Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy

Institute of Neurology, Queen Square, London.
New England Journal of Medicine (Impact Factor: 54.42). 04/2006; 354(9):924-33. DOI: 10.1056/NEJMoa054693
Source: PubMed

ABSTRACT Progressive multifocal leukoencephalopathy (PML) was reported to have developed in three patients treated with natalizumab. We conducted an evaluation to determine whether PML had developed in any other treated patients.
We invited patients who had participated in clinical trials in which they received recent or long-term treatment with natalizumab for multiple sclerosis, Crohn's disease, or rheumatoid arthritis to participate. The clinical history, physical examination, brain magnetic resonance imaging (MRI), and testing of cerebrospinal fluid for JC virus DNA were used by an expert panel to evaluate patients for PML. We estimated the risk of PML in patients who completed at least a clinical examination for PML or had an MRI.
Of 3417 patients who had recently received natalizumab while participating in clinical trials, 3116 (91 percent) who were exposed to a mean of 17.9 monthly doses underwent evaluation for PML. Of these, 44 patients were referred to the expert panel because of clinical findings of possible PML, abnormalities on MRI, or a high plasma viral load of JC virus. No patient had detectable JC virus DNA in the cerebrospinal fluid. PML was ruled out in 43 of the 44 patients, but it could not be ruled out in one patient who had multiple sclerosis and progression of neurologic disease because data on cerebrospinal fluid testing and follow-up MRI were not available. Only the three previously reported cases of PML were confirmed (1.0 per 1000 treated patients; 95 percent confidence interval, 0.2 to 2.8 per 1000).
A detailed review of possible cases of PML in patients exposed to natalizumab found no new cases and suggested a risk of PML of roughly 1 in 1000 patients treated with natalizumab for a mean of 17.9 months. The risk associated with longer treatment is not known.

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Available from: Gary A Fahle, Aug 22, 2015
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    • "Reactivation of JCV occurs usually in immunecompromised or AIDS patients. JCV infection has gained importance to neurologists after the report of two PML cases in multiple sclerosis (MS) patients who received natalizumab [1]. The tremendous advances in the understanding of MS pathology and pharmacotherapy have improved the patients' outcomes significantly. "
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    ABSTRACT: Background. Multiple sclerosis (MS) therapeutics entered a new era after the development of anti-JC virus (anti-JCV) antibody assay that assesses the risk of development of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab. Objective. To determine the prevalence of anti-JCV antibody among MS patients in Kuwait. Methods. Using the national MS registry, demographics and disease characteristics of MS patients who were screened for anti-JC virus antibody were collected. The prevalence of anti-JCV antibody seropositivity and its association with demographic and disease characteristics were evaluated. Results. Out of 110 screened MS patients for anti-JCV antibodies, 65.5% were females. Mean age and disease duration were 29.23 ± 8.55 and 5.39 ± 5.04 years, respectively. 47.3% of patients were already on natalizumab and 52.7% of patients were screened for stratification to either natalizumab or a different Disease Modifying Therapy (DMT). The overall prevalence of anti-JC virus antibody was 40%. Gender (P = 0.69), disease duration (P = 0.11), and number of natalizumab infusions (P = 0.64) were not associated with seropositivity. Patients aged ≥30 years were more likely to be seropositive (P = 0.01). Conclusion. The prevalence of anti-JCV antibody is slightly lower than what is reported in published studies. Seropositivity was associated with an increasing age of MS patients.
    01/2014; 2014:861091. DOI:10.1155/2014/861091
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    • "There is an evidence that patients may, in exchange for therapeutic benefits, be willing to accept greater levels of risk than are actually posed by some therapies (Calfee, 2006; Johnson et al., 2007a, 2007b). Drug therapies for MS offer a range of potential benefits, but they may also involve lifethreatening risks, including liver failure, leukemia, and progressive multifocal leukoencephalopathy (Brassat et al., 2002; Francis et al., 2003; Yousry et al., 2006). Yet patients may be misinformed particularly by means of internet information, misinterpret the results of scientific research (Jadad et al., 2000; Kaplan and Brennan, 2001), have unrealistic expectations of treatment benefits and harms, and clinicians may be poor judges of a patient′s values (O′Connor et al., 2007). "
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    ABSTRACT: Shared decision making (SDM) is concerned with patient involvement into medical decisions and chronic conditions such as Multiple sclerosis (MS), with only partially effective treatments leading to potential severe side effects, conflicting evidence, and uncertain evidence on outcomes, constitute a typical condition for SDM. As treatment options increase and patients participate more intensively in decisions, the need for evidence-based information (EBI) becomes clear. Natural history (NH) studies of MS represent the basic sources for required EBI and are especially useful to contribute to the practical exercise of prognosis formulation and to enable the evaluation of effectiveness in the context of treatment. Several of these identify early clinical factors predictive of the course of MS but there is no consensus method for determining the long term progression of disability and evolution of individual patients on the basis of observations on the early stages of the disease, which constitutes a major challenge for the practicing neurologist. Aiming at delivering more reliable prognosis estimation, this study combines the distribution of patients reaching specific levels of disability within defined time periods as determined in NH studies, with disability curves and severity scores as a function of time, in terms of percentiles and deciles respectively, derived from longitudinal data analysis studies. A computer agent-based simulation model was implemented as a comprehensive and easy to utilize tool able to predict and monitor progression of disability in MS patients, and to support the neurologist discussing prognosis scenarios with the individual patient for effective SDM.
    05/2013; DOI:10.1016/j.msard.2013.04.001
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    • "Antibodies against JCPyV were detected in over 80% of humans worldwide (Weber et al., 1997) and consequently their presence in water may not represent a significant health risk for most of the population. The pathogenicity of JCPyV is commonly associated with progressive multifocal leukoencephalopathy (PML) in immunocompromised states and has attracted attention due to its reactivation in some patients with multiple sclerosis and other autoimmune diseases when treated with immunomodulators (Berger and Major, 1999; Yousry et al., 2006). The kidneys and bone marrow are sites of chronic and latent infection with JCPyV, which is also excreted in the urine of healthy individuals and patients with PML (Kitamura et al., 1990; Koralnik et al., 1999). "
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    ABSTRACT: Molecular techniques and virus concentration methods have shown that previously unknown viruses are shed by humans and animals, and may be transmitted by sewage-contaminated water. In the present study, 10-L river-water samples from urban areas in Barcelona, Spain and Rio Janeiro, Brazil, have been analyzed to evaluate the viral dissemination of human viruses, validating also a low-cost concentration method for virus quantification in fresh water. Three viral groups were analyzed: (i) recently reported viruses, klassevirus (KV), asfarvirus-like virus (ASFLV), and the polyomaviruses Merkel cell (MCPyV), KI (KIPyV) and WU (WUPyV); (ii) the gastroenteritis agents noroviruses (NoV) and rotaviruses (RV); and (iii) the human fecal viral indicators in water, human adenoviruses (HAdV) and JC polyomaviruses (JCPyV). Virus detection was based on nested and quantitative PCR assays. For KV and ASFLV, nested PCR assays were developed for the present study. The method applied for virus concentration in fresh water samples is a one-step procedure based on a skimmed-milk flocculation procedure described previously for seawater. Using spiked river water samples, inter- and intra-laboratory assays showed a viral recovery rate of about 50% (20-95%) for HAdV, JCPyV, NoV and RV with a coefficient of variation ≤50%. HAdV and JCPyV were detected in 100% (12/12) of the river samples from Barcelona and Rio de Janeiro. Moreover, NoV GGII was detected in 83% (5/6) and MCPyV in 50% (3/6) of the samples from Barcelona, whereas none of the other viruses tested were detected. NoV GGII was detected in 33% (2/6), KV in 33% (2/6), ASFLV in 17% (1/6) and MCPyV in 50% (3/6) of the samples from Rio de Janeiro, whereas KIPyV and WUPyV were not detected. RV were only analyzed in Rio de Janeiro and resulted positive in 67% (4/6) of the samples. The procedure applied here to river water represents a useful, straightforward and cost-effective method that could be applied in routine water quality testing. The results of the assays expand our understanding of the global distribution of the viral pathogens studied here and their persistence in the environment.
    Water Research 03/2013; 47(8). DOI:10.1016/j.watres.2013.02.043 · 5.32 Impact Factor
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