Long-term assessment of No Evidence of Disease Activity with natalizumab in relapsing multiple sclerosis

doi:10.1016/j.jns.2016.03.025

Journal of the Neurological Sciences

Volume 364, 15 May 2016, Pages 145-147

https://doi.org/10.1016/j.jns.2016.03.025 Get rights and content

Highlights

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The NEDA status is an important goal for treating patients with relapsing MS.
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34% of patients treated with natalizumab maintained the NEDA over 7 years.
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42% of patients discontinued natalizumab due to PML concerns.
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3 out of 4 patients discontinuing natalizumab for PML concerns did not maintain the NEDA status.
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Fewer pre-natalizumab relapses and lower EDSS score were associated with long-term NEDA.

Abstract

In this study we assessed the proportion of patients with relapsing multiple sclerosis (R-MS) who had No Evidence of Disease Activity (NEDA-3), defined as absence of relapses, absence of confirmed disability worsening, and absence of radiological activity (detected by magnetic resonance imaging of the brain and spinal cord) up to 7 years after starting natalizumab. Out of 152 patients considered, 58 were still on treatment and 94 discontinued treatment after a median time of 3 years. According to an intention-to-treat approach, 52 (34%) patients maintained the NEDA status at the end of follow-up. The proportion of patients with NEDA increases to 41% after excluding from the analysis 64 patients who discontinued natalizumab due to concerns about progressive multifocal leukoencephalopathy. Our findings suggest that natalizumab may ensure higher proportion of patients achieving sustained long-term disease remission than that previously reported with self-injectable treatments (< 10%).

Graphical abstract

Introduction

The No Evidence of Disease Activity (NEDA) has been proposed as a new outcome measure for relapsing multiple sclerosis (R-MS) based on (i) absence of relapses, (ii) absence of sustained disability worsening, defined as ≥ 1-point increase at Expanded Disability Status Scale (EDSS) confirmed 6 months apart; (iii) absence of radiological activity, seen on magnetic resonance imaging (MRI) as gadolinium-enhancing lesions or new/enlarged T2-hyperintense lesions (NEDA-3) [1]. More recently, this composite outcome has been implemented by considering also the absence of brain volume loss (NEDA-4) [2].

Rotstein and coll. [3] report data on the long-term persistence of NEDA-3 in 219 patients with R-MS followed up to 7 years. They found that only 17 of 216 (7.9%) recruited patients maintained NEDA status after 7 years, despite the disease-modifying treatments (DMTs). Consistently, De Stefano and coll. [4] found that only 8 of 91 (9%) recruited patients had NEDA-4 after a 10-year follow-up period. Both articles suggest that NEDA is difficult to sustain long-term even in patients treated with DMTs. However, most of the patients enrolled in both studies received self-injectable DMTs [3], [4]; therefore, it has been argued that more effective DMTs, such as natalizumab or modern therapies, may ensure a greater proportion of patients reaching NEDA [1], [2], [3], [4].

In the present study, we sought to investigate the long-term outcome, defined as NEDA-3, in a post-marketing cohort of patients who started natalizumab.

Section snippets

Participants

We considered data on 152 R-MS patients (105 women, 47 men) who started natalizumab from February 2007 to October 2008, and were regularly followed up to 7 years at the MS clinic of S. Andrea Hospital, Sapienza University, Rome, Italy.

Their demographic and clinical characteristics at natalizumab start were as follows: mean ± standard deviation (SD) age: 35 ± 9 years; mean (± SD) time since first symptom: 10 ± 6 years; median EDSS score: 3.0 (interval: 1.5–6.5); median number of relapses in prior year: 2

Results

At follow-up, 52 (34%) patients had NEDA-3, 79 (52%) were free from clinical relapses, 98 (64%) were free from disability worsening, and 54 (37%) were free from MRI activity (see Fig. 1). Over the 7-year follow-up, 94 (62%) patients discontinued treatment after a median time of 3 years (interval: from 3 months to 6.2 years) for the following reasons: concerns about progressive multifocal leukoencephalopathy (PML) (n = 64); anti-natalizumab antibodies (n = 15); adverse events (n = 10), including one

Discussion

Our findings suggest that natalizumab may ensure higher proportion of patients achieving sustained long-term disease remission than that reported with self-injectable DMTs (34% versus 9% and 7.9%) [3], [4]. The extension data of the CARE-MS I pivotal trial on alemtuzumab showed a 40% proportion of patients who had NEDA-3 five years after treatment beginning [5]. Therefore, we may predict that novel and more effective DMTs, such as monoclonal antibodies, will increase the proportion of patients

Authors' contribution

LP: study design, statistical analysis, manuscript drafting; FF: data collection and manuscript revising; CP: study design, data interpretation, and manuscript revising.

Funding source

This research was carried out using information collected during normal patient care, and extra time spent in data analysis and interpretation was part of educational programmes within the University; no external source of funding was required.

Competing interests

None.

Disclosures

LP has received consulting and/or lecture fees and travel grant from Biogen, Genzyme, Novartis and Teva. CP has received consulting and/or lecture fees and/or research funding and travel grant from Almirall, Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Roche and Teva. FF has nothing to disclose.

Ethics approval

This study was conducted in accordance with the International Conference on Harmonization Guidelines of Good Clinical Practice and the Declaration of Helsinki. In no way did this study interfere in the Care received by patients. The Ethical Committee of Sapienza University provided exemption of approval for post-authorisation observational studies. Each patient involved in this study signed an informed consent before collecting, storing and analysing individual data.

Acknowledgements

None.

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No evidence of disease activity (NEDA) is becoming a gold standard in the evaluation of disease modifying therapies (DMT) in relapsing-remitting multiple sclerosis (RRMS). NEDA-3 status is the absence of relapses, new activity on brain MRI, and disability progression. NEDA-4 meets all NEDA-3 criteria plus lack of brain atrophy.
Aim of this study was to investigate the prevalence of two-year NEDA-3, NEDA-4, six-month delayed NEDA-3 (6mdNEDA-3), and six-month delayed NEDA-4 (6mdNEDA-4) in a cohort of patients with RRMS. Six-month delayed measures were introduced to consider latency of action of drugs.
Observational retrospective monocentric study. All the patients with RRMS starting DMT between 2015 and 2018, and with 2-year of follow-up, were included. Annualized brain volume loss (a-BVL) was calculated by SIENA software.
We included 108 patients, the majority treated with first line DMT. At 2-year follow-up, 35 % of patients were NEDA-3 (50 % 6mdNEDA-3), and 17 % NEDA-4 (28 % 6mdNEDA-4). Loss of NEDA-3 status was mainly driven by MRI activity (70 %), followed by relapses (56 %), and only minimally by disability progression (7 %).
In our cohort 2-year NEDA status, especially including lack of brain atrophy, was hard to achieve. Further studies are needed to establish the prognostic value of NEDA-3 and NEDA4 in the long-term follow-up.
Effect of disease-modifying treatment on spinal cord lesion formation in multiple sclerosis: A retrospective observational study
2023, Multiple Sclerosis and Related Disorders
Spinal cord lesions in multiple sclerosis (MS) are an important contributor to disability. Knowledge on the effect of disease-modifying treatment (DMT) on spinal lesion formation in MS is sparse, as cord outcome measures are seldom included in MS treatment trials. We aim to investigate whether intermediate- or high-efficacy DMTs (i/hDMT) can reduce spinal lesion formation, compared with low-efficacy DMTs (lDMT) and/or no treatment.
Relapse-onset MS patients with ≥2 spinal MRIs (interval >3 months and <10 years) were retrospectively identified. The i/hDMT-group was defined as patients who were treated with i/hDMTs during ≥90% of spinal MRI follow-up time. Controls received lDMTs and/or no treatment ≥90% of follow-up duration. In a secondary analysis, only patients using lDMT for ≥90% of follow-up were considered controls. Patients were matched using propensity-scores. Cox proportional hazards models were used to estimate the risk of new spinal lesions.
323 patients had ≥2 spinal cord MRIs. 49 satisfied i/hDMT and 168 control group criteria. 34 i/hDMT patients were matched to 83 controls. Patients in the i/hDMT-group were significantly less likely to develop new cord lesions at follow-up (HR 0.29 [0.12–0.75], p = 0.01). When the i/hDMT-group was matched to only controls using lDMT ≥90% of follow-up time (n = 17 and n = 25, respectively), there was no statistically significant difference (HR 1.01 [0.19–5.24], p = 0.99).
Treatment with intermediate- or high-efficacy DMTs reduces the risk of new spinal cord lesions compared with matched patients receiving no treatment and/or lDMTs. No conclusions could be drawn on whether i/hDMTs provide a larger risk reduction compared to only lDMTs (control group receiving lDMTs ≥90% of follow-up time).
Natalizumab treatment of multiple sclerosis — a Danish nationwide study with 13 years of follow-up
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Natalizumab is a widely used high-efficacy treatment in multiple sclerosis (MS). Real-world evidence regarding long-term effectiveness and safety is warranted. We performed a nationwide study evaluating prescription patterns, effectiveness, and adverse events.
A nationwide cohort study using the Danish MS Registry. Patients initiating natalizumab between June 2006 and April 2020 were included. Patient characteristics, annualized relapse rates (ARRs), confirmed Expanded Disability Status Scale (EDSS) score worsening, MRI activity (new/enlarging T2- or gadolinium-enhancing lesions), and reported adverse events were evaluated. Further, prescription patterns and outcomes across different time periods (“epochs”) were analysed.
In total, 2424 patients were enrolled, with a median follow-up time of 2.7 years (interquartile range (IQR) 1.2–5.1). In recent epochs, patients were younger, had lower EDSS scores, had fewer pre-treatment relapses and were more often treatment naïve. At 13 years of follow-up, 36% had a confirmed EDSS worsening. On-treatment ARR was 0.30, corresponding to a 72% reduction from pre-initiation. MRI activity was rare, 6.8% had activity within 2–14 months from treatment start, 3.4% within 14–26 months, and 2.7% within 26–38 months. Approximately 14% of patients reported adverse events, with cephalalgia constituting the majority. During the study, 62.3% discontinued treatment. Of these, the main cause (41%) was due to JCV antibodies, while discontinuations due to disease activity (9%) or adverse events (9%) were less frequent.
Natalizumab is increasingly used earlier in the disease course. Most patients treated with natalizumab are clinically stable with few adverse events. JCV antibodies constitute the main cause for discontinuation.
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Citation Excerpt :
Natalizumab control on inflammation is demonstrated in two clinical trials [1–3] but also in real life [4–13].
Natalizumab is a very effective treatment of multiple sclerosis (MS). Failure is rare and should lead to consider some specific etiologies. The purpose of our study was to describe causes of subacute neurological events under natalizumab.
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A subacute neurological deficit occurred in 35 cases, for 607 patients treated with natalizumab. Ten patients presented natalizumab antibodies, nine had progressive multifocal leukoencephalopathy (PML), five presented an isolated subacute neurological deficit and two had AQP4 antibodies. No myelin oligodendrocyte glycoprotein (MOG) antibodies were found.
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Conocer la eficacia a largo plazo de natalizumab en pacientes con EMRR mediante la evaluación anual del no evidence of disease activity (NEDA), que incluye número de brotes, discapacidad medida con EDSS y parámetros de RM cerebral.
Estudio retrospectivo y multicéntrico (n = 3) de pacientes con EMRR tratados con una o más dosis de natalizumab. Se evaluó el estado NEDA cada año y la seguridad a partir del porcentaje de pacientes que discontinuaron y que presentaron efectos adversos.
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Natalizumab presenta una alta eficacia medida mediante el parámetro de remisión NEDA a largo plazo.
The safety and effectiveness of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in clinical trials. However, due to the limitations of these trials, it is important to know how the condition behaves under long-term clinical practice conditions.
To determine the long-term effectiveness of natalizumab in patients with RRMS by means of annual evaluation of the “no evidence of disease activity” (NEDA) parameter, which includes number of relapses, disability (measured with the Expanded Disability Status Scale), and brain MRI parameters.
We performed a retrospective study of patients with RRMS from 3 centres who were treated with one or more doses of natalizumab. Each year, we evaluated NEDA status and safety based on the percentage of patients who discontinued treatment with natalizumab and experienced adverse reactions.
The study included 89 patients, most of whom received treatment for 2 to 4 years, with a follow-up period of up to 7 years. Natalizumab significantly reduces the radiological and clinical progression of the disease, as well as the annual rate of relapses. The NEDA parameter demonstrates the effectiveness of the drug, with values of 75.28% for year one and 66.67% for year 7. Twenty-five patients (28.1%) dropped out after a median of 4 years. Fourteen of these patients (56%) dropped out due to the appearance of anti–JC virus antibodies, either in isolation or associated with another cause. Four dropouts (16%) were due to treatment ineffectiveness, with one patient dying due to progressive multifocal leukoencephalopathy.
Natalizumab is highly effective as measured by the NEDA long-term remission parameter.
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Citation Excerpt :
In this cohort of RRMS patients, only 5% sustained NEDA status after six years. Although higher percentages of NEDA-3 status have been reported in MS patients under a controlled high-efficacy-only treatment regimen, our results are in line with a real-world cohort treated with mixed therapies where only 7.9% retained this status after seven years (Rotstein et al., 2015, Prosperini et al., 2016). The absence of a six-year cognitive decline as measured by SDMT was achieved in 67.6% of patients, but this proportion decreased to 37.8% when measured by the BRBN.
The demand for better outcome measures in multiple sclerosis (MS) management has been increasingly recognized. Nevertheless, the prognostic impacts of available outcome measures for long-term clinical and especially cognitive disability have not been thoroughly investigated. We, therefore, aimed to explore the sustainability and long-term predictive value of outcome measures in MS.
We studied a cohort of 42 relapsing-remitting MS patients and 30 healthy subjects. Evaluations were performed at baseline and after two (Y2) and six years (Y6), and included neurological and neuropsychological evaluation (BRBN), MRI (3T), and quality of life assessment. Combined clinical and cognitive measures were evaluated, such as minimal and no evidence of disease activity (MEDA and NEDA, respectively). We performed logistic regression with bootstrapping and calculated the diagnostic properties to identify patients who reached six-year clinical and/or cognitive worsening.
NEDA status was observed in up to 30.8% of patients at Y2, but only in 5% at Y6, and did not preclude cognitive decline (SDMT and BRBN). The absence of MRI activity and MEDA status at Y2 were associated with less EDSS worsening in the following years but without impact on cognition. The absence of deterioration on combined clinical/cognitive measures at Y2 (e.g., T25W+ 9HPT + BRBN) was associated with better outcomes in the following years (clinical and cognitive), with moderate to large effect sizes. For the identification of clinical worsening at Y6, best accuracies were found for MEDA (70.6%), and clinical worsening (71.4%), but only MEDA remained in the final model after multivariable logistic regression analysis (OR = 6.81, p = 0.017). For combined clinical and cognitive worsening at Y6, only T25W+ 9HPT + BRBN remained in the final model (OR = 8.5, p = 0.017).
Early MS inflammatory disease activity is associated with future clinical disability. Nevertheless, NEDA was difficult to sustain in the long-term and did not preclude cognitive deterioration. Clinical and cognitive measures combined predicted outcomes better than each one isolated. Our data suggest that the evaluation of more than one cognitive domain yields a better predictive outcome measure.

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Clinical short communicationLong-term assessment of No Evidence of Disease Activity with natalizumab in relapsing multiple sclerosis

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Participants

Results

Discussion

Authors' contribution

Funding source

Competing interests

Disclosures

Ethics approval

Acknowledgements

Mult. Scler. Relat. Disord.

J. Neurol. Sci.

Lancet Neurol.

Freedom from disease activity in multiple sclerosis

Neurology

Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort

JAMA Neurol.

Long-term assessment of no evidence of disease activity in relapsing-remitting MS

Neurology

Durable Efficacy of Alemtuzumab on Clinical Outcomes Over 5 Years in Treatment-naive Patients with Active Relapsing-Remitting Multiple Sclerosis with Most Patients Not Receiving Treatment for 4 Years: CARE-MS I Extension Study. Presented at the 31st ECTRIMS Congress, O152; Barcelona (Spain) 2015

Clinical short communication
Long-term assessment of No Evidence of Disease Activity with natalizumab in relapsing multiple sclerosis