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
Background: Multiple sclerosis (MS) is an inflammatory disease of the CNS that causes progressive neurological disability in most patients. Certain alleles of immunity-associated genes increase risk ...of MS, confirming a role for autoimmune mechanisms in pathogenesis. Activated mononuclear cells infiltrate the CNS and trigger an inflammatory cascade, resulting in demyelination and axonal injury. Non-inflammatory mechanisms also appear to be involved in axonal degeneration but are not fully elucidated. Current therapies are anti-inflammatory, and no available therapy is known to promote myelin repair or maintenance. Leucine-rich repeats and Ig domain-containing, neurite outgrowth inhibitor (Nogo) receptor-interacting protein-1 (LINGO-1) is a potent negative regulator of axonal myelination. Objective/methods : This article provides an overview of the available data on the effects of LINGO-1 antagonists on oligodendrocyte differentiation and remyelination. Results/conclusion: LINGO-1 is a potential target for neuroprotective therapy in that antagonists may promote remyelination in diseases such as MS.
Data are needed on the potential long-term prognostic association of serum neurofilament light in multiple sclerosis (MS).
To evaluate serum neurofilament light as a biomarker associated with ...long-term disease outcomes in clinically isolated syndrome.
This post hoc cohort study used data from the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study, a 36-month, multicenter, placebo-controlled interferon β-1a randomized clinical trial conducted from April 1996 to March 2000, and its long-term (5- and 10-year) extension study from February 2001 to March 2009. Participants included individuals with a symptomatic initial demyelinating event and brain magnetic resonance imaging (MRI) lesions suggestive of MS. Data were analyzed from April 2017 through 2019.
The variable of interest was naturally occurring serum neurofilament light concentration.
Gadolinium-enhancing (Gd+) lesion number, T2 lesion volume, and brain parenchymal fraction, a measure of brain atrophy were measured at baseline and 5 and 10 years. Multivariate regression models evaluated whether age, sex, and baseline covariates, including serum neurofilament light, brain parenchymal fraction, Expanded Disability Status Scale, Gd+ lesion count, and T2 lesion volume, were associated with brain parenchymal fraction changes over 5 and 10 years.
Among 308 included participants (mean SD age, 33.2 7.6 years; 234 76.0% women), baseline serum neurofilament light concentrations were associated with Gd+ lesions (Spearman r = 0.41; P < .001) and T2 lesion volume (Spearman r = 0.42; P < .001). Among covariates for brain parenchymal fraction change, serum neurofilament light concentration had the greatest correlation with change in brain parenchymal fraction at 5 years (Spearman r = -0.38; P < .001) and was the only variable associated with brain parenchymal fraction at 10 years (Spearman r = -0.45; P < .001). Participants in the highest vs lowest baseline serum neurofilament light tertiles showed brain parenchymal fraction reduction at 5 years (-1.83% 95% CI, -1.49% to -2.18% vs -0.95% 95% CI, -0.78% to -1.12%; P < .001) and 10 years (-3.54% 95% CI, -2.90% to -4.17% vs -1.90% 95% CI, -1.43% to -2.37%; P < .001). At 5 years, 6 of 45 participants (13.3%) in the highest neurofilament tertile and 2 of 52 participants (3.8%) in the lowest neurofilament tertile achieved an Expanded Disability Status Scale score of 3.5 or greater.
This cohort study found that higher baseline serum neurofilament light levels were associated with increased brain atrophy over 5 and 10 years. These findings suggest that serum neurofilament light could be a biomarker associated with disease severity stratification in early MS and may help to guide intervention.
ARIA (for acetylcholine receptor-inducing activity), a protein purified on the basis of its ability to stimulate acetylcholine receptor (AChR) synthesis in cultured myotubes, is a member of the ...neuregulin family and is present at motor endplates. This suggests an important role for neuregulins in mediating the nerve-dependent accumulation of AChRs in the postsynaptic membrane. Nerve-muscle synapses have now been analyzed in neuregulin-deficient animals. Mice that are heterozygous for the deletion of neuregulin isoforms containing an immunoglobulin-like domain are myasthenic. Postsynaptic AChR density is significantly reduced, as judged by the decrease in the mean amplitude of spontaneous miniature endplate potentials and bungarotoxin binding. On the other hand, the mean amplitude of evoked endplate potentials was not decreased, due to an increase in the number of quanta released per impulse, a compensation that has been observed in other myasthenic states. Thus, the density of AChRs in the postsynaptic membrane depends on immunoglobulin-containing neuregulin isoforms throughout the life of the animal.
Objective
To assess the independent contributions of clinical measures (relapses, Expanded Disability Status Scale EDSS scores, and neuroperformance measures) and nonclinical measures (new brain ...magnetic resonance imaging MRI activity and serum neurofilament light chain sNfL levels) for distinguishing natalizumab‐treated from placebo‐treated patients.
Methods
We conducted post hoc analyses using data from the AFFIRM trial of natalizumab for multiple sclerosis. We used multivariable regression analyses with predictors (EDSS progression, no relapse, new or enlarging MRI activity, brain atrophy, sNfL levels, and neuroperformance worsening) to identify measures that independently discriminated between treatment groups.
Results
The multivariable model that best distinguished natalizumab from placebo was no new or enlarging T2 or gadolinium‐enhancing activity on MRI (odds ratio; 95% confidence interval: 7.2; 4.7–10.9), year 2 sNfL levels <97.5th percentile (4.1; 2.6–6.2), and no relapses in years 0–2 (2.1; 1.5–3.0). The next best‐fitting model was a two‐component model that included no MRI activity and sNfL levels <97.5th percentile at year 2. There was little difference between the three‐ and two‐component models.
Interpretation
Nonclinical measures (new MRI activity and sNfL levels) discriminate between treatment and placebo groups similarly to or better than clinical outcomes composites and have implications for patient monitoring.
More on Melanoma with Transdifferentiation Panzara, Michael A; Bozic, Carmen; Sandrock, Alfred W
The New England journal of medicine,
07/2008, Letnik:
359, Številka:
1
Journal Article
Recenzirano
To the Editor:
Mullen et al. (Feb. 7 issue)
1
report on two cases of melanoma in patients with multiple sclerosis who received natalizumab. Their letter shows the limited interpretability of ...individual case reports in establishing cause-and-effect relationships. In response to this letter, we performed a meta-analysis of safety data from clinical trials of natalizumab. The incidence of melanoma was similar among patients who received natalizumab (3 of 4250 0.07%) as compared with those who received placebo (2 of 2059 0.10%). Rates of melanoma followed a similar pattern: 0.419 per 1000 patient-years among persons who received natalizumab versus 0.823 per 1000 . . .
To the Editor:
Chen and colleagues (Sept. 10 issue)
1
describe an increased prevalence of JC virus DNA in 19 patients with multiple sclerosis after 12 to 18 months of treatment with natalizumab. ...These findings contrast with results from other groups
2
–
4
and large studies by Biogen Idec and Elan Pharmaceuticals
5
(Table 1).
Data from one ongoing study showed no increase in the prevalence of JC virus in plasma, urine, or peripheral-blood mononuclear cells (PBMCs) after 12 months of natalizumab treatment
2
; another showed no increase in the presence of JC virus in serum for up to 30 months.
3
A third . . .
The objective of this work was to assess the effect of interferon β‐1a (Avonex®) on the rate of development of clinically definite multiple sclerosis and brain magnetic resonance imaging changes in ...subgroups based on type of presenting event, baseline brain magnetic resonance imaging parameters, and demographic factors in the Controlled High‐Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial. After the onset of a first demyelinating event, 383 patients with brain magnetic resonance imaging evidence of subclinical demyelination were treated with corticosteroids and randomly assigned to receive weekly intramuscular injections of 30μg interferon β‐1a or placebo. The treatment effect within subgroups was assessed in proportional hazards models both for the development of clinically definite multiple sclerosis and for a combined outcome of development of clinically definite multiple sclerosis or >1 new or enlarging T2 lesions on brain magnetic resonance imaging. A beneficial effect of treatment was noted in all subgroups evaluated. Adjusted rate ratios for the development of clinically definite multiple sclerosis in the optic neuritis, brainstem–cerebellar, and spinal cord syndrome subgroups were 0.58 (p = 0.05), 0.40 (p = 0.03), and 0.30 (p = 0.01) and for the development of the combined clinically definite multiple sclerosis/magnetic resonance imaging outcome were 0.50 (p < 0.001), 0.41 (p = 0.001), and 0.40 (p = 0.004), respectively. A treatment benefit on both outcome measures also was seen in subgroups based on baseline brain magnetic resonance imaging parameters, gender, and age. Interferon β‐1a is beneficial when initiated at the first clinical demyelinating event in patients with brain magnetic resonance imaging evidence of subclinical demyelination. The beneficial effect is present for optic neuritis, brainstem–cerebellar syndromes, and spinal cord syndromes.
Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based ...immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.
PDF
