University of Munich

Author Of 2 Presentations

Disease Modifying Therapies – Risk Management Oral Presentation

FC02.02 - Update on the risk estimates of progressive multifocal leukoencephalopathy related to fingolimod

Speakers
Presentation Number
FC02.02
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
13:12 - 13:24

Abstract

Background

Progressive multifocal leukoencephalopathy (PML) is a serious and potentially fatal complication of some multiple sclerosis (MS) disease-modifying therapies, including fingolimod. Precise estimates and risk stratification tools are not available for fingolimod-related PML.

Objectives

To estimate the global risk of PML in MS patients receiving fingolimod, and to investigate the effect of treatment duration and age on the risk of PML.

Methods

The number of PML cases identified from the manufacturer safety database, attributed to fingolimod by expert adjudication (based on criteria published by Berger et al. in 2014) as of 28 February 2020, was compared with the estimated global number of fingolimod-treated patients at risk (overall, by treatment duration, and by assumed age at fingolimod treatment initiation).

Results

It was estimated that approximately 299,600 patients were treated with fingolimod globally as of 28 February 2020, corresponding to >778,900 patient-years (PYs) of exposure. Of the 188 suspected PML cases reported during fingolimod treatment, 37 confirmed cases were clearly attributed to fingolimod through expert adjudication. In 17 cases, PML was attributed to previous natalizumab treatment. The remaining 134 cases either had inadequate information to confirm the diagnosis of PML or were classified as either possible or not PML. The estimated incidence rate was 4.75 (95% confidence interval [CI]: 3.34; 6.55) per 100,000 PYs. The estimated crude incidence was 0.12 (95% CI: 0.09–0.17) per 1,000 patients. The incidence of PML appears to increase with treatment duration and approach a plateau at approximately 0.13 per 1,000 patients during Year 5, after which data were scarce. Incidence of PML appears to increase between 30 and 50 years of age and then stabilize but the exact shape of the relationship with age is uncertain due to wide CIs, underlying assumptions, and other unknown confounding factors. For both treatment duration and age at treatment initiation, the precision of the incidence estimates was low due to the small number of cases.

Conclusions

PML risk associated with fingolimod is low. Although, the estimated risk of fingolimod-associated PML appears to increase with cumulative exposure, the precise pattern of this relationship remains uncertain. There may be an increase in PML risk with increased age at treatment initiation, although the exact pattern of this possible relationship is also uncertain.

Collapse
Neuromyelitis Optica and Anti-MOG Disease Oral Presentation

HT07.03 - Prevalence of MOG-Ab in a large cohort of neurological patients

Speakers
Presentation Number
HT07.03
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease
Lecture Time
10:39 - 10:51

Abstract

Background

Myelin oligodendrocyte glycoprotein (MOG) antibody disease is recognized as a distinct nosological entity. In adults, MOG IgG serum antibodies (MOG-Ab) are associated with neuromyelitis optica spectrum disorder (NMOSD) phenotype in particular isolated myelitis and recurrent often bilateral anterior optic neuritis. In children, MOG-Ab are primarily associated with acute disseminated encephalomyelitis. However, an increasing number of clinical phenotypes have been reported to be associated with MOG-Ab.

Objectives

To investigate the seroprevalence of MOG-Ab under consideration of demographics, disease entities and time course in a large cohort of neurological patients.

Methods

Blood samples of 2103 consecutive adult neurologic patients admitted to the neurological department of the Technical University of Munich between 2016-2019 were tested for MOG-IgG using a cell-based assay. In a subgroup of patients, MOG Ab-persistence was analyzed in follow-up samples. For validation selected positive samples were sent to two external laboratories.

Results

We found MOG-Ab in 28 of 2103 (1.33%) patients. High Ab-titers were rare but mostely associated with NMOSD phenotype (8/28), whereas low titers occurred in a wide range of neurological diseases, predominantly in other inflammatory CNS diseases (5/28) and stroke (6/28). Female gender and younger age at disease onset tended to be associated with higher MOG Ab-titers. Follow-up analyzes yielded Ab-persistence over time occurring not only in NMOSD but also in other neurological diseases. External validation confirmed high sensitivity and specificity of our cell-based assay for high titers but considerable variability for low MOG-Ab titer between laboratories.

Conclusions

The present study demonstrates of the occurrence of MOG-Ab in a wide range of neurological diseases. High Ab-titers seem to be specific for NMOSD in adults. Persistent low titer MOG-Ab are also found in non-inflammatory neurological diseases implying that their use for diagnostic purposes is highly limited.

Collapse

Moderator Of 2 Sessions

Charcot Symposium Sat, Sep 12, 2020
Moderators
Session Type
Charcot Symposium
Date
Sat, Sep 12, 2020
Time (ET)
11:00 - 12:30
Parallel Session Fri, Sep 11, 2020
Moderators
Session Type
Parallel Session
Date
Fri, Sep 11, 2020
Time (ET)
12:45 - 14:15

Author Of 7 Presentations

COVID-19 Late Breaking Abstracts

LB1218 - Impact of COVID-19 on MS patients’ access to care and neurologists’ treatment practices worldwide: results from the ECTRIMS survey (ID 2086)

Speakers
Presentation Number
LB1218
Presentation Topic
COVID-19

Abstract

Background

Restrictions imposed by the National and local authorities to mitigate the spread of Coronavirus disease-19 (COVID-19) posed unique challenges in the access to care and management of people with multiple sclerosis (PwMS).

Objectives

To collect data about the impact of the COVID-19 emergency on access to care for PwMS and analyze influence on treatment practices of MS neurologists worldwide.

Methods

Between March and July 2020 the European Committee for Treatment and Research in MS (ECTRIMS) promoted an online survey among Council members and MS specialists worldwide, covering five major areas: general information; MS patient access to care; management of relapses and visits; use of disease modifying therapy (DMT); experience with COVID-19 MS patients.

Results

Three-hundred-sixty neurologists (46% females, median age 48 years) from 52 countries (Europe 68%; Central/South America 17%; North America 10%, others 5%) completed the survey. Seventy-five percent worked within a specialized MS centre, 42% followed > 1000 patients. Ninety-eight percent of respondents reported COVID-19 pandemic had a negative impact on patients’ care. Routine MS clinical activities were suspended in 63% of cases and only urgent visits were guaranteed. Telemedicine services (mainly calls, video-calls, messaging) were provided by 90% of respondents: only in 20% of cases telemedicine was already in use in the practice. Forty-five percent revealed changes in relapse treatment: dosage and/or duration reduction 30%; treatment offered only for severe relapses 36%; treatment delivered at home 28%. As for DMT, 98% of respondents felt no modification was needed for interferons and glatiramer; 48-60% deemed no change was needed for dimethyl fumarate, teriflunomide, fingolimod and siponimod, while nearly 25% considered switching/suspending these agents based on lymphopenia. On the other hand, for natalizumab 31% applied an extended-dose regimen, for cladribine and alemtuzumab 42-52% considered postponing treatment in any case as the best choice. For anti-CD20 monoclonal antibodies, postponing treatment in any case (32%) or based on the patient immunophenotype (25%) were the preferred options. Sixty-one percent of respondents had at least one patient affected by COVID-19, 27% had at least one patient with severe infection; 70% of severe cases were on DMT. Finally, 11% of respondents reported at least one COVID-19 related death and 36% of fatal cases were on DMT.

Conclusions

While analysis of geographic differences is ongoing, the survey highlighted that COVID-19 pandemic is having a major impact on MS care worldwide. Telemedicine has a great potential to mitigate issues and needs to be potentiated/implemented de novo at most centres. As for DMT, major changes regarded cladribine, alemtuzumab and anti-CD20. Collecting standardized, reliable data on the potential impact of DMT on COVID-19 in PwMS is urgently needed to inform appropriate treatment decisions.

Collapse
Biomarkers and Bioinformatics Poster Presentation

P0027 - Are we ready for precision medicine in Multiple Sclerosis? A web-based survey across Europe   (ID 1411)

Presentation Number
P0027
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

We designed a web-based survey to assess the willingness and interest of European neurologists working with MS to implement precision medicine in their routine clinical practice. This study is a part of the EU-funded MULTIPLEMS grant.

Objectives

1) To assess how neurologists across European countries view the role of body-fluid biomarkers in clinical practice; 2) To survey clinical practices of diagnostic work up, therapy selection and monitoring, and frequency of data collection and clinical and paraclinical measurements.

Methods

The survey had three parts: a) demographics of respondents; b) opinion of the role of predictive, diagnostic, disease-activity biomarkers and treatment-response body-fluid biomarkers in clinical practice; c) survey of clinical practice and management of MS cases (including therapy choice and use of biomarkers) by evaluating 5 clinical cases with different characteristics (therapeutic management in drug naive patients and in patients displaying different forms of remaining disease activity, as well as stopping threapy in stable diasease since long).

Results

194 neurologists across 11 European countries responded to the survey, with a mean response rate of 45%. 57.7% were male and the mean age was 49.8 years. The importance of biomarkers in clinical practice was rated from 1 (low) to 7 (high), and it was generally high: 4.1 for predictive and disease-activity biomarkers, 5.2 for treatment-response and 5.7 for diagnostic biomarkers, with neurologists in Belgium, Denmark, Spain, Sweden and UK being the most positive. Determination of cerebrospinal fluid (CSF) oligoclonal bands was considered the most established biomarker for diagnosis (98.5% of neurologists), prediction (56.7%) and disease activity (36.5%), trailed by anti-aquaporin 4 (90.7%) and anti-myelin oligodendrocyte antibodies (85.1%) for diagnosis. Anti-JC (93.8%) and varicella virus (61.9%) and anti-drug (natalizumab (74.7%) and interferon-beta (68.6%)) were considered useful in context of therapy selection and monitoring by most neurologists, while neurofilament levels in CSF and serum and vitamin D levels were less established. Therapeutic management in the five case examples varied widely, likely as a result of differences in local and national guidelines.

Conclusions

European MS neurologists express a positive opinion on the role of body-fluid biomarkers to manage MS in clinical practice, however, these seem still to have had a limited impact on therapeutic management and selection, which also varied markedly across countries. This underscores the need for further research in this area.

Collapse
Biomarkers and Bioinformatics Poster Presentation

P0058 - Decrease of peripheral CD19+ IgG+ B-cells with age and immunotherapy in patients with relapsing remitting Multiple sclerosis. (ID 1459)

Speakers
Presentation Number
P0058
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Little is known about the impact of aging, long term immunotherapy and the combination of both on the immune system in MS.

Objectives

Identification of age and treatment dependent peripheral immune cell changes in MS patients that are distinct from people with other neurological conditions or healthy controls.

Methods

We performed flow cytometric immunophenotyping on whole blood samples of 133 patients with relapsing-remitting MS (range: 17-66 years; median: 39). A cohort of 95 patients with other neurological diseases as well as 13 healthy people served as controls (range: 17-85 years; median: 45). The focus was on characterizing subsets of CD3+ T cells and CD19+ B cells. We used 22 different fluorochromes, split into two panels, labelling well-established surface markers. We observed 20 identifiable subsets in the T cell panel and 15 subsets in the B cell panel. Relative abundance of each identified subset in a sample was plotted against patient age. Linear regression was performed to determine age-related trends. Trend lines of MS and control group were then compared and an F-test used to determine whether slopes significantly differed from one another. As this was an exploratory study, we decided to also compare overall mean values for each parameter between MS and control group, irrespective of age, with a T-test.

Results

We observed a significant age-related decrease in eight subsets and increases in two subsets of the MS-patients. Controls showed a significant decrease in nine subsets and an increase in three. When comparing slopes, all but one were not different between MS patients and controls (p < 0.05). Only the relative abundance of CD19+ IgG+ cells decreased significantly with increasing age in MS patients (p = 0.0007), whereas there was no obvious trend in the control group (p = 0.5887), suggesting the change was specific to the MS group. Comparing slopes of these trend lines with an F-test, significant difference was achieved (p = 0.0261). Omitting age as a factor in the comparison of MS and control patients, we found differences in mean abundance of CD19+ CD27- IgD+ cells (p = 0.0014), CD19+ IgG+ cells (p = 0.0455), CD19+ CD27+ cells (p = 0.0152) and central memory CD3+ CD4+ cells (p = 0.0003). A subgroup analysis comparing CD19+ IgG+ cells in therapy naive (n = 22) and treated (n = 103) patients showed lower mean values in the latter (p = 0.0062), although the treated group did not contain patients that were on B-cell depleting therapy.

Conclusions

Our results show an age-dependent decrease of CD19+ IgG+ B lymphocytes in MS patients which is likely explained by previous immunotherapies. The identified CD19+ IgG+ subgroup represents terminally differentiated populations of B cells. Further studies will focus on their relation to clinical phenotypes, disease trajectories and the impact of different immunotherapies on this subset.

Collapse
Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0263 - Serum neurofilament predicts clinical progression and increases diagnostic accuracy in patients with early multiple sclerosis (ID 1336)

Abstract

Background

Up to date prognostic estimation in newly diagnosed patients is hardly possible while the differentiation between disabling versus more benign courses is of utmost relevance. Reliable blood-based biomarkers that are associated with diagnosis and prognosis of multiple sclerosis (MS) have not been established.

Objectives

Can serum neurofilament light chain measurements serve as a reliable biomarker for diagnostic accuracy and prognosis for multiple sclerosis patients at the time point of diagnosis?

Methods

In a multicenter prospective longitudinal observational cohort, patients with a first diagnosis of multiple sclerosis (MS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers and assessed yearly with a standardized protocol. Patients were offered standard immunotherapies according to national treatment guidelines. Serum NfL concentrations were measured using an ultrasensitive single-molecule array (Simoa).

Results

A possible association between sNfL levels and clinical diagnosis, relapses, MRI parameters and treatment decisions was tested in 814 patients classified according to current (2017) and older (2010) McDonald criteria at time point of diagnosis and two years after study inclusion sNfL levels correlated with number of T2 and Gd+ lesions and clinical relapses. After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036) and increased accuracy of distinction between CIS and RRMS, when including ≥ 90th percentile of sNfL values. Patients receiving disease-modifying treatment (DMT) during the first two years had higher sNfl baseline levels (11.8 pg/ml, 7.5-20.9 pg/ml, n = 727) than patients never receiving DMT (9.5 pg/ml, IQR 6.4-14.1 pg/ml, n = 87, p = 0.002). Longitudinal sNfL levels reflected treatment decisions within the first four years.

Conclusions

sNfL is associated with diagnosis and prognosis of MS patients at the time point of first diagnosis and may be of use for initial treatment stratification.

Collapse
Epidemiology Poster Presentation

P0426 - A systematic assessment of medical diseases and symptoms preceding the first diagnosis of multiple sclerosis (ID 1159)

Speakers
Presentation Number
P0426
Presentation Topic
Epidemiology

Abstract

Background

Previous studies reported that patients who were later diagnosed with multiple sclerosis (MS) showed an altered behavior regarding the use of the healthcare system including increased rates of physician and hospital encounters related to neurological, musculoskeletal and genitourinary as well as psychiatric symptoms up to 10 years before first diagnosis.

Objectives

To explore the occurrence of diseases and symptoms in the 5-year period prior to first diagnosis in patients with multiple sclerosis (MS).

Methods

Using ambulatory claims data we systematically assessed differences in the occurrence of diseases and symptoms in the five years prior to first diagnosis in patients with MS (n=10,524) as compared to patients newly diagnosed with two other autoimmune diseases – Crohn’s disease (n=15,943) and psoriasis (n=99,027) - and individuals without any of these diseases (n=73,430).

Results

Forty-three ICD-10 codes were recorded significantly more frequently for patients with MS in the five years before first diagnosis as compared to controls without autoimmune disease. Many of these findings were confirmed in a comparison to the other two control groups. A high proportion of these ICD-10 codes represent symptoms suggestive of a demyelinating event or other neurological diagnoses. Additionally, six psychiatric diagnoses were recorded more frequently for patients with MS as compared to controls. In a sensitivity analysis excluding patients with symptoms suggestive of an MS relapse or any recordings for neurological diseases prior to first diagnosis, none of these associations remained significant. Six ICD-10 codes were significantly and negatively associated with MS, four of which represented infections of the upper respiratory tract. Here, the negative relations with MS were even more pronounced in the sensitivity analysis.

Conclusions

Our analyses suggest that most of the ICD-10 codes recorded more frequently prior to MS diagnosis are related to misdiagnosed demyelinating events and therefore delayed diagnosis. Other ICD-10 codes more frequently recorded for patients with MS - although not in the sensitivity analysis - included psychiatric diagnoses, which is in accordance with previous studies that report psychiatric disorders as frequent comorbidities in patients with MS. The robust negative association of upper respiratory tract infections with MS diagnosis suggests a link between protection from infection and the occurrence of MS.

Collapse
Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0746 - Purinergic inhibitors protect astrocytes from aquaporin-4 antibody-mediated complement-dependent death (ID 1699)

Speakers
Presentation Number
P0746
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Neuromyelitis optica (NMO) is an autoimmune disease of the CNS characterized by the presence of autoantibodies against the water channel aquaporin 4 (AQP4), which in the CNS is almost exclusively expressed in astrocytes. AQP4-antibody (AQP4-IgG) mediated astrocyte death is the key event in the pathology of NMO. Upon binding, astrocytes undergo a complement-dependent necrosis. Subsequent pathology shows devastating tissue damage including demyelination and axonal loss. Purinergic receptors are known to be upregulated in neuroinflammation and to contribute to neuronal-glial interaction. Indeed, purinergic antagonists, such as Suramin, have been used for the treatment of immune-mediated inflammatory diseases, showing cell-protective effects in complement-mediated cell injury. However, the mechanisms behind their anti-inflammatory properties are not well understood and their effects in NMO are completely unknown.

Objectives

The goal of this study was to investigate effects of purinergic inhibitors in AQP4-IgG mediated pathology in vitro and in vivo

Methods

Here, we tested purinergic inhibitors in vitro, using AQP4- and MOG-transfected cell lines, and in vivo in an NMO mouse model using two-photon microscopy.

Results

The application of Suramin, PPADS and NF449 in vivo prevented AQP4-IgG-mediated complement-dependent astrocyte death. In vitro, purinergic antagonists inhibited the binding AQP4-IgG or MOG-IgG to AQP4 and MOG- transfected cells in a dose dependent manner. Indeed, HPLC based fractionation of IgG molecules on gel filtration column revealed that these inhibitors lead to a subtle unfolding of antibodies, changing their conformational properties. Moreover, this change in antibody geometry impairs the complement binding to the antibody, thus disrupting complement cascade activation.

Conclusions

Our studies demonstrate that purinergic antagonists mainly mediate their inhibitory activity in our antibody mediated NMO model by inhibiting binding and complement activation. This mechanism is of relevance for the use of purinergic inhibitors in cell culture and in vivo models but also for possible application in humans.

Collapse
Invited Presentations Invited Abstracts

TC20.02 - Presentation 02 (ID 648)

Speakers
Authors
Presentation Number
TC20.02
Presentation Topic
Invited Presentations

Presenter Of 1 Presentation

Invited Presentations Invited Abstracts

TC20.02 - Presentation 02 (ID 648)

Speakers
Authors
Presentation Number
TC20.02
Presentation Topic
Invited Presentations

Moderator Of 1 Session

Teaching Course Fri, Sep 11, 2020

Invited Speaker Of 1 Presentation

Invited Presentations Invited Abstracts

TC20.02 - Presentation 02 (ID 648)

Speakers
Authors
Presentation Number
TC20.02
Presentation Topic
Invited Presentations