interruption period.     

Course of relapsing-remitting multiple sclerosis before, during and after natalizumab

The consequences of interruption of natalizumab treatment are incompletely known. The objective was to assess the confirmed annualized relapse rates for patients preceding initiation, during and following suspension of natalizumab therapy. A chart review was conducted and data were analyzed using the Generalized Estimating Equations. During natalizumab therapy the confirmed annualized relapse rate was 0.08, compared to 0.52 (p = 0.0003) during the prior 12 months and to 0.35 (p = 0.0032) during the following 3 to 24 months. Similar results were found when confirmed and unconfirmed were analyzed. To conclude, following cessation of natalizumab therapy disease activity rapidly returned to pre-natalizumab levels.     

Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients

A number of studies have reported flare-up of multiple sclerosis (MS) disease activity after cessation of natalizumab, increasing to a level beyond the pre-natalizumab treatment level. Our aim was to describe the development in clinical disease activity following cessation of natalizumab therapy in a large unselected cohort of highly active patients. We studied 375 highly active patients who had suffered at least two significant relapses within 1 year or three relapses within 2 years, or had been treated with mitoxantrone for highly active disease. All patients had discontinued therapy with natalizumab after at least 24 weeks on therapy, and had been followed 3–12 months (mean 8.9 months) after cessation of natalizumab therapy. The annualised relapse rate before start of natalizumab therapy was 0.94 (95 % confidence interval [CI] 0.88–1.00), 0.47 (95 % CI 0.43–0.52) during natalizumab therapy, 0.63 (95 % CI 0.51–0.76) 1–6 months after natalizumab and 0.55 (95 % CI 0.42–0.70) 7–12 months after natalizumab. However, 83 (22 %) of the patients could be classified as showing rebound of relapses, defined as a higher individual relapse rate after cessation of natalizumab than before natalizumab. These patients had a higher annualised relapse rate during natalizumab therapy. For the whole patient group, the relapse rate after discontinuation did not exceed the pre-natalizumab relapse rate at any time, but 22 % of the patients showed rebound of relapses after discontinuation of natalizumab.     

Headache and Chiari malformation in young age: clinical aspects and differential diagnosis

To evaluate the efficacy and safety of natalizumab in patients with active relapsing–remitting multiple sclerosis (MS). We included 285 MS patients receiving natalizumab. Clinical, neuroradiological and safety data were registered every 6 months. Neutralizing antibodies (NABs) were tested after 6 months of treatment. After 1 year, the annualized relapse rate decreased to 0.26, with a significant reduction compared to the previous year (2.13). At 24 months the proportion of “relapse free” patients was 78% while that of “MRI free” patients was 69%. Considering clinical and MRI cumulative activity, “disease free” patients were 63% at 24 months. A total of 18 patients showed NABs positivity. We reported 34 cases of treatment interruptions. In conclusion, our data confirm the remarkable efficacy of natalizumab in a group of patients with higher disease activity than that of pivotal studies.     

Natalizumab treatment in multiple sclerosis: the experience of S. Andrea MS Centre in Rome

We reported a post-marketing experience of 190 patients affected by relapsing multiple sclerosis on treatment with natalizumab. Clinical findings during pre-treatment period and throughout the study were documented. Magnetic resonance imaging (MRI) scans were performed at baseline and at 6, 12, and 24 months of therapy. Cumulative proportions of patients disease activity free (i.e. absence of relapses, disability progression, MRI activity) were measured as efficacy endpoints. Despite that the baseline characteristics suggested a more severe course of disease in our sample than that of the AFFIRM trial, data on effectiveness of natalizumab were comparable. At 1 year of treatment we found 80 and 70% patients free from relapses and MRI activity, respectively, that is similar to 75 and 62% detected in the AFFIRM trial. Moreover, only 5% of our patients showed a progression of disability after a mean follow-up time of 15 months. Finally, the presence of antibodies anti-Natalizumab was strongly related to the occurrence of relapses (p = 0.002) and MRI activity (p < 0.001) even in the post-marketing experience.

     

Epilepsy in type 1 Chiari malformation

We reported a post-marketing experience of 190 patients affected by relapsing multiple sclerosis on treatment with natalizumab. Clinical findings during pre-treatment period and throughout the study were documented. Magnetic resonance imaging (MRI) scans were performed at baseline and at 6, 12, and 24 months of therapy. Cumulative proportions of patients disease activity free (i.e. absence of relapses, disability progression, MRI activity) were measured as efficacy endpoints. Despite that the baseline characteristics suggested a more severe course of disease in our sample than that of the AFFIRM trial, data on effectiveness of natalizumab were comparable. At 1 year of treatment we found 80 and 70% patients free from relapses and MRI activity, respectively, that is similar to 75 and 62% detected in the AFFIRM trial. Moreover, only 5% of our patients showed a progression of disability after a mean follow-up time of 15 months. Finally, the presence of antibodies anti-Natalizumab was strongly related to the occurrence of relapses (p = 0.002) and MRI activity (p < 0.001) even in the post-marketing experience.     

Clinical and radiological disease reactivation after cessation of long-term therapy with natalizumab

ABSTRACT Naitalizumab is a potent monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (MS); however, little is known about the course of disease after cessation of therapy. The few existing reports describe different courses of disease after treatment discontinuation. Here we report on four MS patients who experienced clear clinical and radiological reactivation of the disease several months after cessation of therapy with natalizumab (15-29 months). In all cases, there was almost no clinical or radiological disease activity during natalizumab therapy. Three patients experienced a severe clinical relapse between 3 and 9 months after therapy cessation. The fourth patient developed cerebral magnetic resonance imaging (MRI) activity showing multiple new gadolinium-enhanced lesions. Due to these observations, it is recommended to weigh up the risk of disease reactivation against the risk of progressive multifocal leukoencephalopathy.     

Health care situation of patients with relapsing–remitting multiple sclerosis receiving immunomodulatory therapy: a retrospective survey of more than 9000 German patients with MS

Background and purpose: First‐line immunomodulatory treatment with interferon‐beta or glatiramer acetate is accepted as effective basic therapy in patients with relapsing–remitting multiple sclerosis (RRMS). However, a considerable portion of patients does not benefit from treatment. Method: To test basic immunomodulatory treatment under real‐life conditions, we retrospectively analyzed clinical and subclinical disease activity within the last 12 months in a cohort of 9916 patients with RRMS, of which 7896 patients were receiving immunomodulatory treatment. In addition, factors associated with treating physicians’ consideration of a switch of current treatment were assessed. Results: The majority of treated patients (approximately 66%) experienced no relapse during the last 12 months. However, in line with common clinical study findings, about one‐third (approximately 34%) of patients had relapses. When MRI data were taken into account, approximately one‐quarter (24%) of patients would qualify for therapy escalation to monoclonal antibody natalizumab. Relapse rate in the preceding year (the year directly prior to the start of retrospective data collection) was strongly associated with considering a switch of current treatment. In addition, therapy switch was more often considered in younger patients. The relationship between MRI findings in the absence of clinical symptoms and consideration of a treatment switch was not as clear. Conclusions: This analysis confirms that disease progression occurs in a considerable proportion of patients with RRMS. These patients should be considered for therapy escalation.     

Pulsed steroids followed by glatiramer acetate to prevent inflammatory activity after cessation of natalizumab therapy: a prospective, 6-month observational study

In this study, the tolerability and safety of treatment with pulsed steroids and glatiramer acetate and the occurrence of clinical and radiological activity after natalizumab (NTZ) cessation in multiple sclerosis (MS) patients were assessed. MS patients with NTZ were discontinued after 2 years of treatment, or if adverse events or disease progressed during NTZ. They were offered as alternative treatment 1 g methylprednisolone per month during 3 months followed by daily 20 mcg glatiramer acetate and were prospectively studied. Adverse events, occurrence of immune reconstitution inflammatory syndrome, clinical exacerbations, and gadolinium-enhancing lesions in MRI performed at 3 and 6 months after NTZ cessation were recorded. EDSS change during follow-up was also recorded. A total of 18 MS patients entered the study and were followed up for a mean of 10 months (range 6–18 months). There were no significant adverse events. At month 3, no patient had clinical or radiological disease activity. At month 6, 16.6% of patients had had a relapse and 55.5% of patients showed gadolinium-enhancing lesions in the MRI. After 6 months, 33.3% of patients had a further relapse. There was no IRIS, severe relapses, or significant difference between EDSS at NTZ discontinuation and after follow-up. The alternative treatment with monthly prednisolone followed by GA prevents the development of IRIS, but not the return to previous inflammatory activity, which occurs between 5 and 6 months after NTZ withdrawal.     

Clinical effects of natalizumab on multiple sclerosis appear early in treatment course

In clinical practice natalizumab is typically used in patients who have experienced breakthrough disease during treatment with interferon beta (IFNβ) or glatiramer acetate. In these patients it is important to reduce disease activity as quickly as possible. In a phase II study, differences between natalizumab and placebo in MRI outcomes reflecting inflammatory activity were evident after the first infusion and maintained through a 6-month period, suggesting a rapid onset of natalizumab treatment effects. To explore how soon after natalizumab initiation clinical effects become apparent, annualized relapse rates per 3-month period and time to first relapse were analyzed in the phase III AFFIRM study (natalizumab vs. placebo) and in the multinational Tysabri^® Observational Program (TOP). In AFFIRM, natalizumab reduced the annualized relapse rate within 3 months of treatment initiation compared with placebo in the overall population (0.30 vs. 0.71; p < 0.0001) and in patients with highly active disease (0.30 vs. 0.94; p = 0.0039). The low annualized relapse rate was maintained throughout the 2-year study period, and the risk of relapse in AFFIRM patients treated with natalizumab was reduced [hazard ratio against placebo 0.42 (95 % CI 0.34–0.52); p < 0.0001]. Rapid reductions in annualized relapse rate also occurred in TOP (baseline 1.99 vs. 0–3 months 0.26; p < 0.0001). Natalizumab resulted in rapid, sustained reductions in disease activity in both AFFIRM and in clinical practice. This decrease in disease activity occurred within the first 3 months of treatment even in patients with more active disease.     

L’IRM est-elle utile dans le suivi des patients atteints de sclérose en plaques ? Oui

The place of magnetic resonance imaging (MRI) in the monitoring of patients with multiple sclerosis (MS) is not codified except during the diagnostic phase. Several studies in the literature have shown that lesion load measured on an MRI done at the beginning of the disease or its increase during the first years had a predictive value, although moderate, on the occurrence of long-term disability as measured by the EDSS. Early worsening of brain atrophy during the early stages of the disease is predictive of worsening cognitive impairment in the following years. Perform an MRI is not required when setting up a first-line disease-modifying therapy (DMT) such as an immunomodulatory treatment but it is useful because it can be used as a reference scan in case of treatment failure. The indications of second-line DMTs, whether prescribed in naive patients with an active disease or after failure of a first-line DMT, are based on combined criteria incorporating MRI data acquired in the previous 3 months compared with a recent MRI. Thus the practical criteria for failure of first-line DMTs are partly based on MRI. During interferon therapy, identification of disease activity on an MRI conducted 1 year after the start of the treatment can predict treatment failure in combination with clinical criteria, such as relapses occurring during the first year. Finally, MRI is essential to the safety monitoring of patients on natalizumab to detect progressive multifocal leukoencephalopathies (PML). In patients at high risk for PML, tested positive for JC virus antibodies and having received natalizumab for more than 2 years, it could be proposed to do a short MRI with FLAIR and diffusion weighted imaging sequences every 3 months to detect preclinical PML.     

L’IRM est-elle utile dans le suivi des patients atteints de sclérose en plaques ? Non

Is regular MRI monitoring useful in clinical practice in multiple sclerosis patients treated with disease modifying therapy (DMT) drugs? My answer is no. Tacking a DMT drug is not by itself a pertinent criterion for requiring a systematic MRI monitoring in MS patients. Five clinical criteria should be taken into consideration before prescribing regular MRI examinations. The clinical form of the disease: MRI monitoring in DMT treated patients, has been demonstrated as useful only in pure relapsing-remitting MS patients. Up to now, there is no convincing demonstration of therapeutic efficacy with any DMT drug, neither first-line nor second-line drugs in patients with primary or secondary progressive MS disease. The duration of the disease, epidemiological data leading to the concept of a two-stage disability progression in MS, emphasizes the importance of treating as early as possible RRMS patients in order to stop accumulation of new focal MRI CNS lesions. In this regard, an annual monitoring for the 5 first years of the disease looks reasonable in order to better personalize the treatment choice among the few approved DMT drugs. The duration of the treatment: a first MRI assessment at month 6 after initiating a new DMT drug is adequate in order to better distinguish responder versus no responder. The persistence of Gado + lesions at 6 months is a strong indication for considering alternative treatment. The disease activity: both criteria, clinical and MRI, are needed to recognized very active or aggressive relapsing MS patients, leading to decide a rapid use of second-line treatment therapy. The treatment choice: in JC positive MS patients treated with natalizumab, the risk of PML is as high as more than 1 % in those JC + MS patients that are treated continuously more than 24 months. A regular MRI monitoring (3 or 6 months) is recommended in order to detect as early as possible MRI abnormalities suggesting PML.     

Efficacy of natalizumab in multiple sclerosis patients with high disease activity: a Danish nationwide study

Introduction:  Previous studies of natalizumab (Tysabri®) in relapsing multiple sclerosis (MS) patients have included patients with moderate disease activity. We studied a patient population with high disease activity.
Patients and Methods:  We analyzed data from 234 consecutive, natalizumab-treated patients, followed for at least 3 months. Three groups of patients were eligible for natalizumab therapy: patients with two or more documented relapses or sustained increase of 2 EDSS points on disease modifying therapy (DMT) in the previous year; patients switching from mitoxantrone; and patients with very active MS as de novo therapy.
Results:  During a median observation time of 11.3 months (range 3.0–21.5) the annualized relapse rate decreased to 0.68 from a pre-treatment rate of 2.53 (73% reduction). We assessed the annualized relapse rate in three subgroups: (i) 0.83 in 14 (6.0%) de novo treated patients; (ii) 0.71 in 175 (74.8%) patients with ≥2 relapses or sustained increase in EDSS of ≥2 points on a first-line DMT; and (iii) 0.56 in 45 (19.2%) patients switching from mitoxantrone. Nine anaphylactoid reactions, two severe, were reported. Out of 215 patients 7 (3%) were persistently positive for antibodies to natalizumab.
Conclusions:  Tysabri appears to be effective in MS patients with high disease activity, but the relapse rate was higher than in the pivotal study after the first treatment year. This is likely to reflect differences in disease activity before the initiation of natalizumab treatment.     

Traitement d’induction dans la sclérose en plaques : place du natalizumab

Background

Current treatment options for first-line immunotherapy in relapsing-remitting multiple sclerosis (MS) are recombinant interferon-β and glatiramer acetate. However, these therapies are only partially effective and certain patients may fail to respond. For this reason, it is important to elaborate alternative treatment strategies. Induction therapy represents a more aggressive approach in which powerful drugs are used right from the beginning to tackle the disease process hard and early. Natalizumab is a powerful monoclonal antibody approved for the treatment of relapsing-remitting MS and is known to silence disease activity.

Methods

We describe here the early outcome at 1 month and at 6 months of three patients treated with natalizumab for relapsing-remitting MS.

Results

All three patients had a high disease activity before the initiation of natalizumab, with 4, 8 and 5 gadolinium-enhancing lesions on brain MRI respectively. On the MRI scans made at 1 month after the first infusion, and at 6 months, there was no more gadolinium-enhancement and no new T2-lesion. Clinically, they did not experience any relapse.

Discussion

In these three cases, natalizumab showed a dramatic efficacy: the patients became “disease activity free” right from the first infusion. To our knowledge, natalizumab is not classically used as an induction therapy, unlike mitoxantrone. However, this treatment has potential hematological and cardiac toxicity and its use can be limited. Thus, in JC virus negative patients, natalizumab could be an interesting alternative treatment.

Conclusion

Our report suggests that induction strategy with natalizumab may be applicable in patients with aggressive multiple sclerosis. A study of more similar cases may be interesting to confirm these preliminary results.     

Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing‐remitting multiple sclerosis

Background: Natalizumab (Tysabri) is a monoclonal antibody that was recently approved for the treatment of relapsing‐remitting multiple sclerosis (RRMS). Our primary objective was to analyse the efficacy of natalizumab on disability status and ambulation after switching patients with RRMS from other disease‐modifying treatments (DMTs). Methods: A retrospective, observational study was carried out. All patients (n = 45) initiated natalizumab after experiencing at least 1 relapse in the previous year under interferon‐beta (IFNB) or glatiramer acetate (GA) treatments. The patients also had at least 1 gadolinium‐enhancing (Gd+) lesion on their baseline brain MRI. Expanded Disability Status Scale (EDSS) scores, and performance on the Timed 25‐Foot Walk Test and on the Timed 100‐Metre Walk Test were prospectively collected every 4 weeks during 44 weeks of natalizumab treatment. Brain MRI scans were performed after 20 and 44 weeks of treatment. Results: Sixty‐two per cent of patients showed no clinical and no radiological signs of disease activity, and 29% showed a rapid and confirmed EDSS improvement over 44 weeks of natalizumab therapy. Patients with improvement on the EDSS showed similar levels of baseline EDSS and active T1 lesions, but had a significantly higher number of relapses, and 92% of them had experienced relapse‐mediated sustained EDSS worsening in the previous year. A clinically meaningful improvement in ambulation speed was observed in approximately 30% of patients. Conclusions: These results indicate that natalizumab silences disease activity and rapidly improves disability status and walking performance, possibly through delayed relapse recovery in patients with RRMS who had shown a high level of disease activity under other DMTs.     

Natalizumab vs interferon beta 1a in relapsing-remitting multiple sclerosis: a head-to-head retrospective study

Background – No head‐to‐head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS). Aim – To retrospectively compare the efficacy of natalizumab vs IFN beta 1a SC (44 μg; Rebif^®) on clinical and radiological findings in two matched cohorts of patients with MS. Patients and methods – We retrospectively enrolled two cohorts of 42 patients (F/M: 35/7) with relapsing‐remitting multiple sclerosis treated with natalizumab or IFN beta 1a for at least 12 consecutive months. Outcome measures were annualized relapse rate (ARR), changes in expanded disability status scale (EDSS) score, and number of contrast‐enhancing lesions (CELs) at magnetic resonance imaging (MRI). Results – In both groups, the ARR in the 12 months of treatment was lower than in the 12 months before therapy (0.24 vs 1.50 in natalizumab‐treated group, P < 0.0000; 0.55 vs 1.10 in IFN beta 1a‐treated group, P = 0.0006), being the effect of natalizumab significantly stronger (P = 0.0125). EDSS reduction was significantly different between the two groups in favor of natalizumab (P = 0.0018). The frequency and number of CELs per patient were decreased in both groups. In the second year, the treatment affected ARR and EDSS progression in the two groups of patients similarly to the first year, whereas number of CELs decreased more significantly in natalizumab group (P = 0.008). Conclusions – After 12 and 24 months of therapy, natalizumab was more effective than IFN beta 1a SC on both disease activity and disability progression. Prospective head‐to‐head studies would be helpful to further evaluate the differences observed in the MRI outcomes.     

Kinetics and incidence of anti-natalizumab antibodies in multiple sclerosis patients on treatment for 18 months

Natalizumab is a monoclonal antibody shown to be highly effective in the treatment of relapsing-remitting multiple sclerosis (RRMS). Patients treated with natalizumab can develop antibodies directed against this agent that may affect the efficacy and safety of the drug. In this observational study, the kinetics of the appearance and the incidence of anti-natalizumab antibodies were followed prospectively for 18 months in a cohort of 64 consecutive patients treated with natalizumab for relapsing MS. Blood samples were drawn immediately before starting natalizumab therapy and each month afterwards. The presence of antibodies against natalizumab was assessed by enzyme-linked immunosorbent assay (ELISA) in all patients. Anti-natalizumab antibodies were detected in nine (14.1%) natalizumab-treated patients, three (4.68%) of whom were transiently positive while six (9.37%) were persistently positive (these patients discontinued natalizumab). All positive titres were observed during the first 4 months of treatment. One patient with a hypersensitivity reaction also had persistent antibodies. We conclude that antibodies against natalizumab develop early, within the first 6 months of therapy with natalizumab. Although no antibodies were detected after 4 months of therapy in this particular study, this does not rule out their development later on in exceptional cases.     

Natalizumab is effective in multiple sclerosis patients switching from other disease modifying therapies in clinical practice

Natalizumab is one option for multiple sclerosis patients responding poorly to classical immunomodulators, but pilot studies did not point to its effectiveness as a second-line therapy. Aim of this study was to assess the efficacy of natalizumab as second-line therapy in patients switching from disease modifying therapies (DMTs) in a clinical setting. We retrospectively selected patients who had been treated with natalizumab for at least 12 months after switching from one or more DMTs. We collected clinical and neuroradiological data and we analysed the reduction in annualised relapse rate (ARR), the change of Expanded Disability Status Scale (EDSS) and the reduction of contrast-enhancing lesions (CELs) at magnetic resonance imaging (MRI) of the brain at 12 months of natalizumab and of previous DMT therapy. Fifty patients were included in the analysis (11 males, 39 females).We observed a reduction of ARR on natalizumab (p = 0.000) and a statistically significant different trend of relapse event between the two treatments (p = 0.0149). EDSS was stable during natalizumab therapy whilst it showed an increase on DMTs (p = 0.0244). The number of CELs decreased significantly (p = 0.006) during the 12 months of treatment with natalizumab, whilst it was stable on DMTs. Natalizumab showed to decrease ARR, stabilize EDSS, increase the percentage of CELs free patients and decrease the number of CELs in a group of 50 poor responders to classical DMT, after the first 12 months of therapy.