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.

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 Long-Term Persistence with Injectable Therapy in Relapsing-Remitting Multiple Sclerosis: An 18-Year Observational Cohort Study

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0123824 ◽  
Author(s):  
Simon Zhornitsky ◽  
Jamie Greenfield ◽  
Marcus W. Koch ◽  
Scott B. Patten ◽  
Colleen Harris ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cohort Study ◽  
Observational Cohort Study ◽  
Relapsing Remitting ◽  
Observational Cohort ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

scholarly journals Exit Strategies in Natalizumab-Treated RRMS at High Risk of Progressive Multifocal Leukoencephalopathy: a Multicentre Comparison Study

2021 ◽  
Author(s):  
Aurora Zanghì ◽  
Antonio Gallo ◽  
Carlo Avolio ◽  
Rocco Capuano ◽  
Matteo Lucchini ◽  
...  
Keyword(s):  
High Risk ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Safety Profile ◽  
Primary Study ◽  
Relapsing Remitting ◽  
Exit Strategies ◽  
Magnetic Resonance Imaging Mri ◽  
Anti Cd20 ◽  
Post Hoc ◽  
Relapsing Remitting Multiple Sclerosis

Abstract The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing–remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome. Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach. Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs). Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA. Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis. The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpBOCR 0.485, CI 95% 0.264–0.893, p = 0.020). This result was confirmed also for 12-month MRI activity (ExpBOCR 0.248 CI 95% 0.065–0.948, p = 0.042). No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes. AEs were similar among the 3 groups. Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies. All investigated DMTs showed a good safety profile.

Smoking affects the interferon beta treatment response in multiple sclerosis

Neurology ◽  
2018 ◽  
Vol 90 (7) ◽  
pp. e593-e600 ◽  
Author(s):  
Eva R. Petersen ◽  
Annette B. Oturai ◽  
Nils Koch-Henriksen ◽  
Melinda Magyari ◽  
Per S. Sørensen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Relapse Rate ◽  
Interferon Beta ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
End Of Treatment ◽  
Relapsing Remitting ◽  
Observational Cohort ◽  
Treatment Register ◽  
Relapsing Remitting Multiple Sclerosis

ObjectiveTo investigate whether smoking in patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta (IFN-β) is associated with the relapse rate and whether there is an interaction between smoking and human leukocyte antigen (HLA)–DRB1*15:01, HLA-A*02:01, and the N-acetyltransferase-1 (NAT1) variant rs7388368A.MethodsDNA from 834 IFN-β–treated patients with RRMS from the Danish Multiple Sclerosis Biobank was extracted for genotyping. Information about relapses from 2 years before the start of treatment to either the end of treatment or the last follow-up visit was obtained from the Danish Multiple Sclerosis Treatment Register. Smoking information came from a comprehensive questionnaire.ResultsWe found that the relapse rate in patients with RRMS during IFN-β treatment was higher in smokers compared to nonsmokers, with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 1.021–1.416, p = 0.027) and with an IRR increase of 27% per pack of cigarettes per day (IRR 1.27, 95% CI 1.056–1.537, p = 0.012). We found no association or interaction with HLA and the NAT1 variant.ConclusionIn this observational cohort study, we found that smoking is associated with increased relapse activity in patients with RRMS treated with IFN-β, but we found no association or interaction with HLA or the NAT1 variant.

scholarly journals Co-occurrence of two cases of progressive multifocal leukoencephalopathy in a natalizumab “infusion group”

2012 ◽  
Vol 19 (9) ◽  
pp. 1213-1215 ◽  
Author(s):  
J Havla ◽  
A Berthele ◽  
T Kümpfel ◽  
M Krumbholz ◽  
A Jochim ◽  
...  
Keyword(s):  
Progressive Multifocal Leukoencephalopathy ◽  
Sequence Comparison ◽  
Jc Virus ◽  
Dna Amplification ◽  
Viral Transmission ◽  
Viral Dna ◽  
Infusion Group ◽  
Relapsing Remitting ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Coding Control

We observed two cases of progressive multifocal leukoencephalopathy (PML) that occurred in the same “infusion group”. The group consisted of four patients with relapsing–remitting multiple sclerosis (RRMS) who had been treated with natalizumab (NAT) in the same medical practice for more than four years at the same times and in the same room, raising concerns about viral transmission between members of the infusion group. DNA amplification and sequence comparison of the non-coding control region (NCCR) of JC virus (JCV) present in cerebrospinal fluid (CSF) samples from PML patients #1 and #2 revealed that the amplified JCV sequences differed from the JCV archetype. The NCRR of the viral DNA was unique to each patient, arguing against the possibility of viral transmission between patients. Statistical considerations predict that similar co-occurrences of PML are likely to happen in the future.

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.

D-dimer levels for Risk Stratification in Patients with Suspected COVID-19 – A Prospective Observational Study

2021 ◽  
Vol 20 (3) ◽  
pp. 193-203
Author(s):  
AS Jauslin ◽  
◽  
J Kellett ◽  
M Brabrand ◽  
NR Simon ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Prospective Observational Study ◽  
Observational Cohort Study ◽  
Control Group ◽  
Age And Gender ◽  
Group Methods ◽  
Observational Cohort ◽  
Patient Groups ◽  
And Gender ◽  
D Dimer

Background: Elevated D-dimer levels have been observed in COVID-19 and are of prognostic value, but have not been compared to an appropriate control group. Methods: Observational cohort study including emergency patients with suspected or confirmed COVID-19. Logistic regression defined the association of D-dimer levels, COVID-19 positivity, age, and gender with 30-day-mortality. Results: 953 consecutive patients (median age 58, 43% women) presented with suspected COVID-19: 12 (7.4%) patients with confirmed SARS-CoV-2-infection died, compared with 28 (3.5%) patients without SARS-CoV-2-infection. Overall, most (56%) patients had elevated D-dimer levels (≥0.5mg/l). Age (OR 1.07, CI 1.05-1.10), D-dimer levels ≥0.5mg/l (OR 2.44, CI 0.98-7.39), and COVID-19 (OR 2.79, CI 1.28-5.80) were associated with 30-day-mortality. Conclusion: D-dimer levels are effective prognosticators in both patient groups.

John Cunningham Virus Status, Seroconversion Rate, and the Risk of Progressive Multifocal Leukoencephalopathy in Polish John Cunningham Virus-Seronegative Patients with Relapsing-Remitting Multiple Sclerosis

2020 ◽  
Vol 83 (5) ◽  
pp. 487-492
Author(s):  
Katarzyna Kapica-Topczewska ◽  
Francois Collin ◽  
Joanna Tarasiuk ◽  
Agata Czarnowska ◽  
Monika Chorąży ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Jc Virus ◽  
Seroconversion Rate ◽  
John Cunningham Virus ◽  
Increased Risk ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

<b><i>Introduction:</i></b> Presence of anti-JC-virus antibodies (JCVAbs) is associated with the increased risk of natalizumab (NAT)-related progressive multifocal leukoencephalopathy (PML). Little is known about seroconversion rate and time to seroconversion in relapsing-remitting multiple sclerosis (RRMS) patients treated with NAT in Poland. The aim of the study was to assess the true risk of PML, seroconversion rate, and time to seroconversion in all JCVAb-negative RRMS patients treated with NAT in Poland. <b><i>Methods:</i></b> Demographic and clinical data of all Polish RRMS patients treated with NAT reimbursed by National Health Fund (NFZ) were prospectively collected in electronic files using the Therapeutic Programme Monitoring System provided by NFZ. The assessment of JCVAb presence (without collection of JCVAb index value) in serum (Unilabs, STRATIFY JCV: anti-JCV antibody ELISA) was done at the beginning of therapy and then repeated every 6 months. The maximum follow-up time was 4 years. In Poland, since 2013, according to the NFZ drug program guidance, only patients with negative JCVAb test have started treatment with NAT. <b><i>Results:</i></b> In all Polish multiple sclerosis centers, 210 negative JCVAb RRMS patients with at least 9 (±3) months of observation (146 females, 64 males, and the median age at baseline: 33 years) were included in the study. During the follow-up period, JCVAb status changed from negative to positive in 34 patients (16.2%). For half of the patients, the seroconversion was diagnosed 1 year after starting NAT treatment. In 4 patients (1.9%) during follow-up, JCVAb status changed again from positive to negative. In Poland, before establishment of NFZ drug program, 4 cases of PML in patients treated with NAT in clinical trials were diagnosed. In the NFZ drug program, since 2013, no patient treated with NAT has been diagnosed with PML. <b><i>Conclusions:</i></b> NAT therapy in JCV-seronegative RRMS patients is safe and results in the absence of PML cases. In Poland, JCV seroconversion rate is similar to that observed in other European countries.

Sign in / Sign up

Export Citation Format

Share Document