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Joep Killestein - One of the best experts on this subject based on the ideXlab platform.
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abnormalities and erythroblasts in peripheral blood of multiple sclerosis patients treated with Natalizumab
Multiple sclerosis and related disorders, 2019Co-Authors: Johannis A Van Rossum, Bernard M J Uitdehaag, Zoe L E Van Kempen, Louise Schilder, Birgit I Lissenbergwitte, Joep KillesteinAbstract:Abstract Background In Natalizumab treated patients several hematopoietic abnormalities including erythroblasts, myeloblasts and neutrophilic precursors in peripheral blood have been described. So far, long term effects of the hematopoietic changes have not been reported. Objective To describe hematopoietic abnormalities in longitudinally monitored MS patients treated with Natalizumab. Patients treated with dimethyl fumarate, teriflunomide and fingolimod served as controls. Secondly, the relation between Natalizumab serum levels and the occurrence of hematopoietic abnormalities was explored. Methods 212 Natalizumab treated patients were included, 91 patients with available baseline samples (998 follow-up samples) were compared with patients with dimethyl fumarate (n = 166, 1154 samples), teriflunomide (n = 38, 228 samples) and fingolimod (n = 114, 853 samples). One hundred twenty one patients without baseline samples (1952 follow-up samples) were included in the follow-up group. Results More than half of all Natalizumab treated patients developed hematopoietic abnormalities, almost a quarter had erythroblasts. Natalizumab use was associated with an increased risk of developing abnormalities in comparison to oral treatment, with a corrected hazard ratio of 2.3, 10.0 and 8.1 in comparison to fingolimod, dimethyl fumarate and teriflunomide respectively. No difference in developing abnormalities was observed in relation to Natalizumab serum concentrations. None of the patients developed a hematologic malignancy during follow up. Conclusion Hematopoietic abnormalities are common during Natalizumab treatment. Given the lack of consequences of this finding during long-term follow-up, it is generally justifiable to refrain from further diagnostic procedures when observing hematopoietic abnormalities in patients using Natalizumab.
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john cunningham virus conversion in relation to Natalizumab concentration in multiple sclerosis patients
European Journal of Neurology, 2017Co-Authors: Z L E Van Kempen, Cyra E Leurs, A De Vries, Anke Vennegoor, T Rispens, Mike P Wattjes, Joep KillesteinAbstract:Background and purpose Infection with the John Cunningham virus (JCV) is required for the development of progressive multifocal leukoencephalopathy, the feared complication of Natalizumab treatment in multiple sclerosis patients. The JCV seroconversion rate seems higher in Natalizumab treated patients than in the normal population, with an unknown cause. Methods Natalizumab concentration was correlated to JCV antibody status and seroconversion in a large cohort of multiple sclerosis patients. Results One hundred and thirty-five patients were included. No correlation was found between Natalizumab concentration and JCV status, JCV seroconversion or JCV index. Conclusions Higher Natalizumab concentrations do not explain the increased JCV seroconversion rate in Natalizumab treated patients.
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the chameleon of neuroinflammation magnetic resonance imaging characteristics of Natalizumab associated progressive multifocal leukoencephalopathy
Multiple Sclerosis Journal, 2013Co-Authors: Mike P Wattjes, Joep Killestein, Nancy Richert, Esther Sanchez, Petur Snaebjornsson, Diego Cadavid, Frederik BarkhofAbstract:Natalizumab is a monoclonal antibody against α4-integrin approved for the treatment of multiple sclerosis (MS) due to a positive effect on clinical and magnetic resonance imaging (MRI) outcome measures. However, one relatively rare but serious side effect of this drug is a higher risk of developing progressive multifocal leukoencephalopathy (PML). Since the FDA approval, more than 300 Natalizumab-associated PML cases have been documented among more than 100,000 treated MS patients. MRI is a crucial tool in the surveillance of patients treated with Natalizumab in order to detect possible signs of PML in the asymptomatic stage. Although classical imaging characteristics of PML are well established, MRI findings in Natalizumab-associated PML, particularly in early disease stages, show rather new and heterogeneous imaging findings including different patterns of inflammation with contrast enhancement. This review provides a comprehensive overview of the heterogeneous imaging findings in Natalizumab-associated...
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the chameleon of neuroinflammation magnetic resonance imaging characteristics of Natalizumab associated progressive multifocal leukoencephalopathy
Multiple Sclerosis Journal, 2013Co-Authors: Mike P Wattjes, Joep Killestein, Nancy Richert, Esther Sanchez, Petur Snaebjornsson, Diego Cadavid, Marlieke De Vos, Frederik BarkhofAbstract:Natalizumab is a monoclonal antibody against α4-integrin approved for the treatment of multiple sclerosis (MS) due to a positive effect on clinical and magnetic resonance imaging (MRI) outcome measures. However, one relatively rare but serious side effect of this drug is a higher risk of developing progressive multifocal leukoencephalopathy (PML). Since the FDA approval, more than 300 Natalizumab-associated PML cases have been documented among more than 100,000 treated MS patients. MRI is a crucial tool in the surveillance of patients treated with Natalizumab in order to detect possible signs of PML in the asymptomatic stage. Although classical imaging characteristics of PML are well established, MRI findings in Natalizumab-associated PML, particularly in early disease stages, show rather new and heterogeneous imaging findings including different patterns of inflammation with contrast enhancement. This review provides a comprehensive overview of the heterogeneous imaging findings in Natalizumab-associated PML in the context of the underlying pathophysiology, histopathology, and the diagnostic procedure. We describe the MRI patterns of PML lesion evolution and complications including immune reconstitution inflammatory syndrome (IRIS). Finally, we present guidelines to differentiate MRI findings in PML from inflammatory demyelinating lesions, to facilitate the early diagnosis of PML in patients treated with Natalizumab.
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punctate lesion pattern suggestive of perivascular inflammation in acute Natalizumab associated progressive multifocal leukoencephalopathy productive jc virus infection or preclinical pml iris manifestation
Journal of Neurology Neurosurgery and Psychiatry, 2013Co-Authors: Mike P Wattjes, Joep Killestein, Lonneke Verhoeff, Willemijn Zentjens, Erik Van Munster, Frederik Barkhof, Jeroen J J Van EijkAbstract:Natalizumab (Tysabri, Biogen-Idec Inc, Cambridge, Massachusetts, USA) is an effective drug for the treatment of multiple sclerosis (MS). Patients treated with Natalizumab are at higher risk of developing progressive multifocal leukoencephalopathy (PML). MRI has become crucial in the drug surveillance in terms of an early (preferably presymptomatic) detection and monitoring of Natalizumab-associated PML with special regard to the occurrence of an immune reconstitution inflammatory syndrome (IRIS).1 Natalizumab-associated PML is characterised by rather heterogeneous imaging findings particularly in the early disease course. Recently, a rare PML imaging pattern with punctiform enhancing lesions has been described in a patient with an asymptomatic course of Natalizumab-associated PML.2 It remains unclear what this inflammation pattern in acute PML represents regarding the underlying histopathology and possible consequences of the disease progression or PML-IRIS development. In this case report, we describe a patient with acute Natalizumab-associated PML presenting with punctate enhancing lesions suggestive of perivascular inflammation and discuss the importance of correctly interpreting this imaging finding in terms of differentiating productive JC virus infection from early presymptomatic PML-IRIS manifestation. A 45-year-old female with relapsing-remitting MS (5 years disease duration, EDSS 2.0) complained of subacute slurred speech and mild ataxia of her right arm after completing 51 infusions of Natalizumab. Natalizumab treatment was immediately discontinued. She had tested positive for serum antibodies against JC virus 6 months earlier. MRI showed multifocal classical PML lesions in the cerebellum and supratentorial brain. In addition, a group of small punctate T2-/FLAIR-hyperintense and contrast-enhancing lesions was identified in the deep white matter of the left parietal lobe, suggesting a perivascular distribution pattern with …
Ludwig Kappos - One of the best experts on this subject based on the ideXlab platform.
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longer duration of Natalizumab exposure may lessen return of disease activity following a switch from Natalizumab to an oral therapy modelling real world data from relapsing remitting multiple sclerosis rrms patients in the tysabri observational program top p6 379
Neurology, 2018Co-Authors: Tim Spelman, Maria Trojano, Ludwig Kappos, Helmut Butzkueven, Heinz Wiendl, Karen Rosales, Stephanie Licata, Nolan CampbellAbstract:Objective: To model the effect of Natalizumab exposure duration on return of disease activity after switching to an oral therapy. Background: Natalizumab is highly effective for treating RRMS. Understanding what factors affect disease activity return after discontinuing Natalizumab may support informed decision-making when considering discontinuation and therapy switch. Design/Methods: Included patients (N=660) enrolled in TOP as of November 2016 and switched to an oral therapy (fingolimod [n=568], dimethyl fumarate [n=81], or teriflunomide [n=11]) for ≥1 year after ≥2 years on Natalizumab. Post-treatment-switch relapse predictors were compared using adjusted Cox models (covariates: age, sex, symptom onset, Expanded Disability Status Scale (EDSS) score, prior relapses, washout time, and Natalizumab exposure duration). Models analyzed the exposure duration variable as continuous (by year) or categorical either by quintiles (≤2.5, 2.5–3. 3–3.5, 3.5–4, and >4.5-year) or by median (>3 vs ≤3 years). Results: When evaluated as a continuous variable, longer Natalizumab exposure was associated with reduced postswitch relapse risk (hazard ratio [HR]: 0.87; P=0.019). The Kaplan-Meier estimated probability of relapse at 4 years post switch was highest for patients with ≤2.5 years on Natalizumab (51.9%); differences between other quintiles were minimal (range 34.6%–39.3% for 2.5–3. 3–3.5, 3.5–4, and >4.5-year duration intervals). The likelihood of postswitch relapse was lower for patients with Natalizumab exposure >3 years vs ≤3 years (HR: 0.76; P=0.040). Other significant covariates were baseline EDSS score, prior relapses, and washout time. Analyses characterizing these findings’ robustness will also be presented. Conclusions: Natalizumab exposure duration is a significant independent predictor of postNatalizumab disease activity risk. For patients with >3 years on Natalizumab, the risk of post-treatment-switch disease activity appeared to lessen, though reasons for this decrease (underlying changes to the disease and/or Natalizumab effectiveness over time, differences in populations choosing to stay on Natalizumab or discontinue Study Supported by: Biogen Disclosure: Dr. Butzkueven has nothing to disclose. Dr. Wiendl has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Abbvie, Actelion, Alexion, Biogen, Cognomed, Evgen, F. Hoffmann-La Roche Ltd, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA. Dr. Wiendl has received research support from Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme. Dr. Trojano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Merck Serono, Novartis, Sanofi, Teva. Dr. Trojano has received research support from Biogen, Merck Serono, Novartis. Dr. Kappos has received research support from Bayer HealthCare Pharmaceuticals, Biogen, F. Hoffmann-La Roche Ltd and Genentech,Novartis, Research grants from: the European Union, Roche Research Foundation, Swiss Multiple Sclerosis Society and Swiss National Research Foundation. Dr. Spelman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis. Dr. Rosales has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Licata has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Ho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Campbell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen.
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radiologic ms disease activity during Natalizumab treatment interruption findings from restore
Journal of Neurology, 2015Co-Authors: Michael D Kaufman, Jérôme De Seze, Ralf Gold, Ludwig Kappos, Bruce A C Cree, Robert J Fox, Hanspeter Hartung, Douglas Jeffery, Xavier Montalban, Bianca WeinstockguttmanAbstract:The objective of this study is to characterize the timing and extent of radiologic MS disease recurrence during the 24-week Natalizumab treatment interruption period in RESTORE. RESTORE was a randomized, partially placebo-controlled exploratory study. Natalizumab-treated patients with no gadolinium-enhancing (Gd+) lesions at screening (n = 175) were randomized 1:1:2 to continue Natalizumab (n = 45), switch to placebo (n = 42), or switch to other therapies (n = 88) for 24 weeks. MRI assessments were performed every 4 weeks. Predictors of increased numbers of Gd+ lesions during Natalizumab treatment interruption were evaluated. The numbers of Gd+ lesions were compared with retrospectively collected pre-Natalizumab MRI reports and data from placebo-treated patients from two historical randomized clinical trials. Gd+ lesions were detected in 0 % (0/45) of Natalizumab patients, 61 % (25/41) of placebo patients, and 48 % (39/81) of other-therapies patients during the randomized treatment period. Gd+ lesions were detected starting at week 12; most were observed at week 16 or later. Thirteen percent (14/107) of patients had >5 Gd+ lesions on ≥1 (of 6) scans during the randomized treatment period versus 7 % (7/107) of patients pre-Natalizumab (based on medical record of a single scan). Younger patients and those with more Gd+ lesions pre-Natalizumab were more likely to have increased MRI activity. Distribution of total and persistent Gd+ lesions in RESTORE patients was similar to placebo-treated historical control patients. In most patients, recurring radiological disease activity during Natalizumab interruption did not exceed pre-Natalizumab levels or levels seen in historical control patients.
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long term safety and effectiveness of Natalizumab redosing and treatment in the strata ms study
Neurology, 2014Co-Authors: Paul Oconnor, Chris H Polman, Andrew D Goodman, Ludwig Kappos, Fred D Lublin, Richard A Rudick, Fiona Forrestal, Kathy Hauswirth, Lynda M Cristiano, Petra DudaAbstract:Objectives: Report long-term safety and effectiveness of Natalizumab over 240 weeks in the prospective, observational, open-label Safety of TYSABRI Re-dosing and Treatment (STRATA) Study. Methods: Patients (N = 1,094) previously enrolled in Natalizumab multiple sclerosis clinical trials received Natalizumab 300 mg IV every 4 weeks, up to 240 weeks. Serious adverse events, Expanded Disability Status Scale (EDSS) scores, and annualized relapse rates were analyzed. Results: At data cutoff (February 9, 2012), Natalizumab exposure was 3,460 patient-years; a median of 56 (range 1–70) infusions were received. Serious adverse events, including progressive multifocal leukoencephalopathy, were consistent with Natalizumab9s known profile. Upon Natalizumab re-exposure, rates of anti-Natalizumab antibodies and hypersensitivity reactions were 3% and 5% overall, and 40% and 24% among patients with 1 to 2 prior Natalizumab doses. Patients originally randomized to placebo/another disease-modifying therapy vs Natalizumab in previous studies had significantly higher EDSS scores at STRATA baseline; this difference persisted over 240 weeks. EDSS scores generally remained stable. Patients initially randomized to Natalizumab had lower annualized relapse rates over 240 weeks. Conclusions: Serious adverse events were consistent with Natalizumab9s known safety profile; short exposure with a gap before redosing was associated with higher incidences of anti-Natalizumab antibodies and hypersensitivity reactions. Stability of EDSS scores and consistently low relapse rates over 5 years of Natalizumab treatment are consistent with its known efficacy profile. Classification of evidence: This study provides Class III evidence that in patients with relapsing-remitting multiple sclerosis, Natalizumab stabilizes EDSS scores, decreases relapse rates, and is associated with an increased risk of progressive multifocal leukoencephalopathy.
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risk stratification for progressive multifocal leukoencephalopathy in patients treated with Natalizumab
Multiple Sclerosis Journal, 2012Co-Authors: Per Soelberg Sorensen, Ralf Gold, Gavin Giovannoni, Ludwig Kappos, Xavier Montalban, Eva Havrdova, Gilles Edan, Antonio Bertolotto, Bernd C Kieseier, Tomas OlssonAbstract:Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with Natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV). We searched PubMed and used current data from the Natalizumab global safety database to assess risk factors and quantify the risk of PML. Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in Natalizumab-treated patients. With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV. The availability of this assay provides an additional option for risk stratification of PML in patients using or considering Natalizumab therapy. Recommendations for clinical management of patients with MS and use of Natalizumab are provided based on the presence of these three risk factors. The identification of risk factors that increase the likelihood of PML in Natalizumab-treated patients can facilitate benefit-risk discussions between health care professionals and patients. Continued research and data collection will further develop our understanding of PML and the mechanisms by which these risk factors contribute to its development.
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risk stratification for progressive multifocal leukoencephalopathy in patients treated with Natalizumab
Multiple Sclerosis Journal, 2012Co-Authors: Per Soelberg Sorensen, Ralf Gold, Gavin Giovannoni, Ludwig Kappos, Xavier Montalban, Eva Havrdova, Gilles Edan, Antonio Bertolotto, Bernd C Kieseier, Tomas OlssonAbstract:Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with Natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV). We searched PubMed and used current data from the Natalizumab global safety database to assess risk factors and quantify the risk of PML. Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in Natalizumab-treated patients. With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV. The availability of this assay provides an additional option for risk stratification of PML in patients using or considering Natalizumab therapy. Recommendations for clinical management of patients with MS and use of na...
Ralf Gold - One of the best experts on this subject based on the ideXlab platform.
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radiologic ms disease activity during Natalizumab treatment interruption findings from restore
Journal of Neurology, 2015Co-Authors: Michael D Kaufman, Jérôme De Seze, Ralf Gold, Ludwig Kappos, Bruce A C Cree, Robert J Fox, Hanspeter Hartung, Douglas Jeffery, Xavier Montalban, Bianca WeinstockguttmanAbstract:The objective of this study is to characterize the timing and extent of radiologic MS disease recurrence during the 24-week Natalizumab treatment interruption period in RESTORE. RESTORE was a randomized, partially placebo-controlled exploratory study. Natalizumab-treated patients with no gadolinium-enhancing (Gd+) lesions at screening (n = 175) were randomized 1:1:2 to continue Natalizumab (n = 45), switch to placebo (n = 42), or switch to other therapies (n = 88) for 24 weeks. MRI assessments were performed every 4 weeks. Predictors of increased numbers of Gd+ lesions during Natalizumab treatment interruption were evaluated. The numbers of Gd+ lesions were compared with retrospectively collected pre-Natalizumab MRI reports and data from placebo-treated patients from two historical randomized clinical trials. Gd+ lesions were detected in 0 % (0/45) of Natalizumab patients, 61 % (25/41) of placebo patients, and 48 % (39/81) of other-therapies patients during the randomized treatment period. Gd+ lesions were detected starting at week 12; most were observed at week 16 or later. Thirteen percent (14/107) of patients had >5 Gd+ lesions on ≥1 (of 6) scans during the randomized treatment period versus 7 % (7/107) of patients pre-Natalizumab (based on medical record of a single scan). Younger patients and those with more Gd+ lesions pre-Natalizumab were more likely to have increased MRI activity. Distribution of total and persistent Gd+ lesions in RESTORE patients was similar to placebo-treated historical control patients. In most patients, recurring radiological disease activity during Natalizumab interruption did not exceed pre-Natalizumab levels or levels seen in historical control patients.
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risk stratification for progressive multifocal leukoencephalopathy in patients treated with Natalizumab
Multiple Sclerosis Journal, 2012Co-Authors: Per Soelberg Sorensen, Ralf Gold, Gavin Giovannoni, Ludwig Kappos, Xavier Montalban, Eva Havrdova, Gilles Edan, Antonio Bertolotto, Bernd C Kieseier, Tomas OlssonAbstract:Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with Natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV). We searched PubMed and used current data from the Natalizumab global safety database to assess risk factors and quantify the risk of PML. Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in Natalizumab-treated patients. With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV. The availability of this assay provides an additional option for risk stratification of PML in patients using or considering Natalizumab therapy. Recommendations for clinical management of patients with MS and use of Natalizumab are provided based on the presence of these three risk factors. The identification of risk factors that increase the likelihood of PML in Natalizumab-treated patients can facilitate benefit-risk discussions between health care professionals and patients. Continued research and data collection will further develop our understanding of PML and the mechanisms by which these risk factors contribute to its development.
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risk stratification for progressive multifocal leukoencephalopathy in patients treated with Natalizumab
Multiple Sclerosis Journal, 2012Co-Authors: Per Soelberg Sorensen, Ralf Gold, Gavin Giovannoni, Ludwig Kappos, Xavier Montalban, Eva Havrdova, Gilles Edan, Antonio Bertolotto, Bernd C Kieseier, Tomas OlssonAbstract:Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with Natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV). We searched PubMed and used current data from the Natalizumab global safety database to assess risk factors and quantify the risk of PML. Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in Natalizumab-treated patients. With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV. The availability of this assay provides an additional option for risk stratification of PML in patients using or considering Natalizumab therapy. Recommendations for clinical management of patients with MS and use of na...
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successful management of Natalizumab associated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis
JAMA Neurology, 2010Co-Authors: A Schroder, Kerstin Hellwig, Carsten Lukas, Ralf A Linker, Ralf GoldAbstract:Objective: To describe a case of successful clinical management of Natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multiple sclerosis. Design: Case report. Setting: University hospital. Patient: A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 Natalizumab infusions. Interventions: Immediate plasma exchange was combined for removal of Natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids. Results: After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favorable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML. Conclusions: In the setting of early diagnosis and consequent treatment, Natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.
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Natalizumab and progressive multifocal leukoencephalopathy what are the causal factors and can it be avoided
JAMA Neurology, 2010Co-Authors: Clemens Warnke, Hanspeter Hartung, Petra D Cravens, Til Menge, Michael K Racke, Jeffrey L Bennett, Elliot M Frohman, Benjamin Greenberg, Scott S Zamvil, Ralf GoldAbstract:Natalizumab (Tysabri) was the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS). After its initial approval, 3 patients undergoing Natalizumab therapy in combination with other immunoregulatory and immunosuppressive agents were diagnosed with progressive multifocal leukoencephalopathy (PML). The agent was later reapproved and its use restricted to monotherapy in patients with relapsing forms of MS. Since reapproval in 2006, additional cases of PML were reported in patients with MS receiving Natalizumab monotherapy. Thus, there is currently no convincing evidence that Natalizumab-associated PML is restricted to combination therapy with other disease-modifying or immunosuppressive agents. In addition, recent data indicate that risk of PML might increase beyond 24 months of treatment.
Chris H Polman - One of the best experts on this subject based on the ideXlab platform.
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long term safety and effectiveness of Natalizumab redosing and treatment in the strata ms study
Neurology, 2014Co-Authors: Paul Oconnor, Chris H Polman, Andrew D Goodman, Ludwig Kappos, Fred D Lublin, Richard A Rudick, Fiona Forrestal, Kathy Hauswirth, Lynda M Cristiano, Petra DudaAbstract:Objectives: Report long-term safety and effectiveness of Natalizumab over 240 weeks in the prospective, observational, open-label Safety of TYSABRI Re-dosing and Treatment (STRATA) Study. Methods: Patients (N = 1,094) previously enrolled in Natalizumab multiple sclerosis clinical trials received Natalizumab 300 mg IV every 4 weeks, up to 240 weeks. Serious adverse events, Expanded Disability Status Scale (EDSS) scores, and annualized relapse rates were analyzed. Results: At data cutoff (February 9, 2012), Natalizumab exposure was 3,460 patient-years; a median of 56 (range 1–70) infusions were received. Serious adverse events, including progressive multifocal leukoencephalopathy, were consistent with Natalizumab9s known profile. Upon Natalizumab re-exposure, rates of anti-Natalizumab antibodies and hypersensitivity reactions were 3% and 5% overall, and 40% and 24% among patients with 1 to 2 prior Natalizumab doses. Patients originally randomized to placebo/another disease-modifying therapy vs Natalizumab in previous studies had significantly higher EDSS scores at STRATA baseline; this difference persisted over 240 weeks. EDSS scores generally remained stable. Patients initially randomized to Natalizumab had lower annualized relapse rates over 240 weeks. Conclusions: Serious adverse events were consistent with Natalizumab9s known safety profile; short exposure with a gap before redosing was associated with higher incidences of anti-Natalizumab antibodies and hypersensitivity reactions. Stability of EDSS scores and consistently low relapse rates over 5 years of Natalizumab treatment are consistent with its known efficacy profile. Classification of evidence: This study provides Class III evidence that in patients with relapsing-remitting multiple sclerosis, Natalizumab stabilizes EDSS scores, decreases relapse rates, and is associated with an increased risk of progressive multifocal leukoencephalopathy.
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Natalizumab drug holiday in multiple sclerosis poorly tolerated
Annals of Neurology, 2010Co-Authors: Joep Killestein, Anke Vennegoor, Eva M M Strijbis, Alexandra Seewann, Bob W Van Oosten, Bernard M J Uitdehaag, Chris H PolmanAbstract:It has been suggested that Natalizumab-associated progressive multifocal leukoencephalopathy may be prevented by structured interruptions of treatment. Evidence supporting such a drug holiday is not yet available. Here we present initial observations in 10 multiple sclerosis patients who were stringently monitored up to 6 months after discontinuation of the infusions. Cumulatively, a combination of clinical relapse and new and/or enhanced lesions on magnetic resonance imaging had occurred in 7 of 10 patients. Although numbers are small, our data suggest that in patients who were switched to Natalizumab because of disease activity despite first-line treatment, a Natalizumab drug holiday without reinstatement of alternate disease-modifying therapy is poorly tolerated.
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assessment of jc virus dna in blood and urine from Natalizumab treated patients
Annals of Neurology, 2010Co-Authors: Richard A Rudick, Chris H Polman, Paul Oconnor, Andrew D Goodman, Leonid Gorelik, Soma Ray, Nancy M Griffith, Stephanie A Jurgensen, Fiona Forrestal, Alfred SandrockAbstract:Objective Analyses were conducted to determine the clinical utility of measuring JC virus (JCV) DNA in blood or urine of Natalizumab-treated multiple sclerosis (MS) patients to predict the risk of progressive multifocal leukoencephalopathy (PML). Methods A total of 12,850 blood and urine samples from nearly 1,400 patients participating in Natalizumab clinical trials were tested for JCV DNA using a commercially available quantitative polymerase chain reaction (qPCR) assay. A subset of these samples was also tested using a more sensitive qPCR assay developed at the National Institutes of Health (NIH). Results At the time Natalizumab dosing was suspended, JCV DNA was detected in plasma by the commercial assay in 4 of 1,397 (0.3%) patients; the NIH assay confirmed these positive samples and detected JCV DNA in an additional 2 of 205 (1%) patients who tested negative with the commercial assay. None of these 6 JCV DNA positive patients developed PML. In a 48-week study testing the safety of Natalizumab redosing, JCV DNA was detected in plasma of 6 of 1,094 (0.3%) patients, none of whom developed PML. Urine at baseline and week 48 was assessed in 224 patients; 58 (26%) were positive at baseline, and 55 (25%) were positive after 48 weeks of Natalizumab, treatment. JCV DNA was not detected in peripheral blood mononuclear cells from any of these 1,094 patients before or after Natalizumab treatment. In 5 patients who developed PML, JCV DNA was not detected in blood at any time point before symptoms first occurred. Interpretation Measuring JCV DNA in blood or urine with currently available methods is unlikely to be useful for predicting PML risk in Natalizumab-treated MS patients. Ann Neurol 2010
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effect of Natalizumab on clinical and radiological disease activity in multiple sclerosis a retrospective analysis of the Natalizumab safety and efficacy in relapsing remitting multiple sclerosis affirm study
Lancet Neurology, 2009Co-Authors: Eva Havrdova, Steven Galetta, Gavin Giovannoni, Chris H Polman, Paul Oconnor, Michael Hutchinson, Theodore J Phillips, David W Bates, Dusan Stefoski, Fred D LublinAbstract:Summary Background The efficacy of Natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether Natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity. Methods Post-hoc analyses of data from the AFFIRM study were done to determine the effects of Natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two. Findings 383 (64%) of 596 patients taking Natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25·4%, 95% CI 18·7–32·1%, p Interpretation Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies. Funding Biogen Idec.
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a randomized placebo controlled trial of Natalizumab for relapsing multiple sclerosis
The New England Journal of Medicine, 2006Co-Authors: Chris H Polman, Gavin Giovannoni, Ludwig Kappos, Fred D Lublin, Eva Havrdova, Michael Hutchinson, David H Miller, Theodore J Phillips, A Wajgt, M ToalAbstract:BACKGROUND: Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of Natalizumab in patients with relapsing multiple sclerosis. METHODS: Of a total of 942 patients, 627 were randomly assigned to receive Natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. RESULTS: Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the Natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with Natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the Natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the Natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving Natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent). CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).
Gavin Giovannoni - One of the best experts on this subject based on the ideXlab platform.
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Natalizumab associated progressive multifocal leucoencephalopathy a practical approach to risk profiling and monitoring
Practical Neurology, 2012Co-Authors: David M Hunt, Gavin GiovannoniAbstract:Natalizumab reduces relapse frequency, delays onset of disease progression and improves disease outcomes in relapsing-remitting multiple sclerosis (MS) and is a cost-effective treatment for rapidly evolving severe relapsing-remitting MS. However, it is associated with the development of progressive multifocal leucoencephalopathy (PML), a serious opportunistic brain infection caused by a neurotropic strain of the JC virus (JCV). Until May 2011, 83 300 patients had received Natalizumab for MS. One hundred and twenty-four patients had developed PML, of whom 23 (19%) died. In order to maximise the benefit-risk ratio of Natalizumab for MS patients it is important to develop a strategy for risk profiling and monitoring for PML. Central to this is an understanding of the biology of the JCV and the emerging clinical picture of Natalizumab-associated PML. This paper reviews the evidence for managing the risk of PML in Natalizumab-treated patients and the authors propose an algorithm for risk profiling and risk management. Key features of this algorithm include risk stratification based on emerging risk factors, heightened clinical vigilance for the clinical features of Natalizumab-associated PML and considerations for temporary and permanent cessation of Natalizumab dosing.
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risk stratification for progressive multifocal leukoencephalopathy in patients treated with Natalizumab
Multiple Sclerosis Journal, 2012Co-Authors: Per Soelberg Sorensen, Ralf Gold, Gavin Giovannoni, Ludwig Kappos, Xavier Montalban, Eva Havrdova, Gilles Edan, Antonio Bertolotto, Bernd C Kieseier, Tomas OlssonAbstract:Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with Natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV). We searched PubMed and used current data from the Natalizumab global safety database to assess risk factors and quantify the risk of PML. Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in Natalizumab-treated patients. With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV. The availability of this assay provides an additional option for risk stratification of PML in patients using or considering Natalizumab therapy. Recommendations for clinical management of patients with MS and use of Natalizumab are provided based on the presence of these three risk factors. The identification of risk factors that increase the likelihood of PML in Natalizumab-treated patients can facilitate benefit-risk discussions between health care professionals and patients. Continued research and data collection will further develop our understanding of PML and the mechanisms by which these risk factors contribute to its development.
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risk stratification for progressive multifocal leukoencephalopathy in patients treated with Natalizumab
Multiple Sclerosis Journal, 2012Co-Authors: Per Soelberg Sorensen, Ralf Gold, Gavin Giovannoni, Ludwig Kappos, Xavier Montalban, Eva Havrdova, Gilles Edan, Antonio Bertolotto, Bernd C Kieseier, Tomas OlssonAbstract:Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with Natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV). We searched PubMed and used current data from the Natalizumab global safety database to assess risk factors and quantify the risk of PML. Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in Natalizumab-treated patients. With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV. The availability of this assay provides an additional option for risk stratification of PML in patients using or considering Natalizumab therapy. Recommendations for clinical management of patients with MS and use of na...
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Natalizumab associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis lessons from 28 cases
Lancet Neurology, 2010Co-Authors: David B Clifford, Gavin Giovannoni, Andrea Deluca, David M Simpson, Gabriele Arendt, Avindra NathAbstract:Summary Background Treatment of multiple sclerosis with Natalizumab is complicated by rare occurrence of progressive multifocal leukoencephalopathy (PML). Between July, 2006, and November, 2009, there were 28 cases of confirmed PML in patients with multiple sclerosis treated with Natalizumab. Assessment of these clinical cases will help to inform future therapeutic judgments and improve the outcomes for patients. Recent developments The risk of PML increases with duration of exposure to Natalizumab over the first 3 years of treatment. No new cases occurred during the first two years of Natalizumab marketing but, by the end of November, 2009, 28 cases had been confirmed, of which eight were fatal. The median treatment duration to onset of symptoms was 25 months (range 6–80 months). The presenting symptoms most commonly included changes in cognition, personality, and motor performance, but several cases had seizures as the first clinical event. Although PML has developed in patients without any previous use of disease-modifying therapies for multiple sclerosis, previous therapy with immunosuppressants might increase risk. Clinical diagnosis by use of MRI and detection of JC virus in the CSF was established in all but one case. Management of PML has routinely used plasma exchange (PLEX) or immunoabsorption to hasten clearance of Natalizumab and shorten the period in which Natalizumab remains active (usually several months). Exacerbation of symptoms and enlargement of lesions on MRI have occurred within a few days to a few weeks after PLEX, indicative of immune reconstitution inflammatory syndrome (IRIS). This syndrome seems to be more common and more severe in patients with Natalizumab-associated PML than it is in patients with HIV-associated PML. Where next? Diagnosis of Natalizumab-associated PML requires optimised clinical vigilance, reliable and sensitive PCR testing of the JC virus, and broadened criteria for recognition of PML lesions by use of MRI, including contrast enhancement. Optimising the management of IRIS reactions will be needed to improve outcomes. Predictive markers for patients at risk for PML must be sought. It is crucial to monitor the risk incurred during use of Natalizumab beyond 3 years.
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effect of Natalizumab on clinical and radiological disease activity in multiple sclerosis a retrospective analysis of the Natalizumab safety and efficacy in relapsing remitting multiple sclerosis affirm study
Lancet Neurology, 2009Co-Authors: Eva Havrdova, Steven Galetta, Gavin Giovannoni, Chris H Polman, Paul Oconnor, Michael Hutchinson, Theodore J Phillips, David W Bates, Dusan Stefoski, Fred D LublinAbstract:Summary Background The efficacy of Natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether Natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity. Methods Post-hoc analyses of data from the AFFIRM study were done to determine the effects of Natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two. Findings 383 (64%) of 596 patients taking Natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25·4%, 95% CI 18·7–32·1%, p Interpretation Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies. Funding Biogen Idec.
