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Friday, February 7, 2020

Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site

 2020 Jan-Dec;12(1):1713648. doi: 10.1080/19420862.2020.1713648.

Abstract

LINGO-1 is a membrane protein of the central nervous system (CNS) that suppresses myelination of axons. Preclinical studies have revealed that blockade of LINGO-1 function leads to CNS repair in demyelinating animal models. The anti-LINGO-1 antibody Li81 (opicinumab), which blocks LINGO-1 function and shows robust remyelinating activity in animal models, is currently being investigated in a Phase 2 clinical trial as a potential treatment for individuals with relapsing forms of multiple sclerosis (AFFINITY: clinical trial.gov number NCT03222973). 

Li81 has the unusual feature that it contains two LINGO-1 binding sites: a classical site utilizing its complementarity-determining regions and a cryptic secondary site involving Li81 light chain framework residues that recruits a second LINGO-1 molecule only after engagement of the primary binding site. Concurrent binding at both sites leads to formation of a 2:2 complex of LINGO-1 with the Li81 antigen-binding fragment, and higher order complexes with intact Li81 antibody. To elucidate the role of the secondary binding site, we designed a series of Li81 variant constructs that eliminate it while retaining the classic site contacts. These Li81 mutants retained the high affinity binding to LINGO-1, but lost the antibody-induced oligodendrocyte progenitor cell (OPC) differentiation activity and myelination activity in OPC- dorsal root ganglion neuron cocultures seen with Li81. The mutations also attenuate antibody-induced internalization of LINGO-1 on cultured cortical neurons, OPCs, and cells over-expressing LINGO-1. Together these studies reveal that engagement at both LINGO-1 binding sites of Li81 is critical for robust functional activity of the antibody.

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PMID: 31928294 PMCID: PMC6973334 DOI: 10.1080/19420862.2020.1713648




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Volunteers needed for Community Research Study on aging and physical disability


           For more information call: 1.866.928.2114
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Thursday, February 6, 2020

8 Ways MS Is Different for Women

Multiple sclerosis (MS) is considered an autoimmune condition that affects the brain and spinal cord of the central nervous system. The disease affects women more often than men.
According to the National Multiple Sclerosis Society, women may be up to three times more likely than men to get MS. The disease can also cause symptoms specific to women. But women and men share most of the same symptoms of MS.

The MS symptoms that primarily affect women seem to relate to hormone levels.
Some researchers think that having lower levels of testosterone may play a role. Others think fluctuations in female hormones may be a factor.
More research is needed to determine the true causes of these symptom differences.
The main symptoms that affect women more than men include menstrual problems, pregnancy-related symptoms, and menopause issues.

Menstrual problems

Research has shown that some women have increased MS symptoms during their periods. That may be because of a drop in estrogen levels during that time.
Symptoms that worsened for study participants included weakness, imbalance, depression, and fatigue.

Pregnancy-related symptoms

Some good news for women with MS: Research has found that MS has no effect on fertility. That means that MS won’t keep you from getting pregnant and giving birth to a healthy child.
In even better news, for most women, MS symptoms actually stabilize or improve during pregnancy, especially during the second and third trimesters. However, it’s common for them to return following delivery.

Menopause

Some research has found that in some women, MS symptoms get worse after menopause. As with menstrual symptoms, this may be due to a drop in estrogen levels caused by menopause.
Studies have shown that hormone replacement therapy (HRT) helps ease these symptoms for postmenopausal women.
However, HRT has also been linked with increased risk of breast cancer, heart disease, and stroke. If you have questions about whether HRT might be helpful for you in managing your MS symptoms after menopause, talk to your doctor.

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In general, MS symptoms are the same for both women and men. But the symptoms vary for everyone depending on the location and severity of nerve damage caused by inflammation.
Some of the most common MS symptoms are listed below.

Muscle symptoms    - click here to continue reading 



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Tuesday, February 4, 2020

Disability in multiple sclerosis A reference for patients and clinicians

Abstract

Objective:

To create a reference table of disability outcomes in multiple sclerosis (MS) that would enable patients to rank their disability relative to others' with similar disease duration and to develop a cost-effective research tool for comparing MS severity across patient populations and time periods.

Methods:

The North American Research Committee on Multiple Sclerosis (NARCOMS) Registry collects disability data from patients with MS on a validated, 9-point Patient-Determined Disease Steps (PDDS) scale. We compiled the Disability Expectancy Table, which displays cumulative frequencies of PDDS scores for each year of disease duration, from 0 to 45 years. We also tabulated disease duration–adjusted mean ranks of PDDS scores, referred to as Patient-derived MS Severity Scores (P-MSSS).

Results:

The cohort consisted of 27,918 NARCOMS enrollees, 72.7% of whom were female and 90.1% of whom were white. Mean age at symptom onset was 30.1 ± 10.1 years, and age at enrollment was 47.1 ± 11.0 years. The Disability Expectancy Table and P-MSSS afford a detailed overview of disability outcomes in a large MS cohort over a 45-year period. In the first year of disease, 15% of patients reported need of ambulatory aid, and 4% needed bilateral assistance or worse; after 45 years of disease, 76% of patients required ambulatory aid, and 52% bilateral assistance or worse. Proportion of patients who reported minimal or no interference in daily activities (PDDS ≤ 1) declined from 63% in the first year to 8% after 45 years of disease.

Conclusion:

The Disability Expectancy Table allows individual patients to determine how their disability ranks relative to NARCOMS enrollees with the same disease duration. P-MSSS may be used to compare disability across patient populations and to track disease progression in patient cohorts. P-MSSS does not require a formal neurologic examination and may therefore find wide applicability as a practical and cost-effective outcome measure in epidemiologic studies.

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A Framework for Estimating the Burden of Chronic Diseases: Design and Application in the Context of Multiple Sclerosis


Abstract

Background: When population-based databases are unavailable, nationwide assessments of the disease burden of multiple sclerosis (MS) resort to clinical, administrative or convenience-sampled data sources, which may produce results of limited external validity. Our aim was to develop a framework for estimating measures of occurrence of chronic diseases, and more broadly disease burden, that mitigate these limitations and to apply this framework to estimate the prevalence of multiple sclerosis (MS) in Switzerland.
Methods: We developed a 7-step framework which implements the combination of several data sources together with a resampling and critical appraisal approach. The framework was applied to estimate the MS prevalence for 2016 in Switzerland, for which four distinct data sources (Swiss MS registry, Swiss national MS treatment registry, MediService database, and Swiss MS cohort study) were combined. Results were reviewed by disease experts and compared to earlier Swiss estimates and current prevalence estimates from other countries.
Results: We estimate that in the year 2016 between 14,650 and 15,700 persons with MS have been living in Switzerland, yielding a period prevalence of 174–187/100,000 inhabitants. Compared to the last estimate in 1986, we detected a substantial increase of MS diagnoses which coincides with a higher number of diagnoses in women below the age of 65.
Conclusions: Internationally, Switzerland is a high-prevalence country for MS, although estimates were somewhat lower than recent evaluations of Northern European countries. In addition, we corroborate previous reports that the prevalence increase coincides with a higher number of MS diagnoses among women. The proposed framework has wide applicability and the potential to place estimates of disease occurrence and burden with imperfect data availability on more solid grounds.

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A new way to estimate neurologic disease prevalence in the United States: Illustrated with MS


Lorene M. Nelson, PhD, MS,corresponding author Mitchell T. Wallin, MD, MPH, Ruth Ann Marrie, MD, PhD, W.J. Culpepper, PhD, Annette Langer-Gould, MD, PhD, Jon Campbell, PhD, Stephen Buka, ScD, Helen Tremlett, PhD, Gary Cutter, PhD, Wendy Kaye, PhD, Laurie Wagner, MPH, Nicholas G. Larocca, PhD, and for the United States Multiple Sclerosis Prevalence Workgroup


Abstract

Objective

Considerable gaps exist in knowledge regarding the prevalence of neurologic diseases, such as multiple sclerosis (MS), in the United States. Therefore, the MS Prevalence Working Group sought to review and evaluate alternative methods for obtaining a scientifically valid estimate of national MS prevalence in the current health care era.

Methods

We carried out a strengths, weaknesses, opportunities, and threats (SWOT) analysis for 3 approaches to estimate MS prevalence: population-based MS registries, national probability health surveys, and analysis of administrative health claims databases. We reviewed MS prevalence studies conducted in the United States and critically examined possible methods for estimating national MS prevalence.

Results

We developed a new 4-step approach for estimating MS prevalence in the United States. First, identify administrative health claim databases covering publicly and privately insured populations in the United States. Second, develop and validate a highly accurate MS case-finding algorithm that can be standardly applied in all databases. Third, apply a case definition algorithm to estimate MS prevalence in each population. Fourth, combine MS prevalence estimates into a single estimate of US prevalence, weighted according to the number of insured persons in each health insurance segment.

Conclusions:  By addressing methodologic challenges and proposing a new approach for measuring the prevalence of MS in the United States, we hope that our work will benefit scientists who study neurologic and other chronic conditions for which national prevalence estimates do not exist.
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Long term effect of delayed treatment on disability in patients with paediatric onset multiple sclerosis: A prospective Danish cohort study.


Abstract

BACKGROUND:

A consensus of early treatment with disease-modifying therapies (DMT) in multiple sclerosis (MS) has been reached based on several observational and experimental studies in adults. However, paediatric onset (PO)MS appears phenotypically different from adult onset MS, characterized by increased relapse rate and pronounced radiological activity on MRI. The objective of this study was to investigate the long-term consequences of delayed treatment start in POMS on disability in a real-world, population-based setting.

METHODS:

Based on prospectively collected data from The Danish Multiple Sclerosis Registry, we defined a cohort of MS patients with onset before the age of 18 years, who were born in 1980 or later, and started treatment with a DMT between 1998 and 2018. The POMS cohort was stratified according to treatment start within 2 years of onset (N = 140) or later (N = 151). Annualised relapse rate in each study group was compared using a negative binomial regression; and Cox proportional hazard model was used to estimate hazard ratios (HR) of time to sustained Expanded Disability Status Scale (EDSS) score 4, 6-month confirmed EDSS worsening and 6-month confirmed EDSS improvement, respectively, according to disease duration.

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RESULTS:

The POMS cohort had a total median follow-up time of 7.7 years (interquartile range 4.6-11.6). There was no association between risk of relapses in patients with delayed treatment start compared to earlier treatment start. Patients starting on a DMT later than 2 years after onset had a 2.52-fold increased risk of reaching sustained EDSS 4 compared to those starting within 2 years of onset (HR=2.52, 95% confidence interval (CI)=1.01-6.34). For every year increment from onset to start of first DMT, the risk of reaching sustained EDSS 4 increased by 17% (HR=1.17, 95% CI=1.05-1.30). In line with this, the risk of reaching confirmed EDSS worsening was increased by 44% compared to those starting earlier, although not statistically significant (HR=1.44, 95% CI=0.95-2.19). Starting on a DMT later was associated with 61% decreased chance of confirmed EDSS improvement compared to those starting earlier (HR=0.39, 95% CI=0.26-0.59). For every year increment from onset to starting DMT, the risk of confirmed EDSS improvement decreased by 10% (HR=0.90, 95% CI=0.84-0.96).

To Read the CONCLUSIONS:


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