scholarly journals Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients

2017 ◽  
Vol 24 (11) ◽  
pp. 1453-1460 ◽  
Author(s):  
Cyra E Leurs ◽  
Zoé LE van Kempen ◽  
Iris Dekker ◽  
Lisanne J Balk ◽  
Mike P Wattjes ◽  
...  
Keyword(s):  
Disease Activity ◽  
Lymphocyte Count ◽  
Odds Ratio ◽  
Jc Virus ◽  
Observational Cohort Study ◽  
Relapsing Remitting ◽  
Natalizumab Treatment ◽  
Observational Cohort ◽  
Carry Over ◽  
Relapsing Remitting Multiple Sclerosis

Background: Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus–positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0–3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months. Objective: We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts. Methods: From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups (<6 weeks, 6–8 weeks, >8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment. Results: Patients with a WO period of >8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4–32.8) compared to patients with a WO period of <6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity. Interpretation: A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus–positive patients remains uncertain.

scholarly journals Ocrelizumab after natalizumab in JC-virus positive relapsing remitting multiple sclerosis patients

2021 ◽  
Vol 7 (2) ◽  
pp. 205521732110138
Author(s):  
ZYGJ van Lierop ◽  
AA Toorop ◽  
EME Coerver ◽  
EAJ Willemse ◽  
EMM Strijbis ◽  
...  
Keyword(s):  
Jc Virus ◽  
Alternative Therapy ◽  
Disease Suppression ◽  
Relapsing Remitting ◽  
Patients At Risk ◽  
Observational Cohort ◽  
Carry Over ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

Ocrelizumab is often used as an alternative therapy in natalizumab-treated MS patients at risk for progressive multifocal leukoencephalopathy (PML). Our objective was to assess efficacy and safety of JC-virus positive patients switching (either directly or indirectly) from natalizumab to ocrelizumab. Forty-two patients were included from an observational cohort (median follow-up 21 months). No evidence of disease activity was found in 83% of direct switchers and 50% of indirect switchers. Two direct switchers were diagnosed with carry-over PML. Our data support a direct switch for adequate disease suppression, although carry-over PML illustrates the dilemma when choosing between a direct or indirect switch.

Personalized extended interval dosing of natalizumab in MS

Neurology ◽  
2020 ◽  
Vol 95 (6) ◽  
pp. e745-e754
Author(s):  
Zoé L.E. van Kempen ◽  
Erwin L.J. Hoogervorst ◽  
Mike P. Wattjes ◽  
Nynke F. Kalkers ◽  
Jop P. Mostert ◽  
...  
Keyword(s):  
Disease Activity ◽  
Extension Phase ◽  
T2 Lesions ◽  
Relapsing Remitting ◽  
Natalizumab Treatment ◽  
Mri Scans ◽  
Secondary Endpoints ◽  
Trough Concentrations ◽  
Relapsing Remitting Multiple Sclerosis

ObjectiveTo determine whether natalizumab efficacy is maintained when switching to personalized extended interval dosing based on individual natalizumab trough concentrations in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsThis was a prospective multicenter single-arm trial with 1 year follow-up and a 1-year extension phase. Participants were adult persons with RRMS treated with natalizumab without disease activity in the year prior to enrollment. The natalizumab treatment interval was based on longitudinal natalizumab trough concentrations. Patients received 3 monthly MRI scans, relapse assessments, and disability scoring during follow-up. The primary endpoint was the occurrence of gadolinium-enhancing lesions on MRI. Secondary endpoints were new/enlarging T2 lesions on MRI and relapses and progression on the Expanded Disability Status Scale (EDSS) during follow-up and extension phase.ResultsSixty-one patients were included. Eighty-four percent extended the interval from a 4-week interval to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI] 0%–7.4%) during follow-up. No new/enlarging T2 lesions (95% CI 0%–7.4%) or relapses (95% CI 0%–7.4%) were reported during follow-up and in the extension phase. Median EDSS was comparable at baseline (3.0, interquartile range [IQR] 2.0–5.0) and after follow-up (3.0, IQR 2.0–5.0).ConclusionPersonalized extended interval dosing did not induce recurrence of MS disease activity. Natalizumab efficacy was maintained in stable patients with RRMS receiving personalized extended interval dosing based on individual natalizumab concentrations.Classification of evidenceThis study provides Class IV evidence that personalized extended interval dosing of natalizumab does not result in recurrence of disease activity in stable patients with RRMS.

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

2010 ◽  
Vol 17 (4) ◽  
pp. 490-494 ◽  
Author(s):  
Michael D Kaufman ◽  
R Lee ◽  
HJ Norton
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Relapse Rate ◽  
Generalized Estimating Equations ◽  
Chart Review ◽  
Relapsing Remitting ◽  
Annualized Relapse Rate ◽  
Natalizumab Treatment ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Relapse Rates

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.

Natalizumab-associated progressive multifocal leukoencephalopathy is not preceded by elevated drug concentrations

2016 ◽  
Vol 23 (7) ◽  
pp. 995-999 ◽  
Author(s):  
Zoé LE van Kempen ◽  
Cyra E Leurs ◽  
Anke Vennegoor ◽  
Mike P Wattjes ◽  
Theo Rispens ◽  
...  
Keyword(s):  
Progressive Multifocal Leukoencephalopathy ◽  
Preliminary Evidence ◽  
Observational Cohort Study ◽  
Serum Samples ◽  
Drug Concentrations ◽  
Relapsing Remitting ◽  
Relevant Risk Factor ◽  
Observational Cohort ◽  
Patient Groups ◽  
Relapsing Remitting Multiple Sclerosis

Background: In recent years, a small but increasing number of neurologists choose to extend dose intervals of natalizumab with the aim of reducing the risk of progressive multifocal leukoencephalopathy (PML). This idea is based on the hypothesis that high drug concentrations increase the risk of PML. Objective: We investigated the relation between longitudinal natalizumab concentrations in patients who developed PML and patients who did not develop PML. Methods: In a prospective observational cohort study of 219 patients with relapsing–remitting multiple sclerosis treated with natalizumab, serum samples were taken every 12 weeks prior to natalizumab infusion. In this cohort, 5 patients developed PML and were matched with 10 patients from the cohort who did not develop PML. Natalizumab concentrations were measured in available samples, and the longitudinal results were compared between the two patient groups. Results: Mean natalizumab concentrations in the five patients developing PML was 18.9 µg/mL (standard deviation (SD): ±13.4) versus 23.8 µg/mL (SD: ±11.5) of the control patients. Furthermore, we did not observe a clear rise in concentration levels in patients subsequently developing PML. Conclusion: Our results provide preliminary evidence that contradicts the hypothesis that exposure to elevated concentrations of natalizumab is a relevant risk factor of developing PML.

Natalizumab discontinuation after PML risk stratification: outcome from a shared and informed decision

2012 ◽  
Vol 18 (8) ◽  
pp. 1193-1196 ◽  
Author(s):  
Carmen Tur ◽  
Mar Tintoré ◽  
Angela Vidal-Jordana ◽  
Joaquín Castilló ◽  
Ingrid Galán ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Jc Virus ◽  
Risk Groups ◽  
Serological Status ◽  
Relapsing Remitting ◽  
Natalizumab Treatment ◽  
Group A ◽  
Risk Treatment ◽  
Group B ◽  
Relapsing Remitting Multiple Sclerosis

Multifocal progressive leukoencephalopathy (PML) is associated with JC virus (JCV) seropositivity, past immunosuppression, and natalizumab treatment for two years or more. The aim of our study was to investigate the rate of treatment discontinuation after stratifying for the three risk factors in a group of 104 natalizumab-treated patients with relapsing–remitting multiple sclerosis. We investigated JCV serological status in our population. We then divided patients into groups according to their PML risk. Treatment indication was reassessed. Of the patients, 64 (61.5%) were JCV seropositive. Amongst seropositive patients on natalizumab for 2 years or more, 10 had received immunosuppression (group A), and 38 had not (group B). After an informed and shared decision-making process, 6/10 (60%) from group A compared with 9/38 (23.7%) from group B discontinued treatment ( p=0.027). In groups A and B, discontinuation also depended upon doctors’ views ( p=0.019, group A; p=0.010, group B) and clinical outcomes ( p=0.021, group A). No-one from low–intermediate risk groups discontinued. The decision to discontinue natalizumab treatment is complex, even when clear PML risk rates are described. Clinical outcomes and doctors’ idiosyncrasies play a crucial part in patients’ final choice.

scholarly journals JC Virus-DNA Detection Is Associated with CD8 Effector Accumulation in Peripheral Blood of Patients with Multiple Sclerosis under Natalizumab Treatment, Independently from JC Virus Serostatus

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Maria A. Zingaropoli ◽  
Marco Iannetta ◽  
Simona Pontecorvo ◽  
Elena Anzivino ◽  
Carla Prezioso ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Peripheral Blood ◽  
Jc Virus ◽  
Healthy Donors ◽  
Increased Risk ◽  
Relapsing Remitting ◽  
Polyomavirus Jc ◽  
Natalizumab Treatment ◽  
Blood And Urine Samples ◽  
Relapsing Remitting Multiple Sclerosis

Although natalizumab (anti-α4 integrin) represents an effective therapy for relapsing remitting multiple sclerosis (RRMS), it is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). The aim of this study was to explore natalizumab-induced phenotypic changes in peripheral blood T-lymphocytes and their relationship with JCV reactivation. Forty-four patients affected by RRMS were enrolled. Blood and urine samples were classified according to natalizumab infusion number: 0 (N0), 1–12 (N12), 13–24 (N24), 25–36 (N36), and over 36 (N>36) infusions. JCV-DNA was detected in plasma and urine. T-lymphocyte phenotype was evaluated with flow cytometry. JCV serostatus was assessed. Ten healthy donors (HD), whose ages and sexes matched with the RRMS patients of theN0 group, were enrolled. CD8 effector (CD8 E) percentages were increased in natalizumab treated patients with detectable JCV-DNA in plasma or urine compared to JCV-DNA negative patients (JCV−) (p<0.01andp<0.001, resp.). Patients with CD8 E percentages above 10.4% tended to show detectable JCV-DNA in plasma and/or urine (ROC curvep=0.001). The CD8 E was increased when JCV-DNA was detectable in plasma or urine, independently from JCV serology, forN12 andN24 groups (p<0.01). As long as PML can affect RRMS patients under natalizumab treatment with a negative JCV serology, the assessment of CD8 E could help in the evaluation of JCV reactivation.

Clinical outcomes in patients who discontinue natalizumab therapy after 2 years in the Tysabri® Observational Program (TOP)

2020 ◽  
pp. 135245852091792 ◽  
Author(s):  
Helmut Butzkueven ◽  
Maria Trojano ◽  
Ludwig Kappos ◽  
Tim Spelman ◽  
Heinz Wiendl ◽  
...  
Keyword(s):  
Disease Activity ◽  
Clinical Outcomes ◽  
Treatment Duration ◽  
Oral Therapy ◽  
Relapse Risk ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Natalizumab Treatment ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Observational Program

Background: Natalizumab is a highly efficacious therapy for relapsing–remitting multiple sclerosis (RRMS). Patients who discontinue natalizumab may experience return of MS disease activity. Objective: The aim of this study was to analyze predictors of post-natalizumab disease activity return. Methods: The Tysabri® Observational Program (TOP) is an ongoing observational study of natalizumab-treated RRMS patients. Patients discontinuing natalizumab are encouraged to remain in TOP. Results: Analyses included 3221 TOP patients. After ⩾2 years on natalizumab, relapse risk was twice as high for patients who switched to an oral therapy ( n = 660, hazard ratio (HR) = 2.18, p < 0.001) and three times as high for patients who switched to an injectable therapy ( n = 95, HR = 3.02, p < 0.001) as for those who stayed on natalizumab ( n = 2466). Relapse rates after switching remained below pre-natalizumab rates. In patients who switched to an oral therapy, higher relapse risk was predicted by longer washout time, more pre-natalizumab relapses, higher Expanded Disability Status Scale score at natalizumab initiation, and shorter natalizumab treatment duration. Conclusion: Patients who stayed on natalizumab had better clinical outcomes than those who switched to an oral or injectable therapy after ⩾2 years on natalizumab. These results highlight modifiable risk factors for disease activity return (e.g. natalizumab treatment duration and washout duration) to consider when making treatment decisions.

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